a study of a single case of atraumatic brain injury mdl

Latest Update — 11 May 2014

A study of a single case of atraumatic brain injury in a five-month old infant and arising from the administration of the DPT Vaccine in 1960

[Previous Title] Redefining MDL’s Brain Damage:

Aiding the design of her future care

Inside this damaged head there is a long history of pain and suffering but by the very nature of that damage she cannot tell you how she feels. There is a need for compassion and understanding that is given freely to others who suffer the consequences of different sorts of adversity. It is my hope that MDL will not have suffered in vain but that this study will encourage others to take it further so that there can be a fund of knowledge that prevents others from carrying the same burden of oppression.

Introduction

MDL received damage to her brain in 1960 following two doses of DPT vaccine from which she suffered encephalitis and convulsions. There was no pre-morbid history and the health visitor noted ‘normal development’ in her report just prior to the first event. A photograph taken at that time seems to confirm that opinion. [See ifc] It was later determined that the cause of this damage was the pertussis element of the vaccine which at that time was given to children in the form of whole-cell virus. Most of the reactions to whole-cell DPT injection are thought to be from the pertussis component.

British research in the 1980s into whole-cell DTP1, which is now rarely available in developed countries, suggested that such severe neurologic events occur after approximately 1 in 140,000 doses of the DPT vaccine (0.0007%).

In 1994, the Institute of Medicine of the US National Academy of Sciences published a report stating that if the first symptoms of neurological damage occurred within the first seven days following vaccination with whole-cell pertussis vaccine, the evidence was compatible with the possibility that it could be the cause of permanent brain damage in otherwise apparently healthy children.

There has been little scientific research into the way in which the DPT whole-cell vaccine brings about the damage to the brain. However, there has been some work done on this in an effort to try and discover how it might be possible. 2,3

1 Miller D; Wadsworth J; Diamond J & Ross E. Pertussis vaccine and whooping cough as risk factors in acute neurological illness and death in young children. Dev Biol Stand. 1985;61:389-94.

2 Challoner, A. http://www.scribd.com/doc/19408267/Brain-Damage-Caused-by-Vaccination

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The nature of the brain damage so caused does not follow a pattern that is evident from case to case due to the sporadic nature of the precipitating event, the age of onset and the varying characteristics of individual brains. This causes a great deal of difficulty for those who are called upon to care for affected individuals and often it is found that their brain damage is ignored because it is too complicated for people to understand; even by the professionals.

It is much more tempting and less intellectually challenging to believe that the person just lacks intelligence and therefore giving credence to a view that they should be included in the Learning Disability Service provision. This egregious error has serious consequences for those who are truly brain damaged. Dealing with the brain damaged individual, calls up much more serious scientific knowledge and understanding of neuropsychology. By subverting assessments into a lower classification of need there is a pseudo-legitimate encouragement for the use of lesser skills in both assessment and quality of care.

Contemporary research indicates that juvenile traumatic brain injury evolves into a chronic brain disorder and this process starts almost immediately after the injury. Atraumatic brain injury (aTBI) refers to physical trauma to the brain that arises from non-physical means such as toxins passing the blood/brain barrier and these lead to cognitive and other dysfunctions. ATBI is particularly serious in infants and young children, often leading to long-term functional impairments. Although clinical research is useful for quantifying and observing the effects of these injuries, few studies have empirically assessed the long-term effects of juvenile TBI (jTBI) on behaviour and histology. 4

Magnetic resonance imaging and histological data reveals that the effects of jTBI are evolving for up to 6 months post-injury, with reduced cortical thickness, decreased corpus callosum area and CA1 neuronal cell death in jTBI animals distant to the impact site. These findings suggest that this model of jTBI produces long-term impairments comparable to those reported clinically. Although some deficits are stable over time, the variable nature of other deficits (e.g., memory) suggest that the effects of a single jTBI produce a chronic brain disorder with long-term complications. (Kamper et al ibid, 2013)

Age of onset is a very important aspect of outcome. Until fairly recently, the impact of early brain insult [EBI] has been considered to be less significant than for later brain injuries, consistent with the notion that the young brain is more flexible and able to reorganize in the context of brain insult. However, Anderson et al have reviewed childhood head trauma through a range of ages from pre-natal to after age ten years. This study aimed to evaluate this notion by comparing cognitive and behavioural outcomes for children sustaining EBI at different times from gestation to late childhood. 5

Groups were similar with respect to injury and demographic factors. Children were assessed for intelligence, academic ability, everyday executive function and behaviour. Results showed that children with EBI were at increased risk for impairment in all domains assessed. Furthermore, children sustaining EBI before age 2 years recorded global and significant cognitive deficits, while children with later EBI performed closer to normal expectations, suggesting a linear association between age at insult and outcome. In contrast, for behaviour, children with EBI from 7 to 9 years performed worse than those with EBI from 3 to 6 years, and more like those with younger insults, suggesting that not all functions share the same pattern of vulnerability with respect to age at insult.

3 Challoner, A. http://www.scribd.com/doc/25042444/Towards-a-Better-Understanding-of-

Early-Atraumatic-Brain-Injury

4 Kamper JE, Pop V, Fukuda AM, Ajao DO, Hartman RE, Badaut J. Juvenile traumatic brain injury evolves into a chronic brain disorder: Behavioral and histological changes over 6months. Exp Neurol. 2013 Dec;250:8-19. doi: 10.1016/j.expneurol.2013.09.016.

5 Anderson, A.; Spencer-Smith, M.; Rick Leventer R.; Lee Coleman, L.; Anderson, P.; Williams, J.; Greenham, M. & Rani Jacobs, R. Childhood brain insult: can age at insult help us predict outcome? Brain (2009) 132 (1): 45-56.

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Knowledge arises from a variety of conceptions: A priori knowledge or justification is independent of experience (for example 'all bachelors are unmarried'); a posteriori knowledge or justification is dependent on experience or empirical evidence (for example 'some bachelors are very happy'). A posteriori justification makes reference to experience; but the issue concerns how one knows the proposition or claim in question—what justifies or grounds one's belief in it.

Knowledge in MDL’s case is based almost entirely on experience. She does not have the capacity for mental consideration of abstract ideas. She does not ‘think’ about things unless they are imposing themselves upon her attention.

Suppose we take as an example a cabbage that is lying on the table. We would normally be able to respond to that vision in whatever way was necessary to satisfy our curiosity and we would do it with out thinking very much about it.

Given the same situation, MDL would probably ignore it unless you drew it to her attention by asking questions about it. We could ask her:

� What is it? [On a good day she might be able to name it, but not always.]

� Where is it? [She might say ‘on the table’ or perhaps ‘in the kitchen’ — it would depend upon where her thoughts were situated at the time.

� What is it for? [she might say eating, but more likely cooking, or even more likely for putting in the cupboard]

� What shall we do with it? [She would very probably say, ‘put it away’ — she does not like to see any food lying around if it is not part of a ready meal.]

It is possible that for someone who has recent brain damage after good mental development that they may:

� Not recognise it as a cabbage. [anomia]6

� See it as something they know they have seen before but cannot name it. [Anomic aphasia, also known as amnesic (or amnestic) aphasia, and nominal aphasia.]

� If it is on the kitchen table along with other items it may not be seen as an individual item and if taken away from the group it would not be missed. [ Simultanagnosia]

� Recognise it as something they have seen before but cannot say what it is for. [associative agnosia]

� Recognise it but have no idea how to use it or when to use it. [associative agnosia]

With subjects like MDL, there is a tendency to want to relate such problems to mental health interpretations and practices because those are what the Learning Disability Service normally deals with. However, this is a serious over-simplification, not to say, an erroneous one if the subject is primarily brain damaged and has some antecedent learning problems as a result of that damage. The two cannot be combined or the benefits of proper assessment and care will be forfeited to the subject’s misfortune.

This paper has two purposes: one, of demonstrating the problems that MDL has acquired through her brain injury and two, to offer a very great saving in time for those who need to know how this rare type of brain damage affects an individual who has been misunderstood for so long. Due to the

6 In, “The Case of Anna H”, who had anomia, the neurologist/writer Oliver Sacks noted that:

“When I showed her some kitchen matches, she recognized them at once, visually, but could not say the word 'match,' saying instead, 'That is to make fire.' ”

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long-term administration of psychotropic drugs she is unable to offer any cooperation in a neurological assessment and that makes such an assessment impossible.

____________________

The Central Nervous System (CNS)

There are three major divisions of the central nervous system - the spinal cord, the sub-cortex and the cortex. The cortex is the outer layer of the brain; these two are considered here.

The neurons of the central nervous system form a cohesive structure which floats in the cerebrospinal fluid (CSF). Within the central nervous system, the spinal cord includes the neurons housed in the bony casing of the spinal vertebrae, while the cortical level is repre-sented by the neurons of the outer layers of the cerebral hemispheres. The subcortical level includes those cells of the CNS which lie above the spinal cord and below the cortex.

The Brain In evolutionary terms the brain consists of a primitive central core — the brain stem, the thalamus and the cerebellum. This group of structures is collectively referred to as the limbic system. The outer layer of the brain — the new brain or neocortex — has evolved upon the limbic system. Despite this evolutionary division, the various structures are interconnected in a complex fashion.

The brain stem forms a stalk which supports the other brain structures. It contains ascending and descending fibres which transmit information to or from higher brain centres. There are also neurons within the brain stem which relay incoming information directly to motor efferents. These brain stem reflexes include sucking, swallowing, sneezing, coughing, yawning, breathing, and the control of blood pressure. That the reflexes are organized within the brain stem is demonstrated by their presence in children born without a cerebral cortex.

The cells in the central part of the brain stem make up the reticular formation. This region receives input from all sensory systems and maintains a continuous barrage of impulses as-cending to the cortex. The reticular formation is involved in the control of sleeping, waking and many other physiological and behavioural functions.

Located on top of the brain stem but still deep beneath the surface of the brain is the thalamus. A major function of the thalamus is to relay information to and from the cortex. Many nuclei of the thalamus receive input from sensory afferent fibres and project it to the cortex.

All senses except smell have relay centres in specific nuclei of the thalamus. Within these nuclei sensory information is modified before being relayed to the cortex. Some thalamic nuclei relay information from the cortex down through the spinal cord to the skeletal muscles. Other thalamic nuclei are involved in coordination of reflex movements of the eyeball and the pupillary reflex.

Surrounding the thalamus is a number of long nuclei. A group of these nuclei which form the basal ganglia are associated primarily with movement, whereas others appear to play a major role in emotional and regulatory behaviours.

Another structure important for movement control is the cerebellum, which is situated on the top surface of the brain stem and below the cortex. The cerebellum acts to smooth and refine muscular action. The cerebellum works with information from equilibrium sensors (vestibular sensory system) and information concerning the position of limbs and the stretch

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of muscles (proprioceptors). In addition, the cerebellum ensures that motor commands from higher centres are coordinated and result in well-regulated movement.

There are an enormous number of muscles involved in even simple actions such as using a knife and fork, or walking. A professional card player can deal cards with exceptional speed and precision. This probably involves ‘reading off’ a carefully prepared program of this action which is stored and refined by the cerebellar neurons. Loss of even simple abilities can follow brain damage to the areas that control them.

Situated in front of and slightly below the thalamus is the hypothalamus. This brain region is important in the regulation of glandular secretions, eating, drinking, sexual behaviour, emotional behaviour, and body temperature. The hypothalamus is unusual in that it manufactures chemicals (hormones) which are transmitted, via the bloodstream, to the adjacent pituitary gland. Hypothalamic hormones control the pituitary gland's manufacture of a number of hormones which are carried by the blood stream to control both the manufacture and release of the hormones of other glands. Thus the hypothalamus func-tions as an important link between the brain and the glandular effector system.

Pituitary Dysfunction after Traumatic Brain Injury Partial or complete pituitary dysfunction affects 33-50% of all traumatic brain injury (TBI) survivors and is a significant contributor to the overall disability burden. The hypophyseal vessels are anatomically vulnerable to raised intracranial pressure and pituitary ischaemia or haemorrhage. Post-traumatic hypopituitarism (PTHP) can affect all grades of severity of injury and is often difficult to diagnose, as its features largely overlap with common post-concussive symptoms. PTHP has a wide range of manifestations, including fatigue, myopathy, cognitive difficulties, depression, behavioural changes or life-threatening complications such as sodium dysregulation and adrenal crisis. A full investigation of the hypothalamic-pituitary axis requires specialized neuroendocrine assessment, including stimulation tests, as random hormone levels can be misleading in this context. Patients with PTHP may receive suboptimal rehabilitation unless the underlying hormone deficiency is identified and treated. 7

This dysfunction is important for all, however until recently there has been little knowledge gained on this potential complication in children and adolescents. Traumatic brain injury carries a considerable burden of disabilities and leads to a variety of endocrine dysfunctions in 28-69% of adult acute head-injured patients. In the acute posttraumatic phase, adrenal insufficiency and electrolyte disorders are critical conditions. 8

Acerini et al have shown that hypopituitarism may occur after both mild and severe TBI, with growth hormone and gonadotrophin deficiencies appearing to be most common abnormalities. Central precocious puberty has also been documented. They suggest that given the critical role of anterior pituitary hormones in the regulation of growth, pubertal and neurocognitive development in childhood, early detection of hormone abnormalities following TBI is important; and that a multidisciplinary approach should be a follow-up together with endocrine assessment for the long-term management and rehabilitation of children and adolescents who survive moderate to severe head injury. 9

Later research by Auble et al emphasizes that endocrine dysfunction is common after accidental traumatic brain injury. However they say that prevalence of endocrine dysfunction after inflicted traumatic brain injury (iTBI) is not known. In their research the objective was to examine endocrinopathy in children after moderate to severe iTBI.

7 Zaben M, El Ghoul W, Belli A. Post traumatic head injury pituitary dysfunction. Disabil

Rehabil. 2012 Jul 10.

8 Einaudi, S & Bondone, C. The effects of head trauma on hypothalamic pituitary function in children and adolescents. Current Opinion in Pediatrics 19(4):465 (2007) PMID 17630613.

9 Acerini, CL. & Tasker, RC. Traumatic brain injury induced hypothalamic pituitary dysfunction a paediatric perspective. Pituitary 10(4):373 (2007) PMID 17570066.

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This showed that children with history of iTBI had a high risk for endocrine dysfunction, including elevated prolactin and growth abnormalities. This effect of inflicted TBI has not been well-described in the literature. Larger, multi-center, prospective studies would provide more data to determine extent of endocrine dysfunction in iTBI. They recommend that any child with history of iTBI be followed closely for growth velocity and pubertal changes; and suggest that if growth velocity is slow, prolactin level and a full endocrine evaluation should be performed. 10

Following assessment of children (aged two months to 20 years) after TBI, Casano-Sancho recommended that there should be prospective follow-up of children after there injury. Firstly, because the impairment of pituitary function cannot be predicted, and secondly, to avoid the potential consequences of pituitary dysfunction. They also consider that prospective clinical trials are needed before recommending a systematic screening after TBI and/or Growth Hormone Therapy either in post-pubertal children or in pre-pubertal children who grow normally. 11

It is therefore very important to be aware of the fact that physical or chemical damage to these areas may also bring about hormonal dysfunction.

The Cortex The most conspicuous parts of the human brain are the two folded masses which together form the cerebral hemispheres. The two hemispheres are separated by a deep fissure running from front to back, beneath which they are connected by a bundle of fibres called the corpus callosum. The corpus callosum is the largest and most important of the connecting or commissural fibre systems of the brain.

Each hemisphere is approximately the size of a clenched fist. Each hemisphere is filled largely by message-carrying fibres. However, much of the work of the brain is done in the cells which form the outermost layers of the cerebral hemispheres. These layers are called the cortex.

The importance of the cortex is indicated by the fact that primitive organisms, such as fish and frogs, have no real cortex. As behavioural complexity increases, the size of the cortex increases correspondingly. The appearance of the cortex tends to change with the com-plexity of the organism. In primitive animals such as the rat the cortex is smooth, whereas in primates the cortex is convoluted with large folds (fissures) and ridges (gyri). The convolutions greatly increase the surface area of the cortex although much of it is hidden from view.

Many fissures may slightly differ from individual to individual but the large fissures are fairly constant. These main fissures are the central fissure and the lateral fissure, which facilitate the division of each hemisphere into four lobes - the frontal lobe, the parietal lobe, the temporal lobe, and the occipital lobe. These divisions simplify the relating of brain function to cortical location.

All sensory systems have neural pathways which terminate in sensory projection areas of the cortex. This does not imply a direct connection between receptors and the cortex but rather a sequence of neurons. The sensory projection areas of both hemispheres are generally of equal size.

10 Auble B; Rose S; Bollepalli S; Weis T; Makoroff K; Khoury J & Colliers T. Hypopituitarism in

pediatric survivors of inflicted traumatic brain injury. J Neurotrauma. 2013 Sep 12.

11 Casano-Sancho P; Suárez L; Ibáñez L; García-Fructuoso G; Medina J & Febrer A. Pituitary dysfunction after traumatic brain injury in children is there a need for ongoing endocrine assessment? Clin Endocrinol (Oxf). 2013 May 7. doi: 10.1111/cen.12237.

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The cortical projection areas are essential for the proper sensing of particular stimuli. Visual information projects to the occipital lobe, auditory information to the temporal lobe, somato-sensory information (touch, pressure, etc.) to the parietal lobe.

Parts of each projection area appear to serve as primary areas (since damage to them leads to total loss of that sensation). Regions bordering each primary projection appear to serve an integrative function. For example, damage to the occipital lobes may result in some loss of vision although the eyes and optic nerves are in perfect working order. Damage to regions bordering on the visual cortex results in normal visual sensation but with deficits in integrating the visual sensation experienced. The results support the view that, while for conscious perception the appropriate part of the cortex needs to be intact, rudimentary sensory functioning can continue without it.

The motor and somato-sensory maps have two features in common. First, there is virtually a total cross-over of somato-sensory input and motor output. The left hemisphere receives information about the right side of the body and controls movements of limbs on that side and vice-versa.

Learning and Memory Disturbances of Perception People with damage to the cortex just in front of the visual projection areas are still capable of visual sensations, but these sensations are not adequately integrated. The general name for this type of perceptual disturbance is agnosia (‘not knowing’).

One variety of agnosia is the inability to recognize faces. Such cases reflect the problems of testing brain-damaged people. Are patients simply misunderstanding the questions, or do they have defective perceptual ability? Exhaustive individual testing is required to overcome these problems. In addition to these functions it now seems that areas of the parietal lobe may play an important part in directing eye movements and perhaps even directing attention.

Other cortical regions are critical for the integration or recognition of auditory and tactile material and they are centred around the major auditory and somato-sensory projection areas.

Memory of Skilled Movements Damage to association areas around the motor strip (in front of the central fissure) affects the memory of skilled movements. These patients are unable to remember or organize the sequence of movements making up particular skills. They can copy but cannot initiate the movement. The general name for this loss of motor memory is apraxia.

Geschwind 12 defines apraxias as “disorders of the execution of learned movement which cannot be accounted for by weakness, incoordination or sensory loss, or by incomprehen-sion of or inattention to commands”. He quotes the example of a patient who could carry out commands with his right hand (e.g. combing his hair or using a hammer), but when told to use his left hand made no response. He could copy the task with his left hand if the examiner performed it, but was apparently unable to integrate the movement sequence himself. The fact that he could copy the task with his left hand rules out weakness or in-coordination. Further, as he could perform the task with his right hand, inattention, uncooperativeness or incomprehension were also ruled out.

Damage to association areas of the left temporal lobe produces language disturbances. A loss of language ability, due to brain damage, is called aphasia. Such disruptions are not primarily due to sensory or motor deficits, but to the inadequate handling of symbolic processes.

12 Geschwind, N. Specializations of the Human Brain. Sci Am. 1979 Sep;241(3):180-99.

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The two major cortical areas for language — Broca's area and Wernicke's area — are linked neurally. The location and extent of these areas has been the subject of dispute, and they do not have definite anatomical boundaries. Damage to these areas produces gradients of language loss.

Broca's area is at the base of, and just in front of, the central fissure. If it is damaged, disturbances of speech production result. These patients have great difficulty in speaking, and what speech they have is emitted slowly, with great effort and poor articulation. Some may have only a one-word vocabulary, and few can produce whole sentences. In addition, a similar disability usually occurs in their written language. However, they generally comprehend both spoken and written language.

The language loss produced by damage to Broca's area is not due simply to paralysis or muscular problems — patients can often sing the tune of a melody using ‘la-la’. The essential deficit is one of integration because the neural machinery that integrates language production is damaged. It may be that Broca's area governs the transformation of language into speech or writing.

Wernicke's area is a region in the left temporal lobe, below the lateral fissure and adjacent to the primary projection area for hearing; damage to this area results in the inability to understand both speech and writing. In those so affected, speech and writing are produced effortlessly but are essentially meaningless — a scrambled sequence of meaningless, inappropriate and often unintelligible words and non-words. Interestingly, the basic grammatical skeleton appears preserved but there is a lack of denotation. Wernicke's area seems to govern the recognition and synthesis of language patterns.

There are close neural connections between Wernicke's area and Broca's area. Geschwind (Idem) believes that the act of speaking involves the formulation of a concept into an auditory form in Wernicke's area, and then relaying it to Broca's area where the language is put into the complex programming of the speech organs.

Language association areas in the non-dominant hemisphere Language functions appear to be controlled by association areas in the left hemisphere of the brain. This raises a question about the function of the comparable regions of the right hemisphere. It was once thought that the right hemisphere was relatively unimportant since massive strokes to the right hemisphere had very little effect on language. However, the significance of the association areas in the right hemisphere is now becoming evident. The evidence is derived largely from the study of patients with damage to the corpus callosum, so that their two hemispheres function relatively independently. Other evidence has come from patients with massive damage to their left (dominant) hemisphere, so that they are totally without language functions (global aphasics). For some skills the right hemisphere is superior to the left.

Spatial abilities (such as copying block-designs) and musical abilities are apparently more disrupted by damage to the right hemisphere than to the left. Thus the right hemisphere is not illiterate. Furthermore, it has been found that people who have lost the use of the association areas in their left, (dominant) hemisphere, have considerable residual semantic and syntactic capacities which can be realized through response systems other than speech. Gazzaniga 13 found that such patients can perform many language operations using only their right hemisphere and, for example, could quickly learn the, “same or different” judgements.

FRONTAL LOBES

13 Gazzaniga, MS & Hillyard, SA. Language and Speech Capacity of the Right Hemisphere.

Neuropsychologia, 1971, Vol. 9, pp. 273 to 280. Pergamon Press.

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The two frontal lobes constitute approximately 25% of brain volume, yet the functions of this massive amount of brain remain obscure. The frontal lobes were once believed to be the seat of intelligence, since the most intelligent animals appear to have the largest frontal lobes. Recent evidence suggests, however, that the role played by the frontal lobes is considerably more complex.

In the early 1930s, Jacobsen removed both frontal lobes from the brains of a group of monkeys14. After they had recovered from the operation they were subjected to a number of behavioural tests. The monkeys were found to perform particularly poorly on a delayed response task. Each monkey was shown a piece of food which was then hidden under one of two cups; after a short delay the animal had to select that cup. A correct response yielded the food. Since the monkeys without frontal lobes performed poorly on this task, Jacobsen concluded that the frontal lobes were important for immediate memory. However, recent evidence suggests that this interpretation is not correct. If the monkeys were in darkness during the delay, their performance was near normal, suggesting that the frontal lobes play a role in attention or distractibility rather than immediate memory. This interpretation is consistent with the findings of research on human subjects with frontal lobe damage.

There is a useful source of evidence that comes from testing normal people who have accidentally suffered frontal lobe damage (for example, through war or car accidents). Post-operatively such people do not become imbeciles, hence it is unlikely that intelligence is localized in the frontal lobes. Generally, behavioural changes due to frontal lobe damage are subtle, affecting both intellectual behaviour and personality. It should be noted however that these research subjects were fully mentally developed adults prior to their brain injury. The outcome is not the same if the injury occurs during very early infancy or before the brain has developed to any significant degree to life outside the womb.

The behaviour of patients with frontal lobe damage is generally stereotyped or perseverative. It appears that these people find it difficult to let go of a concept once it is formed. Humans with damage to the frontal lobes are easily distracted. This distractibility may be reflected in their response to tests of intellectual functioning, although overall intelligence test scores are typically unchanged. These patients also have difficulty explaining the meaning of complex material, or in picking out significant objects in a picture. Luria 15 characterizes these difficulties as follows:

“In normal subjects the derivation of the meaning of a picture develops because of well-structured analytic or synthetic activity. In frontal patients this derivation is disturbed by ancillary associations evoked by fragmentary observations”.

The thinking of these patients is often described as being very concrete — they have difficulty explaining the meaning of a metaphor and in perceiving object relations and analogies.

In addition to intellectual changes, subtle changes in personality often occur; for example, there is a tendency to become more extroverted, while exhibiting a lack of purpose or initiative. The fact that the loss of the frontal lobes has no measurable effect on intelligence test scores may be due to the unreliability of the intelligence tests used. They may be neither measuring the correct things nor weighting various sub-tests appropriately. 16

14 Jacobsen, CF. Functions of Frontal Association Area in Primates. Arch Neurol

Psychiatry. 1935;33(3):558-569.

15 Luria AR & Homskaya ED. Disturbances in the regulative role of speech with frontal lobe lesions. In: Warren JM, Akert K, eds. The Frontal Granular Cortex and Behaviour. New York: McGraw Hill, 1964.

16 Atrens, D & Curthoys, I. The Neurosciences and Behaviour: An Introduction. Academic Press 1982.

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CLINICAL AND ANATOMIC ASPECTS For over a century, the frontal lobes have been an enigma to brain scientists. Significant progress has been made in the past several decades, but many anatomic and functional aspects remain mysterious. The frontal lobes, particularly in humans, are massive in relation to other, better understood cortical areas, and it was long considered that the frontal lobes were the seat of human intelligence. This proved untrue, at least as intelligence is defined by psychometric testing. The functions of the frontal lobes in human behaviour remain a mystery.17

In 1973 the great Russian psychologist A. R. Luria18 proposed a simple outline of brain func-tions. He suggested that subcortical structures, particularly the midbrain and diencephalon, functioned to produce tonic regularity. He further stated that the posterior cortex — the premotor and motor aspects of the frontal lobe and all cortex posterior to these areas — carried out primary sensorimotor functions, and that the comparatively massive prefrontal cortex functioned to regulate mental activities. This tripartite description of mental functions was further elaborated by Albert19 who suggested the terms fundamental, instrumental, and superordinate to define the activities of the brainstem, posterior cortex, and prefrontal cortex respectively.

The frontal lobe is the largest lobe in the brain, yet often it is not specifically evaluated in routine neurologic examinations. This may in part be due to the attention to detail and to the rigorous testing strategies that are required to probe frontal lobe functions. As successful completion of any cognitive task considered a frontal lobe function requires multiple brain regions both within and outside the frontal lobe. Dysfunctions of the frontal lobe can give rise to relatively specific clinical syndromes. When a patient's history suggests frontal lobe dysfunction, detailed neurobehavioral evaluation is necessary.

Classic neuroanatomy divides the cortical surface of the frontal lobes into three major segments:

1. Motor — the narrow strip of cortical tissue located just anterior to the rolandic fissure;

2. Pre-motor — the larger area of frontal tissue anterior to the motor strip that acts as a motor association cortex (Brodmann areas 6 and 8); and

3. Pre-frontal — the vast amount of frontal cortex anterior to the pre-motor cortex, including a significant amount of the anterior/lateral cortex, most of the medial frontal cortex, and the entire orbital frontal cortex.

In the classification suggested by Luria (idem) the motor and pre-motor areas of the frontal lobes would be included in the sensori-motor division and the pre-frontal cortex would carry out the regulatory activities. The prefrontal regulatory functions are important for psychology.

Given the unique connectivity between the frontal regions and deeper brain structures, lesions of these areas or their connections generate relatively distinctive clinical behaviours.

• The dorso-lateral frontal cortex is concerned with planning, strategy formation, and executive function. Patients with dorso-lateral frontal lesions tend to have apathy, personality changes, abulia20, and lack of ability to plan or to sequence actions or

17 Benson, DF & Miller, BL. Frontal Lobes: Clinical and Anatomic Aspects. . In Feinberg, T E &

Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

18 Luria AR. The Working Brain: An Introduction to Neuropsychology (Haig B, trans). New York, Basic Boooks; 1973.

19 Albert ML. Subcortical dementia, in Katzman R, Terry RD, Bick KI (eds): Alzheimer's Disease, Se-nile Dementia and Related Disorders. New York, Raven Press, 1978, pp 173-180.

20 Abulia is a state in which an individual seems to have lost will or motivation. It is not a separate condition; rather, it is a symptom associated with various forms of brain injury. It may

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tasks. These patients have poor working memory for verbal information (if the left hemisphere is predominantly affected) or spatial information (if the right hemisphere bears the lesion brunt).

• The frontal operculum contains the centre for expression of language. Patients with left frontal operculum lesions may demonstrate Broca aphasia and defective verb retrieval, whereas patients with exclusively right opercular lesions tend to develop expressive aprosodias (See page 42).

• The orbitofrontal cortex is concerned with response inhibition. Patients with orbitofrontal lesions tend to have difficulty with disinhibition, emotional lability, and memory disorders. Patients with such acquired sociopathy, or pseudo-psychopathic disorder, are said to have an orbital personality. Personality changes from orbital damage include impulsiveness, puerility, a jocular attitude, sexual disinhibition, and complete lack of concern for others.

• Patients with superior mesial lesions affecting the cingulate cortex typically develop akinetic mutism21.

• Patients with inferior mesial (basal forebrain) lesions tend to manifest anterograde and retrograde amnesia and confabulation.

Of considerable significance in discussion of the neural basis of prefrontal psychological functions are the connections of frontal cortex with other brain areas. The prefrontal cortex receives direct or indirect input from most ipsilateral cortical areas and from the opposite hemisphere via callosal connections. In addition, prefrontal cortex receives strong input from a number of significant subcortical sources:

1. The limbic system,

2. The reticular system,

3. The hypothalamus, and

4. Neurotransmitter systems.

The pre-frontal cortex is the only cortical area that receives strong sensori-motor, limbic, and reticular input. Additional input of hypothalamic and autonomic data and the effects of many neurotransmitters place prefrontal cortex in a strong position to monitor both intrinsic and extrinsic stimuli and to exert regulatory control of brain functions.

Pre-frontal Functions Behavioural functions performed by the prefrontal cortex have proved difficult to delineate. To date, almost all information has been derived from behavioural aberrations seen following frontal brain damage. In the past several decades some psychological tests aimed directly at the assessment of prefrontal function have been devised (see Wisconsin Card Sorting Test (WCST)22 below p 11), and, more recently, psychological testing has been combined with functional brain imaging techniques to provide valuable insights. In general, however, psychological tests of prefrontal function demand inferences from data obtained through primary sensori-motor functions, which of themselves may be impaired. A second problem in studying prefrontal function is a lack of clearly delineated neuropathology.

The main domains affected include: Complex motor behaviour (see Limb Apraxia below, p53) Planning & sequencing (See Acalculia below, p52) Attention (see Limb Apraxia below, p54)

occur in association with a variety of conditions, including stroke, brain tumor, traumatic brain damage, bleeding into the brain, and exposure to toxic substances.

21 Akinetic mutism: A state in which a person is unspeaking (mute) and unmoving (akinetic).

22 Grant AD & Berg EA. A behavioural analysis of reinforcement and ease of shifting to new responses in a Weigl-type card sorting. J Exp Psychol 38:404411,1948

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Memory (See several references — access via Index) Language (see ‘Aspects of Aphasia & Agraphia’ below, p. 43)

It is the damage to the frontal lobes and its consequences that confound those who attempt to assess MDL.

Perhaps because of these problems, the underlying impairment in frontally damaged patients has yet to be satisfactorily established. Some of the characteristics that appear in MDL’s damage to this area are:

v Little spontaneity of behaviour v Unconcern about non-personal matters v Low overt emotion (not including sympathetic system induced anxiety23) v Reduced ability to plan ahead

The cognitive impairments of patients with prefrontal damage are apparent in a variety of tasks. The domains affected include complex motor behaviour; planning and sequencing, attention, memory, and language. (See trans-cortical motor aphasia – p 50) In comparison with other types of brain damage which disrupt cognitive development, frontal damage acquired early in life appears to provide the neurological substrate for a special type of learning disability in the realms of insight, foresight, social judgement, empathy, and complex reasoning 24.

There have been those who have felt that MDL has at times shown inappropriate behaviour towards others. However, this stems from the fact that she has a lack of recognition of another’s personal space. She does not have the ability to judge social situations and how and when to approach other people. At times there is also increased motor activity and almost always this is as a result of anxiety.

Many toxins can affect the cerebral cortex and in those cases the symptom picture is as defuse as in MDL’s case. The toxins from the DPT vaccination of course are the cause of her brain damage.

COGNITIVE AND NEUROPSYCHOLOGICAL ASPECTS As mentioned above, the prefrontal cortex plays a crucial role in normal intelligent behaviour. However, a more precise characterization of the functions of prefrontal cortex has been elusive. A wide range of tasks have been found to be sensitive to prefrontal damage. One of the most common is the WCST, in which patients are given a series of cards and asked to sort them by placing each into one of four piles. The cards vary according to three attributes:

the number of objects drawn on the card, the shape of the objects, and their colour.

The piles are to be started beneath four reference cards, which also vary along these same dimensions, so that each possible value of each attribute will be represented in exactly one pile. The subject is given a deck of cards and asked to place each, in sequence, into one of the four piles. The only feedback given to the subject is the word right or wrong after

23 When we are faced with something that is frightening, the body floods the system with

adrenaline. This hormone attempts to help us to deal with the 'danger'. Adrenaline activates the Sympathetic Nervous System which is a sub-branch of the Autonomic Nervous System. It controls specific bodily organs to prepare us for fight or flight. These reactions are beyond the control of our consciousness and can be responsible for anxiety. The anxiety is maintained if we cannot respond with either fight or flight.

24 Price, BH; Daffner KR; Stowe RM & Mesulam, MM. The comportmental learning disabilities of early frontal lobe damage. Brain : a journal of neurology, Vol. 113 ( Pt 5) (October 1990), pp. 1383-1393.

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each card.

MDL would be incapable of making any successful attempt at this test. She would not understand the instructions but also she would not be able to recognise the differences between the cards and therefore would not be able to complete the sequencing tasks.

Milner25,26 tested a variety of neurosurgical patients on the WCST and found that as compared to patients with lesions elsewhere in the brain, patients with damage to the dorso-lateral prefrontal cortex made an unusually high number of errors and achieved fewer categories. These differences can be attributed mainly to perseveration. While the dorso-lateral prefrontal group committed non-perseverative errors at rates similar to those of the control groups, their rates of perseverative errors were significantly higher. A number of other studies have confirmed the basic finding that the WCST is particularly sensitive to frontal damage. 27,28,29

Sequencing Tasks The term sequencing can describe anything from concrete motor sequences, such as sequences of hand motions, to more abstract behavioural se-quences, such as the morning routine of preparing to go to work. Of the sequencing errors made by frontal-damaged patients, many but not all are perseverative in nature. 30,31

A number of studies of simple manual and oral movement sequences have indicated that frontal lesions are most disruptive of these abilities. 32,3334 Anecdotal reports suggest that the problem extends to the sequencing of more abstract kinds of actions. For example, Pen-field and Evans35 describe a patient who could perform all the individual actions necessary to prepare a meal but could not actually prepare the meal without someone to tell her the order in which to do things.

Tasks that require planning of a sequence in advance may also depend on the frontal areas. Shallice36 tested frontal-damaged patients on the Tower of London test, a variant of the Tower of Hanoi game, designed specifically to require subjects to use advance planning. Left-frontal damaged patients showed a disproportionate impairment at this task.

25 Milner B. Effects of different brain lesions on card sorting. Arch Neurol 9:90-100, 1963.

26 Milner B. Some effects of frontal lobectomy in man, in Warren J, Akert K (eds): The Frontal Granular Cortex and Behavior. New York: McGraw-Hill, 1964.

27 Drewe EA. The effect of type and area of brain lesion on Wisconsin Card Sorting Test performance. Cortex 10:159-170, 1974.

28 Nelson HE. A modified card sorting test sensitive to frontal lobe defects. Cortex 12:313-324, 1976.

29 Anderson SW; Damasio H; Jones RD & Tranel D. Wisconsin card sorting test performance as a measure of frontal lobe damage. J Clin Exp Neuropsychol13:909-922, 1991.

30 Luria AR. Two kinds of motor perseveration in massive injury of the frontal lobes. Brain 88:1-10, 1965.

31 Sandson J & Albert M. Varieties of perseveration. Neuropsychologia 22:715-732, 1984.

32 Jason GW. Manual sequences learning after focal cortical lesions. Neuropsychologia 23:483-496, 1985.

33 Kimura D. Left-hemisphere control of oral and brachial movements and their relation to communication. Phi/os Trans R Soc Lond B 298:135-149,1982.

34 Kolb B. & Milner B. Performance of complex arm and facial movements after focal brain lesions. Neuropsychologia 19:491-503, 1981.

35 Penfield W & Evans J. The frontal lobe in man: A clinical study of maximum removals. Brain 58:115133,1935.

36 Shallice T. Specific impairments of planning. Philos Trans R Soc Lond B 298:199-209, 1982.

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Verbal Fluency Asked to produce words beginning with a particular letter, frontal-damaged patients (even those with no overt aphasic signs) will typically produce few unique responses, often repeating earlier responses. This frequently reported clinical finding has been supported by a variety of experimental studies. Although her understanding of words is reasonable, MDL cannot complete semantic tests like offering words that begin with a particular letter.

An early study by Milner (1964 idem) demonstrated that patients with left frontal damage were impaired at a written test of verbal fluency when compared to a group with temporal lobe excisions. Benton37 later confirmed the relative importance of the left frontal areas in the now more common oral version of the test. More recently, Janowsky and co-workers38 compared verbal fluency in frontal-damaged patients with a variety of control groups and found that patients with left or bilateral frontal lesions but not right frontal lesions were impaired at verbal fluency. Jason (idem) found deficits in gesture fluency in frontal-dam-aged groups. MDL also has very little gesture activity which again seems to confirm her frontal damage.

Neuro-imaging studies have tended to confirm the importance of prefrontal areas in fluency tasks. Parks and co-workers39 used positron emission tomography (PET) to compare the brain activity of subjects performing a verbal fluency task with controls in a resting state and found increases in activation bilaterally in both the frontal and temporal lobes.

Context Memory Although most frontal-damaged patients are not amnesic, they have nevertheless been found to have impairments on certain memory tasks. The most widely documented impairments involve memory for contextual information, either the source of a correctly recalled fact or its temporal context. Schacter40 has applied the term spatio-temporal context to the type of memory that is impaired in frontal-damaged patients.

In conditional associative learning, frontal-damaged patients are impaired at learning and associating between a set of stimuli (e.g., coloured lights) and a set of available responses (e.g., a set of abstract designs). 41,42 Lesions placed in the posterior dorso-lateral prefrontal cortex of nonhuman primates (an area adjacent and posterior to the lesions causing impairments in self-ordered tasks) will markedly impair performance on conditional association learning tasks in which the monkey must perform different responses conditional upon the presence of a particular stimulus.43 Furthermore, Petrides and colleagues have shown that performance of a conditional associative learning task in normal human subjects activates this same region of posterior dorso-lateral frontal cortex44.

37 Benton AL. Differential behavioural effects of frontal lobe disease. Neuropsychologia 6:53-60,

1968.

38 Janowsky JS; Shimamura AP & Squire LR. Source memory impairment in patients with frontal lobe lesions. Neuropsychologia 27:1043-1056, 1989.

39 Parks RW; Loewenstein DA & Dodrill KL, et al. Cerebral metabolic effects of a verbal fluency test: A PET scan study. J Clin Exp Neuropsycholl0:565575,1988.

40 Schacter DL. Memory, amnesia, and frontal lobe dysfunction. Psychobiology 15:21-36, 1987.

41 Petrides M. Deficits on conditional associative learning tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia 23:601-614,1985.

42 Petrides M. Nonspatial conditional learning impaired in patients with unilateral frontal but not unilateral temporal-lobe excisions. Neuropsychologia 28:137-149,1990.

43 Petrides M. Deficits in non-spatial conditional associative learning after periarcuate lesions in the monkey. Behav Brain Res 16:95-101, 1985.

44 Petrides M; Alivisatos B; Evans AC & Meyer E. Dissociation of human mid-dorsolateral from posterior dorsolateral frontal cortex in memory processing. Proc Natl Acad Sci USA 90:873-877, 1993.

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MDL can respond with recognition of words presented to her on a card but fails to memorize the word for recall when the card is not in view. Likewise if she is verbally presented with a choice of three items she will inevitably choose the last one. However, when presented with the same three items visually, she may well choose differently. Although she has not been examined or assessed in these contextual abilities, it is almost certain that MDL would not complete satisfactorily tasks of self-order and conditional associative learning.

Janowsky and colleagues45 investigated memory for recently learned facts and memory for the source of the facts in a group of frontal damaged patients. Although the patients were normal in their ability to recall the facts, they frequently attributed the facts to incorrect sources. Shimamura and co-workers46 found that frontal damaged patients, while unimpaired at recall and recognition of words printed on cards, were impaired at placing the cards in their original sequence of presentation. They also tested the same patients on a similar test of famous events (from 1941 to 1985), also finding that frontal-damaged patients recognized the events but were impaired at judging the decade in which the events occurred.

Theories of Frontal Lobe Function Theories of frontal lobe function vary in the breadth of phenomena they are intended to explain. In some cases they are aimed at explaining performance in just one task, whereas in others they are intended to account for most or all of the cognitive changes that follow prefrontal damage.

Given the diversity of tasks affected by prefrontal damage, from the execution of simple manual sequences to the sorting of cards according to abstract categories, it might seem unlikely that prefrontal cortex has a single underlying cognitive function. Although most patients who are impaired at one task will also be impaired at some others, across-the-board impairment is rare. Prospects for a unified theory of frontal lobe function seem even slimmer when the known functional anatomy of the frontal lobes is considered.

Pre-frontal cortex alone includes the frontal eye fields, which are implicated in the control of voluntary eye movements, and Broca's area, which is implicated in language processes. Dorso-lateral prefrontal damage is more closely associated with cognitive deficits, while orbito-frontal damage seems to be related to more obvious changes in personality. Consistent and reliable differences in function have been found even between different areas within the dorso-lateral areas (Petrides 1993 idem)). Hemispheric asymmetries have been widely noted. The left frontal lobe is more strongly and more often implicated in tasks that involve verbal materials, while the right is most clearly implicated in some tasks in-volving non-verbal materials. 47 Some frontal-damaged patients seem to show perseveration at a variety of tasks, ranging from concrete motor tasks to the sorting of cards into abstract categories.48,49

Abstract Thinking Goldstein 50,51 proposed that the frontal lobes were especially important for abstract thought and that the ‘abstract attitude’ could not be adopted by 45 Janowsky JS; Shimamura AP & Squire LR. Source memory impairment in patients with frontal

lobe lesions. Neuropsychologia 27:1043-1056, 1989.

46 Shimamura AP; Janowsky JS & Squire LR. Memory for the temporal order of events in patients with frontal lobe lesions and amnesic patients. Neuropsychologia 28:803-813, 1990.

47 Kimberg, DY; D’Esposito, M & Farah, MJ. Frontal Lobes: Cognitive and Neuropsychological Aspects. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

48 Luria AR. Two kinds of motor perseveration in massive injury of the frontal lobes. Brain 88:1-10, 1965.

49 Sandson J & Albert M. Varieties of perseveration. Neuropsychologia 22:715-732, 1984.

50 Goldstein K. Mental changes due to frontal lobe damage. J PsychoI17:187-208, 1944.

51 Goldstein K & Scheerer M. Abstract and concrete behavior: An experimental study with special tests. Psychol Monogr 43:1-151,1941.

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patients with extensive frontal damage. Although it may well be true that many frontal-damaged patients think concretely, this hypothesis does not explain many of the central phenomena of frontal damage. MDL seems to have little ability for abstract thought.

Planning Many authors have attributed a planning function to the frontal lobes 52,53,54 and Duncan55 has framed this idea in terms of recent cognitive science models of problem solving. He proposes that human purposive activity requires a list of goals and a set of action structures resembling scripts. Goal-directed behaviour is produced by a process similar to that of Newell and Simon's56 means-end analysis. In effect, the goals inhibit those action structures that are not relevant to their achievement. The authors suggest that a defect in the use of the goal list to constrain behaviour is responsible for the behaviour of frontal-damaged patients. This account can explain failure on many but not all of the tasks mentioned earlier. For example, it does not explain context memory difficulties. MDL always needs to be reminded about how many things are done and what to do next. Planning ability is not something that she seems to have or to know about.

Inhibition The theory that the frontal lobes serve an inhibitory function, suppressing dominant action tendencies in favour of more goal-appropriate behaviour, has been proposed recently to account for a variety of data, including normal human development and physiologic experiments with monkeys. Diamond57 has argued, from the development of reaching behaviours of infants and infant monkeys, that the prefrontal cortex serves such a function in inhibiting inappropriate reaches to formerly rewarded locations. She also suggests that this explanation may generalize to explain frontal deficits at the WCST as well as ‘capture’ behaviour, the intrusion of familiar but contextually inappropriate actions that have sometimes been noted after frontal damage.

Similarly, Dempster58 has proposed that inhibitory functions in the frontal cortex, in particular the suppression of irrelevant stimuli or associations, may account for a wide variety of patterns in both cognitive development and cognitive aging as well as data from frontal damaged patients. Roberts and co-workers59 argue that frontal inhibitory processes (as well as working memory – see below p 106) underlie patterns of performance in normal and patient groups at anti-saccade tasks60. This gives support for the view that frontal and/or


53 Benton AL. Differential behavioural effects of frontal lobe disease. Neuropsychologia 6:53-60, 1968.

54 Luria AR & Homskaya ED. Disturbance in the regulative role of speech with frontal lobe lesions, in Warren JM, Akert K (eds): The Frontal Granular Cortex and Behavior. New York: McGraw-Hill, 1964, pp 353-371.

55 Duncan J. Disorganisation of behaviour after frontal lobe damage. Cog Neuropsychol 3:271-290, 1986.

56 Newell A & Simon HA. Human Problem Solving. Englewood Cliffs, NJ: Prentice Hall, 1972.

57 Diamond A. Developmental progression in human infants and infant monkeys, and the neural bases of inhibitory control of reaching, in Diamond A (ed): The Development and Neural Bases of Higher Cognitive Functions. New York: NY Academy of Science Press, 1989.

58 Dempster FN. The rise and fall of the inhibitory mechanism: Toward a unified theory of cognitive development and aging. Dev Rev 12:45-75, 1992.

59 Roberts RJ; Hager LD & Heron C. Prefrontal cognitive processes: Working memory and inhibition in the antisaccade task. J Exp Psychol Gen 123:374393,1994.

60 The anti-saccade task In the laboratory, behavioural paradigms have been developed to study the ability of the brain to respond flexibly to our environment. The anti-saccade task has become one of the most popular tasks because it contains a manipulation of stimulus–response compatibility that decouples stimulus encoding and response preparation. In this task, the participant is instructed that, after presentation of a peripheral target, they must look away to its mirror position. Correct performance on this task requires two steps. The subject must first suppress the automatic response to look at the target (pro-saccade) and then transform the location of the stimulus into a voluntary motor command to

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basal ganglia dysfunction is present in neurological patients with pathology in these brain regions.

Supervisory Attentional System According to Shallice 61,62,63 the frontal lobes instantiate a supervisory attentional system (SAS). Although this system is not needed for routine action, which is controlled by learned associations between stimuli in the environment and possible action, it serves to override these associations when stimuli or goals are novel. Thus, frontal damaged patients, in whom the SAS is damaged, are no longer able to exert goal-directed control over their actions but simply respond to stimuli.

This theory accords well with much of the observed behaviour of frontal-damaged patients. For instance, it predicts that they should behave more normally in familiar situations than in unfamiliar ones. It also accords with the slow learning evidenced by many patients in the WCST, as their behaviour seems very much like the slow learning of an associative module combined with the tendency of more familiar, routinely made responses to emerge even when inappropriate.

It is well established that in adults who have had normal development of social behaviour, damage to certain sectors of prefrontal cortex produces a severe impairment of decision-making and disrupts social behaviour, although the patients so affected preserve intellectual abilities and maintain factual knowledge of social conventions and moral rules. 64, 65, 66, 67, 68, 69

Little is known for certain, however, about the consequences of comparable damage occurring before the maturation of the relevant neural and cognitive systems, namely in infancy, because such cases are exceedingly rare. Information about the early onset condition is vital to the elucidation of how social and moral competencies develop from a neurobiological standpoint.

A number of questions have arisen in this regard. First, would early-onset lesions lead to the appearance of persistent defects comparable to those seen in adult-onset lesions, or would further development and brain plasticity reduce or cancel the effects of the lesions and prevent the appearance of the defects? Second, assuming early-onset lesions cause

look away from the target (anti-saccade). Performance on the anti-saccade task can be contrasted with performance on the pro-saccade task in which the location of the sensory stimulus and the goal of the saccade are compatible, requiring a direct sensory–motor transformation. In the anti-saccade task, stimulus location and saccade goal are decoupled; the direct response must be suppressed and the stimulus vector must be inverted into the saccade vector.


62 Shallice T. From Neuropsychology to Mental Structure. Cambridge, England: Cambridge University Press, 1988.

63 Shallice T. & Burgess P. Higher-order cognitive impairments and frontal lobe lesions in man, in Levin HS, Eisenberg HM, Benton AL (eds): Frontal Lobe Function and Dysfunction. New York: Oxford University Press, 1991.

64 Damasio, A. R., Tranel, D. & Damasio, H. in Frontal Lobe Function and Dysfunction (eds. Levin, H. S., Eisenberg, H. M. & Benton, A. L.) 217–229 (Oxford Univ. Press, New York, 1991).

65 Damasio, A. R. Descartes' Error. (Grosset/Putnam, New York, 1994).

66 Damasio, A. R. The somatic marker hypothesis and the possible functions of the prefrontal cortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 351, 1413–1420 (1996). MEDLINE

67 Grafman, J. in Structure and Functions of the Human Prefrontal Cortex (eds. Grafman, J., Holyoak, K. J. & Boller, F.) 337–368 (1995).

68 Shallice T. & Burgess, P. W. Deficits in strategy application following frontal lobe damage in man. Brain 114, 727–741 (1991). MEDLINE

69 Stuss, D. T. & Benson, D. F. The Frontal Lobes (Raven, New York, 1986).

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a comparable defect, would there be a dissociation between disrupted social behaviour and preserved factual social knowledge, as seen in the adult-onset condition, or would the acquisition of social knowledge at factual level be compromised as well? 70 Anderson et al found that the cognitive and behavioural profiles resulting from early prefrontal damage resembled, in several respects, the profiles resulting from adult-onset damage. However, unlike adult-onset patients, early-onset patients could not retrieve complex social knowledge at the factual level, and may never have acquired such knowledge. The case of MDL might add some relevant information to the answer to those questions.

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The Neurosciences of Behaviour — An Introduction

Brain injury is an active disease process with a variety of lifelong consequences, unique to each person. In order to understand the problems in a damaged brain it helps to have knowledge of how the normal brain works. Information is passed to various parts of the brain not only from its intrinsic parts but also from all other areas of the body (the periphery). Assuming that the nerve supply to these peripheral areas is in good order there will be connections between the parts of the brain which makes it the ‘central command’ structure.

The complexity of the brain adds difficulty to our understanding of how the brain develops, matures and functions. Both structural and molecular components define brain functional connectivity, and its alteration may result in developmental, behavioural and social deficits71. Furthermore, changes in the brain during the development of a person can also provide information about when and where the diseased brain loses functional connectivity.72 Jeffrey Neul proposes that studying the functional networks in people with autism and other neurodevelopmental disorders, and correlating changes with functional connectivity in animal models of these diseases, will uncover the mechanisms of normal and abnormal development and suggest possible treatment strategies.73

Neurons and Neurotransmitters

The pathways along which ‘messages’ are sent are called neurons. A neuron has three main structural features, a cell-body or soma, an axon and a number of dendrites. Dendrites are branch-like extensions of the cell-body, the number and arrangement of which vary enormously from neuron to neuron. Generally, the function of dendrites is to carry information to the cell-body. Most receptors and neurons have a special tubular extension of the cell-body — the axon — which, in general, carries information away from the cell-body. Axons vary considerably in both the number of branches or collaterals they make, and in their length.

The space between two nerve cells is called the synaptic gap. This gap is extremely narrow and it prevents a pre-synaptic action potential from jumping between the two cells. Instead, the action potential causes the nerve terminals to release certain chemicals which diffuse rapidly across the gap where they can then alter the membrane permeability of the post-synaptic cell. Thus we see that transmission of information within cells is an electrical

70 Anderson, SW; Bechara, A; Damasio, H; Tranel, D. & Damasio, AR. Impairment of social and

moral behavior related to early damage in human prefrontal cortex. Nature Neuroscience; November 1999 Volume 2 Number 11 pp 1032 – 1037

71 Atrens, D. & Curthoys, I. The Neurosciences of Behaviour. Academic Press; Australia, 1982.

72 Ting, JT & Feng, G. Found in Translation. Nature Medicine; Vol 17, No. 11; Nov. 2011.

73 Neul, JL. The mystery of developing connections. Nature Medicine; Vol 17, No. 11; Nov. 2011.

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process, whereas transmission of information between cells is a chemical process. Therefore, information transmission in the nervous system is, in effect, an electro-chemical process.

Every sensation, perception or thought, and every physiological or behavioural response depends on micro-chemical events. Dramatic changes in perception and behaviour resulting from the modulation by drugs of neurotransmitter activity is one of the most powerful, exciting and potentially dangerous discoveries man has ever made. A key to understanding this rapidly expanding area, psycho-pharmacology, lies in the understanding of the life cycle or metabolism of neurotransmitters.

Most neurotransmitters are either amino acids or are synthesized from amino acids. Although some amino acids may be synthesized in the brain, it appears that the majority are obtained from the breakdown of food proteins. Thus dietary factors can potentially influence behaviour by regulating the availability of these precursors of neurotransmitters. However, this should not be misinterpreted as supporting “brain diets” or “psycho-dietetics”. Under most conditions, precursor availability is a relatively minor factor in the regulation of neurotransmitter metabolism.

Amino acids are transported by the blood stream from the gastro-intestinal tract to the brain where they are extracted by energy-dependent uptake mechanisms. Once released into the synaptic gap, the action of the various neurotransmitters is rapidly terminated by chemical and physiological means. Chemical termination is achieved by enzymes which transform the neurotransmitters into inactive (or at least less active) products called metabolites. The metabolites may in turn be broken down and eventually excreted from the body. Consequently, measuring the levels of selected transmitter metabolites in the blood, cerebrospinal fluid, urine, saliva and so on provides an index of the activity of a particular transmitter system in the brain. Because of the ease with which blood and urine samples can be taken, the analysis of metabolites in these fluids is a widely used clinical and experimental index of brain function. However this is an indirect measure and may be confounded by many extraneous variables.

Physiological termination of neurotransmitter action involves the re-uptake of the transmitter into the pre-synaptic terminal. It may be thought of as a neuro-chemical recycling process, in which the un-metabolized transmitter is ‘repackaged’ and released again.

The relative importance of enzymatic versus re-uptake inactivation varies according to the particular neurotransmitter system. For example, acetylcholine is inactivated by an enzyme (acetylcholinesterase), whereas noradrenalin is primarily inactivated by re-uptake. The enzymes monoamine oxidase (MAO) and catechol-o-methyl transferase serve a relatively minor role in the inactivation of noradrenalin.

If either of these inactivation mechanisms malfunctions, serious disturbances in neural and, consequently, physiological and behavioural processes can occur. For example, the inactivation of the enzyme acetylcholinesterase at the neuromuscular junction results in a surplus of acetylcholine and the over-activation of the muscle. It is in this manner that nerve gases and snake venoms exert their toxic effects. By preventing transmitter breakdown, they cause sustained muscle activation which manifests itself as violent and uncontrollable muscle spasms that may result in death. Insecticides of the organophosphate variety block transmitter breakdown in insect nervous systems and, in high doses, are similarly toxic in humans. There are a variety of abnormalities in transmitter metabolism that have been associated with phenomena as diverse as migraine headaches and schizophrenia.

The exact biological basis of the development of functional connectivity is still an open question. Strictly anatomical developmental changes are clearly important for dispersed brain regions to form functional connections. However, there is additional complexity that arises in neural circuits, as many functional pathways do not have direct monosynaptic structural connections but rather are generated across multiple synaptic connections.

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Additionally, functional networks can be reversibly altered by non-structural mechanisms. For example, altering neuro-modulatory neurotransmitters such as dopamine74 or serotonin75 can modulate functional connectivity in disease states. Thus, although anatomical changes are clearly important in the formation of functional networks, additional direct monosynaptic structural connections are generated across multiple synaptic connections.

A major challenge in neuroscience has been to develop methods to assay and bridge information between different levels of circuit organization. Although considerable advances have furthered our understanding of how molecular, cellular, and electrical processes within a cell relate to the functioning of a local neural circuit, we are just now beginning to have tools capable of relating local to global changes in functional connectivity and, ultimately, to behaviour. Perhaps combining these experimental techniques with rs-fcMRI in animal models and relating this to human rsfcMRI may help to bridge these organizational levels to better understand brain development during both health and disease. (Neul, Idem, 2011)

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Localization of Brain Lesions and Developmental Functions

Modern research (post-injury and also, mainly post- childhood) has contributed greatly to the understanding of MDL ’s brain damage and its consequences.

However, this needs to be referenced to factors tha t can be identified as worthwhile contributors to improving her care and establishing a purposeful lifestyle that does n ot compromise the abilities to which she can reasonabl y aspire.

MDL’s self-confidence arises from her successful achievements; the less she is able to do, the fewer achievements she gains and the lower her confidence becomes — this is a self-fuelling regression. She then relies on perseveration with soft toys and magazine pictur es. There needs to be a constant drive to improve her abiliti es and this should progress to more macro actions than jigsaws and threading beads. That said, these fingers/mind-rel ated activities are important and they should be used we ll and judiciously.

Brain Damage

Brain injury caused by head trauma or stroke affects all brain cells, including neurons; glial cells such as astrocytes, microglia, and oligodendrocytes; blood vessel cells; and cells that produce and recycle cerebrospinal fluid (CSF), which line the brain’s ventricles. In addition to causing direct cell damage and cell loss, brain injuries disrupt blood flow and the blood-

74 Kelly C, et al. L-dopa modulates functional connectivity in striatal cognitive and motor

networks: A double-blind, placebo-controlled study. J Neurosci 29:7364–7378; 2009.

75 Anand, A; Li, Y; Wang, Y; Wu, J; Gao, S; Lubna Bukhari, B; Vincent P Mathews, VP; Kalnin, A & Mark J Lowe, MJ. Antidepressant Effect on Connectivity of the Mood-Regulating Circuit: An fMRI Study. Neuropsychopharmacology (2005) 30, 1334–1344, 27 April 2005.

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brain barrier (a barrier that allows only selective molecules to pass from the bloodstream and come in contact with neurons and astroglial cells). Brain injuries also interfere with the production, distribution, and reabsorption of CSF and cause changes in the metabolism and function of cells not only in close proximity to the dying tissue but also in more remote brain regions functionally and anatomically connected with the injured area. Advances in diagnostic medicine, with the exception of certain cases with mild or questionable cognitive impairment, have changed the typical referral question to the neuropsychologist from one that attempts to determine if the patient has neurologic disease or not. 76

In most cases, the presence of ‘brain damage’ has been clinically established and often verified radiologically. However, the behavioural repercussions of brain damage vary with the nature, extent, location, and duration of the lesion; with the age, sex, physical condition, and psychosocial background and status of the patient; and with individual neuro-anatomical and physiological differences.

Not only does the pattern of neuropsychological deficits differ with different lesion characteristics and locations, but two persons with similar pathology and lesion sites may have distinctly different neuropsychological profiles. 77,78,79 Cognitive outcome varies according to the severity of the initial injury but there is found to be a variation in outcomes amongst patients who have similar injuries. McAllister et al have suggested that this difference might be due to modulation of the neural response by the individual’s genes and cite brain-derived neuro-trophic factor as a possible influence. 80

In contrast, patients with damage at different sites may present similar deficits81 . Thus, although ‘brain damage’ may be useful as an organizing concept for a broad range of behavioural disorders, when dealing with individual patients the concept of brain damage only becomes meaningful in terms of specific behavioural dysfunctions and their implications regarding underlying brain pathology.82

Neurons continuously receive, process, and integrate information from the whole body, including the brain, and send out signals to other neurons and cells in the periphery. Neurons do not work in isolation; they form intricate circuitry, the function of which is directly or indirectly influenced by all other cellular components of the brain tissue. Brain injury affects neuronal circuitry by causing the death of neurons and glial cells and destroying connections between them. This includes the cellular extensions (dendrites and axons) through which neurons receive and emit signals by means of molecules called neurotransmitters. Brain injury often leads to excessive accumulation of neurotransmitters in the brain tissue, in particular glutamate, which can over-stimulate neurons and cause neuronal death. (Pekna & Pekna, Idem)

76 Pekna, Marcela & Pekna, Milos. The Neurobiology of Brain Injury. Cerebrum, July 2012

77 De Bleser, R. Localisation of aphasia: Science or fiction. In G. Denes et al. (Eds.), Perspectives on cognitive neuropsychology. Hove, UK: Erlbaum; 1988.

78 Howard, D. Language in the human brain. In M.D. Rugg (Ed.), Cognitive neuroscience. Cambridge, MA: MIT Press; 1997.

79 Luria, A.R. Traumatic aphasia. The Hague: Mouton; 1970.

80 McAllister, TW; Tyler, AL; Flashman, LA; Rhodes, CH; McDonald, BC; Saykin, AJ; Tosteson, TD; Tsongalis, GJ & Moore, JH. Polymorphisms in the Brain-Derived Neurotrophic Factor Gene Influence Memory and Processing Speed One Month after Brain Injury. Journal of Neurotrauma, Online ahead of Print: March 2, 2012

81 Naeser, M.A., Palumbo, C.L., Helm-Estabrooks, N., et al. Severe non-fluency in aphasia: Role of the medial subcallosal fasciculus plus other white matter pathways in recovery of sponta-neous speech. Brain, 112, 1-38; 1989.

82 Lezak, MD; Howieson, DB; Loring, DW. Neuropsyhcological Assessment. OUP, New York; 2004.

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Patients who are chronically treated with antipsychotic drugs show changes in brain structure. There is strong support for this view from Chege et al who, using resonance imaging findings, have found that there is Iincreasing evidence to suggest that antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral cortex. They used automated analysis techniques to map the regions that show maximal impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat cortex. Guided by these imaging findings, they undertook a focused postmortem investigation with stereology. [My emphasis]

Their results showed decreases in the volume and thickness of the anterior cingulate cortex (ACC) after chronic APD treatment, regardless of the APD administered. Postmortem analysis confirmed these volumetric findings and demonstrated that chronic APD treatment had no effect on the total number of neurons or S100β+ astrocytes in the ACC but that in contrast there was an increase in the density of these cells.

This study demonstrates region-specific structural effects of chronic APD treatment on the rat cortex, primarily but not exclusively localized to the ACC. At least in the rat, these changes are not due to a loss of either neurons or astrocytes and are likely to reflect a loss of neuropil.83 This study highlights the power of this approach to link magnetic resonance imaging findings to their histopathological origins. The results show such changes after only eight weeks of treatment and Lindsay has been ‘treated’ continuously with olanzapine for many years.84

Hemispheric cerebral dominance

The most important change in our conception of the differences between the two cerebral hemispheres was initiated by the studies of Hécaen85,86 and Zangwill87 and their co-workers which demonstrated conclusively that patients with right-hemisphere disease show a very high frequency of specific visuo-perceptual, visuo-spatial and visuo-constructional defects. Thus, the scattered findings of earlier investigators were confirmed. In effect these studies, indicating that the right hemisphere also possessed distinctive functional properties in the mediation of behaviour, invalidated the doctrine of exclusive left hemisphere dominance and put in its place the more egalitarian concept of asymmetry of hemispheric function.

The Hécaen-Zangwill initiative had a number of consequences. Its implications led to a widespread exploration of the role that the right hemisphere might be playing in the mediation of various aspects of mentation88. The result was that a remarkably diverse array of capacities and attributes, far beyond the visuo-perceptual and visuo-constructional

83 In neuroanatomy, a neuropil, which is sometimes referred to as a neuropile, is a region

between neuronal cell bodies in the gray matter of the brain and spinal cord (i.e. the central nervous system). It consists of a dense tangle of axon terminals, dendrites and glial cell processes. It is where synaptic connections are formed between branches of axons and dendrites.

84 Chege,W.; Natesan, S.; Modo, M.; Cooper, JD.; Williams, SCR. & Kapur, S. Reduced Cortical Volume and Elevated Astrocyte Density in Rats Chronically Treated with Antipsychotic Drugs—Linking Magnetic Resonance Imaging Findings to Cellular Pathology. Biol. Psych. published online 21 October 2013 doi:10.1016/j.biopsych.2013.09.012.

85 Hécaen, H., Ajuriaguerra, J. & Massonet, J. Les troubles visuoconstructifs par lesion parieto-occipitale droite. Encephale 40,122-179; 1951.

86 Hécaen, H., Penfield, W., Bertand, C. & Malmo. R. The syndrome of apractagnosia due to lesions of the minor hemisphere. Arch. Neurol. Psychiat. 75,400-434; 1956.

87 McFie, J., Piercy, M.P. & Zangwill, O.L. Visual-spatial agnosia associated with lesions of the right cerebral hemisphere. Brain 73,167-190; 1950.

88 Mentation — The process of thinking

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abilities described by Hécaen and Zangwill, were ascribed to operations in the right hemisphere.

A list of these is shown in the Table One. As will be seen, in addition to sensory and motor functions, the inventory includes attentional processes, levels of awareness, and affective reactivity. It was obvious that a simple verbal vs. non-verbal dichotomy could not account for these presumed differences in hemispheric specialization, and a number of other cognitive dimensions were proposed, as shown in Table Two. Taken singly, none of these was more adequate than the verbal/non-verbal dichotomy and finally the suggestion was made that a multi-dimensional criterion might be the answer.

Table One: Performances mediated by the right hemisphere

Vision

� Discrimination of configurations (e.g. complex shapes)

� Spatial orientation (e.g. route finding, directions, geography)

� Recognition of familiar faces, unfamiliar faces, facial expression

� Stereopsis 89

� Mental rotation

Audition

� Sound localization

� Discrimination of pitch, loudness, timbre

� Perception of emotional oral speech

� Identification of persons by voice

� Understanding of metaphoric speech

Somesthesis 90

� Object and form perception

� Perception of spatial stimuli (e.g. direction of lines drawn on skin)

Motor

� Simple reaction time

� Music: instrumental performance

� Singing

� Prosody in speech

� Motor persistence

General

� Arousal and attention

� Preparatory set 91

� Awareness of hemispace 92

89 Stereopsis — the perception of three-dimensional shape from any source of depth.

90 Somesthesis — the faculty of bodily perception.

91 Diversity in behavioral responses to sensory stimuli has been attributed to variations in preparatory set.

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� Mood (euphoria/dysphoria93)

Table Two: Left hemisphere/right hemisphere dichotomies

� Verbal vs. non-verbal

� Serial vs. parallel

� Analytic vs. holistic

� Controlled vs. creative

� Logical vs. pictorial

� Propositional vs. appositional 94

� Rational vs. intuitive

� Social vs. physical

However, it also became evident that the specialization of the right hemisphere for any function was not nearly as sharp as was the specialization of the left hemisphere for language. The studies of Conrad95 and Russell & Espir96 on right-handed soldiers who had been rendered aphasic by penetrating wounds apparently confined to a single hemisphere confirmed what had long been assumed, namely, that ‘crossed’ aphasia (i.e. produced by a right hemisphere lesion in a right-handed patient) was a rare occurrence.

In Conrad's study the observed frequency was 6 per cent and in the better controlled study of Russell & Espir it was 1.8 per cent. But when the same analysis was applied to disabilities associated with lesions of the right hemisphere, the findings were rather different. Studies by Arrigoni & De Renzi97 and Benton98 found that the frequency of ‘crossed’ constructional apraxia in right-handed patients with left hemisphere lesions was 32 per cent and 28 per cent, respectively. Similarly, Benton & Van Allen99 , investigating impairment in facial recognition in patients with unilateral disease, found that 23 per cent had left hemisphere lesions. 100

92 Hemispatial neglect, also called hemiagnosia, hemineglect, unilateral neglect, spatial

neglect, unilateral visual inattention, hemi-inattention or neglect syndrome is a neuropsychological condition in which, after damage to one hemisphere of the brain, a deficit in attention to and awareness of one side of space is observed. It is defined by the inability for a person to process and perceive stimuli on one side of the body or environment that is not due to a lack of sensation.

93 Dysphoria — disquiet or restlessness.

94 The cognitive differences between the left and right hemispheres have been characterized as propositional vs. appositional.

95 Conrad, K. Ueber aphasischer Sprachstoerungen bei Linkshaendern. Nervenarzt 20,148-154. Damasio, A.R. (1992): Aphasia. New Eng. J. Med. 326,531-539; 1949.

96 Russell, W.R. & Espir, M.L.E. Traumatic aphasia. Oxford & London: Oxford University Press; 1961.

97 Arrigoni, G. & De Renzi, E. Constructional apraxia and hemispheric locus oflesion. Cortex 1, 170-197. Babinski, J. (1914): Contribution 11 l'etude des troubles mentaux dans l'hemipMgie organique cerebrale (anosagnosie). Rev. Neural. 22,845-848; 1964.

98 Benton, AL. Constructional apraxia and the minor hemisphere. Confinia Neurologica 29,1-16; 1967.

99 Benton, A. L. & Van Allen, M. W. Impairment in facial recognition in patients with cerebral disease. Cortex, 4, 344-358; 1968.

100 See also — http://web-us.com/brain/LRBrain.html

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These observations showed that, although there was indeed asymmetry of hemispheric function, this asymmetry was itself asymmetric, so to speak, with a much more clear specialization of function in the left hemisphere than in the right. Later studies of normal subjects added other dimensions to the topic. Employment of the dichotic listening procedure and of tachistoscopic visual half-field stimulation101 disclosed considerable instability in their performances from one testing session to another and even within the course of a single testing session102,103,104 .

Specific instructions and duration of stimulus exposure were also found to be significant determinants of the degree of differential hemispheric participation in a performance like facial recognition105 . These indications of flexibility in function and inter-hemispheric communication in normal subjects could not help but raise doubts about the validity of simple interpretations of the defective performances of patients with unilateral brain disease.

The organization of memory during developmental age

Temporo-mesial structures are critical for the organization of long term declarative memories during developmental age. This means that the architecture of the anatomical structures is established very early in life. Very early lesions can cause memory deficits of different severity and typology and are age-related. Very early lesions (particularly of the hippocampus) irreversibly compromise the capacity to acquire complex modalities of verbal and social communication and to organize a personal and unique cognitive map.

Social communication involves influencing what other people think and feel about themselves. Theory of mind (connotative) refers to communicative interactions involving one person trying to influence or understand the mental and emotional state of another, paradigmatic examples of which are irony and empathy.

Dennis et al report how children with traumatic brain injury understand ironic criticism and empathic praise, on a task requiring them to identify speaker belief and intention for direct conative speech acts involving literal truth, and indirect speech acts involving either ironic criticism or empathic praise. Deficits in understanding the social, conative function of indirect speech acts like irony and empathy have widespread and deep implications for social function in children with traumatic brain injury. 106

Later lesions cause amnesia of different severity, with impairment of episodic memory and preservation of semantic memory if the lesion is localized to the hippocampus, or the impairment of both types of memory in case of hippocampus and para-hippocampus

101 Tachistoscopic visual half-field stimulation: Uses an apparatus that projects a series of

images onto a screen at rapid speed to test visual perception, memory

102 Pizzarniglio, L., DePascali, C. & Vignati, A. Stability of dichotic listening test. Cortex 10, 203-205. Rieger, e. (1909): Ueber Apparate in dem Him. Arbeiten aus der Psychiatrischen Klinik Wuerzburg 5, 176-192; 1974.

103 Blumstein, S., Goodglass, H. & Tartter, V. The reliability of ear advantage. Brain Lang. 2,226-236. Boller, F. (1973): Destruction of Wernicke's area without language disturbance. Neuropsychologia 11, 243-246; 1975.

104 Turkewitz, G. & Ross, P. Changes in visual field advantage for facial recognition. Cortex 19, 179-185; 1983.

105 Galper, E. & Costa, L. Hemispheric superiority for recognizing faces depends upon how they are learned. Cortex 16, 21-38; 1980.

106 Dennis M; Simic N; Agostino A; Taylor HG; Bigler ED; Rubin K; Vannatta K; Gerhardt CA; Stancin T & Yeates KO. Irony and empathy in children with traumatic brain injury. J Int Neuropsychol Soc. 2013 Jan 21:1-11.

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localization. More particularly, the temporo-mesial structures are critical for the development of long-term declaratory memories. 107

Damage to the hippocampus or to some of its connections such as the fornix produces deficits in learning about the places of objects and about the places where responses should be made. For example, humans with damage to the hippocampal system or fornix are impaired in object-place memory tasks in which not only the objects seen, but where they were seen, must be remembered. Further, neurotoxic lesions that selectively damage the primate hippocampus impair spatial scene memory. Also, fornix lesions impair conditional left-right discrimination learning, in which the visual appearance of an object specifies whether a response is to be made to the left or the right. 108, 109

Evidence from Monti et al suggests that a history of head trauma is associated with memory deficits later in life. The majority of previous research has focused on moderate-to-severe traumatic brain injury (TBI), but recent evidence suggests that even a mild TBI (mTBI) can interact with the aging process and produce reductions in memory performance. This study examined the association of mTBI with memory and the brain by comparing young and middle-aged adults who have had mTBI in their recent (several years ago) and remote (several decades ago) past, respectively, with control subjects on a face-scene relational memory paradigm while they underwent functional magnetic resonance imaging (fMRI). 110

In observations of hippocampal volumes from high-resolution structural images Monti et al have also shown that middle-aged adults with a head injury in their remote past had impaired memory compared to gender, age, and education matched control participants, consistent with previous results in the study of memory, aging, and TBI. Their findings extended previous results by demonstrating that these individuals also had smaller bilateral hippocampi, and had reduced neural activity during memory performance in cortical regions important for memory retrieval. These results also indicate that a history of mTBI may be one of the many factors that negatively influence cognitive and brain health in aging. (Idem)

One way of relating the impairment of spatial processing to other aspects of hippocampal function is to note that this spatial processing involves a snapshot type of memory, in which one whole scene must be remembered. This memory may then be a special case of episodic memory, which involves an arbitrary association of a particular set of events which describe a past episode.111 Further, the non-spatial tasks impaired by damage to the hippocampal system may be impaired because they are tasks in which a memory of a particular episode or context rather than of a general rule is involved. Further, the deficit in paired associate learning in humans may be especially evident when this involves arbitrary associations between words.112

The evidence provided from a historical case known as HM and many others after him made it possible to arrive at the definition of a memory system organized into short- and

107 Riva, D; Saletti, V; & Nichelli, F. The organization of memory in temporo-mesial structures in

developmental age. In, Riva, D; & Benton, A. Localization of Brain Lesions and Developmental Functions. John Libby, London; 2000.

108 Rolls, ET. Memory, Attention and Decision-Making. OUP; 2008.

109 Petrides, M. Deficits on conditional associative-learning tasks after frontal- and temporal-lobe lesions in man. Neuropsychologia 23; 601-614.

110 Monti JM; Voss MW; Pence A; McAuley E; Kramer AF & Cohen NJ. History of mild traumatic brain injury is associated with deficits in relational memory, reduced hippocampal volume, and less neural activity later in life. Front Aging Neurosci. 2013 Aug 22;5:41 PMID 23986698.

111 Rolls, ET. The primate hippocampus and episodic memory; in, Dere, Huston & Easton (Eds) Episodic Memory Research; Elsevier, Amsterdam, 2008.


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long-term components. Long-term memory is sub-divided into implicit (or procedural) and explicit (or declarative) memory.113,114 Procedural memory is at most only partially conscious and consists of a collection of different skills; it is expressed by means of ‘activities’, does not respond to the criterion of true/false; progressively increases with experience, and generally represents a predisposition to behave in a particular way on the basis of previous memories. On the contrary, declarative memory is conscious and expressed by means of words, concepts and propositions; it is also expressed by means of images and the recall of previously encountered facts and events.

Declarative memory is further sub-divided into semantic and episodic memory. Semantic memory (See also p 38) represents our knowledge of the world beyond any context or temporal parameters, is automatically expressed and lives in the present; episodic memory is based on facts/events occurring in a precise temporal and spatial context in which the fundamental reference point is the person remembering. Amnesia is therefore related to the long-term declarative memory115 . Given the existence of different types of memory, it follows that they are processed by different brain areas and based on different neuronal circuits. 116

Short-term memory is probably processed by the inferior parietal lobe (although not everybody agrees on this point); declaratory long-term memory is processed by the temporo-mesial structures, in particular, the hippocampus and para-hippocampal regions, whereas procedural memory seems to be processed by the striatum and the cerebellum.

Given that different brain areas process different components of the memory system, it follows that these components may be independently deficient depending on the damaged area. Short-term memory deficits can therefore exist in the presence of a perfectly functioning long-term memory, and vice versa; a deficient declaratory memory in the presence of an intact procedural memory, and vice versa; and a deficient semantic memory in the presence of an integral episodic memory and vice-versa117,118 .

In Mishkin and Eichenbaum's model of the anatomy of the temporo-mesial structures, the memory is seen as being very flexible and based on representations stored in the neocortex in a highly precise and sophisticated manner. 119,120

Systematic studies of animal temporo-mesial structures have made it possible to validate the model in an irrefutable manner.121,122,123 A rat's hippocampus is the site of spatial

113 Tulving, E. Episodic and semantic memory. In: Organization of memory, eds. E. Tulving & W.

Donaldson. New York: Academic Press, 1972.

114 Tulving, E. In: Elements of episodic memory. Oxford: Oxford University Press; 1983.

115 Baddeley, A. The human memory (1982). Italian edn. La memoria umana. Bologna: II Mulino; 1984.

116 Gabrieli, J.D.E., Brewer, J.B., Desmond, J.E. & Glover, G.H. Separate neural bases of two fundamental memory processes in the human medial temporal lobe. Science 276, 264-266; 1997.

117 Baddeley, A. The human memory (1982). Italian edn. La memoria umana. Bologna: II Mulino; 1984.

118 Ellis, W.A. & Young, A.W. Memory. In: Human cognitive neuropsychology. Hove, London, Hillsdale:; 1988.

119 Mishkin, M., Suzuki, W., Gadian, D.G. & Vargha-Khadem, F. Hierarchical organization of cognitive memory. Phil. Trans. Roy. Soc. London (B) 352,1461-1467; 1997.

120 Eichenbaum, H. How does the brain organize memory? Science 277,330-332; 1997.

121 Mishkin, et al, Idem. 1997.

122 Suzuki, W.A & Amaral, D.G. Perirhinal and parahippocampal cortices orille macaque monkey: cortical afferents. J. Compo Neurol. 350, 497-533; 1994.

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memory, but actually provides what is nothing less than a cognitive map of the entire ecological space in which it is capable of navigating by using the procedures, moves and anticipations of events that come from previous individual experiences. It has also been found that primates have the possibility of taking advantage of a cognitive map of their episodic experiences.

Kitamura et al have shown however, that whilst the hypothalamus is a key brain structure for learning and memory. Recall of some associative and spatial memories initially depends on the hippocampus, but that hippocampal dependency progressively decays over time, a process that is associated with a gradual increase of neocortex-dependency.124

It has been suggested that the quality of original memories also transforms from a precise (i.e., detailed) form to a less precise (i.e., more schematic or generic) form with similar time course. 125,126,127 The question arises of whether changes in the quality of the original memories depend on the shift in brain regions on which the recall of these memories relies, i.e., whether the hippocampus is always required for the precision of memories. This is an important question for understanding physiological significances of the hippocampal-cortical complementary memory systems.

In the study by Kitamura et al, found clear indication that the association with fear masks the actual precision of place memory. Moreover, in contextual fear conditioning, the experimental subjects (mice) showed the freezing responses even for unconditioned place in recent memory test, whereas in the non-associative place recognition test mice did not show any adaptation behaviour even for similar place in remote memory test. Therefore, the conclusions of previous studies using contextual fear conditioning 128,129,130 need to be validated by non-associative protocol. Thus, they examined the contribution of hippocampal function on the precision of remote place memory by non-associative place recognition test.

Using this procedure, they found that the place memory is precisely maintained for 28 days, which may require α-CaMKII-dependent plasticity in the cortex, and that the retrieval of remote place memory (not recent memory) does not require hippocampal function. These results indicate that the quality of a place memory does not correlate with the brain region on which that memory depends. Moreover, they found that the inactivation of hippocampal function does not inhibit the precision of remote place memory. These results

123 Suzuki, W.A & Amaral, D.G. Topographic organization of the reciprocal connections between

monkey entorhinal cortex and the perirhinal and parahippocampal cortices. J. Neurosci. 14, 1856-1877; 1994.

124 Kitamura, T; Reiko Okubo-suzuki, R; Takashima, N; Murayama, A; Hino, T; Nishizono, H; Kida, S. & Inokuchi, K. Hippocampal function is not required for the precision of remote place memory. Molecular Brain 2012, 5:5 doi:10.1186/1756-6606-5-5

125 Nadel L, & Moscovitch M. Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 1997, 7:217-227.

126 Moscovitch M; Nadel L; Winocur G; Gilboa A. & Rosenbaum RS. The cognitive neuroscience of remote episodic, semantic and spatial memory. Curr Opin Neurobiol 2006, 16:179-190.

127 McKenzie S. & Eichenbaum H. Consolidation and reconsolidation: two lives of memories? Neuron 2011, 71:224-233.

128 Winocur G; Moscovitch M. & Sekeres M. Memory consolidation or transformation: context manipulation and hippocampal representations of memory. Nat Neurosci 2007, 10:555-557.

129 Wiltgen BJ; Zhou M; Cai Y; Balaji J; Karlsson MG; Parivash SN; Li W. & Silva AJ. The hippocampus plays a selective role in the retrieval of detailed contextual memories. Curr Biol 2010, 20:1336-1344.

130 Wang SH; Teixeira CM; Wheeler AL & Frankland PW. The precision of remote context memories does not require the hippocampus. NatNeurosci 2009, 12:253-255.

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indicate that the hippocampal function is not required for the precision of remote place memory. This is consistent with a human case study in which a patient with bilateral extensive hippocampal damage showed intact memories for places learned long ago, but not intact recent place memory131. Eight patients with bilateral hippocampal damage were able to recall their remote autobiographical memories. 132 Thus, the quality of original place memories is not determined by brain regions on which the memory depends.

Ablation of the anterior portion of the temporal lobe + amygdala + part of the hippocampus or excision of the temporal cortex/neocortex (excluding the amygdala and hippocampus) or selective ablation of the amygdala and hippocampus cause learning and delayed recall deficits respectively relating to verbal or non-verbal stimuli (the latter being generally less severe). The underlying pathogenic mechanism could be the disconnection of the cortex from the hippocampus: although the neocortex is still capable of storing the memories, it cannot pass them to the hippocampus and the para-hippocampal structures, and so they cannot be recalled as such or rearranged133 .

These results show that the temporo-mesial structures also process long-term declarative memory at developmental age. This not only means that the architecture of the anatomical structures is established very early in life, but also that an early lesion affecting these structures cannot be compensated for by the establishment of alternative pathways and, furthermore, that the degree of impairment is age-related (i.e. it is greater in patients who are affected at a younger age).

Very early lesions of (particularly) the hippocampus irreversibly compromise the possibility of acquiring complex modalities of verbal and social communication, as well as the possibility of organizing an absolutely personal cognitive map. Later lesions only cause amnesias of various degrees of severity, with impairment of episodic; but the preservation of semantic memory, if localized to the hippocampus; or the impairment of both in cases that involve both the hippocampus and para-hippocampus.

These results not only confirm that dissociations between the various components of the memory system are also possible at a very early developmental age, but also confirm the structure of the circuit. The cortex/neocortex faithfully stores the information. The para-hippocampal regions codify the information belonging to the same categories in a contiguous manner, and are also capable of re-evoking simple connections with the cortex/neocortex under the impulse of simple stimuli, particularly if they are contiguous and mono modal. The hippocampus analyses different elements of various experiences and stimuli, acquired in different spatio-temporal contexts and via a wide range of modalities (sight, touch, smells, sounds, emotions, etc.), and is capable of relating them to each other in a myriad of different combinations and in a totally flexible and inexhaustible manner.

Studies of the temporo-mesial structures therefore not only highlight specific neuropsychological deficits, but also provide an extremely interesting insight into the pathologies typical of childhood development, such as infantile autism.

_______

131 Teng E & Squire LR. Memory for places learned long ago is intact after hippocampal

damage. Nature 1999, 400:675-677.

132 Bayley PJ; Hopkins RO & Squire LR. Successful recollection of remote autobiographical memories by amnesic patients with medial temporal lobe lesions. Neuron 2003, 38:135-144.

133 Jones-Gotman, M., Zatorre, RJ., Olivier, A, Andermann, F., Cendes, F., Stauton, H., McMackin, D., Siegel, A.M. & Wieser, H.G. Learning and retention of words and designs following excision from medial or lateral temporal-lobe structures. Neuropsychologia 35, 963-973; 1997.

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Basal ganglia lesions — Language and Neuropsychological Dysfunction

There is not much knowledge about the behavioural consequences of subcortical and basal ganglia lesions during childhood. They are a group of grey matter nuclei located deep in the cerebral hemispheres. These include, among others, the caudate nucleus, the lenticular nucleus (with an outer part called the putamen and an inner part, the globus pallidus) and a larger and more posterior nucleus, the thalamus. While the first two are involved in motor functions, (they are part of the extra-pyramidal system134), the latter receives all the sensory information travelling into the brain.

These subcortical structures are connected to each other and to the cerebral cortex in multiple and complex ways but, in general, the fibres travel from the different parts of the cortex to the striatum (name given both to the caudate and the putamen), from there they project into the pallidus, from the pallidus they travel to the thalamus and from there they go back to the cortex. These loops are called the cortico-striato-pallido-thalamo-cortical loops, which subserve multiple functions. Some of them have an activating or modulatory role on the overlying cortex.

For many years the basal ganglia were thought to be responsible for motor functions only. However, with the advent of brain imaging (CT and MRI scans) it became clear that deep hemisphere lesions could interfere with behaviour. The first studies on this matter were published in the early 1980s on adult patients with deep hemispheric stroke and focused on language and hemispatial neglect.135,136,137 But soon other papers followed, describing cases of memory, behavioural and emotional disturbances138,139. Animal experiments corroborated the role of these structures in a variety of cognitive functions and behaviour140.

The difficulty in establishing such clinico-anatomical correlations is not just due to the fact that single lesions (particularly the vascular ones) tend to damage multiple areas. The main methodological problem is that the symptoms caused by purely sub-cortical lesions can result from different pathogenic mechanisms. The basal ganglia have a direct effect on behaviour since they integrate cortico-subcortical neuronal networks subserving language and other complex behaviours. But these structures may also have an indirect effect upon cognitive functions, as they may produce a depression of the metabolic activity of the overlying cortex, as has been demonstrated with the PET scan141 .

Aram & Eiselle142 divided their patients by an anterior/posterior anatomical axis. According 134 See: http://www.neurophysiology.ws/extrapyramidalsystem.htm

135 Watson, RT., Valenstein, E. & Heilman, KM. Thalamic neglect. Possible role of the medial thalamus and nucleus reticularis in behaviour. Arch. Neurol. 38,501-506; 1981.

136 Damasio, A.R., Damasio, H., Rizzo, M., Varney, N. & Gersh, F. Aphasia with nonhemorrhagic lesions in the basal ganglia and internal capsule. Arch. Neural. 39, 15-20; 1982.

137 Naeser, M.A., Alexander, M.P., Helm-Estabrooks, N., Levine, H., Laughlin, S.A. & Geschwind, N. Aphasia with predominantly subcortical lesions sites. Description of three capsular/putaminal aphasia syndromes. Arch. Neurol. 39,2-14; 1982.

138 Habib, M. & Poncet, M. Perte de l'elan vital, de l'interet et de l'affectivite (syndrome athymhorrnique) au cours de lesions lacunaires des des corps stries. Rev. Neural. 144,571-577;1988.

139 Mendez, M.F., Adams, N.I. & Lewandowski, KS. Neurobehavioural changes associated with caudate lesions. Neurology 39, 349-354; 1989.

140 Divac, I. & Oberg, R.G.E. Subcortical mechanisms in cognition. In: Neuropsychological disorders associated with subcortical lesions, eds. G. Vallar, S.F. Cappa & Claus-W. Wallesch, pp. 42-60. Oxford: Oxford University Press; 1992.

141 Metter, E.J., Riege, W.H., Hanson, W.R, Jackson, CA., Kempler, D. & Lancker, D. Subcortical structures in aphasia. An analysis based on (F-18) fluorodeoxyglucose, positron emission tomography and computed tomography. Arch. Neurol. 45, 1229-1234; 1988.

142 Aram, D. & Eisele, J. Language development following subcortical lesions in children. Paper presertted at the European Meeting of the International Neuropsychological Society, Funchal, Portugal; 1993.

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to these authors, ‘anterior’ lesions tend to produce non-fluent types of speech and good auditory comprehension. ‘Posterior lesions’, on the other hand, may cause comprehension disorders, fluent aphasia (conduction type) or no aphasia at all. In both locations there are motor disorders of speech (dysarthria143 and hypophonia144), and both have a good prognosis for total recovery (If the injury is sustained at a post-developmental age). On the contrary, if the lesion involves simultaneously the anterior and the posterior subcortical structures, then the defects are more severe and persistent. Several years after the lesion, these patients remain dysfluent and obtain low scores in several language measures.

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Subcortical lesions and the right hemisphere The data concerning subcortical lesions of the right hemisphere in children are even sparser than for left hemisphere lesions.

One known case is an 8-year-old-girl145 with a coagulation disorder (aplastic anaemia) who developed a right thalamic haematoma. On the acute stage she was drowsy and had a mild left hemiparesis but she recovered from this motor defect and was examined 1 month later. At that time it was noticed she tended not to use her left upper limb unless she was specifically requested. During simultaneous movements of both hands, she tended to forget the left hand movements, a phenomenon called ‘motor’ neglect. She also had a marked visuo-spatial impairment, but no visuo-spatial neglect.

MDL does not use her left hand unless absolutely necessary and she has less control over directed movements of her left leg than her right. Thus, she is capable of wiping her right foot on the door mat in a normal fashion but she cannot do that with her left side.

Subcortical structures are specialized from an early age: there are right/left differences, identical to the ones found in adults. One of the main differences of subcortical damage between adults and children is the better outcome for immediate recovery in the latter. However, long term effects can occur, especially when children were aphasic in the acute stage (in particular, learning difficulties). The pathogenesis of symptoms observed in association with subcortical damage probably involves direct mechanisms and indirect effects upon the overlying cortex.

It will be seen then that MDL’s brain damage, because of its very early incidence and its diffuse nature, did not allow for recovery in the sense reported above.

In conclusion: motor and visual neglect and visuo-spatial disturbances can occur in children following subcortical damage to the right hemisphere, just as in adults146 . However, children tend to recover quickly. If they are not examined in the acute stage of illness it is unlikely that these defects will be found. There seem to be no major long term effects, although Aram & Ekelman147 reported that these patients tend to have a performance IQ below verbal IQ, when compared to controls.

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143 Dysarthria — a motor speech disorder resulting from neurological injury and it is

characterized by poor articulation (cf. aphasia: a disorder of the content of speech). Any of the speech subsystems (respiration, phonation, resonance, prosody, and articulation) can be affected, leading to impairments in intelligibility, audibility, naturalness, and efficiency of vocal communication.

144 Hypophonia — a weak voice due to incoordination of the vocal muscles.

145 Ferro, J.M. & Martins, I.P. Some new aspects of neglect in children. Behav. Neurol. 3, 1-6; 1990.

146 Ferro, J.M., Kertesz, A. & Black, S.E. Subcortical neglect: quantitation, anatomy and recovery. Neurology 37,1487-1492; 1987.

147 Aram, D.M. & Ekelman, B.L. Scholastic aptitude and achievement among children with unilateral brain lesions. Neuropsychologia 26, 903-916; 1988.

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Childhood aphasic syndromes and the localization of lesions

The study of acquired childhood aphasia (ACA) has made significant progress in the past 20 years. From highlighting fundamental differences between childhood and adulthood aphasia for more than a century, it has evolved since the late 1970s towards an acknowledgement of fundamental similarities between both148 . Regarding the clinical picture, it is clear that the traditional view asserting the universality of non-fluency in ACA is no longer tenable. Other types of semiological149 pictures co-exist besides the classically reported non-fluent type. They may even correspond to syndromes which infrequently occur in adults. Moreover, neuro-radiological data support the current opinion that in children, lesion location and clinical picture are interrelated in a similar manner as in adults.150

In a comprehensive review of aphasic syndromes, Damasio151 defines aphasia as, “a disturbance of the comprehension and formulation of language caused by dysfunction in specific brain regions”. Adult aphasics, he continues, “can no longer accurately convert the sequences of non-verbal mental representations that constitute thought into the symbols and grammatical organization that constitute language” [p. 531].

Conversely, the generation of mental representations corresponding to a sentence that is heard or seen, is also defective in aphasia. Damasio (idem, 1992) further emphasizes that aphasia is neither a disorder of perception (deafness, for instance, does not hinder language comprehension through other channels than the auditory one) nor a motor speech disorder (dysarthria, for instance, leaves language formulation intact).

Finally, aphasia is not a disorder of the basic thought processes such as those occurring in schizophrenia. Aphasia can result from any neurological lesion that affects the cerebral hemispheres, provided that language-related areas are involved; these include: vascular diseases, traumatic head injuries, tumours, infectious diseases, degenerative or toxic processes, convulsive disorders. These aphasic syndromes are defined by the anatomy of the lesion rather than by the language characteristics, but different patterns of language difficulties have also been described. 152

148 Woods, B.T. Acquired aphasia in children. In: Handbook of clinical neurology.

Neurabehavioural disorders, ed. J.A.M. Frederiks, vol. 46, pp. 147-157. Amsterdam: Elsevier Science Publishers; 1985.

149 Semiology — a science which studies the role of signs as part of social life.

150 Paquier, P; & van Dongen, H. Aphasic syndromes and localization of lesions in children. In, Riva, D; & Benton, A. Localization of Brain Lesions and Developmental Functions. John Libby, London; 2000.

151 Damasio, AR. Aphasia. N. Engl. J. Med. 326,531-539; 1992.

152 Kirshner, H.S. Classical aphasia syndromes. In: Handbook of neurological speech and language disorders, ed. H.S. Kirshner, pp. 57-89. New York: Marcel Dekker; 1995.

Type of aphasia Spontaneous speech Auditory

Comprehension Repetition

Site of lesion

(left hemisphere)

Global aphasia Non-fluent, scant,

stereotyped utterances

Impaired Impaired Large perisylvian or separate

anterior and posterior damage

Broca’s aphasia Non-fluent, poorly

articulated, dysprosodic,

Largely preserved

Impaired Frontal (inferior and posterior)

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Table Three — Main aphasia syndromes according to traditional asphasiology

(Damasio, 1992 & Kirshner, 1995)

ACA = arteria cerebri anterior; ACM = arteria cerebri media; ACP = arteria cerebri posterior. *When fluent speech becomes completely incomprehensible because of excessive errors, the aphasia is termed jargon aphasia.

The shaded rows show the likely types of aphasia that affect MDL. However, MDL’s present medication regime does affect the neurology of her mouth and she cannot control salivation and has some problems with chewing and therefore swallowing. Her speech is affected and not only because she does not open her mouth very far when talking and this causes her to speak through teeth that are almost together. From past experience it is found that when the medication is considerably reduced or no longer prescribed, these symptoms disappear.

It is significant that MDL’s aphasia is worse when she is heavily medicated. As communication is such an important aspect of MDL’s care, there does need to be a more intelligent approach made towards this supposed ‘treatment’.

MDL’s speech has deteriorated since 2004 in that she now shows para-grammatism, i.e. errors in the use of grammatical rules, resulting in incorrect verb tenses. For instance instead of saying, “he bought”, she now might say, “he buyed”.

Delineation of acquired childhood aphasia From the preceding it should not be assumed that in adults the use of the term aphasia implies that language had already

153 Conduite d'approche — refers to the tendency, most evident in conduction aphasics, to

make repeated attempts at a word (e.g., for pretzel, "trep . . . tretzle . . . trethle . . . tredfles . . . ki") that do not necessarily result in closer approximations to the target.

agrammatic

Transcortical motor aphasia

Non-fluent, decreased speech initiation, effortful,

perseverative, stutter-like, poorly articulated

Largely preserved

Largely preserved

Anterior or superior to Broca’s area (ACA-ACM watershed

area)

Mixed transcortical

aphasia

Non-fluent, scant, stereotyped

utterances, echolalic Impaired

Largely preserved

Massive hemispheric damage with sparing of perisylvian area

Wernicke’s aphasia

Fluent, abundant, well articulated,

melodic, paraphasic, paragrammatic*

Impaired Impaired Temporal (superior and

posterior)

Transcortical sensory aphasia

Fluent, paraphasic, well articulated,

melodic, echolalic Impaired

Largely preserved

Posterior or inferior to Wernicke’s area (ACM- ACP watershed

area)

Conduction aphasia

Fluent, phonemic paraphasias, well

articulated, melodic, conduites

d’approche 153

Largely preserved

Impaired Supramarginal gyrus, insula,

arcuate fasciculus,

Anomie aphasia

Fluent, empty, circumlocutory , well

articulated, word-finding pauses,

melodic

Largely preserved

Largely preserved

No specific localization

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been acquired prior to lesion onset. In children, on the contrary, the term has been used in reference to a number of language impairments attributable to both developmental and acquired disorders. Thus, congenital, developmental and acquired aphasia have been distinguished. According to Vargha-Khadem et al154 , congenital aphasia is a language disorder caused by early and extensive cerebral lesions in the thalamo-cortical projection system. Due to such demonstrable structural lesions, children with congenital aphasia fail to develop normal language functions.155

Following Woods156, developmental aphasia (also called ‘developmental dysphasia’ or ‘specific language impairment’) refers to, “a level of language function that is significantly below age norms, has always been so (i.e. it has not been arrested at, nor has it declined from an earlier level) and is not adequately accounted for by general mental retardation, peripheral sensory or motor defects, severe emotional disturbance, or major environmental deprivation.” [p.139] Aram157 emphasizes that a frank neurological basis is not apparent in developmental aphasia. Both congenital and developmental aphasia share the common feature that the pathological process which prevents the normal development of language is already present before language skills begin to emerge.

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Cognitive deficit after closed head injury in children

Development of the human prefrontal cortex has been elucidated in neuro-anatomic studies which have shown that the density of synaptic contacts peaks by age 11 years.158 Consistent with the developmental changes in synaptogenesis, positron emission tomography has indicated that the glucose metabolic rate in frontal cortex increases with age, reaching a peak by age 9 years159.

Confirmatory observations concerning the heterogeneity of functional maturation of sub-regions of the frontal lobes in humans are limited, particularly in view of the rarity of discrete lesions confined to one of these areas in children. Although studies of children sustaining discrete prefrontal lesions are sparse, there is minimal evidence for apparent sparing of function analogous to Goldman's observations in infant monkeys subjected to dorso-lateral lesions.160,161

On the contrary case reports have suggested that early bi-frontal lesions can interfere with cognitive growth particularly in learning to appreciate the perspective of others and in both

154 Vargha-Khadem, F., Watters, G.V. & O'Gorman, AM. Development of speech and language

following bilateral frontal lesions. Brain Lang. 25, 167-183; 1985.

155 Landau, W.M., Goldstein, R. & Kleffner, F.R. Congenital aphasia: a clinicopathologic study. Neurology 10,915-921; 1960.

156 Woods, B.T. Developmental dysphasia. In: Handbook of clinical neurology. Neurabehavioural disorders, ed. J.A.M. Frederiks, vol. 46, pp. 139-145. Amsterdam: Elsevier Science Publishers; 1985.

157 Aram, D.M. Acquired aphasia in children. In: Acquired aphasia, ed. M.T. Sarno, pp. 425--453. Orlando: Academic Press; 1991.

158 Huttenlocher, P.R Synaptic density in human frontal cortex: developmental changes and effects of aging. Brain Res. 163, 195-205; 1979.

159 Chugani, H.T., Phelps, M.E. & Mazziotta, J.C. Positron emission tomography study of human brain functional development. Ann. Neurol. 22,487-497; 1987.

160 Goldman, P.S. Functional recovery after lesions of the nervous systems. 3. Developmental processes in neural plasticity. Recovery of function after CNS lesions ininfant monkeys. Neurosci. Res. Progr. Bull. 12, 217-222; 1974.

161 Goldman, P.S. & Alexander, G.E. Maturation of prefrontal cortex in the monkey revealed by focal reversible cryogenic depression. Nature 267, 613-615; 1977.

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moral and social development162,163. However, developmental studies have raised the possibility that various cognitive capacities subserved by the prefrontal region are heterogeneous in respect of their rate of functional maturation.

Using a task analogous to the delayed response, Diamond & Goldman-Rakic164 found that human infants between 6 and 12 months began to reach for a location where an object was previously hidden. This finding, which brought into question the view that the prefrontal region becomes functionally mature late in childhood (e.g. at about 10 years), has been interpreted as evidence for the heterogeneous developmental trajectories of the diverse functions subserved by the prefrontal region.

Executive function (EF) The term refers to the distinct, but related cognitive abilities which depend primarily on a network or system comprised by the prefrontal area and its major connections. Although this definition (or its variants) is widely accepted, there is no consensus concerning the specific cognitive abilities which comprise EFs. To build consensus on this aspect of cognitive development, the National Institute of Child Health and Development in the United States sponsored a workshop in 1994 which focused on EFs in children. The workshop proceedings reflected the diversity of EFs and our rudimentary understanding of interrelationships. It was also clear that there is variation in the purported relationship of development to the maturation of various sub-regions of the prefrontal region.165 While acknowledging these limitations, the workshop participants reached consensus on the following EFs:

Flexibility in problem solving This refers to the capacity for shifting response strategy according to changes in the environment.

Temporal organization of behaviour

Planning This EF refers to the capacity for setting goals and maintaining an action sequence in working memory.

Resource allocation This EF refers to the computational capacity of the brain for manipulation or transformation of information such as performing concurrent tasks which involve divided attention.

Inhibition In proposing inhibition as an EF, the workshop participants referred to the capacity for switching from initiation to termination of a response at the appropriate time. (This seems to correspond to some aspects of perseveration.)

Self regulation This EF refers to the capacity for self-monitoring, including cognitive performance such as utilizing strategies to enhance memory or study skills and the capacity to monitor one's behaviour in relation to external constraints or according to an internal representation which guides behaviour.

Working memory See Index for references to this, but in particular, p. 108.

162 Price, B.H., Daffner, KR, Stowe, RM. & Mesulam, M.M. The comportmental learning disabilities

of early frontal lobe damage. Brain 113,1383-1393; 1990.

163 Williams, D. & Mateer, C.A. Developmental impact of fronta11obe injury in middle childhood. Brain Cognition 20,196—204; 1992.

164 Diamond, A & Goldman-Rakic, P.S. Comparison of human infants and rhesus monkeys on Piaget's A-not-B task: evidence for dependence on dorsolateral prefrontal cortex. Exp. Brain Res. 74,24-40; 1989.

165 Levin, HS. & Chapman, SB. Contribution of frontal lobe lesions to cognitive deficit after closed head injury in children. In, Riva, D; & Benton, A. Localization of Brain Lesions and Developmental Functions. John Libby, London; 2000.

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Language in children with early brain damage

Although specific features characterize the acquisition of particular languages, researchers have identified a set of milestones that children pass through as they grapple with learning their native tongue. Overall, the findings suggest that initially, at least, both hemispheres are implicated in initiating the language acquisition process, and that rather than being localized to the left hemisphere, as is true for the vast majority of adults, language as it is being acquired is a rather broadly distributed function.

In the realm of language, Lenneberg (1967) found that children with early onset strokes do not suffer the same irreversible damage as adults with homologous lesions. Together these findings raised the possibility that children's brains, unlike those of adults, are flexible and reflect a wider potential for assuming diverse behavioural functions. According to the strongest view of this hypothesis of equipotentiality, any area of the brain could assume responsibility for any behavioural function.

Lenneberg also suggested that the plasticity, or flexibility, responsible for this broad potential decreased substantially by adolescence when the brain had lateralized, and different cortical areas had assumed responsibility for specific behavioural functions.

Our brains enable us to perceive and interact with the outer world. Synaptic connections between neurons can be adjusted to respond flexibly to changes in the environment, for example when we learn. In addition, plasticity mechanisms play important roles during early development, even before we are born, to prepare the neuronal circuitry for processing sensory information when we open our eyes.

The demands for synaptic plasticity keep changing during the course of a lifetime. At the first developmental stage of life, neuronal networks are being built in the brain in order to prepare itself for dealing with the outside world after birth (enabling perceptions and the programming of innate behavior). To accomplish this, synaptic contacts are being shaped in the absence of sensory input. In the next phase of life, the infant has to absorb and process a great deal of new information in short time (parents, family, language, cultural behavior), which demands high levels of synaptic plasticity. At the mature stage the need for synaptic plasticity becomes gradually less urgent: a picture of the outside world is made that only incidentally requires adaptation.166 It is very clear, that synaptic plasticity mechanisms are important for the establishment of the neuronal circuitry. Therefore, disruptions of developmental plasticity mechanisms have long-lasting consequences for cognition and behavior. 167, 168, 169, 170

Developmental disorders and other neuropsychiatric illnesses such as autism, schizophrenia, ADHD, anxiety disorders, depression or addiction, can be caused genetically171, but also

166 Lohmann, C & Kessels, HW. The Developmental Stages of Synaptic Plasticity J Physiol. 2013

Oct 21. [Epub ahead of print]

167 Zoghbi HY (2003). Postnatal Neuro-developmental Disorders: Meeting at the Synapse? Science 302, 826-830.

168 Castren E, Elgersma Y, Maffei L, & Hagerman R (2012). Treatment of neurodevelopmental disorders in adulthood. J Neurosci 32, 14074-14079.

169 Bhakar AL, D+Âlen G+, & Bear MF (2012). The Pathophysiology of Fragile X (and What It Teaches Us about Synapses). Annu Rev Neurosci 35, 417-443.

170 Sudhof TC (2008). Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903-911.

171 Vorstman JA & Ophoff RA (2013). Genetic causes of developmental disorders. Curr Opin Neurol 26, 128-136.

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through physical, hormonal or pharmacological impact during gestation or birth, and through stressful events during birth or early childhood172. Therefore, the mapping of active plasticity mechanisms during the phases of development may provide insights into the specific causes of developmental disorders. Further research integrating molecular, physiological and behavioral aspects will provide a more complete map of synaptic plasticity mechanisms during the different phases of brain development and may inform us at what stage the brain is particularly sensitive to errors in mechanisms of synaptic plasticity and how interventions may prevent cognitive deficits. (Lohmann et al)

In the ensuing years, additional studies in children with brain damage have noted subtle yet persistent language deficits in children with early brain damage. Reviews have been written by a number of researchers, including Hécaen173, Riva & Cazzaniga174, Vargha-Khadem175 , Aram176,177 and Eisele & Aram.178,179

While all of these studies have contributed to our understanding of language functions in children with neurological dysfunction, many have included children who incurred damage at different ages, and these studies have come to differing conclusions regarding the nature and role of the left hemisphere in language development. The goal over the last twenty years has been to understand the development of brain-language relations from the beginning of life by following the course of language development in children with early unilateral focal brain damage. All of the children in this group suffered their cerebral insult before six months of age, that is, pre-linguistically. By prospectively chronicling their language development from infancy to adolescence, we can begin to address the following basic questions:

1. Localization of function

To what degree is language specified early on? Do behavioural patterns correlate with site of brain damage? Are they comparable to those of adults with homologous injuries?

2. Neuroplasticity

Do behavioural deficits persist or is there recovery of function over time?

Does the deficit express itself differentially over time?

172 Insel TR & Fernald RD (2004). How the brain processes social information: searching for the

social brain. Annu Rev Neurosci 27, 697-722.

173 Hécaen, H. Acquired aphasia in children and the ontogenesis of hemispheric functional specialization. Brain Lang. 3, 114-134; 1976.

174 Riva, D. & Cazzaniga, L. Late effects of unilateral brain lesions sustained before and after age one. Neuropsychologia 24, 423-428; 1986.

175 Vargha-Khadem, F. & Polkey, C.E. A review of cognitive outcome after hemi-decortication in humans. In: Recovery from brain damage: Advances in experimental medicine and biology, eds. ED. Rosen & D.A. Johnson, 325, pp. 137-171. New York: Plenum Press; 1992.

176 Aram, D. Language sequelae of unilateral brain lesions in children. In: Language, communication and the brain, ed. F. Pluin, pp. 171-197. New York: Raven Press; 1988.

177 Aram, D. Review of language development in children with focal brain injury. Paper presented to the Venice Conference on Developmental Neuropsychology, Venice (San Servolo). (Published in Italian in: Neuropsicologia in eta evolutiva, eds. D. Riva, A. Benton & H. Levin. Milan: Franco Angeli; 1991.

178 Eisele, J. & Aram, D. Comprehension and imitation of syntax following early hemisphere damage. Brain Lang. 46, 212-231; 1994.

179 Eisele, J. & Aram, D. Lexical and grammatical development in children witH early hemisphere damage: a cross-sectional view from birth to adolescence. In: Handbook of child language, eds. P. Fletcher & B. MacWhinney. Oxford: Basil Blackwell; 1995.

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3. The nature of the language acquisition process

How flexible is the language acquisition process itself? Is the process fairly rigid or are there many ways to approach learning a language?

All of the children were delayed in onset of language regardless of whether the injury was RHD or LHD. The children at 10-17 months who had right posterior damage were more delayed in comprehension than those with other focal lesions. Toddlers, 19-31 months with either L or R frontal damage were more delayed in production but this was transient. Those aged 20-44 months with left temporal damage had more delays in the production of vocabularies and produced shorter utterances. MDL had a good vocabulary so that seems to confirm her RHB damage.

Interesting though this research is, all of the children involved had focal injury and not the diffuse damage sustained by MDL. However, we can interpolate and gain some comparisons that are useful in relating MDL’s damage to her ability.

Narratives Once children are producing sentences and are well along in mastering the basic morphological structures of their language, linguistic development involves developing more sophisticated discourse skills and using particular syntactic structures with increasing frequency and effectiveness.

Beginning at about age three and a half to four years, we see an increasing ability to recruit particular linguistic structures for specific discourse purposes, e.g. to provide clearer directions, relate more coherent stories, to tell better jokes. In light of this developmental transition, researchers have used narratives to investigate multiple aspects of language and discourse in pre-school and school-age children who are developing typically.

According to the adult model, we would expect a child with LHD to have problems with morphology and syntax whereas those aspects of language would be spared in children with RHD. In contrast, those with RHD would be expected to make fewer inferences, and show problems with discourse coherence.

This research into narratives shows clearly that MDL’s diffuse brain damage makes her neurological functioning worse than that experienced by the focal injury group.

MDL has always told very short stories without much imagination and again that is a worse effect than that shown by focal inured children. This difference increases dramatically as focally injured children reach 7-10 years and clearly shows that MDL has diffuse damage to areas of cognition. She still makes tense-making errors, e.g. ‘singed’ rather than ‘sang’ — though she has made more of these errors since she was put onto the present medication regime in 2004.

She has also, in this period, begun to make pronominal errors, for example, she will say ‘him’ when referring to a female and ‘her’ when referring to a male. Strangely, these mistakes are not consistent.

MDL does not employ complex syntax. She would say ‘boy went to sleep’; ‘dog ran away’; rather than, ‘while the dog was sleeping, the dog ran away’. She has also got beyond using the connective, ‘and’, and does not use ‘because’, ‘since’ or ‘when’ for example. However, as a child she often used to ask, “why?”

In any case, research shows that those with focal RHD only catch up later in school years. One can only speculate as to whether MDL’s failure to ‘catch-up’ is due to the diffuse nature of her brain damage, or to the lack of social contact with ‘normal’ peers.

The research regarding the issue of neuro-plasticity shows the fairly rapid acquisition of the morpho-syntax of English in the children with early brain damage regardless of lesion site and that is strong evidence of the flexibility of the developing brain. In those morpho-syntactic structures examined, it was found that for the mandatory grammatical functions,

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the children in the focal lesion group were initially delayed, but they eventually performed within the normal range.

These findings for this particular group of research projects with children who have early focal brain damage have shown that, overall, children with brain damage are delayed in the acquisition of language, regardless of side of lesion, but eventually do go on to acquire the lexicon and grammar and be competent speakers of English.

It is clear that just as different aspects of language develop at different points in time so, too, do the deficits change over time. In sum, language development continues in the face of early unilateral brain damage, and although recruiting alternative neural means, the children with early focal brain damage follow a similar, but delayed, behavioural path to their typically developing counterparts. Additionally the data suggest that the brain areas suited to acquire language may be more broadly distributed than those necessary to maintain language functioning once it has been acquired.

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Non-verbal learning disabilities

Researchers view the significant disruption of right hemispheral systems in children (and, in some cases, adults) to be a sufficient condition for the appearance of the syndrome of non-verbal learning disabilities (NLD). At the same time, it is clear that aetiologies which involve direct disruption of right hemispheral systems are not necessary for the exhibition of the syndrome. 180

Characteristics and dynamics of the NLD syndrome The principal clinical manifestations (content) and dynamics of the NLD syndrome, identified through a process of intensive clinical examination, are as follows:

(1) Bilateral tactile-perceptual deficits, usually more marked on the left side of the body. Evidence of simple tactile imperception and suppression tends to subside with age, but problems in dealing with complex tactile input tend to persist.

(2) Bilateral psychomotor coordination deficiencies, often more marked on the left side of the body. Relatively simple motor skills, such as finger tapping and static steadiness, tend to normalize with advancing years. Complex psychomotor skills, especially when required within a novel framework, tend to worsen relative to age-based norms.

(3) Outstanding deficiencies in visual-spatial-organizational abilities. Simple visual discrimination, especially for material that is verbalizable, usually approaches normal levels with age. Complex visual-spatial-organizational skills, especially when required within a novel framework, tend to worsen relative to age-based norms.

(4) Extreme difficulty in adapting to novel and otherwise complex situations. An overreliance on prosaic, rote (and, in consequence, inappropriate) behaviours in such situations. Capacity to deal with novel experiences usually remains poor, or even worsens, with advancing age.

(5) Marked deficits in non-verbal problem-solving, concept-information, hypothesis-testing, and the capacity to benefit from positive and negative informational feedback in novel or otherwise complex situations. Included are significant difficulties in dealing with cause-effect relationships and marked deficiencies in the

180 Rourke, BP. Non-verbal learning disabilities: development of the syndrome and the model. .

In, Riva, D; & Benton, A. Localization of Brain Lesions and Developmental Functions. John Libby, London; 2000.

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appreciation of incongruities (e.g. age-appropriate sensitivity to humour). Such deficiencies tend to persist, and even worsen, with advancing age.

(6) Very distorted sense of time. This is reflected in poor estimation of elapsed time during common activities, and poor estimation of time of day. (This deficit may not appear spontaneously; it usually requires a very direct attempt to elicit it.)

(7) Very well-developed rote verbal capacities, including extremely well-developed rote verbal memory skills. 'Memory' for complex verbal material is usually very poor, probably as a result of poor initial comprehension of such material.

(8) Much verbosity of a repetitive, straightforward, rote nature. Content disorders of language and very poor psycholinguistic pragmatics. Misspellings are almost exclusively of the phonetically accurate variety. Little or no speech prosody, except on an imitative basis. Excessive reliance upon language as a principal means for social relating, information gathering, and relief from anxiety.

(9) Outstanding relative deficiencies in mechanical arithmetic as compared to proficiencies in reading (word-recognition) and spelling. Comprehension of, as opposed to rote memory for, complex text may continue to be very poor with ad-vancing age.

(10) Significant deficits in social perception, social judgement, and social interaction skills.

At a very elementary level, MDL might be seen as someone with NLD. However, on a closer and longer examination, it will be seen that this superficial assessment would be wrong as she shows only some of the characteristics of NLD and in others she shows a far greater disability.

The model that is used to identify the principal or primary dimensions of NLD syndrome are deficits in visual-perceptual-organizational abilities, complex psychomotor skills, and tactile perception, in addition to difficulties in dealing with novelty. Primary assets include proficiency in most rote verbal and some simple motor and psychomotor skills. 181 Confirmation of these dimensions as primary arises from the results of several studies.182,183

The primary neuropsychological deficits experienced by the child with NLD are seen as having to do with aspects of tactile and visual perception, complex psychomotor skills, and the capacity to deal adaptively with novel material. Such deficits would be expected to eventuate in disordered tactile and visual attention and stunted exploratory behaviour; in turn, problems in memory for material delivered through the tactile and visual modalities as well as deficits in concept-formation and problem-solving would be expected to ensue. This set of deficits would be expected to eventuate in particular linguistic deficiencies. (Rourke, 2000, idem)

The academic and psychosocial/adaptive deficiencies are the sequelae of these neuropsychological deficits. It is especially important to note that this set of neuropsychological deficits is expected to lead, in a necessary way, to a particular configuration of problems in psychosocial/adaptive behaviour both within and without the academic situation. (Rourke, 2000, idem)

181 Rourke, B.P. Nonverbal learning disabilities: the syndrome and the model. New York: Guilford

Press; 1989.

182 Casey, J.E., Rourke, B.P. & Picard, E.M. Syndrome of nonverballearning disabilities: age differences in neuropsychological, academic, and socioemotional functioning. Dev. Psychopathol. 3,329-345; 1991.

183 Harnadek, M.C.S. & Rourke, B.P. Principal identifying features of the syndrome of nonverbal learning disabilities in children. J. Learning Disabilities 27,144-154; 1994.

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Growing evidence indicates that multiple types of brain injury, including traumatic brain injury, are dynamic conditions that continue to change years after onset. For a subset of individuals who incur these injuries, decline occurs over time and is likely due to progressive neurodegenerative processes, comorbid conditions, aging, behavioural choices, and/or psychosocial factors. Deterioration, whether directly or indirectly associated with the original brain injury, necessitates a clinical approach as a chronic health condition, including identification of risk and protective factors, protocols for early identification, evidence-based preventive and ameliorative treatment, and training in self-management.184 It is important therefore for those with an early-life brain injury that it can be assessed and researched by neurologists or neuropsychologists in order to provide a proper management approach.

One example of possible treatment is with omega-3 polyunsaturated fatty acids (PUFAs). These are compounds that have a structural role in the nervous system and are essential for neuro-development. It has been shown that there is therapeutic potential in neurotrauma with the use of docosahexaenoic acid and eicosapentaenoic acid.

Michael-Titus et al suggest that traumatic brain injury (TBI) and spinal cord injury (SCI) can lead to major disability and have a significant socioeconomic cost and that there is an unmet need for acute neuro-protection and for treatments that promote neuro-regeneration. Their research shows that acute administration of omega-3 PUFAs after injury and dietary exposure before or after injury improve neurological outcomes in experimental SCI and TBI. The mechanisms involved include decreased neuro-inflammation and oxidative stress, neurotrophic support, and activation of cell survival pathways. However, this review raises questions that must be addressed before successful clinical translation.

In traumatic brain injury, oxidation and inflammation have been linked to poorer cognitive outcomes. Theadom and colleagues have investigated the effects of Enzogenol on loss of cognitive functioning following traumatic brain injury. Enzogenol is a flavonoid-rich extract from Pinus radiata bark with antioxidant and anti-inflammatory properties that has been shown to improve working memory in healthy adults. 185

The investigators found that Enzogenol was safe and well tolerated. Trend and breakpoint analyses showed a significant reduction in cognitive failures after 6 weeks. Improvements in the frequency of self-reported cognitive failures were found to stabilize shortly after the half-way period of the study. Overall, Enzogenol supplementation was found to be safe and well tolerated in people after mild TBI, and may improve cognitive functioning in this patient population. (Idem)

MDL has only some of the assets normally found in NLD but most of the deficits. It has been found on examination of the brains of some of those assessed as having NLD, that there can be significant tissue destruction within the right cerebral hemisphere.

It seems that in MDL’s case, the lack of ability in many, if not all, of those associated with NLD will have come to her by means of post-natal damage to particular areas of her brain that are connected to the functions that are lost or disabled. This is confirmed in the work of Ewing Cobbs et al and Fletcher Levin in their work on traumatic brain injury.186,187

184 Corrigan JD & Hammond FM. Traumatic brain injury as a chronic health condition. Arch Phys

Med Rehabil. 2013 Jun;94(6):1199-201

185 Theadom A; Mahon S; Barker-Collo S; McPherson K; Rush E; Vandal AC & Feigin VL. Enzogenol for cognitive functioning in traumatic brain injury. Eur J Neurol. 2013 Aug;20(8):1135-44.

186 Ewing-Cobbs, L., Fletcher, J. M. & Levin, H.S. Traumatic brain injury. In: Syndrome of nonverbal learning disabilities: neurodevelopmental manifestations, ed. B.P. Rourke, pp. 433-459. New York: Guilford Press; 1995.

187 Fletcher, J.M. & Levin, H. Neurobehavioral effects of brain injury in children. In: Handbook of pediatric psychology, ed. D.K Routh, pp. 258-295. New York: Guilford Press; 1988.

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The Neuropsychology of Brain Damage as it relates to MDL

Using the Lesion Method to locate brain damage188

The lesion method aims at establishing a correlation between a circumscribed region of brain damage, a lesion and a pattern of alteration in some aspect of an experimentally controlled cognitive or behavioural performance. The brain-damaged region is conceptualized as part of a large-scale network of cortical and sub-cortical sites that operate in concert, by virtue of their interlocking connectivity, to produce a particular function.

The lesions may have been produced by neurologic disease alone or incurred in the process of treating it (e.g., a surgical procedure). They may be small or large and may be studied in vivo or at post mortem. The indispensable requirements are that lesions be stable, well demarcated, and referable to a neuro-anatomic unit.

The lesion approach provided the first method in what was to become neuroscience. In the very least, it dates to Morgagni's demonstration of an association between unilateral brain disease and contra-lateral sensory and motor disabilities. Bouillaud's and Broca's finding of a correlation between speech and focal damage to the frontal lobe are reasonable signposts to mark the modern era of lesion studies.

It is now accepted that the classically discovered links between certain brain regions of the cerebral cortex and signs of neuropsychological dysfunction have been validated and they remain a staple of clinical neurology, and allow for relatively accurate predictions of localization of damage from neurologic signs. That is, more often than not, the presence of certain neuropsychological defects indicates to the clinical expert that there is dysfunction in a specific brain area. These valid links, however, should not be taken to mean that the functions disturbed by the lesion were inscribed in the tissue that the lesion destroyed. The complex psychological functions, which usually constitute the target of neuropsychological studies in humans, are not localizable at that level. The new technique permits a direct identification of gyri and sulci, comparable to what can be achieved at the autopsy table in a post mortem brain after the meninges have been removed.189

Thompson et al have devised, implemented, and tested a technique for creating a comprehensive probabilistic atlas of the human cerebral cortex, based on high-dimensional fluid transformations. The goal of the atlas is to detect and quantify subtle and distributed patterns of deviation from normal cortical anatomy, in a 3D brain image from any given subject. The method that is used takes a 3D MR image of a new subject and a high-resolution surface representation of the cerebral cortex is automatically extracted. The algorithm then calculates a set of high-dimensional volumetric maps, fluidly deforming this surface into structural correspondence with other cortical surfaces, selected one by one from an anatomic image database. The family of volumetric warps so constructed encodes statistical properties of local anatomical variation across the cortical surface.

188 Damasio, H. & Damasio, AR. The Lesion Method in Behavioural Neurology and

Neuropsychology. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

189 Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

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Additional strategies are developed to fluidly deform the sulcal patterns of different subjects into structural correspondence. A probability space of random transformations, based on the theory of anisotropic Gaussian random fields, is then used to encode information on complex variations in gyral and sulcal topography from one individual to another. 190

The neural architectures revealed by neuro-anatomy and neuro-physiology and the cognitive architectures revealed by experimental neuropsychology suggest that single-centre functions, single-purpose pathways, and unidirectional cascades of information process are unrealistic. Moreover, the residual performance that follows focal brain insults, and the ensuing patterns of recovery, suggest that knowledge must be widely distributed, at multiple neural levels, and complex psychological functions must emerge from the cooperation of multiple components of integrated networks.

Two key developments made human lesion studies rewarding again. First, lesion studies in non-human primates brought major advances to the understanding of the neural basis of vision and memory, as demonstrated, among others, by Mishkin and colleagues. Second, the advent of CT and MRI scans began to permit human lesion studies in vivo. It is apparent now that the lesion method is indispensable to cognitive neuroscience, especially when it comes to human studies. The new lesion method is not concerned with ‘localizing func-tions’, nor is it a contest for ‘localizing lesions’. It is a means to test, at systems level, hypotheses regarding both neural structure and cognitive processes. What investigators from Dejerine to Geschwind gleaned from single cases can now be replicated systematically in a suitable group of subjects. Hypotheses old and new, including some advanced by the pioneer neuropsychologists, can be tested experimentally.

In using this method of locating lesions in MDL’s brain it should always be remembered that her brain was injured at a very early stage and its later development could not therefore be normal. In other words we are not dealing with a mature brain that has subsequently been damaged.

Problems of an Adverse Living Environment

There are two distinct aspects to MDL’s brain functioning:

1. The original damage caused by the vaccination (this appears to be largely to the right-side of the brain and probably the connections to and from the amygdala, hippocampus and hypothalamus).

2. The subsequent damage/alteration that has been brought about by environmental issues such as stress 191,192,193,194,195,196,197,198 anxiety199,200,201 and medication202,203,204,205,206,207,208,209,210.

190 Thompson, P M.; MacDonald, D; Mega, M S.; Holmes, C J.; Evans, A C &; Toga, A W. Detection

and Mapping of Abnormal Brain Structure with a Probabilistic Atlas of Cortical Surfaces. Journal of Computer Assisted Tomography: July/August 1997 - Volume 21 - Issue 4 - pp 567-581.

191 http://www.fi.edu/learn/brain/stress.html#how

192 Ulrich-Lai,Y M. & Herman, J P. Neural regulation of endocrine and autonomic stress responses. Nature Reviews Neuroscience 10, 397-409 (2009)

193 Arnsten, A F T. Stress signalling pathways that impair prefrontal cortex structure and function. Nature Reviews Neuroscience 10, 410-422 (2009)

194 Roozendaal, B; McEwen, B S & Chattarji, S. Stress, memory and the amygdala. Nature Reviews Neuroscience 10, 423-433 (2009)

195 Lupien, S J; McEwen, B S; Gunnar, M R & Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Reviews Neuroscience 10, 434-445 (2009)

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It has long been accepted that psychotropic drugs can bring about tardive dyskinesia211 and akathisia212. These symptoms can become a larger problem because of the danger that the brain will be damaged by the intrusion of the medication over a long period of time. So, the pathological process or processes that underlie the development of tardive dyskinesia are not just neurochemical in nature, but affect brain structure. Compared with those without tardive dyskinesia, patients with tardive dyskinesia show a pattern of volume reductions in predominantly subcortical regions, including the basal ganglia and the thalamus. Within the basal ganglia, volume reductions are seen in the caudate nucleus, to a lesser extent in the putamen, and only marginally in the globus pallidus. The patients with tardive dyskinesia, but not those without, show significant volume reductions in the basal

196 Feder, A; Nestler, E J & Charney, D S. Psychobiology and molecular genetics of resilience.

Nature Reviews Neuroscience 10, 446-457 (2009)

197 Joëls, M & Baram, T Z. The neuro-symphony of stress. Nature Reviews Neuroscience 10, 459-466 (2009)

198 Soliman A, Udemgba C, Fan I, Xu X, Miler L, Rusjan P, Houle S, Wilson AA, Pruessner J, Ou XM, Meyer JH. Convergent Effects of Acute Stress and Glucocorticoid Exposure upon MAO-A in Humans. J Neurosci. 2012 Nov 28;32(48):17120-17127.

199 Soo, C & Tate, R. Psychological treatment for anxiety in people with traumatic brain injury (Review). The Cochrane Collaboration and published in The Cochrane Library; 2009, Issue 3

200 Vasa RA, Grados M, Slomine B, Herskovits EH, Thompson RE, Salorio C, Christensen J, Wursta C, Riddle MA, Gerring JP. Neuroimaging correlates of anxiety after pediatric traumatic brain injury. Biol Psychiatry. 2004 Feb 1;55(3):208-16.

201 Hiott DW & Labbate L. Anxiety disorders associated with traumatic brain injuries. NeuroRehabilitation. 2002;17(4):345-55.

202 Dorph-Petersen KA, Pierri JN, et al. The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys. Neuropsychopharmacology 9 March 2005

203 Christensen, E. Neuropathological investigations of 28 brains from patients with dyskinesia. Acta Psychiatrica Scandinavica, 46,14-23, 1970

204 Baribeau, J. Tardive dyskinesia and associated cognitive disorders: a convergent neuropsycological and neurophysiological approach. Brain and Cognition 23, 40-55, 1993.

205 Paulsen, J S. Neuropsychological impairment in tardive dyskinesia. Neurospsychology 8, 227-241. 1994.

206 Sachdev, P. Negative symptoms, cognitive dysfunction, tardive akathisia and tardive dyskinesia. Acta Psychiatr Scand. 93, 451-459. 1996.

207 Madsen, A. Neuroleptics in progressive structural brain abnormalities in psychiatric illness. The Lancet, 352, 784-785. Sept. 5, 1998.

208 Tsai, G. Markers of glutamergic neurotransmission and oxidative stress associated with tardive dyskinesia. American Journal of Psychiatry, 155, 1207-1213. 1998.

209 Wade, JB; Lehmann, L; Hart, R; Linden, D; Novak, T & Hamer R. Cognitive Changes Associated with Tardive Dyskinesia. Neuropsychiatry, Neuropsychology and Behavioural Neurology; Vol.1; No 3; pp217-227; 1989.

210 Yang SY; Liao YT; Liu HC; Chen WJ; Chen CC; & Kuo CJ. Antipsychotic drugs mood stabilizers and risk of pneumonia in bipolar disorder: a nationwide case-control study. J Clin Psychiatry. 2013 Jan;74(1):e79-86. doi: 10.4088/JCP.12m07938.

211 Tardive dyskinesia was first named and classified in 1964. By the early 1960s, symptoms associated with tardive dyskinesia were apparent in approximately 30 percent of psychiatric patients treated with antipsychotic medications, linking the development of the condition to these drugs.

212 In very general terms, akathisia is a movement disorder and it is characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless. It can be a side effect of medications.

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ganglia compared with the healthy controls but both groups had smaller volumes than controls in other affected areas. 213

Kim et al have reviewed the risks associated with the use of antipsychotic medications. They have concluded that second-generation antipsychotics (SGAs) are powerful pharmacologic tools when used to treat a wide array of psychiatric conditions. They also comment that their use is not just limited to psychosis but may also extend to mania, depression, anxiety and even autism spectrum disorders. To treat these conditions, most SGAs are dosed daily and used chronically. Evidence to date suggests that the risk of tardive dyskinesia is probably lower with SGAs as compared to first-generation antipsychotics, but tardive dyskinesia will still occur with SGAs, and this was seen in the cases that they reviewed. Prospective, large-scale studies involving antipsychotic-naïve patients exposed to SGAs would show the true risk and incidence of SGA-induced EEG dyskinesia. 214

Amann et al studied the effects of the atypical antipsychotics quetiapine and olanzapine, and the typical antipsychotic haloperidol on EEG patterns retrospectively in 81 patients under stable monotherapy with either drug (quetiapine: n=22, olanzapine: n=37, haloperidol: n=22). These three subgroups were compared with a control group of healthy subjects (n=30) which were matched regarding sex and age. Diagnoses of patients were schizophrenia (DSM-IV 295.xx, n=61), brief psychotic disorder (DSM-IV 298.8, n=9), schizoaffective disorder (DSM-IV 295.70, n=8) and delusional disorder (DSM-IV 297.1, n=3). There were no statistically significant differences regarding demographic characteristics between the groups.

Digital EEG recordings were retrieved from a database and visually assessed by two independent investigators, and one blinded regarding medication. One patient from the quetiapine group (5%), 13 olanzapine patients (35%), five of the haloperidol patients (23%) and two subjects of the control group (7%) had an abnormal EEG.

Epileptiform activity was observed in four patients (11%) of the olanzapine group, and none in the others. EEG abnormalities were statistically significantly increased with dose in the olanzapine group, in contrast to patients treated with haloperidol, quetiapine or healthy subjects. They concluded that EEG abnormalities seemed to occur rarely in patients treated with quetiapine comparable to the control group, but significantly more often with haloperidol and olanzapine, possibly due to different receptor profiles of these substances.215

Wichniak et al investigated whether EEG slowing during olanzapine treatment was related to therapy outcome and sleepiness in patients with schizophrenia. Olanzapine was found to induce slowing of EEG activity in the majority of patients, but their background EEG activity remained mostly unchanged. In patients at high olanzapine doses (10 mg/day) the paroxysmal slow wave activity was found in as many as 25% of cases, while sharp waves were found in 32% of patients. The EEG slowing during olanzapine treatment was not related to the treatment outcome. Moreover, no direct relationships were found between the presence of sleepiness in EEG recordings, treatment outcome and type as well as dose of medication used. These findings suggest that the relationship between EEG slowing and treatment outcome during olanzapine treatment is not as strong as that during clozapine treatment or ECT. They suggest that further investigation of this aspect is needed using more

213 Sarró, S. et al. Structural brain changes associated with tardive dyskinesia in schizophrenia.

BJPsych. July 2013 203:51-57; doi:10.1192/bjp.bp.112.114538.

214 Kim, J; MacMaster, E & Schwartz, TL. Tardive dyskinesia in patients treated with atypical antipsychotics: case series and brief review of etiologic and treatment considerations. Drugs in Context 2014; 3: 212259. doi: 10.7573/dic.212259.

215 Amann BL; Pogarell O; Mergl R; Juckel G; Grunze H; Mulert C & Hegerl U. EEG abnormalities associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and healthy subjects. Hum Psychopharmacol. 2003 Dec;18(8):641-6.

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complex study designs. In addition they also propose that EEGs should be performed both before and during antipsychotic medication when the patient’s state is stabilized. 216

A later study by Deaner et al undertook a naturalistic observational study into EEG alterations in patients under olanzapine treatment with a special regard to olanzapine dose and plasma concentration. They suggest that EEG control recordings should be mandatory during olanzapine treatment. Twenty-two in-patients of a psychiatric university ward were involved and all of them had a normal alpha-EEG before drug therapy, and did not suffer from brain-organic dysfunctions, as verified by clinical examination and cMRI scans.

EEG and olanzapine plasma levels were determined under steady-state conditions (between 18 and 22 days after begin of treatment). In 9 patients (40.9%), pathological EEG changes (one with spike-waves) consecutive to olanzapine treatment were observed. The dose of olanzapine was significantly higher in patients with changes of the EEG than in patients without changes. In patients with EEG changes, the blood plasma concentration of olanzapine tended to be higher also. The sensitivity of olanzapine dosage to predict EEG changes was 66.7%. EEG abnormalities during olanzapine treatment are common. And are significantly dose dependent. Thus, EEG control recordings should be mandatory during olanzapine treatment with special emphasis on dosages exceeding 20 mg per day, although keeping in mind that EEGs have only a limited predictive power regarding future epileptic seizures. 217

The underlying cause of akathisia is still far from clear. There appears to be dopamine receptor blockade in the mesocortical dopamine system. PET studies show D2 receptor occupancy in the striatum plays a role and noradrenergic and serotonergic systems also appear to he involved. Antipsychotics with potent 5HT receptor antagonism show a lower incidence of akathisia and some 5HT2 antagonists e.g. cyproheptadine, have therapeutic efficacy. There is a possible association between low iron status and akathisia in patients with restless legs syndrome. There have been a number of subtypes of akathisia proposed, although a lack of consensus in the use of the terms is evident. Most authors refer to acute, tardive (arising at least six months after the continuous use of the medication), chronic, withdrawal and pseudoakathisia. 218 The Barnes Akathisia Scale is the most widely used rating scale for akathisia. This scale includes objective and subjective items such as the level of the patient's restlessness.

Mills has suggested that even when child psychiatrists can agree about the boundary between healthy and disordered moods and behaviors in children, misdiagnosis remains a problem and goes on to say that there are children who need treatment who are not getting it and children who do not need treatment who are. 219 A further question is, should children have the right to a psychotropic medication-free childhood?

This idea is also put forward by Parens & Johnston 220 who ask:

216 Wichniak A; Szafranski T; Wierzbicka A; Waliniowska E & Jernajczyk W.

Electroencephalogram slowing, sleepiness and treatment response in patients with schizophrenia during olanzapine treatment. J Psychopharmacol. 2006 Jan;20(1):80-5. Epub 2005 Oct 4.

217 Degner D; Nitsche MA; Bias F; Rüther E & Reulbach U. EEG alterations during treatment with olanzapine. Eur Arch Psychiatry Clin Neurosci. 2011 Oct;261(7):483-8.

218 Nelson, DE. Akathisia - A Brief Review. SMJ; 2001;46: 133-134.

219 Mills, C. Psychotropic Childhoods Global Mental Health and Pharmaceutical Children. Article first published online: Children & Society; 9 DEC 2013; DOI: 10.1111/chso.12062; John Wiley & Sons Ltd and National Children's Bureau, 2013.

220 Parens, E. & Johnston, J. Mental Health in children and Adolescents. In, From Birth to Death and Bench to Clinic: The Hastings Center Bioethics Briefing Book for Journalists, Policymakers,

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• Are children being overmedicated?

• Is normal childhood behaviour being medicalized?

• What is the long-term safety of psychotropic drugs?

• How effective and safe is it to use those drugs that have only been tested in adults?

What is needed is a policy that allows children to thrive and one that tries to find the ultimate wellbeing so that there is a possibility of the child being as much a complete and rational human being as he can be helped to be. This can often be achieved by placing the child in the right environment, one that can hopefully be cultivated without any institutional placement and preferable without being removed from home and family.

Kane et al, in an updated review focusing on second-generation antipsychotics (SGAs), found that in seventy-seven trials akathisia was observed with the use of all the SGAs. The akathisia incidence reported in bipolar disorder trials was generally higher compared with schizophrenia trials. The incidence reported for first-generation antipsychotics was consistently higher than that reported for SGAs, regardless of the patient population studied. They concluded that akathisia remains a concern with the use of SGAs; and that more accurate and standardized evaluations are required for a better understanding of the nature and incidence of akathisia.221

There have been increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and treatment with these medications. 222

He et al have reported that treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. They identified antagonism of histamine H1 receptors as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear.

They explored the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Their data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase signalling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue.

They suggest that antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1

and Campaigns, ed. Mary Crowley (Garrison, NY: the Hastings center, 2008), Chapter 22; 101-106.

221 Kane JM; Fleischhacker WW; Hansen L, Perlis R; Pikalov A 3rd & Assunção-Talbott S. Akathisia an updated review focusing on second-generation antipsychotics. J Clin Psychiatry. 2009 Apr 21. [Epub ahead of print]

222 Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19 Suppl 1:1-93.

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receptor and its downstream signalling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.223

These findings have been confirmed in 2014 by Goswami et al; their research has shown that atypical antipsychotic agents produce significant disturbances in blood glucose and lipid profile levels. Olanzapine treatment is associated with high risk of abnormal metabolic changes. They draw attention to the need for prescribers to be aware about detailed pharmacological information medications and that the prescribing of atypical antipsychotics should be considered after assessment and the taking of the patient’s history including personal and family, general and laboratory parameter measurement. Atypical antipsychotics should be avoided in high risk patients like those who suffer from obesity, insulin resistance, hypertension and hyperlipidaemia. Thus prescription of antipsychotic agents must be based on patient’s metabolic parameters and they should be measured during the course of treatment. 224

Second generation antipsychotics (SGAs) are widely prescribed to treat various disorders, most notably schizophrenia and bipolar disorder; however, SGAs can cause abnormal glucose metabolism that can lead to insulin-resistance and type 2 diabetes mellitus side-effects by largely unknown mechanisms. Weston-Green et al have explored the potential candidature of the acetylcholine (ACh) muscarinic M3 receptor (M3R) as a prime mechanistic and possible therapeutic target of interest in SGA-induced insulin dysregulation.

Studies have identified that SGA binding affinity to the M3R is a predictor of diabetes risk; indeed, olanzapine and clozapine, SGAs with the highest clinical incidence of diabetes side-effects, are potent M3R antagonists. Pancreatic M3Rs regulate the glucose-stimulated cholinergic pathway of insulin secretion; their activation on β-cells stimulates insulin secretion, while M3R blockade decreases insulin secretion. Genetic modification of M3Rs causes robust alterations in insulin levels and glucose tolerance in mice. Olanzapine alters M3R density in discrete nuclei of the hypothalamus and caudal brainstem, regions that regulate glucose homeostasis and insulin secretion through vagal innervation of the pancreas. Furthermore, studies have demonstrated a dynamic sensitivity of hypothalamic and brainstem M3Rs to altered glucometabolic status of the body. Therefore, the M3R is in a prime position to influence glucose homeostasis through direct effects on pancreatic β-cells and by potentially altering signaling in the hypothalamus and brainstem. SGA-induced insulin dysregulation may be partly due to blockade of central and peripheral M3Rs, causing an initial disruption to insulin secretion and glucose homeostasis that can progressively lead to insulin resistance and diabetes during chronic treatment. 225

One of the drugs that has been prescribed for MDL over a long period of time is olanzapine. Olanzapine works by blocking the receptors in the brain on which dopamine acts. It increases the concentrations of the dopamine metabolites DOPAC and HVA in striatum and nucleus accumbens. In addition it antagonizes the pergolide-induced decrease of striatal DOPA concentrations in rats treated with gammabutyrolactone and NSD1015 and increased striatal 3-methoxytyramine concentrations in nomifensine-treated rats (but not after gammabutyrolactone administration), suggesting that olanzapine blocks terminal and somatodendritic autoreceptors on dopamine neurons. These findings provide evidence

223 He M; Deng C & Huang XF. The role of hypothalamic H1 receptor antagonism in

antipsychotic-induced weight gain. CNS Drugs. 2013 Jun;27(6):423-34. doi: 10.1007/s40263-013-0062-1.

224 Goswami, NN; Gandhi, AM: Patel, PP & Dikshit, RK. An evaluation of the metabolic effects of antipsychotic medications in patients suffering from psychiatric illness. Journal of Applied Pharmaceutical Science Vol. 4 (04), pp. 014-019, April, 2014. Available online at http://www.japsonline.com DOI: 10.7324/JAPS.2014.40403 ISSN 2231-3354

225 Weston-Green, K; Huang, X; & Deng, C. Second Generation Antipsychotic-Induced Type 2 Diabetes: A Role for the Muscarinic M3 Receptor. CNS Drugs; October 2013.

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that olanzapine antagonizes dopamine, serotonin, -adrenergic and muscarinic receptors in vivo, consistent with its high affinity for these receptor sites in vitro.226 There are therefore cognitive impairments that can be observed in cases where there is disturbed dopamine transmission as a result of antipsychotic drug treatment.227 Veselinović et al show in their findings that modulation of dopaminergic systems affects primarily the speed of information processing, attention and learning. This would seem to be a contrary support mechanism for those with learning disability and should not be prescribed unless they advantages outweigh the disadvantages.

This situation can easily be made worse if olanzapine is prescribed as part of an antipsychotic polypharmacy. (APP) Pre-clinical studies underpinning neurobiological hypotheses in APP are lacking. Evidence supporting the efficacy of APP is limited with modest beneficial clinical relevance. APP is associated with several serious adverse effects and increased health costs. In the absence of more convincing pre-clinical support and clinical evidence, van Bennekom et al advise adherence to existing guidelines and limiting combinations of antipsychotics (in consideration with other pharmacotherapeutic, somatic and psychotherapeutic options) to patients with clozapine-refractory psychosis in well-evaluated individual trials that might need 10 weeks or more.228 There is much evidence that olanzapine gives rise to Extrapyramidal symptoms. Hill et al put the risk at about 9-10%229; this was confirmed by Woerner et al. 230

It is interesting to note that patients do not always have the same perceptions about the risks of using drugs as healthcare professionals. In a study of 400 health-care professionals (278 general practitioners, 76 pharmacists, and 46 pharmaco-vigilance professionals) and 153 non-professionals, the healthcare professionals ranked anticoagulants and anti-inflammatory drugs as carrying the highest risk in a list of 13 categories; psychotropic drugs (“sleeping pills” and “tranquillisers”) were next. In contrast, the non-professionals ranked the psychotropic drugs (“sleeping pills”, “tranquillisers”, and “antidepressants”) highest.231

(See Fear Conditioning - p 84 and Sleep - p 105)

MDL’s pattern of deterioration has developed markedly since 2004 and it will require the diminution of medication and an improvement in MDL’s social environment before it can be seen if there are prospects of recovery.

She has been seriously affected by ill-thought-out changes to her home life and by interference to her life in general by those who have no knowledge of the effects that such changes can have. Environmental security and familiarity are very important stabilising

226 Bymaster, FP; Hemrick-Luecke, SK; Perry, KW; & Fuller, RW. Neurochemical evidence for

antagonism by olanzapine of dopamine, serotonin, α1-adrenergic and muscarinic receptors in vivo in rats. Psychopharmacology; Volume 124, Numbers 1-2, 87-94, DOI: 10.1007/BF02245608.

227 Veselinović, T; Schorn, H; Vernaleken, IB; Hiemke, C; Zernig, G; Gur, R; & Gründer,G. Effects of antipsychotic treatment on cognition in healthy subjects. J Psychopharmacol April 2013 vol. 27 no. 4 374-385.

228 van Bennekom, MWHL; Gijsman, HJ; & Zitman, FG. Antipsychotic polypharmacy in psychotic disorders: a critical review of neurobiology, efficacy, tolerability and cost effectiveness. J Psychopharmacol April 2013 vol. 27 no. 4 327-336.

229 Hill AL; Sun B; & McDonnell DP. Incidences of Extrapyramidal Symptoms in Patients With Schizophrenia after Treatment With Long-Acting-Injection (Depot) or Oral Formulations of Olanzapine. Clin Schizophr Relat Psychoses. 2013 Feb 21:1-23.

230 Woerner, MG; U Correll, CU; Alvir, JMJ; Greenwald, B; Delman, H; & Kane, JM. Incidence of Tardive Dyskinesia with Risperidone or Olanzapine in the Elderly: Results from a 2-Year, Prospective Study in Antipsychotic-Naïve Patients. Neuropsychopharmacology (2011) 36, 1738–1746.

231 Talbot, J. & Aronson, JK. (Eds) Stephens’ Detection and Evaluation of Adverse Drug Reactions: Principles and Practice, Sixth Edition. [In Process — to be published 2012] John Wiley & Sons, Ltd.

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components in the life of someone with MDL’s type of brain injury. Cognition, learning and the retrieval of learned memories are degraded dramatically by removing them to strange situations; particularly if this also involves a change of carers and others who are important persons in their lives.

In clinical neuro-psychology, the environmental context in which learning occurs can be a very important factor that affects retrieval in humans and other animals and much debate has centred on whether the brain is more likely to degenerate following adverse environmental changes. Placing the subject back into the same context in which the original learning occurred can greatly facilitate retrieval. The very well-known effects of context in the human memory literature can arise in a very simple way.

An implication of this explanation is that context effects will be especially important at late stages of memory or information processing systems in the brain for the information from a wide range of modalities will be mixed; some of that information could reflect the context in which the learning takes place. One part of the brain where such effects may be strong is the hippocampus, which is implicated in the memory of recent episodes, and which receives inputs derived from most of the cortical information processing streams, including those involved in space232.

There is a popular belief that an active mental life may delay the cognitive deterioration associated with normal aging. Animal studies also support the concept that environment can influence brain development 233. It is therefore of considerable importance to MDL that her environment supports all of her potential activities and that nothing is done that subverts that aim.

It is to the carer’s advantage to know how to keep MDL happy and to gain her confidence. A good carer will become a communication exchange wherein she will understand MDL’s unspoken demeanour and she will find the ways to explain things to MDL so that there is an avoidance of confrontation. MDL has had to learn some self-protection strategies over the years and most of these involve closing down rather than opening up. Carers have to find ways of letting MDL find peace with herself because only through that will she become settled in her environment. When she is at peace she will be quite and unobtrusive, getting on with her own activities. It is only when she becomes anxious and uncertain that she takes refuge in perseveration.

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SEMANTIC MEMORY IMPAIRMENTS

The term semantic memory refers to our general knowledge of the objects, people, and events of the world234. The facts that Paris is the capital of France, birds have feathers, and a desk is a piece of furniture, are examples of semantic memory. More particular knowledge, tied to an individual's personal experience, is considered episodic memory rather than semantic memory. Examples of the latter include the facts that you bought this book at a certain store or ate a certain food for breakfast this morning. Neurologic disease and damage can affect semantic memory disproportionately. Semantic memory is at least partially dissociable from other forms of memory, language, and cognition, generally as a result of degenerative diseases. It appears to depend on temporal cortex, with some

232 Rolls, ET. Memory, Attention and Decision-making: A unifying computational neuroscience

approach. OUP; Oxford; 2008 (pp 568-569)

233 Ostrosky-Solís, F. Can Literacy Change Brain Anatomy? International Journal of Psychology, Psychology Press; June 2004; ISBN: 978-1-84169-968-4

234 Tulving E. Episodic and semantic memory. In, Tulving E, Donaldon W (eds): Organization of Memory. New York: Academic Press, 1972.

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degree lateralization to the left suggested.235

The information about episodic events recalled from the hippocampus is seen to be used to help form semantic memories. For example, remembering many particular journeys could help to build a geographic cognitive map in the neocortex. The hippocampus and neocortex would thus be complementary memory systems, with the hippocampus being used for rapid, ‘on the fly’, unstructured storage of information involving activity potentially arriving from many areas of the neocortex; while the neocortex would gradually build and adjust, on the basis of much accumulating information, the semantic representation.236

In some cases it appears that knowledge from certain semantic categories is disproportionately impaired, suggesting that the neural bases of semantic memory are subdivided by semantic category. Category-specific semantic memory impairments are sometimes confused with category-specific impairments in name retrieval and visual recognition. The face-specificity of prosopagnosia (see, p 64) affects visual recognition only. In contrast, category-specific semantic memory impairments are manifest in all tasks that require knowledge of the object, whether they involve vision, language, or other modalities of stimulus and response. The most common category-specific semantic memory impairment affects knowledge of living things.

Yim et al in studying the relationship between facial affect recognition and cognitive functioning after traumatic brain injury, concluded that: impairment in several cognitive processes may contribute to facial affect recognition deficits in TBI, in particular non-verbal memory, working memory and speed of processing. Furthermore, executive functioning may not be a critical factor in facial affect recognition, but would most likely be important in deciding what to do once facial affect is perceived. 237 (See page 41 for factors that might be introduced in order to try and improve cognitive functioning.)

The first report of impaired knowledge of living things was made by Warrington and Shallice238, who described three patients who had survived herpes encephalitis. Although the patients were impaired across the board at tasks such as picture naming and defining words, they were dramatically worse when the pictures or words represented animals and plants than when they represented artefacts. In subsequent years numerous other reports appeared of similar cases, generally suffering damage to temporal cortex from herpes encephalitis, closed head injury or, less frequently, cerebro-vascular or degenerative disease. Category-specific disorders of semantic memory are distinct from the disorders related to amnesia, despite the implication of temporal brain regions in both.

Building on the hypothesis of Allport239, that semantic memory is subdivided into different sensori-motor modalities (e.g., visual knowledge, tactile knowledge, and motor knowledge; Warrington and Shallice (1984, idem) proposed a different kind of alternative explanation for category-specific knowledge deficits. They suggested that living and non-living things may differ from one another in their reliance on knowledge from different sensori-motor modalities, with living things being known predominantly by their visual and other sensory attributes.

235 Farah, MJ & Grossman, M. Semantic Memory Impairments. In Feinberg, T E & Farah, M J.

Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.


237 Yim J; Babbage DR; Zupan B, Neumann D & Willer B. The relationship between facial affect recognition and cognitive functioning after traumatic brain injury. Research Reports -Brain Injury 27(10):1155 (2013) PMID 23895556.

238 Warrington EK& Shallice T. Category specific semantic impairments. Brain 107:829-854, 1984.

239 Allport DA. Distributed memory, modular subsystems and dysphasia, in Newman S, Epstein R (eds): Current Perspectives in Dysphasia. Edinburgh: Churchill Livingstone, 1985.

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Impaired knowledge of living things could result from an impairment of visual knowledge. Similarly, nonliving things might be known predominantly by their function, an abstract form of motoric representation, and impaired knowledge of non-living things could result from an impairment of functional knowledge. This interpretation has the advantage of parsimony, in that it invokes a type of organization already known to exist in the brain-modality-specific organization rather than invoking an organization based on semantic categories such as aliveness.

The idea that certain brain regions are specialized for representing knowledge about living things has naturally aroused some scepticism and prompted a search for alternative explanations of apparently impaired knowledge of living things. The simplest alternative explanation is that the impairment is an artefact of the greater difficulty of retrieving knowledge about living things. It has been suggested that when difficulty is equated across living and nonliving test items, the selectivity of the semantic memory impairment disappears.240,241 However, the selectivity has also been shown to be reliable in two cases when multiple measures of difficulty are accounted for242.

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Elements of Language and Communication

As a result of the fundamental discoveries of Broca and Wernicke that focal lesions in the left hemisphere cause spectacular deficits in the verbal aspects of language, clinical studies of human communication have, for the most part, focused on the aphasias. These studies led to the (then) widely held belief that language is a dominant function of the left hemisphere, with the right hemisphere being relegated to a ‘minor’ or ‘non-dominant’ role in language and behaviour.

Broca’s aphasia arises from a lesion in areas on the left hemisphere and leads to non-fluent speech, agrammatism, paraphasias, anomia, and poor repetition. Lesions anterior, superior, and deep to (but sparing) the Broca area produce abnormal syntax and grammar but repetition and automatic language are preserved. This disorder is known as transcortical motor aphasia and uninhibited echolalia is common. Memory disturbances only develop with lesion extension into the septal nucleus of the basal forebrain. Appreciation of verbal humour is most impaired in right frontal polar pathology243. (See also page 33)

Over the last three decades, however, considerable evidence has accrued to support the thesis that communication functions are distributed between the hemispheres244. The left is primarily concerned with processing the verbal, syntactic, and other language-related functions such as pantomime, pragmatics, denotation, and the linguistic and dialectal aspects of prosody245, while the right is primarily concerned with processing affective

240 Funnell E & Sheridan J. Categories of knowledge? Unfamiliar aspects of Jiving and non-living

things. Cogn Neuropsychol9:135-154, 1992.

241 Stewart F; Parkin AJ & Hunkin NM. Naming impairments following recovery from herpes simplex encephalitis: Category specific? Q J Exp Psychol 44A:261-284, 1992.

242 Farah MJ; McMullen PA & Meyer MM. Can recognition of living things be selectively impaired? Neuropsychologia 29:185-193, 1991.

243 Price, BH; Daffner KR; Stowe RM & Mesulam, MM. The comportmental learning disabilities of early frontal lobe damage. Brain : a journal of neurology, Vol. 113 ( Pt 5) (October 1990), pp. 1383-1393.

244 Ross, ED. The Aprosodias. . In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

245 PROSODY is a non-verbal or supra-segmental feature of language that conveys various levels of information to the listener, including linguistic, affective (attitudinal and emotional), dialectical, and idiosyncratic data. The acoustical features underlying prosody include pitch, intonation, melody, cadence, loudness, timbre, tempo, stress, accent, and pauses. Although

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prosody, gestures, and certain word-related functions such as connotation, thematic inference, and comprehension of non-literal phrases and complex linguistic relations.

In addition, both focal cerebral blood flow and positron emission tomography scanning studies have established an active role for the right hemisphere in language. The most intensively analyzed right hemispheric function has been affective prosody and gestures.

Language and communication are characterized by four major constituents: the lexicon (vocabulary), syntax (grammar), prosody, and kinesics. The segment is the smallest articulated feature of a language, which, in nontechnical terms, is most closely allied with the syllable. Segments, therefore, might be thought of as the primary building blocks for creating the words that form the lexicon. Words, in turn, are concatenated into grammatical relationships to form phrases, sentences, and discourse. It is the segmentally related or verbal-propositional features of language that are primarily disrupted by focal left-brain injury, thus causing aphasic syndromes. Kinesics refers to the limb, body, and facial movements associated with language and communication. (Ross, 1997, idem) Disturbances in the production and comprehension of pantomimal kinesics have been firmly linked to left brain damage. All studies to date have found that disorders of pantomime are almost always due to LBD, resulting in aphasic disturbance.

In case that should tempt one to consider that relationship to MDL’s brain damage and may be puzzled by why MDL’s behaviour seems paradoxical in those respects, it should be remembered that some of her lacks in prosody and kinesics may have arisen because of the very early time in her life when her brain damage occurred and the fact that she did not have the opportunity to learn these important characteristics of language because she lacked the usual interaction with normal children of comparable age. Indeed it is salutary to recognise that when such interaction did take place, through very limited opportunities, other children sensed her difference and, unconsciously perhaps, her communicative immaturity and conducted their communication with her in a selective and elementary manner in much the same way that adults do with toddlers.

Another confounding factor though is that as a child she would sit by her mother as she played the piano and sing songs that she read from the music sheet having picked up the tune by ear. It should also be added that MDL was introduced to the sound of music both instrumental and voice from a very early age; indeed from before her brain damage occurred. It is only since 2004 that MDL’s response to music has changed. Quite often now she does not want to listen to music or song. Music that at one time entertained her and which she enjoyed listening to now frequently produces tears. It is interesting to wonder why.

Adolphs and others tell us that in humans, the emotional reactions that can be triggered by stimuli also play a role in complex aesthetic judgements. Building on lesion studies that have shown dissociations between identifying melodies or recognizing emotion from music246, a recent functional imaging study found that highly emotional music, which resulted in ‘shivers down the spine’ in the listener, activated a set of para-limbic structures including the ventral striatum, amygdala, and orbitofrontal cortex247. Just how to categorize the emotion triggered by such stimuli remains a challenging issue, as it appears

the pre-eminence of the propositional aspects of language is well accepted, developmental studies have established that the earliest building blocks of language are prosodic-intonational rather than verbal-segmental features. As children acquire the verbal-segmental features of language, prosodic phenomena eventually become embedded and carried by the articulatory line.

246 Peretz I. Brain specialization for music. New evidence from congenital amusia. Ann N Y Acad Sci 2001, 930:153-165.

247 Blood AJ & Zatorre RJ. Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion. Proc Natl Acad Sci USA 2001, 98:11818-11823.

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distinct from mere happiness248.

Gestural kinesics has not been well studied neurologically until fairly recently, although occasionally clinical researchers have mentioned that gestural activity may be preserved in aphasic patients.249,250 The first paper to specifically address the possible relationship of gestures to right brain damage and loss of affective prosody was published in 1979 by Ross and Mesulam251. They observed that lesions of the right frontal operculum may cause complete loss of spontaneous gestural activity in the non-paralyzed right face and limbs without any disturbance in praxis. The suggestion was made, therefore, that the gestural behaviour as opposed to pantomime was a dominant function of the right hemisphere. Since then a number of studies have lent further support to this hypothesis by showing that the right hemisphere is specialized not only for producing gestures but also for com-prehending their meaning. (Ross, 1997, idem) MDL does not use gestures to convey meaning nor does she seem to understand any that are made by others.

Gesture can be as affected as language in cases of autism because all the communicative skills are diminished. When evaluating the problems found in autism there are studies showing that language and gesture may be mediated by common neural systems.252 Language and gesture milestones advance together in typical children growing up. It has been shown that there is a close correlation between the first word production and what is called "gestural naming," usually in the 12 to 18 month age group.253 In studies of young autistic children, word production does not begin until recognitory gestures have appeared.254

Further evidence for language-gesture links in early development comes from a study of handedness, which shows a right-hand bias in typical children before they begin to speak; the right-handed bias is greatest for gestures with communicative or symbolic content).255

In infants, linguistic knowledge is not thought to be innate and is not localized in a clear and compact place in the brain, but the infant brain is not a tabula rasa either: it is already highly differentiated at birth, and certain regions are biased from the beginning toward modes of information processing that are particularly useful for language. (Coleman, Idem, 2005) However, if there is a developmental problem, the infant brain is thought to be highly plastic, which permits alternative ‘brain plans’ for language to emerge if the standard situation does not hold.256 Since social interaction with another human being affects speech learning, children with autism are at risk especially if they prefer non-speech signals to "motherese."

Some mute individuals with autism clearly have an oral dyspraxia; they have hypomobile, atrophic tongues, suggestive of cranial nerve involvement. But the neural networks that

248 Adolphs, R. Neural systems for recognizing emotion. Current Opinion in Neurobiology 2002;

Apr; 12(2): 169-77.

249 Critchley M. The Language of Gesture. London: Edward Arnold, 1939.

250 Hughlings-Jackson J. On affections of speech from diseases of the brain. Brain 38:106-174, 1915.

251 Ross ED & Mesulam MM. Dominant language functions of the right hemisphere? Prosody and emotional gesturing. Arch NeuroI36:144-148, 1979.

252 Bates E. & Dick F. Language, gesture and the developing brain. Developmental Psycho-biology 40:293-31: 2002.

253 Coleman, M. Other Neurological Signs & Symptoms in Autism. In, The Neurology of Autism. Mary Coleman [Ed.]. New York, OUP; 2005

254 Happe F. & Frith U. The neuropsychology of autism. Brain 119:1377-1400; 1996.

255 Bates E; O'Connell B; Vaid J; Sledge P & Oakes L. Language and hand preference in early development. Developmental Neuropsychology 2:1-5; 1986.

256 Bates E. Language and the infant brain. Journal of Communication Disorders 32:195205; 1999.

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control speech are difficult to evaluate in mute patients with autism. Perhaps one reason there is so little consistent work is that the circuits underlying vocal control are extremely complex. They consist of essentially three components: laryngeal activity, supralaryngeal (articulatory) activity, and respiratory movements.257

Voluntary control of vocalization, in contrast to involuntary vocal reactions such as shouts of pain, require the forebrain to be intact. The motor neurons controlling vocalization are located in nuclei of the pons, medulla, and ventral horn of the spinal cord and need facilitation and coordination by many additional nuclei ranging from the supplementary motor area of the frontal lobe all the way down to the cerebellum. (Coleman, Idem, 2005)

Although Hughlings-Jackson suggested over a hundred years ago that the right hemisphere may have a dominant role in emotional communication, the first clinical study of affective prosody was published in 1975 by Heilman and co-workers258. They assessed the ability of patients with right and left hemispheric strokes in the posterior sylvian distribution to recognize the affective content of verbally neutral statements that were spoken with various emotional intonations. Right brain-damaged patients were markedly impaired on the task as compared with normals and mildly aphasic left-brain-damaged patients. In a follow-up study, Tucker and colleagues 259 found that right but not left-brain-damaged patients also had great difficulty in inserting affective variation into verbally neutral sentences on request and on a repetition task.

In 1979, Ross and Mesulam (idem) described two patients with infarctions of the right anterior supra-sylvian region verified by computed tomography. Neither patient was aphasic or apraxic, but both complained bitterly of their almost total inability to insert affective variation into their speech and gestural behaviour. Neither patient seemed to have difficulty in perceiving affective displays in others, and both insisted that they could feel and experience emotions inwardly.

Based on these patients and the previous publications by Heilman and associates it was hypothesized that:

1. the right hemisphere was dominant for organizing the affective-prosodic components of language and gestural behaviour and,

2. the functional/anatomic organization of affective language in the right hemisphere was analogous to the organization of propositional language in the left hemisphere. (Ross, 1997, idem)

An issue not resolved however, was whether the prosodic deficits from right brain damage also involved the linguistic aspects of prosody. Subsequent studies have looked more carefully at this issue in both right- and left brain-damaged patients. The composite data indicate that the linguistic features of prosody may be impaired by either right or left brain damage but that the affective components seem to be disrupted exclusively by right brain damage. (Ross, 1997, idem)

MDL has no spontaneous gestural activity; there is a loss of affective prosody in her speech and she does not produce gestures and probably has difficulty comprehending their meaning in most cases.

All prosodic systems and not just affective prosody are modulated by the right brain. 257 Jurgens U. Neural pathways underlying vocal control. Neuroscience Biobehavioral Review

26:235-258; 2002.

258 Heilman KM; Scholes R & Watson RT. Auditoryaffective agnosia: Disturbed comprehension of affective speech. J Neurol Neurosurg Psychiatry 38:69-72,1975.

259 Tucker DM; Watson RT & Heilman KM. Discrimination and evocation of affectively intoned speech in patients with right parietal disease. Neurology 27:947-950, 1977.

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Acquired aprosodias in children260 and developmental disorders of affective prosody associated with aberrant psychosocial development resulting from early right brain dam-age261,262,263 have been reported that are comparable with the syndromes of acquired aphasia in children and developmental dyslexia. However, although others have shown disturbances in the production and comprehension of affective prosody in LBD, it is still generally maintained that it is the dominant function of the right brain.

Ross and colleagues (Idem) added to this affirmation by assessing affective prosody in a series of right-brain-damaged and left-brain-damaged patients using a quantitative testing paradigm in which the verbal-articulatory demands were progressively reduced by using token sentences in which various emotions are carried by words, a repeated monosyllable ("ba ba ba ba ba ba"), and an asyllabic articulation ("aaaaaahhhhhhh"). In the left-brain-damaged patients, reducing the verbal-articulatory load caused statistically robust improvement in their ability to comprehend and produce affective prosody on a repetition task, whereas no improvement occurred in the right-brain-damaged patients. These findings, therefore, sustain the hypothesis that affective prosody is both a dominant and a lateralized function of the right hemisphere and lend strong support to research by Blonder and co-workers (1991, idem) and Bowers and associates (1993, idem) & 264 suggesting loss of affective-communicative representations caused by right brain damage as the theoretical basis for the aprosodias, similar to loss of verbal-syntactic representations caused by left brain damage as the theoretical basis for the aphasias265.

The aprosodias represent disturbances of graded emotional behaviour encompassing both affective prosody and gestures. These behaviours are organized predominantly at the level of the neocortex as part of the language-related systems of communication. (Ross, 1997, idem)

Aspects of Aphasia & Agraphia that affect MDL

Aphasia is a condition characterized by either partial or total loss of the ability to communicate verbally or using written words. A person with aphasia may have difficulty speaking, reading, writing, recognizing the names of objects, or understanding what other people have said. Aphasia is caused by a brain injury, as may occur during a traumatic accident or when the brain is deprived of oxygen during a stroke. It may also be caused by a brain tumour, a disease such as Alzheimer's, or an infection like encephalitis (as in MDL’s case). Aphasia may be temporary or permanent. Aphasia does not include speech impediments caused by loss of muscle control. [Verbal/Speech apraxia is a speech disturbance in which language comprehension and muscle control are retained, but the memory of how to use the muscles to form words is not.

Language comprehension is a complex process that involves the analysis of the acoustic and phonologic properties of input as well as the recognition of syntactic and lexical

260 Bell WL; Davis DL; Morgan-Fisher A & Ross ED. Acquired aprosodias in children. J Child Neurol

5:19-26, 1989.

261 Weintraub S & Mesulam MM. Developmental learning disabilities of the right hemisphere: Emotional, interpersonal, and cognitive components. Arch NeuroI40:463-468, 1983.

262 Manaoch DS; Sandson TA & Weintraub S. The developmental social-emotional processing disorder is associated with right hemisphere abnormalities. Neuropsychiatr Neuropsychol Behav Neurol 8:99-105, 1995.

263 Voeller KKS. Right hemisphere deficit syndrome in children. Am J PsychoI143:1004-1009, 1986.

264 Bowers D; Bauer RM & Heilman KM. The nonverbal affect lexicon: Theoretical perspectives from neuropsychological studies of affect perception. Neuropsychology 7:433-444, 1993.

265 Ross ED; Stark RD & Yenkosky JP. Lateralization of affective prosody in brain and the callosal integration of hemispheric language functions. Brain Lang. 1997; 56:27-54.

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elements. 266 This rapid parallel processing of input and matching it to linguistic precepts is a dominantly left hemispheric function, although the right hemisphere has been shown to recognize words and syntax to a certain degree. 267,268 Wernicke has postulated that the auditory association area plays a monitoring role in language output and that its damage results in paraphasic, faulty speech.

In the past 20 years, fresh interest has come to clinical aphasia research from two directions: modern neuro-imaging and cognitive neurosciences. Together, they have additionally provided tools to carry out aphasia-related language experiments in normal brains. Furthermore, old questions such as cerebral laterality, the influence of handedness, the effects of gender and bilingualism on aphasia, and the mechanisms of recovery have been re-explored. 269

The description of syndromes of aphasia arose out of much the same motivation as the identification of other clinical neurologic syndromes; the need to identify clinically useful associations between specific clusters of signs and the likely anatomy of the lesion producing them. The most clinically transparent signs of aphasia have generally been taken to be independent signs of brain damage. Thus, syndromes have been constructed out of reduced language output as well as impaired comprehension, repetition, and naming. Disorders of written language have been divided into additional syndromes only as reading and writing have been impaired beyond spoken language impairments. Using three independent signs will generate eight syndromes, assuming naming to be impaired in all aphasics. (Alexander idem)

The series of MDL’s preserved handwriting and typing examples show a clear deterioration in her writing since 2004. These problems include not only her ability to write words and sentences but also to do so in straight lines that are evenly written on the page. She cannot draw a straight line or draw a simple shape of an object that is next to her writing paper. Her attempts at drawing presently consists of continuous spiralling circles whatever it is that she has been invited to draw.

She has not been able to use her typewriter since 2004 because of the affects of her experiences since that time. When she was able to do so, her typing was efficient. However, over time she appeared to lose the ability to start a new line appropriately. Prior to that she could copy type very well, and would correct her spelling mistakes by using the back-key, putting a forward slash through the incorrect letter and then typing the correct one.

MDL learned to type at her first school from the age of about five. She had her own typewriter both at school and at home where she was always happy to entertain herself copy-typing from books and magazines. She could also make up very simple stories (one or two line) and type them as she did so.

This ability that has been lost (hopefully temporarily) shows the amount of deterioration over the last few years.

Some areas of aphasia that have affected MDL are:

266 Liebermann AM; Cooper FS; Shankweiler DR & Staddert-Kennedy M. Perception of the speech

code. Psychol Rev 74:431-461,1967.

267 Zaidel E. Auditory vocabulary of the right hemisphere following brain bisection or hemidecortication. Cortex 12:191-211, 1976.

268 Moscovitch M. Right hemisphere language. Top Lang Disord 1:41-61, 1981

269 Alexander, M P. Aphasia: Clinical and Anatomic Aspects. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

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Reduced language output Impaired comprehension Repetition Naming Also; disorders of written language where reading and writing have been impaired beyond the spoken language impairments.

She also seems to have apraxic agraphia — she cannot achieve oral spelling.

For the 10 percent of the population that is left-handed and for the approximately 2 to 5 percent of the right-handed population that becomes aphasic after a right-brain lesion (crossed aphasia), some modifications of the clinical rules are required. (MDL is right-handed and has a right brain lesion.)

For left-handers, the phenomenology of aphasia is complicated by the very issue of left-handedness. More than right-handers, all left-handers are not created equal; they vary greatly in degree and nature of hemispheric specialization for language. For both populations the phenomenology is further complicated by irregularities in lateral dominance for other typically lateralized functions, such as praxis 270 and some aspects of visuo-spatial function.

Broca’s Aphasia Many of the aspects of this condition fit MDL’s reduced communication skills. In Broca's aphasia, language output is non-fluent — that is, it is reduced in phrase length and grammatical complexity. This reduction can range from no recognizable output or repeated meaningless utterances to short, truncated phrases using only the most meaning-laden words (substantives). There is usually considerable hesitation and delay in production. Speech quality is impaired. Articulation is poor (dysarthria271). Melodic line is disrupted (dysprosody 272), partly due to dysarthria but often more than just secondary to it. Volume is usually reduced at first (hypophonia). With time, speech takes on hyperkinetic (dystonic and spastic) qualities. Language comprehension is adequate although rarely normal. Response to word recognition tasks, simple commands, and routine conversation is generally good. Response to multistep commands and complex syntactical requests is generally poor. Repetition is poor, although often better than speech. Relational words (functors — articles, conjunctions, modifiers, etc.) may be produced in repetition, but they are exceedingly uncommon in spontaneous speech. Written language parallels the spoken, although some patients, while never regaining useful speech, develop writing that is telegraphic. Naming is usually poor, but it may be surprisingly good in chronic patients. All types of errors can occur, although semantic errors are most typical for substantive words. 273 Objects are frequently named better than are actions.

Broca's aphasia is commonly accompanied by: bucco-facial apraxia274, and ideomotor apraxia275 of the left arm (or both arms in the non-paretic case). MDL has failings in these

270 Praxis is the process by which a theory, lesson, or skill is enacted, practised, embodied, or

realized. It may also refer to the act of engaging, applying, exercising, realizing, or practising ideas.

271 Dysarthria is a speech disturbance caused by lack of control over the muscles used in speaking, perhaps due to nerve damage, but also it can be caused by the effects of some psychotropic medications.

272 DYSPROSYDY is a change in voice quality that gives rise to a foreign-accent syndrome.

273 Ardila A. & Rosselli M. Language deviations in aphasia: A frequency analysis. Brain Lang 44:165-180, 1993.

274 Buccofacial or orofacial apraxia. Difficulty carrying out movements of the face on demand. For example, an inability to lick one's lips or whistle.

275 Ideomotor Apraxia is a neurological disorder characterized by the inability to correctly imitate hand gestures and voluntarily pantomime tool use, e.g. pretend to brush one's hair.

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areas. Many patients have fractional syndromes of Broca's aphasia. Because all of these fractional disorders are still taxonomically closer to Broca's aphasia than to any of the other seven classic diagnoses, many aphasia systems will classify them all as Broca's aphasia.276

Broca's aphasia has been associated with lesions from several structures outside Broca's area. Involvement of only Broca's area is usually followed by good recovery277. Recovered Broca's aphasics often regain their fluency and syntax, but articulatory and prosodic aspects of language may remain affected and the clinical condition widely known as verbal apraxia continues. 278 (But these relate to late onset injury)

Kertesz et al evaluated lesion location in Broca's aphasics who were divided at the median for poor and good recovery. In both groups, certain structures showed significant involvement (more than 50 percent). These were the inferior frontal gyrus, especially the pars opercularis and triangularis, and the insula. The difference between patients with persisting Broca's aphasia and those who show good recovery was most prominent in the involvement of the pre-central, post-central, and supra-marginal gyri in the cases of poor recovery. The sub-cortical regions showed significant differences in the involvement of the putamen and the caudate, which was twice as frequent in the persistent cases. 279

In analyzing reports of Broca's aphasia, it is crucial to understand the taxonomic rules of the report's assessment tool. If all fractional cases are considered Broca's aphasia, the clinico-anatomic correlations will seem imprecise. This is an example of the difficulty inherent in building syndromes with polytypic qualities. Analysis of the clinico-anatomic relationships within these fractional cases may be much more informative than lumping them all together on the basis of some overlap with the full syndrome. (Alexander idem)

Transcortical Aphasia There is a possibility of MDL having this condition but there is a need for further investigation as the literature seems to be based entirely on a subject population that had normal brain development prior to a trauma.

The syndrome includes the possibility of associated motor deficits depending upon the site of the lesion. Those with cortical or sub-cortical lesions seem to have a fundamental deficit in generative language tasks, i.e. they lack capacity to generate complex syntax when asked an open-ended question. They do not have timely access to the range of syntax needed to answer the question.

Patients with transcortical sensory aphasia who have semantic jargon usually have far more posterior lesions, usually in the watershed area between the middle cerebral and posterior cerebral circulation. 280 These patients are distinguished by preserved repetition. Sometimes the term semantic aphasia is applied to patients with similar behaviour. Recovery is usually rapid unless the syndrome evolves from a more severe lesion initially producing Wernicke's aphasia. Mixed transcortical aphasia has features of both the motor and sensory symptoms and tends to have a poor prognosis, with non-fluency persisting and not all comprehension returning, depending on the aetiology. It occurs relatively

276 Mazzocchi F. & Vignolo LA. Localisation of lesions in aphasia: Clinical-CT scan correlations in

stroke patients. Cortex 15:627-654, 1979.

277 Mohr JP. Broca's area and Broca's aphasia, in Whitaker H, Whitaker HA (eds): Studies in Neu-rolinguistics. New York, Academic Press, 1976, vol 1, pp 201-235.

278 Kertesz A. Aphasia and Associated Disorders: Taxonomy, Localization and Recovery. New York, Grune & Stratton, 1979.

279 Kertesz, A. What do we learn from recovery from aphasia? In Waxman, SG (ed). Advances of Neurol ogy. Functional Recovery in Neurological Disease. New York, Raven Press, 1988, vol 47 , pp 277 -292.

280 Kertesz A; Sheppard A & MacKenzie RA. Localization in transcortical sensory aphasia. Arch Neurol 39:475-478, 1982.

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uncommonly and the recovery patterns have not been described extensively (Kertesz idem).

Most of Alexander’s research was based on information from the investigation of stroke patients but there are some parallels to be drawn in MDL’s case and those of Broca’s and Transcortical Aphasia are the ones that seem most relevant to her behaviour. The only reference to encephalitis is to do with that following herpes simplex and that is not helpful in understanding MDL’s case.

It is important to remember that in MDL’s case:

1. Her age at which her brain damage occurred

2. That her linguistic ability has been much better than it is now and this may well be

due to the effects of further brain damage. (See page 13)

3. That her present linguistic ability is affected by a lack of concentration and

sometimes it seems by tiredness.

It must be remembered that we all perform better in ideal circumstances — even in the things in which we show proficiency. In this context MDL has suffered the trauma of an instantaneous removal from her homes; transferred in her environment to places that are strange; to be cared for by people she did not know. Those conditions are bad enough and will challenge even someone who knows the reasons. Imagine the psychological effect on someone who does not understand why and who cannot ask why because asking requires rationality and an understanding of other people and their motives. MDL has neither of these attributes and she still suffers from the loss of her cultural milieu.

Recovery After Aphasia Kertesz writes on Recovery after Aphasia281 but this relies on subject research with those who already had normal linguistic capability before trauma or other causative incidents. Wernicke282 postulated that much of the recovery from aphasic symptoms is affected by right hemispheric compensation. This of course could not apply in MDL’s case. Subsequently, Henschen283 restated this principle, which was named Henschen's principle. Von Monakow284 formulated his diaschisis theory on observations with aphasics and on the analogy of spinal shock, which was well established by physiologists. He even said: “The temporary nature is one of the most important

characteristics of aphasia”. Diaschisis is an active process by which acute brain damage deprives the surrounding or functionally connected areas from a trophic influence initially causing a more severe deficit than would be expected from the loss of affected area alone. The deprived areas recover by acquiring re-innervation from the original source or a neuron or become active after adapting to the state of partial denervation. (Kertesz idem)

Animal experiments and clinical observations suggested that ‘silent’ areas or structures, not usually involved in the functions that were lost due to a specific structure damaged, take over the function or account for the compensation. This was called vicariation or vicarious functioning by Fritsch and Hitzig285, who observed the recovery of hemiplegia in dogs after removing the motor cortex.

281 Kertesz, A. Recovery After Aphasia. In Feinberg, T E & Farah, M J. Behavioural Neurology and

Neuropsychology. McGraw-Hill, New York, 1997.

282 Wernicke C. Die neueren Arbeiten über Aphasie. Fortschr Med 4:371-377,1886

283 Henschen SE. Klinische und anatomische ßeitrage zur Pathologie des Gehirns. Stockholm, Nordiska Bokhandel, vols 5-7,1920-1922.

284 von Monakow C. Die Lokalisation im Grosshirn und der Abbau der Funktionen durch corticale Herde. Wiesbaden, Bergmann, 1914.

285 Fritsch GT & Hitzig E. Über die elektrische Erregbarkeit des Grosshirns. Archiv Anat Physiol 300-332,1870.

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The CNS is considered as a dynamically organized network capable of substitution and change of function rather than as permanently determined distinct centres. Functional plasticity is quite extensive and reorganization of cerebral networks is evident from converg-ing sources. Nevertheless, there is a finite amount of cortex subserving certain functions, so that, when damaged in humans, permanent deficits result.

There is a prevalent view among speech and rehabilitation specialists showing that younger patients recover better, but the issue of age as a factor in recovery is more complex than it appears on the surface. (See page 2) Age is a major variable in recovery if one takes into consideration the superior recovery rates of immature individuals. This is called the Kennard

principle, after a series of experiments in animals indicating much better recovery in the young. 286 ‘Recovery’ means a return wholly or in part to a previous state.

For MDL, this would be a return to her abilities at the age of nine or ten years at which point in her life, she was most capable.

It is widely accepted that the goal of aphasia rehabilitation is to maximize functional communication skills. There is less agreement on the optimal route to that goal. Speech-language pathologists are exposed to a broad range of approaches and are expected to make informed decisions about the best treatment for an individual patient based on a number of factors (e.g., aetiology, severity, type of aphasia, and so on). They are trained to view aphasia as a complex cognitive/linguistic/communication disorder requiring intervention that addresses the social as well as the linguistic needs of the client 287, 288 in addition to working with patients in a variety of settings (acute care hospitals, rehabilitation units, home care, and outpatient facilities) throughout the phases of recovery.

Differences aside, speech-language pathologists typically perform three basic functions: assessment, treatment, and outcome evaluation. The initial assessment is critical for establishing the diagnosis of aphasia and differentiating it from other neuro-pathologies such as dementia and dysarthria, communicating with other professionals and the patient's family, setting goals, and developing a treatment plan. Following a program of treatment, an outcome evaluation is performed to determine how well the goals have been met. Each of these three functions (assessment, treatment, and outcome evaluation) is carried out at several levels of analysis. It should be remembered that these consideration refer primarily to adult stroke patients, but there is some relevance for MDL.

When a child sustains brain damage, the plasticity of the brain probably allows for almost complete compensation by the homologous hemisphere, whether it is related to a hemi-spherectomy in a young child 289 or childhood aphasia due to other aetiologies. 290 In addition to the plasticity, however, one should also consider that children have different aetiologies, such as infection and trauma, causing a different aphasia from that of strokes.291

Multiple lesions confound the pattern of recovery. Several small lesions produce an accumulating deficit, the sum of which is less than the deficit caused by a single large

286 Kennard MA. Age and other factors in motor recovery from precentral lesions in monkeys. Am

J PhysioI115:138-146,1936.

287 Chapey R. An introduction to language intervention strategies in adult aphasia, in Chapey R (ed): Language Intervention Strategies in Adult Aphasia, 2d ed. Baltimore, MD: Williams & Wilkins, 1986, pp 2-11.

288 Wepman J. Aphasia therapy: Some "relative" comments and some purely personal prejudices, in Sarno M (ed): Aphasia-Selected Readings. New York: Appleton-Century-Crofts, 1972.

289 Basser LS. Hemiplegia of early onset and the faculty of speech with special reference to the effects of hemispherectomy. Brain 85:427-460, 1962.

290 Martins IP & Ferro JM. Recovery of acquired aphasia in children. Aphasiology 6:431-438, 1992.

291 Woods BT & Teuber HL. Changing patterns of childhood aphasia. Ann Neurol 3:273-280, 1978.

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lesion. This has been observed clinically by Dax 292 in the description of recovery from motor aphasia. From the point of view of localization, more complex behaviours are likely to have widespread input and will be affected by lesions in many areas. (Kertesz idem)

The added lesion effect 293 has been studied physiologically in animals and is a model to explain why slowly growing tumours cause so much less deficit than the functional loss of a sudden large lesion. Accumulating lesions avoid the diaschisis effect of a single large lesion. There is often a critical stage when the amount of deficit becomes irreversible. MDL’s injury was said to be ‘sporadic’ and one must therefore accept that she had multiple lesions.

Traumatic aphasia usually recovers well unless it is related to penetrating head injury. 294,295. Persisting dysarthria296 is common in severe trauma, and this often disrupts communication to such a degree that the extent of posttraumatic aphasia is difficult to determine.

It is said that most recovery occurs in the first 2 to 3 months. Recovery curves show an exponential decrease in the 3- to 6-month interval, a 6- to 12- month interval reaching a plateau after 1 year. 297, 298. However, studies have shown some further recovery after one year, even though some of these were only a few patients who improved with treatment. It is impossible to relate these studies to MDL as there wasn’t any diagnosis made of brain injury until some four years after the event. Comparisons with intra-cerebral haemorrhages are also of no help as these often tend to displace tissues rather than to destroy them, in certain parts of the haemorrhage at any rate. Major haemorrhages, on the other hand, are quite destructive, and the patients are less likely to survive because of the intra-ventricular extension or oedema.

These studies that have considered the factors in recovery are researched with patients who have had late onset symptoms; thus none of these are applicable to MDL’s case. That said, and as previously noted, MDL made some recovery from her encephalitis at five months of age but successive life-event traumas have caused a comparable regression to that which might have accompanied a new mal-event for someone who suffered a late onset injury.

Of course we do not know either which areas of her brain were immediately damaged by the vaccination or which areas were affected consequently. Neither do we know how much recovery there was initially, nor how much damage accrued later and whether it was serial damage — nor therefore do we know the sequence. In terms of behaviour however, we know that she acquired a substantial advantage from her education at Pictor House where she attended from 1964 to 1969. We know that when she was forced to leave that school on the grounds of catchment area only, she regressed scholastically and emotionally and her deterioration after recovery can be seen to date from that time.

Agraphia: is traditionally defined as an acquired disorder of writing, although current

292 Dax M. Lesions de la moitie gauche de l'encephale coincidant avec l'oubli des signes de la

pensee (lu a Montpellier en 1836). Gaz Hebd Med Chir 2:259262,1865.

293 Ades HW & Raab DH. Recovery of motor function after two-stage extirpation of area 4 in monkeys. J Neurophysiol 9:55-60, 1946.

294 Kertesz A. & McCabe P. Recovery patterns and prognosis in aphasia. Brain 100:1-18, 1977.

295 Ludlow C; Rosenberg J & Fair C, et al: Brain lesions associated with nonfluent aphasia fifteen years following penetrating head injury. Brain 109:55-80, 1986.

296 Dysarthria — Poor articulation (diction).

297 Poeck K; Huber W & Willmes K. Outcome of intensive language treatment in aphasia. J Speech Hear Disord 54:471-479, 1989.

298 Broida H. Language therapy effects in long term aphasia. Arch Phys Med Rehabil58:248-253, 1977.

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usage also includes disorders of spelling299. Breakdown in writing may occur at any level of production, including the paragraph and sentence level. However, agraphia has typically been studied at the word level. At this level, dysfunction may be the result of either linguistic or motor disturbances. These disturbances may either be unique to the writing or spelling systems (pure agraphia) or more generalized, with associated neuropsychological dysfunction.

Typically, the agraphia is described as being similar to the aphasias300. Therefore, the non-fluent agraphias consist of sparse output with effortful processing and agrammatism, while the fluent agraphias consist of normal output, easy production, and normal sentence length. The non-fluent agraphias are usually associated with clumsy calligraphy and the fluent agraphias with well-formed letters (Benson et al, idem). However, some studies 301 have described patients with Broca's aphasia and noted that their agraphia more closely resembled the agraphia of patients with Wernicke's aphasia than the agraphias of other patients with Broca's aphasia. This reflects the dissociation of aphasia and agraphia first described by Ogle. 302

Agraphia and Confusion The sum of MDL’s brain damage easily includes confusion at certain times. This isn’t delusional confusion nor, of course, the confusion of dementia. It is the confusion that accompanies attempts to unfathom uncertainties when the brain does not have the connections or, is unable to use them, in order to make sense of communication from other people or to interpret environmental situations. This is at its worse when those who are caring for MDL do not understand her disability or how it affects her. MDL senses this uncertainty in others and yet she does not have the communicational abilities to inform the carer how or why they are not connecting with her.

Patients with acute confusional states frequently have agraphia 303. Chedru and Geschwind found agraphia in 33 of 34 cases of acute confusion. Their patients had disruption of linguistic performance with spelling and syntactical disturbances. They also had motor impairment and spatial impairment with poorly formed and improperly placed letters.

Semantic Agraphia Semantic agraphia is due to a disruption of semantic influence on spelling output304. Patients with this disorder have trouble incorporating meaning into spelling and writing.305,306 The error made by these patients is most commonly that of homophone confusions, such as writing knight when asked to write night, as in “The moon comes out at night”. Lesion sites associated with semantic agraphia include those

299 Roeltgen, DP. Agraphia. In Feinberg, T E & Farah, M J. Behavioural Neurology and


300 Benson DF & Cummings JL. Agraphia, in Vinken PJ; Bruyn GW; Klawans HL & Frederiks JAM (eds): Clinical Neuropsychology. New York: Elsevier, 1985, vol 45, pp 457-472.

301 Roeltgen DP & Heilman KM. Review of agraphia and proposal for an anatomically-based neuropsychological model of writing. Appl Psycho ling 6:205230,1985.

302 Ogle JW. Aphasia and agraphia. Report of the Medical Research Counsel of St. George's Hospital (London) 2:83-122, 1867.

303 Chedru F. & Geschwind N. Writing disturbances in acute confusional states. Neuropsychologica 10: 343-354, 1972.

304 Rothi LJG; Roeltgen DP & Kooistra CA. Isolated lexical agraphia in a right-handed patient with a posterior lesion of the right cerebral hemisphere. Brain Lang 30:181-190,1987.

305 Patterson K. Lexical but nonsemantic spelling? Cogn Neuropsychol 3:341-367, 1986.

306 Rapcsak SZ & Rubens AB. Disruption of semantic influence on writing following a left prefrontal lesion. Brain Lang 38:334-344, 1990.

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regions typically associated with trans-cortical aphasias with impaired comprehension.307,308

To have a clear view of the complicated semantics of language that most of us develop without too much trouble but that creates difficulties for those with semantic aphasia see: http://ocw.nctu.edu.tw/course/syntax/W3III.pdf

____________

TABLE FOUR

Agraphia & Aphasia: their connections

1. NON-FLUENT AGRAPHIA

A) Agraphia and Broca's aphasia 309,310

i) Poor grapheme production

ii) Agrammatism

B) Agraphia and trans-cortical motor aphasia 311

2. FLUENT AGRAPHIA

A) Agraphia and conduction aphasia (Marcie et al, Idem)

B) Agraphia and Wernicke's aphasia (Marcie et al, Idem & Kaplan et al, idem)

C) Agraphia and anomia (Benson et al, idem)

____________

Agraphia and Praxic or Spatial Disturbances Apraxic agraphia is described

as difficulty in writing letters, writing spontaneously, and writing to dictation 312,313,314,315 . Copying or oral spelling are usually less impaired. Patients affected by this syndrome are usually able to type or use anagram letters. The lesions causing apraxic agraphia are usually in the parietal lobe, especially the superior parietal lobule19 opposite the preferred

307 Roeltgen DP & Rapcsak SZ. Acquired disorders of writing and spelling, in Blanken G, Dittmann

J, Grimm H (eds): Linguistic Disorders and Pathologies: An International Handbook. Berlin: De Gruyter, 1993, pp 262-278.

308 Hatfield FM. & Patterson KE. Phonological spelling. Q J Exp PsychoI 35A:451-468, 1983.

309 Marcie P & Hecaen H. Agraphia, in Heilman KM, Valenstein E. (eds): Clinical Neuropsychology. New York: Oxford University Press, 1979, pp 92-127.

310 Kaplan E & Goodglass H. Aphasia-related disorders, in Sarno MT (ed): Acquired Aphasia. New York: Academic Press, 1981, pp 303-325.

311 Rubens AB. Transcortical motor aphasia, in Whitaker H, Whitaker HA (eds): Studies in Neuro-linguistics. New York: Academic Press, 1976, vol 1, pp 293-303.

312 Roeltgen DP. Agraphia, in Heilman KM, Valenstein E (eds): Clinical Neuropsychology. 3d ed. New York: Oxford University Press, 1993, pp 63-89.

313 Marcie P & Hecaen H. 1979, idem

314 Hecaen H. & Albert ML. Human Neuropsychology. New York: Wiley, 1978.

315 Leischner A. The agraphias, in Vinken PJ, Bruyn GW (eds): Disorders of Speech, Perception and Symbolic Behavior. Amsterdam: North-Holland, 1969, pp 141-180.

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hand (dominant parietal lobe). In contrast, lesions in the parietal lobe ipsilateral316 to the preferred hand (non dominant parietal lobe) are traditionally associated with spatial agraphia. Patients with this disorder typically duplicate strokes and have spatial disturbances in their writing. This includes trouble writing on a horizontal line and writing only on the right side of the paper. It is frequently associated with the neglect syndrome. 317 With spatial agraphia, there may also be letter omissions or additions within orthographic groupings (e.g., syllables or morphologic units).

Acalculia Acalculia is defined as an impairment of the ability to calculate. It is used interchangeably with the term dyscalculia, although some authors have suggested reserving the term acalculia for a complete inability to calculate and using the term dyscalculia in cases where some ability to calculate remains. Here, the use the term acalculia refers to both forms of impairment.

Acalculia is a frequently appearing deficit following damage to the left posterior region of the brain, but it can occur following damage to other brain regions. It is a significant functional deficit for patients, since it may restrict their ability to engage in financial activities. It is also an opportunity for clinical researchers interested in the organization of cognitive architectures, response execution, lexical-semantic stores, and the cooperation between fact-based and analogue-scaled cognitive processes to study these processes within the context of a relatively narrow domain of knowledge.

The condition is a common developmental disorder and is a frequent concomitant of acute and progressive left posterior hemispheric lesions in children and adults. It can affect a patient’s ability to balance a cheque book, make change, use a temperature gauge, etc. Clinically, it is important as it allows for the assessment of number processing and calculation.

Studying number processing and calculation in acalculic patients can also show the cognitive architecture and computational demands of a relatively encapsulated cognitive function by revealing patterns of spared and impaired abilities across individual patients. Given that numbers and calculation represent a relatively closed information processing system with a limited number of rules and symbols, it makes for an ideal domain of study. (Rhawn, idem)

There are a number of general classification schemes for describing forms of acalculia, which have divided acalculia into three broad types; 318

� Type 1 is a secondary form of acalculia due to deficits in verbal processing.

� Type 2 is also a secondary form of acalculia and is due to deficits in visuo-spatial processing.

� Type 3 is the primary form of acalculia; which is independent of (but may coexist with) any other cognitive deficit.

A primary acalculia has been described in individual cases and made up approximately 6 percent of acalculic patients with right-hemispheric lesions and 23 percent of acalculic

316 IPSILATERAL Being on the same side of the body as the brain injury; the converse is

CONTRALATERAL.

317 Roeltgen, DP. Agraphia. In In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

318 Levin HS; Goldstein FC & Spiers P A. Acalculia, in Heilman K, Valenstein E (eds): Clinical Neuropsychology. New York, Oxford University Press, 1993, pp 91-118.

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patients with left-hemispheric lesions. 319

Acalculia is often associated with other cognitive impairment by virtue of the location of the lesions that cause primary acalculia and because of the relationship of the domain-specific calculation procedures to other cognitive processes.

Finger agnosia (See below p. 60), agraphia, and right-left discrimination are frequently observed together with acalculia following left posterior cortical lesions, but each symptom may occur as frequently with other symptoms. This tetrad of symptoms is known collectively as the Gerstmann syndrome, and its appearance has been associated with lesions of the left angular gyrus.320,321

Other symptoms associated with primary acalculia have included alexia322,323, visuo-spatial deficits, and conduction aphasia. On-line serial calculations may involve working memory processes. Thus, a breakdown in serial calculation (as opposed to simple fact retrieval) may be associated with a general deficit in working memory, word fluency, or planning. [See section on ‘Cognition and Working Memory’ below, page 108]

The Gerstmann syndrome symptom collection at first may seem like the odd quartet. Odd, that is, until it is remembered that pre-literate calculation depended upon counting, numerosity, and magnitude estimation. Since counting often relied upon fingers, with fingers on different hands representing different quantities, it should not be completely surprising that calculation, finger recognition, left-right discrimination, and writing ability could all be impaired following an angular gyrus lesion.

The angular gyrus is located within the inferior parietal lobe of the brain. Developmentally, of all cortical regions, the inferior parietal lobule is one of the last to mature both functionally and anatomically. Hence, many capacities mediated by this area (e.g. reading, calculation, the performance of reversible operations in space) are late to develop appearing between the ages of 5-8 years. 324 It will be seen therefore that with such a late development of that area, MDL’s brain damage can have interfered with the development and maturation of it.

MDL has at times been able to ‘count’ from one to ten but this may be purely an exercise in memory and she is unable to use numbers for any form of calculation. Even when she was able to recite this sequence she would not have been able to use any of the individual numbers in a simple calculation. She may possibly at best have been able to say, for instance, what comes after eight and be able to say nine. However she would not be able to give you an answer to the question what is one plus one or two minus one. She would not understand what plus and minus meant and how to apply those in a calculation. She has no idea of monetary value and at the present time if she is asked how much an item is worth she will always say, “one money”. She knows what money is and she knows that we exchange money for goods but she has no idea of the concept of monetary value or worth.

319 Grafman, J. & Rickard, T. Acalculia. In Feinberg, T E & Farah, M J. Behavioural Neurology

and Neuropsychology. McGraw-Hill, New York, 1997.

320 Mazzoni M; Pardossi L. & Cantini R, et al: Gerstmann syndrome: A case report. Cortex 26:459-467, 1990.

321 Moore MR; Saver JL; Johnson KA. & Romero JA. Right parietal stroke with Gerstmann's syndrome: Appearance on computed tomography, magnetic resonance imaging, and single-photon emission computed tomography. Arch Neurol 48:432-435, 1991.

322 Alexia (acquired dyslexia) occurs when damage to the brain causes a patient to lose the ability to read. It is also called word blindness, text blindness or visual aphasia.

323 Damasio, Antonio R. Varieties and Significance of the Alexias. Archieves of Neurology 34 (6): 325–326; 1977.

324 Rhawn, JR. Neuropsychiatry, Neuropsychology, Clinical Neuroscience. Academic Press, New York, 2000.

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She also has little or no understanding of the calendar or periods of time. Thus, if you tell her something is happening next week she will have no idea of the practical use of that information. Even the days of the week present a challenge to her. She does not know the sequence of days in a week and a particular day will only have significance if something important for her happens as a regular occurrence on that day.

Primary acalculia can take the form of either global or selective deficits in a large number of number processing and calculation abilities. A large number of studies have implicated left posterior lesions in primary acalculia, most often in the vicinity of the left angular and supra-marginal gyri. 325 In particular, the evidence suggests that arithmetic facts and calculation procedures are preferentially stored in that brain region. Despite the strong association of acalculia and left posterior quadrant lesions, there are certain characteristics of acalculia that have led to the suggestion of a right-hemispheric contribution.

The overwhelming evidence suggests that arithmetic facts and calculation procedures are stored in the left parietal cortex. However, a contribution of frontal lobe 326 and right parietal processes is also implicated. A more precise delineation of these contributions awaits further investigation. (Grafman, et al, idem)

_______

Disorders of Skilled Movements, Perception and Awareness

Apraxia is an inability to correctly perform learned skilled movements. In part, it is defined by what it is not. 327 Patients with impaired motor performance induced by weakness, sensory loss, tremors, dystonia, chorea, ballismus, athetosis, myoclonus, ataxia, and seizures are not considered apraxic. Patients with severe cognitive, memory, motiva-tional, and attentional disorders may have difficulty performing skilled motor acts because they cannot comprehend, cooperate, remember, or attend, but these deficits are also not considered apraxic. 328

Limb apraxia may be the most frequently unrecognized behavioural disorder associated with cerebral disease. Apraxia may go unrecognized as many physicians and other health professionals do not test for limb apraxia and are not aware of the nature of errors that are associated with it or that it may be a disabling disorder. (Heilman et al, idem)

The subtypes of limb apraxia are defined by the nature of errors made by the patient and the means by which these errors are elicited. Lipmann329 subdivided limb apraxic disorders into three types:

• melokinetic ( or limb-kinetic), • ideomotor, and • ideational

In addition there are three additional forms of apraxia:

• disassociation apraxia,

325 Grafman, J & Rickard, T. Acalculia. In Feinberg, T E & Farah, M J. Behavioural Neurology and


326 Tohgi H; Saitoh K & Takahashi S, et al: Agraphia and acalculia after a left prefrontal (F1, F2) infarction. J Neurol Neurosurg Psychiatry 58:629-632, 1995.

327 Geschwind N. Disconnection syndromes in animals and man. Brain 88:237-294, 585-644, 1965.

328 Heilman, KM; Watson, RT & Rothi, LG. Disorders of Skilled Movements: Limb Apraxia . In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

329 Liepmann H. Apraxia. Erbgn Ges Med 1:516543,1920.

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• conduction apraxia, and • conceptual apraxia.

The apraxias are differentiated by the types of errors made by the patient and the means by which these errors are elicited. (Heilman et al, idem)

Apraxia Testing The physician must perform a thorough neurologic examination to be certain that abnormal performance is not induced by the non apraxic motor, sensory, or cognitive disorders mentioned above. The presence of elemental motor defects does not prohibit apraxia testing; however, the examiner must interpret the results with the knowledge gained from the neurologic examination. (Heilman et al, idem)

Both the right and left arm and hands should be tested independently. Patients should be requested to pantomime to verbal command (e.g., “Show me how you would use a pair of scissors”). All patients should also be asked to imitate the examiner’s motor acts. The examiner may want to perform both meaningful and meaningless gestures for the patient to imitate.

Independent of the results of the pantomime and imitation tests, the patient should be given actual objects and tools and asked to demonstrate how to use the tool or object. One should test transitive movements (i.e., using a tool or instrument) and intransitive movements (i.e., communicative gestures not using tools, such as waving good-bye). When having a patient pantomime, in addition to giving verbal commands, the examiner may also want to show the patient a tool or a picture of the tool or object that the patient is required to pantomime. It may be valuable to see if the patient can recognize transitive and intransitive pantomimes performed by the examiner and discriminate between those that are well and poorly performed. The patient should be given a task that requires several motor acts in sequence. Last, one may want to learn if the patient knows what tools operate on what objects (e.g., hammer and nail), what action is associated with each tool or object, and how to fabricate tools to solve mechanical problems.

In limb kinetic apraxia, there is a loss of the ability to make finely graded, precise, individual finger movements. Limb kinetic apraxia occurs in the limb contra-lateral to a hemispheric lesion. This is confirmed by Heilman et al:

“Whereas in right-handed individuals, ideomotor apraxia (IMA) is almost always associated with left-hemisphere lesions, in left-handers IMA is usually associated with right-hemisphere lesions. Ideomotor apraxia can be induced by lesions in a variety of structures, including the corpus callosum, the inferior parietal lobe, and the supplementary motor area. IMA has also been reported with sub-cortical lesions that involve basal ganglia and white matter.” (Idem)

It is unlikely that MDL would be able to complete these tests and therefore it must be a possibility that she has some level of apraxia. However, it must also be considered if MDL’s apraxia is brought about through other neurological damage as she cannot perform these tests with either limb.

The Agnosias

This condition relates to disturbances of the recognition of objects (agnosia) and faces (prosopagnosia). Freud introduced the term agnosia but he used it to describe damage that affected previously learned knowledge.

The first studies of the neuropsychological deficits relating to object recognition were carried out at the end of the 19th century, and their current classification still uses the

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terminology introduced by Lissauer330 and Freud331 .

Lissauer proposed distinguishing the deficits affecting the ability to discriminate stimuli and perceive consciously from those affecting the ability to interpret what is seen. These two subtypes were respectively defined apperceptive and associative ‘mental blindness’. However, the concept of mental blindness was very generic and based on theoretical data rather than empirical observations. It consisted of a broad group of disturbances, including the ability to distinguish colours and identify differences between new shapes and models, as well as specific disturbances relating to the perception of objects.

Lissauer described a patient (Gottlieb L.) who made mistakes in identifying everyday objects. He appeared confused when he tried using cutlery to eat and had difficulty in dressing himself, but was able to copy drawings and showed no signs of any intellectual deficit. According to Lissauer, this was an example of associative blindness. However, the descriptions of apperceptive disturbances were rather vague, being seen more as a prerequisite for the onset of other disturbances than as a specific deficit in itself.

Apperceptive agnosia One might wonder whether apperceptive agnosics should be considered agnosics at all, given that the definition of agnosia above excludes patients whose problems are caused by elementary visual impairments. The difference between apperceptive agnosics and patients who fall outside of the exclusionary criteria for agnosia is that the former have relatively good acuity, brightness discrimination, colour vision, and other so-called elementary visual capabilities. Despite these capabilities, their perception of shape is markedly abnormal.

Recognition of real objects may be somewhat better than recognition of geometric shapes, although this appears to be due to the availability of cues such as size and surface properties such as colour, texture, and specularity rather than object shape. In most cases of apperceptive agnosia, the brain damage is diffuse.

Some authors have used the term apperceptive agnosia for other, quite different types of visual disorders, including two forms of simultanagnosia and an impairment in recognizing objects from unusual views or under unusual lighting conditions. Simultanagnosia is a term used to describe an impairment in perception of multi-element or multi-part visual displays. When shown a complex picture with multiple objects or people, simulanagnostics typically describe them in a piecemeal manner, sometimes omitting much of the material entirely and therefore failing to interpret the overall nature of the scene being depicted. MDL quite definitely has these characteristics.

The greatest difficulty in terms of diagnosis is to determine the limits of the alterations in primary visual functions that are compatible with a picture of agnosia. In order to be able to speak of a selective perceptual deficit, it is necessary to demonstrate the existence of sufficient sensory visual capacities; consequently, visual field, visual acuity, and the discrimination of colours and depth must all be normal — [In MDL, these are normal].

Patients with apperceptive agnosia fail at object recognition tasks because they are unable to organize sensory data into the structured perceptual units that make it possible to reconstruct their shape and so recognize them. The tests at which they are deficient are those requiring the recognition of objects seen from an untypical angle, the identification of a particular figure mixed with others in an overlapping complex, the matching of identical drawings of different sizes, and the copying of drawings. [These deficiencies are all evident in MDL.]

The lesion responsible for apperceptive agnosia generally involves the right parietal lobe. Studies have shown that patients with right posterior lesions are capable of performing

330 Lissauer, H. (1890): Ein Fall von Seelenblindheit nebst einem Beitrag zur Theorie derselben.

Archiv Psychiatrie, 21, 222-270. Translated into English and reprinted In: Lissauer on agnosia. Cognitive neuropsychology (1988), vol. 5, ed. M. Jackson, pp. 155-192.

331 Freud, S. Zur Auffassung der Aphasien. Vienna: Deuticke; 1891.

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shape discrimination tests within the limits of normal levels, but are severely impaired when it comes to tests involving unconventional perspectives and incomplete figures332 .

The first interpretation of apperceptive agnosia was made by Warrington & James333, who defined it as a disturbance of the perceptive categorization that makes it possible to provide a structural definition of objects (i.e. their distinctive elements and the spatial relationships between them). This definition is based on Marr's object recognition computational model.334,335.

It should be noted that there can be great difficulty in testing MDL for apperceptive agnosia because the parts of her brain that are not damaged may be under-developed and she cannot use them effectively to compensate for permanent loss. However, the more obvious deficiencies are noted above (bold).

Associative agnosia One can speak of associative agnosia when it is possible for patients to analyse and integrate the perceptive structure of the stimulus, and when there are no alterations in its internal representation. A pure deficit of this type is quite rare.

Associative agnosia has been explained in three different ways that suggest different answers to the question — is associative agnosia a problem with perception, memory, or both? The simplest way to explain agnosia is by a disconnection between visual representations and other brain centres responsible for language or memory. For example, Geschwind 336 proposed that associative agnosia is a visual-verbal disconnection. This hypothesis accounts well for agnosics' impaired naming of visual stimuli, but it cannot account for their inability to convey recognition non-verbally and may therefore be more suited to explaining optic aphasia, a form of anomia limited to an impaired naming of

visual stimuli. Associative agnosia has also been explained as a disconnection between visual representations and medial temporal memory centres.337 However, this would account for a modality-specific impairment in new learning, not the inability to access old knowledge through vision.338

The inadequacies of the disconnection accounts lead us to consider theories of associative agnosia in which some component of perception and/or memory has been damaged. Perhaps the most widely accepted account of associative agnosia is that stored visual memory representations have been damaged. According to this type of account, stimuli can be processed perceptually up to some end-state visual representation, which would normally be matched against stored visual representations. In associative agnosia, the stored representations are no longer available and recognition therefore fails. Note that an assumption of this account is that two identical tokens of the object representation normally exist, one derived from the stimulus and one stored in memory, and that these are compared in the same way as a database might be searched in a present-day computer. This account is not directly disconfirmed by any of the available evidence. However, there are some reasons to question it and to suspect that subtle impairments in perception may

332 Warrington, E.K. & Taylor, A.M. The contribution of the right parietal lobe to object

recognition. Cortex 9, 152-164; 1973.

333 Warrington, E.K. & James, M. Visual apperceptive agnosia: a clinico-anatomical study. Cortex 24, 13-32; 1988.

334 Marr, D. Visual information processing: The structure and creation of visual representation. Phil. Trans. Roy. Soc. (Lond.), B290, 199-218; 1980.

335 Marr, D. Vision. San Francisco: W.H. Freeman; 1982.

336 Geschwind N. Disconnexion syndromes in animals and man: Part II. Brain 88:585-645, 1965.

337 Albert ML; Soffer D; Silverberg R & Reches A. The anatomic basis of visual agnosia. Neurology 29:876- 879, 1979.

338 Farah, MJ & Feinberg, TE. Visual Object Agnosia. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

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underlie associative agnosia. (Farah et al Idem) MDL has problems in these areas. The tests that patients with associative agnosia fail to complete successfully are those requiring knowledge of an object's functional and semantic characteristics. As a consequence, there may be many semantic errors in a visual denomination task, considerable difficulties in a test involving semantic categorization (grouping stimuli belonging to the same category, selecting those figures from a group that have close associative links, etc.), and difficulties relating to semantic attributes that are not present in the figure itself (e.g. when a black and white drawing of a horse is presented and the subject is asked questions such as:

Is it an animal?

Is it dangerous?

Does it live at home? etc.).

Because of MDL’s multiple sites of brain damage she would probably not answer the second two of these questions. It would be better in her case if the questions were:

What is in this picture?

Where does it live?

What does it eat?

MDL can recognise familiar things which late onset associative agnosia patients may not be able to. For instance she will recognize:

a tea pot

a sugar bowl (if it has sugar in it)

She will also recognize a towel and not call it a face cloth or a handkerchief. However, she will not know a hand towel from a tea towel (unless over a long period of time she can associate the colours or patterns if they remained consistent).

The lesion responsible for associative agnosia is generally circumscribed to the occipito-temporal regions of the left hemisphere.

According to the model of Humphreys & Riddoch339, associative agnosia consists of an inability to connect the output of a perceptive analysis made at the stage of object recognition with a more general underlying knowledge.

One interesting aspect emerging from the study of Sartori & Job340 is the possibility that agnosic disturbances may be limited to only some semantic categories. The patients they described presented a deficit in the recognition of stimuli belonging to the category of foods and living things (animals, fruit and vegetables), but not in relation to non-living objects (clothes, furniture and means of transport). The opposite disturbance has also been observed341, although it is much rarer. The existence of a dual dissociation suggests that the information relating to the two semantic categories is processed in a different manner. Humphreys & Riddoch342 sustain that the greatest difficulties encountered by patients with associative agnosia for the categories of living things can be explained by the fact that their greater perceptive similarity requires a more profound analysis. However, although this

339 Humphreys, G.W. & Riddoch, M.J. The fractionation of visual agnosia. In: Visual object

processing: a cognitive approach, eds. G.W. Humphreys & M.J. Riddoch. London: Erlbaum; 1987.

340 Sartori, G. & Job, R. : The oyster with four legs: a neuropsychological study of the interaction of visual and semantic information. Cognitive Neuropsychol. 5,677-709; 1988.

341 Warrington, E.K. & McCarthy, R.A. Categories of knowledge: further fractionation and an attempted integration. Brain 110,1273-1296; 1987.

342 Humphreys, G.W. & Riddoch, M.J. Object agnosias. In: Clinical neurology: international practice and research, ed. C. Kennard. London: Bailliere Tindall; 1993.

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interpretation is capable of explaining the behaviour of patients with a specific deficit in the structural knowledge of objects, in the case of those in which the disturbance affects the semantic store, it is necessary to hypothesize that the impairment lies exclusively at the level of semantic knowledge and is manifested regardless of whether the stimulus is presented visually or verbally.343

Prosopagnosia The term prosopagnosia, which was coined by Bodamer 344, refers to the inability to recognize the faces of known people, whose identification is preserved when it can be based on acoustic information (the voice) or non-physiognomic visual stimuli (the way of walking or dressing, or postural stance). It is also known as facial agnosia or face blindness.

Until recently, it was thought that very few people suffered from prosopagnosia. The condition has traditionally been studied in individuals who acquire the disorder following neurological damage (typically from stroke or head injury), and a handful of case studies were reported in the literature in the 20th century. However, it has recently become clear that many more people suffer from prosopagnosia without experiencing neurological damage. This form of the disorder is commonly referred to as ‘developmental’ or ‘congenital’ prosopagnosia and these individuals simply fail to develop normal face processing abilities despite normal intellectual and perceptual functions. Developmental Prosopagnosics have suffered from the face recognition impairment for most of their lives, perhaps since birth. Recent evidence suggests there may be a genetic contribution to developmental prosopagnosia, and several case studies report at least one first-degree relative who also suffers from the face recognition impairment.

MDL can recognise familiar faces but cannot always remember their name. She has greater difficulty in recognising faces from photographs. In her case it is not a genetic condition as suggested above for some sufferers. However, because of her brain damage there has probably been a lack of development or a failure in neurological connections that contribute to her particular disability in this area.

The ascendancy of the right over the left hemisphere in processing faces is beyond question, having been confirmed by many normal and clinical studies. What is a matter of debate is whether this asymmetry of function is so marked as to cause the inability to recognize familiar faces following a lesion confined to the right side or if bilateral damage is necessary to produce this result. 345

Bodamer 346 was cautious in drawing anatomic inferences from his cases, since they lacked autopsy, but he remarked that both showed evidence of bilateral lesions. Fifteen years later, a review of the available clinical cases 347 emphasized the presence in a substantial proportion of them of left visual field defects, a sign pointing to right brain damage.

It was speculated that damage to this side played a crucial role in causing prosopagnosia. Although this paper was very influential in drawing attention to the possible specialization of the right hemisphere in face processing, its relevance to the anatomic basis of prosopagnosia was questioned by a subsequent review focusing on case reports with

343 Silveri, M.C. & Gainotti, G. Interaction between vision and language in category specific

impairment. Cognitive Neuropsychol. 5,677-709; 1988.

344 Bodamer, J. Die Prosopagnosie. Archiv fUr Psychiatrie und Nervenkrankheiten 179, 6-53; 1947.

345 Renzi, E de. Prosopagnosia. . In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

346 Bodamer J. Die Prosopagnosie. Arch Psychiatr Nervenkrank 179:6-53, 1947.

347 Hecaen H & Angelergues R. Agnosia for faces (prosopagnosia). Arch NeuroI7:92-100, 1962.

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necroscopy documentation 348, which pointed out that all of the patients had bilateral damage. New pathologic studies 349,350 corroborated this finding. Although Meadows (idem) was cautious in drawing definite conclusions from his review of the literature — since there were also a few patients in whom surgery had shown a disease confined to the right hemisphere and in some bilateral cases the left lesion was located in areas having no relation to the processing of visual information — the view that bilateral damage is a necessary condition for the occurrence of Prosopagnosia 351 gained overwhelming consensus. Yet the exceptions to the ‘bilaterality of damage’ rule remarkably increased with the introduction of neuro-imaging procedures, which made it possible to localize the lesion in a much greater number of patients.

It must be stressed that while this source of information cannot compete with autopsy in terms of accuracy of localization, it has the great advantage of being available in practically every prosopagnosic, not only in those that come to autopsy (which may represent a biased sample) and that is available at the same time testing is carried out. A review of the pertinent literature published up to 1992 352 brought out 27 patients with evidence on computed tomography (CT) or magnetic resonance imaging (MRI) — complemented in five cases by positron emission tomography (PET) — of damage restricted to the right hemisphere, plus three cases with surgical documentation and one following right hemi-spherectomy.

The pendulum is, therefore, shifting again toward the ‘unilaterality of lesion’ thesis, to the effect that damage to the right brain may be sufficient to cause prosopagnosia. In face recognition there is a dimension showing a wide range of functional variation in humans, such that only a minority of them have these skills preponderantly represented in the right brain.

Developmental agnosia Very few studies refer to agnosic disturbances during the age of development, but it is not clear whether this is due to a tendency to neglect or misclassify this type of deficit, or the fact that it is really a rare condition. In 1968, Gordon reported the cases of two children affected by epileptic seizures who had difficulties in recognizing objects353 .

The first seems to be compatible with the description of simultanagnosia in adults: the child presented occipito-temporal EEG abnormalities and performed a recognition task adequately if the figures were presented individually, but not if more than one figure was presented at the same time. The other child presented bilateral occipital EEG abnormalities and had difficulty in recognizing large objects. However, neither of these cases seems to be a convincing example of object agnosia.

As far as face recognition is concerned, a large number of studies have described the development of this ability and the disturbances that may be encountered during the age of development.

348 Meadows IC. The anatomical basis of prosopagnosia. J Neurol Neurosurg Psychiatry 37:489-

501, 1974.

349 Cohn R; Neumann MA & Wood DI. Prosopagnosia: A clinicopathological study. Ann Neural 1:177182, 1977.

350 Nardelli E; Buonanno F & Coccia G, et al: Prosopagnosia: Report of four cases. Eur Neural

21:289297, 1982.

351 Desimone R. Face-selectivity cells in the temporal cortex of monkeys. J Cogn Neurosci 3:1-8, 1991

352 De Renzi E; Perani D & Carlesimo GA, et al. Prosopagnosia can be associated with damage confined to the right hemisphere: An MRI and PET study and a review of the literature. Neuropsychologia 32:893-902, 1994.

353 Gordon, N. Visual agnosia in childhood: VI. Preliminary communication. Dev. Med. Child Neurol. 10, 377-379; 1968.

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Many of them have demonstrated that new-born infants show a preference for faces over any other type of visual stimulus within the first few minutes of being born, which suggests that they already have some structural information available concerning facial characteristics. This information probably forms part of a primitive (hard-wired) system; this will relate to another theory that suggests that there is a region located around the upper temporal sulcus of the right hemisphere that is genetically programmed to process faces.

Any damage or dysfunction in this area at birth or before could give rise to prosopagnosia in children. Face recognition seems to become a specialization of the right hemisphere as early as four months after birth. 354

This could mean that there was a start being made towards face recognition before MDL’s brain damage.

Finger Agnosia In 1930, the Austrian neurologist Josef Gerstmann observed in a few patients a concomitant impairment in discriminating their own fingers, writing by hand, distinguishing left from right and performing calculations. He claimed that this tetrad of symptoms constituted a syndromal entity and assigned it to a lesion of the dominant parietal lobe and suggested that it was due to damage of a common functional denominator. Ever since, these claims have been debated and an astute synopsis and sceptical discussion was presented in 1966 by MacDonald Critchley in his William Gowers lecture.355 In opening his lecture he gave an account of the patient described by Josef Gerstmann356 , who— amongst other deficits— is unable to name her fingers and identify her own or the examiner’s individual digits on request.

Gerstmann called this symptom ‘finger-agnosia’ which Critchley considered to be ‘an ill-chosen expression’. In 1927, Gerstmann described two new cases and proposed that difficulty with writing forms part of the emerging syndrome. Further observations add yet more phenomena and, by 1930, the descriptive tetrad is complete: ‘Gerstmann’s syndrome’ now consists of finger-agnosia, dysgraphia, dyscalculia and right–left disorientation; and it localizes to the left angular gyrus — a region assumed by Gowers to be a higher visual centre. (Compston, Idem)

Nonetheless, Gerstmann's syndrome has continued to intrigue both clinical neurologists and researchers in neuropsychology, and more frequently than not is described in textbooks as an example of parietal lobe damage. Benton has revisited the chequered history of this syndrome, which can be seen as a case study of the dialectic evolution of concepts in neuropsychology. In light of several modern era findings of pure cases he conclude that it is legitimate to label the conjunction of symptoms first described by Gerstmann as a ‘syndrome’, but that it is very unlikely that damage to the same population of cortical neurons should account for all of the four symptoms. Instead, he proposed that a pure form of Gerstmann's syndrome might arise from disconnection, via a lesion, to separate but co-localized fibre tracts in the subcortical parietal white matter, a hypothesis for which he has recently provided evidence using combined imaging of functional and structural organization in the healthy brain. This has previously been described as part of the ‘Gerstmann syndrome’ 357, which is a combination of finger agnosia with right-left con-

354 Riva, D; Saletti, V; & Nichelli, F. The organization of memory in temporo-mesial structures in

developmental age. In, Riva, D; & Benton, A. Localization of Brain Lesions and Developmental Functions. John Libby, London; 2000.

355 Compston, A. The enigma of Gerstmann’s syndrome (The William Gowers lecture delivered on 2 December 1965). By Macdonald Critchley. [Brain 1966: 89; 183–198]; Brain 133 (2): 314-316; 2010.

356 Writing from Vienna in 1924 (Wiener Klinische Wochenschrift 1924: 37; 1010–1012).

357 Gerstmann J. Zur Symptomatologie der Hirnliisio· nen im Obergangsgebiet der unteren Parietal- und mittleren Occipitalwindung. Nervenarzt 3:691696,1930.

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fusion, acalculia, and agraphia. However, it has been demonstrated that these are unrelated symptoms, which may or may not happen to occur together. 358

Finger agnosia has been considered as a minor form of auto-topagnosia (Gerstmann, idem) but whereas auto-topagnosia as characterized by errors in pointing to proximal body parts has been observed exclusively in patients with left brain damage, finger agnosia occurs with approximately equal frequency in patients with left and right brain damage. (Poeck, Sauguet, Gainotti; idem) & 359 . It has already been mentioned that there are patients with auto-topagnosia in whom identification of fingers is preserved. If they are compared with those right-brain-damaged patients who have difficulties with the localization of fingers but not with pointing to proximal body parts (Sauguet idem), there emerges a double dissociation between auto-topagnosia and finger agnosia.

Common neuropsychological wisdom would suggest that a task which is sensitive to both left and right-hemispheric damage does not tap a single psychological function. Presumably, disturbances of finger localization have different reasons in left- and right-brain-damaged patients.

The value of verbal tasks of finger identification has been called into question because they may be more sensitive to language disorders than to defective orientation on the body. 360,361 However, a considerable number of brain-damaged patients fail on nonverbal tasks of finger localization, like pointing on a drawing of a hand to fingers touched on the patient's own hand (Poeck et al; Sauguet et al, idem) & 362.

However, we do have to be careful when assessing MDL especially using the lesion method. It can be tempting to assume that a deficiency is due to a lesion in a particular area, even more so when that area is already involved in other deficiencies. It has to be remembered that due to the array of MDL’s developmental problems she may not perform well in tasks of recognition because she has not been educated in them.

MDL knows that she has a thumb and she may even be aware that her fifth finger is called her ‘little finger’ but she does not know the names of the other fingers. That is not a lack of perception per se but a lack in naming. Likewise she knows what ears are for; she knows that she has ears and if she was asked to point to someone’s ear in a picture she may well be successful. The particular aspect of MDL’s problem then, in her type of agnosia, is that if she was asked to touch her own ear (which of course she cannot see) then she would not be able to do it. If her ear itched then she would find it but could not do so on command. This situation applies to all parts of her body that she cannot see. This then must be considered, for her, not so much a lack in body perception but a failure in her proprioceptor system.

Visual Object Agnosia The condition of visual object agnosia refers to the impairment of object recognition in the presence of relatively intact elementary visual perception, memory, and general intellectual function. Although MDL might appear to suffer with this problem, in her case it may not be due to standard patho-physiology.

358 Benton AL. The fiction of the ‘Gerstmann syndrome’. J Neurol Neurosurg Psychiatry 24:176-

181, 1961.

359 Kinsbourne M & Warrington EK. A study of finger agnosia. Brain 85:47-66, 1962.

360 Poeck K & Orgass B. An experimental investigation of finger agnosia. Neurology 19:801-807, 1969.

361 Sauguet J; Benton AL & Hecaen H. Disturbances of the body schema in relation to language impairment and hemispheric locus of lesion. J Neurol Neurosurg Psychiatry 34:496-501, 1971.

362 Gainotti G; Cianchetti C & Tiacci C. The influence of the hemispheric side of lesion on nonverbal tasks of finger localization. Cortex 8:364-381, 1972.

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Her inability (at times) not to recognise objects that she has seen before and could name at some earlier point in time may have more to do with her present memory ability and a general confusional state than with the patho-physiology associated with this disability.

Disorders of Perception There is a considerable amount of information and research on this subject and it falls into two sections — disorders that follow left brain damage (LBD) and those that follow right brain damage (RBD). For the sake of relevance the following will relate to RBD unless there is a necessary corollary that includes LBD.

Right brain-damaged patients perform more poorly than left brain-damaged patients on a series of elementary space perception tasks, from point localization to depth perception and detection of line orientation both in a bi-dimensional and in a three-dimensional space.363

The superiority of the right hemisphere for this kind of task, brought out by cerebral damage, is paralleled by the left visual field advantage, shown by normal subjects in conditions of lateralized tachistoscopic projection. 364 The same hemispheric asymmetry is also found in both normals 365 and in brain-damaged patients366,367 and is likely responsible for the prominent contribution of the right hemisphere to tactile nonsense-shape discrimination.

Patients with RBD have been found to perform more poorly than patients with LBD on a task where they had to run the forefinger of the ipsilateral hand along the raised outlines of a meaningless block and then to recognize it on a multiple-choice visual display368 . The same selective impairment of RBD patients was reported when they were asked to manipulate a nonsense shape and then to match it to sample. 369

LeDoux and his colleagues investigated a patient with a visuo-spatial disturbance characteristic of posterior right hemisphere disease who was examined under different conditions of stimulus presentation. The visuo-spatial defect, which was shown by the failure to perceive abnormalities concerning the left side of objects and the misperception of spatial relations, was present under conditions of unrestricted visual exposure. However, when the stimulus material was briefly exposed in the right visual field, performance improved substantially. These data suggest that the visuo-spatial defect seen after right hemisphere disease is attributable to factors other than the incapacity of the left hemisphere to process visuo-spatial information. Their observations, together with other evidence, lead them to question those theories of cerebral lateralization based on the notion that visuo-spatial processing is special to the right hemisphere370.

By far the most common way to demonstrate an impairment of spatial skills in brain-

363 De Renzi, E. Visuo-spatial and Constructional Disorders. In Feinberg, T E & Farah, M J.

Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

364 De Renzi E. Disorders of Space Exploration and Cognition. Chichester, England, Wiley, 1982.

365 Benton AL; Varney NR & Hamsher de SK. Visuo-spatial judgment: A clinical test. Arch Neurol 35:364367,1978.

366 De Renzi E; Faglioni P & Scotti G. Judgment of spatial orientation in patients with focal brain damage. J Neurol Neurosurg Psychiatry 34:489-495, 1971.

367 Fontenot DJ & Benton AL. Tactile perception of direction in relation to hemispheric locus of lesion. Neuropsychologia 9:83-88, 1971.

368 De Renzi E & Scotti G. The influence of spatial disorders in impairing tactual discrimination of shapes. Cortex 5:53-62, 1969.

369 Bottini G; Cappa S; Sterzi R & Vignolo LA. Intramodal somaesthetic recognition disorders following right and left hemisphere damage. Brain 118:395-399,1995.

370 LeDoux JE: Smylie CS; Ruff R; & Gazzaniga MS. Left hemisphere visual processes in a case of right hemisphere symptomatology. Implications for theories of cerebral lateralization. Arch Neurol. 1980 Mar; 37(3):157-9

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damaged patients is to ask them to copy drawings or three-dimensional patterns, a task that demands accurate analysis and reproduction of the spatial arrangement and the reciprocal relation of the elements (lines, or blocks) composing the model. Copying draw-ings is a task that enjoys particular popularity in clinical practice because it is easy to administer at the bedside and is the simplest way to bring out constructional apraxia. This symptom, known to neurologists for more than sixty years 371, consists in the inability to assemble the elements of a two-dimensional or three-dimensional whole, respecting their orientations and spatial relationships.

MDL likes to do jig-saw puzzles but she can only manage to deal with those that have large-sized pieces. She does not seem to have the ability to recognise the shape of the piece in terms of part of it reciprocating with another. She used the picture on each individual piece and matches it by colour first; she always needs to be prompted to look for similarities but of course as these are only partial images it takes time for the whole picture and the parts of it to be represented in her memory. When this has been achieved she takes delight in being able to ‘work it out’ by herself.

Constructional skills are required by many mechanical tasks and children's games, and they also enter into a number of non-verbal mental tests, such as the block-design and picture-assembly sub tests of the Wechsler Adult Intelligence Scale (WAIS). However, the more complex the task, the less specific its impairment because of the great number of skills it involves; it is, therefore, more appropriate to study constructional apraxia with simpler tests (e.g., copying geometric drawings of increasing complexity, three-dimensional block constructions, and the spatial arrangement of sticks).

Kleist (idem) viewed constructional apraxia as a left parietal deficit, due to the disruption of a centre (tentatively localized in the left angular gyrus) that would represent the interface between the analysis of visuo-spatial information and the planning of hand movements. On this assumption, the deficit would be attributable to neither a perceptual nor an executive impairment but to the stage where movement programs, which are organized by the left hemisphere, must be monitored by spatial analysis. However, this hypothesis was abandoned when subsequent studies showed that constructional apraxia is by no means limited to left parietal damage and is indeed as frequent or even more frequent following right brain damage.

Since this side of the brain is not involved in the organization of actions, while it plays a prominent role in space perception, it seemed logical to conceive of constructional apraxia associated with right brain damage as dependent on defective visuo-spatial analysis. What about the nature of constructional apraxia following left brain damage?

The discussion revolved around the question of whether it differs from right constructional apraxia in terms of frequency, severity, quality of errors, and impairment of other cognitive abilities with which it is associated. In the sixties, the view prevailed that the deficit underlying constructional apraxia is basically apraxic when the lesion affects the left hemisphere (which is dominant for praxis) and agnosic when it affects the right hemisphere (which is dominant for space perception), and it was proposed372 to reserve the term constructional apraxia for the deficit shown by LBD patients and that of visuo-spatial agnosia for the deficit shown by RBD patients. However, this dichotomy has not passed the test of time.

Looking at the question of the frequency and severity of constructional apraxia in unselected samples of patients with unilateral hemispheric damage; contrasting findings have been reported. A scrutiny373 of the relevant papers has pointed out that, while the

371 Kleist K. Gehirnpathologie. Leipzig, Barth, 1934.

372 McFie J & Zangwill OLO. Visual-constructive disabilities associated with lesions of the left cerebral hemisphere. Brain 83:243-260, 1960.

373 De Renzi E. Disorders of Space Exploration and Cognition. Chichester, England, Wiley, 1982

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incidence of constructional apraxia in RBD patients was approximately the same across the studies (about one third of patients were impaired), in LBD samples, it was much more variable, ranging from 14 to 37 per cent. What made the difference was apparently the type of test employed to assess constructional apraxia: the percentage of LBD patients with constructional apraxia was low when performance was tested with tasks such as block designs, which are part of intelligence scales and involve more than constructional abilities, while it was at the same level as that found in RBD patients when tested with simpler tasks.

It is reasonable to suspect that the choice of complex tests entailed the exclusion from the investigation of aphasics with severe comprehension deficits, resulting in a sampling bias that is all the more risky as there is evidence that constructional apraxia is significantly associated with receptive language impairment, even when it is measured with elementary copying tasks374,375. Also, differences in the severity of the disorder were remarkably reduced when the hemispheric samples were unselected, and they were seldom consistent enough to reach significance.

If quantitative scores do not reliably discriminate RBD from LBD patients, are there clues in the quality of their performance that suggest whether their disability has a perceptual or motor origin? The only sign that has been consistently verified in RBD patients is failure to reproduce left-sided details, a manifestation of their neglect of the left side of space. (De Renzi,1997 idem)

Flöel and colleagues have determined that the right hemisphere is predominantly involved in tasks associated with spatial attention. However, left hemispheric dominance for spatial attention can be found in healthy individuals, and both spatial attention and language can be lateralized to the same hemisphere. Their research suggests that it is not the hemispheric side, but the intra-hemispheric pattern of activation that is the distinct feature for the neural processes underlying language and attention. 376

Another approach to the discrimination of the mechanisms underlying constructional apraxia in the two hemispheric groups has been the search for a differential association between constructional disability and the performance on tests taxing manipulative skills and space perception, respectively. It has been hypothesized that left apraxics would score poorly on the former but not on the latter, while right apraxics would show the opposite pattern. (De Renzi,1997 idem)

The evidence that constructional apraxia reflects the disruption of different abilities, depending on the damaged side, is at most suggestive but has not been unequivocally demonstrated. Although an executive impairment remains a possible component of the defective performance of LBD patients, visuo-spatial disorders are likely to be influential in both hemispheric groups. (De Renzi,1997 idem)

The anatomical correlates of constructional apraxia are in keeping with the assumption that spatial disorders contribute to the difficulty of both hemispheric groups but that executive disorders may also play a role in LBD patients.

Parietal damage is a frequent anatomic correlate of constructional apraxia after damage to either hemisphere, although the association is closer in RBD patients than in LBD

374 Arena R & Gainotti G. Constructional apraxia and visuoperceptive disabilities in relation to

laterality of cerebral lesion. Cortex 14:463-473, 1978.

375 Benton AL. Visuoconstructive disability in patients with cerebral disease: Its relationship to side of lesion and aphasic disorder. Doc OphthalmoI34:6776, 1973.

376 Flöel A; Jansen A; Deppe M; Kanowski M; Konrad C; Sommer J; & Knecht S. Atypical hemispheric dominance for attention: functional MRI topography. J Cereb Blood Flow Metab. 2005 Sep; 25(9):1197-208.

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patients377. It must, however, be added that the reproduction of a structured model is a sequential task that requires a certain degree of planning and is, therefore, liable to be sensitive to the functioning of frontal structures. 378 Indeed, there is evidence that frontal damage may result in constructional apraxia379 and that the performance improves if planning cues are provided.380 Supportive of the idea that different mechanisms underlie parietal and frontal constructional apraxia is the finding that the disorder is associated with poor performance on a line bisection task in RBD patients having damage to the parieto-occipital cortex but not in those with frontal, sub-cortical damage. 381

Since the introduction of imaging techniques in clinical practice, it has been increasingly recognized that sub-cortical structures contribute to cognitive functions, and disorders of language, praxis, lateralized attention, and so on have been reported following damage to basal nuclei. The same holds for constructional apraxia, whose incidence and severity do not differ in sub-cortical as compared to cortical lesions382. Whether the deficit is due to the interruption of pathways connecting cortical areas, resulting in their hypo-metabolism or to the specific participation of basal nuclei in the performance is a matter of debate for this as well as for other cognitive disorders.

Disorders of Spatial Memory MDL does have problems of spatial memory and it is highly probable that these are due to RBD. However, due to her injury being pre-mental development, it is impossible to know how she compensated for this deficit once mental development began. This ability is of course one that develops later in childhood, once there is an ongoing demand for it.

Thus if she had a draughts board in front of her that had four black draughts on it, each on a white square and she was asked to move them to four black squares, she probably could not do it. She can follow instructions for one item at a time, e.g. please give me the red cube; but she wouldn’t remember that if she was asked to give the same cube again five minutes later if the colour wasn’t mentioned.

MDL does also have visual field defects in that she cannot point to objects that she has just seen if she were to closes her eyes. Indeed this would be a difficult assessment to make for she is unable to close her eyes on request.

Both RBD and LBD patients with visual field defects have a reduced spatial memory span. 383 The impairment is not attributable to the visual field deficit per se or to scanning and misreaching disorders. It is, therefore, likely that the presence of visual field defects merely points to the posterior location of lesions. In some patients the spatial short-term memory deficit is so striking as to be also apparent in everyday life. Unlike short-term memory, long-term spatial memory has been found to be associated with right-sided lesions. (De Renzi, 1997 idem)

Topographical Disorientation The most striking manifestation of spatial 377 Ajuriaguerra J; Hécaen H & Angelergues R. Les apraxies: Variétés cliniques et latéralisation

lésionelle. Rev Neurol 102:566-594, 1960.

378 Luria AR & Tsvetkova LS. The programming of constructive activity in local brain injuries. Neuropsychologia 2:95-108, 1964.

379 Benton AL. Differential behavioural effects in frontal lobe disease. Neuropsychologia 6:53-60, 1968

380 Pillon B. Troubles visuoconstructifs et méthodes de compensation: Resultats de 85 patients atteints de lésions cérébrales. Neuropsychologia 19:375-383, 1981.

381 Marshall RS; Lazar RM & Binder JR, et al: Intrahemispheric localization of drawing dysfunction. Neuropsychologia 32:493-501, 1994.

382 Kirk A & Kertesz A. Subcortical contribution to drawing. Brain Lang 21:57-70; 1993.

383 De Renzi E; Faglioni P & Previdi P. Spatial memory and hemispheric locus of lesion. Cortex 13:424433, 1977.

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memory deficit is topographic disorientation — namely, the inability to find one's way in a familiar environment and to learn new paths, in the absence of global amnesia, severe mental deterioration, or disorders of visual perception and exploration.

The basic deficit underlying the patient's difficulty is the inability to retrieve an abstract map of the route, which specifies the spatial relationships defining the position of a place with respect to other places and the subject and to transform them in guidelines for walking.

It seems that MDL may have developed a macro-sense of direction within a prescribed field. This only relates to location but she has little spatial memory for objects in a localised field. Even so, there is always a topographical disorientation.

Landmark recognition and spatial map construction are the main mental operations that assist navigation through familiar surroundings, and their discrete disruption underlies two forms of route-finding disability, topographic agnosia and topographic amnesia. 384 The nature of topographic agnosia has not been extensively investigated. The failure to identify a specific building might result from perceptual impairment that prevents the appreciation of the small, distinctive features identifying an exemplar of a category whose elements are similar or from the inability to match the perceived building with its representation stored in memory. The problem is whether the agnosia is class-specific or extends to other categories (e.g., faces) that demand the recognition of the stimulus in its uniqueness.

Failure to recognize familiar environments is by no means a constant feature of patients with topographic disorientation; even when it is present, it may not be the main reason for route-finding disability. The amnestic nature of this form of topographic disorientation is confirmed by the patient's failure to give a verbal description of the route, to trace it on a road map, and to draw a map of a familiar place. Patients endeavour to find salient objects, but these are of little help because they are devoid of orientation value and do not tell them, for instance, whether they must proceed straight ahead, or turn left. Of course, agnosic and amnesic disorders can coexist in the same patient, as both are dependent on right hemispheric damage.

The study of the anatomic correlates of topographic disorientation has pointed out the crucial role played by the posterior regions of the brain, especially of the right hemisphere. In some cases damage is bilateral but in others it is confined to the right side, where the areas more frequently involved are the parietal lobe and the medial occipito-temporal cortex. (De Renzi, 1997 idem)

In MDL’s case there are difficulties mainly of a cognitive nature due to her lack of understanding and of communication. So we don’t know how much she can actually compensate for her particular brain damage or how much of her difficulty is due to a lack of experience in having to locate herself in a familiar environment. She is never out alone, or at least has not been so for over twenty-five years. However, it is interesting again to compare her later situation with that when she was a child. At the age of eight or nine she could walk by herself from home to a post box and post a letter and then return home whilst being unaccompanied for the whole journey. The post box was out of sight from the entrance to her home. In her present situation of the last twenty years she has over-riding anxiety and this will further diminish her cognitive ability and also introduce sympathetic system involvement.

She does recognise familiar environments but not necessarily how to find them. She always recognises the approach to her own home and will go to the door without hesitation. If she is in the garden, then she can find her way back to the door of the house and would do so even if there were other house doors adjacent. Should she find herself several streets away from her home she may not be able to find her own way back home until she had made the journey on foot twenty or thirty times over a short period. This is important because she 384 Paterson A & Zangwill OL. A case of topographical disorientation associated with a

unilateral cerebral lesion. Brain 68:188-121, 1945.

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also does suffer from memory decay and if she was away from her home for say a year, she would need time to reorient herself to what was once familiar. These failings are essentially a consequence of RBD. (See also Prosopagnosia above – p64)

In MDL’s case the knowledge of the location of her brain lesions is entirely academic for there cannot be any possibility of their reversal. The essential need to understand them then, relates completely to the explanation of her deficits so that they can be a source of positivity in dealing with her care and its planning.

The overall problems with the assessment by neurologists of MDL’s neurological deficits are made difficult by the fact that most recognised tests are based on the variations between post-trauma abilities and pre-trauma abilities. MDL had no pre-traumatic abilities that are of use to us in these contexts and her brain had to develop skills from the non-damaged parts.

This is an entirely individual process and there cannot be any predictions made as to how that would proceed. That is why, in her case, we can only work backwards and plot her lack of neurological capabilities on the brain map and so try to find some developmental characteristics that fit in with what is known about the consequences of damage in particular areas.

Another consideration arising from MDL’s brain damage and the time of its occurrence is that she is not aware that she has a neurological deficiency — indeed she is obviously unable to have the knowledge of anything so complicated as that sort of understanding. She has not experienced any pre-injury life of consequence and that remains in her consciousness and what we haven’t experienced we cannot know what it would be like if we had experienced it. There is then no emergent concern for MDL to try to re-engage or re-capture what might have been there before. Firstly because she was far too young to have experiential events to which she can relate and, secondly, she did not have a development of consciousness to a level where such memories could be formed.

This is why it is so important not to categorise her as Learning Disabled as that is too simplistic a condition and unless all of her behaviour and neurological characteristics are related to brain areas then she can neither be properly assessed nor can her care be planned adequately.

The Proprioceptor System In some neuro-biological dysfunctions there can be distortions in the sensory system of the body. Without proper neurobiological support, the ability to touch, see, and hear can be distorted. When vestibular and proprioceptor systems are inadequate, such perceptions as the ability to know where one is in space, to have a sense of time, and even to have a sense of humour can be distorted in such a way that the individual has difficulty perceiving the world correctly. Visual, auditory, and tactile responses must be able to perceive, interpret and process information so that we can learn about the world around him/her. Without good sensory integration, learning and behaviour is more difficult and the individual often feels uncomfortable about him-/herself, and cannot easily cope with ordinary demands and stress. 385

The proprioceptor system consists of sensory information caused by contraction and stretching of muscles and by bending, straightening, pulling and compression of the joints between the bones. Because there are so many muscles and joints in the body, the proprioceptor system is almost as large as the tactile system. Most proprioceptor input is processed in areas of the brain that do not produce conscious awareness. Without good automatic responses, such things as eye-hand coordination are very difficult.

Connected to these is the vestibular system that is the sensory system which responds to the position of the head in relation to gravity and accelerated or decelerated movement. 385 Ayers, A. J. Sensory Integration and the Child, Western Psychological Services, 1979, 191pp.

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There are two types of vestibular receptors in the inner ear in a structure called the labyrinth. One type of receptor responds to the force of gravity. The other type of receptor is in the semicircular canals in the ear. These canals are responsible for our sense of movement. The vestibular system is a unifying system. All other types of sensation are processed in reference to this basic vestibular information. The activity in the vestibular system provides a ‘framework’ for the other aspects of our experience. Vestibular input seems to ‘prime’ the entire nervous system to function effectively. When the vestibular does not function in a consistent and accurate way, the interpretation of other sensations will be inconsistent and inaccurate, and the nervous system will have trouble ‘getting started’.

The visual system has become our major means of relating to space, but the vestibular, proprioceptor and tactile systems must contribute to visual development and function. Together these systems allow us to move about in space, catch a ball, and process the visual body language of others. In order to process more abstract information such as reading, writing, spelling or calculation, such visual abilities as visual-motor, visual perceptual, visual spatial, visual memory, visual figure-ground and visual closure capacities must be in place. These capacities only work well when the tactile, vestibular and proprioceptor systems are intact. It is clear that for MDL these systems have faults and are not well coordinated.

I mention this here not only because it is associated but also because it is another area in which MDL has problems. She never closes her eyes except when asleep; and that may be one problem that may cause a deficiency in sleep initiation (but see below). She also does not like to have her head in line with her body when she is lying down. She only seems comfortable when lying if her head is inclined forwards by about thirty degrees from the horizontal. She will resist all attempts to get her to lie in a completely prone position.

Ideomotor apraxia Ideomotor apraxia is a symptom of left brain damage, which is usually considered as a disorder of motor control. 386,387,388,389 (See Memories of Skilled Movements — p 5.) In particular, defective imitation of gestures has been considered as testifying a deficit of motor execution. In the words of de Renzi, “Since the examiner provides the model and the patient has only to copy it, errors can only be due to a deficit of motor execution”. (De Renzi, idem) This argument seems to be particularly convincing if novel and meaningless gestures are to be imitated. Whereas imitation of familiar and meaningful gestures could be mediated by pre-existing knowledge of the gestures’ spatial configuration, imitation of meaningless gestures appears to test a direct route from visual perception to motor execution. 390,391,392

There is, however, an alternative interpretation of the task demands of imitation of meaningless gestures. It proposes that general topographic knowledge about the human body mediates the transition from visual perception to motor execution. 393,394,395,396

386 Liepmann H. Drei Aufsiitze aus dem Apraxiegebiet. Berlin: Karger, 1908.

387 Poeck K. The two types of motor apraxia. Arch Ital Bioi 120:361-369, 1982.

388 de Renzi E. Apraxia, in Boller F, Grafman J (eds): Handbook of Neuropsychology. New York: Elsevier, 1990, vol 2,.pp 245-263.

389 Heilman KM & Rothi UG. Apraxia, in Heilman KM, Valenstein E (eds): Clinical Neuropsychology. New York: Oxford University Press, 1993, pp 141-164.

390 Barbieri C & de Renzi E. The executive and ideational components of apraxia. Cortex 24:535-544,1988.

391 Rothi UG; Ochipa C & Heilman KM. A cognitive neuropsychological model of limb praxis. Cog Neuropsychol 8:443-458, 1991.

392 Roy EA & Hall C. Limb apraxia: A process approach, in Proteau L, Elliott D (eds): Vision and Motor Control Amsterdam: Elsevier, 1992, pp 261-282.

393 Morlaas J. Contribution à l'étude de l'apraxie. Paris: Amédée Legrand, 1928.

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The idea that defective imitation of gestures is due to a lack of topographic knowledge about the human body likens it to autotopagnosia. The parallel between defective imitation of meaningless gestures and autotopagnosia was strengthened by a study by Goldenberg who examined imitation of three kinds of gestures:

• for imitation of hand postures, the patients were required to copy different positions of the hand relative to the head while the configuration of the fingers remained invariant;

• for imitation of finger postures, patients were asked to replicate different configurations of the fingers, and the position of the whole hand relative to the body was not considered for scoring;

• for imitation of combined gestures, both a defined position of the hand relative to the body and defined configuration of the fingers were required. (Goldenberg, idem)

Regardless of whether imitations of hand positions and finger configurations were tested each on their own or together, they proved to show differential susceptibility to left and right brain damage. Whereas imitation of finger configurations was about equally impaired in left- and right-brain-damaged patients, defective imitation of hand positions occurred exclusively in left-brain-damaged patients, and whereas controls as well as right- brain-damaged patients committed fewer errors with hand positions than with finger configura-tions, the reverse was the case in left-brain-damaged patients. This dissociation between gestures requiring orientation relative to the proximal body and gestures requiring orientation within the hand closely resembles the above-mentioned dissociation between autotopagnosia and finger agnosia.

A lack of general knowledge about the human body should lead to errors regardless of whether gestures are to be replicated on another body or on oneself. Indeed, patients who display apraxia on imitation of hand positions commit more errors than either left-brain-damaged patients without apraxia or right-brain-damaged patients when trying to replicate the same positions on a manikin.

Pantomime comprehension and ideomotor apraxia397

Mariella Pazzaglia from the IRCCS Fondazione Santa Lucia and University of Rome ‘La Sapienza’, describes a rapidly growing body of clinical research on the complex interplay of both production and comprehension mechanisms in actions derived from gesture comprehension studies described in patients with apraxia.

Gesture comprehension deficit correlates with damage to the opercular and triangularis portions of the inferior frontal gyrus, two regions that are involved in complex aspects of action-related processing. In contrast, no such relationship seems to be found with lesions centred on the inferior parietal cortex. These research findings suggest that lesions to left frontal regions that are involved in planning and performing actions are causatively

394 Goldenberg G. Imitating gestures and manipulating a manikin - The representation of the

human body in ideomotor apraxia. Neuropsychologia 33:63-72, 1995.

395 Goldenberg G; Hermsdörfer J & Spatt J. Ideomotor apraxia and cerebral dominance for motor control. Cog Brain Res. 1996; 3:95-100.

396 Goldenberg G. Defective imitation of gestures in patients with left and right hemisphere lesions. J Neurol Neurosurg Psychiatry. 1996; 61: 176-180.

397 Rothi LJ, Heilman KM, Watson RT. Pantomime comprehension and ideomotor apraxia. J Neurol Neurosurg Psychiatry 1985;48:207–10.

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associated with deficits in the recognition of the correct execution of meaningful gestures.398

The inextricable link between action perception and action execution was reported for the first time in a neuropsychological study of apraxia patients (Rothi et al, 1985). In that article, Rothi et al not only provided the first direct evidence of the existence of a bidirectional relationship between action perception and motor activity, but also provided causative information on the neural structures involved in the visual mapping of actions in patients with brain damage. Using a non-verbal paradigm, the authors identified a clear association between a deficit in performing gestures and the ability to recognise the pantomime of gestures appropriately in left hemisphere-lesioned patients with apraxia but not in those with aphasia.

These observations suggest that the representational aspects of gestures prevent action imitation and influence the execution of a given movement, typically affected in apraxia. Patients with apraxia presented lesions centred, mainly on the parietal cortex, but extending into the frontal regions. The authors revealed that, although both frontal and parietal structures are involved in the execution of actions, the left posterior regions seem to be primarily linked to the specific ability to comprehend the meaning of pantomime. This anatomical and functional investigation of apraxia patients highlighted, for the first time, a series of unexpected characteristics of these sensorimotor areas.

In fact, a decade later, neurophysiological research performed in monkeys showed that these two areas, which probably host mirror neurons, are the core regions of the system of action observation and execution. 399, 400, 401, 402 In particular, it has been claimed that direct matching between action perception and execution is enabled by neural activity that overlaps largely in the inferior frontal gyrus and the inferior parietal lobe.403 One interpretation of such data is that motor system modulation during action perception facilitates and assists the reading of the actions of others and promotes readiness to predict movements and perform actions.404

It is also known that patients with parietal damage and impaired ability to imitate or discriminate an observed action lose the capacity to monitor early phases of planning of their own movements.405 Apraxia patients with injury in parietal areas not only have major

398 Pazzaglia M, Smania N, Corato E, Aglioti SM. Neural underpinnings of gesture discrimination in patients with limb apraxia. J Neurosci 2008;28:3030–41.

399 Fogassi L, Ferrari PF, Gesierich B, Rozzi S, Chersi F, Rizzolatti G. Parietal lobe: from action organization to intention understanding. Science 2005;308:662–7.

400 Gallese, V; Fadiga, L; Fogassi L; & Rizzolatti G. Action recognition in the premotor cortex. Brain 1996;119:593–609.

401 di Pellegrino G, Fadiga L, Fogassi L, Gallese V, Rizzolatti G. Understanding motor events: a neurophysiological study. Exp Brain Res 1992;91:176–80.

402 Grafton ST, Arbib MA, Fadiga L, Rizzolatti G. Localization of grasp representations in humans by positron emission tomography. 2. Observation compared with imagination. Exp Brain Res 1996;112:103–11.

403 Pazzaglia, M; Smania, N; Elisabetta Corato, E; & Maria Aglioti, S. Neural Underpinnings of Gesture Discrimination in Patients with Limb Apraxia. JNeurosci. 19 March 2008, 28(12): 3030-3041; doi: 10.1523 5748-07.2008.

404 Kalenine S, Buxbaum LJ, Coslett HB. Critical brain regions for action recognition: lesion symptom mapping in left hemisphere stroke. Brain 2010;133:3269–80.

405 Fontana AP, Kilner JM, Rodrigues EC, Joffily M, Nighoghossian N, Vargas CD, Sirigu A. Role of the parietal cortex in predicting incoming actions. Neuroimage. 2012 Jan 2;59(1):556-64. Epub 2011 Jul 23.

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problems in comprehending actions but also frequently exhibit failure of the anticipatory motor process that drives forthcoming movements via predictive mechanisms.406

In MDL’s case then and considering that she has an extreme lack of knowledge about the human body and also that she cannot, on command, locate parts of her own body by name, it would seem that she is affected more by general apraxia than by ideomotor apraxia.

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The Emotional Brain Significant progress has been made in identifying brain regions involved in certain domains

of emotional behaviour, particularly fear. Most of this advance in knowledge has evolved

from animal models of emotion, although extensions of this work into human populations

have begun to be established407.

Early research showed that emotional expression appeared to be mediated by diencephalic

structures, including the thalamus and hypothalamus, located below the cortex but above

the midbrain. 408,409 In addition, the diffuse sympathetic arousal in the periphery seemed to

be too undifferentiated to determine distinct emotional states410. Later it was determined411

that the emotional circuit consisted of the hypothalamus, anterior thalamus and the

cingulate cortex. The ante-limbic system concept, has been primarily linked to cognitive

functions, such as declarative memory 412, spatial cognition, 413,414 and contextual /

configural / relational processes.415,416,417 Subsequent work has consistently implicated the

amygdala in emotional processing. 418 Thus, the inclusion of the amygdala may explain the

long-standing survival of the limbic system concept as a model for emotional processing in

the brain.

406 Pazzaglia, M; Pizzamiglio, L; Pes, E; Maria Aglioti, S. The Sound of Actions in Apraxia. Current

Biol.Vol 18, Issue 22, 25 November 2008, Pages 1766–1772.

407 LaBar, KS & LeDoux, JE. Emotion and the Brain: An Overview. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

408 Kotter R & Meyer N. The limbic system: A review of its empirical foundation. Behav Brain Res 52:105-127,1992.

409 LeDoux JE. Emotion, in Plum F (ed): Handbook of Physiology: I. The Nervous System. Higher Functions of the Brain. Bethesda, MD: American Physiological Society 1987, vol 5, pp 419-460.

410 LeDoux JE. Emotion and the limbic system concept. Concepts Neurosci 2:169-199, 1991

411 Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry 79:217-224, 1937.

412 Squire LR. Mechanisms of memory. Science 232:1612-1619, 1987

413 O'Keefe J & Nadel L. The Hippocampus as a Cognitive Map. Oxford, England: Clarendon, 1978.

414 Nadel L. Hippocampus and space revisited. Hippocampus 1:221-229, 1991.

415 Hirsh R. The hippocampus and contextual retrieval of information from memory: A theory. Behav Bioi 12:421-444, 1974.

416 Sutherland RJ & Rudy JW. Configural association theory: The role of the hippocampal formation in learning, memory, and amnesia. Psychobiology 17:129-144, 1989.

417 Cohen NJ & Eichenbaum H. Memory, Amnesia, and the Hippocampal System. Cambridge, MA: MIT Press, 1993.

418 LeDoux JE. Emotion and the amygdala, in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 339-352.

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Emotions and our Mental Life

We've all felt love and hate and fear and anger and joy; but what is it that ties mental states like these together into the bundle that we commonly call ‘emotions’? What makes this bundle so different from other mental packages, ones that we are less inclined to use the term ‘emotion’ for? How do our emotions influence every other aspect of our mental life, shaping our perceptions, memories, thoughts, and dreams? Why do our emotions often seem impossible to understand? Do we have control over our emotions or do they control us? Are emotions cast in neural stone by our genes or taught to the brain by the environment? Can we have unconscious emotional reactions and unconscious emotional memories? Can the emotional slate ever be wiped clean, or are emotional memories permanent? 419

You may have opinions, and even strong ones, about the answers to some of these questions, but whether your opinions constitute scientifically correct answers can't be determined by intuitions alone. Occasionally, scientists turn everyday beliefs into facts, or explain the workings of intuitively obvious things with their experiments. However, facts about the workings of the universe, including the one inside your head, are not necessarily intuitively obvious. Sometimes, intuitions are just wrong — the world seems flat but it is not —and science's role is to convert these commonsense notions into myths, changing truisms into ‘old wives' tales’. Frequently, though, we simply have no prior intuitions about something that scientists discover — there is no reason why we should have deep-seated opinions about the existence of black holes in space, or the importance of sodium, potassium, and calcium in the inner workings of a brain cell. Things that are obvious are not necessarily true, and many things that are true are not at all obvious. (LeDoux, Idem)

LeDoux views emotions as biological functions of the nervous system. He believes that figuring out how emotions are represented in the brain can help us understand them. This approach contrasts sharply with the more typical one in which emotions are studied as psychological states, independent of the underlying brain mechanisms. Psychological research has been extremely valuable, but an approach where emotions are studied as brain functions is far more powerful. (Idem)

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The Hypothalamus

The hypothalamus may be thought of as the anatomical axis about which the other major limbic areas (septum, amygdala, hippocampus, and neocortex) are organized. Physiologically, its demonstrated importance to both endocrine and autonomic functions indicates its probable involvement in emotions, sex and aggression. Cannon postulated the idea some 50 years ago, and there is now considerable supporting evidence.

Some of the most interesting experiments in this area have been conducted by Flynn and associates at Yale University. Flynn found that electrical stimulation of the lateral hypo-thalamus in cats evoked a deliberate, stealthy and well-organized form of predatory aggression which he called ‘quiet stalking attack’. In contrast, medial hypothalamic stimulation evoked an explosive, hissing, spitting and clawing type of predation called ‘affective attack’. In each case the objective of the attack was the same — killing the rat. However, this was virtually the only similarity between the two types of aggression.

Results from experiments in which the two hypothalamic components have been lesioned are not in complete accordance with the stimulation results. For example, destruction of the lateral hypothalamus appears to reduce aggressiveness (along with the vigour of almost every other behaviour). On the other hand, a cat with a lateral hypothalamic lesion

419 LeDoux, J. The Emotional Brain: The mysterious underpinnings of emotional life. Weidenfeld &

Nicholson, London; 1998

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on only one side of the brain will show great interest in, and possibly attack, a rat in one half of its visual field, while completely ignoring a rat in the other half of its visual field. The results argue against the loss of predatory aggression as being a generalized disturbance. So, with respect to the involvement of the lateral hypothalamus in predatory aggression, the lateral hypothalamic stimulation and lesion results are complementary.

The case with respect to medial hypothalamic involvement in aggression is not as clear. Since stimulation of the medial hypothalamus produces affective attack, it would be reasonable to expect that lesions of the medial hypothalamus would inhibit the same behaviour. However, medial hypothalamic lesions almost universally produce a marked increase in most forms of aggression. This type of paradoxical result in the study of emo-tionality often characterizes experimental manipulations of limbic function.

Regulation of Body Temperature In human beings the body temperature is maintained at an average of 36·8°C (98·4°F). This is the optimum temperature for the many complex chemical processes to occur. If the temperature is raised the metabolic rate is increased and if it is lowered the rate of metabolism is reduced. To ensure this constant temperature a fine balance is maintained between heat produced in the body and heat lost to the environment.

The centre controlling temperature is situated in the cerebrum and involves a group of nerve cells in the hypothalamus called the heat regulating centre. There is also a group of nerve cells in the medulla oblongata known as the vasomotor centre which controls the calibre of the blood vessels, especially the small arteries and the arterioles, and they control the amount of blood which circulates in the capillaries in the dermis.

The heat regulating centre and vasomotor centre are thought to be extremely sensitive to the temperature of the blood and any significant change stimulates them to activity. From these centres sympathetic nerves convey impulses to the sweat glands, arterioles and the arrector muscles of the hairs in the skin.

Destruction of the anterior hypothalamus destroys the ability to cope with heat stress, but it does not affect the ability to cope with cold stress. Conversely, destruction of the posterior hypothalamus destroys the ability to cope with cold stress without affecting the response to heat stress. Complementary data come from studies in which hypothalamic function has been altered by electrical stimulation through implanted electrodes. Electrical stimulation of anterior hypothalamus results in decreased body temperature and a suppression of shivering in the cold. Electrical stimulation of the posterior hypothalamus results in increased body temperature and shivering, even in a warm environment. These results indicate that the anterior hypothalamus facilitates heat loss, and the posterior hypothalamus facilitates heat production (Atrens, et al, idem).

Of great interest in thermo-regulatory research is Myers' identification of a potential physiological basis for the set-point for body temperature. Myers presents evidence that the temperature set-point is maintained by a balance between sodium (Na +) and calcium (Ca2+) ions in a restricted area of the posterior hypothalamus. Application of Na + ions increases body temperature, whereas application of Ca2+ ions to the same site decreases body temperature. The changes did not occur in response to other ions, such as potassium (K +) or magnesium (Mg2+), nor if the Na + or Ca2 + ions were applied to other parts of the hypothalamus.

Myers claims that the set-point is determined by the ion balance and not by other means. He notes that the subject will actively defend the ion-induced changes over a long period, whereas other hypothalamic manipulations simply impair regulation.

There is therefore a possibility that MDL’s problem when she is saying that she is feeling hot when her skin is cool and her face not flushed could be due to damage in the hypothalamus.

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This then further narrows the area of damage in MDL’s hypothalamus to the lateral aspect as MDL has never shown any form of aggression during the whole of her life.

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The Amygdala and the Neurology of Emotions

Emotional signals, either visual or auditory, can be considered as aspects of both an emotional response and social communication. Recognition of emotion draws on a distributed set of structures that include the occipito-temporal neocortex, amygdala, orbito-frontal cortex and right fronto-parietal cortices. Recognition of fear may draw especially on the amygdala and the detection of disgust may rely on the insula and basal ganglia. Two important mechanisms for recognition of emotions are the construction of a simulation of the observed emotion in the perceiver, and the modulation of sensory cortices via top-down influences. 420 See also Table below.421

The amygdala participates in the recognition of emotional signals via at least two classes of input mechanisms: a subcortical route via the superior colliculus and the pulvinar thalamus, and a cortical route via the visual neocortex. Human lesion studies have consistently found impaired recognition of emotional facial expressions following bilateral amygdala damage, often disproportionate for fear, but sometimes encompassing multiple negative emotions, including fear, anger, disgust, and sadness. It has been argued that the amygdala is principally involved in processing stimuli related to threat and danger, that it triggers cognitive resources to help resolve ambiguity in the environment, or that the emotions whose recognition depends most on the amygdala are related to behavioural withdrawal. (Adolphs, 2002a, idem)

This impairment may be intensified when a brain injured person needs to recognise emotional facial expressions of individuals of different ethnic backgrounds. There seems to be an increasing amount of evidence which indicates that humans have significant difficulties in understanding emotional expressions in those who are from a different ethnic culture. There is, in these cases, a reduction in the recognition accuracy and, if available, a stronger amygdala activation. Derntl et al have undertaken research into this with non-brain injury subjects. This revealed bilateral amygdala activation to emotional expressions in Asian and European subjects. However, in the Asian sample, a stronger response of the amygdala emerged and was paralleled by reduced recognition accuracy, particularly for angry male faces. They also observed a significant inverse correlation between duration of presence and amygdala activation.

The study revealed that bilateral amygdala activation was required in order to understand emotional expressions in Asian and European females and males. In the Asian sample, a stronger response of the amygdala bilaterally was observed and this was paralleled by reduced performance, especially for anger and disgust depicted by male expressions. Taken together, while gender exerts only a subtle effect, culture and duration of presence as well as gender of poser are shown to be relevant factors for emotion processing, influencing not only behavioural but also neural responses in female and male immigrants. This suggests that in brain injured patients the ethnic background of their nurses and carers may have some importance.422

Unilateral damage to the amygdala generally results in more subtle impairments. An 420 Adolphs, R. Neural systems for recognizing emotion. Current Opinion in Neurobiology 2002;

Apr; 12(2): 169-77.

421 Adolphs R. Recognizing emotion from facial expressions: psychological and neurological mechanisms. Behav Cognit Neurosci Rev 2002, 1:21-61.

422 Derntl, B; Habel, U; Robinson, S; Windischberger, C; Kryspin-Exner, I; Gur, RC & Moser, E. Culture but not gender modulates amygdala activation during explicit emotion recognition. BMC Neuroscience 2012, 13:54 doi:10.1186/1471-2202-13-54. Published: 29 May 2012

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impaired ability to learn new emotional facial expressions correlated with the extent of unilateral amygdala damage423, and two studies424,425 found that subjects with damage to the right amygdala were impaired, as a group, in their recognition of negative emotions from facial expressions. (Adolphs, 2002a, idem)

TABLE FIVE

The Indelibility of Emotional Memory

The finding that when the medial prefrontal cortex is damaged, routine fear conditioning becomes resistant to extinction has another important implication. It also suggests that extinction prevents the expression of conditioned fear responses but does not erase the implicit memories that underlie these responses. 426 Extinction, in other words, involves the cortical control over the amygdala's output rather than a wiping clean of the amygdala's memory slate.

The idea that extinction does not involve the erasure of emotional memories but instead prevents their expression is consistent with a number of findings about conditioned responses. 427,428,429 Pavlov, for example, found that extinguished responses would simply recover spontaneously with the passage of time. It is also known that if a rat is conditioned by pairing a tone and shock in one box, and the fear response elicited by the tone is completely extinguished in another box, the conditioned response elicited by the tone will be renewed if the rat is returned to the original training box. An extinguished response can also be reinstated by giving the rat an exposure to the unconditioned stimulus or, importantly, to other forms of stressful stimulation. Stress, in other words, can bring back

423 Boucsein K; Weniger G; Mursch K; Steinhoff BJ & Irle E. Amygdala lesion in temporal lobe

epilepsy subjects impairs associative learning of emotional facial expressions. Neuropsychologia 2001, 39:231-236.

424 Anderson AK; Spencer DD; Fulbright RK & Phelps EA. Contribution of the anteromedial temporal lobes to the evaluation of facial emotion. Neuropsychology 2000, 14:526-536.

425 Adolphs R; Tranel D & Damasio H. Emotion recognition from faces and prosody following temporal lobectomy. Neuropsychology 2001, 15:396-404

426 LeDoux, J E; Romanski, L. M; & Xagoraris, A E. Indelibility of subcortical emotional memories. Journal of Cognitive Neuroscience 1, 238-43; 1989.

427 Bouton, ME. & Peck, CA. Context effects on conditioning, extinction, and reinstatement in an appetitive conditioning preparation. Animal Learning and Behavior 17, 188-98; 1989.

428 Bouton, ME., & Swartzentruber, D. Sources of relapse after extinction in Pavlovian and instrumental learning. Clinical Psychology Review 11, 123-40; 1991.

429 Bouton, M E. Conditioning, remembering, and forgetting. Journal of Experimental Psychology: Animal Behavior Processes 20, 219-31; 1994.

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extinguished, or perhaps weakly established, but unextinguished, conditioned responses. 430 Each of these examples demonstrates that emotional memories are not erased by extinction but are simply held in check. Extinguished memories, like Lazarus, can be called back to life.

Unconscious fear memories established through the amygdala appear to be indelibly burned into the brain. They are probably with us for life. This is often very useful, especially in a stable, unchanging world, since we don't want to have to learn about the same kinds of dangers over and over again. But the downside is that sometimes the things that are imprinted in the amygdala's circuits are maladaptive. In these instances, we pay dearly for the incredible efficiencies of the fear system.

Psychiatrist Roger Pitman has astutely noted that findings from studies of fear conditioning in rats have important implications for how anxiety is treated431. The classic treatment, based on Mowrer's and Miller's theory, was to force the patient to be exposed to the anxiety-causing stimuli without allowing any avoidance or escape behaviour and thereby try to extinguish the anxiety that the stimuli elicit. But in light of the indelibility of the amygdala's hold on traumatic memories, he suggests a bleaker, though perhaps more realistic, assessment. We may not be able to get rid of the implicit memories that underlie anxiety disorders. If this is the case, the best we can hope for is to exercise control over them. In MDL’s case by controlling her environment.

It is becoming clear then that emotions may be tied to certain parts of the brain but that does not mean that one emotion sits in a particular spot and jumps to the alert phase when something happens that frightens you. As an analogy, let’s look at something you probably do almost every day — try to start your car. You switch on the ignition and turn the key or press the button — nothing happens. Now it is no good assuming that it is the switch that is wrong (of course it could be, but unlikely). There are several things that might be contributing to your engine failing to start and they may need differing skills to put that right.

So, with fear, you might be frightened because of a memory; or a noise that triggers your emotion; or a threatening stranger approaches you; or you wake up from a bad dream. There will be a common physiological reaction in varying degrees of intensity resulting from any of these but the beginnings of the trigger may start in different parts of the brain before being centralised into a voluntary or involuntary action. Noise sensitivity is also an important and under-researched symptom that can result from traumatic brain injury.432

Sometimes referred to as hyperacusis, when it is a marked intolerance to normal environmental sound, noise sensitivity is a common symptom in patients with tinnitus, Williams syndrome, autism, and other neurologic diseases. It has been suggested that an imbalance of excitation and inhibition in the central auditory system may play an important role in hyperacusis. Recent studies found that noise exposure, one of the most common causes of hearing loss and tinnitus, can increase the auditory cortex (AC) response, presumably by increasing the gain of the AC. Noise exposure induces a decrease of sound evoked potential in the inferior colliculus. However, significant increases of AC response including sound evoked potentials and the spike firing rates of AC neurons were noted by Sun et al.433

430 Jacobs, WJ. & Nadel, L. Stress-induced recovery of fears and phobias. Psychological Review

92, 512-31; 1985.

431 Shalev, AY; Rogel-Fuchs, Y; & Pitman, RK. Conditioned fear and psychological trauma. Biological Psychiatry 31,863-65; 1992.

432 Landon J; Shepherd D; Stuart S; Theadom A & Freundlich S. Research Reports — Hearing every footstep: noise sensitivity in individuals following traumatic brain injury. Neuropsychol Rehabil. 2012 Jun;22(3):391-407.

433 Sun W; Deng A; Jayaram A & Gibson B. Noise exposure enhances auditory cortex responses related to hyperacusis behavior. Brain Res. 2012 Feb 9. [Epub ahead of print]

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This research suggests that noise exposure induces hyper-excitability of AC presumably by increasing the post-synaptic response of AC neurons and that noise exposure can cause exaggerated sound reactions which may be related with the enhanced responsiveness of the AC neurons.

Some of these behaviours will be consistent with your commonsense intuitions about fears that you have faced in the past; whereas others will seem unlikely if not strange and unaccountable. Every new incident that causes you to have the emotion of fear will be stored in readiness for the next time it happens. As will your reaction to them. Being startled could be the initiating trigger of your fear but if you have realized afterwards that you reacted too strongly, your brain will store that reaction and the next time you could be startled by the same event you will respond less actively. Eventually if you recognize that the ‘trigger’ was something completely harmless and put you in no danger, then your reaction would move on to extinction. That means that your brain would tell you instantly ‘not to bother about it’, and so you wouldn’t.

Now, here is the interesting bit, if parts of the brain that deal with fear are damaged then the ‘extinction’ response may not work; or it may take longer to learn and so allow for the signal to give a weaker response. It has been found that the way in which extinction works can involve different parts of the brain depending upon when the extinction process began.

Behavioural evidence indicates that extinction is a form of inhibitory learning. Extinguished fear responses reappear with the passage of time (spontaneous recovery), a shift of context (renewal), and unsignaled presentations of the unconditioned stimulus (reinstatement). However, there is also evidence to suggest that extinction is an ‘unlearning’ process corresponding to depotentiation of potentiated synapses within the amygdala. Because depotentiation is induced more readily at short intervals following long-term potentiation induction and is not inducible at all at a sufficient delay, it may be that extinction initiated shortly following fear acquisition preferentially engages depotentiation ‘unlearning’, whereas extinction initiated at longer delays recruits a different mechanism.

Myers et al, investigated this possibility through a series of behavioural experiments examined the recoverability of conditioned fear following extinction. Consistent with an inhibitory learning mechanism of extinction, rats extinguished 24–72 h following acquisition, exhibited moderate to strong reinstatement, renewal, and spontaneous recovery. In contrast, and consistent with an erasure mechanism, rats extinguished 10 min to 1 h after acquisition exhibited little or no reinstatement, renewal, or spontaneous recovery. These data support a model in which different neural mechanisms are recruited depending on the temporal delay of fear extinction. 434

Justin, et al also found that, short acquisition-extinction intervals (immediate extinction) can lead to either more or less spontaneous recovery than long acquisition-extinction intervals (delayed extinction). 435 Langton et al found that repetitive aversive experiences prior extinction learning can prevent a facilitating of extinction. 436

Despite the common perception that anxiety and fear are linked, they are distinctly different emotions. “Fear is a physical response to danger,” says Daniel R. Weinberger of the National Institute of Mental Health’s Clinical Brain Disorders Branch. “Anxiety is a

434 Myers, K M; Ressler, K J & Davis, M. Different mechanisms of fear extinction dependent on length of time since fear acquisition. Learning & Memory; 2006. 13: 216-223.

435 Johnson, JS; Escobar, M & Kimble, WL. Long-term maintenance of immediate or delayed extinction is determined by the extinction-test interval. Learning & Memory; 2010. 17: 639-644

436 Langton, JM & Richardson, R. The effect of D-cycloserine on immediate vs. delayed extinction of learned fear. Learning & Memory; 2010. 17: 547-551

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psychological response to perceived danger.” Fear is generated by a specific stimulus. Seeing a snake in the grass, for example, can trigger a fear response. Anxiety, which is not necessarily tied to a specific stimulus, is a feeling of being at risk, but from no imminent danger. Though of course for those who have a loss of skills in time-relation, that could be nullified and the threat could seem to be immediate until relieved either by reassurance or by a change in environment.

A good deal is now known about the neural circuitry involved in how conditioned fear can augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as shock pathways that project via the thalamus and perirhinal or insular cortex to the basolateral amygdala. In addition, fear and anxiety emanate from different regions of the amygdala. 437

Michael Davis tells us that the fear response comes from the central nucleus of the amygdala, the region responsible for commands for bodily responses associated with fear. Anxiety originates in an area responsible for emotions that mediates slower-onset, longer-lasting behavioural responses that may persist after a perceived threat terminates. (Idem)

Davis has studied the fear process called extinction, in which fear is reduced after repeated exposure to a fearful event without adverse consequences. He found that a receptor for a particular protein called N-methyl-D-aspartate (NMDA) in the amygdala is critical for the extinction of a conditioned fear. Davis also discovered that a compound called D-cycloserine (DCS) injected into rats’ amygdalas enhanced the function of the NMDA receptor and accelerated fear extinction. The idea is not to replace exposure therapy, but to speed it up.

LeDoux puts forward several hypotheses about the brain and emotion.

1. The proper level of analysis of a psychological function is the level at which that function is represented in the brain. Psychology textbooks often carve up the mind into functional pieces, such as perception, memory, and emotion. These are useful for organizing information into general areas of research but do not refer to real functions. The various classes of emotions are mediated by separate neural systems that have evolved for different reasons. The system we use to defend against danger is different from the one we use in other systems. The feelings that result from activating these different systems do not have a common origin.

2. The brain systems that generate emotional behaviours are highly conserved through many levels of evolutionary history. All animals, including people, have to satisfy certain conditions to survive in the world and fulfil their biological imperative to pass their genes on to their offspring. At a minimum, they need to obtain food and shelter, protect themselves from bodily harm, and procreate. This is as true of insects and worms as it is of fish, frogs, rats, and people. Each of these diverse groups of animals has neural systems that accomplish these behavioural goals. Within the animal groups that have a backbone and a brain (fish, amphibians, reptiles, birds, and mammals, including humans), it seems that the neural organization of particular emotional behavioural systems — like the systems underlying fearful, sexual, or feeding behaviours — is similar across species. This does not imply that all brains are the same. It means instead that our understanding of what it is to be human involves an appreciation of the ways in which we are like other animals as well as the ways in which we are different.

3. The system that detects danger is the fundamental mechanism of fear, and the behavioural, physiological, and conscious manifestations are the surface responses it orchestrates. This is not meant to imply that feelings are unimportant. It means that if we want to understand feelings we have to dig deeper.

437 Davis, M. Neural Systems Involved in Fear and Anxiety Measured With Fear-Potentiated

Startle. American Psychologist, November 2006. p741-756.

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4. If emotional feelings and emotional responses are effects caused by the activity of a common underlying system, we can then use the objectively measurable emotional responses to investigate the underlying mechanism and, at the same time, illuminate the system that is primarily responsible for the generation of the conscious feelings. Understanding emotions in the human brain is clearly an important quest, as most mental disorders are emotional disorders.

5. Conscious feelings, like the feeling of being afraid or angry or happy or in love or disgusted, are in one sense no different from other states of consciousness, such as the awareness that the roundish, reddish object before you is an apple; that a sentence you have just heard was spoken in a particular foreign language or that you've just solved the mystery of where you left your car keys. What differs between the state of being afraid and the state of perceiving red is not the system that represents the conscious content (fear or redness) but the systems that provide the inputs to the system of awareness. There is but one mechanism of consciousness and it can be occupied by mundane facts or highly charged emotions. Emotions easily push mundane events out of awareness, but non-emotional events (like thoughts) do not so easily displace emotions from the mental spotlight — wishing that anxiety or depression would go away is usually not enough.

6. Emotions are things that happen to us rather than things we will to occur. Although people set up situations to modulate their emotions all the time — going to the cinema or amusement parks; having a tasty meal; consuming alcohol and other recreational drugs — in these situations, external events are simply arranged so that the stimuli that automatically trigger emotions will be present. We have little direct control over our emotional reactions. Anyone who has tried to fake an emotion, or who has been the recipient of a faked one, knows all too well the futility of the attempt.

While conscious control over emotions is weak, emotions can flood consciousness. This is so because the wiring of the brain at this point in our evolutionary history is such that connections from the emotional systems to the cognitive systems are stronger than connections from the cognitive systems to the emotional systems. Once emotions occur they become powerful motivators of future behaviours; they chart the course of moment-to-moment action as well as set the sails toward long-term achievements. Also, our emotions can get us into trouble. When fear becomes anxiety; desire gives way to greed or annoyance turns to anger; anger to hatred; friendship to envy; love to obsession or pleasure to addiction; our emotions start working against us. Mental health is maintained by emotional hygiene, and mental problems, to a large extent, reflect a breakdown of emotional order. Emotions can have both useful and pathological consequences. (LeDoux, 1998, idem)

Recent advances in understanding brain function have been greatly benefited by the decomposition of global behavioural constructs into component parts or sub-domains. This approach has led to the discovery of parallel processing streams in vision438 and to the development of multiple memory systems in the brain.439,440,441

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438 Ungerleider LG & Mishkin M. Two cortical visual systems, in Ingle DJ, Goodale MA, Mansfield

RJW (eds): Analysis of Visual Behavior. Cambridge, MA: MIT Press, 1982.

439 Tulving E & Schacter DL. Priming and human memory systems. Science 247:301-306, 1990.

440 Weiskrantz L. Problems of learning and memory: One or multiple memory systems? Phil Trans R Soc Lond B 329:99-108, 1990.

441 Squire LR; Knowlton B & Musen G. The structure and organization of memory. Annu Rev Psychol 44:453-495, 1993.

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Social Behaviour and the Amygdala

David Amaral, 442 has presented animal data on the neuroanatomy of the amygdala and its connections with the orbitofrontal and temporal cortices. This was done with a view toward developing a larger picture of how the amygdala affects social behaviour — through which one could investigate how disruptions of amygdaloid connections might affect social impairments of functioning such as autism.

He suggested that early works by Brothers443 and Rosvald and colleagues444,445 were important in understanding these connections. Rhesus dominance hierarchies were disrupted when a subject had progressive amygdaloid lesions and was then reintroduced to a troupe. This permitted the inference that the amygdala was related to the emitting of socially appropriate behaviours, and that its lesions disrupted that functioning. Connections of the amygdala with the neocortex, basal forebrain, hippocampus, thalamus, and hypothalamus supported this.

Transmission of high-level sensory information to these centres is thought to influence or modify incoming sensory information at an early stage. Initially, the hypothesis was that positive or negative valence was assigned to the incoming sensory stimulus by outputs from the amygdala, and that other brain centres were aligned to produce approach or avoidance reactions. With this view, the amygdala was regarded as essential for social interactions. However, evaluation of the primates in a variety of social situations (viz. unconstrained dyad situations) resulted in discovering that the animals with bilateral lesions appeared more social and affiliative rather than less, and appeared less reluctant to confront novel stimuli. The lesioned animals also responded differently from other lesioned animals, in contrast with controls. Here too, increased social and affiliative behaviours occurred, rather than less.

With this observation of releasing social inhibitions, the social function of the amygdala was redefined as a ‘brake’ to inhibit behaviour and permit the animal time for evaluation of specific environmental stimuli (both inanimate objects and other organisms) with regard to assessing dangerousness. If dangerousness is perceived, then other brain areas are orchestrated to produce appropriate behavioural responses — integrating sensory, motor, visceral, and autonomic responses.

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Anxiety and Stress

Anxiety, according to Mowrer, motivates us to deal with traumatic events in advance of their occurrence; and because anxiety reduction brings about relief or security, it is a powerful reinforcer of instrumental behaviours (arbitrary responses that are learned because they satisfy some need or accomplish some goal). Responses that reduce anxiety are thus learned and maintained. 446

442 Amaral D. Amygdala, social behavior and autism. Program and abstracts of the American

Academy of Child and Adolescent Psychiatry 49th Annual Meeting; October 22-27, 2002; San Francisco, California. Institute IIIB.

443 Brothers L. The social brain: a project for integrating primate behavior and neurophysiology in a new domain. Concepts Neurosci. 1990;1:27-51.

444 Rosvald HE, Mirsky AF, Sarason I. Amygdalectomy and social behavior. J Comp Physiol Psychol. 1954;11:10-93.

445 Rosvald HE, Mirsky AF, Sarason I, Bransome ED, Beck LM. A continuous performance test of brain damage. J Consult Psychol. 1956;90:343-350.

446 Mowrer, O. H. A stimulus-response analysis of anxiety and its role as a reinforcing agent. Psychological Review, 1939; 46:553-565.

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Mowrer felt that anxiety is initially learned much like Watson had suggested — stimuli that are present during painful or traumatic events acquire the capacity to elicit anxiety. As anxiety is uncomfortable; when the stimuli that elicit it are present the anxious person will be motivated to change the circumstances, to remove herself from where the anxiety-causing stimuli are, and to avoid such situations in the future. The reduction in anxiety that these re-sponses produce then reinforces the behaviours and perpetuate their performance. This is often useful, but sometimes it leads to neurotic symptoms.

Consider a real-life example. A man is mugged in a lift. From that day on, he becomes afraid of riding in lifts. He avoids them as much as possible. He consults a therapist, who tries to reassure him that it is highly unlikely that he will be mugged again in a lift, especially if he rides at busy times. But the reassurance is not helpful. The man must get to his office on the thirteenth floor. This makes him anxious. In spite of the inconvenience that it causes him, each day he takes the stairs. The reduction in anxiety that results from taking the stairs, according to Mowrer's theory, maintains the neurotic behaviour of taking the stairs.

For someone with brain damage like MDL’s they often cannot, “be motivated to change the circumstances, to remove herself from where the anxiety-causing stimuli are, and to avoid such situations in the future”. Firstly, they are usually not able to physically remove themselves from any situation as they are always under someone’s control who may not feel the anxiety as does the brain-damaged person or may even be causing it. Secondly, they may not have the neurological capacity to reduce the anxiety of their own volition and this has to be done for them if possible. So, not only do the carers have to think for the person but they also have to act. Frequently, there will be conflict here with the PC brigade. More and more since this idea was set loose amongst society, especially disabled society, there has been a reluctance to do anything that might be seen as a direct imposition of able will against disabled will. Commonsense must prevail and circumstances alter cases.

Stress as a cause of illness is a well-established aetiology.447 It has now been established that there is a retrospective biomarker for extended stress and Karlen et al have found that cortisol in hair might well serve as such a marker of increased cortisol production that reflects exposure to major life stressors and possibly psychological illnesses with important implications for clinical practice.448 The experiencing of serious life events seems to be more important in raising cortisol levels in hair than does perceived stress. This has considerable importance for MDL in that it is relatively simple to measure cortisol from cut hair. The researchers used hair from the posterior vertex (apex) area. The cortisol was measured using a competitive radioimmunoassay in methanol. The extracts of hair had been frozen in liquid nitrogen and mechanically pulverised.

There is ample evidence that psychological stress (PS) adversely affects many diseases. (Soliman et al, Idem, 2012) Recent evidence has shown that intense stressors can increase inflammation within the brain, a known mediator of many diseases. 449 Barnum et al found that adolescent mice subjected to chronic PS had increased basal expression of inflammation within the midbrain. Chronic unpredicted stress and chronic PS mice also had an impaired inflammatory response to a subsequent lipopolysaccharide challenge and PS mice displayed increased anxiety and depressive-like behaviours following chronic stress. (Idem)

447 Soliman A, Udemgba C, Fan I, Xu X, Miler L, Rusjan P, Houle S, Wilson AA, Pruessner J, Ou XM,

Meyer JH. Convergent Effects of Acute Stress and Glucocorticoid Exposure upon MAO-A in Humans. J Neurosci. 2012 Nov 28;32(48):17120-17127.

448 Karlen, J; Ludvidsson, J; Frostell, A; Theodorsson, E; & Faresjo, T. Cortisol in hair measured in young adults - a biomarker of major life stressors? BMC Clinical Pathology; 2011, 11: 12 Published: 25 October 2011.

449 Barnum, CJ; Pace, TWW; Hu, F; Neigh, GN & Tansey, MG. Psychological stress in adolescent and adult mice increases neuroinflammation and attenuates the response to LPS (lipopolysaccharide ) challenge. Journal of Neuroinflammation 2012, 9:9 (16 January 2012)

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This research indicated that adult mice, subjected to acute predatory stress, had increased gene expression of inflammatory factors. It concluded that the results demonstrate that predatory stress, an ethologically relevant stressor, can elicit changes in neuro-inflammation and behaviour. (Idem)

Traumatic Stress

The difference between a fear conditioning theory of phobia and PTSD is one of where the conditioning process gets its strength. In the case of prepared phobic learning, the conditioned stimulus makes the learning especially strong. The unconditioned stimulus is typically unpleasant and may even be painful, but is not necessarily extraordinary.

However, in the case of PTSD, the conditioned stimulus events are less notable than the unconditioned stimulus. PTSD, in fact, is defined in DMS-III-R as involving a trauma that is far outside the realm of experiences in ordinary life.

Once we assume that the trauma in PTSD is an extraordinary event, a fairly standard view of the way the amygdala mediates conditioned fear provides a plausible account of this disorder. Until recently, we didn’t know exactly what combination of factors came together to make up the horrendous events at the neuronal level, but it was easily imagined that such a neural condition existed; one that bombards the amygdala with

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electrical and chemical signals that are particularly potent as reinforcers of Pavlovian conditioning. These powerful reinforcing stimuli are then linked synaptically with the sounds, sights, and smells of the events, which also reach the amygdala. Later, the occurrence of these same conditioned stimuli, or stimuli related to them, elicit profound fear responses by reactivating these powerfully potentiated amygdala circuits.

Very recently, Simmons et al 450 have used a multiple control group design for testing the hypothesis that trauma disrupts emotional circuits relevant to face processing, and that the subsequent development of PTSD is related to less engagement of frontal top-down circuitry 451,452.

Soldiers exposed to combat in Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) are at high risk for post-traumatic stress disorder (PTSD)453. Breslau 454 & Boscarino 455 recognised that PTSD is an aversive reaction to a life-threatening, emotionally salient event that is associated with increased mortality and morbidity. The majority of those who experience such an event have a substantial stress response456 that is characterized by activation in physiological and neuroendocrine systems. 457,458,459,460 Such stress responses are associated with hyper-activation in the insula and amygdala brain structures that are involved in processing emotional information.461,462

450 Simmons, AN; Matthews, SC; Strigo, IA; Baker, DG; Donovan, HK; Motezadi, A; Stein, MB; &

Martin P Paulus, MP. Altered amygdala activation during face processing in Iraqi and Afghanistani war veterans Biology of Mood & Anxiety Disorders 2011, 1:6 Publication date 12 October 2011 ISSN 2045-5380

451 Shin LM; Rauch SL; & Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci 2006, 1071:67-79.

452 Liberzon I; & Sripada CS. The functional neuroanatomy of PTSD: a critical review. Prog Brain Res 2008, 167:151-169.

453 Hoge CW; Auchterlonie JL; & Milliken CS. Mental health problems, use of mental health services, and attrition from military service after returning from deployment to Iraq or Afghanistan. JAMA 2006, 295:1023-1032.

454 Breslau N. The epidemiology of posttraumatic stress disorder: what is the extent of the problem? J Clin Psychiatry 2001, 62(Suppl 17):16-22.

455 Boscarino JA. Posttraumatic stress disorder and mortality among U.S. Army veterans 30 years after military service. Ann Epidemiol 2006, 16:248-256.

456 North CS; Nixon SJ; Shariat S; Mallonee S; McMillen JC; Spitznagel EL; & Smith EM. Psychiatric disorders among survivors of the Oklahoma City bombing. JAMA 1999, 282:755-762.

457 Geracioti TD Jr; Carpenter LL; Owens MJ; Baker D;, Ekhator NN; Horn PS; Strawn JR; Sanacora G; Kinkead B; Price LH; & Nemeroff CB. Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression. Am J Psychiatry 2006, 163:637-643.

458 Bremner JD; Vythilingam M; Anderson G; Vermetten E; McGlashan T; Heninger G; Rasmusson A; Southwick SM; & Charney DS. Assessment of the hypothalamic-pituitary-adrenal axis over a 24-hour diurnal period and in response to neuroendocrine challenges in women with and without childhood sexual abuse and posttraumatic stress disorder. Biol Psychiatry 2003, 54:710-718.

459 Liberzon I; Abelson JL; Flagel SB; Raz J; & Young EA; Neuroendocrine and psychophysiologic responses in PTSD: a symptom provocation study. Neuropsychopharmacology 1999, 21:40-50.

460 Bremner JD; Licinio J; Darnell A; Krystal JH; Owens MJ; Southwick SM; Nemeroff CB; & Charney DS. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 1997, 154:624-629.

461 Simmons AN; Paulus MP; Thorpe SR; Matthews SC; Norman SB; & Stein MB. Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence. Biol Psychiatry 2008, 64:681-690.

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Amygdala activation has been strongly linked to negative affective states in fear processing463,464,465 and PTSD. 466,467,468,469 A number of studies have successfully used face tasks to probe affective circuits such as the amygdala to better understand affective symptomatology in PTSD. 470,471,472,473,474,475 These findings suggest strongly that PTSD is related to amygdala hyper-activation, it has also been suggested that the experience of emotional trauma in and of itself may relate to significant differences in the functioning of emotional processing circuits. (Simmons, et al, Idem; 2011)

Exposure to combat where there is a risk of death (in other words, Criterion A for the diagnosis of PTSD476; can have significant psychiatric or cognitive repercussions477 even when it does not result in PTSD. However, one important difference between those exposed to trauma who develop PTSD versus those who do not may be in the increased

462 Etkin A; & Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional

processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 2007, 164:1476-1488.

463 Shin LM; & Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuro-psychopharmacology 2010, 35:169-91.

464 Barad M; Gean PW; & Lutz B. The role of the amygdala in the extinction of conditioned fear. Biol Psychiatry 2006, 60:322-328.

465 Rudy JW; Huff NC; & Matus-Amat P. Understanding contextual fear conditioning. Neurosci Biobehav Rev 2004, 28:675-685.

466 Rauch SL; Shin LM; & Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biol Psychiatry 2006, 60:376-382.

467 Shin LM, et al (Idem). Ann N Y Acad Sci 2006, 1071:67-79.

468 Hull AM. Neuroimaging findings in post-traumatic stress disorder. Systematic review. Br J Psychiatry 2002, 181:102-110.

469 Simmons AN; & Matthews SC. Neural circuitry of PTSD with or without mild traumatic brain injury: a meta-analysis. Neuropharmacology 2011 [Epub ahead of print].

470 Bryant RA; Kemp AH; Felmingham KL; Liddell B; Olivieri G; Peduto A; Gordon E; Williams LM. Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: An fMRI study. Hum Brain Mapp 2008, 29:517-523

471 Fonzo GA; Simmons AN; Thorp SR; Norman SB; Paulus MP; & Stein MB. Exaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder. Biol Psychiatry 2010, 68:433-441.

472 Bryant RA, et al. (idem)Hum Brain Mapp 2008, 29:517-523.

473 Shin LM; Wright CI; Cannistraro PA; Wedig MM; McMullin K; Martis B; Macklin ML; Lasko NB; Cavanagh SR; Krangel TS; Orr SP; Pitman RK; Whalen PJ; & Rauch SL. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 2005, 62:273-281.

474 Armony JL; Corbo V; Clement MH; & Brunet A. Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions. Am J Psychiatry 2005, 162:1961-1963.

475 Protopopescu X; Pan H; Tuescher O; Cloitre M; Goldstein M; Engelien W; Epstein J; Yang Y; Gorman J; LeDoux J; Silbersweig D; & Stern E. Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry 2005, 57:464-473.

476 American Psychiatric Association: Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th edn. Washington, DC: American Psychiatric Association; 2000.

477 Vasterling JJ; Proctor SP; Amoroso P; Kane R; Heeren T; & White RF. Neuropsychological outcomes of army personnel following deployment to the Iraq war. JAMA 2006, 296:519-529.

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avoidance of aversive experiences and emotions478. This maladaptive response to aversive emotions following trauma may enhance and maintain symptoms of PTSD479 by diminishing the likelihood of fear extinction480 .

Recent neural models of PTSD and trauma exposure suggest that the functional networks associated with the amygdala may be of similar importance to understanding emotional processing as the amygdala itself481. These theories posit that PTSD is, in part, a manifestation of ineffective top-down modulation of the amygdala and limbic circuitry by the prefrontal cortex.482,483 This model has been proposed as a mechanism for the depersonalization seen in PTSD484. For example, it has been shown that reduced functional connections between the amygdala and prefrontal cortex relate to increased levels of depersonalization following emotional trauma, suggesting that impaired functioning of this prefrontal modulatory network may be related to clinical symptoms in traumatized individuals. 485

Earlier studies have shown that, using a simple face-matching task, there is a clinically meaningful differences in amygdala activation in groups with mood and anxiety disorders486,487,488 and shown significant changes in response to psychopharmacological intervention.489,490 A simple face-matching task has also been successful in delineating differences in functionally connected networks in psychiatric populations491. While face tasks do not use trauma-related stimuli and do not directly provoke re-experiencing symptoms in PTSD, they do require appraisal of social emotions, thus they appear to provide a method to measure affective circuitry in a theoretically and clinically meaningful way.

478 Foa EB; & Kozak MJ. Emotional processing of fear: exposure to corrective information. Psychol

Bull 1986, 99:20-35.

479 Krause ED; Kaltman S; Goodman LA; & Dutton MA. Avoidant coping and PTSD symptoms related to domestic violence exposure: a longitudinal study. JTrauma Stress 2008, 21:83-90.

480 Foa EB. Psychological processes related to recovery from a trauma and an effective treatment for PTSD. Ann N Y Acad Sci 1997, 821:410-424.

481 Liberzon I; & Sripada CS. The functional neuroanatomy of PTSD: a critical review. Prog Brain Res 2008, 167:151-169.

482 Shin LM. et al (Idem); Ann N Y Acad Sci 2006, 1071:67-79.

483 Liberzon I, et al. (idem) Prog Brain Res 2008, 167:151-169.

484 Sierra M; & Berrios GE. Depersonalization: neurobiological perspectives. BiolPsychiatry 1998, 44:898-908.

485 Lanius RA; Williamson PC; Boksman K; Densmore M; Gupta M; Neufeld RW; Gati JS; & Menon RS. Brain activation during script-driven imagery induced dissociative responses in PTSD: a functional magnetic resonance imaging investigation. Biol Psychiatry 2002, 52:305-311.

486 Matthews SC; Strigo IA; Simmons AN; O'Connell RM; Reinhardt LE; & Moseley SA. A multimodal imaging study in U.S. veterans of Operations Iraqi and Enduring Freedom with and without major depression after blast-related concussion. Neuroimage 2011, 54(Suppl 1):S69-S75.

487 Matthews SC; Strigo IA; Simmons AN; Yang TT; & Paulus MP. Decreased functional coupling of the amygdala and supragenual cingulate is related to increased depression in unmedicated individuals with current major depressive disorder. J Affect Disord 2008, 111:13-20.

488 Stein MB; Simmons AN; Feinstein JS; & Paulus MP. Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry 2007, 164:318-327.

489 Arce E; Simmons AN; Lovero KL; Stein MB; & Paulus MP. Escitalopram effects on insula and amygdala BOLD activation during emotional processing. Psychopharmacology (Berl) 2008, 196:661-672.

490 Paulus MP; Feinstein JS; Castillo G; Simmons AN; & Stein MB. Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch Gen Psychiatry 2005, 62:282-288.

491 Matthews SC, et al (idem). J Affect Disord 2008, 111:13-20.

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Conditioned stimuli activate the amygdala unconsciously, but at the same time reach the temporal lobe memory system and can lead to the recall of the initial trauma or to the recall of recent episodes in which the initial trauma is relieved. These conscious memories, together with the awareness of now being in a state of strong emotional arousal (due to the unconscious activation of fear responses through the amygdala), then gives rise to conscious anxiety and worry. These cognitions about the emotional arousal, in turn, flow from the neocortex and hippocampus to further arouse the amygdala. The bodily expression of the amygdala's responses keeps the cortex aware that emotional arousal is ongoing, and further facilitates the anxious thoughts and memories. The brain enters into a vicious cycle of emotional and cognitive excitement and, like a runaway train, just keeps picking up speed.

It seems that in PTSD, as for phobic learning, the direct projections to the amygdala from subcortical sensory processing regions are involved. If this were so, it would explain why the attacks are so impulsive and uncontrollable and tend to generalize so readily. As noted below, the subcortical pathways are quick and dirty transmission routes. They turn the amygdala on and start emotional reactions before the cortex has a chance to figure out what it is that is being reacted to. Since these pathways are not very capable of distinguishing between stimuli, generalization readily occurs.

Perhaps trauma, for some reasons (genetic or experiential) in some persons, biases the brain in such a way that the thalamic pathways to the amygdala predominate over the cortical ones, allowing these low-level processing networks to take the lead in the learning and storage of information. Later exposure to stimuli that even remotely resemble those occurring during the trauma would then pass, like greased lightning, over the potentiated pathways to the amygdala, unleashing the fear reaction. Quite possibly, it is harder for one to gain conscious wilful control over these subcortical pathways. At the same time, because conscious memories are formed during anxiety attacks, the bodily sensations associated with those attacks, when recognized consciously, become potent elicitors or at least facilitators of anxiety.

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FEAR CONDITIONING: A MODEL SYSTEMS APPROACH

Background and Definitions Threatening stimuli produce a variety of species-typical defensive responses, such as changes in autonomic activity (e.g., heart rate, arterial pressure, skin conductance, pupillary dilation), endocrine function (‘stress’), behavioural reactions, reflex modulation (fear-potentiated startle), and pain sensitivity.

However, response to pain can be modified by anti-anxiety drugs and tranquilisers. Pain is unique in that it is the only sense that has a major emotional component. The sensory and emotional aspects of pain can be dissociated by certain drugs. For example, high doses of anti-anxiety agents such as certain tranquilizers do not seriously impair discrimination between stimuli ranging from painless to extremely painful. However, even though subjects may report certain stimuli as being excruciatingly painful they do not seem to care. The drug appears to leave the sensory aspects of pain intact, while almost completely suppressing the emotional aspects. Traditional pain-killers like morphine suppress the sensation of pain itself.

This repertoire of fear reactivity is largely biologically innate; however, through learning, novel stimuli can come to control these responses through their association with threatening stimuli492. Because the set of stimuli and responses involved in fear conditioning is relatively simple and well defined, it has been possible to track the neural pathways

492 Blanchard DC & Blanchard RJ. Innate and conditioned reactions to threat in rats with

amygdaloid lesions. J Comp Physiol PsychoI81:281-290, 1972.

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mediating this type of emotional memory formation.

Using modern neuro-anatomic, behavioural, and electro-physiologic recording techniques, researchers have begun to uncover the neural circuits involved in emotional learning and memory as measured by fear conditioning. Across several species and experimental paradigms, the amygdala has emerged as a brain region critical for the learning and/or expression of conditioned fear associations.493,494,495,496,497,498

Lesions of the amygdala disrupt the development of conditioned fear responses. A number of pharmacologic agents with anxiolytic properties used in the treatment of human anxiety disorders have been localized to action sites within the amygdala499.

The pathways by which sensory information reaches the amygdala for emotional evaluation in fear conditioning have also been detailed, particularly in the auditory domain. The direct pathway may function to prime the amygdala to respond quickly to danger, leaving more intricate analysis of the incoming signal for the cortical pathway. This neurobiological warning signal can grant organisms an evolutionary advantage by rapidly communicating the existence of potentially threatening environmental stimuli. Either of these transmission routes is sufficient to mediate conditioned fear to single auditory cues but the cortical pathway may be necessary for appropriate responses to tones that must be discriminated from one another. These parallel input pathways converge in the lateral nucleus of the amygdala, which serves as a sensory interface to the region. Neurons in the lateral nucleus that respond to acoustic input are also sensitive to somato-sensory stimulation. (LaBar, 1997, idem)

Whilst it is clear that the amygdala plays a central role in the computation of emotional stimulus value, there is recent evidence that other brain regions make contributions to aspects of emotional processing within a fear-conditioning framework. The integrity of the hippocampus, for example, is not essential for conditioning to simple phasic cues but is critical for conditioning to contextual stimuli 500,501,502 . These findings are consistent with

493 LeDoux JE. In search of an emotional system in the brain: Leaping from fear to emotion and

consciousness, in Gazzaniga M (ed): The Cognitive Neurosciences. Cambridge, MA: MIT Press, 1995, pp 1049-1062.

494 Kapp BS; Wilson A & Pascoe J, et al. A neuroanatomical systems analysis of conditioned bradycardia in the rabbit, in Gabriel M, Moore J (eds): Learning and Computational Neuroscience: Foundations of Adaptive Networks. Cambridge, MA: MIT Press, 1990, pp 53-90.

495 LeDoux JE. Information flow from sensation to emotion: Plasticity in the neural computation of stimulus value, in Gabriel M, Moore J (eds): Learning and Computational Neuroscience: Foundations of Adaptive Networks. Cambridge, MA: MIT Press, 1990, pp 3-52.

496 Davis M. The role of the amygdala in conditioned fear, in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 255-306.

497 Fanselow MS. Neural organization ofthe defensive behavior system responsible for fear. Psycho nom Bull Rev 1:429-438, 1994.

498 Sananes CB & Davis M. N-Methyl-D-aspartate lesions of the lateral and basolateral nuclei of the amygdala block fear-potentiated startle and shock sensitization of startle. Behav Neurosci 106:7280,1992.

499 LaBar, KS & LeDoux, JE. Emotion and the Brain: An Overview. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

500 Kim JJ & Fanselow MS. Modality-specific retrograde amnesia of fear. Science 256:675-677,1992.

501 Phillips RG & LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274285,1992.

502 Phillips RG & LeDoux JE. Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. Learn Mem 1:34-44, 1994.

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cognitive theories regarding the role of the hippocampus in complex stimulus processing.503,504,505,506 This contextual information may be important in allowing organisms to learn and remember the environmental sub texts in which threatening stimuli occur. The hippocampus may be exerting its influence via anatomic interactions with the amygdala. These connections provide a neural passageway by which higher-order cognitive and mnemonic processes can trigger and shape emotional experience, and vice versa.

In addition, lesions of the ventro-medial pre-frontal cortex selectively interfere with the extinction of emotional learning in fear conditioning studies. 507, 508 . This result extends the long-observed perseveration phenomena following prefrontal cortex damage509,510 into the emotional domain. The extinction process appears to involve active brain processing511, which may be regulated by prefrontal-amygdala projections512. The neural traces laid down in amygdala neurons during emotional learning are relatively indelible, and their suppression requires neocortical input. 513,514 If extended into human populations, these results may have clinical relevance for neurologic patients with persistent affective disorders

Fear Conditioning in Humans Human subjects do exhibit reliable conditioned fear responses515,516,517 although these responses may be influenced somewhat by certain personality characteristics518,519 and cognitive processes520. Despite its success in animal

503 Nadel L. Hippocampus and space revisited. Hippocampus 1:221-229, 1991.

504 Hirsh R. The hippocampus and contextual retrieval of information from memory: A theory. Behav Bioi 12:421-444, 1974

505 Sutherland RJ & Rudy JW. Configural association theory: The role of the hippocampal formation in learning, memory, and amnesia. Psychobiology 17:129-144, 1989.

506 Cohen NJ & Eichenbaum H. Memory, Amnesia, and the Hippocampal System. Cambridge, MA: MIT Press, 1993

507 Morgan MA; Romanski LM & LeDoux JE. Extinction of emotional learning: Contribution of medial prefrontal cortex. Neurosci Left 163:109-113, 1993.

508 Morgan MA & LeDoux JE. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. Behav Neurosci 109:681-688, 1995.

509 Fuster JM. The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal Lobe, 2d ed. New York: Raven Press, 1989

510 Janowsky JS; Shimamura AP; Kritchevsky M & Squire LR. Cognitive impairment following frontal lobe damage and its relevance to human amnesia. Behav Neurosci 103:548-560, 1989.

511 Falls WA; Miserendino MJD & Davis M. Extinction of fear-potentiated startle: Blockade by infusion of an NMDA antagonist into the amygdala. J Neurosci 12:854-863, 1992.

512 Amaral DG; Price JL; Pitkanen A & Carmichael ST. Anatomical organization of the primate amygdaloid complex, in Aggleton IP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 1-66.

513 Rolls ET. A theory of emotion and consciousness, and its application to understanding the neural basis of emotion,in Gazzaniga M (ed): The Cognitive Neurosciences. Cambridge, MA: MIT Press, 1995, pp 1091-1106.

514 LeDoux IE; Romanski LM & Xagoraris AE. Indelibility of subcortical emotional memories. J Cogn Neurosci 1:238-243, 1989.

515 Hodes RL; Cook EW & Lang PJ. Individual differences in autonomic response: Conditioned association or conditioned fear? Psychophysiology 22: 545-560, 1985.

516 Grillon C; Ameli R & Woods SW, et al. Fear-potentiated startle in humans: Effects of anticipatory anxiety on the acoustic blink reflex. Psychophysiology 28:588-595, 1991.

517 Fredrickson M; Annas P & Georgiades A, et al. Internal consistency and temporal stability of classically conditioned skin conductance responses. Bioi Psychol 35:153-163, 1993.

518 Eysenck HJ. The conditioning model of neurosis. Behav Brain Sci 2:155-199,1979.

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research, fear conditioning has not been widely used in the neuropsychological assessment of human brain function, where little is known about the neural basis of emotion.

It has been shown that, as in other species, the integrity of the medial temporal lobe is important for conditioned emotional learning in humans, although assessment of the relative contributions of particular structures within this region must await future investigation in patients with more restricted damage and functional imaging studies in healthy adults. (LaBar, 1997 idem) Fear conditioning paradigms have also been proposed as a model system for studying emotional processing in clinical populations with affective and traumatic memory disorders.521,522

The amygdala has been implicated in aspects of fear regulation in both human523,524,525 and non-human studies. 526 The amygdala also appears to be involved in stimulus reward learning527,528 and may contribute to dysfunction characterized by other disorders of affect (Aggleton, 1992, idem). Gray 529 has incorporated the septo-hippocampal system into a behavioural inhibition model of anxiety and stress, with an emphasis on its role in cognitive monitoring and coping strategies. This conception reflects how cognitive influences enter into emotional networks and complements the investigation of the role of the hippocampus in more complex aspects of conditioned fear. (LaBar, 1997, idem)

The integrity of the orbitofrontal cortex is critical for the appropriate adjustment of behavioural responses to changing reinforcement contingencies, which may account for some of the emotional deficits following frontal lobe damage530. The orbitofrontal cortex may also function as a link between internal somatic states and social perceptions in the

519 Guimaraes FS; Hellewell J & Hensman R, et al. Characterization of a psychophysiological

model of classical fear conditioning in healthy volunteers: Influence of gender, instruction, personality and placebo. Psychopharmacology 104:231-236, 1990.

520 Davey G (ed): Cognitive Processes and Pavlovian Conditioning in Humans. Chichester, England: Wiley, 1987.

521 Ohman A. Fear-relevance, autonomic conditioning, and phobias: A laboratory model. in Sjoden PO, Bates S, Dockens WS (eds): Trends in Behavior Therapy. New York: Academic Press, 1979, pp 107-133.

522 Charney DS; Deutch A Y, & Krystal JH, et al. Psychobiologic mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry 50:294-305, 1993.

523 Adolphs R; Tranel D; Damasio H & Damasio AR. Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature 372:669-672, 1994.

524 Aggleton JP. The functional effects of amygdala lesions in humans: A comparison with findings from monkeys, in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 485-504.

525 Halgren E. Emotional neurophysiology of the amygdala within the context of human cognition, in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 191-228.

526 Slotnick BM. Fear behavior and passive avoidance deficits in mice with amygdala lesions. Physiol Behav 11:717-720, 1973.

527 Gaffan D. Amygdala and the memory of reward, in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1992, pp 471-484.

528 Everitt BJ & Robbins TW. Amygdala-ventral striatal interactions and reward-related processes, in Aggleton JP (ed): The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley- Liss, 1992, pp 401-430.

529 Gray JA. The Psychology of Fear and Stress. 2d ed. Cambridge, England: Cambridge University Press, 1987

530 Rolls ET. A theory of emotion and consciousness, and its application to understanding the neural basis of emotion,in Gazzaniga M (ed): The Cognitive Neurosciences. Cambridge, MA: MIT Press, 1995, pp 1091-1106.

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guidance of behaviour531, and prefrontal-cingulate-amygdala connectivity with effector structures seems to be particularly important for mediating socio-emotional interactions.

Thus, particular structures of the limbic forebrain appear to play distinct roles in affective processing, some of which can be understood as relating to more general functions of these regions outside of the emotional domain. Of the structures comprising the limbic system hypothesis, the amygdala has been most consistently linked with emotional stimulus evaluation, a function originally attributed to the hypothalamus by previous theorists.

There seems undeniable evidence that the amygdala research carries an important message that is connected with MDL’s emotional and anxiety problems. What is not known is if the problem is within the amygdala or whether it is to do with the interconnections between it and other parts of the brain. MDL’s fear responses need of course to be well understood because if they are not, then there could be confusion about the origins of them and how to mitigate the outcomes. This means that each component should be analysed so that it can be ascertained if a lasting fear is due to a failure of extinction or whether it is due to a reasonable objection to environmental influences. Consideration also needs to be given to the fact that MDL does not easily understand or learn coping strategies.

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EMOTIONAL DISORDERS IN RELATION TO UNILATERAL BRAIN DAMAGE

The hypothesis of hemispheric specialization for psychological phenomena other than language and cognitive functions, such as emotions and affect, is a recent one in the history of neuropsychology. Up to that time, clinical studies of emotional disorders did not attribute any differences between left and right brain lesions.

The problem of a possible hemispheric asymmetry in the regulation of emotions was raised by some clinical observations made around fifty years ago. They were independently made during pharmacologic inactivation of the right and left hemispheres and during observation of the emotional behaviour of unilaterally brain-damaged patients.532,533 The interest of these early clinical studies does not reside only in the fact that they called the attention of neuropsychologists to a problem that had been previously substantially neglected. It also stems from the fact that the theoretical models proposed by those who made these clinical observations later served to orient most of the experimental studies devised to clarify the links between emotions and hemispheric specialization. 534 Gainotti found that there was a response of either appropriate or inappropriate forms of emotional reaction, depending upon the sided location of the injury.

Emotion perception forms an integral part of social communication, and is critical to attain developmentally appropriate goals. This skill, which emerges relatively early in development is driven by increasing connectivity among regions of a distributed socio-cognitive neural network, and may be vulnerable to disruption from early childhood TBI. 535

531 Damasio A; Tranel D & Damasio H. Somatic markers and the guidance of behavior: Theory

and preliminary testing, in Levin H, Eisenberg H, Benton A (eds): Frontal Lobe Function and Dysfunction. New York: Oxford University Press, 1991, pp 217-229.

532 Gainotti G. Reaction ‘catastrophiques’ et manifestations d'indifférence au cours des atteintes cérébrales. Neuropsychologia 7:195-204, 1969.

533 Gainotti G. Emotional behavior and hemispheric side of the lesion. Cortex 8:41-55, 1972.

534 Gainotti G. Emotional Disorders in Relation to Unilateral Brain Damage. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

535 Ryan NP; Anderson V; Godfrey C; Beauchamp MH; Coleman L; Eren S; Rosema S; Taylor K & Catroppa C. Predictors of very long-term sociocognitive function after pediatric traumatic brain injury. J Neurotrauma. 2013 Oct 22. [Epub ahead of print]

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Ryan et al (idem) found that survivors of severe childhood TBI had significantly poorer emotion perception than controls and young adults with mild to moderate injuries. Furthermore, poorer emotion perception was associated with reduced volume of the posterior corpus callosum and the presence of frontal pathology. They considered that their research findings lent support to the vulnerability of the immature 'social brain' network to early disruption, and underscored the need for context-sensitive rehabilitation that optimized early family environments to enhance recovery of emotion perception skills after childhood TBI.

Green et al found that patients with recently acquired TBI are impaired in their ability to perceive emotions in faces. Diffuse axonal injury (DAI) alone may cause facial emotion perception deficits. 536 They examined whether facial emotion perception was compromised in adults with recent traumatic brain injury (TBI). Few studies have examined emotion perception in TBI; those that have, examined chronic patients only. Recent and chronic TBI populations differ according to degree of functional reorganization of the brain, use of compensatory strategies, and severity of cognitive impairments—any of which might differentially affect presentation of emotion perception deficits. A secondary aim of the study was to utilize the TBI population—in whom DAI is a cardinal neurological feature—to examine the suggestion of Adolphs et al. See below—[Journal of Neuroscience 20(7) (2000) 2683] that damage to white matter tracts should give rise to emotion perception deficits.

Thirty TBI participants were involved in the study and 30 age-matched controls were tested. A 2 x 3 mixed design was employed. The dependent variable was accuracy on neutral and emotional face perception tests. It was found that (1) The TBI group performed significantly less accurately than the matched controls on the facial emotion perception tasks, whereas the groups performed equivalently on a non-emotional face perception control task. (2) A sub-group of TBI participants without evidence of focal injury to areas of the brain most commonly implicated in facial emotion perception was as impaired on the emotion perception tasks as a second sub-group who had sustained focal lesions to these areas. This suggests an alternative neurological mechanism for deficits in the first sub-group, such as DAI.

Comprehension and Expression of Emotions in Right- and Left-brain-Damaged Patients Since the exact nature of the emotional modifications observed after right and left brain injury remain controversial, a large series of investigations were undertaken to clarify this issue by means of experiments with both normal subjects and patients with unilateral hemispheric damage. Although these investigations have explored various aspects of the emotional behaviour, the attention of neuropsychologists has been focused mainly on the most cognitive components of emotions, namely the comprehension of emotional stimuli and the (facial or vocal) expression of emotions. This was partly due to the assumption that the type of information processing typical of the right hemisphere (and characterized by a syncretic and holistic rather than by a sequential and analytical style) may be particularly suited to the treatment of emotional information537.

The methodology of investigations conducted on patients with focal brain injury has consisted in matching the capacity of right- and left brain-damaged patients to comprehend and/or express emotions at the facial level or through the tone of voice. Following this research strategy, several authors have shown that right-brain-damaged patients are consistently impaired in recognizing emotions expressed through tone of voice538,539,540 in the identification of facial emotional expressions541,542 and in the ability to

536 Green RE, Turner GR, Thompson WF. Deficits in facial emotion perception in adults with recent traumatic brain injury. Neuropsychologia. 2004;42(2):133-41.

537 Tucker DM. Neural substrates of thought and affective disorders, in Gainotti G, Caltagirone C (eds): Emotions and the Dual Brain. Heidelberg: SpringerVerlag, 1989, pp 225-234.

538 Ross ED. The aprosodias. Arch Neurol 38:561569,1981.

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express emotions through facial movements543,544 or with the prosodic contours of speech545.

According to Adolphs et al, although lesion and functional imaging studies have broadly implicated the right hemisphere in the recognition of emotion, neither the underlying processes nor the precise anatomical correlates are well understood. They analyzed focal brain lesions as a function of task performance in 108 subjects by coregistration in a common brain space, and statistical analyses of their joint volumetric density revealed specific regions in which damage was significantly associated with impairment.

This showed that recognizing emotions from visually presented facial expressions requires right somatosensory-related cortices. The findings are consistent with the idea that we recognize another individual's emotional state by internally generating somatosensory representations that simulate how the other individual would feel when displaying a certain facial expression. Follow-up experiments revealed that conceptual knowledge and knowledge of the name of the emotion draw on neuroanatomically separable systems. Right somatosensory-related cortices thus constitute an additional critical component that functions together with structures such as the amygdala and right visual cortices in retrieving socially relevant information from faces. 546

On the other hand, investigations conducted on normal subjects have allowed a better control of the hypothesis, assuming a different specialization of the right and left hemispheres for negative and positive emotions, respectively. Even if some studies have supported the hypothesis of an interaction between hemisphere and positive or negative emotional valence, most have failed to confirm it. On the contrary, the great majority of these investigations have substantially confirmed the hypothesis of a general superiority of the right hemisphere for functions of emotional comprehension and expression. (Gainotti, 1997, idem)

This fact has led some authors to hypothesize that right hemispheric dominance for emotions may mainly concern the communicative aspects of emotional behaviour rather than other, more basic components of emotions. This line of thought has been developed in particular by Ross (idem), who has suggested that disorders of nonverbal communication might be the primary defect of right-brain-damaged patients and that emotional disturbances usually observed in these patients may simply be a consequence of their basic inability to comprehend and express emotions. (Gainotti, 1997, idem)

539 Benowitz LI; Bear DM & Rosenthal R, et al: Hemispheric specialization in nonverbal

communication. Cortex 19:5-11, 1983.

540 Blonder LX; Bowers D & Heilman KM. The role of the right hemisphere in emotional communication. Brain 114:1115-1127, 1991.

541 Bowers D; Bauer RM; Coslett HB & Heilman KM. Processing of faces by patients with unilateral hemisphere lesions: Dissociation between judgments of facial affect and facial identity. Brain Cogn 4:258272, 1985.

542 Borod JC; Koff E; Perlman-Lorch M & Nicholas M. The expression and perception of facial emotion in brain-damaged patients. Neuropsychologia 24:169180,1986.

543 Blonder LX; Burns A & Bowers D, et al. Right hemisphere facial expressivity during natural conversation. Brain Cogn 21:44-56, 1993.

544 Green, RE; Turner, GR; & Thompson, WF. Deficits in facial emotion perception in adults with recent traumatic brain injury. Neuropsychologia. 2004;42(2):133-41.

545 Tucker DM; Watson RT & Heilman KM. Discrimination and evocation of affectively intoned speech in patients with right parietal disease. Neurology 27:947-950, 1977

546 Adolphs R; DamasioH; Tranel D; Cooper G & Damasio AR. A Role for Somatosensory Cortices in the Visual Recognition of Emotion as Revealed by Three-Dimensional Lesion Mapping. The Journal of Neuroscience, 1 April 2000, 20(7): 2683-2690

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According to this viewpoint, the indifference reaction of right-brain damaged patients should not be considered as an inappropriate form of emotional behaviour but simply the consequence of a basic inability to correctly evaluate emotional signals and to express an otherwise intact emotional experience.

However, Gainotti (1997, idem)believes that the data suggesting right hemispheric dominance for functions of emotional communication may have been overemphasized in previous studies and that the emotional indifference of right-brain-damaged patients can-not simply be considered the consequence of a defect of emotional communication. However, because of the diffuse brain damage that MDL has suffered and the way that she behaves in these contexts must give some credence to the other view, especially as research has not yet reached MDL’s type of brain damage.

Kucharska-Pietura et al recognize the importance of the right hemisphere in emotion perception but also note that its precise role is disputed. They compared the performance of 30 right hemisphere damaged (RHD) patients, 30 left hemisphere damaged (LHD) patients, and 50 healthy controls on both facial and vocal affect perception tasks of specific emotions.547

The results showed that right hemisphere patients were markedly impaired relative to left hemisphere and healthy controls on test performance. This included labelling and recognition of facial expressions and recognition of emotions conveyed by prosody. It was observed at the level of individual basic emotions, positive versus negative, and emotional expressions in general. The impairment remained highly significant despite co-varying for the group's poorer accuracy on a neutral facial perception test and identification of neutral vocal expressions. They considered that these data confirm the primacy of the right hemisphere in processing all emotional expressions across modalities, both positive and negative.

The results of investigations conducted in right- and left-brain-damaged patients seem to show that right hemispheric damage disrupts not only the communicative aspects of emotions but also the generation of the autonomic components of the emotional response and therefore the inner experience of emotions. Data consistent with the hypothesis of a leading role of the right hemisphere in the generation of the autonomic components of emotions and of the concomitant emotional experience have also recently been obtained during lateralized presentation of emotionally laden films to normal subjects. These authors found that both the increase of diastolic and systolic blood pressure and the subjective rating of the intensity of the emotional experience were higher during presentation of the film to the right rather than to the left hemisphere. (Gainotti, 1997, idem)

Tompkins et al have studied the relationship between neuropsychological functioning and emotion recognition and they examined in eleven individuals with moderate to severe TBI and a control group of 13 individuals matched for age, sex, and education. Emotion recognition stimuli were from Ekman and Friesen's pictures of facial affect. The group with TBI showed neuropsychological deficits consistent with those commonly found following moderate to severe TBI. The group with TBI also identified significantly fewer emotion recognition stimuli than the control group. The number of correctly identified emotion recognition stimuli was significantly correlated with measures of verbal cognitive processing in the group with TBI. These findings suggest that the role of left hemisphere brain mechanisms in the recognition of facial (nonverbal) emotion may be more important than previously recognized. 548

547 Kucharska-Pietura, K; Phillips, ML; Gernand, W; & David, AS. Perception of emotions from

faces and voices following unilateral brain damage. Neuropsychologia; Volume 41, Issue 8, 2003, 1082-1090.

548 Allerdings, MD; & Alfano, DP. Neuropsychological correlates of impaired emotion recognition following traumatic brain injury. Brain Cogn. 2006 Mar;60 (2): 193-4.

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Callahan et al in studying deficits that were found in patients with facial emotion recognition revealed that they displayed a liberal bias when rating facial expressions, leading them to associate intense ratings of incorrect emotional labels to sad, disgusted, surprised and fearful facial expressions. These findings are generally in line with prior studies which also report important facial affect recognition deficits in TBI patients, particularly for negative emotions.549

Ready to Fear

A behavioural psychologist, Neal Miller550 had been attempting to work out in detail how fear might serve as a drive, like hunger or sex; an internal signal that motivates one to act in a way that reduces the drive. Just as a hungry animal looks for food, a fearful one tries to get away from the stimuli that arouse fear. He trained rats to avoid being shocked by jumping over a hurdle that separated two compartments whenever a buzzer sounded.

The first phase involved fear conditioning — the buzzer came on and the rats were shocked. Then, through random actions, they learned that if they jumped over the hurdle during the buzzer, they could avoid getting shocked. Once the rat figured this out, it would jump every time it heard the buzzer, even if the shock was turned off. The shock was no longer present and was thus no longer the motivator. The avoidance response seemed, as Mowrer had suggested, to be maintained by the anticipation of shock, by the fear elicited by the warning signal. However, to prove that fear was the motivator, Miller changed the rules for the rat.

Previously, when the rat jumped over the hurdle, the buzzer went off, and turning the buzzer off seemed to be sufficient reinforcement to keep the rat jumping. But now the buzzer stayed on when the rat jumped and would only go off if the rat pressed a lever; once this was learned Miller changed the game again, forcing the rat to learn still another response to turn the buzzer off.

While the initial response was learned because it allowed the rat to avoid the shock, the subsequent ones were never associated with the shock. They were reinforced by the fact that they turned off the sound. According to Miller, the findings showed that fear is a drive, an internal energizer of behaviour, and that behaviours that reduce fear are reinforced and thereby become habitual ways of acting (note, however, that ‘fear’ is an internal bodily signal, like hunger, and does not necessarily refer to subjective, consciously experienced fear in this theory).

In the early 1970s, Martin Seligman, an experimental psychologist, whilst studying conditioned fear in animals, pointed out some striking differences between human anxiety and laboratory conditioned fear551. Especially important to Seligman was the fact that avoidance conditioning extinguishes quickly if the animal is prevented from making the avoidance response and alternative solutions for escape or avoidance are not provided. Recall that Miller's rats kept jumping over the hurdle when the buzzer sounded even when the shock was turned off. (See Above)

They never had the chance to find out that the shock was off because they kept jumping. But Seligman's point is that if the hurdle is replaced with a wall, thus preventing the avoid-

549 Callahan BL; Ueda K; Sakata D; Plamondon A & Murai T. Liberal bias mediates emotion

recognition deficits in frontal traumatic brain injury. Brain Cogn. 2011 Dec;77(3):412-8.

550 Miller, N E Studies of fear as an acquirable drive: I. Fear as motivation and fear reduction as reinforcement in the learning of new responses. Journal of Experimental Psychology 38, 89-10; 1948.

551 Seligman, M E P (1971). Phobias and Preparedness. Behavior Therapy 2, 307-20; 1971.

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ance response, the rat soon learns that the buzzer is no longer followed by a shock and begins to ignore the buzzer. If the wall is now removed and the hurdle returned, jumping no longer occurs in response to the buzzer. Forcing the rat to see that the buzzer doesn't lead to danger extinguishes the fear and this leads to the extinction of the neurotic avoidance response. In contrast, telling an acrophobic that no one has ever accidentally fallen off the Empire State Building and that he will be just fine if he goes to the top, or forcing him to go up there to prove the point, does not help, and can even make the fear of heights worse rather than better. Human phobias seem more resistant to extinction, and more irrational, than conditioned fears in animals.

The key to this difference, in Seligman's view, is the fact that while laboratory experiments use arbitrary, meaningless stimuli (flashing lights or buzzers), phobias tend to involve specific classes of highly meaningful objects or situations (insects, snakes, heights). He argued that perhaps we are prepared by evolution to learn about certain things more easily than others, and that these biologically driven instances of learning are especially potent and long lasting. Phobias, in this light, reflect our evolutionary preparation to learn about dan-ger and to retain the learned information especially strongly.

In a relatively stable environment, it is generally a good bet that the dangers a species faces will change slowly. As a result, having a ready-made means of rapidly learning about things that were dangerous to one's ancestors, and theirs, is in general useful. But since our environment is very different from the one in which early humans lived, our genetic preparation to learn about ancestral dangers can get us into trouble, as when it causes us to develop fears of things that are not particularly dangerous in our world. (Le Doux, 1998, idem)

Shall we be Frightened — or not?

You encounter a rabbit whilst walking along a path in the woods. Light reflected from the rabbit is picked up by your eyes. The signals are then transmitted through the visual system to your visual thalamus, and then to your visual cortex, where a sensory representation of the rabbit is created and held in a short-term visual object buffer. Connections from the visual cortex to the cortical long-term memory networks activate relevant memories (facts about rabbits stored in memory as well as memories about past experiences you may have had with rabbits). By way of connections between the long-term memory networks and the working memory system, activated long-term memories are integrated with the sensory representation of the stimulus in working memory, allowing you to be consciously aware that the object you are looking at is a rabbit.

A few strides later down the path and you come across a snake coiled up next to a log. Your eyes also pick up on this stimulus. Conscious representations are created in the same way as for the rabbit — by the integration in working memory of short-term visual representations with information from long-term memory. However, in the case of the snake, in addition to being aware of the kind of animal you are looking at, long-term memory also informs you that this kind of animal can be dangerous and that you might be in danger.

According to cognitive appraisal theories, the processes described so far would constitute your assessment of the situation and should be enough to account for the ‘fear’ that you are feeling as a result of encountering the snake. The difference between the working memory representation of the rabbit and the snake is that the latter includes information about the snake being dangerous. These cognitive representations and appraisals in working memory are not enough to turn the experience into a full-blown emotional experience. Something else is needed to turn cognitive appraisals into emotions, to turn experiences into emotional experiences. That something, of course, is the activation of the system built by evolution to deal with dangers; and that crucially involves the amygdala.

Many people, but not all, who encounter a snake in a situation such as the one described

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will have a full-blown emotional reaction that includes bodily responses and emotional feelings. 552 This will only occur if the visual representation of the snake triggers the amyg-dala. A whole host of connections will then be activated. Activation of these is what makes the encounter with the snake an emotional experience, and the absence of activation is what prevents the encounter with the rabbit from being one. 553

Neurons in the area of the thalamus that project to the primary auditory cortex are narrowly tuned — they are very particular to what they will respond. However, cells in the thalamic areas that project to the amygdala are less particular — they respond to a much wider range of stimuli and are said to be broadly tuned. Music will sound the same to the amygdala by way of the thalamic projections but quite different by way of the cortical projections. So when two similar stimuli are used in a conditioning study, the thalamus will send the amygdala essentially the same information, regardless of which stimulus it is processing, but when the cortex processes the different stimuli it will send the amygdala different signals. If the cortex is damaged, the animal has only the direct thalamic pathway and thus the amygdala treats the two stimuli the same — both elicit conditioned fear.

Although the thalamic system cannot make fine distinctions, it has an important advantage over the cortical input pathway to the amygdala. That advantage is time. In a rat it takes about twelve milliseconds (twelve one-thousandths of a second) for an acoustic stimulus to reach the amygdala through the thalamic pathway, and almost twice as long through the cortical pathway. The thalamic pathway is thus faster. It cannot tell the amygdala exactly what is there, but can provide a fast signal that warns that something dangerous may be there. It is a quick and dirty processing system.

Imagine walking in the woods. A crackling sound occurs. It goes straight to the amygdala through the thalamic pathway. The sound also goes from the thalamus to the cortex, which recognizes the sound to be a dry twig that snapped under the weight of your boot, or that of a rattlesnake shaking its tail. But by the time the cortex has figured this out, the

552 Erdelyi, M H. The recovery of unconscious (inaccessible) memories: Laboratory studies of

hypermnesia. In The psychology of learning and motivation: Advances in research and theory, G. Bower, ed. (New York: Academic Press), pp. 95-127; 1984.

553 If, in your past, you have experienced rabbits in association with some trauma or stress, then the rabbit too could serve as a trigger stimulus that would turn on the amygdala and its outputs.

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amygdala is already starting to defend against the snake. The information received from the thalamus is unfiltered and biased toward evoking responses. The cortex's job is to prevent the inappropriate response rather than to produce the appropriate one. Alternatively, suppose there is a slender curved shape on the path. The curvature and slenderness reach the amygdala from the thalamus, whereas only the cortex distinguishes a coiled up snake from a curved stick. If it is a snake, the amygdala is ahead of the game. From the point of view of survival, it is better to respond to potentially dangerous events as if they were in fact the real thing than to fail to respond. The cost of treating a stick as a snake is less, in the long run, than the cost of treating a snake as a stick. (LeDoux, 1998, Idem)

So we can begin to see the outline of a fear reaction system. It involves parallel transmission to the amygdala from the sensory thalamus and sensory cortex. The subcortical pathways provide a crude image of the external world, whereas more detailed and accurate representations come from the cortex. While the pathway from the thalamus only involves one link; several links are required to activate the amygdala by way of the cortex. Since each link adds time, the thalamic pathway is faster. Interestingly, the thalamo-amygdala and cortico-amygdala pathways converge in the lateral nucleus of the amygdala. In all likelihood, normally both pathways transmit signals to the lateral nucleus, which appears to play a pivotal role in coordinating the sensory processes that constitute the conditioned fear stimulus. Once the information has reached the lateral nucleus it can be distributed through the internal amygdala pathways to the central nucleus, which then unleashes the full repertoire of defensive reactions. 554

The amygdala and emotions

What is it about the activation of the amygdala that converts an experience into an emotional experience? To understand this we need to consider some of the various consequences of activating the amygdala. This sequence of neurological events provide the basic ingredients that, when added to the working memory with short-term sensory representations and the long-term memories activated by these sensory representations, there is created an emotional experience.

Ingredient 1 — Direct Amygdala Influences on the Cortex: The amygdala has projections to many cortical areas. 555 In fact the projections of the amygdala to the cortex are considerably greater than the projections from the cortex to the amygdala. In addition to projecting back to cortical sensory areas from which it receives inputs, the amygdala also projects to some sensory processing areas from which it does not receive inputs. For example, in order for a visual stimulus to reach the amygdala by way of the cortex, the stimulus has to go through the primary cortex, to a secondary region, and then to a third cortical area in the temporal lobe (which does the short-term buffering of visual object information). This third area then projects to the amygdala. The amygdala not only projects back to this area but also to the other two earlier visual processing regions.

As a result, once the amygdala is activated, it is able to influence the cortical areas that are processing the stimuli that are activating it. This might be very important in directing attention to emotionally relevant stimuli by keeping the short-term object buffer focused on the stimuli to which the amygdala is assigning significance. The amygdala also has an impressive set of connections with long-term memory networks involving the hippocampal system and areas of the cortex that interact with the hippocampus in long-lasting information storage.

554 Johnson-Laird, PN. The computer and the mind: An introduction to cognitive science

(Cambridge: Harvard University Press; 1988).

555 Amaral, D G; Price, J L; Pitkanen, A. & Carmichael, S T. Anatomical organization of the primate amygdaloid complex. In The amygdala: Neurobiological aspects of emotion, memory, and mental dysfunction, J. P. Aggleton, ed. (New York: Wiley-Liss), pp. 1-66; 1992.

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These pathways may contribute to the activation of long-term memories relevant to the emotional implications of immediately present stimuli. Although the amygdala has relatively meagre connections with the lateral prefrontal cortex, it sends rather strong connections to the anterior cingulate cortex, one of the other partners in the frontal lobe working memory executive circuitry. It also sends connections to the orbital cortex, another component of working memory that may be especially involved in working memories that are about rewards and punishments.

Mild traumatic brain injury (MTBI) is often associated with selective impairment of both working memory and the executive functions. Research indicates that one of the commonest deficits present in MTBI patients falls in the domain of WM. Kumar et al suggest that MTBI may lead to WM deficits as the contribution of executive processes to support the working memory is diminished following MTBI.556

Abstract Deficits in working memory working memory are a common consequence of pediatric traumatic brain injury (TBI) and are believed to contribute to difficulties in a range of cognitive and academic domains. Working memory is the brain's ability to collect, retain and use information that's needed in order to perform tasks and respond to immediate demands. Treble et al used brain imaging studies that measured verbal and visuospatial working memory via a group of children that sustained a TBI and a control group that did not. Reduced integrity of the corpus callosum after TBI may disrupt the connectivity between bilateral frontoparietal neural networks underlying. 557

The comparisons showed that children who had experienced this problem demonstrated poorer visuospatial skills and working memory that are often associated with disruptions found in brain connectivity between neural networks that underlie working memory.

Through the study, the authors proposed that the identification of neruoanatomical biomakers may be indicative of changes found in the brain's microstructure that could allow for early identification of children who may be at an increased risk for impaired working memory and for earlier intervention.

Reduced microstructural integrity of the corpus callosum, particularly in subregions connecting parietal and temporal cortices, may act as a neuropathological mechanism contributing to long-term working memory deficits. The future clinical use of neuroanatomical biomarkers may allow for the early identification of children at highest risk for WM deficits and earlier provision of interventions for these children.

This research confirms a longstanding belief that the corpus callosum is consistently involved with traumatic brain injury, and the study's specific analyses of callosal integrity, together with its evaluation of working memory in a pediatric brain-injured population, make this a particularly important contribution to the field of pediatric TBI.

By way of these connections with specialized short-term buffers, long-term memory networks, and the networks of the frontal lobe, the amygdala can influence the information content of working memory. There is obviously a good deal of redundancy built into this system, making it possible for the conscious awareness of amygdala activity to come about in several ways.

To summarize: the connections from the amygdala to the cortex allow the defence

556 Kumar S, Rao SL, Chandramouli BA, Pillai S. Reduced contribution of executive functions in

impaired working memory performance in mild traumatic brain injury patients. Clin Neurol Neurosurg. 2013 Jan 29.

557 Treble A; Hasan KM; Iftikhar A; Stuebing KK; Kramer LA; Cox CS Jr.; Swank PR & Ewing-Cobbs L. Working memory and corpus callosum microstructural integrity after pediatric traumatic brain injury: a diffusion tensor tractography study. J Neurotrauma. 2013 Oct 1;30(19):1609-19. doi: 10.1089/neu.2013.2934. Epub 2013 Aug 24.

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networks of the amygdala to influence attention, perception, and memory in situations where we are facing danger. At the same time though, these kinds of connections would seem to be inadequate in completely explaining why a perception, memory, or thought about an emotional event should ‘feel’ different from one about a non-emotional event. They provide working memory with information about whether something good or bad is present, but are insufficient for producing the feelings that come from the awareness that something good or bad is present. For this we need other connections as well.

Pathways to the Amygdala

Information about external stimuli reaches the amygdala by way of direct pathways from the thalamus as well as by way of pathways from the thalamus to the cortex to the amygdala.

The direct thalamo-amygdala path is a shorter and thus a faster transmission route than the pathway from the thalamus through the cortex to the amygdala. However, because the direct pathway bypasses the cortex, it is unable to benefit from cortical processing.

As a result, it can only provide the amygdala with a crude representation of the stimulus. It is thus a quick and dirty processing pathway. The direct pathway allows us to begin to respond to potentially dangerous stimuli before we fully know what the stimulus is. This can be very useful in dangerous situations.

However, its utility requires that the cortical pathway be able to override the direct pathway. It is possible that the direct pathway is responsible for the control of emotional responses that we don't understand. This may occur in all of us some of the time, but may be a predominant mode of functioning in individuals with certain emotional disorders.

Ingredient 2 — Amygdala-Triggered Arousal: In addition to the direct influences of the amygdala on the cortex, there are a number of indirect channels through which the effects of amygdala activation can impact on cortical processing. An extremely important set of such connections involves the arousal systems of the brain.

It has long been believed that the difference between being awake and alert, on the one

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hand, and drowsy or asleep on the other is related to the arousal level of the cortex.558 When you are alert and paying attention to something important, your cortex is aroused. When you are drowsy and not focusing on anything, the cortex is in the unaroused state. During sleep, the cortex is in the unaroused state, except during dream sleep when it is highly aroused. In dream sleep, in fact, the cortex is in a state of arousal that is very similar to the alert waking state, except that it has no access to external stimuli and only processes internal events559.

When arousal occurs, cells in the cortex and in the thalamic regions that supply the cortex with its major inputs, become more sensitive.560,561 They go from a state in which they tend to fire action potentials at a very slow rate and more or less in synchrony to a state in which they are generally out of sync but with some cells being driven especially strongly by incoming stimuli.

While much of the cortex is potentially hypersensitive to inputs during arousal, the systems that are processing information are able to make the most use of this effect. For example, if arousal is triggered by the sight of a snake, the neurons that are actively involved in processing the snake, retrieving long-term memories about snakes, and creating working memory representations of the snake are going to be especially affected by arousal. Other neurons are inactive at this point and don't reap the benefits. In this way, a very specific information processing result is achieved by a very nonspecific mechanism. This is a wonderful system.

A number of different systems appear to contribute to arousal. Four of these are located in regions of the brain stem. Each has a specific chemical identity, which means the cells in each contain different neurotransmitters that are released by their axon terminals when the cells are activated.

One group makes acetylcholine (ACh), another noradrenalin, another dopamine, and another serotonin. A fifth group, also containing ACh, is located in the forebrain, near the amygdala. The axons of each of these cell groups terminate in widespread areas of the forebrain. In the presence of novel or otherwise significant stimuli the axon terminals release their neurotransmitters and ‘arouse’ cortical cells, making them especially receptive to incoming signals.

Arousal is important in all mental functions. It contributes significantly to attention, perception, memory, emotion, and problem solving. Without arousal, we fail to notice what is going on — we don't attend to the details. But too much arousal is not good either. If you are over-aroused you become tense and anxious and unproductive. You need to have just the right level of activation to perform optimally. 562

Emotional reactions are typically accompanied by intense cortical arousal. Certain emotion theories around the mid-20th century proposed that emotions represent one end of an arousal continuum that spans from being completely unconscious (in a coma), to asleep; to awake but drowsy; to alert; to emotionally aroused. This high level of arousal is, 558 Moruzzi, G. & Magoun, HW. Brain stem reticular formation and activation of the EEG.

Electroencephalography and Clinical Neurophysiology 1, 455-73; 1949.

559 Hobson, J A, & Steriade, M. Neuronal basis of behavioral state control. In Handbook of Physiology. Section 1: The Nervous System. Vol. 4: Intrinsic Regulatory Systems of the Brain. V. B. Mountcastle, ed. (Bethesda, MD: American Physiological Society), pp. 701-823; 1986.

560 This applies to arousal occurring during waking states. Arousal also occurs during sleep, especially dream or REM sleep. In this case the cortex becomes insensitive in external inputs and is focused instead on internal stimuli. [Hobson and Steriade (I 986); McCormick and Bal·· (I994)].

561 McCormick, DA. & Bal, T. Sensory gating mechanisms of the thalamus. Current Opinion in Neurobiology 4, 550-56; 1994.

562 This is generally known in psychology as the Yerkes-Dodson law.

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in part, the explanation for why it is hard to concentrate on other things and work efficiently when you are in an emotional state. Arousal helps lock you into the emotional state you are in. This can be very useful (you don't want to get distracted when you are in danger), but can also be an annoyance (once the fear system is turned on, it's hard to turn it off — this is the nature of anxiety).

Although each of the arousal systems probably contributes to arousal in the presence of stimuli that are dangerous or that warn of danger, it appears that interactions between the amygdala and the nearby ACh-containing system in the forebrain are particularly important.563,564 This ACh-containing system is called the nucleus basalis. Damage to the amygdala or to the nucleus basalis prevents stimuli that warn of danger, like conditioned fear stimuli, from eliciting arousal. Moreover, stimulation of the amygdala or the nucleus basalis elicits cortical arousal artificially. The administration of drugs that block the actions of ACh in the cortex prevents these effects on arousal of conditioned stimuli, amygdala stimulation, or nucleus basalis stimulation from occurring. Together, these and other findings suggest that when the amygdala detects danger it activates the nucleus basalis, which then releases ACh throughout the cortex. The amygdala also interacts with the other arousal systems located in the brain stem, and the overall effect of amygdala activation on arousal certainly involves these as well.

Although there are a number of different ways that the nucleus basalis cells can be turned on, the way they are turned on by a dangerous stimulus is through the activity of the amygdala. (Kapp et al, idem, 1992) Other kinds of emotional networks most likely have their own ways of interacting with the arousal systems and altering cortical processing.

Arousal occurs to any novel stimulus that we encounter and not just to emotional stimuli. The difference is that a novel but insignificant stimulus will elicit a temporary state of arousal that dissipates almost immediately but arousal is prolonged in the presence of emotional stimuli. If you are face-to-face with a predator it is crucial that you do not lose interest in what is going on or be distracted by some other event. While this seems so obvious as to be silly, it is only so because the brain does it so effortlessly.

Why is arousal perpetuated to emotional but not to other stimuli? Again, the answer probably has to do with the involvement of the amygdala. The arousal elicited by a novel stimulus does not require the amygdala. Instead, it is mediated by direct inputs from sensory systems to arousal networks. It appears in fact that the cortex arouses itself since sensory stimuli first go to the cortex and are then sent back to the brain stem and these in-puts trigger the arousal system, which then arouses the cortex565.

These kinds of arousal effects quickly habituate. If the stimulus is meaningful, say dangerous, then the amygdala is brought into the act and it also activates arousal systems. This adds impetus to keep arousal going. The continued presence of the stimulus and its continued interpretation by the amygdala as dangerous continues to drive arousal systems, and these systems, in turn, keep cortical networks that are processing the stimulus in a state of hypersensitivity. The amygdala, it should be noted, is also the recipient of arousal system axons, so that amygdala activation of arousal systems also helps keep the amygdala aroused. These are self-perpetuating, vicious cycles of emotional reactivity. Arousal locks you into whatever emotional state you are in when arousal occurs, unless something else occurs that is significant enough and arousing enough to shift the focus of arousal. It can be seen then that damage to this system may cause MDL’s arousal system to continue to be

563 Kapp, BS; Whalen, PJ; Supple, WE, & Pascoe, JP. Amygdaloid contributions to conditioned

arousal and sensory information processing. In The amygdala: Neurobiological aspects of emotion, memory, and mental dysfunction, J. P. Aggleton, ed. (New York: Wiley-Liss); 1992.

564 Weinberger, NM. Retuning the brain by fear conditioning. In The cognitive neurosciences, M S Gazzaniga, ed. (Cambridge: MIT Press), pp. 1071-90; 1995.

565 Lindsley, D B. Emotions. In Handbook of Experimental Psychology, S. S. Stevens, ed. (New York: Wiley), pp. 473-516; 1951.

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active when otherwise it would have been refocused either through cognitive interaction or by appropriate involvement of another person.

The information content provided by arousal systems is weak. The cortex is unable to discern that danger (as opposed to some other emotional condition) exists from the pattern of neural messages it receives from arousal systems. Arousal systems simply say that some-thing important is going on. The combination of non-specific cortical arousal and specific information provided by direct projections from the amygdala to the cortex allows the establishment of a working memory that says that something important is going on and that it involves the fear system of the brain. These representations converge in working memory with the representations from specialized short-term memory buffers and with representations from long-term memory triggered by current stimuli and by amygdala processing. The continued driving of the amygdala by the dangerous stimulus keeps the arousal systems active, which keeps the amygdala and cortical networks actively engaged in the situation as well. Cognitive inference and decision making processes controlled by the working memory executive become actively focused on the emotionally arousing situation, trying to figure out what is going on and what should be done about it. All other inputs that are vying for the attention of working memory are blocked out.

We now have many of the basic ingredients for a complete emotional experience; but one more is needed.

Ingredient 3 — Bodily Feedback: The activation of the amygdala results in the automatic activation of networks that control the expression of a variety of responses: species-specific behaviours (freezing, fleeing, fighting, facial expressions), autonomic nervous system (ANS) responses (changes in blood pressure and heart rate, piloerection, sweating), and hormonal responses (release of stress hormones, like adrenaline and adrenal steroids, as well as a host of peptides, into the bloodstream). The ANS and hormonal responses can be considered together as visceral responses — responses of the internal organs and glands (the viscera). When these behavioural and visceral responses are expressed, they create signals in the body that return to the brain.

This system has not got to be learned or developed during childhood, it is hard-wired an all humans have it. Despite that and as Rees explains, the (ANS) has been strikingly neglected in Western medicine. Despite its profound importance for regulation, adjustment and coordination of body systems, it lacks priority in training and practice and receives scant attention in numerous major textbooks. The ANS is integral to manifestations of illness, underlying familiar physical and psychological symptoms. When ANS activity is itself dysfunctional, usual indicators of acute illness may prove deceptive. Recognising the relevance of the ANS can involve seeing the familiar through fresh eyes, challenging assumptions in clinical assessment and in approaches to practice. 566

Its importance extends from physical and psychological well-being to parenting and safeguarding, public services and the functioning of society. Exploration of its role in conditions ranging from neurological, gastrointestinal and connective tissue disorders, diabetes and chronic fatigue syndrome, to autism, behavioural and mental health difficulties may open therapeutic avenues. The ANS offers a mechanism for so-called functional illnesses and illustrates the importance of recognising that ‘stress’ takes many forms, physical, psychological and environmental, desirable and otherwise. (Idem)

Evidence of intrauterine and post-natal programming of ANS reactivity suggests that neonatal care and safeguarding practice may offer preventive opportunity, as may greater understanding of epigenetic change of ANS activity through, for example, accidental or psychological trauma or infection. Dr Rees’ paper was written in order to

566 Rees, CA. Lost among the trees? The autonomic nervous system and paediatrics. Arch Dis

Child 2012-301863.

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accelerate recognition of the importance of the ANS throughout paediatrics, and of the potential physical and psychological cost of neglecting it.

The opportunities are enormous for bodily feedback during emotional reactions to influence information processing by the brain and the way we consciously feel. Nevertheless, much debate has occurred over whether feedback has any effect on emotional experience and if so how much. William James is the father of the feedback theory. He argued that we do not cry because we are sad or run from danger because we are afraid, but instead we are sad because we cry and are afraid because we run. James was attacked by Cannon, who argued that feedback, especially from the viscera, would be too slow and undifferentiated to determine what emotion you are feeling at the moment. Let's ignore the fact that James included somatic as well as visceral feedback in his theory for now and just consider the validity of Cannon's claims about the viscera.

In Cannon's day, the visceral systems were indeed thought to respond uniformly in all situations. However, we now know that the ANS, which controls the viscera, has the ability to respond selectively, so that visceral organs can be activated in different ways in different situations. Recent studies show, for example, that different emotions (anger, fear, disgust, sadness, happiness, surprise) can be distinguished to some extent on the basis of different autonomic nervous system responses (like skin temperature and heart rate) 567,568.

The main hormone that was thought to be important for emotional experience in Cannon's time was adrenaline, which is under the control of the ANS and thus was thought to respond uniformly in different situations. However, we now know that there are steroid and peptide hormones that are released by body organs during emotional arousal and that travel in the blood to the brain. It is conceivable that activation of different emotional systems in the brain results in different patterns of hormone release from body organs, which in turn would produce different patterns of chemical feedback to the brain that could have unique effects in different emotions.

Regardless of their specificity, though, visceral responses have relatively slow actions, too slow in fact to be the factor that determines what emotion you experience in a given moment. At a minimum, it takes a second or two for signals to travel from the brain to the viscera and then for the viscera to respond and for the signals created by these responses to return to the brain. For some systems the delay is even longer. It's not so much the travel time from the brain to the organs by way of nerve pathways that is slow, it's the response time of the organs themselves. Visceral organs are made up of what is called ‘smooth muscle’, which responds much more slowly than the striated muscles that move our skeleton during behavioural acts. Also, for hormonal responses, the travel time in the blood to the brain can be slow, and for some hormones (like adrenal steroids) the effects on the brain can require the synthesis of new proteins and can take hours to be achieved.

On the other hand, emotional states are dynamic. For example, fear can turn into anger or disgust or relief as an emotional episode unfolds; and it is possible that visceral feedback contributes to these emotional changes over time. While arousal is non-specific and tends to lock you into the state you are in when the arousal occurs, unique patterns of visceral, especially chemical, feedback have the potential for altering which brain systems are active and thus may contribute to transitions from one emotion to another within a given emotional event.

So Cannon was right about the inability of visceral responses to determine emotional feelings, but more because of their slow time course than their lack of specificity. At the same time, though, Cannon's critique was somewhat inappropriate given that James had

567 Ekman, P; Levenson, R W; & Friesen, W V. Autonomic nervous system activity distinguishes among emotions. Science 221, 1208-10; 1983.

568 Levenson, RW. Autonomic nervous system differences among emotions. Psychological Science 3, 23-27; 1992.

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argued for the importance of somatic as well as visceral feedback. And the somatic system clearly has the requisite speed and specificity to contribute to emotional experiences (it takes much less than a second for your striated muscles to respond to a stimulus and for the sensations from these responses to reach your cortex). This point was noted many years ago by Sylvan Tomkins and was the basis of his facial feedback theory of emotion569, which has been taken up and pursued in recent years by Carroll Izard. 570,571

While most contemporary ideas about somatic feedback and emotional experience have been about feedback from facial expressions, a recent theory by Antonio Damasio, the somatic marker hypothesis, calls upon the entire pattern of somatic and visceral feedback from the body572. Damasio proposes that such information underlies ‘gut feelings’ and plays a crucial role in our emotional experiences and decision making processes.

When all the interactions between the various systems are taken together, the possibilities for the generation of emotion-specific patterns of feedback are staggering. This is especially true when considered from the point of view of what would be necessary to scientifically document the existence of these patterns, or, even more difficult, to prove that feedback is not important.

One approach to this problem has been to study emotional feelings in persons who have spinal cord injuries, in whom the flow of information from the brain to the body and from the body back to the brain is interrupted to a great degree. An early study claimed that patients with the most severe damage had a dulling of the intensity of emotional feelings and a reduction in the range of emotions experienced, lending support to the idea that feedback plays an important role573. Later studies suggest that the first study was flawed and that when the experiment is done properly no deficits in emotional feelings result574.

However, spinal cord injury does not completely interrupt information flow between the brain and body. For example, spinal cord injury can spare the vagus nerve, which transmits much information from the visceral organs to the brain, and it also fails to interfere with the flow of hormones and peptides from the brain to the body and from the body to the brain. In addition, the nerves controlling facial movements and sending sensations from facial movements back to the brain are intact, since these go directly between the brain and face without going through the spinal cord. Failure to find a dulling of emotional experiences, or a restriction of the range of emotional experiences, in these patients does not really prove anything.

There is one remaining argument against a contribution of feedback to emotion that needs to be considered. Although somatic responses, like facial or somatic muscle movements, have the requisite speed and specificity to contribute to emotional feelings, it has been argued that these cannot do the trick either. The same response (like running) can occur during different emotions (running to obtain food or to escape from danger) and diametrically opposed responses can occur during the same emotion (we can run or freeze in fear). While these comments are obviously true, it is important to remember that bodily feedback occurs in a biological context. Bodily feedback, when detected by the brain, is recorded by the systems that produced the responses in the first place. Although we may

569 Tomkins, S S. Affect, imagery, consciousness (New York: Springer; 1962).

570 Izard, C E. Human emotions (New York: Plenum; 1977).

571 Izard, C E. Basic emotions, relations among emotions, and emotion-cognition relations. Psychological Review 99, 561-65; 1992.

572 Damasio, A. Descarte's error: Emotion, reason, and the human brain (New York: Grosset/Putnam; 1994).

573 Hohmann, G W. Some effects of spinal cord lesions on experienced emotional feelings. Psychophysiology 3; 1966.

574 Bermond, B; Nieuwenhuyse, B; Fasotti, L; & Schuerman, J. Spinal cord lesions, peripheral feedback, and intensities of emotional feelings. Cognition and Emotion 5,201-20; 1995.

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run both to get food and to escape from danger, the feedback from the somatic and visceral responses that return to the brain will interact with different systems in these two instances. The feedback from running from danger will find the food-seeking system idle but the defence system active. The same pattern of feedback can have unique contributions when it interacts with specific brain systems.

William James said that he found it impossible to imagine an emotional experience occurring in the absence of the bodily responses that accompany it — he didn't believe in disembodied emotions575. LeDoux agrees with this view for several reasons. (Idem) Most of us feel our emotions in our body, which is why we have such expressions as ‘an aching heart’ and a ‘gut-wrenching’ experience. While personal experience is not a good way to prove anything (we've seen the perils of introspection as scientific data), there's nothing wrong with using it as a takeoff point for a more penetrating analysis. Also, the evidence against feedback playing a role is weak — the spinal cord studies are inconclusive at best. In addition, there is plenty of feedback available during emotional responses, and quite a bit of it is fast enough and specific enough to play a role in subjective experiences. Finally, studies by Paul Ekman and by Robert Zajonc have shown that feedback is indeed used.576,577,578 For example, Ekman had subjects move certain facial muscles. Unbeknownst to the subjects, they were being made to exhibit the facial expressions characteristic of different emotions. They then had to answer some questions about their mood. It turns out that the way the subjects felt was significantly influenced by whether they had been wearing positive or negative emotion expressions. Putting on a happy face may not be such a bad idea when you are feeling blue.

There is one other way, though, that should be mentioned. It involves what Damasio calls ‘as if’ loops. In certain situations, it may be possible to imagine what bodily feedback would feel like-if it occurred. This ‘as if’ feedback then becomes cognitively represented in working memory and can influence feelings and decisions.

So, this is how the brain arranges emotional feeling. It includes all the things needed to turn an emotional reaction into a conscious emotional experience. There is a specialized emotion system that receives sensory inputs and produces behavioural, autonomic, and hormonal responses. Also, cortical sensory buffers that hold on to information about the currently present stimuli. In addition we have got a working memory executive that keeps track of the short-term buffers, retrieves information from long-term memory, and interprets the contents of the short-term buffers in terms of activated long-term memories. We also have cortical arousal; and, finally, we have bodily feedback-somatic and visceral information that returns to the brain during an act of emotional responding.

When all of these systems function together a conscious emotional experience is inevitable. When some components are present and others lacking, emotional experiences may still occur, depending on what's there and what's not.

The above section on the amygdala and emotions should allow considerable thought to be given to MDL’s care situation. When the processes that are described are fully understood and set against her inability to rationalise through a failed system of cognition, it can be seen not only just how frightening it can be for someone to be in an environment where they do not feel safe but also increasingly so because they know that either the person who is caring for them understands their fears and relieves them or does neither. Being in a position of not feeling free to escape is not only a physical but also a mental suffering.

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575 James, W. Principles of psychology (New York: Holt; 1890).

576 Ekman, P. Facial expressions of emotion: New findings, new questions. Psychological Science 3, 34-38; 1992.

577 Ekman, P. Facial expression and emotion. American Psychologist 48; 1993.

578 Adelman, PK. & Zajonc, RB. Facial efference and the experience of emotion. Annual Review of Psychology 40, 249-80; 1989.

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Emotion and Medication

The automatic nature of emotional habits can be extremely useful, allowing you to avoid routine dangers without having to give them much thought. However, when emotional habits become anxiety disorders, then the rigid unextinguishable learning that typifies avoidance behaviour becomes a liability. (LeDoux, 1998, Idem)

Many of the leading drugs for treating anxiety have been developed because of their efficiency in reducing avoidance behaviour in animals. For example, if a rat is shocked when it steps off a platform in a test chamber, it will remain on the platform when it is placed in the chamber the next day. However, if the rat is given Valium just before being placed on the platform on the second day, it will be much more likely to step off the platform to figure out if the danger still exists. In other words, the rat is less fearful, less anxious, about the situation when it receives the drug. (But only if it has the ability to be able to cognitively decide if the danger still exists.)

As Mowrer and Miller579,580 proposed, avoidance learning is usually thought of as taking place in two stages. First, fear conditioning occurs. Then, a response is learned because it supposedly reduces the learned fear. We know that the amygdala is required for the fear conditioning part, but the brain mechanisms involved in the instrumental avoidance response are less clearly understood. It seems that structures like the basal ganglia, frontal cortex, and hippocampus may be involved.581,582,583,584,585 There is controversy as to just where in the brain drugs like Valium have their anxiety-reducing effects. (Gray, 1982, Idem) &586. In fact they probably act in a number of places.

Let's consider how a drug like Valium might work in the amygdala. Valium belongs to the class of drugs known as benzodiazepines. These drugs have natural receptors in the brain. When you take Valium, it binds to the benzodiazepine receptors all over the brain. These receptors do a very specific thing. They facilitate the effects of the inhibitory neurotransmitter, GABA. So you basically increase inhibition in a variety of brain areas. In some brain regions, this will not have any consequence for anxiety because that region is not involved in that function. Basically, if a brain region is involved in anxiety, whatever it does during anxiety-provoking situations, it will probably do less of it in the presence of Valium.

For example, the lateral nucleus is the sensory-input region of the amygdala. The increase of inhibition in this region will raise the threshold for anxiety. Stimuli that would normally elicit fearful responses through the amygdala no longer do so. Jeffrey Gray has proposed that the anti-anxiety drugs work through the hippocampus (albeit indirectly). (Gray, 1982, idem)

579 Miller, N E Studies of fear as an acquirable drive: I. Fear as motivation and fear reduction as

reinforcement in the learning of new responses. Journal of Experimental Psychology 38, 89-10; 1948.

580 Mowrer, O. H. A stimulus-response analysis of anxiety and its role as a reinforcing agent. Psychological Review, 1939; 46:553-565.

581 Gray, JA. The neuropsychology of Anxiety. New York, OUP; 1982.

582 Gray, JA The psychology of fear and stress, Vol. 2; New York: Cambridge University Press; 1987.

583 LeDoux, JE. Emotional memory systems in the brain. Behavioural Brain Research 58, 69-79; 1993.

584 Sarter, ME & Markowitsch, HJ. Involvement of the amygdala in learning and memory: A critical review, with emphasis on anatomical relations. Behavioral Neuroscience 99, 342-80; 1985.

585 Isaacson, RL. The limbic system. New York: Plenum; 1982.

586 Nagy, J; Zambo, K; & Decsi, L. Anti-anxiety action of diazepam after intraamygdaloid application in the rat. Neuropharmacology 18, 573-76; 1979.

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This may be true as well, reducing the ability of explicit memories to make us anxious and afraid.

One Way Valium Might Reduce Fear and Anxiety.

Valium and some other anti-anxiety drugs act by increasing the ability of inhibitory neurons to prevent excitatory transmission. When we are under the influence of Valium, external emotional stimuli (as well as thoughts) are less capable of producing emotional responses, in part (perhaps) because of an action on GABA inhibitory neurons in the amygdala.

The brain circuits of avoidance are far less clear than the circuits of fear conditioning. Avoidance is more complex: it involves fear conditioning plus instrumental learning. Also, there are many ways in which avoidance conditioning studies can be performed and a great variety of responses can be conditioned this way. Avoidance responses are arbitrary. Anything that reduces the exposure to fear-eliciting events can be an avoidance response. These factors make the brain systems of avoidance more difficult to track down.

Another factor that needs to be considered is that the clinical trials through which these drugs are assessed for efficacy are done with subjects who have undamaged brains. Using them on patients who have known brain damage is outside the drug safety procedures and is very much a suck-it-and-see method of treatment — one that may do more harm than good.

Some points to remember You can't have a conscious emotional feeling of being afraid without aspects of the emotional experience being represented in working memory. Working memory is the gateway to subjective experiences, emotional and non-emotional ones, and is in-dispensable in the creation of a conscious emotional feeling.

You can't have a complete feeling of fear without the activation of the amygdala. In the presence of a fear-arousing stimulus, and the absence of amygdala activation (for example, if your amygdala were damaged), you might use your cognitive powers to conclude that in situations like this you usually feel ‘fearful’, but the fearful feelings would be lacking because of the importance of amygdala inputs to working memory, of amygdala--triggered arousal, and of amygdala-mediated bodily responses that produce feedback. Cognitive mechanisms, like ‘as-if’ loops, might compensate to some extent, but they can't fully. (Of course if the cognitive processes are not working properly then there are other considerations that might bring about a different result.)

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There is now research information on several patients with amygdala damage.587,588,589 However, these people had a congenital disorder. Whenever the brain is damaged in early life, there are numerous compensatory mechanisms. For example, if the visual cortex is damaged, the auditory cortex can take on some visual functions. We have to be very cautious in using negative findings in patients with developmental disorders to infer what normally goes on in the brain.

You can't have a sustained feeling of fear without the activation of arousal systems. These play an essential role in keeping conscious attention directed toward the emotional situation, and without their involvement emotional states would be fleeting. You might be temporarily aroused but your emotion would dissipate as soon as it occurred. Although all novel stimuli activate arousal systems; particularly important to the persistence of emotional responses and emotional feelings is the activation of arousal systems by the amygdala. Amygdala-triggered arousal not only arouses the cortex but also arouses the amygdala, causing the latter to continue to activate the arousal systems, creating the vicious cycles of emotional arousal.

You can't have a sustained emotional experience without feedback from the body or without at least long-term memories that allow the creation of ‘as-if’ feedback. But even ‘as-if’ feedback has to be taught by real-life feedback. The body is crucial to an emotional experience, either because it provides sensations that make an emotion feel a certain way right now or because it once provided the sensations that created memories of what specific emotions felt like in the past.

You probably can have an emotional feeling without the direct projections to the cortex from the amygdala. These help working memory know which specialized emotion system is active, but this can be figured out indirectly. Nevertheless, the emotion will be different in the absence of this input than it would be in its presence.

You can have an emotional feeling without being conscious of the eliciting stimulus —without the actual eliciting stimulus being represented in a short-term cortical buffer and held in working memory. Stimuli that are not noticed, or that are noticed but their implications are not, can unconsciously trigger emotional behaviours and visceral re-sponses. In such situations, the stimulus content of working memory will be amplified by the arousal and feedback that result, causing you to attribute the arousal and bodily feelings to the stimuli that are present in working memory. However, because the stimuli in working memory did not trigger the amygdala, the situation will be misdiagnosed. If there is nothing in particular occupying working memory, you will be in a situation where your feelings are not understood. If emotions are triggered by stimuli that are processed unconsciously, you will not be able to later reflect back on those experiences and explain why they occurred with any degree of accuracy.

Contrary to the primary supposition of cognitive appraisal theories, the core of an emotion is not an introspectively accessible conscious representation. Feelings do involve conscious content, and we don't necessarily have conscious access to the processes that produce the content. Even when we do have introspective access, the conscious content is not likely to be what triggered the emotional responses in the first place. The emotional responses and the conscious content are both products of specialized emotion systems that operate unconsciously.

Conscious emotional feelings and conscious thoughts are in some sense very similar. They both involve the symbolic representation in working memory of sub-symbolic processes carried out by systems that work unconsciously. The difference between them is not due to

587 Adolphs, R; Tranel,D; Damasio, H; & Damasio, A R. Fear and the human amygdala. Journal of

Neuroscience 15,5879-91; 1995.

588 Bechara, A; Tranel, D; Damasio, H; Adolphs, R; Rockland, C; & Damasio, A R. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science 269, 1115-18; 1995..

589 Young, AW; Aggleton, J P; Hellawell, DJ; Johnson, M; Broks, P; & Hanley,JR. Face processing impairments after amygdalotomy. Brain 118, 15-24; 1995.

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the system that does the consciousness part but instead is due to two other factors. One is that emotional feelings and mere thoughts are generated by different sub-symbolic systems. The other is that emotional feelings involve many more brain systems than do thoughts.

When we are in the throes of emotion, it is because something important, perhaps life threatening, is occurring, and much of the brain's resources are brought to bear on the problem. Emotions create a flurry of activity all devoted to one goal. Thoughts, unless they trigger emotional systems, don't do this. We can daydream while doing other things, like reading or eating, and go back and forth between the daydream and the other activities. If we are faced with danger or other challenging emotional situations, we don't have time to spare nor do we have available mental resources. The whole self gets absorbed in the emotion. As Klaus Scherer has argued, emotions cause a mobilization and synchronization of the brain's activities.590,591,592

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Sleep

Sleep is not simply a passive lapse from wakefulness. Rather, both sleep and wakefulness are actively maintained by discrete areas of the brain stem and other brain areas as well. A number of experimenters have shown that electrical and chemical stimulation of certain parts of the thalamus and hypothalamus could also induce sleep or wakefulness. These experiments illustrate the point that brain functions are rarely centred. Instead, they are typically represented by systems which may extend over large areas of the brain.

Sumpter et al studied subjects who had suffered moderate-severe pediatric traumatic brain injury (TBI). Significantly more sleep problems were parent-reported. There was no evidence of circadian rhythm disorders, and daytime napping was not prevalent. Moderate-severe pediatric TBI was associated with sleep inefficiency in the form of sleep onset and maintenance problems. This preliminary study indicates that clinicians should be aware of sleep difficulties following pediatric TBI, and their potential associations with cognitive and behavioral problems in a group already at educational and psychosocial risk. Where concerted action has not been given to this problem and this has not been part of a care plan it can be a difficulty for parents and carers as well as the subject. 593

An equally important implication of these experiments is that the short-term effects of brain lesions may be very different from the long-term effects. Consequently, the many lesion experiments which still focus almost exclusively on short-term effects may provide an incorrect view of the functions subserved by various parts of the brain. This is particularly true when the lesions produce impairment of or a reduction in any function.

The Chemistry of Sleep Knowledge about the chemical nature of the brainstem neurons increased dramatically in the early 1960s when the Swedish anatomists Kjell Fuxe and Anica Dahlstrom demonstrated that the pons harboured neurons whose widely branching axons distributed two chemical substances throughout the brain. Neurons for each chemical were located in their own defined area of the pons (such an area is called a nucleus). The neurons of the midline raphe nuclei were the main source of 590 Scherer, KR. Neuroscience projections to current debates in emotion psychology. Cognition

and Emotion 7, 1-41; 1993.

591 Leventhal, H. & Scherer, K. The relationship of emotion to cognition: A functional approach to a semantic controversy. Cognition and Emotion 1, 3-28; 1987.

592 Scherer, KR. On the nature and function of emotion: A component process approach. In Approaches to emotion, K. R. Scherer and P. Ekman, eds. (Hillsdale, N]: Erlbaum), pp. 293-317; 1984.

593 Sumpter RE; Dorris L; Kelly T & McMillan TM. Pediatric sleep difficulties after moderate-severe traumatic brain injury. J Int Neuropsychol Soc. 2013 Apr 22:1-6.

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the neurotransmitter serotonin (5-hydroxy-tryptamine), and the neurons of the nucleus locus coeruleus, a major source of the neurotransmitter norepinephrine. Both were known to be neurotransmitters that tended to inhibit the cells they contacted. But because of their widespread and diffuse distribution and the long course of their action they came to be called neuromodulators, indicating that they set the response mode of the brain rather than conveying sensory or motor data. Serotonin and norepinephrine belong to a class of substances called biogenic amines; hence, neurons that release these two neurotransmitters are referred to as aminergic. Because these two substances were known to play an important role in the control of the cardiovascular and gastrointestinal systems, they were immediate and strong candidates for a central role in controlling the state of the brain. It was as if the brain had its own nervous system, a brain within a brain as it were. 594

Another neurotransmitter, called acetylcholine, was also suspected to play a role in sleep. Unlike serotonin or norepinephrine, acetylcholine is excitatory; that is, it causes cells to fire. Neurons that release acetylcholine are called cholinergic and cells that respond to it are called cholinoceptive.

The dominant theory of the brain mechanisms of sleep had been developed by Jouvet and his colleagues. Basically, Jouvet's theory depicts two brain stem sites that are anatomically and neuro-chemically distinct: one controls slow wave sleep and the other controls REM sleep. Jouvet observed that damage to the brain stem raphe complex produced insomnia. The raphe complex was shown to be the site of origin of many of the forebrain serotonin neurons. Drugs which reduced serotonergic function also produced insomnia. These data formed the core of a raphe-serotonergic theory of slow-wave sleep595.

It was also reported that damage to the brain stem locus coeruleus eliminated REM sleep. The locus coeruleus was shown to be the site of origin of many of the forebrain noradrenalin neurons. Drugs which reduced noradrenergic function tended to eliminate REM sleep. All of these data suggest that sleep-wakefulness cycles are far more neuro-chemically complex than was originally believed.

Having previously emphasized the role of acetylcholine in REM sleep, Jouvet proposed in 1966 596 that the brainstem exerted its control of non-REM sleep via serotonin and of REM sleep via norepinephrine. The idea was that each neurotransmitter caused a different state via its influence on neurons throughout the brain. These latter two conclusions, though based on solid pharmacological data, have not been confirmed by physiological or by biochemical studies, but Jouvet's earlier postulate that acetylcholine enhances REM sleep has been fully confirmed.

If, as Jouvet's work had clearly indicated, there were both a clock and a trigger for the periodic REM sleep episode in the pons, it should be possible to identify specific neurons in both. Using the microelectrode technique, Hobson and McCarley found that some cells turned on and others turned off in REM sleep (Hobson, 1989, Idem). The REM-off cells were the real surprise, because they were the very neurons in the raphe and locus coeruleus that Jouvet's pharmacological studies had predicted should be on. The REM-on cells did not release serotonin or norepinephrine but did possibly release acetylcholine.

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594 Hobson, JA. Sleep. Scientific American Library: HPHLP; New York, 1989.

595 Jouvet, M. Sleep and Altered States of Consciousness (edit. by Kety, S. S., Evarts, E. V., and Williams, H. L.), 86 (Williams and Wilkins, Baltimore, 1967).

596 Jouvet, M. Sleep and Altered States of Consciousness (edit. by Kety, S. S., Evarts, E. V., and Williams, H. L.), 86 (Williams and Wilkins, Baltimore, 1967).

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Cognition and Working Memory

M D L’ s w o rk i ng m em or y ha s b e e n s e r i o u s ly a f f e c t ed b y h e r b ra i n i n j u ry b o t h I n t e r m s o f t h e s t r u c t u r e s t h a t w e r e d a m a g ed a nd t h e f a i l u r e o f so m e d e v e l op m e n t a l p r o ce s s e s t ha t f o l l ow e d ; a d d ed t o t h i s a r e t h e p r o b l e m s t h a t h a v e a c c r u ed d u e t o t h e l a ck o f n o r m a l s o c ia l c o n t a c t s w i t h h e r p ee r s d u r i ng c h i l d ho o d .

I t i s im p or t a n t t h e r e f o r e t o u nd e rs t a nd th e w a y i n w h i c h w or k in g m em o ry a f f e c t s ou r c o g n i t i v e p r o c e ss e s a n d ho w M D L ’ s d e f i c i t s i n t h i s a r ea a f f e c t h e r e m o t i o na l l i f e a n d c om m un i c a t io n a b i l i ty a s a r e s u l t o f d a m a g e t o h e r p r e f r o n ta l c o r t e x a nd i t s c o n n e c t i o n s t o o t h e r b r a i n a r ea s .

Working Memory ‘Working memory’ is a form of short-term memory that is often exemplified by the times when information is being held on line for the purpose of performing computations on it (analogous to a mental scratch pad). Fuster597,598 provided the first detailed account of the role of working memory in prefrontal processes. He describes the role of the prefrontal cortex as that of integrating temporally distributed information, a complex process which he attributed partly to short-term working memory. Contrasting this view with SAS-like executive accounts of prefrontal function599, he writes: “The prefrontal cortex would not superimpose a steering or directing function on the remainder of the nervous system, but rather, by expanding the temporal perspectives of the system, it would allow it to integrate longer, newer, and more complex structures of behaviour.”

Goldman-Rakic600 has also proposed a working-memory account of frontal lobe function on the basis of extensive research with non-human primates. Building on the well-established relationship between the prefrontal cortex and delayed-response tasks, she argues that the prefrontal cortex is responsible for maintaining information (“representational memory”) that is later used to guide action. Funahashi and colleagues601,602 have carried out a variety of lesion studies and single-unit recording studies to establish the role of prefrontal cortex in working memory, primarily with monkeys trained to perform spatial working-memory tasks.

597 Fuster JM. The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal

Lobe. New York: Raven Press, 1980.

598 Fuster JM. The prefrontal cortex and temporal integration, in Jones EG, Peters A (eds): Cerebral Cortex: Vol 4. Association and Auditory Cortices. New York: Raven Press; 1985.

599 Supervisory attentional system (SAS) — a loosely defined collection of brain processes that are responsible for planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information.

600 Goldman-Rakic PS. Circuitry of primate prefrontal cortex and regulation of behavior by representational memory, in Plum F, Mountcastle V (eds): Handbook of Physiology, The Nervous System: V. Bethesda, MD: American Physiological Society, 1987.

601 Funahashi S; Bruce CJ & Goldman-Rakic PS. Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J Neurophysiol 61:331349,1989.

602 Funahashi S; Bruce CJ & Goldman-Rakic PS. Dorsolateral prefrontal lesions and oculomotor delayedresponse performance: Evidence for mnemonic ‘scotomas’. J Neurosci 13:1479-1497, 1993.

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Neuro-imaging studies in humans603,604,605,606 suggest that similar working-memory processes are located pre-frontally in the human brain. Goldman-Rakic (1987, idem) has suggested that the association between prefrontal cortex and working memory can, in principle, explain a range of human cognitive impairments following focal frontal lesions as well as other non-focal pathologies affecting prefrontal cortex. The proposal that working memory impairment could underlie the range of cognitive changes seen after prefrontal damage first found direct support in the work of Cohen and Servan-Schreiber607.

Working-memory accounts of prefrontal function are favoured for a number of reasons608:

First, they are parsimonious, in that working-memory theories contain only the individual processing components needed to perform the task without needing a central executive (such as the SAS) to coordinate these components (and to serve as the locus of damage when explaining patient behaviour).

Second, they have proven capable of explaining a wider range of seemingly disparate impairments than other non-executive theories (Cohen, 1992 idem)609.

Third, they are supported by a wealth of evidence from monkey neurophysiology and, in-creasingly, from neuro-imaging studies in humans. For instance, Fougnie and Marois have found that the hallmark of both visual attention and working memory is their severe capacity limit. People can attentively track only about four objects in a multiple object tracking (MOT) task and can hold only up to four objects in visual working memory (VWM). It has been proposed that attention underlies the capacity limit of VWM. They tested this hypothesis by determining the effect of varying the load of a MOT task performed during the retention interval of a VWM task and comparing the resulting dual-task costs with those observed when a VWM task was performed concurrently with another VWM task or with a verbal working memory task. Instead of supporting the view that the capacity limit of VWM is solely attention based, the results indicated that VWM capacity is set by the interaction of visuospatial attentional, central amodal, and local task-specific sources of processing.610

Fourth, they suggest a way of resolving what is perhaps the central problem of the neuro-psychology of the frontal lobe function — the paradox of dissociable impairments with an unintuitive compelling ‘family resemblance’.

If we assume that working memory is compartmentalized in the prefrontal cortex according to what is being represented in memory (for which evidence exists), then performance in

603 Cohen J; Forman S & Braver T, et al. Activation of prefrontal cortex in a nonspatial working

memory task with functional MRI. Hum Brain Mapping 1:293-304, 1994.

604 D'Esposito M; Shin RK & Detre JA, et al. Object and spatial working memory activates dorsolateral prefrontal cortex: A functional MRI study. Soc Neurosci Abstr 21:1498, 1995.

605 D'Esposito M; Detre J & Alsop D, et al. The neural basis of the central executive system of working memory. Nature 378:279-281, 1995.

606 Jonides J; Smith E & Koeppe R, et al. Spatial working memory in humans as revealed by PET. Nature 363:623-625, 1993.

607 Cohen JD & Servan-Schreiber D. Context, cortex, and dopamine: A connectionist approach to behavior and biology in schizophrenia. Psychol Rev 99:4577,1992.

608 Kimberg, DY; D’Esposito, M & Farah, MJ. Frontal Lobes: Cognitive and Neuropsychological Aspects. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

609 Kimberg DY & Farah MJ. A unified account of cognitive impairments following frontal lobe damage: The role of working memory in complex, organized behavior. J Exp Psychol Gen 122:411-428, 1993.

610 Fougnie, D. & Marois, R. Distinct Capacity Limits for Attention and Working Memory. Psychological Science. 6; V17; 2006 pp 526-534.

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different tasks can be impaired or spared depending on which types of working memory have been damaged. Nevertheless, according to working-memory accounts, there is an underlying commonality among the tasks sensitive to prefrontal damage namely, their dependence on working memory. 611

Buffers A critical component of Baddeley’s working memory model is the existence of verbal mid-spatial storage buffers612. The cognitive concept of a buffer translated into neural terms would propose that temporary retention of task-relevant information requires transfer of that information to a part of the brain that is dedicated to the storage of information. Presumably, such buffers are analogous to a computer’s RAM, which serves as a cache for information transferred from the hard drive that is processed by a CPU. Consistent with this interpretation of a working memory ‘buffer’, many descriptions of cognitive models of working memory refer to the information being ‘in’ or ‘out’ of working memory.

Relation of Specialized Short-Term Buffers,

Long-Term Explicit Memory and Working Memory.

Stimuli processed in different specialized systems (such as sensory, spatial, or language systems) can be held simultaneously in short-term buffers. The various short-term buffers provide potential inputs to working memory, which can deal most effectively with only one of the buffers at a time. Working memory integrates information received from short-term buffers with long-term memo-ries that are also activated.

For example, in a recent review of working memory, Repovs & Baddeley613 state that, “the function of the articulatory rehearsal process is to retrieve and rearticulate the contents held in this phonological store and in this way to refresh the memory trace. Further, while speech input enters the phonological store automatically, information from other modalities enters the phonological store only through recoding into phonological form, a process

611 Kimberg, DY; D’Esposito, M & Farah, MJ. Frontal Lobes: Cognitive and Neuropsychological

Aspects. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997.

612 Baddeley, A. Working memory. New York, NY: Oxford University Press; 1986.

613 Repovs, G.& Baddeley, A. The multi-component model of working memory: explorations in experimental cognitive psychology. Neuroscience 139, 5-2; 2006.

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performed by articulatory rehearsal”. Later, the authors refer to, “focal shifts of attention to memorized locations that provide a rehearsal-like function of maintaining information active in spatial working memory”. Thus, one question that neuro-scientific data can address regarding how the brain implements working memory processes is whether such buffers or storage sites exist in distinct parts of the brain to support the active maintenance of task-relevant information.

A cognitive model of working memory, put forward by Cowan614,615 proposes that the, ‘contents of working memory’ are not maintained within dedicated storage buffers, but rather are simply the subset of information that is within the focus of attention at a given time. He describes an embedded-processes model where working memory comes from hierarchically arranged faculties comprising long-term memory, the subset of working long-term memory that is currently activated and the subset of activated memory that is the focus of attention. These ideas are similar to that put forth by Anderson616 who referred to working memory as those representations currently at a high level of activation. Thus, task-relevant representations are not in working memory, but they do have levels of activation that can be higher or lower. After use, for example, representations may be temporarily more active or ‘primed’. In this formulation, working memory does not have a size, or maximum number of items, as a structural feature. Instead, performance on working memory tasks is determined by the level of activation of relevant representations, and the discriminability of activation levels between relevant and irrelevant representations617 .

Again, in neural terms, Cowan’s or Anderson’s cognitive model of working memory would predict that information that is represented throughout the brain is not transferred to an independent buffer or storage site, but rather that temporary retention of task-relevant information is mediated by the activation of the neural structures that represent the information being maintained or stored (for a further discussion of these and related ideas, see Ruchkin, et al 618. In other words, the temporary retention of a face, for example, would require activation of cortical areas that are involved in the perceptual processing of faces.

From a neuroscience perspective, it is counter-intuitive that all temporarily stored information during goal-directed behaviour requires specialized dedicated buffers. Clearly, there could not be a sufficient number of independent buffers to accommodate the infinite types of information that need to be actively maintained to accommodate all potential or intended actions.

For instance, in a system with only two buffers, such as verbal and visuo-spatial, how would the retention of odours or tactile sensations, which cannot always be recoded into verbal or visuo-spatial representations, be accomplished? More recently, an additional episodic buffer has been proposed to be a store capable of multi-dimensional coding that allows the binding of information to create an integrated episode619 . However, even with the addition of this buffer, Baddeley’s working memory model cannot accommodate storage of all possible types of information processed by the human brain (it is important to note, however, that this was not probably the original intent of his model).

614 Cowan, N. Evolving conceptions of memory storage, selective attention, and their mutual

constraints within the human information processing system. Psycho I. Bull. 104, 163-171; 1988.

615 Cowan, N. An embedded-process model of working memory. In Models of working memory: mechanisms of active maintenance and executive control (eds A. Miyake & P. Shah), pp. 62-101. Cambridge, UK: Cambridge University Press; 1999.

616 Anderson, J. R. The architecture of cognition. Cambridge, MA: Harvard University Press; 1983.

617 Kimberg, D. Y., D'Esposito, M. & Farah, M. J. Cognitive functions in the prefrontal cortex-working memory and executive control. Curro Dir. Psychol. Sci. 6, 185-192; 1997.

618 Ruchkin, D. S., Grafman, J., Cameron, K. & Berndt, R. S. Working memory retention systems: a state of activated long-term memory. Behav. Brain Sci. 26, 709-728, discussion 728-777; 2003.

619 Baddeley, A. The episodic buffer: a new component of working memory? Trends Cogn. Sci. 4, 417—423; 2000

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Alternatively, in Cowan’s proposal, which does not rely on the concept of specialized dedicated storage buffers, active maintenance or storage of task-relevant representations could be implemented with a neural system where memory storage occurs in the very same brain circuitry that supports the perceptual representation of information. Such a neural system presumably would be more flexible and efficient than one that transfers information back and forth between dedicated storage buffers. Obviously, there is still work to be done to test these competing hypotheses.

Cognition and Working Memory The influence of memory on perception is an example of what cognitive scientists sometimes call top-down processing, which contrasts with the build-up of perceptions from sensory processing, known as bottom-up processing.

Working memory, in short, sits at the crossroads of bottom-up and top-down processing systems and makes high-level thinking and reasoning possible. Stephen Kosslyn, a leading cognitive scientist, puts it this way:

Working memory ... corresponds to the activated information in long-term memories, the information in short-term memories, and the decision processes that manage which information is activated in the long-term memories and retained in the short-term memories .... This kind of working memory system is necessary for a wide range of tasks, such as performing mental arithmetic, reading, problem solving and . . . reasoning in general. All of these tasks require not only some form of temporary storage, but also interplay between information that is stored temporarily and a larger body of stored knowledge620.

How, then, does working memory work in the brain? Studies conducted in the 1930s by C.F. Jacobsen provide the foundation for our understanding of this problem621. He trained monkeys using something called the delayed response task. The monkey sat in a chair and watched the experimenter put a raisin under one of two objects that were side by side. A curtain was then lowered for a certain amount of time (the delay) and then the monkey was allowed to choose. In order to get the raisin, the monkey had to remember not which object the raisin was under but whether the raisin was under the left or the right object.

Correct performance, in other words, required that the monkey holds in its mind the spatial location of the raisin during the delay period (during which the playing field was hidden from view). At very short delays (a few seconds), normal monkeys did quite well, and performance got predictably worse as the delay increased (from seconds to minutes). However, monkeys with damage to the prefrontal cortex performed poorly, even at the short delays. On the basis of this and research that followed, the prefrontal cortex has come to be thought of as playing a role in temporary memory processes, processes that we now refer to as working memory.

Previously attention has been drawn to the role of the medial prefrontal cortex in the extinction of emotional memory. In contrast, it is the lateral prefrontal cortex that has most often been implicated in working memory. The lateral prefrontal cortex is believed to exist only in primates and is considerably larger in humans than in other primates622. It is not surprising that one of the most sophisticated cognitive functions of the brain should involve this region.

In recent years, the role of the lateral prefrontal cortex in working memory has been studied extensively by the laboratories of Joaquin Fuster at UCLA and Pat Goldman-Rakic at Yale.623,624,625,626 Both researchers have recorded the electrical activity of lateral prefrontal

620 Kosslyn, SM., and Koenig, O. Wet mind: The new cognitive neuroscience; New York:

Macmillan; 1992.

621 Jacobsen, CE; & Nissen, HW. Studies of cerebral function in primates: IV. The effects of frontal lobe lesions on the delayed alternation habit in monkeys. Journal of Comparative and Physiological Psychology 23, 101-12; 1937.

622 Preuss, TM. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered. Journal of Cognitive Neuroscience 7, 1-24; 1995.

623 Fuster, JM. The prefrontal cortex. New York: Raven; 1989).

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neurons while monkeys performed delayed response tasks and other tests requiring short-term storage. They have shown that cells in this region become particularly active during the delay periods. It is likely that these cells are actively involved in holding on to the information during the delay.

Prefrontal Cortex and Working Memory There is now a critical mass of studies that find lateral Prefrontal Cortex (PFC) activity in humans during delay tasks. (See Curtis & D’Esposito627) For example, in a functional magnetic resonance imaging (fMRI) study using an oculomotor delay task identical to that used in monkey studies, it was observed that not only the frontal cortex activity during the retention interval but also the magnitude of the activity, correlated positively with the accuracy of the memory-guided saccade that followed later.

This relationship suggests that the fidelity of the actively maintained location is reflected in the delay-period activity628. Thus, the existence of persistent neural activity during blank memory intervals of delay tasks is a powerful empirical finding, which lends strong support for the hypothesis that such activity represents a neural mechanism for the active maintenance or storage of task-relevant representations.

The necessity of the PFC for the active maintenance of task-relevant representations has been demonstrated by studies that have found impaired performance on delay tasks in monkeys with selective lesions of the lateral PFC 629,630 .

However, monkey physiology studies recording from other brain areas and human fMRI studies of working memory have also found that the PFC is not the only region that is active during the temporary retention of task-relevant information. For example different brain regions are involved during the performance of the oculomotor delayed response task. Specifically, different brain regions were active depending on whether the task required the temporary maintenance of retrospective (e.g. past sensory events) or prospective (e.g. representations of anticipated action and preparatory set) codes.

This study demonstrated not only that many different brain regions exhibit persistent neural activity during active maintenance of task-relevant information, but also that a unique network of brain regions are recruited depending on the type of information being actively maintained. The fMRI data also support the notion that even within the domain of spatial information, separable neural mechanisms are engaged for the active maintenance of ‘motor’ plans versus ‘spatial’ codes. Moreover, given that the task only required the

624 Goldman-Rakic, PS. Circuitry of primate prefrontal cortex and regulation of behavior by

representational memory. In Handbook of physiology. Section 1: The nervous system. Vol. 5: Higher Functions of the Brain, F. Plum, ed. (Bethesda, MD: American Physiological Society, pp. 373-417; 1987.

625 Goldman-Rakic, PS. Working memory and the mind. In Mind and brain: Readings from Scientific American magazine, W. H. Freeman, ed. (New York: Freeman), pp. 66-77; 1993.

626 Wilson, FAW; Scalaidhe, SP; & Goldman-Rakic, PS. Dissociation of object and spatial processing domains in primate prefrontal cortex. Science 260, 1955-58; 1993.

627 Curtis, C. E. & D'Esposito, M. Persistent activity in the prefrontal cortex during working memory. Trends. Cogn. Sci. 7,415—423; 2003.

628 Curtis, C. E., Rao, V. Y. & D'Esposito, M. Maintenance of spatial and motor codes during oculomotor delayed response tasks. J. Neurosci. 24, 3944-3952; 2004.

629 Bauer, R. H. & Fuster, J. M. Delayed-matching and delayed-response deficit from cooling dorsolateral prefrontal cortex in monkeys. Q. J. Exp. Psychol. B 90, 293-302; 1976.

630 Funahashi, S., Bruce, C. J. & Goldman-Rakic, P. S. Dorsolateral prefrontal lesions and oculomotor delayed-response performance: evidence for mnemonic "scotomas". J. Neurosci. 13, 1479-1497; 1993.

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oculomotor system, it is probable that distinct neural circuitry will be recruited when the motor act involves other modalities, such as speech or limb output631 .

Thus, this is the first piece of evidence that the concept of specialized buffers (for, say, verbal versus spatial information) may not map adequately onto neural architecture. Rather, the findings appear more consistent with a system in which active maintenance involves the recruitment of the same circuitry that represents the information itself, with different circuits for different types of spatial information (e.g. visual versus oculomotor).

Similar findings exist when the ‘visual’ component of working memory is investigated with neuro-scientific methods. For example, in another fMRI study632 , the participants were asked to learn a series of faces, houses and face-house associations and they were scanned while performing a delayed match-to-sample (DMS) and delayed paired -associate (DPA) task with these stimuli.

Results showed that delay-period activity within category-selective inferior temporal sub-regions reflected the type of information that was being actively maintained — the fusiform gyrus showed enhanced activity when participants maintained previously shown faces on DMS trials, and when subjects recalled faces in response to a house cue on DPA trials. Likewise, the para-hippocampal gyrus showed enhanced activity when participants maintained previously shown houses on DMS trials and when they recalled houses in response to a face cue on DPA trials.

These fMRI findings are consistent with several monkey neuro-physiological studies which have also shown that temporal lobe neurons exhibit persistent stimulus-selective activity in tasks requiring the active maintenance of visual object information across short delays 633,634,635. Again, like spatial and motor codes, active maintenance of visual stimuli is mediated by the activation of cortical regions that also support processing of that information, perceptual in this case.

Neuro-scientific studies of verbal working memory, which has been most extensively studied by behavioural methods; (Vallar & Shallice, provide a similar view regarding the neural mechanisms underlying working memory636 ). Consistently, performance on tasks that tap the ‘phonological loop’, as conceptualized by Baddeley, engage a set of brain regions that are thought to be involved in phonological processing. For example, using functional neuro-imaging techniques during verbal working memory tasks, the left inferior parietal lobe, posterior inferior frontal gyrus (Broca’s area), premotor cortex and the cerebellum are typically activated637,638 .

631 Hickok, G., Buchsbaum, B., Humphries, C. & Muftuler, T. Auditory-motor interaction revealed

by fMRI: speech, music, and working memory in area Spt. J. Cogn. Neurosci. 15, 673-682; 2003.

632 Ranganath, C., Cohen, M. X., Dam, C. & D'Esposito, M. Inferior temporal, prefrontal, and hippocampal contributions to visual working memory maintenance and associative memory retrieval. J. Neurosci. 24, 3917-3925; 2004.

633 Miyashita, Y. & Chang, H. S. Neuronal correlate of pictorial short-term memory in the primate temporal cortex. Nature 331,68-70; 1988.

634 Miller, E. K., Li, L. & Desimone, R. Activity of neurons in anterior inferior temporal cortex during a short-term memory task. J. Neurosci. 13, 1460-1478; 1993.

635 Nakamura, K. & Kubota, K. Mnemonic firing of neurons in the monkey temporal pole during a visual recognition memory task. J. Neurophysiol. 74, 162-178; 1995.

636 Vallar, G. & Shallice, T. Neuropsychological impairments of short-term memory. Cambridge, UK: Cambridge University Press; 1990.

637 Paulesu, E., Frith, C. D. & Frackowiak, R. S. The neural correlates of the verbal component of working memory. Nature 362,342-345; 1993

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However, is this network of brain regions also responsible for the active maintenance of non-phonological language representations (e.g. lexical-semantic)? For visual word recognition, a functionally specialized processing stream is thought to exist within inferior temporal cortex, representing visual words at increasingly higher levels of abstraction along a posterior-to-anterior axis. 639

Intracranial electrophysiological recordings, for example, (Nobre et al 640 ) show that posterior inferior temporal cortex differentiates letter strings from non-linguistic complex visual objects. Brain activity in more anterior inferior temporal cortical regions, in contrast, distinguishes words from non-words and is affected by the semantic context of words, indicating that anterior inferior temporal cortex holds more elaborate linguistic representations (see also Marslen-Wilson & Tyler 641 and Patterson 642).

To demonstrate that there is distinct neural circuitry supporting the active maintenance of non-phonological language representations, D’Esposito 643 explored the role of language regions within the left infero-tempora1 cortex (ITC) that are involved in visual word recognition and word-related semantics. Using tMRI, he first localized a visual ‘word form’ area within inferior temporal cortex area and then demonstrated that this area was involved in the active maintenance of visually presented words during a delay task. 644 Specifically, he found that this area was recruited more for the active maintenance of words than pseudo-words (i.e. orthographically legal and pronounceable non-words). Maintenance of pseudo-words should not elicit strong sustained activation in such brain regions, as no stored representations pre-exist for these items. These results suggest that verbal working memory may be conceptualized as involving sustained activation of all relevant pre-existing cortical language (phonological, lexical or semantic) representations.

If working memory maintenance processes reflect the prolonged activation of the same brain regions that support online processing, evidence for cortical activity in the absence of stimuli should be evident not only in association cortex but also within primary cortical regions. This indeed is the case as such effects have been observed in primary olfactory 645, visual 646,647 and auditory cortex.648,649 Thus, the neuro-scientific data presented here is

638 Awh, E., Jonides, J., Smith, E. E., Schumacher, E. H., Koeppe, R. A. & Katz, S. Dissociation of

storage and rehearsal in verbal working memory: evidence from PET. Psycho I. Sci. 7, 25-3; 1996.

639 Cohen, L. & Dehaene, S. Specialization within the ventral stream: the case for the visual word form area. Neuroimage 22,466—476; 2004.

640 Nobre, A. C., Allison, T. & McCarthy, G. Word recognition in the human inferior temporal lobe. Nature 372, 260-263; 1994.

641 Marslen- Wilson, W D. & Tyler, L. K. Morphology, language and the brain: the decompositional substrate for language comprehension. Phil. Trans. R. Soc. B 362, 823-836; 2007.

642 Patterson, K. The reign of typicality in semantic memory. Phil. Trans. R. Soc. B 362, 813-821; 2007.

643 D'Esposito, M. From cognitive to neural models of working memory. Phil. Trans. R. Soc. B. 29 May 2007; vol. 362 no. 1481 761-772

644 Fiebach, C. J., Rissman, J. & D'Esposito, M. Modulation of infero-temporal cortex activation during verbal working memory maintenance. Neuron 51, 251-261; 2006.

645 Zelano, c., Bensafi, M., Porter, J., Mainland, J., Johnson, B., Bremner, E., Telles, C., Khan, R. & Sobel, N. Attentional modulation in human primary olfactory cortex. Nat. Neurosci. 8, 114-120; 2005.

646 Klein, I., Paradis, A. L., Poline, J. B., Kosslyn, S. M. & Le Bihan, D. Transient activity in the human calcarine cortex during visual-mental imagery: an event-related fMRI study. J. Cogn. Neurosci. 12(Suppl. 2), 15-23; 2000.

647 Singer, W. & Gray, C. M. Visual feature integration and the temporal correlation hypothesis. Annu. Rev. Neurosci. 18,555-586; 1995.

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consistent with most, if not all, neural populations being able to retain information that can be accessed and kept active over several seconds, via persistent neural activity in the service of goal-directed behaviour.

Baddeley’s original advance (Idem, 1986) was to move us from the concept of short-term memory that accounted only for the storage of representations, to the concept of working memory as a multi-component system that allows for both storage and processing of temporarily active representations. Likewise, Logie650 considered working memory as a ‘mental workspace’ that cannot only hold but is also able to manipulate activated representations.

If working memory is defined as simultaneous storage and processing, then these tasks would probably be considered to assess short-term memory rather than working memory. Thus, it is probably fair to say that the concept of working memory as a non-unitary system that allows for both storage and processing has gained popular acceptance. However, less progress has been made regarding the neural mechanisms underlying the ‘processing’ component of working memory as compared with the ‘storage’ component651 (although see Petrides652).

D’Esposito also proposes (Idem) that any population of neurons within primary or unimodal association cortex can exhibit persistent neuronal activity, which serves to actively maintain the representations coded by those neuronal populations. Areas of multimodal cortex, such as PFC and parietal cortex, which are in a position to integrate representations through connectivity to unimodal association cortex, are also critically involved in the active maintenance of task-relevant information (see also Burgess et al 653 ; Stuss & Alexander654.

Miller & Cohen 655 have proposed that in addition to the recent sensory information, integrated representations of task contingencies and even abstract rules (e.g. if this object then this later response) are also maintained in the PFC. This is similar to what Fuster656 has long emphasized, namely that the PFC is critically responsible for temporal integration and the mediation of events that are separated in time but contingent on one another. In this way, the PFC may exert ‘control’ in that the information it represents can bias the posterior unimodal association cortex in order to keep neural representations of behaviourally

648 Calvert, G. A., Bullmore, E. T., Brammer, M. J., Campbell, R., Williams, S. C., McGuire, :P. K.,

Woodruff, P. W, Iversen, S. D. & David, A. S. Activation of auditory cortex during silent lipreading. Science 276, 593-596; 1997.

649 Kraemer, D. J., Macrae, C. N., Green, A. E. & Kelley, W M. Musical imagery: sound of silence activates auditory cortex. Nature 434,158.; 2005.

650 Logie, R. H. Visuo-spatial working memory. Hove, UK: Erlbaum; 1995.

651 D’Esposito, M. From Cognitive to neural models of working memory. In Driver, J; Haggard, P; & Shallice, T. Mental Processes in the Human Brain. OUP, New York; 2007

652 Petrides, M. Frontal lobes and working memory: evidence from investigations of the effects of cortical excisions in nonhuman primates. In Handbook of neuropsychology, vol. 9 (eds F. Boller & J. Grafman), pp. 59-84. Amsterdam, The Netherlands: Elsevier Science B.Y; 1994.

653 Burgess, P. W, Gilbert, S. J. & Dumontheil, I. Function and localization within rostral prefrontal cortex (area 10). Phil. Trans. R. Soc. B 362,887-899; 2007.

654 Stuss, D. T. & Alexander, M. P. Is there a dysexecutive syndrome? Phil. Trans. R. Soc. B 362, 901-915; 2007.

655 Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 4, 167-202; 2001.

656 Fuster, J. The prefrontal cortex: anatomy, physiology, and neuropsychology of the frontal lobes. New York, NY: Raven Press; 1997.

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relevant sensory information activated when they are no longer present in the external environment657,658,659,660.

In a real world example, when a person is looking at a crowd of people, the visual scene presented to the retina may include a myriad of angles, shapes, people and objects. However, if that person is a police officer looking for an armed robber escaping through the crowd, some mechanism of suppressing irrelevant visual information while enhancing task-relevant information is necessary for an efficient and effective search. Thus, neural activity throughout the brain that is generated by input from the outside world may be differentially enhanced or suppressed, presumably from top-down signals emanating from integrative brain regions such as PFC, based on the context of the situation. Thus, in this formulation, the processing component of working memory is that the control of actively maintained representations within primary and unimodal association cortex stems from the representational power of multimodal association cortex, such as the PFC, parietal cortex and/or hippocampus.

If the PFC, for example, stores the rules and goals, then the activation of such PFC representations will be necessary when behaviour must be guided by internal states or intentions. As Miller & Cohen661 elegantly state, putative top-down signals originating in PFC may permit ‘the active maintenance of patterns of activity that represent goals and the means to achieve them. They provide bias signals throughout much of the rest of the brain, affecting visual processes and other sensory modalities, as well as systems responsible for response execution, memory retrieval, emotional evaluation, etc. The aggregate effect of these bias signals is to guide the flow of neural activity along pathways that establish the proper mappings between inputs, internal states and outputs needed to perform a given task’.

Computational models of this type of system have created a PFC module (e.g. O’Reilly et al662.) that consists of ‘rule’ units whose activation leads to the production of a response other than the one most strongly associated with a given input. Thus, ‘this module is not responsible for carrying out input-output mappings needed for performance. Rather, this module influences the activity of other units whose responsibility is making the needed mappings’ (e.g. Cohen et al663 ). Thus, there is no need to propose the existence of a homunculus (e.g. central executive) in the brain that can perform a wide range of cognitive operations which are necessary for the task at hand.

D’Esposito has used a delay task to directly study the neural mechanisms underlying top-down modulation by investigating the processes involved when participants were required

657 Fuster, J. M. Cortical dynamics of memory. Int. J. Psychophysiol. 35, 155-164; 2000.

658 Ranganath, C., Cohen, M. X., Dam, C. & D'Esposito, M. Inferior temporal, prefrontal, and hippocampal contributions to visual working memory maintenance and associative memory retrieval. J. Neurosci. 24, 3917-3925; 2004.

659 Miller, B. T. & D'Esposito, M. Searching for "the top" in top-down control. Neuron 48, 535-538; 2005

660 Postle, B. R. Delay-period activity in the prefrontal cortex: one function is sensory gating. J. Cogn. Neurosci. 17, 1679-1690; 2005.

661 Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 4, 167-202; 2001.

662 O'Reilly, R. C., Noelle, D. C., Braver, T. S. & Cohen, J. D. Prefrontal cortex and dynamic categorization tasks: representational organization and neuro-modulatory control. Cereb. Cortex 12, 246-257; 2002.

663 Cohen, J. D., Dunbar, K. & McClelland, J. L. On the control of automatic processes: a parallel distributed processing account of the Stroop effect. Psychol. Rev. 97, 332-36; 1990.

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to enhance relevant and suppress irrelevant information664 . During each trial, participants observed sequences of two faces and two natural scenes presented in a randomized order.

The tasks differed in the instructions informing the participants how to process the stimuli:

(i) remember faces and ignore scenes,

(ii) remember scenes and ignore faces, or

(iii) passively view faces and scenes without attempting to remember them.

In each task, the period in which the cue stimuli were presented was balanced for bottom-up visual information, thus allowing us to probe the influence of goal-directed behaviour on neural activity (top-down modulation). In the two memory tasks, the encoding of the task-relevant stimuli requires selective attention and thus permits the dissociation of physiological measures of enhancement and suppression relative to the passive baseline.

There appears to be at least two types of top-down signal, one that serves to enhance task-relevant information and another that serves to suppress task-relevant information. It is well documented that the nervous system uses interleaved inhibitory and excitatory mechanisms throughout the neuro-axis (e.g. spinal reflexes, cerebellar outputs and basal ganglia movement control networks). Thus, it may not be surprising that enhancement and suppression mechanisms may exist to control cognition.665,666 By generating contrast via both enhancements and suppressions of activity magnitude and processing speed, top-down signals bias the likelihood of successful representation of relevant information in a competitive system.

Though it has been proposed that the PFC provides a major source of the types of top-down signals that D’Esposito has described, this hypothesis largely originates from suggestive findings rather than direct empirical evidence. However, a few studies lend direct causal support to this hypothesis (see also Vuilleumier & Driver667 ).

Clearly, there are other areas of multimodal cortex such as posterior parietal cortex, and the hippocampus, that can also be the source of top-down signals. For example, the hippocampus has been proposed to be specialized for ‘rapid learning of arbitrary information which can be recalled in the service of controlled processing’. Moreover, input from brainstem neuro-modulatory systems probably plays a critical role in modulating goal-directed behaviour. For example, the dopaminergic system probably plays a critical role in cognitive control processes.

The overall goal of cognitive neuroscience as a discipline is to determine the biological basis of the mind. As an interdisciplinary discipline that has evolved from both neuroscience and psychology, cognitive neuroscientists consume data derived from each of these disciplines in their attempt to advance cognitive theory as well as determine how the brain implements cognitive function. Advances made in understanding the cognitive and neural basis of working memory provide examples of this synergy. D’Esposito suggests that future studies must continue to consider both cognitive and neural data. Research

664 Gazzaley, A., Cooney, J. W., McEvoy, K., Knight, R. T. & D'Esposito, M. Top-down

enhancement and suppression of the magnitude and speed of neural activity. J. Cogn. Neurosci. 17, 1-11. 2005.

665 Knight, R. T., Staines, W R., Swick, D. & Chao, L. L. Prefrontal cortex regulates inhibition and excitation in distributed neural networks. Acta. Psychol. (Amst) 101, 159-178; 1999.

666 Shimamura, A. P. The role of the prefrontal cortex in dynamic filtering. Psychobiology 28, 207-218; 2000.

667 Vuilleumier, P. & Driver, J. Modulation of visual processing by attention and emotion: windows on causal interactions between human brain regions. Phil. Trans. R. Soc. B 362, 837-855; 2007.

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thus far suggests that working memory can be viewed as neither a unitary nor a dedicated system. A network of brain regions, including the PFC, is critical for the active maintenance of internal representations that are necessary for goal-directed behaviour. Thus, working memory is not localized to a single brain region but probably is an emergent property of the functional interactions between the PFC and the rest of the brain.

The contribution of the lateral prefrontal cortex to working memory is still being explored. However, considerable evidence suggests that the lateral prefrontal cortex is involved in the executive or general purpose aspects of working memory. For example, damage to this region in humans interferes with working memory regardless of the kind of stimulus in-formation involved. (Fuster, 1989, Idem) &668.

Further, brain imaging studies in humans have shown that a variety of different kinds of working memory tasks result in the activation of the lateral prefrontal cortex.669,670,671,672 In one recent study, for example, subjects were required to perform a verbal and a visual task either one at a time or at the same time673. The results showed that the lateral prefrontal cortex was activated when the two tasks were performed together, thus taxing the executive functions of working memory, but not when the tasks were performed separately.

The lateral prefrontal cortex is ideally suited to perform these general purpose working memory functions. It has connections with the various sensory systems (like the visual and auditory systems) and other neocortical systems that perform specialized temporary storage functions (like spatial and verbal storage) and is also connected with the hippocampus and other cortical areas involved in long-term memory (Fuster, idem, 1989; Goldman-Rakic, 1987, idem)&674,675. In addition, it has connections with areas of the cortex involved in movement control, allowing decisions made by the executive to be turned into voluntarily performed actions (Fuster, idem, 1989; Goldman-Rakic, 1978, idem). Recent studies have begun to show how the lateral prefrontal cortex interacts with some of these areas. However, the best understood are the interactions with temporary storage buffers in the visual cortex.

Cortical visual processing begins in the primary visual area located in the occipital lobe (the rear-most part of the cortex). This area receives visual information from the visual thalamus, processes it, and then distributes its outputs to a variety of other cortical regions. Although the cortical visual system is enormously complex676, the neural pathways responsible for two aspects of visual processing are fairly well understood. These involve the determination of

668 Petrides, M. Frontal lobes and behaviour. Current Opinion in Neurobiology 4, 207-11; 1994.

669 Petrides, M; Alivsatos, B; Meyer, E; & Evans, AC. Functional activation of the human frontal cortex during the performance of verbal working memory tasks. Proceedings of the National Academy of Sciences USA 90, 878-82; 1993.

670 Jonides, J; Smith, EE; Keoppe, RA; Awh, E; Minosbima, S; & Mintun, M.A. Spatial working memory humans as revealed by PET. Nature 363, 623-25; 1993.

671 Grasby, PM; Firth, CD; Friston, KJ; Bench, C; Frackowiak, RSJ; & Dolan, RJ. Functional mapping of brain areas implicated in auditory-verbal memory function. Brain 116, 1-20; 1993.

672 Swartz, BE; Halgren, E; Fuster, JM; Simpkins, E; Gee, M; & Mandelkern, M. Cortical metabolic activation in humans during a visual memory task. Cerebral Cortex 5,205-14; 1995.

673 D'Esposito, M; Detre, J; Alsop, D; Shin, R; Atlas, S; & Grossman, M. The neural basis of the central executive system of working memory. Nature 378,279-81; 1995.

674 Reep, R. Relationship between prefrontal and limbic cortex: A comparative anatomical review. Brain, Behavior and Evolution 25, 5-80; 1984.

675 Uylings, HBM; & van Eden, CG. Qualitative and quantitative comparison of the prefrontal cortex in rat and in primates, including humans. Progress in Brain Research 85, 31-62; 1990.

676 Van Essen, DC. Functional organization of primate visual cortex. In Cerebral cortex, A. Peters and E. G. Jones, eds. (New York: Plenum), pp.259-328; 1985.

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‘what’ a stimulus is and ‘where’ it is located.677,678 The ‘what’ pathway involves a processing stream that travels from the primary visual cortex to the temporal lobe and the ‘where’ pathway goes from the primary cortex to the parietal lobe.

Goldman-Rakic and colleagues recorded from cells in the parietal lobe ‘where’ pathway during short-term memory tests requiring the temporary remembering of the spatial location of visual stimuli. They found that cells there, like cells in the lateral prefrontal cortex, were active, suggesting that they were keeping track of the location, during the delay. (Goldman-Rakic, 1987, idem)

The parietal and frontal regions in question are anatomically interconnected — the parietal area sends axons to the prefrontal region and the prefrontal region sends axons back to the parietal area. These findings suggest that the parietal lobe visual area works with the lateral prefrontal cortex to maintain information about the spatial location of visual stimuli in working memory. Similarly, Robert Desimone found evidence for reciprocal interactions be-tween the visual areas of the temporal lobe (the ‘what’ pathway) and the lateral prefrontal cortex in studies involving the recognition of whether a particular object had been seen recently679. The maintenance of visual information in working memory thus appears to crucially depend on interactions between the lateral prefrontal region and specialized areas of the visual cortex.

Le Doux suggests that this involvement of specialized short-term buffers in the sensory systems and a general-purpose working memory mechanism in the prefrontal cortex is a very complicated system. The prefrontal cortex itself seems to have regions that are specialized, at least to some degree, for specific kinds of working memory functions. Such findings, however, do not discredit the notion that the prefrontal cortex is involved in the general-purpose or executive aspects of working memory since only some cells in these areas play specialized roles. Interactions between the general-purpose cells in different areas may coordinate the overall activity of working memory. It is thus possible that the executive functions of the prefrontal cortex might be mediated by cells that are distributed across the different prefrontal subsystems rather than by cells that are collected together in one region. (Le Doux, 1998, idem)

The pathway from the specialized visual areas tells the prefrontal cortex ‘what’ is out there and ‘where’ it is located (bottom-up processing). The prefrontal cortex, by way of pathways back to the visual areas, primes the visual system to attend to those objects and spatial locations that are being processed in working memory (top-down processing). These kinds of top-down influences on sensory processing are believed to be important aspects of the executive control functions of working memory.

Recent studies, especially by Goldman-Rakic and associates, have raised questions about the role of the prefrontal cortex as a general purpose working memory processor. (Wilson et al, 1993; Idem) For example, they have found that different parts of the lateral prefrontal cortex participate in working memory when animals have to determine ‘what’ a visual stimulus is as opposed to ‘where’ it is located, suggesting that different parts of the prefrontal cortex are specialized for different kinds of working memory tasks. While these findings show that parts of the prefrontal cortex participate uniquely in different short-term memory tasks, they do not rule out the existence of a general-purpose workspace and a set of executive functions that coordinate the activity of the specialized systems, especially

677 Ungerleider, LG; & Mishkin, M. Two cortical visual systems. In Analysis of visual behavior, D. J.

Ingle, M. A. Goodale, and R. ]. W. Mansfield, eds. (Cambridge: MIT Press), pp. 549-86; 1982.

678 Ungerleider, LG; & Haxby, J. What and wher;'in the human brain. Current Opinion in Neurobiology 4, 157-65; 1994.

679 Desimone, R; Miller, EK; Chelazzi, L; & Lueschow, A. Multiple memory systems in the visual cortex. In The cognitive neurosciences, M. S. Gazzaniga, ed. (Cambridge: MIT Press), pp. 475-86; 1995.

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since the tasks studied did not tax the capacity of working memory in a way that would reveal a limited capacity system.

Studies that have taxed the system, like imaging studies in humans, suggest that neurons in the lateral prefrontal cortex are part of a general-purpose working memory network. At the same time, it is possible, given Goldman-Rakic's findings that the general-purpose aspects of working memory are not localized to a single place in the lateral prefrontal cortex but instead are distributed over the region. That this may occur is suggested by the fact that some cells in the specialized areas of the lateral pre-frontal cortex participate in multiple working memory tasks. (Petrides, 1994, Idem)

There is also evidence that the general purpose functions of working memory involve areas other than the lateral prefrontal cortex. For example, imaging studies in humans have shown that another area of the frontal lobe, the anterior cingulate cortex, is also activated by working memory and related cognitive tasks. (D’Esposito, et al, 1995, Idem) &680,681

Relation of the "What" and "Where" Visual Pathways to Working Memory.

Visual information, received by the visual cortex, is distributed to cortical ar-eas that perform specialized visual processing functions. Two well-studied specialized functions are those involved in object recognition (mediated by the ‘what’ pathway) and object location (mediated by the ‘where’ pathway). These specialized visual pathways provide inputs to the prefrontal cortex (PFC), which plays a crucial role in working memory. The specialized systems also receive inputs back from the PFC, allowing the information content of working memory to influence further processing of incoming information. Leftward-going arrows represent bottom-up processing and

680 Corbetta, M; Miezin, FM; Dobmeyer, S; Shulman, GL; & Petersen, SE. Selective and divided

attention during visual discriminations of shape, color, and speed: Functional anatomy by positron emission tomography. Journal of Neuroscience 11, 2383-2402; 1991.

681 Posner, M; & Petersen, S. The attention system of the human brain. Annual Review of Neuroscience 13, 25-42; 1990.

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rightward-going ones top-down processing.

Like the lateral pre-frontal cortex, the anterior cingulate region receives inputs from the various specialized sensory buffers, and the anterior cingulate and the lateral pre-frontal cortex are anatomically interconnected. (Fuster, 1989, Idem) &682. Moreover, both regions are part of what has been called the frontal lobe attentional network, a cognitive system involved in selective attention, mental resource allocation, decision making processes, and voluntary movement control683. It is tempting to think of the general purpose aspects of working memory as involving neurons in the lateral prefrontal and anterior cingulate regions working together.

One other area of the prefrontal cortex, the orbital region, located on the underneath side of the frontal lobe, has emerged as important as well. Damage to this region in animals interferes with short-term memory about reward information, about what is good and bad at the moment 684, and cells in this region are sensitive to whether a stimulus has just led to a reward or punishment 685,686,687. Humans with orbital frontal damage become oblivious to social and emotional cues and some exhibit sociopathic behaviour. 688 This area receives inputs from sensory processing systems (including their temporary buffers) and is also intimately connected with the amygdala and the anterior cingulate region. The orbital cortex provides a link through which emotional processing by the amygdala might be related in working memory to information being processed in sensory or other regions of the neocortex.

There is still much to be learned about working memory and its neural basis. It is not clear, for example, whether both the temporary workspace and the executive functions are actually located in the frontal cortex. It is possible that the prefrontal areas do not store anything but instead just control the activity of other regions, allowing the activity in some areas to rise above the threshold for consciousness and inhibiting the activity of the others. In spite of the fact that we still have much to learn, the researchers in this area have made considerable progress on this very tough, and very important, problem. (LeDoux, Idem, 1998

This very complicated span of neural activity is carried out in our brains without us having to think about it consciously. However, with subjects like MDL, who have damage to some of the areas involved, it can be seen why there is a failure of certain cognitive and social skills and it is important to portray these difficulties as being influenced by her brain damage and not by lack of intellect.

From the extensive research noted above there can be no doubt that MDL’s behavioural symptoms stem to a great extent from damage to the frontal lobes. It can also be

682 Goldman-Rakic, PS. Topography of cognition: Parallel distributed networks in primate

association cortex. Annual Review of Neuroscience 11, 137-56; 1988.

683 Posner, M. Attention as a cognitive and neural system. Current Directions in Psychological Science 1, 11-14; 1992.

684 Gaffan, D; Murray, EA; & Fabre-Thorpe, M. Interaction of the amygdala with the frontal lobe in reward memory. European Journal of Neuroscience 5, 968-75; 1993.

685 Thorpe, SJ; Rolls, ET; & Maddison, S. The orbitofrontal cortex: Neuronal activity in the behaving monkey. Experimental Brain Research 49, 93-115; 1983 .

686 Rolls, ET. Neurophysiology and functions of the primate amygdala. In The amygdala: Neurobiological aspects of emotion, memory, and mental dysfunction, J. P. Aggleton, ed. (New York: Wiley-Liss), pp. 143-65; 1992.

687 Ono, T & Nishijo, H. Neurophysiological basis of the KliiverBucy syndrome: Responses of monkey amygdaloid neurons to biologically significant objects. In The amygdala: Neurobiological aspects of emotion, memo,); and mental dysfunction, J. P. Aggleton, ed. (New York: Wiley-Liss), pp. 167-90; 1992.

688 Damasio, A. Descartes error: Emotion, reason, and the human brain. New York: Grosset/Putnam; 1994.

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understood just how difficult it is to predict how MDL’s brain damage affects the processing of information and to what extent the deficiencies of her working memory adds to these problems. Consider — as individuals there is not a conscious understanding from moment to moment of how our brains are dealing with the constant flow of information. We only know such things as a lack of comprehension and a failure of memory; these events occur in what we consider to be a brain that is working normally. If our brains do not work as well today as they did say a year ago, then we have the ability to compare the two phases of our life. MDL has to cope with a disabled brain without any knowledge of what the situation would be if it hadn’t been damaged. Even if changes have taken place in her brain since the original injury, she does not have the ability to know why or even to question why.

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Non-verbal Learning Disability689

Various learning disability phenotypes have been ascribed to the right hemisphere (RH) dysfunction and sometimes packaged together as RH learning disability, often based on a simplistic equation of left hemisphere (LH) with verbal and RH with nonverbal functioning. Conversely, the RH has been credited with specific roles in some ostensibly LH-based verbal learning disabilities690. These attributions are speculative. However, Minshew regards Non-verbal Learning Disability as being restricted to verbal individuals with IQs above 70. 691

By definition, learning disability excludes underlying structural brain damage. Therefore, external validation by means of a consistently localized lesion site is not available. Neuropsychological analysis may point to underlying structural brain damage and to an underlying processing deficit of known localizing significance. But even if one ventures to equate the localizing values of comparable acquired and developmental deficits, there remains little demonstrated correspondence between the functional specializations of the hemispheres and patterns of academic achievement.

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Pervasive Development Disorders

The category of pervasive developmental disorder (PDD) was introduced to classification systems in 1980 when it became clear that autism was not a psychotic disorder and could no longer be classified with the childhood psychoses. The term was coined to reflect the full range of IQs in autism, the selective nature of the deficits, and the severity of their impact on adaptive function. The PDD diagnostic category is stipulated for disorders char-acterized by specific qualitative impairments in social interactions, verbal and nonverbal language and their use for communication, symbolic and imaginative play, and abstract reasoning and related complex behaviour. Impairments are selective — i.e., disproportionate to age and IQ expectations — and also have distinctive qualitative characteristics. (Minshew, 1997, Idem)

It has been said that people with autism suffer from a lack of “central coherence”, the cognitive ability to bind together a jumble of separate features into a single, coherent object or concept692. Ironically, the same can be said of the field of autism research, which 689 Kinsbourne, M. Nonverbal Learning Disability. In Feinberg, T E & Farah, M J. Behavioural

Neurology and Neuropsychology. McGraw-Hill, New York, 1997

690 Bakker D & Licht R. Learning to read: Changing horses in mid-stream, in Pavlidis GT, Fisher DF (eds): Dyslexia: Its Neuropsychology and Treatment. New York: Wiley, 1986, pp 87-96.

691 Minshew, NJ. Pervasive Developmental Disorders: Autism and Similar Disorders. In Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997

692 Frith U. Autism: explaining the enigma. Oxford: Blackwell; 1989.

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all too often seems a fragmented tapestry stitched from differing analytical threads and theoretical patterns. Defined and diagnosed by purely behavioural criteria, autism was first described and investigated using the tools of behavioural psychology. More recent years have added brain anatomy and physiology, genetics, and biochemistry, but results from these new domains have not been fully integrated with what is known about autistic behaviour. The unification of these many levels of analysis will not only provide therapeutic targets for prevention and remediation of autism but can also provide a test case for theories of normal brain and cognitive development. Autism research therefore has much to learn from and much to offer to the broader neuroscience community. 693

A variety of other more subtle or nonspecific abnormalities-ranging from delayed motor development and hyperactivity to relative insensitivity to pain, sound sensitivity, and exag-gerated fears-are often also present but are 'considered minor or peripheral features. From the beginning it was clear that there were disorders other than autism in this category, but the capacity for differentiating and defining them was essentially nonexistent. The classification and criteria for these disorders remain in evolution. (Minshew, 1997, Idem)

Clinically, autism is defined by a “triad” of deficits comprising impaired social interaction, impaired communication, restricted interests, and repetitive behaviours. Although in some cases speech never develops fully or never develops at all, in other cases, speech may be present but so inflexible and unresponsive to context that it is unusable in normally paced conversation; often, speech is limited to echolalia or confined to narrow topics of expertise in which discourse can proceed without conversational interplay. The communicative impairment extends also to nonverbal signals such as gaze, facial expression, and gesture.

Elison et al have found that Infants at seven months of age who go on to develop autism are slower to reorient their gaze and attention from one object to another when compared to seven-month-olds who do not develop autism, and this behavioral pattern is in part explained by atypical brain circuits. The study concluded that atypical visual orienting is an early feature of later emerging autistic spectrum disorder and is associated with a deficit in a specific neural circuit in the brain. These findings suggest that seven-month-olds who go on to develop autism show subtle, yet overt, behavioral differences prior to the emergence of the disorder. They also implicate a specific neural circuit, the splenium of the corpus callosum, which may not be functioning as it does in typically developing infants who show more rapid orienting to visual stimuli. 694

There also may be a connection between this disturbance noted in the splenium in autistic spectrum disorder and what may be earlier brain damage. Damage that accounts for permanent cognitive impairment in patients with mild traumatic brain injury (mTBI) can be shown by diffusion tensor imaging to involve diffuse axonal injury. It has also been suggested that the thalamus may play an important role in the development of clinical sequelae in mTBI. By variously altered diffusion tensor imaging- and diffusional kurtosis imaging-derived measures, this is shown in the thalamus and the internal capsule. In addition to these regions, patients examined more than 1 year after injury also show similar differences in the splenium of the corpus callosum and the centrum semiovale. Cognitive impairment was correlated in this research with mean kurtosis in the thalamus and the internal capsule. These findings suggest that combined use of diffusion tensor imaging and diffusional kurtosis imaging provides a more sensitive tool for identifying brain injury. In addition the authors suggest that mean kurtosis in the thalamus might be useful for early prediction of permanent brain damage and cognitive outcome. 695

693 Belmonte, MK; Allen, G; Beckel-Mitchener, A; Boulanger, LM; Carper, RA; & Webb, SJ.

Autism and Abnormal Development of Brain Connectivity. Journal of Neuroscience, October 20, 2004 • 24(42):9228 –9231

694 Elison, JT; Piven, J & Schultz, RT. Atypical brain circuits may cause slower gaze shifting in infants who later develop autism. American Journal of Psychiatry (3/20/2013).

695 Grossman, EJ; Ge, Y; Jensen, JH; Babb, JS; Miles, L; Reaume, J; Silver, JM; Grossman, RI & Inglese, M. Thalamus and Cognitive Impairment in Mild Traumatic Brain Injury: A Diffusional Kurtosis Imaging Study. J Neurotrauma. 2012 Sep;29(13):2318-27. doi: 10.1089/neu.2011.1763.

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Social behaviours, too, are beset by a lack of flexibility and rapid coordination: children with autism do not coordinate attention between objects of mutual interest and the other people, who may be interested in them, often engage in “parallel play” at the edge of a group rather than joining in cooperative play, and do not engage in pretend play. Intense and narrowly focused interests tend to concentrate on systems696 that operate deterministically and repeatably according to tractable sets of rules, whether these are abstract and complex systems such as computers or role-playing games or very concrete and simple systems such as toilets or washing machines.

Critical to identifying the causal factors of autism, and key to its relevance to normal development, is the recognition that autism is actually the extreme of a spectrum of abnormalities. Milder phenotypes on this spectrum include Asperger syndrome697 in which language is relatively unimpaired, and the “Broader Autism Phenotype” in which characteristic cognitive traits are present sub-clinically698. The combination of this broad variation of phenotypes and a 60–90% concordance rate in identical twins699 suggests a large number of genetic and environmental biasing factors700.

In addition to the central coherence paradigm, autism has been variously characterized as a deficit of executive function701, complex information processing702, theory of mind703, and empathy.704

696 Baron-Cohen, S. The extreme male brain theory of autism. Trends Cogn Sci 6:248 –254; 2002.

697 Wing, L. Asperger’s syndrome: a clinical account. Psychol Med 11:115–129; 1981.

698 Dawson, G.; Webb, S.; Schellenberg, GD; Dager, S; Friedman, S; Aylward, E & Richards, T. Defining the broader phenotype of autism: genetic, brain, and behavioral perspectives. Dev Psychopathol 14:581– 611; 2002.

699 Bailey, A; Le Couteur, A; Gottesman, I; Bolton, P; Simonoff, E; Yuzda, E & Rutter ,M. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77; 1995

700 Muhle, R; Trentacoste, SV & Rapin I. The genetics of autism. Pediatrics 113:e472– e486; 2004.

701 Ozonoff, S; Pennington, B & Rogers, SJ. Executive function deficits in high-functioning autistic individuals: relationship to theory of mind. J Child Psychol Psychiatry; 32:1081–1105; 1991.

702 Minshew, NJ; Goldstein, G & Siegel DJ. Neuropsychologic functioning in autism: profile of a complex information processing disorder. J Int Neuropsychol Soc 3:303–316; 1997.

703 Baron-Cohen S; Leslie AM. & Frith U. Does the autistic child have a “theory of mind’’? Cognition 21:37– 46; 1985.

704 Baron-Cohen, S. The extreme male brain theory of autism. Trends Cogn Sci 6:248 –254; 2002.

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Figure Potential effects of network connectivity patterns on brain activation. In the network on the left, a combination of strong local connectivity within delimited groups of neural units and selective long-range connectivity between local groups constitutes a computational structure within which information can be efficiently represented and efficiently propagated. Inputs (double arrows) evoke representations that are easily differentiable from noise (single arrow) and can be linked across regions, yielding high computational connectivity. In the network on the right, strongly connected sub-regions are not appropriately delimited and differentiated, and computationally meaningful long-range connections fail to develop. The brain images at bottom, from a visual attention task, display distributed patterns of functional activation in the normal brain (left) and abnormally intense and regionally localized activation in the autistic brain (right), a pattern that may stem from such differences at the network level. 705

Each of these theories is a valid description of many aspects of the autistic syndrome but each, in answering unsolved questions at one level of explanation, introduces them at another. Recent attempts at a theoretical synthesis have focused on abnormal neural connectivity, and, superficially, there seems some disagreement as to whether this abnormality involves a surfeit706,707 or a deficit708,709 of connectivity. The picture is complicated by the fact that the term “connectivity” admits more than a single meaning.

Conceptually, we can differentiate local connectivity within neural assemblies from long-range connectivity between functional brain regions. On another axis, we can also separate the physical connectivity associated with synapses and tracts from the computational connectivity associated with information transfer. Physically, in the autistic brain, high local connectivity may develop in tandem with low long-range connectivity (Just et al., Idem, 2004), perhaps as a consequence of widespread alterations in synapse elimination and/or formation710.

Furthermore, indiscriminately high physical connectivity and low computational connectivity may reinforce each other by failing to differentiate signal from noise, (Rubenstein and Merzenich, Idem 2003); Belmonte et al., Idem 2004) (See Figure below).

705 Belmonte, MK; Allen, G; Beckel-Mitchener, A; Boulanger, LM; Carper, RA; & Webb, SJ.

Autism and Abnormal Development of Brain Connectivity. Journal of Neuroscience, October 20, 2004 • 24(42):9228 –9231.

706 Rubenstein,JL & Merzenich, MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2:255–267; 2003.

707 Belmonte, MK & Baron-Cohen, S. Normal sibs of children with autism share negative frontal but not positive sensory abnormalities: preliminary evidence from fMRI during processing of visual distractors. Soc Neurosci Abstr 30:582.10; 2004.

708 Brock, J; Brown, CC; Boucher, J & Rippon, G. The temporal binding deficit hypothesis of autism. Dev Psychopathol 14:209 –224; 2002.

709 Just, MA; Cherkassky, VL; Keller, TA & Minshew, NJ. Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity. Brain 127:1811–1821; 2004.

710 Sporns, O; Tononi, G & Edelman, GM. Theoretical neuroanatomy: relating anatomical and functional connectivity in graphs and cortical connection matrices. Cereb Cortex 10:127–141; 2000.

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This model is consistent not only with the impairments in higher-order cognition described by the diagnostic triad but also with impairments of motor coordination711, perceptual abnormalities such as high visual motion coherence thresholds712 and broad tuning of auditory filters713, abnormal growth within regions of local but not long-range white-matter projections714, and the substantial co-morbidity of epilepsy with autism715 (Ballaban-Gil and Tuchman, 2000).

Although MDL sometimes appears to show signs of autistic spectrum disorder (ASD), it has been shown that damage to specific areas of the brain can produce symptoms that mimic some of those of autism. 716

As IQ declines in autism, abstract reasoning falls disproportionately, whereas immediate recall and visuo-spatial ability are usually preserved. The predictable outcome with increasing severity of such a profile is mental retardation with an unusual preservation of memory for details and visuo-spatial ability and unusually poor adaptive behaviour relative to IQ. (Minshew, 1997, Idem)

It is obvious that MDL does not show these characteristics and she does not have the symptoms of classical autism; therefore it is perhaps unhelpful to suggest that she has ASD. However, it will have been noted that some of the neurological deficits that MDL does have and that have arisen from her initial brain damage are comparable to some characteristics of ASD. Neurological studies in autism have demonstrated predominant deficits in abstract reasoning and problem solving abilities; higher-order language abilities and complex memory abilities.

Neurophysiology of Autism The neurophysiology of autism is largely a research issue, aside from the clinical usefulness of brain stem auditory evoked potentials in assessing hearing. One recent summary of this literature has emphasized the occurrence of hearing loss in this population and has advocated vigorous evaluation of hearing status. 717

Neurophysiologic functioning in autism has been demonstrated to be characterized by abnormalities in cognitive potentials with preservation of early and middle latency poten-tials. From a patho-physiologic perspective, this profile implicates complex cognitive processes and higher brain regions. A recent study of eye movement physiology in autism20 has revealed a similar profile with prominent abnormalities in cortically controlled eye movements subserved by frontal and parietal circuitry and intact basic and reflex eye movements subserved by sub-cortical and posterior fossa structures. (Minshew, 1997, Idem)

From long observation of MDL’s behaviour and assessment of her attributes and limitations it

711 Teitelbaum, P; Teitelbaum, O; Nye, J; Fryman, J & Maurer, RG. Movement analysis in infancy

may be useful for early diagnosis of autism. Proc Natl Acad Sci USA 95:13982–13987; 1998.

712 Milne, E; Swettenham, J; Hansen, P; Campbell, R; Jeffries, H & Plaisted, K. High motion coherence thresholds in children with autism. J Child Psychol Psychiatry 43:255–263; 2002.

713 Plaisted, K; Saksida, L; Alcantara, JI & Weisblatt, EJL. Towards an understanding of the mechanisms of weak central coherence effects: experiments in visual configural learning and auditory perception. Philos Trans R Soc London B Biol Sci 358:375–386; 2003.

714 Herbert, MR; Ziegler, DA; Makris, N; Filipek, PA; Kemper, TL; Normandin, JJ; Sanders, HA; Kennedy, DN & Caviness Jr, VS. Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 55:530–540; 2004.

715 Ballaban-Gil, K & Tuchman R. Epilepsy and epileptiform EEG: association with autism and language disorders. Ment Retard Dev Disabil Res Rev 6:300 –308; 2000.

716 Challoner, A. Abnormal Brain Structure and Autism. http://www.scribd.com/doc/9635846/Abnormal-Brain-Structure-and-Autism-

717 Klin A. Auditory brainstem responses in autism: brain stem dysfunction or peripheral hearing loss. J Autism Dev Dis 23:15-35, 1993.

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is clear that the above description by Minshew and Klin does not bear any resemblance to MDL.

Neuropathology of Autism The description of the neuropathology of autism 718 has been limited to the examination of a small number of cases and to clinical pathology methods. Quantitative measurements of cell number and structure volume are notably lacking. The neuro-pathologic abnormalities described in autism are subtle overall and consist of a 100- to 200-g increase in brain weight in most cases and histologic abnormalities in the limbic system and cerebellum.

In the small, compact gray matter structures of the limbic system, the neurons were immature in appearance and exhibited a truncation in dendritic tree development. In addition, there was an increase in cell-packing density, which appeared to be the consequence of a decrease in the neuropil. In the cerebellum, there was a decrease in Purkinje and granule cells throughout the hemispheres but greatest in neocerebellar regions. These findings have been of major importance in providing definitive, evidence of the neurologic basis of autism and have characterized it as a disorder of neuronal organization.

More recent research by Belmonte et al has involved work on abnormal neural connectivity and used it to show explanatory framework within which genetic and neuro-pathological findings on autism may be unified with neuroanatomy, neurophysiology, and behaviour. Communication between these levels of analysis promises a greater understanding of mechanisms underlying both normal and pathological development of neural and cognitive systems and has the potential to render a multiplicity of experimental and theoretical approaches more coherent. 719

Autism and Anxiety

Studies exploring the relationships of anxiety with autism720,721 and the amygdala in autism722 led to the conclusions that:

1. the amygdala is not essential for social behaviour;

2. pathology of the amygdala may not be the basis for impaired functioning in autism; and

3. impairments of amygdala functioning in autism may produce effects through influencing fear and anxiety that are commonly co-morbid in autism, and that in turn might exacerbate other causes of social impairment.

In another set of studies, 723,724,725 in which primates had amygdala lesions placed shortly after birth, (as opposed to studying lesions made in mature animals), Dr. Amaral established

718 Bauman ML & Kemper TL. Neuroanatomic observations of the brain in autism, in Bauman ML,

Kemper TL (eds): The Neurobiology of Autism. Baltimore: Johns Hopkins University Press, 1994, pp 86-101.

719 Belmonte, MK; Allen, G; Beckel-Mitchener, A; Boulanger, LM; Carper, RA; & Webb, SJ. Autism and Abnormal Development of Brain Connectivity. Journal of Neuroscience, October 20, 2004 • 24(42):9228 –9231

720 Muris P, Steerneman P, Merckelbach H, Holdrinet I, Meesters C. Comorbid anxiety symptoms in children with pervasive developmental disorders. J Anxiety Disord. 1998;12:387-393.

721 Gillott A, Furniss F, Walter A. Anxiety in high-functioning children with autism. Autism. 2001;5:277-286.

722 Thomas KM, Drevets WC, Dahl RE, et al. Amygdala response to fearful faces in anxious and depressed children. Arch Gen Psychiatry. 2001;58:1057-1063.

723 Amaral DG. The primate amygdala and the neurobiology of social behavior: implications for understanding social anxiety. Biol Psychiatry. 2002;51:11-17.

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that the amygdala was not necessary for gaining or acquiring social knowledge in the first place.

Data were also presented about a patient who had an Urbache Wiethe syndrome with bilateral lesions of the amygdala. This interesting patient was referenced as ‘extensively studied’ by Adolphs and colleagues.726,727,728 This patient was impaired in her ability to recognise fearful faces, yet she could easily perceive happiness or other emotions in faces. Of note, she otherwise lived a normal life, which is remarkable for someone without an amygdala. The conclusion from this case and others suggests that the amygdala is not essential for normal social behaviour and that damage in this area does not necessarily lead to autistic behaviour.

Patho-physiology of Autism The patho-physiology of the clinical syndrome of autism is controversial, with multiple different hypotheses as to the central neuro-psychologic deficit and central nervous system localization. Regardless of differences, current theories propose a primary deficit in higher-order cognitive abilities and localization at the neural systems level or at multiple levels of the neuraxis. The predominant theories propose a core deficit in executive functions729, control of attention730, or complex in-formation processing731. Localizations proposed for these deficits include frontal systems, frontal cortex-parietal cortex-neocerebellar vermis, and generalized involvement of neocortical systems, respectively.

It can be seen that damage to these areas post-natally may produce autistic-type deficits. It is said that treatment of autism and similar disorders involves primarily an environmental and behavioural approach, as there are no medications with demonstrated efficacy against the primary deficits in autism. Academic intervention should employ a model that is the converse of the traditional learning disability approach, with a particular emphasis on interpretative and problem-solving deficits. (Minshew, 1997, Idem)

Behaviour Modification in Autism In terms of behaviour modification, which is the mainstay of treatment, several guidelines are essential to the successful application of such techniques to individuals with pervasive developmental disorders. The underlying principle is the recognition that autism and the pervasive developmental disorders directly involve the very skills that are the basis of adaptive function in society and thus the capacity for adapting to real life. Thus, these individuals should not be expected to adapt to the environment but rather the environment should be adapted to them.

724 Prather MD, Levenex P, Mauldin-Jourdain ML, et al. Increased social fear and decreased fear

of objects in monkeys with neonatal amygdala lesions. Neuroscience. 2001;106:653-658.

725 Emery NJ, Capitanio JP, Mason WA, Machado CJ, Mendoza SP, Amaral DG. The effects of bilateral lesions of the amygdala on dyadic social interactions in rhesus monkeys (Macaca mulatta). Behav Neurosci. 2001;115:515-544.

726 Adolphs R, Tranel D, Damasio AR. The human amygdala in social judgment. Nature. 1998; 393): 470-474.

727 Adolphs R, Tranel D, Damasio H, Damasio A. Impaired recognition of emotion in facial expressions following bilateral damage to the human amygdala. Nature. 1994;372:669-672.

728 Adolphs R, Tranel D, Damasio H, Damasio AR. Fear and the human amygdala. J Neurosci. 1995; 15:5879-5891.

729 Ozonoff S; Strayer DL & McMahon WM, et al. Executive function abilities in autism: An information processing approach. J Child Psychol Psychiatry 35:659-685, 1994.

730 Courchesne E; Townsend JP & Akshoomoff NA, et al. A new finding: Impairment in shifting attention in autistic and cerebellar patients, in Broman SH, Grafman J (eds): Atypical Deficits in Developmental Disorders: Implications for Brain Function. Hillsdale, NJ: Erlbaum, 1994, pp 101-317.

731 Minshew NJ; Goldstein G & Siegel DJ. Profile of neuropsychologic functioning in autism: A generalized disorder of complex information processing. J Int Neuropsychol Soc. 3, 303-316; 1997.

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Second, staff should be highly familiar with the deficits in autism and their behavioural manifestations, so that these individuals are not expected to do things that involve their deficits and that odd behaviour which is not hindering the individual’s function is accepted as hard-wired rather than targeted for change because it looks odd to others.

Difficulty in coping with the presence of others and with change and ritualistic obsessive compulsive behaviour are the sources of most undesirable behaviour. Thus, if a behaviour problem develops, the social demands and amount of change occurring in the environment at the time need to be assessed to determine if they exceed the individual's usual tolerance limits. Rituals that do not interfere with function should generally be respected as a means of coping with change.

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The Neuro-behavioural Examination of Children

With any neurological/behavioural/competence-based assessment of MDL, there has to be a continuous reference to and reliance on determining what is her ‘age norm’ for any tasks and this must of necessity begin with a realisation that her brain injury occurred at the age of five/six months.

From that, there has to be an understanding of what her developmental milestones were together with her behavioural and neurological characteristics up to the age of say 18 years. To this one must add the impact of trauma that she has received — including environmental, emotional and physical events — so that adjustments can be made to aid the discovery of what, for her, is an age-appropriate level of assessment; and it may not be equal across all areas.

Thus it may be (say) age four for some assessments and age twelve for others. There will be very few areas, if any, that will allow assessors to view her as an adult in terms of her neurological development especially in relation to communication, emotion and many practical capabilities and these include social relationships.

As Denckla writes732, Apart from such (assessment) tests or tasks themselves, for each of which there is a rationale, there is an aspect of evaluation that goes beyond the term examination and is indispensable to developmental ‘mental status’; this is the history and description of the patient by parents and teachers. Of course, this is shared with all of behavioural neurology, since the literal confines of examination cannot sample complex social, vocational, and communal behaviours relevant to any patient's mental status. For the developmental clinic, how ever, the need to collect and interpret parent- and teacher-derived data relates with urgency to decisions about certain diagnostic ‘entities’ that are shared by professional colleagues in psychiatry and education. Whatever our neurologically based intellectual qualms about some of these ‘diagnoses’, service to the patients demands that data considered to be the basis of these ‘entities’ be included in the neurobehavioral assessment.

Beyond attempts to document "syndromes" that overlap entities recognizable to the schools and clinics where treatment is carried out, the neurobehavioral examination is free to describe the strengths and weaknesses of each patient. Rarely is "localization" or classic brain-behaviour correlation the purpose of the evaluations. Explanation of the cluster of deficits or the profile, consistent with established knowledge of brain organization, helps to legitimize educational approaches or accommodations. Sometimes brain-based explana-tions even serve to clarify prognosis. At the very least, brain-based explanations usually help to avoid irrational or harmful treatments and, for those patients mature enough to attempt

732 Denckla, MB. The Neurobehavioral Examination in Children. In Feinberg, T E & Farah, M J.

Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997

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to understand themselves, self-knowledge and insight are the not inconsiderable benefits. (Idem)

Sumowski and colleagues have shown that higher intellectual enrichment (estimated with education) reduces the negative effect of TBI on cognitive outcomes and thereby supports the cognitive reserve hypothesis in persons with TBI. They believe that future work is necessary to investigate whether intellectual enrichment can build cognitive reserve as a rehabilitative intervention in survivors of TBI.733

It is the failure of professionals to understand these complex issues and there relevance to the examination and assessment of MDL, that she has suffered from incorrect assessments during the whole of her life. The effect of those failures is cumulative with each successive incorrect assessment/diagnosis feeding further diversity and thereby failing to find the correct diagnosis for her condition. That is compounded most severely when it is considered that some of these incorrect diagnoses have subsequently involved the use of psychotropic medication to purportedly relieve conditions from which she was not suffering.

MDL’s sole neuropsychological assessment in her ‘adult’ years was conducted by the assessor alone, having never met her before and he disallowed a parent from being present. This egregious error is used as an example of what not to do when making a pragmatic assessment. From Denckla’s approach (see above), it can be seen just how important are the features of her outline of hoe a neurological assessment should be carried out.

Denckla stresses that what is included in the evaluation is multi-determined. To be unkind, one could call the ‘menu’ of what is included, a ‘hodgepodge’; to be generous, one could call it eclectic and pragmatic. It is not a fixed battery; it changes with conceptual and data driven shifts in the current relevant literatures. For example, there is convergent consensus that phonologic coding skills are the basis for reading acquisition, the inclusion of direct norm-referenced measures of phoneme segmentation, phonologic memory, and reading (decoding) nonsense words became standard in the ‘learning disability’-oriented workup. Depending on the chief complaint, which varies somewhat from patient to patient and age group to age group, only a ‘core’ is invariant; but a certain set of mental status constructs is assessed flexibly, on an individualized basis. As Rita G. Rudel so aptly warned, "Don't assault (patients) with your battery." It will be perfectly obvious and recognizable to any professional trained to engage in the mental status examination that the developmentalist surveys language, attention, memory, visual perception, and (emphatically) motor skills. (Idem)

There is an interesting neurological evaluation to be made from how a subject holds a pencil or a knife and fork. The way these items are grasped indicates the level of motor control. In MDL’s case it is clear that (at present) she has less control over the proximal positions of her fingers and is therefore less able to write or draw effectively or to use a knife and fork to her best advantage. Her control has reverted to a primitive ulnar grasp that controls movement by the forearm rather than more distally.

It is very much an undermining of MDL’s control and of her wellbeing and her self-perceived worth, that she finds herself unable to do the things with her fingers that once she could do. As this is a deterioration from her previous abilities, it could be argued that she has regressed neurologically and one might ask is that an organic remission or is it to do with the long-term medication to which she has been subjected?

733 Sumowski JF; Chiaravalloti N; Krch D; Paxton J & Deluca J. Education attenuates the

negative impact of traumatic brain injury on cognitive status. Arch Phys Med Rehabil. 2013 Dec;94(12):2562-4

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During MDL’s childhood there was no attempt made to assess her through paediatric neurology. This, despite the fact that she was seen five or six times a year by a neurologist from the age of four to eighteen. Of course it has to be recognised that in the 1960s, brain science was still almost in its infancy when it came to understanding atraumatic injuries such as MDL’s. There were some scientific papers available on the subject from about 1965, but the science is not well-documented until the 1980s. As a result MDL’s consultations were almost entirely monitoring exercises (and that probably to assess how her parents were coping) and there was never any attempt to assess her neurological deficiencies. There were occasional attempts to see how she was writing and drawing and some of these documents were filed. It is clear from hindsight that the lack of knowledge of this type of brain injury led to a less than satisfactory outcome for MDL. Instead there was a steady transference to what was then called ‘the mental handicap service’ and that led almost sine qua non to the psychiatric service — and then because that didn’t understand the brain injury, onwards to psychotropic medication from the age of ten years.

AFTERWORD

All those who have researched human neurology have discovered the inherent complexity of the brain and its interlocking functions. There remains controversy in some areas and this may continue as no two brains are alike and no one person’s experience of learning is the same as that of another.

In reviewing this updated neurology research it may help to throw some light on how the deficiencies of MDL’s mental processes can happen but it does not necessarily do more than indicate that her behaviour is bound up in the differences from normal that occur in her brain and that her problems will relate to failures in her neuronal processing.

For those who have been able to see a deeper meaning, it will be clear that none of her damaged areas of brain can be repaired and that the kindest and most caring approach to those problems is to create an environment in which she can find comfort, happiness and a minimum of stress.

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BIBLIOGRAPHY

Feinberg, T E & Farah, M J. Behavioural Neurology and Neuropsychology. McGraw-Hill, New York, 1997

Pennington BF. Diagnosing Learning Disorders: A Neuropsychological Framework. New York: Guilford, 1991.

Atrens, D. & Curthoys, I. The Neurosciences and Behaviour: An Introduction. Academic Press, Sydney, Australia; 1982.

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INDEX

Abstract Thinking......................................... 14 Acetylcholine .............................................. 96 Agraphia .... 10, 43, 44, 49, 50, 51, 52, 53, 61 Amygdala . 23, 36, 41, 70, 71, 73, 74, 75, 76,

78, 80, 81, 82, 83, 84, 85, 86, 87, 88, 92, 93, 94, 95, 96, 97, 98, 101, 102, 103, 104, 120, 127, 128

Amygdala-Triggered Arousal ................... 95 Angular gyrus ......................................... 52, 63 Anxiety ............................. 36, 76, 78, 101, 102 Anxiety and Stress ....................................... 78 Aphasia ....................10, 43, 45, 46, 47, 49, 50 Apperceptive agnosia .............................. 55 Apraxia Testing ............................................ 54 Arousal .................................................... 96, 97 Associative agnosia ................................... 56 Axon terminals ............................................. 96 Basal ganglia lesions .................................. 24 Behaviour Modification in Autism .......... 128 BIBLIOGRAPHY ........................................... 133 Brain and emotion ...................................... 76 Brain Damage ............................................. 18 Brain development ............................... 37, 45 Broca's aphasia .................. 39, 44, 45, 49, 50 Broca's area ........................................... 13, 45 Cerebral laterality ....................................... 43 Childhood aphasic syndromes and the

localization of lesions .............................. 26 Cognition and Working Memory ........... 106 Cognitive deficit after closed head injury

in children ................................................. 28 Conditioned fear ........................................ 76 Conscious feelings ...................................... 77 Context Memory ......................................... 12 Cortex ........................................................... 94 D-cycloserine ............................................... 76 Depotentiation ............................................ 75 Developmental agnosia ........................... 59 Diaschisis ....................................................... 47 Disorders of Perception ............................. 62 Disorders of Spatial Memory ..................... 65 Dopamine .................................................... 96 DTP ................................................................... 1 Dysarthria .......................................... 44, 47, 48 Dysprosody ................................................... 44

Elements of Language and Communication ...................................... 39

Emotion and Medication ........................ 101 Emotional feelings and emotional

responses .................................................. 77 Emotional Memory ..................................... 74 Emotional reactions.................................... 96 Emotions ....................................................... 77 Emotions and our Mental Life ................... 70 Executive function ...................................... 29 Exposure Therapy ........................................ 76 Extinction ................................................ 75, 76 Extinction’ ..................................................... 75 Fear ................................................................ 75 Fear Conditioning .............. 37, 84, 86, 91, 97 Finger agnosia ................................. 52, 60, 61 Frontal Lobe .................................... 13, 87, 94 Gerstmann syndrome .......................... 52, 61 Hemispheric cerebral dominance .......... 19 Henschen's principle .................................. 46 Ideomotor apraxia ............ 45, 54, 68, 69, 70 Justin .............................................................. 75 Langton ........................................................ 75 Language and Neuropsychological

Dysfunction ............................................... 24 Language in children with early brain

damage .................................................... 30 Lateral prefrontal cortex............................ 94 Lateral sulcus/Sylvian fissure ................... 132 LeDoux .......................................................... 71 Left hemisphere/right hemisphere

dichotomies ............................................. 20 Lesion Method ............................................. 34 Limb Apraxia .......................................... 10, 53 Localization of Brain Lesions and

Developmental Functions . 18, 22, 26, 29, 32, 60

Memory of Skilled Movements ................... 5 Miller .............................................................. 90 Mishkin .............................................36, 77, 118 Myers ............................................................. 75 Neuro-behavioural Examination of

Children ................................................... 129 Neurology of Emotions ............................... 73 Neuropathology of Autism ...................... 127

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Neurophysiology of Autism ..................... 126 Non-verbal learning disabilities ................ 32 Non-verbal Learning Disability ................ 121 Noradrenalin ................................................ 96 Parietal damage ......................................... 65 Parietal lobe ...................... 51, 52, 54, 66, 118 Patho-physiology of Autism..................... 128 Performances mediated by the right

hemisphere ............................................... 19 Perirhinal or insular cortex .......................... 76 Pervasive Development Disorders ......... 123 Pre-frontal cortex......................................... 13 Pre-frontal Functions ..................................... 9 Primary acalculia .................................. 52, 53 Proprioceptor System ................................. 67 Prosopagnosia ................................ 58, 59, 67 Ready to Fear .............................................. 90 Rewards and punishments ........................ 94 Right brain damage .. 41, 42, 59, 61, 62, 63,

69 Right brain-damaged .......................... 41, 62 Right hemisphere ... 9, 39, 40, 41, 42, 43, 59,

62, 63, 64, 66, 69, 88, 89, 90, 121, 122 Right-Hemisphere Learning Disability .... 122 Right-Hemisphere Underdevelopment . 121 Seligman ....................................................... 91 Semantic ................................................. 38, 50 Semantic aphasia ....................................... 46 SEMANTIC MEMORY IMPAIRMENTS .......... 38 Sequencing Tasks ........................................ 11 Shall we be Frightened .............................. 92 Sleep ............................................. 37, 105, 106 Spatial Disturbances ................................... 51 Stress .............................. 36, 68, 74, 79, 83, 87

and the amygdala ................................. 81 Cold stress ................................................. 72 Environmental stress ................................ 36 Heat stress ................................................. 72 PTSD ............................................................ 81 Stress hormones ....................................... 98 Conditioned responses to ..................... 74 With anxiety .............................................. 78

Subcortical lesions and the right hemisphere ............................................... 25

Supervisory Attentional System ................. 15 Temporal lobe & Lateral Sulcus .............. 131 Thalamic System .......................................... 93 Thalamus ....... 73, 76, 92, 93, 95, 96, 105, 117 The Agnosias ................................................ 55 The Emotional Brain .............................. 70, 71 The organization of memory during

developmental age ............................... 21 Topographical Disorientation ................... 66 Tower of London test .................................. 12 Transcortical Aphasia ................................. 45 Transcortical sensory aphasia ................... 46 Traumatic Stress ........................................... 79 UNILATERAL BRAIN DAMAGE ..................... 88 Valium ................................................ 101, 102 Verbal Fluency ............................................. 12 Visual cortex ............... 92, 103, 117, 118, 119 Visual Object Agnosia .......................... 56, 62 Visuo-spatial and Constructional Disorders

.................................................................... 62 Weinberger ................................................... 76 Working memory .... 9, 15, 52, 92, 94, 95, 96,

98, 101, 103, 104, 106, 108, 110, 111, 117, 118, 119, 120

a study of a single case of atraumatic brain injury mdl

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