530.302 – Medical Neurosciences Lecture Notes

THE CEREBRAL CORTEX AND THALAMUS

• Overview of the Brain The brain consists of forebrain (thalamus, basal ganglia, hypothalamus, cerebral cortex), midbrain and hindbrain (pons, medulla and cerebellum). The midbrain, pons and medulla are also known as the brain stem. The corpus callosum transmits information between each hemisphere. Contralateral control – the left side of the brain generally controls the right side of the body, and the right side of the brain controls the left side of the body. The human brain is very much dominated by the forebrain. The brain can be divided into lobes: Frontal – superior, middle and inferior frontal gyri Parietal – superior and inferior lobules, and supramarginal and angular gyri Occipital and temporal – superior, middle and inferior temporal gyri The central sulcus lies between the precentral and postcentral gyri; the lateral sulcus is really a fissure; the parietal-occipital fold is best seen from the medial aspect. The brain also contains conduit areas: Primary motor cortex – precentral gyrus (and supplementary area) Primary somatosensory cortex – postcentral gyrus (and supplementary area) Primary visual cortex – cortex lateral to the calcarine sulcus (big supplementary area) Primary auditory cortex – superior temporal gyrus (and transverse gyrus of Heschl) Note that the visual cortex is visuotopically (retinotopically) organised – the left half of the visual field of each eye is interpreted by the right side of the brain, and vice versa (note the optic chiasm). Other areas are specific to the dominant hemisphere of the brain (left for most people):

Broca’s area (posterior 1/3 inferior frontal gyrus) – motor control of speech (engrams) Wernicke’s area (posterior 2/3 superior temporal gyrus) – recognition aspects Arcuate fasciculus – connects Broca’s and Wernicke’s areas

Sensory/motor/conduction aphasias Note the association of right-sided hemiplegia with speech problems (in stroke cases) Inferior parietal lobule (especially the supramarginal/angular gyrus) – integration/interpretation

of visual and auditory input for reading and writing Exner’s area (superoinferior 1/3 middle frontal gyrus) – motor aspects of reading and writing Functions of the non-dominant cortex include non-verbal language, emotional expression, spatial skills (3D), conceptual understanding and artistic/musical skills. Damage leads to spatial disorientation, inability to recognise familiar objects, and loss of musical appreciation. Note that the size of the superior temporal gyrus is larger in the dominant hemisphere – this means the lateral fissure is at a different angle on either side of the brain. Associational cortex has a number of functions, depending on localisation: Frontal lobe – intelligence, mood, personality, behaviour, cognitive function Parietal lobe – spatial skills, 3D recognition, shapes, faces, abstract perception Temporal lobe – memory, mood, aggression, intelligence Note 3 major neurotransmitters (monoamines) – noradrenaline, serotonin and dopamine The cerebral cortex is supplied by the circle of Willis (carotid and vertebral arteries): Anterior cerebral artery – superior, anterior of cortex, including medial surfaces Middle cerebral artery – most of the lateral aspect of the brain (common infarcts)

530.302 – Medical Neurosciences Lecture Notes Posterior cerebral artery – occipital lobe, medial aspect of the temporal lobe

• Cellular Organisation of the Cerebral Cortex There are 14,000 x 106 neurons in the cerebral cortex, consisting of two basic types: Pyramidal cells (10-70μm) – apical/basal dendrites, long axon – efferent (Golgi type I) Granule/stellate cells (6-10μm) – round cells, short axons – local circuit (Golgi type II) The grey matter can be divided into allocortex (3 laminae) medial to the rhinal/collateral sulcus, and the neocortex more frontally (6 laminae):

Supragranular Molecular (I) External granular (II) External pyramidal (III) Granular Internal granular (IV) Infragranular Internal pyramidal (V) Multiform VI Projection fibres (V) – cell bodies in the internal pyramidal lamina subcortical structures Association and commissural (efferent) fibres (III) – cell bodies in the external pyramidal layer Specific afferent fibres (IV) – sensory data from outside of the cortex layer IV (corticipetal) Associational and commissural afferents (I-III) – cortex/nervous system layers I-III and VI Note that the cerebral cortex differs in composition depending on the local cortical function:

Agranular cortex – predominant III, V and VI layers (pyramidal) – note giant (Betz) cells e.g. precentral gyrus (primary motor cortex)

Granular (koniocortex) cortex – predominant II and IV layers (granular cells) e.g. primary sensory cortices

Homotypical cortex – e.g. associational cortex (prefrontal, parietal associational, temporal)

• Thalamus and Internal Capsule The thalamus is the ‘toll gate’ for the cerebral cortex, performing the preliminary analysis of all information. It consists of two hemispheres (connected by interthalamic adhesions) and has grey matter with a lamina of myelinated fibres that divides it into a number of compartments: Ventral nuclear group – anterior, lateral and posterior nuclei (VA, VL, VP) Geniculate bodies (metathalamus) – medial and lateral (MGB and LGB) Anterior, medial and lateral nuclear groups The VA-VL unit sends information to the motor cortex (anterior part legs) – it receives input from the cerebellum and basal ganglia, and feedback from the cerebral cortex. The VP nucleus sends information to the primary somatosensory cortex (lateral part legs). It analyses touch, pressure, pain and temperature information from the trigeminothalamic medial lemniscus and spinothalamic tracts. The LGB consists of six different cell layers – information from specific parts of the visual field is processed by specific parts of this nucleus. The MGB gets input from the auditory pathway and passes it to the primary auditory cortex. Medial dorsal nucleus prefrontal cortex Lateral nuclear group parietal and temporal cortex Anterior nuclear group limbic system (cortex?)

530.302 – Medical Neurosciences Lecture Notes

THE SPINAL CORD AND BRAIN STEM

• Spinal Cord The spinal cord extends from the foramen magnum to the lower border of L1 vertebra. It terminates in the conus medullaris (and cauda equina), although the pia mater continues as the filum terminale (~20 cm in length) to the level of the posterior coccyx (passing through the termination of the arachnoid mater and dura mater, about 15 cm inferior to the conus medullaris). Note that CSF can be extracted from the subarachnoid space between L3 and L4 vertebrae. NB: the spinal cord is encased in a dural sac (note that the endosteal and meningeal dura fuse) that extends to (and fuses at) the level of S2 vertebrae. This sac is lined with arachnoid mater, and this also terminates at S2 vertebrae. There is a cervical enlargement (C3-T1) and a lumbrosacral enlargement (L1-S) associated with lower motor neurones (limb innervation). While there is no intrinsic segmentation in the structure of the spinal cord, paired spinal nerves can be divided as follows: 8 cervical nerves (note there are only 7 cervical vertebrae) 12 thoracic nerves 5 lumbar nerves 5 sacral nerves 1 coccygeal nerve The dorsal root fibres (6-8 rootlets) of each spinal nerve unite in the vertebral formation and join with ventral roots. They then enter the dorsolateral sulcus (medial and lateral bundles); the efferent fibres exit the ventrolateral sulcus. Structurally, a dorsal median sulcus and ventral median fissure are also present. White matter in the spinal cord is located peripherally, while grey matter is more central. Note that there is a large ventral grey horn in the cervical and lumbar regions, but not in the thoracic region (as there is no limb innervation here). There is also less white matter at the base of the spinal cord compared to the top. The grey matter in the spinal cord is divided into laminae: Dorsal horn: Posteromarginal nucleus (I) Substantia gelatinosa (II) Nucleus proprius (III and IV) Laminae V and VI Intermediate zone (VII): Intermediolateral nucleus (T1-T2) – preganglionic sympathetics

Dorsolateral nucleus of Clarke (T1-L2) Ventral horn: Medial motor nucleus (VIII, some IX)

Lateral motor nucleus (IX) The white matter is divided into funiculi: Dorsal funiculus: Gracile fasciculus – discriminative sensory fibres, lower limb medulla Cuneate fasciculus – discriminative sensory fibres, upper limb medulla Lateral funiculus: Lateral corticospinal motor column Anterior funiculus: Lateral spinothalamic (pain and temperature sensation) Propriospinal tract: Carries interspinal neurons (short are central; long are peripheral)

• Cerebrospinal Fluid and Intracranial Pressure Functions of CSF:

1. Maintains constant environment for neurons and glia (metabolites, toxins) 2. Mechanical cushion for brain 3. May act as a conduit for peptide hormones

530.302 – Medical Neurosciences Lecture Notes CSF is located in the ventricles and subarachnoid space

1. Anatomy a. Dura mater – falx cerebri and tentorial notch are important clinical areas b. Leptomeninges (arachnoid and pia mater) c. Virchow-Robin spaces – perivascular space produced from invaginations of

the pia mater where blood vessels enter/exit the brain and spinal cord d. Ependyma (single layer of cells lining the ventricles)

2. CSF flow – produced mainly in the lateral ventricles a. 3rd ventricle via left and right interventricular foramina (Monro) b. 4th ventricle via cerebral (Sylvian) aqueduct c. subarachnoid via 1 midline (Magendie) and 2 lateral (Luschka) foramina

3. CSF production – most produced by the choroid plexus in the lateral ventricles, though secretion through the ependyma may also be involved

a. Production involves filtration across the choroidal capillary wall, followed by active secretion by choroidal epithelium (microvillous, BB barrier)

b. Figures i. 0.35mL/min (500mL/day) ii. Total volume is 140mL – complete turnover 3-4 times daily

4. CSF absorption a. Most by unidirectional bulk flow in arachnoid villi ( superior sagittal sinus) b. Some molecules (especially lipophilic) diffuse into brain and capillaries c. Active transport of some solutes by the choroid plexus

5. CSF composition a. White blood cells – <5x106/L (no PMNs or red blood cells) b. Protein – <0.45g/L c. Glucose – >2.5mmol/L

i. Depends on blood glucose (2/3 level) and brain metabolism Hydrocephalus ( dementia, ataxic gait, urinary incontinence/urgency) may be caused by:

1. Impaired CSF absorption – impaired CSF drainage, defective arachnoid villi 2. Obstruction to CSF pathways 3. Overproduction of CSF – choroid plexus papilloma

Treatment may be mediated by removal of the cause (e.g. tumour) or insertion of a shunt between the lateral ventricles and the peritoneal cavity or right atrium. The blood-brain barrier acts with the CSF to preserve homeostasis of neurons and glia. It is comprised of epithelial cells of the choroid plexus, and endothelial cells of brain capillaries.

1. Important features a. Morphological constraints – tight junctions between endothelial cells, fewer

pinocytotic vesicles, thicker basement membrane, more mitochondria (active transport) and astrocytic foot processes

b. Biochemical constraints determine function – molecular weight, lipid solubility, ionisation at physiological pH, protein binding (restricts entry)

i. Normal molecules that enter the brain are small and lipophilic or have specific transporters (active transport/facilitated diffusion)

2. Disorders a. Disruption of tight junctions paracellular passage across tight junctions and

increased vesicular transport across endothelial cells b. Formation of new blood vessels in tumours with leaky capillaries

Intracranial pressure may be measured by lumbar puncture (L3-4 space in the midline below the spinous process of L3) or a tube inserted into the ventricles or subdural space.

1. Maintenance of ICP – normal levels are 65-195mmH2O(5-15mmHg) a. Intracranial contents (brain, blood, CSF) are fixed in volume b. Increase in volume of one component must be accompanied by decrease in

another – when this fails, ICP raises and cerebral blood flow falls i. Cerebral perfusion pressure = ABP – ICP

2. Factors affecting ICP – arterial blood pressure, venous pressure, thoracic pressure, posture, PaCO2, PaO2, temperature

530.302 – Medical Neurosciences Lecture Notes 3. Compensatory mechanisms

a. Displacement of CSF into spinal canal b. Distensibility of dura (mainly lumbosacral) c. Increase in CSF absorption d. Collapse of cerebral veins e. Plasticity of brain (compression, displacement)

4. Intracranial hypertension may be caused by a mass lesion a. ICP increases if the lesion reaches a critical mass (compensatory

mechanisms fail), or obstructs the cerebral venous system or CSF pathways. b. Damage may be due to cerebral ischaemia or secondary tissue displacement

• Brain Stem Base Tegmentum Roof Plate Midbrain Basis pedunculi (crus

cerebri) – corticobulbar, corticospinal and corticopontine tracts

Substantia nigra, red nucleus, cranial nuclei IV

Corpora quadrigemina – superior and inferior colliculi

Pons Pars basilaris, pontine nuclei

Cranial nuclei V-VIII

Medulla Pyramids Inferior olivary nucleus, Medial lemniscus, cranial nuclei IX-XII

The base extends through the midbrain, pons and medulla. The tegmentum is present throughout the brainstem – a major component of this is the reticular formation. This consists of small areas of grey matter interspersed with threads of white matter – it has both sensory and motor function. Note the raphe nuclei of the reticular formation, which have major projections (to the cortex?). It regulates muscle tone, and involves the reticular activating system to alert the cortex to incoming sensory signals - note that the cranial nerve nuclei are embedded in the reticular formation (lateral parvicellular, medial magnicellular). Corticobulbar fibres terminate on these nuclei. Another part of the tegmentum is the medial lemniscus that extends through the medulla, pons and midbrain. It consists of white matter, and contains axons that convey nerve impulses from the medulla to the thalamus for discriminative touch, proprioception, pressure and vibration sensations. The roof plate is only found in the midbrain. The midbrain (mesencephalon) extends from the pons to the diencephalon – the cerebral aqueduct passes through this structure, connecting the third and fourth ventricles. The anterior portion contains the cerebral peduncles (crus cerebri) that contain motor fibres (corticopontine, corticospinal and corticobulbar). The superior cerebellar peduncles connect the midbrain with the cerebellum. The posterior portion of the midbrain is called the tectum (roof plate) and contains four rounded elevations (corpora quadrigemina). The two superior elevations (superior colliculi) serve as a reflex centre for movements of the eyes, head and neck in response to visual stimuli. The inferior colliculi are reflex centres for movements of the head and trunk in response to auditory stimuli. The midbrain also contains the left and right substantia nigra, which control subconscious muscle activities. The red nuclei are also present – cerebellum and cerebral cortex fibres

530.302 – Medical Neurosciences Lecture Notes synapse here to coordinate muscle movement (in association with the basal ganglia and cerebellum). The pons is a bridge connecting the spinal cord with the brain, and parts of the brain with each other. The corticopontine fibres terminate in the pontine nuclei, and axons cross over to reach the cerebellum (forming the middle cerebellar peduncles). The longitudinal axons belong to the motor and sensory tracts that connect the medulla with the midbrain. Nuclei for cranial nerves V, VI, VII and VIII can also be found in the pons, along with the pneumotaxic area and the apneustic area (respiration). The medulla oblongata is the continuation of the superior portion of the spinal cord and forms the inferior part of the brain stem. Within the medulla are all ascending and descending white matter tracts, and many nuclei (grey matter) that regulate various functions. There are two pyramids on the anterior aspect of the medulla, containing the largest motor tracts that pass from the cerebrum to the spinal cord (corticobulbar and corticospinal). Just superior to the junction of the medulla and spinal cord, the pyramids decussate (85% of corticospinal fibres). On the dorsal aspect, the right and left nucleus gracilis and nucleus cuneatus can be found – some ascending sensory axon terminals form synapses in these nuclei, and postsynaptic neurons relay information to the thalamus on the opposite side. The medulla also contains the cardiovascular centre, medullary rhythmicity area, nuclei of origin for cranial nerves (VIII, IX, X, XI and XII), and the olivary nucleus that communicates with the cerebellum by paired tracts (inferior cerebellar peduncles).

• Brain Stem: Somatosensory Pathways The medial bundle of dorsal root fibres consists of thick myelinated fibres conveying discriminative touch, pressure and proprioceptive information. These divide into short ascending and descending collaterals; travelling ipsilaterally to the nucleus proprius, dorsal nucleus of Clarke and the ventral grey horn. 25% of the medial bundle fibres also give long ascending primary branches. These pass in the dorsal funiculus to the cuneate and gracile nuclei of the medulla, forming the spinal part of the central pathway of discriminative sensation. Secondary neurons cross over (internal arcuate fibres) at the medulla and terminate in the thalamus (VPL/VPM); tertiary neurons travel from the thalamus via the internal capsule to the postcentral gyrus. The lateral bundle of dorsal root fibres consists of finely myelinated and unmyelinated fibres, conveying pain and temperature information. These pass along the dorsolateral tract of Lissauer and bifurcate into short ascending and descending branches; terminating in the substantia gelatinosa. Secondary neurons decussate at their level of entry in the ventral white commissure within the spinal cord, travelling through the anterolateral tract to ascend to the thalamus (VPL) and postcentral gyrus. They also terminate in other parts of the thalamus that send axons to other cortical areas, so pain may be diffuse. Tertiary neurons connect the thalamus to the cortex. Note that the pain and temperature pathway decussates lower than the discriminative touch pathway:

1. Dissociated sensory loss due to a lesion on the spinal cord – loss of discriminative information on the same side as the lesion, loss of pain and temperature information on the other side as the lesion.

530.302 – Medical Neurosciences Lecture Notes 2. Associated sensory loss due to a lesion at the medulla or higher – loss of

discriminative and pain/temperature information on the opposite side of the lesion (both pathways have decussated).

Three different types of motoneurons also enter the ventral root – α motor neurons (extrafusal fibres of striated muscle), γ motor neurons (intrafusal fibres of muscle spindles) and intermediolateral motor neurons (autonomic ganglia, smooth muscle). Ipsilateral and contralateral interconnections can be found in each spinal segment and between spinal segments – these form the fasciculi proprii adjacent to the spinal grey matter.

• Spinal Cord: More Detail on Tracts

The spinothalamic tract comprises axons of nociceptive-specific and wide-dynamic range neurons in laminae I, V-VII of the dorsal horn. Lateral fibres (dorsal horn and intermediate grey zone) convey pain and temperature information; ventral fibres (nucleus proprius) convey light touch information. These project to the contralateral side of the spinal cord to ascend in the anterolateral white matter, terminating in the thalamus. Electrical stimulation results in pain, while lesions result in marked reduction in pain sensation (on the side opposite to the lesion).

The spinocerebellar tract comprises axons in the ventrolateral and lateral funiculi. Posterior fibres convey subconscious proprioception information from the same side of the cerebellum (muscle spindles). Anterior fibres carry impulses from the opposite side of the cerebellum (Golgi tendon organs). The tracts ascend to the medulla, and pass through the inferior cerebellar peduncle (posteriorly) and superior cerebellar peduncle (anteriorly). Note that the anterior fibres receive input from the opposite side, but the axons recross within the cerebellum.

The corticospinal tracts convey nerve impulses from the motor cortex to skeletal muscles on the opposite side of the body (lateral for limbs, anterior for axial). Axons of upper motor neurons descend from the cortex into the medulla. 90% of these decussate and enter the contralateral spinal cord to form the lateral tract, entering the anterior grey horn on the same side to provide input to lower motor neurons. The remaining 10% form the anterior tract, entering the anterior grey horn on the opposite side to provide input to lower motor neurons.

The corticobulbar tract conveys nerve impulses from the motor cortex to skeletal muscles of the head and neck. Axons of upper motor neurons descend into the brain stem – some cross to the

530.302 – Medical Neurosciences Lecture Notes opposite side while others remain uncrossed. They provide input to lower motor neurons in the nuclei of cranial nerves III through XII, excepting VIII.

The rubrospinal tract conveys impulses from the red nucleus to skeletal muscles on the opposite side of the body to govern precise, discrete movements of the hands and feet. The tectospinal tract conveys impulses from the superior colliculus to skeletal muscles on the opposite side of the body to move the head and eyes in response to visual stimuli. The vestibulospinal tract conveys impulses from the vestibular nucleus to regulate muscle tone

from maintaining balance on the same side of the body. The lateral reticulospinal tract conveys motor impulses from the reticular formation to muscles that facilitate flexor reflexes and decrease muscle tone in the axial skeleton. The medial reticulospinal tract conveys motor impulses from the pons to facilitate extensor reflexes and increase tone in the axial skeleton. THE SOMATIC SENSATION SYSTEM

• Overview of the Somatosensory System The somatosensory system has receptors distributed throughout the body that encode touch, temperature, body position (kinaesthesia) and pain.

1. Touch receptors are typically immediately deep to the skin (prominent in pigs) a. Meissner’s corpuscles are rapidly adapting receptors for discriminative touch b. Type I cutaneous mechanoreceptors are slowly adapting receptors for

discriminative touch c. Type II cutaneous mechanoreceptors are slowly adapting receptors for

heavy, continuous touch sensations 2. Temperature receptors are most likely free nerve endings (previously thought to be

type II cutaneous mechanoreceptors). They are found at different depths and have different initial rates of fire.

3. Muscle spindles consist of intrafusal muscle fibres enclosed in spindle-shaped connective tissue fibres. The central area lacks actin and myosin, but contains type Ia fibres (large diameter) and type II fibres (small diameter) which wrap around the intrafusal fibres in a spiral.

4. Golgi tendon organs are proprioceptors found at tendon-muscle junctions. They consist of a thin capsule of connective tissue around a few collagen fibres wrapped in type Ib fibres.

For each stimulus, the somatosensory system must encode a number of things:

1. Quality (type) a. Adequate stimulus – the stimulus to which the receptor responds with the

lowest threshold 2. Magnitude

a. Digital encoding b. Temporal summation c. Spatial summation

3. Location a. Receptive fields

530.302 – Medical Neurosciences Lecture Notes b. Two-point discrimination c. Somatotopy

4. Temporal patterns – a. Rapidly adapting receptors b. Slowly adapting receptors c. Ensemble coding

• Pain Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage (or described in terms of such damage). It is subjective, and can be reported in absence of any likely pathophysiological cause. Different perceptions of pain are caused by different levels of nociceptor response and/or different endorphin levels. There is a variable link between pain and injury: Injury without pain – congenital insensitivity Pain without injury – (Lesch-Nyhan disease), migraine, trigeminal neuralgia Pain disproportionate to severity of injury – passing a kidney stone Pain after healing of an injury – avulsion of the brachial plexus, allodynia Pain is mediated by a number of mechanisms:

1. Receptors 2. Pathways 3. Perception 4. Referred pain - often reflects embryological development 5. Descending control (serotonin, endorphin, encephalin dorsal horn) 6. Ascending control (gate control theory)

Nociceptors are sensors for temperature, mechanical pressure and chemicals (H+, K+, prostaglandins and other inflammatory mediators). They have a set threshold, and send action potentials proportionate to the magnitude of the sensation via fibres to the spinal cord. A fibres – fast, myelinated (fast primary pain) C fibres – slow, unmyelinated (blunt secondary pain) There are four different types of nociceptors:

1. Mechanical (A) – respond to high threshold mechanical stimuli (5-1000x that of touch receptors). They have a graded discharge – the highest thresholds are activated by moving stimuli.

2. Mixed mechanical and thermal a. Fine myelinated afferents respond to noxious heat (>45°C) and high

threshold mechanical stimuli b. C afferents respond to noxious cold (<15°C) and high threshold mechanical

stimuli 3. Polymodal (C) – respond to high threshold mechanical stimuli, noxious heat and

irritant chemicals. They may be sensitised by heat. 4. Silent (C) – not normally active, but may become excitable during inflammation

There are three commonly described pathways between nociceptors and the sensory cortex – notably, one of these is polysynaptic in the spinal grey matter (experiment on rats and multiple lesions made on either side of the spinal cord, pain still transmitted). Nociceptive input is processed mainly in the dorsal horn by the influence of neurotransmitters, descending pathways and other sensory input. It is then transmitted to the brainstem (arousal, respiration, hypertension), the thalamus (emotion) and the cortex (pain – especially chronic).

• Analgesia and Analgesic Drugs

530.302 – Medical Neurosciences Lecture Notes There are three recognised primary aspects to anaesthesia – pain, suppression of reflexes, and sleep. Note that the maintenance of gaseous exchange (O2 in, CO2 out) is equally as important – FIO2 > 21%, adequate barometric pressure, clear airway, VT, frequency, CO. Pain can also be categorised to acute pain (illness/injury, gets better), chronic non-cancer pain (> 6 months or past the time of healing), and cancer pain. Reasons for pain relief: ‘Good’ – humanitarian Functional improvement Economic benefits (e.g. reducing admission period) Chronic pain – treatment and prevention aspects WHO classifies analgesic drugs as:

Simple analgesics – paracetamol, NSAIDs, acupan Weak opiates – dextroproporyphene, codeine, tramadol Strong opiates – morphine, methadone, pethidine, fentanyls

Other drugs may be used as adjuvants in atypical types of pain – tricyclic antidepressants, anticonvulsants, antiarrhymics, local anaesthetics Paracetamol is a non-opiod – it has minimal toxicity and nearly complete bioavailability. However, it can induce methemoglobinemia and haemolytic anaemia in patients with glucose-6-phostphatase deficiency. Also, centrilobular liver necrosis occurs following overdose due to the formation of n-acetyl-p-benzoquinone (antidote is acetylcysteine). NSAIDs act by inhibition of cyclo-oxygenase, and are effective for pain caused by inflammation and distension of soft tissues, bones and joints; but are not effective in pain of a neurogenic nature. They have a central anti-pyretic effect by preventing pyrogen-induced release of prostaglandins in the hypothalamus. Note however that prostaglandins protect the stomach mucosa, and thromboxane A is required post-operatively to minimise bleeding. Leukotrienes are also produced in excess when the cyclo-oxygenase pathways are blocked. Selective COX inhibition does not constitutive COX1 (physiologically protective), but blocks COX2 (inflammatory). Opioids are drugs that bind to opioid receptors located supraspinally (periaqueductal grey, periventricular grey, area postrema), spinally (substantia gelatinosa of the dorsal horn), and peripherally after injury. Opioid G protein (inhibits adenylate cyclase, lowers cAMP) coupling to ion channels (increased intracellular Ca+2) early intermediate genes Effects include analgesia, anxiolysis, cough suppression, euphoria, sedation and constipation. Opioids can also induce respiratory depression, nausea and vomiting, visceral spasms and dysphoria. Respiratory depression is typically only an issue after pain subsides – also note that in acute renal failure there can be residual opioid due to impaired clearance. THE MOTOR SYSTEMS OF THE BRAIN

• Basal Ganglia and Movement Systems The basal ganglia consist of several interconnected subcortical nuclei with major projections to the cerebral cortex, thalamus and certain brain stem nuclei. They receive input from the cerebral cortex and thalamus, and send their output to the cortex and brain stem. The striatum is a large bilateral structure consisting of the caudate nucleus, the putamen and the ventral striatum. Except at its most anterior pole, it is divided into the caudate nucleus

530.302 – Medical Neurosciences Lecture Notes and putamen by the internal capsule. It is the major recipient of inputs to the basal ganglia from the cerebral cortex, thalamus and brain stem. It projects to the globus pallidus and substantia nigra, which give rise to the major output projections of the basal ganglia. The globus pallidus lies medial to the putamen (lateral to the internal capsule) and is divided into external and internal segments. Note the claustrum, which function is unknown. The internal segment is related functionally to the pars reticulata of the substantia nigra, and has cells responsive to GABA. Note – putamen + globus pallidus = lenticular nucleus The substantia nigra consists of pars reticulata and pars compacta. The pars compacta is dorsal to the pars reticulata, and contains dopaminergic cells (with neuromelanin). The ventral-tegmental area (medial extension of the pars compacta) is also rich in neuromelanin. This substance is converted to melanin if too much dopamine is produced – in Parkinson’s the cells die and no pigmentation is visible. The subthalamic nucleus is closely connected anatomically with both segments of the globus pallidus and the substantia nigra – it is located below the thalamus and above the anterior part of the substantia nigra. The glutaminergic cells in this nucleus are the only excitatory projections in the basal ganglia – damage can lead to death by ballismus. The basal ganglia must communicate with the sensorimotor cortex (upper and lower motor neurons) to influence movement. This is achieved as follows:

1. Cells across the entire cortex project onto the striatum via the corticostriate projection, using glutamate as a transmitter

2. Striatopallidal and striatonigral projections are negative, and use GABA as a transmitter

3. Nigrostriatal and nigropallidal projections have receptor mediated inhibitory (D2) and excitatory (D1) effects. They use dopamine as a neurotransmitter.

4. There are also reciprocal connections: a. Globus pallidus subthalamic nucleus b. Globus pallidus reticular formation and thalamus c. Thalamus sensorimotor cortex

Disease or damage to the basal ganglia results in mood/cognitive changes, difficulty initiating movements, involuntary movements and muscle tone defects. Parkinson’s disease is characterised by mood (emotionally flat), bradykinesia/hypokinesia, tremor at rest (‘pill-rolling’) and rigidity. The pathology is due to the death of cells in the pars compacta, resulting in a dopamine deficiency in the striatum – inactivating the nigrostriatal pathway. Symptoms tend to present first on one side (80% cell death) before spreading bilaterally. Treatment includes:

1. Dopamine replacement (requires L-dopa to cross the blood-brain barrier) 2. Cell transplantation of dopaminergic cells to the striatum (foetal cells) – note ‘frozen

addicts’, stem cells in the hippocampus and striatum 3. Gene therapy 4. Pallidotomy (internal segment of globus pallidus – output pathways, note proximity of

optic tract) or thalamotomy can help with tremors by reducing gabinergic activity. 5. A stimulator placed in the globus pallidus interna or the thalamus with a modulating

frequency can also reduce the magnitude of tremors (deep brain stimulation) Huntington’s disease is a much more rare disease of the basal ganglia. It is inherited as a dominant gene (trinucleotide repeats) and causes behavioural/cognitive changes, hyperkinesia and involuntary movements. Pathologically, it is due to a loss of gabinergic projections in the striatum. Treatment is very symptom-dependent, and includes advances into gene therapy and neuron replacement.

530.302 – Medical Neurosciences Lecture Notes

• The Cerebellar and Pyramidal Systems The cerebellum is divided into several distinct regions, each of which receives projections from different portions of the brain and spinal cord and projects to different motor systems. It influences the motor system by evaluating disparities between intention and action, and by adjusting the motor centres during motion. Functions of the cerebellum:

1. Rate, timing, force of contraction 2. Coordination of muscles of equilibrium 3. Tone of muscles

This is mediated by three factors:

1. The cerebellum is provided with extensive information (goals, commands, feedback) associated with the programming and execution of movement.

2. The output projections of the cerebellum are focussed mainly on the pre-motor and motor systems of the cerebral cortex and brain stem (control spinal interneurons and motor neurons directly)

3. Synaptic transmission on the circuit modules can be modified Damage to the cerebellum disrupts the spatial accuracy and temporal coordination of movement ( intention tremor, ataxia). It impairs balance and reduces muscle tone, and markedly impairs motor learning and certain cognitive functions The cerebellum is comprised of an outer mantle of grey matter, internal white matter, and 3 pairs of deep nuclei – the fastigial, interposed (globose and emboliform) and dentate. It is connected to the dorsal aspect of the brain stem by three symmetrical pairs of tracts:

1. Inferior cerebellar peduncle – olivocerebellar fibres (related to initiation), vestibulocerebellar fibres, dorsal spinocerebellar tract

2. Middle cerebellar peduncle – pontocerebellar fibres 3. Superior cerebellar peduncle – efferents to thalamus/motor cortex, ventral

spinocerebellar tract The three mediolateral regions of the body of the cerebellum and the flocculonodular node receive different afferent inputs, project to different parts of the motor systems, and represent distinct functional subdivisions.

1. Mediolateral regions – note that the vermis and intermediate hemisphere (spinocerebellum/palaecerebellum) are the only regions to receive somatosensory input from the spinal cord

a. Vermis – receives visual, auditory and vestibular input, as well as somatic sensory input from the head and proximal parts of the body ( posture, locomotion, gait). It projects via the fastigial nucleus to cortical and brain stem regions associated with the medial descending systems.

b. Intermediate part of the hemisphere – receives somatosensory information from the limbs. It projects via the interposed nucleus to lateral corticospinal and rubrospinal systems to control the distal muscles of the limbs and digits.

c. Lateral part of the hemisphere (neocerebellum) – receives input exclusively from the cortex. Its output is mediated by the dentate nucleus, which projects to motor, pre-motor and prefrontal cortices. It is involved with planning and mental rehearsal of complex motor actions, and in the conscious assessment of movement errors.

2. Flocculonodular node (archicerebelluim/vestibulocerebellum) – receives input directly from primary vestibular afferents. It projects to the lateral vestibular nuclei, and is related to controlling balance and eye movement.

The efferent projections of the cerebellar system can be summarised as follows:

1. Ascending projections via the thalamus to upper motor neurons in the motor cortex 2. Descending projections via the vestibular nuclei, reticular formation and red nucleus

to the lower motor neurons in the spinal cord

530.302 – Medical Neurosciences Lecture Notes Disorders of the cerebellum result in distinctive signs and symptoms:

1. Truncal and gait ataxia 2. Limb ataxia 3. Dysarthria (loss of speech articulation) 4. Abnormal eye movements (nystagmus – rhythmic, oscillatory movements) 5. Vertigo and/or nausea and vomiting

Tone may be normal or reduced. Power, tendon reflexes, plantar responses and sensation are normal. Note that many cerebellar diseases also affect other parts of the nervous system. Aetiology of cerebellar disease:

1. Congenital abnormalities 2. Inherited, degenerative diseases of the cerebellum 3. Inflammation, demyelination (e.g. multiple sclerosis, autoimmune disease) 4. Tumours (primary, metastatic) 5. Vascular disease (ischaemia, haemorrhage) 6. Infections (bacteria, virus, prions) 7. Metabolic disorders (hypoxia, ischaemia, hyperthermia, toxins, vitamin deficiency)

The corticospinal tract is the means by which the brain controls voluntary movements. It passes from the motor cortex, through the posterior limb of the internal capsule and brain stem to terminate on lower motor neurons on the opposite side of the spinal cord. Note the prominence of the layer V pyramidal cells (Betz cells). The corticobulbar/corticonuclear tract is also part of the pyramidal system, but passes from the motor cortex, through the genu of the internal capsule. In the area of the midbrain and pons, it sends fibres to cranial nerve nuclei on the opposite side of the brain stem.

• Motoneurons and Motor Units Acute Chronic Focal Trauma or Vascular Neoplasms Diffuse Toxins or Infections Degenerative Motoneurons (lower motor neurons) are found in the motor nuclei in the spinal cord (anterior horn cells) and in the brainstem (CN III-VII, IX-XII). They consist of two types:

1. Alpha motoneurons – extrafusal muscle fibres, responsible for force generation a. Fast firing (elements of FF motor units) b. Slow firing (elements of S motor units)

2. Gamma motoneurons – intrafusal muscle fibres, control excitability of stretch receptors in muscle spindles. Adjacent to alpha motoneurons – note co-activation.

Components of a motor unit:

1. Cell body of one (alpha) motoneuron 2. Axon (divides into many branches) 3. All neuromuscular junctions (synapses) formed by a single motoneuron 4. All muscle fibres (extrafusal muscle fibres) innervated by one motoneuron (5-2000)

S type motor units – slow twitch, little/no fatigue, small tetanic tension, early recruitment FF type motor units – fast twitch, fatigable, large tetanic tension, late recruitment Some S type motor units fire almost always (except during REM sleep). They are the best suited for carrying sustained but small loads. Note that weak contractions can be graded with greater precision – however, exercise is necessary to prevent FF unit atrophy. Inputs to alpha motoneurons (note the contribution of excitatory and inhibitory inputs):

1. Descending pathways a. Corticospinal (pyramidal) tract b. Rubrospinal tract c. Vestibulospinal tract

530.302 – Medical Neurosciences Lecture Notes d. Tectospinal tract (from superior colliculus) e. Reticulospinal tract (excitatory lateral, inhibitory medial)

2. Spinal interneurons – Ia inhibitory interneurons, Renshaw cells 3. Muscle receptors

a. Ia afferents from muscle spindles – monosynaptic excitation b. Golgi tendon organs – disynaptic inhibition c. Nociceptive receptors in the skin d. Joint receptors

The monosynaptic stretch reflex (latency 25-30ms knee) is evoked from muscle spindles by stretch or vibration. It is stimulus dependent, symmetrical, and does not fatigue. It is comprised of:

a. Receptors – annulospiral muscle spindle endings b. Afferents – Ia afferents (fast) c. Synaptic delay – glutaminergic excitatory synapses on alpha motoneurons d. Efferents – axons of alpha motoneurons e. Effectors – homonymous or synergistic muscle

Note that it may be facilitated by voluntary contraction of other muscles (Jendrassik manoeuvre), can be evoked by electrical stimulation of Ia afferents (H-reflex), and reflex relaxation of antagonistic muscles occurs via Ia inhibitory interneurons (reciprocal inhibition).

• Diseases of Motoneurons and Motor Units Diseases of motor units:

1. Myopathies a. Myotonic muscular dystrophy – stiffness, slowness of relaxation, wasting

i. Inherited (dominant) – males and females equally affected (up to 2000 triple CTG repeats in c19 coding for myotonin)

b. Myasthenia gravis (autoimmune) – fewer ACh binding sites smaller EPP c. Botulism – toxin impairs ACh release at all peripheral cholinergic synapses

weakness of striated and smooth muscle (somatic/autonomic) 2. Neuropathies

a. Axotomy – injury of axons i. Changes in the distal segment (Wallerian degeneration) ii. Changes in the proximal segment (chromatolysis)

b. Peripheral neuropathies – motor and/or sensory. Most common are the demyelinating conditions (diabetic neuropathy, Guillain-Barre syndrome, adrenoleucodystrophy).

3. Sequence of events in motoneuron degeneration: a. Terminal degeneration b. Wallerian degeneration c. Myelin debris d. Microglia macrophage infiltration e. Chromatolysis (breakdown of rough ER) f. Axonal regeneration (1-4mm/day) by arrays of Schwann cells

Lower motoneuron disease – affects motoneurons in the spinal cord and brainstem

1. Symptoms: a. Atrophy and muscle wasting/weakness or paralysis b. Flaccidity - decreased/abolished muscle tone c. Depressed/abolished stretch reflexes d. Fasciculations (activation of single motor units) and fibrillations (activation of

single muscle fibres) e. Flexor or absent plantar reflex

2. Diseases affecting cell bodies: a. Poliomyelitis – viral infection causing selective neural/muscular degeneration b. Syringomyelia – cystic dilation in the spinal cord (usually cervical), anterior

horn degeneration, atrophy of the hand

530.302 – Medical Neurosciences Lecture Notes i. Expansion into the medulla – wasting of the tongue, soft palate,

pharynx and vocal cords (IX + XIII) ii. Loss of pain and temperature in affected segments on the same

side as the lesion c. Amyotrophic lateral sclerosis – muscle wasting and spasticity (increased

stretch reflexes) due to degeneration of anterior horn cells, motor nuclei of the brain stem (but not II, IV and VI) and upper motor neurons (corticospinal)

i. Pathogenesis 1. Autoimmune hypothesis – Ca+2 channel antibodies 2. Oxidative stress hypothesis – superoxide dismutase mutation 3. Excitotoxic hypothesis – lower abundance of GluR2 subunits

of AMPA receptors, predisposing to higher Ca+2 flux

• Injuries of the Spinal Cord and Brainstem Lesions Injuries of the spinal cord

1. Hemisection of the spinal cord (Brown-Sequard syndrome) a. Motor defects (ipsilateral)

i. Monoplegia – disruption of the corticospinal and rubrospinal tracts ii. Hyperactive reflexes (Babinski, clonus) – disruption of reticulospinal

and vestibulospinal tracts b. Sensory defects

i. Contralateral loss of pain/temperature sensation (disruption of the spinothalamic tract which decussates spinally) – segmental ipsilateral loss is possible in more extensive lesions

ii. Ipsilateral loss of fine tactile perception and proprioception (disruption of the dorsal column which decussates in the brainstem)

2. Acute complete transection spinal shock (areflexia due to loss of facilitatory inputs from reticulospinal and vestibulospinal tracts)

a. Complete transection at T8 level – symptoms below the level of the lesion i. All conscious sensation lost ii. Flaccid paralysis and areflexia in both legs iii. Blood vessels dilated, blood pressure depressed (related to

preganglionic sympathetics in the lateral grey horn) iv. Thermal sweating absent v. Atonic bladder and bowels vi. Sexual organ dysfunction

b. Incomplete recovery – symptoms below the level of the lesion i. Paresthesia (abnormal sensation due to synaptic reorganisation) ii. Recovery of muscle tone iii. Spasticity/clonus – hyperactive stretch reflexes iv. Tendon reflexes

1. Flexor/withdrawal reflex 2. Extensor plantar reflex (Babinski)

v. Autonomic dysreflexia – increased (or unstable) blood pressure vi. Reflex emptying of bladder and rectum

3. Aspects of patient management – artificial ventilation, ‘Parastep’ 4. CNS recovery - synaptic plasticity, denervation supersensitivity 5. CNS regeneration – note lack of Schwann cells

a. Neutralising antibodies to inhibitory myelin-associated glycoprotein (associated with oligodendrocytes)

b. Neurotrophin 3 (NT-3 growth factor – promotes central axon regeneration) c. Tissue bridges with peripheral nerve d. Tissue bridges with foetal spinal cord e. Injections of neural stem cells

Brainstem lesions

1. Decerebrate rigidity refers to a large increase in the tone of the extensor muscles following transection between the superior and inferior colliculi in the midbrain (above

530.302 – Medical Neurosciences Lecture Notes vestibular nuclei, below the red nucleus). This persists indefinitely, and involves the reticular formation (lost excitatory input to the medial inhibitor area).

2. Other brainstem lesions are more likely to be fatal due to involvement of cardiovascular and respiratory centres, and the reticular activating system. They produce widespread sensory and motor deficits – note cranial nerve nuclei.

• Forebrain Mechanisms of Motor Control

There are two re-entrant pathways involved in the process of movement initiation, and in control of the force and range of muscle contractions:

1. A circuit involving the cerebral cortex, basal ganglia and thalamus 2. A circuit involving the cerebral cortex, brainstem and cerebellum

A cerebrovascular accident is a sudden and focal impairment of function resulting from disorders of blood vessels. Two milder forms exist – transient ischaemic attack (<24 hrs) and reversible neurological deficit (symptoms >24hrs, resolve within 2 days).

1. Causes of stroke a. 80% due to vascular occlusion cerebral/retinal infarct b. 20% due to haemorrhage (cerebral/subarachnoid)

2. Symptoms depend on location of lesion – loss of neurological function in: a. Arm – middle cerebral artery b. Leg – anterior cerebral artery c. Vision (hemianopia) – posterior cerebral artery d. Speech/writing – left perisylvian (opercular) cortex Broca/Wernicke areas

3. Mechanisms of neuronal death a. Hypoxia ATP depletion Na+/K+ pump inhibition neuronal

depolarisation influx of Na+, Cl-, intracellular oedema ( increased ICP) b. Intracellular Ca+2 accumulation necrotic/apoptotic cascade c. Enhanced release of excitatory neurotransmitters also causes Ca+2 influx via

NDMA glutamate receptors d. Cytoplasmic release of free radicals triggered by Ca+2

4. Treatment – aimed at recovering neurons in the penumbra a. Anticoagulants and thrombolytic agents b. Ca+2/Na+ channel blockers – side effects widespread c. Antagonists of excitatory amino acid (NMDA) receptors – counteract

excitotoxicity, side-effects include memory loss d. Experimental oral vaccine in animal models – produces antibodies against

the NR1 subunit of the NMDA receptor. Note that these are normally isolated due to the blood-brain barrier.

Upper motoneuron disease is the term for motor disorders of the corticospinal and corticoreticular tracts, and other extrapyramidal (descending) systems. Muscle paralysis or weakness (without wasting) involving groups of muscles is typical – note that clumsiness and slowness is out of proportion to loss of strength. Important signs:

1. Spastic increase in muscle tone a. Increased resistance to passive movements b. Unidirectional – affects extensors more c. Velocity dependent – spastic catch d. Clasp-knife phenomenon

2. Hyperactive tendon reflexes (clonus) 3. Extensor plantar reflex – an enhanced withdrawal reflex after a pyramidal or

extrapyramidal lesion (release of inhibition) Muscle rigidity is a major sign of Parkinson’s disease – it is seen as bi-directional increased resistance to passive movements. It is velocity independent, and without hyperactive tendon jerks (contrast with spasticity in upper motoneuron disease).

530.302 – Medical Neurosciences Lecture Notes

THE VISUAL SYSTEM (A DAMN SIGHT EASIER THAN 2000)

• Retina: Anatomy and Physiology All vertebrate retinas are composed of three layers of cell bodies and two layers of synapses:

1. Outer nuclear layer – cell bodies of rods and cones 2. Inner nuclear layer – cell bodies of bipolar cells 3. Ganglion cell layer – cell bodies of ganglion cells 4. Outer plexiform layer – photoreceptor-bipolar cell synapse 5. Inner plexiform layer – bipolar-ganglion cell synapse

The retina has two distinct regions – the outer sensory retina consisting of photoreceptors and connecting fibres, and the inner neural retina in which modification and encoding of the visual signal occurs before it is sent to the cerebral cortex via the optic nerve.

1. It is supported by the retinal pigment epithelium, which is essential for: a. Formation of photopigments b. Renewal of photoreceptors c. Reduction of damage from scattered light d. Transportation of water and nutrients to the retina.

2. There are two blood supplies supplying the retina: a. Central retinal artery – low volume, relatively sparse, less circulatory reserve,

autoregulation. O2 extraction percentage is high but volume is small as the inner retina has low metabolic requirements.

b. Choroidal circulation – high volume with a wide-bore, fenestrated capillary bed (choriocapillaris). O2 extraction percentage is low, volume is high (so there is considerable circulatory reserve).

i. High metabolic demand of the outer retina is due to 1. The photoreceptor ‘dark’ current and phototransduction 2. Renewal/breakdown of the outer segments of photoreceptors 3. Intracellular renewal/repair of RPE cells

ii. The choroidal circulation also helps to remove excess heat from metabolic activity and the degradation of excess light (absorbed by melanin and haemoglobin)

c. Note that systemic blood is isolated from the retinal tissue by the inner and outer blood-retinal barriers (endothelium of the retinal vasculature and the RPE respectively)

3. Cellular components of the retina: a. Photoreceptors – rods 2 microns in diameter (1.5 in the fovea), cones taper

down from 6 microns b. Horizontal cells c. Bipolar cells d. Amacrine cells e. Ganglion cells f. Mueller cells

4. Retinal diseases tend to affect the retinal vasculature or the chorioretinal interface – in both cases, this leads to breakdown of the blood-retinal barrier. In the outer retina, dysfunction of photoreceptors and RPE occurs.

Macula = foveal pit + foveal slope + parafovea + perifovea Rods and cones process the visual signal and can be described in terms of performance functions (including rod/cone spectral sensitivity curves, light/dark adaptation curves). Rods are more concentrated in the central visual field and are related to the detection of colour and fine details. Cones are related to detection of peripheral movement.

1. Perception of various parameters may provide indication of dysfunction: a. Form/Spatial vision – measured by visual acuity (varies with contract,

brightness, eccentricity and the testing procedure) b. Colour vision – hue, saturation, brightness and colour interactions are

indicators of cone function and processing of the visual signal

530.302 – Medical Neurosciences Lecture Notes c. Movement – movement detection in the peripheral vs central visual field

reflects rod/cone distribution 2. Clinical testing procedures:

a. Pupil reactions – reflex pathways to light, near and accommodation b. Visual fields – defects may indicate site of lesion c. Visual acuity – relates to contrast, eccentricity, light level, form, movement d. Colour vision – hue, saturation, brightness discrimination e. Refractive error – reflects ocular structures and retinal image formation

Pathology

1. Age related macular degeneration – pigment epithelium degeneration Drusen, fluid leakage behind fovea, foveal cone death

2. Glaucoma – raised intraocular pressure compromises blood vessels of the optic nerve ganglion cell death

3. Retinitis pigmentosa (hereditary) – peripheral rod degeneration night blindness, tunnel vision, black pigment in periphery, thinned blood vessels

4. Diabetic retinopathy – hard exudates of lipid/protein, microaneurysms, new vessels (tortuous)

Nerve impulses from eye to cortex – CN II Eye movements – CN III, IV, VI Sensory information of ocular structures – CN V, VII There are six extraocular muscles – lateral, medial, superior and inferior rectus muscles and the superior and inferior oblique muscles (innervation LR6SO43). These work in yoked pairs – e.g. right LR and left MR work synergistically to produce equal movement of both eyes.

1. Types of eye movement a. Ductions – monocular movements b. Versions – symmetrical, synchronous binocular movements c. Vergences – binocular movements where the eyes move symmetrically and

synchronously in opposite directions 2. Eye movement systems

a. Saccadic (target acquisition) – enables rapid eye movements that relocate fixation of target to the fovea

b. Slow/smooth pursuit (tracking) – keeps a moving target on the fovea c. Vestibular system (stabilising) – maintains target despite head/body motion d. Vergence/fusion system (tracking in depth, image fusion) – controls

convergence/divergence to allow an image on the fovea at all distances 3. Control pathways

a. Supranuclear i. Saccades – contralateral frontal lobe ii. Pursuit movements – ipsilateral occipito-parietal lobe iii. Vestibular fibres run from the semicircular canals to the pons via the

vestibular nuclei b. Internuclear – connections between pons, ocular motor and vestibular nuclei c. Infranuclear – ocular motor nuclei lie close to the midline in the midline (CN III

and IV) and pons (CN V) Pupillary reflexes each have a distinct associated subcortical pathway:

1. Light reflex consists of four neurons (parasympathetic) a. Retina pre-tectal nucleus – note that nasal retinal impulses decussate, but

temporal impulses do not (so contralateral and ipsilateral involvement) b. Pre-tectal nucleus both Edinger-Westphal nuclei (hence bilateral response

to unilateral stimuli) c. Edinger-Westphal nuclei ciliary ganglion via CN III d. Ciliary body sphincter pupillae muscles of the iris

2. Near reflex consists of three components. Note that the it shares the efferent input of the light reflex – so afferent reflex pathway problems may have a light/near dissociation, but efferent reflex pathway problems affect both reflexes.

a. Convergence

530.302 – Medical Neurosciences Lecture Notes b. Accommodation c. Pupil constriction – 3 neurons, respond to proximity to the eye

Sympathetic pathway pupil dilatation

1. Posterior hypothalamus ciliospinal centre of Budge (C8-T2) 2. Ciliospinal centre of Budge superior cervical ganglion 3. Cervical ganglion sympathetic fibres in the ophthalmic division of CN V ciliary

body dilator pupillae muscles

• The Eye as an Optical System Visible light (400-750nm) retina optic nerve optic chiasm optic radiation lateral geniculate nucleus, pre-tectum and superior colliculus Optical degradation at the foveola may be caused by a number of factors:

1. Lens aberrations a. Spherical – peripheral rays are brought to a focus nearer to the lens than

rays through the centre or optical axis i. Normal compensation – cornea is flat peripherally, iris acts as a stop,

retinal cones are more sensitive to axial rays (Stalls-Crawford effect) b. Chromatic – short-wavelength (blue) focussed nearer to the lens

i. Normally, chromatic aberration is limited as photoreceptors are much more sensitive to the central yellow-green wavelengths

2. Light scatter – light is diffracted by components of the optical media. Yellow macular pigment limits chromatic aberration and reduces entry of scattered light.

a. Pathology – dystrophica myotonica 3. Light absorption – cornea and lens absorb UV light, lens absorbs blue light with age

a. Pathology – cataracts, corneal dystrophy (keratoconus) 4. Diffraction – diffraction at the pupil edge blurs the image a series of bright and dark

rings that get progressively fainter. Airy disc in the middle (84% of total energy). 5. Pupil size – dilatation causes spherical aberration; constriction blocks peripheral light

aberrations but diffraction may become significant The eye (~25 mm long) has two refracting/focussing structures:

1. The cornea (40-45 dioptres) a. Measuring the cornea – computerised keratometry

2. The crystalline lens (20 dioptres) a. Transparent, biconvex structure b. Lies behind the iris supported by zonules c. 10 mm diameter, 4 mm thick d. Contributes 1/3 of the focussing power of the eye e. Dioptric power and transparency reduces with age (8 dioptres by 40 years, 2

dioptres by 60 years) Refractive errors (ametropia) are present if the image of a distant target cannot be brought to focus, resulting in a blur circle at the foveola. Note that a pinhole disc selects only axial rays and reduces the size of the blur circle.

1. Emmetropia – normal 2. Ametropia – abnormal. Note the Inuit proposition – ametropia has genetic

predisposition as well as physical reinforcement a. Hypermetropia – short eye, focus behind retina, convex spherical lens

i. Many people with ‘normal’ vision are slightly hypermetropic as the lens can accommodate – evolutionary advantages

b. Myopia – long eye, focus in front of retina, concave spherical lens c. Astigmatism – cornea (or lens) is not spherical. Focal points may be in front,

behind, or both – correction requires a combined spherical/cylindrical lens Clinical/pathological stuff:

1. Keratoconus – cornea becomes conical corneal reshaping or transplantation

530.302 – Medical Neurosciences Lecture Notes 2. Diffracted limited point-spread function – the image of a point like a star is only

distorted by the diffraction of the light due to the pupil. An eye with aberrations will not produce an optimised image of a point.

3. Radial keratotomy – four cut and/or ‘mini RK’. Results up to –3.0 to –4.0 dioptres 4. Excimer laser PRK and LASIK – laser ablation of corneal tissue (~10% regeneration)

a. Optimised laser treatment modifies the PSF of the treated eye towards the diffracted limited PSF

b. 5% minor complications, 1-2% visually significant complications 5. Senile cataract – can be removed by:

a. Intracapsular cataract surgery, intraocular lenses can then be inserted to replace the crystalline lens

b. No-stitch phaco-emulsification with lens replacement

• Visual Pathways – Chapter 27 in Kandel The optic system is comprised of a number of components. Note that the sensory system can be likened to a sensory motor system – deficits are related not only to deficits in detecting stimuli, but also related to loss of appropriate reactions to these stimuli.

1. Object discrimination - form, shape, size, texture 2. Brightness and contrast 3. Spatial frequency 4. Colour 5. Depth perception via retinal disparities (note binocular and monocular cues) 6. Movement – note difference in peripheral and central/foveal movement stimuli

The surface of the retina is divided into the nasal hemiretina and the temporal hemiretina – the left visual hemifield projects onto the nasal hemiretina of the left eye and the temporal hemiretina of the right eye (and vice versa). This gives corresponding points on each retina. Light in the central region of the visual field (binocular zone) is encoded by both eyes; light from the temporal portion (crescent) of the visual field (monocular zone) is encoded only by the ipsilateral nasal hemiretina. The highest resolution is at the area of the macula/fovea. Axons from the ganglion cells in the retina extend through the optic disc, and at the optic chiasm fibres from the nasal hemiretina cross to the opposite side of the brain. Hence, the axons from the left half of each retina project in the left optic tract, carrying a complete representation of the right hemifield of vision (and vice versa). The optic tracts pass to three major subcortical targets – the pretectum, superior colliculus and lateral geniculate nucleus. Note that parallel processing allows encoding of very complicated stimuli.

1. Superior colliculus – structure of alternating grey and white matter layers on the roof of the midbrain. Retinal ganglion cells project directly on the superficial layers to form a map of the contralateral visual field

a. Extensive cortical inputs – deep layers have the same visual field map, but also respond to auditory and somatosensory information

b. Deep layer cells also discharge vigorously before the onset of saccadic eye movements. These cells form a movement map in the intermediate layers (corresponding to the superficial visual map) – for example, cells responding to stimuli in the left visual field with discharge before a leftward saccade.

2. Pretectum – retinal ganglion cells project to this structure (adjacent to the superior colliculus where the midbrain fuses with the thalamus), which then projects bilaterally to preganglionic parasympathetic neurons in the accessory oculomotor nucleus.

a. Mediates pupillary light reflexes 3. Lateral geniculate nucleus (dorsal part) primary visual cortex higher visual areas

in cortex (extrastriate). This is done in an orderly manner, such that in each nucleus there is a retinotopic representation of the contralateral half of the visual field.

a. About half of the neural mass in the nucleus represents the fovea and surrounding area

530.302 – Medical Neurosciences Lecture Notes b. Different layers encode different information with regards to colour and

luminance contrast, and spatial and temporal frequency. i. I, IV, VI – ipsilateral input, II, II, V – contralateral input from retina

1. 2 ventral layers – magnicellular, input from M ganglion cells 2. Interlaminar layer (III) 3. 4 dorsal layers – parvicellular, input from P ganglion cells

4. Other important targets – pulvinar nucleus of the thalamus, lateral geniculate nucleus (ventral part), optic tract nuclei

The large geniculocalcarine tract has a very wide distribution – for example, fibres may loop through the temporal lobe before terminating in the primary visual cortex. Total blindness of ipsilateral eye – lesion in the prechiasmic optic nerve Bitemporal heteronymous hemianopsia – lesion across the optic chiasm Ipsilateral nasal hemianopsia – prechiasmic lesion in temporal hemiretina fibres Contralateral homonymous hemianopsia – postchiasmic lesion in the visual radiation Contralateral lower quadrantic anopsia – postchiasmic lesion in parietal lobe (visual radiation) Contralateral upper quadrantic anopsia – postchiasmic lesion in Myers’ loops (temporal) NEURODEGENERATION Brain damage can occur after acute or chronic insults:

1. Acute – stroke, epileptic seizure, traumatic head injury, perinatal asphyxia 2. Chronic – Alzheimer’s disease, Parkinson’s disease, AIDS dementia, Huntington’s

disease Glutamate functions normally in learning and memory, movement and sensation. It is the main excitatory neurotransmitter in the brain. Receptors can be ionotropic or metabotropic:

1. Ionotropic receptors a. NMDA receptors have binding sites for glutamate, glycine and PCP.

i. The channel normally conducts Ca+2 and Na+, though Mg+2 occupies and blocks the channel (Mg+2 efflux occurs on depolarisation)

ii. Depolarisation + glutamate + glycine opens channel Ca+2 influx depolarisation of the neuron (related to memory)

iii. Phencyclidine binds inside the channel, blocking ion flow (non-competitive antagonist)

b. AMPA/Kainate receptors work in a similar fashion – when glutamate binds, there is an influx of Na+ and depolarisation of the neuron

2. Metabotropic receptors are G-protein linked – glutamate binding increases IP3 and DAG release of Ca+2 from intracellular stores and activation of protein kinase C.

The excitotoxicity theory suggests that excessive activation of glutamate in the brain leads to nerve cell death. Injury leads to excitatory amino acids and increased glutamate levels. This induces pathological activation of AMPA and NMDA, which have two effects:

1. Increased Ca+2 + I (NMDA) delayed nerve cell death (apoptosis) a. Mechanism – possible activation of calcium-sensitive enzymes (biochemical

pathways intrinsic to the neuron) 2. Increased Na+ + I, Cl-, H2O (AMPA) rapid nerve cell death (cell lysis)

Pharmacotherapy involves reducing glutamate release (A1 adenosine receptor agonists – negative feedback system) or by blocking receptors:

1. NMDA – MK 801 or memantine are useful for focal strokes and prolonged seizures, although there may be psychotomimetic side effects.

2. AMPA – NBQX is very effective against global ischaemia, unknown side effects The intracellular cascade triggered by glutamate receptor activated Ca+2 release can also be blocked by

1. Free radical scavengers – neuroprotective effects

530.302 – Medical Neurosciences Lecture Notes 2. Protein kinases – gangliosides 3. Suicide genes – block expression

SYNAPTIC TRANSMISSION

• Mechanisms of Synaptic Transmission Transmitter release is mediated by a number of events:

1. Presynaptic action potential 2. Activation of voltage-dependent Ca+2 channels 3. Increased presynaptic [Ca+2]

a. Mobilisation of vesicles – synapsin bound to vesicles in the reserve pool is phosphorylated by calmodulin allowing release to the release pool

b. Attachment to docking sites at the active zones c. Fusion with the membrane – synaptophysin (Ca+2 binding protein) involved

4. Release of transmitter by exocytosis from presynaptic terminal 5. Reaction of transmitter with postsynaptic receptor 6. Activation of ligand-gated channels (postsynaptic current postsynaptic potential) 7. Action potential – dependent on temporal and spatial summation

Voltage-gated ion channels:

1. Hodgkin-Huxley Na+/K+ channels are necessary for action potential generation and transmission to the synaptic terminal

2. LVA and HVA Ca+2 channels are responsible for an increase in presynaptic [Ca+2] Ligand-gated ion channels:

1. Ionotropic receptors are directly gated, with a single molecule acting as both the receptor and effector

a. Ligand gated ion channels mediating EPSPs are permeable to Na+ and K+ (sometimes Ca+2), while channels mediating IPSPs are permeable to Cl-

b. Include GABA, glycine, glutamate, nicotinic ACh, serotonin 5HT3 receptors i. They are composed of 5 subunits, each with 4 transmembrane

domains that contribute to the selectivity of the channel ii. Pore permeability has important consequences for effects on

membrane potential and cellular function 2. Metabotropic receptors are indirectly gated – recognition of the transmitter and

activation of the effector are carried out by different molecules a. Time course is much slower and longer lasting than directly gated receptors b. Examples:

i. CAMP system – norepinephrine beta-adrenergic receptor cAMP cAMP-dependent protein kinase

ii. IP3-DAG system – acetylcholine muscarinic ACh receptor IP3/DAG Ca+2 release

iii. Arachidonic acid system – histamine histamine receptor arachidonic acid lipoxygenase, cyclo-oxygenase

c. They are formed from a single protein/subunit with 7 membrane-spanning regions – action on cellular function is produced through

i. Direct action of G-proteins on the channel ii. Ion channel phosphorylation by second messenger iii. Regulation of gene expression by phosphorylating transcriptional

regulatory proteins Rapid removal of neurotransmitter is essential after release if the cell is to respond to high frequency inputs. This is achieved through diffusion, enzymatic degradation or re-uptake. Neurotransmitters are substances that are released at a synapse by one neuron, and affect other cells in a specific manner. Defining a neurotransmitter depends on the following criteria:

1. Presynaptic terminals must contain and have the ability to synthesise the compound

530.302 – Medical Neurosciences Lecture Notes 2. Compound must be released from the presynaptic neuron on appropriate stimulation 3. Microapplication to the postsynaptic neuron must mimic presynaptic stimulation 4. A specific mechanism must exist for removing the compound from the site of action

The postsynaptic response is determined by the transmitter released (note high transmitter diversity) and the receptor subtype present on the postsynaptic membrane:

1. Co-release (multiple NTs) – increase the potential complexity of postsynaptic effects 2. Multiple receptor subtypes – increase the information handling capacity of neurons 3. Note that modality-specific information processing is dependent on neurotransmitter

diversity Neuromodulators modulate synaptic transmission by altering the amount of transmitter released form the presynaptic cell, or the response of the postsynaptic receptor to the transmitter. Note that some transmitters can function as both transmitters and modulators.

1. Presynaptic inhibition/facilitation a. Hyperpolarizing or depolarising presynaptic terminal b. Activation of second messenger systems

2. Postsynaptic a. Alteration of Ileak (changes neuronal input resistance) b. Activation of second messenger systems

Diseases are associated with specific transmitter systems:

1. Excitatory amino acids – domoic acid poisoning, Guam disease, neurolathyrism 2. Dopamine – Parkinson’s disease 3. GABA and cholinergic neurons – Huntington’s chorea

• Voltage-Gated Ion Channels The resting membrane potential is determined by the relative permeability of the membrane via ‘leak channels’ to ions (especially Na+ and K+) and the relative concentrations of these. Nernst potential is the equilibrium potential for a given membrane – where electrical and chemical forces are balanced such that there is no net ionic movement.

1. Note that the RMP represents the interactions of the Nernst potential for all ions. 2. At rest, PK >> PNa so the RMP is closer to the Nernst potential for K+ 3. Small changes in membrane potential open voltage-dependent ion channels and

drastically alter the relative permeability of the membrane ( change in potential) 4. The Goldman equation approximates the membrane potential (-65mV) by combining

figures for K+ (-90mV) and Na+ (+55mV) dependent on concentration & permeability Ion selectivity is important – for example, a channel moving K+ and Na+ AP of zero:

1. Proteins in the lipid are hydrophobic; ions are hydrophilic (attract dipolar H2O) 2. Ions become surrounded by the ‘waters of hydration’ (help stabilise the ions) 3. H2O cannot be shed so ions must move through an aqueous pore 4. Ion channels have a hydrophilic domain – within the lumen, interaction with charged

amino acids (binding to the Na+ ion and the H2O molecule) provides ion selection Ion channel structure:

1. Voltage-gated ion channels a. Na+ and Ca+2 – 6-membrane spanning regions (4 repeats)

i. N and C terminals are intracellular b. K+ – 6-membrane spanning regions (4 subunits)

i. Inward rectifiers – 2 membrane spanning regions (4 subunits) 1. S4 – voltage sensor 2. S6 – lines the pore 3. S5-6 – selectivity filter (protein extends back into pore)

2. Ligand-gated ion channels a. NAChR and relatives (GABA, glycine, 5HT3) – 4 membrane spanning

regions (5 subunits)

530.302 – Medical Neurosciences Lecture Notes b. Glutamate – 3 membrane spanning regions (4 or 5 repeats)

i. N terminal extracellular (binds ligand), C terminal intracellular ii. M2 lines the pore and does not completely cross the membrane

Channel diversity

1. K+ channels – most diverse 2. Ca+2 channels – 5 types (L, N, P/Q, R, T)

a. Present drugs operate on L-type channels (dihydropyridines, benzothiazepines, phenylalkylamines) and prevent channel opening

b. Used in cardiovascular diseases 3. Na+ channels – 9 different isoforms for skeletal muscle, heart, neurons, glial cells

a. One channel type (SNS) is only on small nociceptive neurons Channel gating

1. Activation a. Voltage sensor in the S4 region detects transmembrane voltage change b. Conformational change in channels, pore opens

2. Inactivation (some channels, e.g. Na+ in action potentials) a. N terminal forms a plug blocking the channel shortly after it opens b. Repolarisation removes the plug c. ‘Ball and chain’ model – deletions from the N-terminal region increased

speed of inactivation (and vice versa) d. Alternatively – three states: closed, open, inactivated (e.g. Shaker B protein)

Channelopathies

1. Cl- channels a. Cystic fibrosis

i. Most common autosomal recessive disease in Europeans (5% are carriers)

ii. CFTR (CF transmembrane regulator) gene is defective iii. Cl- channel functions, but does not transfer to the membrane properly

2. Ca+ channels – different mutations of brain-specific gene for P/Q type channels: a. Familial hemiplegic migraine b. Episodic ataxia (type 2) c. Chronic spinocerebellar ataxia (type 6)

3. K+ channels a. Episodic ataxia (type 1) b. Long QT syndromes (delayed repolarisation of cardiac action potential) c. Familial inherited neonatal epilepsy

4. Na+ channels – long QT syndrome

• Ligand-Gated Ion Channels: Glutamate Receptors Note desensitisation – current tuns off, but the ligand is still present. Mechanism unknown. Glutamate is responsible for most fast excitatory transmission in the brain – it is the endogenous transmitter for many receptor subtypes. It may act directly (ionotropic) or indirectly (metabotropic) – in general, only the NMDA receptor passes Ca+2.

1. Structure a. Ionotropic receptors – AMPA, Kainate, NMDA

i. Pentamers of different receptor subunits ii. Three identified classes (but probably more) based on

1. Various combinations of receptor subunits a. Homomeric and heteromeric receptors are functional b. Note that NMDAR1 is essential for NMDA function

2. Splice variants a. DNA pre-mRNA removal of exons different

mRNAs due to alternate splicing 3. RNA editing (substitution of different bases)

530.302 – Medical Neurosciences Lecture Notes a. Q/R editing Arg replaces Gln on the M2 region

b. Metabotropic receptors i. Single proteins, 7 transmembrane regions ii. 8 receptor subtypes iii. 3 main functional groups

2. Physiology a. Endogenous agonist for AMPA/Kainate and NMDA receptors b. Effects vary (NMDA Vs non-NMDA)

i. Time course (NMDA slow, longer lasting) ii. Ion selectivity (NMDA are Ca+2 selective) iii. Voltage-dependent Mg+2 block of NMDA

Functional significance of multiple receptor subtypes:

1. Plasticity – long-term potentiation a. Long-term potentiation – experience-dependent modification of synaptic

function (‘cellular memory’) i. Non-NMDA receptor function depolarises cells ii. Removal of voltage-dependent Mg+2 block of NMDA iii. Ca+2 influx (important for induction of LTP) iv. Modification of postsynaptic ligand-gated channels v. Diffusion of retrograde messenger to presynaptic terminal vi. Enhancement of transmitter release

b. Synchronous activity in synaptic terminals in necessary (may be detected by the NMDA receptor).

c. Post-synaptic Ca+2 influx indicates pre- and post-synaptic activity as: i. Presynaptic activity glutamate release ii. Postsynaptic neurone must be depolarised to near-threshold to

remove the Mg+2 block 2. Amyotrophic Lateral Sclerosis

a. 4 main theories: i. Autoimmune ii. Excitotoxicity iii. Viral iv. Free Radicals – familial ALS, superoxide dismutase disorder

b. NMDA receptors i. Excitotoxicity theory is focused on these due to their permeability

to Ca+2 and relationship with apoptosis ii. NMDA receptor antagonists are inconsistent in blocking

excitotoxic events – indicates alternative Ca+2 pathways c. AMPA receptors

i. Made of 5 subunits (GluR1-R4), in-vivo combination unknown ii. GluR2 subunit is responsible for impermeability to Ca+2

1. Post-transcriptional RNA editing at the Q/R site (Gln Arg) Ca+2 impermeability

iii. Low abundance of GluR2 subunits (or problems with RNA editing) excitotoxicity

d. Motor neuron disease – GluR2 hypothesis i. Motoneurons may have a lower GluR2 abundance

(predisposition to increased Ca+2 fluxes excitotoxic damage) ii. Studies only show slightly lower expression of GluR2 in MNs iii. More likely to be related to RNA editing

1. Studies are investigating differences between motoneurons affected (XII, nucleus ambiguus, V) Vs those not typically involved (III, IV, VI)

NEURORADIOLOGY 1895 – Roentgen pioneers the X-Ray

530.302 – Medical Neurosciences Lecture Notes 1896 – William Randolph Hearst commissions Roentgen to take a cathograph of the brain. This was eventually attempted by Edison, taking 21 days before concluding the skull provided an insurmountable obstacle. Around the time of WWI, it was discovered that air entering the cavities of the brain/cranium was visible on X-Ray, allowing the brain to be visualised for the first time. This was essentially the only technique until the 1970s – the pneumocephalogram (air injected into the CSF as a contrast agent). However, this was not very pleasant. At this time, the displacement of the lateral ventricles was being used to predict the location of mass lesions. Alternatively, contrast could be injected into the arteries of the brain and the midline shift interpreted accordingly. Note that the nature of the mass could not be elucidated from the radiograph. The CT was then developed, allowing a number of X-ray ‘slices’ taken and the density of each pixel interpreted mathematically. Following this (~1980s) the MRI was developed (using different physical principals) and allowed sagittal and coronal sections (in addition to 3D reconstructions) for the first time. CT contrast (black white)

1. Air 2. Fat 3. CSF 4. White matter 5. Grey matter 6. Acute haemorrhage (or IV contrast) 7. Bone or calcification (e.g. pineal gland)

Common clinical presentations requiring radiological investigation (note that bleeding is generally the acute presentation requiring immediate intervention):

1. Ultrasound can pick up a number of neonatal problems: a. Germinal bleed haemorrhage – bleeding into choroid ventricles b. Hydrocephalus

2. Subarachnoid haemorrhage – aneurysm (MRI is not useful for fresh [<5 days] blood) a. Sulci get occluded by blood, infiltration into the ventricles (fresh blood sinks

relative to CSF) 3. Subdural haemorrhage – acute or chronic ( MRI), tends to affect infants/elderly

people following trauma (as the brain does not fully fill the cranium) a. Associated swelling/contusion with midline displacement. diffuse/crescent

shaped bleeding from veins between cerebral cortex and dural sinuses b. Chronic intermittent bleeding – blood density varies

4. Extradural haemorrhage – trauma associated with fracture (middle meningeal artery) a. High-pressure bleed (fresh bleeds swirling blood), lens-shaped b. Note corresponding fracture/haemorrhage on the opposite side of the head

5. Differential – intracerebral bleeding, cerebral infarction PERIPHERAL AUDITORY SYSTEM

• An Overview of Hearing Hearing is an essential sense for:

1. Communication 2. Acquiring language and reading skills 3. Localisation of sound sources in space 4. Pleasure and well-being 5. Warning signals

530.302 – Medical Neurosciences Lecture Notes Deafness and tinnitus are major disabilities with high prevalence in the community – these represent a large component of community medical practise:

1. ~11-13% population with significant hearing problems, particularly >50yrs 2. 2.7/1000 children born with severe deafness (mean age of detection 22 months) 3. By age 15, 3.5/1000 children will have a serious hearing problem 4. ~50% of hearing problems in adults is due to noise exposure 5. 1% have significant tinnitus

Hearing loss:

1. Reduced sensitivity to sound 2. Reduced ability to discriminate frequency (sounds are distorted) 3. Reduced hearing in noise (Café effect) 4. Poor speech recognition 5. Poor localisation of sound 6. Tinnitus (persistent) 7. Poor speech 8. Poor reading and language skills

Causes:

1. Middle ear – infections, trauma, congenital 2. Inner ear – noise, ageing, drugs, infections, congenital 3. Brain pathways – tumours, congenital, ischaemia

Frequency range – 10 octaves from 20Hz to 20,000Hz Frequency discrimination – separate two frequencies 0.2% apart Timing discrimination – can distinguish two sounds separated by 6-10 microseconds apart Note that hearing is not the same sensitivity at all frequencies – 150-4000Hz is the optimum range, and this is around where normal speech is represented.

• Functional Anatomy Functions of the auditory system:

1. Brain auditory centres – integration, speech recognition, sound localisation 2. Auditory nerve 3. Ear – detection of sound, mechanoelectrical transduction – intensity, frequency,

temporal features The auditory system comprises the brain, ear and auditory nerve – the peripheral system can be subdivided into an outer, middle and inner ear. The process of sound detection involves the transmission of sound through the middle ear to the inner ear where mechanical vibrations are transduced into neural activity.

1. Outer ear – funnels sound, protects eardrum, assists sound localisation a. Pinna – important for the collection of sound and directing it to the middle ear

– the folds and hollows modify the incoming sound. b. Ear canal

2. Middle ear – air-filled cavity separated from the outer ear by the ear drum. Important for amplification of sound, and filtration of extreme frequencies of sound.

a. Communicates with the nasopharynx via the Eustachian tube (important for aeration and maintaining equal air pressure across the tympanic membrane)

b. Ossicular chain – acts as an impedance transformer to overcome the mismatch between the fluids of the inner ear, and air

3. Inner ear – comprises the three semicircular canals and vestibule of the vestibular system and the spiral cochlea. Involved with sound transduction, analysis of frequency/intensity and noise reduction.

a. Cochlear duct – surrounded by perilymph, filled with endolymph. Divides the perilymphatic space into the scala vestibuli and scala tympani

b. Organ of Corti – attached to the basilar membrane and comprised of the sensory cells (inner and outer hair cells) surrounded by support cells.

530.302 – Medical Neurosciences Lecture Notes Afferents: Type I (glutamate) – myelinated (90%), only IHC, cochlear nucleus Type II – unmyelinated nerves (10%), only OHC, projects to cochlear nucleus Efferents: Arise in the ipsilateral and contralateral superior olivary complex, mostly OHC Central auditory function:

1. Cochlear nucleus – relays nucleus to higher centres and some low-level feature extraction and noise reduction (heart and breathing sounds)

2. Superior olivary nucleus – binaural interactions for sound localisation, auditory reflex centre to activate middle ear muscles

3. Inferior colliculus – binaural hearing, centre for integration with vision and motor systems, sound localisation

4. Auditory cortex – auditory processing, cognitive integration, sound localisation, speech analysis

• Auditory Mechanics and Encoding Outer/middle ear anatomy:

1. Eardrum – three layers (epithelial, fibrous, mucosal) 2. Ear canal – skin lining the canal is self-cleansing 3. Middle ear mucosa 4. Ossicular chain (malleus, incus, stapes)

Sound conduction to the inner ear:

1. Air conduction – displacement of the eardrum and ossicular chain 2. Bone conduction by inertial and compression waves through the skull. Less sensitive

(40-50dB) than air conduction but very important for monitoring voice. a. Conductive hearing loss – very quite voice due to lack of monitoring

Because of higher density of inner ear fluids, the inner ear provides high resistance to vibration for the same force – there is only 0.1% transmitted. This would be equivalent to ~40dB hearing loss. Hence the middle ear acts as a transformer/amplifier to increase the pressure at the stapes to ensure sound transfers to the inner ear:

1. Area ratio – ear drum is a much larger surface area than the stapes 2. Lever ratio – manubrium of the malleus Vs the long arm of the incus 3. Tympanic membrane ratio – conical shape of the tympanic membrane acts as a lever

Displacement of the stapes in the oval window, and the corresponding displacement of the round window, initiates a travelling wave along the basilar membrane and organ of Corti. The cochlea is tonotopically organised – the basal part corresponds to high frequencies; the apical regions correspond to progressively lower frequencies.

1. Lateral movement of the ossicular chain 2. Vertical movement of the organ of Corti 3. Radial movement of the stereocilia

Transduction channels are located on the stereocilia and are operated by fine elastin filaments (passing from the ion channel on the shaft of a stereocilium to he tip of the adjacent stereocilium). Opening or closing the channels increases or decreases a standing current through the apical surface of the hair cell, causing a change in membrane potential (via liberation of calcium / activation of voltage-gated calcium channels). Inner hair cells provide the predominant sensory input to the CNS, while outer hair cells appear to serve as motor cells enhancing the small motion of the cochlear partition.

1. Active cochlear amplifier - frequency tuning is due to an energy-dependent process that injects energy into the travelling wave to overcome viscous damping by the fluid.

2. This is facilitated by sound-induced contraction of the outer hair cells a. Prestin – motor protein which oscillates at a very high rate (electromotile)

3. Otoacoustic emissions (investigated in neonatal deafness)

530.302 – Medical Neurosciences Lecture Notes Each auditory nerve fibre only responds to a restricted range of frequencies and intensities – fibres give a characteristic frequency-tuning curve. Note that the best frequency of the nerve fibre is determined by the location of the inner hair cell it innervates.

1. Place principle – cochlea is a filter and is tonotopically organised so that frequency is detected by spatial representation from base to apex (high frequency sounds)

a. Travelling wave reaches a peak at different points along the cochlear depending on frequency

b. Variations in stiffness of the basilar membrane determine its responsiveness 2. Volley principle – low frequencies are detected by temporal firing of nerve fibres in

time to the frequency of the stimulus (limited by refractory period to <1000Hz) a. Volley of action potentials coincides with every half cycle (depolarisation)

Important consequences

1. Inner hair cell is the predominant sensory input to the central auditory nervous system 2. Cochlea is under efferent (descending) control – regulation of neural outflow 3. Output of each IHC is encoded in many nerve fibres, providng frequency (place or

temporal) and intensity information 4. Tonotopic organization of auditory pathways begins at the cochlea and exists

throughout the auditory system

• Central Auditory Processing Central auditory pathways are responsible for:

1. Sound localisation and lateralization 2. Auditory discrimination 3. Auditory pattern recognition 4. Temporal aspects of audition (resolution, masking, integration, ordering) 5. Auditory performance decrements with competing or degraded signals

Main auditory relay/processing stations (input from CN VIII):

1. Cochlear nucleus (DCN, PVCN, AVCN) – some feature processing, noise reduction a. Each subdivision tonotopic b. Bilateral and unilateral projections to SOC, NLL and IC via lateral lemniscus

1. Complex responses – feature extraction 1. DCN midbrain

2. Secure synapses for timing information 1. PVCN SOC 2. AVCN SOC

2. Superior olivary complex (MSO, LSO) – interaural timing/intensity, spatial localisation and detection of speech in noise.

a. 1st point receiving binaural input – critical for interpretation of binaural signals b. MTB - bilateral projections to IC, mainly contralateral c. PO – origin of efferent connections to the cochlear d. Middle ear reflex

3. Inferior colliculus – interaction with somatosensory and visual systems, complex sound feature extraction

a. Central nucleus – auditory relay centre b. Paracentral nuclei – integrative, multimodality belt area (broad tuning) c. Ipsilateral projections, receives efferents from the cortex

4. Medial geniculate body a. Tonotopic – high frequency medial, low frequency lateral b. Ventral division – sharp tuning, projects to AI (core) c. Medial/dorsal divisions – project to belt/diffuse system around AI

5. Auditory cortex – speech recognition/localisation, interaction with language centres a. AI (core) – tonotopic is isofrequency vertical columns, sharp tuning

1. Summation columns – excited by EE cells 2. Suppression columns – excited by EI cells

b. Belt – receives projections from other thalamic nuclei

530.302 – Medical Neurosciences Lecture Notes c. Reciprocal connections between cortical areas, efferent connections to

brainstem Binaural hearing is important for sound localisation and complex auditory perceptual tasks.

1. Differences in wavelength for high/low frequency sounds is the basis for: a. High frequency localisation – inter-ear differences in intensity (head shadow

effect) b. Low frequency localisation – inter-ear differences in timing/phase. These

sounds wrap around the head with little intensity difference between ears 2. Binaural cellular interactions

a. Some cells in SOC, IC, MGB and auditory cortex get inputs from both ears i. EE cells – excited by input to both ears ii. EI cells – excited by one ear, inhibited by the other

b. Cells with binaural sensitivity are divided into: i. Low frequency units – sensitive to interaural time differences (EE

cells in MSO) ii. High frequency units – sensitive to interaural level differences (EI

cells in LSO) 3. Sound localisation depends on:

a. Interaural cues (duplex theory) – ILDs and ITDs i. Coincidence detector – binaural timing and intensity dependent

neurons at the SOC, IC and cortex b. Spectral cues – interaural, monaural (vertical localisation) c. Auditory spatial maps in the brain represent position of sound in space

Speech coding – speech sounds (phonemes) comprise changes in frequency and intensity with time. Characteristic frequencies are depicted as formants (F1, F2, F3 etc). Speech signals are coded by an array of nerve fibres responsive to different frequencies, giving pattern of the speech phoneme over time.

• Hearing Loss and Ear Disease Ectoderm lateral line system ear plate otocyst primitive ear (otic capsule)

1. Gravity organ – utricle and saccule 2. Balance organs – semicircular canals 3. Sound detection and transmission system – cochlea 4. Impedance matching mechanism – outer and middle ear (from gill clefts) 5. Pressure equalising mechanism – Eustachian tube

Light reflex – indicates (pathological) distortion of the eardrum if absent or altered Facial nerve – important landmark in surgery as it is embedded in the temporal bone Sound collection conduction and impedance matching transmission transduction

propagation interpretation, reflex responses, reflexes Clinical evaluation of hearing:

1. Language tests – difficult/lengthy, only really identify central dysfunction 2. Word tests – words chosen to represent certain frequency ranges 3. Pure tone tests – artificial, but very reproducible

a. Standard levels are arbitrary based on American adolescents b. Does not represent percentage loss c. Can compare bone and air conduction to deduce the root of the problem

i. Tuning fork tests – Weber and Rinne Common diseases of the ear:

1. Conductive hearing problems a. Wax/blockage – loss of impedance matching mechanism b. Acute ear infection (convex eardrum) chronic infection (concave eardrum)

530.302 – Medical Neurosciences Lecture Notes c. Testing for conductive hearing problems – pressure with the best

transmission of sound is the pressure behind the eardrum i. Components – sound generator, measurement of sound in the outer

ear, pressure modulator d. Correction of mechanical problems:

i. Insertion of grommets allow drainage of fluid/mucus through the eardrum and improves oxygen conduction

ii. Replacement/augmentation of middle ear ossicles (piston) iii. Modification of middle ear ossicles (e.g. direct transmission) iv. Eardrum directly adherent to the oval window (round separated)

2. Sensory hearing problems a. Hair cell defects – hearing aids, cochlear implants

i. Occupational hearing damage – tend to affect a range of frequencies ii. Stiffening of the basilar membrane dampening of high frequencies iii. Pump defects fluid loading stretches the membrane dampening

of low frequencies b. Nerve defects – hearing aids have limited application

• Vestibular Physiology Maintenance of balance involves the integration of visual, vestibular, proprioceptive and superficial sensory information. It requires continuous information about the position and motion of all body parts – note that feedback information about the head and eyes must be independent as the eyes can be fixed on a target while the head is in motion. The vestibular system provides information of movement of the head and body by detecting linear and angular acceleration. It projects to the vestibular nuclei via the vestibular part of the vestibulocochlear nerve (note descending outputs from the vestibular nuclei)

1. Inputs – vision, pre-proprioception superficial sensation, labyrinthine activity 2. Descending inputs – cortex, cerebellum, reticular formation, extrapyramidal system 3. Outputs – cortical awareness of motion, control of oculomotor activity, posture, motor

The semicircular canals lie in three planes, each at right angles to each other – the horizontal canal lies at an angle of 30° to the horizontal, while the superior and posterior canals lie vertically and at right angles to each other.

1. The crista ampullaris is a specialised epithelial ridge within the ampulla that contains the vestibular sensory cells.

2. It is covered by the cupula, which is displaced by the flow of endolymph to stimulate the crista (thus detecting angular acceleration).

3. When the head rotates, the endolymph remains stationary for a moment due to its inertia – hence there is an apparent/relative flow of endolymph with respect to the bony canal. This leads to deflection of the cupula and the hair cell stereocilia.

The otolithic organs (macula utriculus and the macula sacculus) are located within the vestibule – these contain sensory hair cells and are covered by a gelatinous mass/membrane.

1. They are responsible for the detection of linear acceleration and static position – the gelatinous mass has CaCO3 crystals (otoconia) that increase its mass and inertia.

Sensory cells in each semicircular canal are oriented the same way, while the hair cells of each macula are oriented in different directions so that the tilt of the head will depolarise some cells and hyperpolarize others on the same side. The vestibular nuclei are subdivided according to location and function. Unfortunately, the f$%%$#% lecturer was talking too quickly so I’ll have to look this up. Physiological aspects:

1. Stimulation of hair cells and nerve fibres a. There is a constant low-level current flowing through the hair cell and resting

discharge in the vestibular nerve

530.302 – Medical Neurosciences Lecture Notes b. Stimulation of the hair cells towards the kinocilium leads to cell depolarisation

and increased nerve activity c. Stimulation of the hair cells in the opposite direction leads to

hyperpolarisation and inhibition of activity in the vestibular nerve 2. Stimulation of the cells of the otolithic organs

a. Cells are stimulated by the action of gravity on the otoconia 3. Semicircular canals in the same plane are organised in pairs bilaterally

a. The lateral or horizontal canals of both ears are paired b. The anterior canal is paired with the posterior canal of the opposite ear c. The polarisation of the sensory cell for a given canal is opposite to it’s pair d. Hence movement in a given direction will cause stimulation on one side, and

inhibition on the other – comparing the discharge pattern determines direction i. Note that this only provides information about rate of change (i.e.

acceleration as opposed to velocity) 4. Physiology of nystagmus

a. Determined by interaction of excitatory and inhibitory connections on both sides

EPILEPSY, SCHIZOPHRENIA, DEPRESSION AND ALZHEIMER’S

• Epilepsy Epilepsy is a group of conditions where people have a tendency towards recurrent seizures due to a chronic, underlying process. Note that a person with a single seizure or recurrent seizures due to a correctable/avoidable process may not necessarily have epilepsy. It is the manifestation of the brain’s response to an insult, and the prognosis depends more on the underlying pathology than the actual seizures the person experiences. The hallmark of epilepsy is an abnormal electrical discharge from the brain. Characteristic EEG signs are:

1. Suppression of background rhythmical activity 2. Rapid spikes (10-20Hz) showing progressive increase in amplitude 3. Fragmentation of spikes by superimposition of slow activity 4. Development of a spike and slow wave activity

Classification of seizures is varied and changes constantly:

1. Partial (localisation-related) – discharge arises and is confined in a part of the brain a. Simple partial seizure – motor, sensory, autonomic, psychic signs b. Complex partial seizure – loss of consciousness c. Partial seizures with secondary generalisation

2. Generalised – diffuse regions of the brain in a bilaterally symmetric pattern a. Absence (petit mal) b. Tonic-clonic (grand mal) c. Tonic d. Atonic e. Myoclonic

3. Unclassified seizures a. Neonatal seizures b. Infantile spasms

Partial seizures tend to indicate a local (structural) abnormality e.g. brain tumour, post traumatic scar tissue, abnormal vascular. It may also be a metabolic insult leading to a local brain insult. Note that not all generalised seizures start off as partial seizures. Individuals with primary generalised seizures are usually in good health – brain function is normal (aside from the tendency to seizure). CT and MR scanning usually indicate no problems – there is a polygenic correlation to this condition, although this has not been clearly elucidated.

530.302 – Medical Neurosciences Lecture Notes Patients with seizures in the temporal lobe have a tendency towards confusion following the seizure, particularly if the seizure arises in the dominant temporal lobe (dysphasia/mutism). Certain drugs can induce seizures in animal models (usually rats) via blockage of NTs. The fundamental principle is an imbalance between excitatory and inhibitory neurotransmitter.

1. Systemic agents a. Blockade of GABAa receptors

i. Bicuculline (competitive antagonist) ii. Picrotoxin (non-competitive antagonist)

Penicillin (enters open GABA channels and occludes them) b. Activation of Glu receptors – kainate, domoic acid c. Unblocking of NMDA receptors – low Mg+2 d. Blockade of Gly receptors – strychnine e. Blockade of K+ currents with 4-aminopyridine

2. Direct effects on cortex (cat model) a. Tetanus toxin b. Penicillin – generalised seizures

3. Kindling – repeated exposure of animal to initially subclinical electrical stimulus a. Changes in ion channels, eventual progression to late recurrent seizures b. Works best in lower animals, difficult to induce in primates c. Not universally accepted – e.g. age-related epilepsy in humans conflicts with

repeated exposure mechanism Receptor stuff relevant to epilepsy:

1. Two receptor types: a. Ionotropic excitatory amino acid receptors

i. Non-NMDA receptors (kainate, AMPA) – 2 glutamate molecules required, relatively impermeable to Ca+2, rapidly activated and inactivated

ii. NMDA receptors – absolute requirement for glycine as a co-agonist, activation and desensitisation much slower than non-NMDA receptors

1. Hyperpolarized state – MG+2 blocks channel and is expelled when the membrane is partially depolarised (positive feedback)

b. Metabotropic receptors i. Excitatory amino acid receptors (3 types), relation with epilepsy

unclear 2. Mechanism:

a. Excitatory transmission: i. Entry of Ca+2 exocytosis of contents of vesicles into synaptic cleft ii. Both NMDA and non-NMDA receptors co-localised at all synapses –

dual component nature of EPSP iii. Modulation of the transmission depending partially on the firing rate

of the nerve fibres b. Inhibitory transmission

i. GABA (glycine) is the major inhibitory neurotransmitter of the brain ii. GABAa and GABAb receptors are present iii. GABAa receptors are chloride channels – binds 2 molecules of

GABA (and other agents including benzodiazepines) Local recurrent circuits allow feedback inhibition and excitation. If there is neuron death, sprouting of unaffected axons occurs – e.g. dentate gyrus of hippocampus, axons of granule cells form new connections within the inner molecular layer. Derangement of this process may be a mechanism behind primary seizures. EEG of patients with localisation-related epilepsy may indicate an interictal spike:

1. Occurs when a group of neurons in a localised area are activated simultaneously in an abnormally hypersynchronised manner

530.302 – Medical Neurosciences Lecture Notes 2. Nerves undergo a large depolarising shift in the membrane potential (200ms)

superimposed with bursts of action potentials a. Generated by a combination of excitatory post synaptic currents, and voltage

dependent Ca+2 currents b. Excessive synchronisation due to activation of recurrent excitatory circuits

3. Depolarising shift is followed by membrane hyperpolarizing potential a. HP generated by voltage dependent currents (K+ and Cl-) and GABA

mediated synaptic inhibition 4. HP replaced by prolonged depolarisation – inhibition in surrounding and projection

areas diminishes, neurons recruited into the excitatory process 5. Development and spread of EP activity in the normal brain is due to a combination of

recurrent circuitry, and normal fq dependent plasticity of excitatory and inhibitory synapses

a. MB also alters NMDA and AMPA components – altered glutamate uptake, altered K+ buffering by glial cells

Seizure spread (propagation) – direct and something else I missed. Antiepileptic drugs have been largely discovered by chance. More recently drugs have been designed to target particular cellular machinery.

1. Excitatory receptors: a. Blockade of Na+ channels in the presynaptic nerve – CBZ, PHT, LTG, VPA b. Blockade of glutamate receptors – most have been too toxic

i. TPM – NMDA receptor ii. FBM – non-NMDA receptor

2. GABA receptors a. GABA transaminase inhibitor – VGB (but excessive GABA is toxic) b. GABA reuptake inhibitor – TGB c. Up-regulation of GABA transmission – TPM, barbiturates, benzodiazepines

• Schizophrenia and Antipsychotics Schizophrenia is a disease of abnormal thought, perception, behaviour, mood and attention – “neurotics build castles in the sky, schizophrenics move in”. Symptoms can be positive (delusions, auditory hallucinations) or negative (withdrawal, flattened mood). Onset tends to occur at 15-35 years, and affects 1% of the population. Suicide is common (10%). Schizophrenic symptoms may be due to overactivity of dopamine systems in the mesolimbic and cortical systems.

1. Affected areas include: a. Substantia nigra compacta (Parkinson’s) caudate-putamen b. Ventral tegmental area (schizophrenia) frontal cortex, nucleus accumbens,

olfactory areas, ventral striatum 2. Evidence for this theory:

a. Amphetamines increase dopamine release paranoid psychosis, exacerbation of schizophrenic symptoms. Blocked by dopamine antagonists

b. Antipsychotic drugs block dopamine receptors, and their ability to bind correlates highly with clinical efficacy and dosage

The other major hypothesis suggests that reduced activity in glutamate systems leads to schizophrenic symptoms.

1. Evidence for this theory: a. Phencyclidine (PCP, angel dust) produces the best model of psychosis (even

better than amphetamine) as it models both positive and negative symptoms i. It is a non-competitive antagonist of the NMDA receptor

b. Neuroleptics also induce glutamate release 2. It is possible that increased dopamine with decreased glutamate and others

(serotonin, NMDA) schizophrenic symptoms

530.302 – Medical Neurosciences Lecture Notes a. Two recent clinical trials show that agonists at the glycine site on the NMDA

receptor (cycloserine, glycine) significantly improve negative symptoms of schizophrenia in combination with traditional neuroleptics

Neuroleptics require 2-3 weeks of chronic use to obtain full therapeutic effect.

1. There are two major categories of antipsychotics: a. Typical (chlorpromazine, haloperidol) – best for positive symptoms

i. 30% have extrapyramidal effects such as Tardive dyskinesias (fly-catching) and Parkinsonian symptoms

ii. Side effects may be due to blockage of D2 receptors in the striatum-nigrostriatal pathway

b. Atypical (clozapine, risperidone) – effects on positive and negative symptoms i. Clozapine does not show extrapyramidal side effects (low D2 affinity) ii. Side effects can include agranulocytosis (not seen with risperidone)

2. These are all dopamine receptor antagonists: a. D1 receptors increased cAMP (greatly increased striatum activity)

i. D5 receptors D1-like b. D2 receptors reduced cAMP (greatly increased striatum)

i. D3 receptors D2-like but increases limbic system ii. D4 receptors D2-like but increases cortex and limbic system

c. Haloperidol and chlorpromazine have equal affinity for D2 and D4 receptors, while clozapine has 10-fold greater affinity for D4 than D2

3. Hence therapeutic effects may be caused by block of D4/D3 receptors in the limbic system and cortex (mesolimbic/cortical dopamine pathway)

4. Another theory is that D2 receptors in the cerebral cortex mediate the antipsychotic effects, and D2 receptors in the striatum mediate the extrapyramidal side effects of neuroleptics (including clozapine)

a. D2 receptors upregulated in the cortex with chronic administration of clozapine, and in cortex and striatum with haloperidol

• Depression and Antidepressants Depression is an episodic, recurrent illness with periods of spontaneous remission, affecting 2% of the population. There are two main types – unipolar depression (decreased mood, appetite, libido, tiredness, self-contempt) and bipolar/manic depression (heightened mood/euphoria, irritability, irrationality, delusions, hallucinations). Depression may be endogenous (unknown origin) or reactive (associated with environmental effects). The simple monoamine theory suggests that depression is a result of a decrease in brain monoamines (noradrenaline, serotonin and dopamine). Evidence:

1. Reserpine (depletes monoamine stores) can induce depression 2. Amphetamines/cocaine (increases monoamines) can increase mood. 3. Antidepressants block re-uptake or metabolism of monoamines

Problems with this theory – while antidepressants produce an immediate increase in monoamine levels, the therapeutic action is delayed and only becomes evident 2-3 weeks after chronic use. Perhaps the therapeutic effect results from a change in brain chemistry/function after chronic use (long-term adaptive changes) Antidepressants produce an acute increase in monoamines by blocking re-uptake into the neuron, or blocking breakdown by monoamine oxidases (MAOa and MAOb).

1. First generation: a. Tricyclics (amitriptyline, imipramine) block noradrenaline and serotonin re-

uptake acutely, showing benefit in 75% of patients (placebo 30-40%) i. Chronic effects – possible decrease in beta1-adrenoceptors ii. Side-effects – antimuscarinic actions

b. MAO inhibitors (phenelzine) irreversibly inhibit MAOs and increase levels of monoamines. Only used in patients who don’t respond to other medications due to peripheral toxicity.

530.302 – Medical Neurosciences Lecture Notes 2. Second generation:

a. Moclobemide – a reversible MAOa selective inhibitor (acute increase in noradrenaline, serotonin).

i. Better than phenelzine as MAOb (dopamine) is not affected b. Fluoxetine (Prozac) – selective serotonin re-uptake inhibitor, better tolerance

Antidepressants in manic depression:

1. Lithium carbonate is the most effective treatment for manic depression. There is a 2-3 week onset of action, with stabilisation of both manic and depressive phases

a. Low therapeutic index – overdose tremor, seizures, coma, death b. No effects on unipolar depression c. Mechanism is dampening of phosphoinositide-mediated neurotransmission?

2. Carbamazepine is also used, especially for rapid cyclers (4-5/year) 3. Sodium valproate may also have some effects and is an alternative for patients who

have poor tolerance/response to lithium

• Memory, Alzheimer’s Disease Memory

1. Biological basis: a. No one theory explains the phenomenon b. There are some anatomical localisations of memory, but this is simplistic c. Thee are a number of steps in the ‘laying down’ of memory d. The simplest is the STM/LTM paradigm

2. Short term memory a. Anticholinergics, trauma, ECT, tiredness all partly or wholly destroy STM b. STM LTM is improved by strychnine and amphetamine (both toxic) c. STM may be largely ‘electrical’ d. May be maintained by acute cholinergic activity in the hippocampus, then

cortex via various pathways e. ST memories may not be ‘lost’ but merely ‘overlayed’

3. Long term memory a. Memories, when fixed, are notoriously hard to erase b. They may be therefore be ‘structurally’ encoded c. Probably encoded in the cortex, but may not have a single location d. Theories of LTM:

i. ‘Modifiable synapse’ theory of Hebb – supported to some extent that neurosurgeons in conscious patients can stimulate the cortex and the patient recalls a particular event

ii. ‘Field’ (holographic) theories e.g. Lashley – some support from the fact that removal of parts of the brain do not destroy a lot of memories. Rats with half the brain removed still retain skills/memory.

iii. Does the brain have enough ‘RAM’ – 1010 neurones with 104 synapses each (total 1014)

Research techniques – blunt trauma, ECT, chemical intervention

1. Evidence of structural changes – no sufficient/exclusive evidence, but: a. Chicks learning in the first few days of life can be shown to have structural,

chemical and electrical changes in parts of the brain b. Sea slugs with simple but large neurones can be shown to undergo

structural, chemical and electrical changes c. Long term potentiation – thin slices of hippocampus can be shown to have

changed electrical activity for some time after stimulation 2. Cholinergic changes

Dementia is a acquired syndrome of persistent and gradual decline of cognitive function after 45-50 years of age. It affects memory as well as other higher cognitive functions (language, visuospatial, reasoning, abstract thinking, personality) sufficient to interfere with usual activities. Note that it occurs in clear consciousness (as opposed to delirium).

530.302 – Medical Neurosciences Lecture Notes Senile dementia of the Alzheimer’s type (SDAT) is the most common type of dementia, with a gradual progression of symptoms not explained by other factors. It is a pathological diagnosis, as the clinical diagnosis is only an educated guess (partly by exclusion). Pathology of SDAT – quite specific, though some overlap with ageing

1. Gross changes – widespread atrophy of the cortex with neuronal cell loss a. Shrinkage of the gyri with widened sulci b. Enlarged ventricles c. Shrinkage of the amygdala and hippocampus

2. Neurofibrillary ngles (intracellular) a. Found within the neurones of SDAT patients, particularly in the cortex and

hippocampus. Rare in the ‘normal’ elderly i. Tau proteins normally bind to tubulin to stabilise microtubules ii. Tau becomes excessively phosphorylated and this impairs its ability

to bind with tubulin tangles consisting of helical filaments b. Correlate well with cognitive impairment

3. Inflammatory reaction 4. Amyloid angiopathy 5. Amyloid plaques (extracellular)

a. Small spherical deposits (especially cortex and hippocampus) consisting of pleated sheets of β-amyloid

i. May be within a cluster of nerve endings with entangled paired helical filaments (neuritic plaques)

ii. β-amyloid is derived from amyloid precursor protein by abnormal cleavage at 2 sites

iii. ApoE4 interacts with β-amyloid to form plaques b. One type of familial SDAT is due to a mutation on Chr21 c. Some mitochondrial genes may be involved d. Also found in ‘normal’ elderly people and do not necessarily lead to SDAT

It remains unclear what amyloid does in the normal brain. It may have a role with long-term potentiation, although amyloid knockout mice do not have any gross effects. Abnormal amyloid is also produced in the normal brain. Therapeutic implications – vaccination, gamma secretase inhibitors. Theories of SDAT:

1. Cholinergic theory a. Blockage of cholinergic receptors in normal brain leads to memory loss b. Cholinergic neurones in the brain are depleted in SDAT

i. SDAT plaques may result from degeneration of cholinergic nerves ii. Improving cholinergic transmission may help/slow the progress

c. Targeting of cholinergic neurotransmission is difficult as it is widespread d. Drugs:

i. Tacrine – acetylcholinesterase inhibitor (first approved SDAT drug) 1. Problems with hepatotoxicity in the majority of patients –

newer selective drugs are more tolerable 2. Not able to halt the progress of the disease or mediate

reversal, but may slow deterioration over the long term ii. Donepezil – competitive acetylcholinesterase inhibitor iii. Exelon – pseudo-reversible acetylcholinesterase inhibitor iv. Memric – cholinergic agonist

2. Other neurotransmitters involved in SDAT a. Noradrenaline – 10-30% loss in cortical activity, moderate level of

denervation, does not correlate with dementia b. Dopamine – relatively little affected in SDAT c. Serotonin – loss of 40-50% cortical innervation and subcortical neurones

i. Less marked than for cholinergic neurones ii. In the living, levels of breakdown products are higher in CSF

(increases level of turnover)

530.302 – Medical Neurosciences Lecture Notes iii. Correlates significantly with the degree of dementia

d. Glutamate may have some relevance 3. Genetic factors:

a. APP gene (chr19) – mutant encodes an abnormal form of APP that is abnormally cleaved (only a small number of cases of early-onset SDAT)

i. Gamma secretase defects may alter levels of APP and have long-term implications for levels of abnormal amyloid

b. ApoE (chr21) – linked with common late-onset familial SDAT i. Occurs as 3 phenotypes (E2 good, E3, E4 bad) ii. Presence of one allele more than doubles the risk of SDAT iii. E4/E4 variant 8x risk over time (most people have it by 80yrs) iv. Cannot be used as a screening test (only minority of SDAT have it)

More on cholinergic theory:

1. Location of cholinergic neurotransmission a. Cortex – no cell bodies of cholinergic neurons (subcortical) b. Synapse with cortical neurons with nicotinic and/or muscarinic receptors c. Cholinergic fibres dense in the amygdala, hippocampus, limbic areas,

temporal lobes d. Related to sleep, arousal, mood, emotions, attention and memory e. Peripheral cholinergic neurotransmission – stimulation side-effects

2. Cholinergic depletion – decreased activity of acetylcholinesterase or the enzyme involved in its synthesis (ChAT)

a. Usually a defect in presynaptic transmission (drug target) b. Post mortem – large decreases in ChAT and acetylcholinesterase c. Loss of cholinergic innervation is bilaterally symmetrical (some variation) d. Nicotinic receptors on cortical neurons are significantly decreased e. Only subcortical cholinergic neurons that project to the cortex are depleted

3. Cholinergic depletion and normal ageing a. Loss of ChAT, acetylcholinesterase and cortical cholinergic nerve fibres is

normal in ageing b. Occurs younger and with greater severity in SDAT

4. Relation to plaques and tangles: a. Modest correlation between degree of cholinergic loss and plaque density b. Experimentally induced subcortical lesions cortical plaques c. Muscarinic stimulation of neurons normal processing of APP, so

cholinergic depletion may lead to excess β-amyloid d. Cholinergic loss may precede other neurotransmitter deficits e. Strong correlation between tangle density and cortical cholinergic fibres loss

5. Caveats: a. Plaques and tangles are not confined to the cholinergic areas alone b. No clear correlation with tangle density and formation

ANAESTHETICS

• Inhalational Anaesthetics Inhalational anaesthetics are used in both induction and maintenance of anaesthesia. They cause reversible loss of consciousness, unresponsiveness to external stimuli and amnesia (note that not all anaesthetics produce muscle relaxation).

1. Types of inhalational agents: a. Liquids which form vapour readily:

i. Halogenated hydrocarbons – halothane, chloroform ii. Ethers – isoflurane, sevoflurane, enflurane, desflurane iii. Hydrocarbons - cyclopropane

b. Vapour at ambient temperature and pressure – nitrous oxide c. Gases – nitrogen, xenon

2. Mode of action – membrane theory

530.302 – Medical Neurosciences Lecture Notes a. Meyer-Overton theory – anaesthetic potency is proportional to lipid solubility

i. non-specific bulk dissolution in lipid bilayer, boundary lipids next to protein, specific hydrophobic sites in protein

b. Multi-site expansion theory – agent dissolved in lipid membrane expansion impairment of ion channel action impaired neuronal function

i. This suggests that it is the number of molecules dissolved in the membrane, and hence the partial pressure exerted by the molecules

ii. Effects are in proportion to partial pressure in blood and brain 3. Anaesthetic uptake

a. Uptake depends on three main factors: i. Production of high alveolar concentration – high inspired

concentration, second gas effect, alveolar ventilation ii. Uptake from alveoli – CO x blood solubility x (PA-PV) iii. Importance of vessel-rich and vessel-poor groups of tissues

b. The speed of onset of anaesthesia depends on maintaining a high alveolar concentration (partial pressure) – the greater the uptake from alveoli to blood, the slower the onset of anaesthesia (expansion theory).

i. The higher the blood solubility, the greater the uptake, the slower the rise in alveolar concentration and the slower the onset of anaesthesia

1. The effect of solubility on rate of induction can be negated via overpressure (i.e. high concentrations at induction)

ii. The higher the cardiac output, the greater the uptake, the slower the rise in alveolar concentration and the slower the onset of anaesthesia

4. Anaesthetic elimination/metabolism a. Exhalation – main route of elimination b. Liver metabolism – varies depending on the agent (halothane highest)

i. Problems include hepatic damage from high liver metabolism (halothane), renal damage from fluoride ions (methoxyflurane)

c. Example – halothane reactive reductive metabolites i. Halothane hepatitis – increased risk with hypoxia, enzyme induction,

previous/recent episodes ii. Direct liver cell damage mild liver dysfunction iii. Combination with endogenous protein hapten autoimmunity

Actions of inhalational anaesthetics:

1. Disruption of axonal and synaptic transmission a. Axonal – interference with impulse conduction b. Pre-synaptic – interference with transmitter release c. Post-synaptic – reduction in post-synaptic response to the transmitter

2. Disruption of receptor function – ACh, catecholamines, serotonin, adenosine, GABA (might enhance effect), glutamate, calcium, endogenous opioids

a. Note that side-effects are dose-dependent 3. Other anatomical sites

a. Brain (RAS, cortex, hippocampus) amnesia b. Spinal cord – inhibition of movement in response to noxious stimulus c. Peripheral nerves involved in local anaesthesia

4. Pharmacodynamics: a. General – dose-dependent respiratory depression, bronchodilatation b. CVS – myocardial depression, eventual decreased CO, vasodilation c. CNS – increased cerebral blood flow, intracranial pressure. Decreased

cerebral oxygen consumption d. Others – muscle relaxation (uterine), potentiation of NM blockers, N+V

The minimum alveolar concentration (MAC) of an anaesthetic agent prevents movement (to a painful stimulus) in 50% of unpremedicated patients breathing the agent in 100% O2.

1. The higher the MAC, the lower the potency and the poorer the lipid solubility 2. MAC-awake is a variation – it is the concentration that permits voluntary response to

command in 50% of cases. This is the concentration that provides amnesia in most patients and is generally ~1/3 MAC.

3. Potency is affected by the intrinsic properties of the drug (oil/lipid solubility)

530.302 – Medical Neurosciences Lecture Notes a. Decrease potency – decreasing age, hyperthermia, chronic EtOH b. Increasing

Balanced anaesthesia is the provision of anaesthesia using general anaesthetics along with specialist drugs:

1. Inhaled anaesthetics are not required at MAC concentrations 2. Neuromuscular blockers prevent movement 3. Analgesics or local anaesthetics for pain 4. Nitrous oxide to provide analgesia and anaesthesia – may be augmented

Types of inhaled anaesthetics:

1. Halothane – cheap, tolerable, no tachycardia, bronchodilatation (non-irritant) a. Cardiac depression, arrhythmias, hepatitis, malignant hyperthermia

2. Isoflurane – medium rate onset/offset, cardiac stability, little increase in ICP a. Tachycardia, coronary steal

3. Enflurane – medium rate onset/offset a. Seizure promotion, respiratory depression, free fluoride ions

4. Sevoflurane – rapid onset/offset, expensive, pleasant a. Elimination may be too rapid, unstable in baralyme compound A

5. Desflurane – very rapid onset/offset, expensive a. Pungency sympathetic stimulation – requires a special vaporiser

6. Nitrous oxide – weak anaesthetic, powerful analgesic, non-irritant a. Expansion of air-filled spaces – N2O diffuses in 40x faster than N2 out b. Inhibition of methionine synthase (DNA synthesis) – bone marrow depression c. Diffusion hypoxia – N2O rapidly excreted at the end of an anaesthetic dilutes

the inspired O2. Counteracted via supplementary O2 d. Pollution – greenhouse effect, possible effects with chronic exposure (not a

good idea with first trimester pregnancy) Benefits of N2O – analgesia, reduces MAC, 2nd gas effect – the rapid uptake at the start of induction results in an increase in the concentration of other anaesthetic agents.

• Local Anaesthetics Local anaesthetics produce reversible depression of nerve conduction when applied to a nerve fibre. Some drugs have weak local anaesthetics properties (pethidine, antihistamines), while others may be biological toxins (tetrodotoxin, saxitoxin) or used specifically as clinical local anaesthetics. Local anaesthetics can be classified structurally as amides or esters. This has implications for the extent of metabolic breakdown, the duration of action and toxicity. Early anaesthetics were esters – broken down by serum cholinesterase and cause hypersensitivity reactions. Normal nerve impulse transmission:

1. Resting phase – channel closed 2. Fibre stimulated – channel opens, sodium enters 3. Cell depolarised – channel closes 4. Potassium exits down concentration and electrical gradients 5. Fibre repolarised – Na/K pump restores balance

Local anaesthetics act by blocking the sodium channel. They are weak bases injected as hydrochloride salts in an acid solution. The tertiary amine group becomes quaternary and is more suitable for injection.

1. LA is injected and pH increases due to higher pH of tissue 2. Drug dissociates and free base is released 3. Free base enters the axon where the pH is lower 4. Reionised base blocks the Na+ channel

530.302 – Medical Neurosciences Lecture Notes The susceptibility of nerves to local anaesthetic action is primarily determined by the type of local anaesthetic and where it is delivered. Nerve fibres also have different sensitivity (small, unmyelinated, slow conducting fibres more sensitive), and active nerves are more susceptible than resting nerves. Use-dependent (phasic) block – local anaesthetic inhibition of sodium channels increases with repetitive depolarisations. No clinical relevance, however. Qualities of local anaesthetics:

1. Speed of onset is related to the pKa – a pKa closer to physiological pH has faster speed of onset, shorter duration (e.g. lignocaine Vs ropivacaine)

a. pKa is the pH at which the drug is 50% ionised and 50% unionised b. Ionised drugs are poorly lipid soluble

2. Duration of action is related to protein binding – higher protein binding has longer duration (e.g. ropivacaine Vs lignocaine)

3. Potency is related to lipid solubility – higher solubility has greater potency (e.g. ropivacaine Vs lignocaine)

4. Absorption depends on the method of administration and physiochemical properties 5. Distribution depends on lipid solubility, regional vascularity and cardiac output 6. Metabolism

a. Esters – plasma cholinesterase b. Amides – N-dealkylation and hydrolysis in the liver

7. Excretion – mainly renal Routes of administration:

1. Topical – skin or mucous membrane e.g. amethocaine, EMLA 2. Infiltration 3. Peripheral nerve blockade – minor, major, plexus 4. Central neuraxial – epidural (cervical, thoracic, lumbar or caudal) or spinal 5. Intravascular – tourniquet facilitates local binding, so no rush when removed

Toxicity and side effects depend on dose, rate of injection and site of injection (interpleural most toxic, infiltration least toxic)

1. Side effects depend on plasma concentration (e.g. 4mg/mL 26mg/mL) – a. Light-headedness visual disturbances muscle twitching convulsions

unconsciousness coma respiratory arrest CVS collapse 2. The CV/CNS ratio is the ratio of dosage or blood levels required to produce

irreversible cardiovascular collapse – lignocaine=7, bupivacaine=4 (more dangerous) 3. Cardiotoxicity – slowing of conduction, myocardial depression, peripheral

vasodilation, arrhythmias, refractory ventricular failure S-ropivacaine – less cardiotoxic, less motor block L-bupivacaine

• Intravenous Anaesthetics Distribution of intravenous drug depends on the organ’s proportion of body mass:

1. Lungs 2. Vessel rich group – heart, brain, kidneys, liver/splanchnic, endocrine 3. Lean group – muscle, skin 4. Fat group 5. Vessel poor group

Recovery from infusions varies depending on agent – diazepam > thiopental > midazolam > ketamine >propofol > etomidate Thiopentone is a barbiturate (introduced 1934) that acts at GABAA receptors, increases the affinity at benzodiazepine receptors and binds in the channel of NMDA receptors.

1. Actions:

530.302 – Medical Neurosciences Lecture Notes a. Brain – potent depressant and anticonvulsant (unconscious in one arm to

brain circulation time) b. CVS – potent depressant (direct myocardial, indirect sympathetic depression)

i. EEG – slow waves delta waves suppression isoelectric EEG c. Respiratory – potent depressant (apnoea, suppression of laryngea reflexes) d. Other – toxic subcutaneously or intra-arterially, anaphylaxis, crosses

placenta, some age-related variations 2. Kinetics:

a. Brief duration of action due to redistribution b. Slow liver metabolism (excretion half-life 12-24 hours)

3. Rapid recovery, but a ‘hangover’ Propofol is an alkyl-phenol (emulsified with soya bean oil and egg phosphatide

1. Actions: a. CNS – potent depressant, not anticonvulsant b. CVS – potent depressant, vasodilation, resets baroreceptors c. Respiratory – potent depressant d. Other – painful but non-toxic if not in vein

2. Kinetics: a. Offset by rapid redistribution and rapid metabolism (excretion half-life 1-1.5hr) b. Recovery rapid, minimal hang-over, antiemetic c. Suitable for infusion

3. Rapid, clear-headed recovery Benzodiazepines work at GABAA receptors (indirectly augment affinity of GABA).

1. Actions: a. Hypnotic, muscle relaxant, anticonvulsant, anxiolytic b. Minimal CVS and respiratory depressant when used as a sole agent c. Potent synergy with other drugs (opioids, IV induction agents)

2. Drugs that work at the benzodiazepine receptor: a. Agonists – e.g. midazolam b. Antagonists – flumazenil (reverses effects of agonists and inverse agonists) c. Inverse agonists – DMCM

3. Dose-related effects – anxiolysis sedation amnesia anticonvulsant (persists) drowsiness muscle relaxation sleep

4. Examples: a. Diazepam

i. Very long acting (24+ hours) ii. Activate metabolites – oxazepam, temazepam, desmethy-diazepam iii. Poor water solubility, irritating IV preparations

b. Midazolam i. Medium duration of action (0.5-1.5 hours after small IV bolus) via

liver metabolism ii. Better IV drug (water-soluble), can also be given orally iii. Potent amnesiac

c. Flumazenil – competitive antagonist to benzodiazepines i. Brief duration of action after IV bolus (15-20 minutes) ii. Reliable reversal of bolus doses of midazolam

1. Re-sedation may occur with longer-acting benzodiazepines or infusions

2. May cause withdrawal syndrome in addicts 3. Sympathetic overactivity – anti-benzodiazepine effect

releases inhibition of side effects of overdose of other drugs iii. Reverses paradoxical reactions to benzodiazepines iv. May be used to diagnose and treat drug overdoses acutely

Ketamine is an arylcyclohexylamine that acts as an antagonist at NMDA receptors. Widely used in emergency situations for surgical procedures (due to minimal respiratory depression)

1. Actions:

530.302 – Medical Neurosciences Lecture Notes a. CNS – dissociative state, may appear awake with eyes open, hallucinations,

analgesia, CNS stimulation. Use of benzodiazepines – amnesia b. CVS – stimulates sympathetic nervous system c. Respiratory – retains laryngeal reflexes, bronchodilator, minimal depression

2. Kinetics: a. Terminal half life of 3 hours b. Metabolism to nor-ketamine (active) c. Duration of action is very dependant on dose

Opioids include the pheynlpiperidines (fentanyl, alfentanil, remifentanil)

1. Opioids are not anaesthetics, but are sedating at high doses 2. Do not guarantee unconsciousness or no recall at any dose 3. Potently synergistic with benzodiazepines unconsciousness, no movement to pain

a. Greater likelihood of CVS and respiratory depression b. However, commonly used for sedation by proceduralists

4. Kinetics: a. Great variation in standard response between individuals, and within

individuals at different instances – requires monitoring b. Variation in response depending on stimuli involved

Intravenous drugs are extremely potent due to their mode of administration. Doses when given need to be carefully titrated.