Lec 1: Brain and Behavior(Functional and Behavioral Neuroanatomy, Neurophysiology and Neurochemistry I and II, Neurogenetics and Psychoneuroendocrinology and Psychoimmunology; Chronobiology) by Dr. Los Banos

FUNCTIONAL AND BEHAVIORAL NEUROANATOMY

NERVOUS SYSTEM: Sensory Systems

o Create an internal representation of the external world.

o A separate map is formed for each sensory modality.

Motor Systemso Enable persons to manipulate their

environment and to influence other’s behavior through communication.

Association (Association Unit)o Unit in the brain wherein sensory input,

representing the external world, is integrated with internal drivers and emotional stimuli.

SENSORY SYSTEMS: Must both detect and discriminate stimuli. Feature extraction – quintessential role of sensory

systems. First transform physical stimuli into neural activity in

the primary sense organs and then refine and narrow the neural activity in a series of higher cortical processing areas.

Neural processing – eliminates irrelevant date from higher representations and reinforces crucial features.

Highest Levels of sensory processing – neural images are transmitted to the association areas to be acted on in the light of emotions and drives.

Two Paradigm for all sensory systems: 1. Nature and Nurture

Genetics and experience Suggested an innate, genetically determined

mechanism of synaptic pattern formation2. Highly specialized brain cells that respond exclusively

to extremely specific stimuli. “Grandmother cell” – a cell that would fire

only when a subject was regarding his or her own grandmother.

The Five Primary Senses:1. Somatosensory System

An intricate array of parallel point-to-point connections from the body surface to the brain.

First sensory system understood in anatomical detail.

6 somatosensory modalities:o Light Toucho Pressureo Paino Temperatureo Vibrationo Proprioception (position sense)

Somatotopic – the organization of nerve bundles and synaptic connections in the

somatosensory system encodes spatial relationships at all levels.

Various receptor nerve terminals act in concert to mediate distinct modalities.

Nerve endings are either fast or slow After sensory fibers enter the spinal cord,

they are sorted into one of the three fiber tracts:

o Some fibers travel locally and synapse within one or two spinal segments. These projections participate in further filtering of the sensory input by suppressing unwanted “noise” to allow sharper delineation of the signal

o Fibers for conscious perception of touch, pain and temperature decussate at the level of entry into the spinal cord and

ascend to the brain in the spinothalamic tract

1. Lateral spinothalamic tract – localized, discrete, acute pains.

2. Medial spinothalamic

tract – along with spinoreticulothalamic pathway: diffuse, chronic pains.

o Fibers for conscious perception of touch, vibration sense and proprioception in the posterior columns, without immediate decussation.

All somatosensory fibers project to, and synapse in, the thalamus. The thalamic neurons preserve the somatotopic representation by projecting fibers to the somatosensory cortex, located immediately posterior to the sylvian fissure in the parietal lobe (Brodmann areas 1,2,3)

Within each band is the sensory homunculus Tactile agnosia or Astereognosis is defined

by the inability to recognize objects based on touch although he primary somatosensory modalities are intact.

Primary somatosensory modalities:o Light toucho Pressureo Vibrationo Proprioception

Strict somatotropic representation exists at each level of the somatosensory system. Neurons extend axons to connect to distant brain regions and a set of axons must therefore sort itself to preserve the somatotropic organization.

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N i n a I a n J o h n “ G ” R a c h e l M a r k J o c e l l e E d o G i e n a

In adults, the classic mapping studies of Wilder Penfield suggested the existence of a homunculus - an immutable corticacl representation of the body surface.

More recent experimental evidence has promoted a more plastic conception than Penfield’s; i.e , shifts in the map occur in response to loss of cortex form stroke and injury.

The cortical map can be rearranged solely in response to a change in the pattern of tactile stimulation of the fingers.

Internal representation of the external world, while static in gross structure, may be continuously modified at the level of synaptic connectivity to reflect relevant sensory experiences.

Cortical representations of sensory input or of memories may be holographic rather than spatially fixed; the pattern of activity, rather than the physical structure, may encode information.

2. Visual System Visual images are transduced into neural

activity within the retina ad are processed through a series of brains cells, which respond to increasingly complex features from the eye to the higher visual cortex.

Visual Pathway:o Optic disk (retina) optic nerve

optic chiasm optic tracts Lateral Geniculate Nucleus (Body) visual cortex

o Retina – Rods and Cones Rods – intesnisty of light Cones – 3 types, respond

most strongly to one of the 3 primary colors.

o Center-surround response – stimulating a point immediately suppresses the response of circle of neighboring cells.

Primary Visual Cortex – respond specifically to lines of a specific orientation. The cells of primary visual cortex projects to Secondary Visual Cortex

Secondary Visual Cortex – respond specifically to particular movements of lines and to angles.

Inferior Temporal Lobe – detects the shape, form, and color of the object. The WHAT questions.

Posterior Temporal Lobe – tracks the location, motion and distance. The WHERE question

Inferior Temporal Cotrices (ITCs)o Left ITC – facial featureso Right ITC – complex shapes

Ocular dominance columns are stripes of cortex that receive input from only one eye, separated by stripes innervated only by fibers for the other eye.

Clinical Implications:Prosopagnosia

Inability to recognize faces

Disconnection of Left ITC from the visual association area in the left parietal

lobeApperceptive Visual Agnosia

Inability to identify and draw items using visual cues, with preservation of other sensory modalities

Bilateral lesions in visual association areas

Associative Visual Agnosia

Inability to name or use objects despite the ability to draw them

Bilateral medial occipitotemporal lesions

Color Agnosia Inability to recognize color despite being able to match it

Dominant occipatl lobe lesions that include splenium of corpus callosum

Color Anomia Inability to name a color despite being able to point it.

Central Achromatopsia

Complete inability to perceive color

Anton’s Syndrome

Failure to acknowledge blindness, possibly owing to interruption of fibers involved in self-assessment

Bilateral occipital lobe lesions

Balint’s Syndrome

Triad:Optic Ataxia (inability to direct optically guided movements); Oculomotor Apraxia (inability to direct gaze rapidly); Simultanagnosia (inability to integrate a visual scene to perceive it as a whole)

Bilateral Parito-occipital lesions

Gerstmann Syndrome

Includes:Agraphia, Acalculia, Right-Left disorientation and Finger agnosia.

Dominant parietal lobe lesions

3. Auditory System Sounds are instantaneous, incremental

changes in ambient air pressure. Pathway:

o Pressure change vibration ossicles endolymph (cochlear spiral) cilia movement (hair cells) generate neural impulses cochlear nerve cochlear nuclei Lateral Lemniscus (Inferior colliculi) Medial Geniculate Nucleus/Body (Thalamus) Primary auditory cortex (Posterior Temporal Lobe)

Lexical Processing - the extraction of vowels, consonants and words from the auditory input, occurs in higher language association areas in the left temporal lobe.

Clinical Implications:

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4. Olfaction Odorants, or volatile chemical cues, enter

the nose, solubilized in the nasal mucus and bind to odorant receptors displayed on the surface of the sensory neurons of the olfactory epithelium

Each neuron in the epithelium displays a unique odorant receptor.

Humans possess several hundred distinct receptor molecules that bind the huge variety of environmental odorants.

The most ancient sense in evolutionary terms

Tightly associated with sexual and reproductive responses.

Pathway:o Binding of odorant/s neural

impulse sensory nerves along cribriform plate olfactory bulb glomeruli Olfactory Cortex

Olfactory signals do not pass through the thalamus.

Vemoronasal Organ is thought to detect pheromones.

5. Taste Sense of taste is believed to discriminate

only broad classes of stimuli: sweet, sour, bitter and salty.

Each modality is mediated through a unique set of cellular receptors and channels.

Pathway:o Soluble chemical binding to mouth

receptors stimulation of gustatory nerves nucleus solitaries of brainstem

MOTOR SYSTEMS The movements of the body muscles are controlled

by the lower motor neurons. The firing motor neurons are regulated by the

summation of upper motor neuron activity. Primitive systems produce gross coordination

movements of the entire bodyo Activation of the rubrospinal tract stimulates

flexion of all limbs whereas activation of the vestibulospinal tract causes all limbs to extend.

Coticospinal tract is at the top of the motor hierarchyo Controls fine movements and which

eventually dominates the brainstem system during the first years of life.

o Upper motor neurons of CST is at the posterior frontal lobe known as motor strip or brodmann area 4.

Basal Ganglia A subcortical group of gray matter nuclei Mediate postural tone Four functionally distinct ganglia:

o Striatumo Pallidumo Substantia nigrao Subthalamic nucleus

Collectively known as the Corpus Striatum, Caudate and Putamen.

Caudate Nucleuso Modulation of motor actso Gatekeeper to allow the motor system to

perform only those acts that are goal directed.

o Failure to perform as gatekeeper: Obsessive-compulsive disorder Tic disorders such as Tourette’s

disordero Overactivity of the striatum owing to lack of

dopaminergic inhibition results in bradykinesia.

o Huntington’s disease Caudate shrinks dramatically Characterized by rigidity

superimposed by choreiformo Thought to influence associative or cognitive

processes Globus pallidus

o Internal or external partso Nested within the concavity of the putameno Receives input from the corpus striatum and

projects fibers to the thalamuso May be severely damaged in Wilson’s

disease and carbon monoxide poisoning. Characterized by dystonic posturing

and flapping movements of arms and legs.

Substantia Nigrao The black substance because of the

presence of melanin pigmento Parkinsons’ disease

Characterized by rigidity and tremor associated with depression

Subthalamic Nucleuso Yield ballistic movements, sudden limb jerks

or such velocity that they are compared to projectile movement

Together, initiating and maintaining the full range of useful movements.

Cerebellum Simple six-cell pattern of circuitry Activated several milliseconds before a planned

movement Ablation renders intentional movements coarse and

tremulous Carefully modulates the tone of agonistic and

antagonistic muscles by predicting the relative contraction needed for smooth motion

Prepared motor plan is used to ensure that exactly

the right amount of flexor and extensor stimuli is sent to the muscles.

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Word Deafness

Characterized by intact hearing for voices but an inability to recognize speech

Damage to the left parietal cortex; Disconnection of the auditory cortex from Wernicke’s area

Auditory Sound Agnosia

Inability to recognize nonverbal sounds, in the presence of intact hearing and speech recognition

Right hemisphere correlate of pure word deafness

Motor Cortex Brodmann area 4, motor strip Somatotopic map of the motor neurons is found. Individual cells within the motor strip cause

contraction of single muscles. Supplementary Motor Area

o Brodmann area 6o Brain region immediately anterior to the

motor stripo Contains cells that when individually

stimulated can trigger more complex movements, by influencing a firing sequence of motor strip cells

Praxis – skillful use of the hands Apraxia – deficits in skilled movements

o 3 levels: Limb-kinetic Ideomotor Ideational

o Limb-kinetic Inability to use the contralateral

hand in the presence of preserved strength

Results from isolated lesions in the supplementary motor area

o Ideomotor Apraxia Inability to perform an isolated

motor act upon command despite preserved comprehension, strength, and spontaneous performance of the same act.

Simultaneously affects both limbs and involves functions so specialized that they are localized to only one hemisphere.

Disconnection of the language comprehension area, Wernicke’s area, from the motor regions causes inability to follow spoken commands

Lesions to the left premotor area may impair the actual motor program as it is generated by the higher-order neurons.

o Ideational apraxia when the individual components of

a sequence of skilled acts can be performed in isolation, but the entire series cannot be organized and executed as a whole.

Autonomic Motor System Parasympathetic System slows the heart rate and

begin the process of digestion Sympathetic System mediated the fight or flight

response, increased heart rate, shunting of blood away from the viscera, and increased respiration

Hypothalamus – brain center that drives the autonomic motor system which houses a set of paired nuclei that appear to control appetite, rage, temperature, blood pressure, perspiration, and sexual drive.

ASSOCIATION SYSTEMS

Primitive Reflex Circuit

Primitive reflex arc may mediate the brisk withdrawal of a limb from a painful stimulus, without immediate conscious awareness

Peripheral stimulation of sensory nerve which in turn directly activates the motor neuron that drives the muscle to contract

This response is strictly local and all-or-none Rarely generate an organism’s behaviors For behaviors, sensory systems project to association

areas where sensory information is interpreted in terms of internally determined memories, motivations, and drives.

Basic Organization of the Brain Korbinian Brodmann

o 47 areas on the basis of cytoarchitectonic distinctions

o Cataloguing that has been remarkably durable as the functional anatomy of the brain has been elucidated

Brainstem and Thalamic reticular activating system provide arousal and set up attention

Posterior cortex integrates perceptions and generates language

Frontal cortex generates programs and executes plans like an orchestra conductor

Hemispheric lateralization of function is a key feature of higher cortical processing.

Primary sensory cortices for touch, vision, hearing, smell and taste are represented bilaterally, however the highest level of feature extraction are generally unified in one brain hemisphere only.

o The clearest known example of hemispheric lateralization is the localization of language functions to the left hemisphere. (Pierre Broca and Karl Wernicke)

Prosody the emotiona and affective components of language, or body language, appears to be localized in a mirror set of brain units in the right hemisphere

Limbic System A circuit of phylogenetically ancient structures Responsible for generating and modifying memories

and for assigning emotional weight to sensory and recalled experience

Amygdala receives fibers from all sensory areas and appears to serve as a gate for the assignment of emotional significance to memories.

• Localization of specific brain functions• Arousal and Attention

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• Arousal – establishment and maintenance of an awake state.Requires at least 3 brain regions:

◦ brainstem: ascending reticular activating system(ARAS) – diffuse set of neurons appears to set thelevel of consciousness.◦ Intralaminar nuclei of thalamus◦ cortex

• ARAS → Intralaminar nuclei of the thalamus → cortex• thalamus and cortex: fire rhythmical burst of neuronal activityat 20 to 40 cycles per second• sleep:burst are not synchronized• wakefulness: ARAS stimulates thalamic intralaminar nucleiwhich in turn coordinates the oscillations of different corticalregions, greater synchronization means higher level ofwakefulness• absence of arousal: stupor and coma• produce stuporous state:

◦ small discrete lesions of the ARAS◦ large bilateral lesions in the hemisperic level

• Maintenance of attention requires intact right frontal lobe• Memory• Immediate memory – functions over a period of seconds

◦ components:▪ phonological – left hemisphere▪ visuospatial – right hemisphere

◦ working memory – ability to store information forseveral seconds, while other, related cognitiveoperation take place on this information. Itincorporates immediate and recent memory.

Dorsolateral prefrontal cortex• recent memory – minutes to days• remote memory – months to years

Brain structures critical to formation of memories◦ medial temporal lobe – houses the hippocampus –adjacent to amygdala: rates the emotionalimportance of an experience and to activate the levelof hippocampal activity accordingly.

▪ Hippocampal place code: a pattern of cellular activation in the hippocampus that corresponds to the animal's location in space.

◦ certain diencephalic nuclei◦ basal forebrain

• declarative or factual memory may be separate within the brainform procedural or skill related memory• amygdala, afferent and efferent fiber tracts of the hippocampus– essential to the formation of memories• left hippocampus – more efficient at forming verbal memories• right hippocampus – form nonverbal memories• memorized motor acts initially require activation of the medialtemporal lobe• Corticalization of motor commands: practice → larger segments of an act necessary to achieve a goal become encoded within discrete areas of the premotor and parietal cortices (left parietal cortex) → much more limited activation of the cortex during highly skilled acts – medial temporal lobe is bypassed.• Within the diencephalon – dorsal medial nucleus and mamillary bodies: necessary for memory formation

◦ damaged in thiamine deficiency states – korsakoff'ssyndrome◦ korsakoff's syndrome: severe inability to form newmemories and a variable inability to to recall remotememories

• alzheimer's disease: degeneration of neurons and theirreplacement by senile plaques and neurofibrillary tangles.

◦ Cognitive decline – loss of synapses◦ Initially, parietal and temporal lobes are affected,relative sparing of frontal lobes◦ early symptoms: loss of memory – temporal lobefunction, impaired syntactical languagecomprehension and visuospatial oranization –parietal lobe function◦ late symptoms: personality changes – frontal lobefunctions• Pick's disease: cortical degeneration syndrome, first affects thefrontal lobe while sparing the temporal and parietal lobes.There are early disinhibition and impaired language expression(frontal dysfunction)• memory loss can also result from disorders of the subcorticalgray matter structures (basal ganglia & brainstem nuclei),diseases of the white matter or both.Language:• Broca's 1865: loss of fluent speech caused by a lesion in theleft inferior frontal lobe• wernicke's 1874: localization of language comprehension tothe left superior temporal lobe• language demonstrates hemispheric localization of function,the hemisphere dominant for language also directs thedominant hand.• Innate tendency to lateralization of language in the lefthemisphere is highly associated with an asymmetry of theplanum temporale – traingular cortical patch on the superiorsurface of the temporal lobe, appears to harbor wernicke'sarea.• Mixed hemispheric dominance for language – absence of theexpected asymmetry of the planum temporale• language comprehension is processed in 3 levels:◦ phonological functioning – individual sounds such asvowels or consonants are recognizes in the inferiorgyrus of the frontal lobes, improves if:▪ lip reading is allowed▪ speech is slowed▪ contextual clues are provided◦ lexical processing – matches the phonological inputwith recognized words or sounds in the individual'smemory. Determines whether the sound is a word ornot. Left temporal lobe: representations of lexicaldata are organized according to semantic category◦ semantic processing – connects the words to theirmeaning. Activates the middle and and superior gyriof the left temporal lobe, whereas the representationof the conceptual content of words is widelydistributed in the cortex• language production: cortical semantic representations → lefttemporal lexical nodes → oromotor phonological processingarea (speech) or graphomotor system (writing)• perception of prosody and appreciation of “body language”requires an intact right hemisphere• developmental dyslexia: unexpected difficulty in learning in thecontext of adequate intelligence, motivation and education• inability to recognize phonemes has been shown to be the bestpredictor of reading disability◦ occipital lobe -identification of letters◦ inferior frontal lobe – phonological processing◦ superior and middle gyri of the left temporal lobe –semantic processing• developmental nonverbal learning disorder: right hemispheredysfunction. Characterized by poor fine motor control of the lefthand, deficits in visuoperceptual organization, problems withmathematics, and incomplete or disturbed socialization.• Music is represented predominantly in the right hemisphere,

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but full complexity of musical ability involves both hemispheres

Emotion:• derives from basic drives: feeding, sex, reproduction, pleasure, pain, fear, and aggression• drives centered in the limbic system• distinct human emotions: affectation, pride, guilt, pity, envy,and resentment – largely learned, most likely represented inthe cortex• frontal cortex: regulation of drives• left hemisphere: analytical mind, has limited emotionalrepertoire. Damage: produces intellectual disorder & loss ofnarrative aspect of dreams• Right hemisphere: dominant for affect, socialization and bodyimage. Damage: produces affective disorders, loss of visualaspect of dreams, and a failure to respond to humor, shadingsof metaphor, and connotations.• Anosognosia: denial of illness and of the ability to move the left hand in cases of right hemispheric injury.• Temporal lobe: exhibits a high frequency of epileptic foci andtemporal lobe epilepsy (TLE)

◦ proposed TLE personality – hyposexuality emotionalintensity perseverative approach to interactions(viscosity).◦ Left TLE - may generate references to personaldestiny and philosophical themes and may display ahumorless approach to life◦ Right TLE – may display excessive emotionality,ranging from elation to sadness◦ reverse TLE personality – bilateral injury of thetemporal lobes. Lesion resembles the one describedin kluver-bucy syndrome◦ Kluver-Bucy syndrome: hypersexuality, placidity,tendency to explore the environment with the mouth, inability to recognize the emotional significance of a visual stimuli and constantly shifting attention(hypermetamorphosis)

• Prefontal cortices influence mood in a complementary way.Activation of:

◦ left prefrontal cortex – lifts the mood. Lesion:depression, uncontrollable crying◦ right prefrontal cortex – causes depression. Lesion:laughter, euphoria, and witzelsucht (a tendency tojoke and make puns)

• Papez 1973: delineated the limbic system.• Papez circuit: hippocampus, fornix, mamillary bodies, anteriornucleus of the thalamus, cingulate gyrus• boundaries of limbic system was expanded to include:amygdala, septum, basal forebrain, nucleus accumbens, andorbitofrontal cortex.• Amygdala: improtant gate through which internal and externalstimuli are integrated. Damage: ablate the ability to distinguishfear and anger in other people's voices and facial expressions.But preserved ability to recognize happiness, sadness, ordisgust• Schizophrenia: affect, associations, ambivalence and autism.Has reduction in brain weight of the gray matter and may havereduced volume of the hippocampus, amygdala, andparahippocampal gyrus. May have selective reduction infrontal lobe activity.

Frontal lobe function• region that determines how the brain acts on its knowledge,constitute a category unto themselves.

Four subdivisions:◦ first 3: motor strip, supplemental motor area, andbroca's area◦ 4th, most anterior division – prefrontal cortex

3 regions of the prefrontal cortex:◦ orbitofrontal◦ dorsolateral◦ medial

• frontal lobe injury impairs the executive functions: motivation,attention, and sequencing of actions• bilateral frontal lobe lesions: changes in personality – howpeople interact with the world• Frontal lobe syndrome: slowed thinking, poor judgement,decreased curiosity, social withdrawal, and irritability.• Specific prefrontal lobe syndromes

Orbitofrontal region:• causes disinhibition, irritability, lability, euphoria, and lack ofremorse.• Insight and judgement are impaired; patients are distractable• features are similar to: antisocial personality disorder,intermittent explosive disorder, and episodic dyscontrolsyndrome• may produce a state of “pseudopsychopathy”

Dorsolateral region:• executive headquarters of the brain• lesions may lead to: deficiencies of planning, monitoring,flexibility, and motivation.• Patients may be unable to use foresight, and feedback tomaintain goal directedness, focus and sustained effort• appears inattentive and undermotivated, cannot plan novelcognitive activity, exhibits tendency to linger on a trivial thought• may also produce mood disorders

Medial region:• ablation of this region may produce profound apathy,characterized by limited spontaneous movement, gesture, andspeech• extreme: state of akinetic mutism, without any initiation ofactivity at all

Development• nervous system: CNS and PNS• CNS: Brain and spinal cord• PNS: all sensory, motor, and autonomic fibers and gangliaoutside the CNS• development: both CNS and PNS arise form a commonprecursor – neural tube ← folding of neural plate ← ectoderm• embryonic development:

◦ neural tube itself → CNS◦ ectoderm immediately superficial to the neural tube→ neural crest → PNS

Central Nervous System• life cycle of a neuron: cell birth → migration to the adult position→ extension of an axon → elaboration of dendrites →synaptogenesis → onset of chemical neurotransmission1.Individual neurons are born in proliferative zones locatedalong the inner surface of the neural tube• peak of neuronal proliferation: middle of 2nd trimester. 250000neurons born each minute.2. First 6 mos of gestation: glial - guided (astrocytic glial fibers) neuronal migration in the cerebral cortex• heterotopia – group of incorrectly placed neurons . Fails toreach the cortex and reside in ectopic positions. Causesepilepsy and highly associated with mental retardation• many neurons lay an axon down as they migrate, while others do not initiate axon outgrowth until they have reached their cortical targets• axons subsequently detach from the subplate neurons andproceed superficially to synapse on the true cortical cells,

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subplate neurons then degenerate3.Synaptogenesis occurs at a furious rate from the 2ndtrimester through the first 10 years of life.• Peak of synaptogenesis occurs within the first 2 postnatalyears: as many as 30 million synapses form each second• ensheathment of axons by myelin begins prenatally; largelycomplete in early childhood but does not reach its full extentuntil the 30's4.Onset of chemical neurotansmission

Neurophysiology and Neurochemistry• An important determinant of the quality of thought is theefficiency of the information processing by individual neurons• Single neurons communicate by:

◦ interpreting their chemical environment◦ instantly changing chemical cues to electrical activityfor transport down axons◦ efficiently translating the electrical data into finelymodulated secreteable chemical emissions withwhich to influence other neuronal or nonneuronalcells

• Electrical impulses facilitate instantaneous responses• Chemical mileu – important to the maintenance of fidelity of the brain's image of the world

• BASIC ELECTROPHYSIOLOGY• Membranes and Charge• Resting state: intracellular (-), extracellular (+)• charge gradient is maintained across the hydrophobic plasmamembrane:

◦ semipermeable, lipid bilayer with embeddedcholesterol molecules and numerous proteins (ionpumps, ion channels, neurotransmitter receptors)

• Ion pumps and ion channels maintain gradient of cations:◦ potassium ions: 15 – 20 times more concentratedinside neurons◦ sodium ions: 8 – 15 times less concentrated insideneurons

• Principal ion pump: Na-K ATPase exchange pump• Principal ion channels: Na, K, Ca, Cl• hydrophobic neuronal membrane isolates positive andnegative ions• charge can be released when channels• open allowing the passage of ions through the membrane• electrical potential follows the equations of Ohm's Law: E=IR

◦ E: transmembrane potential◦ I: current◦ R: resistance

• Ion Channels• Protein pores that allow the flow of ions unimpeded throughthe membrane and cause changes in membrane potential• selective for specific ions• glycoproteins• resting state: closed• opens in response to:

◦ binding of ligands into receptors: ligand – gated ionchannels◦ changes in membrane potential: voltage – gated ionchannels

• Ligand-gated ion channels• 3 general types:

◦ direct-coupled: neurotransmitter acts directly◦ G protein coupled: neurotransmitter → receptorprotein → activates G protein → activates ionchannels◦ second-messenger-coupled: activated by a secondmessenger product of some physically removedreceptor

• Ligands:◦ excitatory neurotransmitters – opens cation channels that depolarize the membrane and increase likelihood of the generation of an action potential eicit EPSP.◦ Inhibitory neurotransmitters – open chloride channels that hyperpolarize the membrane and decrease the likelihood of an action potential. Elicits IPSP.

▪ CNS Ca channel blockers – treatment of bipolar disorder▪ Dantrolene – skeletal muscle Ca channel blocker, treatment of Neuroleptic malignant sydnrome

• Action Potentials (AP):• resting, intracellular: -70 to -80 mV• action potential:• brief (0.1 to 2 ms) wave of reversal of membrane potential that moves along an axon• ligand-gated ion channels open → sodium enters the cell →inner surface of the membrane less negatively charged relativeto the outside → opening of voltage-gated Na channels →inward flow of Na (+ charge inside) → depolarization ofmembrane and initiation of (AP)• spike threshold – the point at which the interior of themembrane is sufficiently less negatively charged to cause theopening of Na channels. Approx. -55mV• ion channels:

◦ initial: Na channels, makes the interior (+) charged◦ then, Ca2+ channels open, further contributes to thespike of action potential. Also activates ion channelsthat carry an outgoing flow of K+ ions

• afterhyperpolarization: result of activation of K+, inside of themembrane is more negatively charged than baseline.Contributes to the refractory period. Another action potentialcannot be generated during this period.• Rate of local spread of an action potential determines the rateof conduction of the impulse along the nerve.• Myelin sheaths – highly hydrophobic substance that completely prevents passage of ions. Reduces the number of times the AP must trigger neighboring voltage-gated ion channels in order to conduct an impulse along that distance of axon.• Nodes of ranvier – gaps of bare axonal membrane, separatesmyelin sheaths.• AP at nodes of ranvier → AP jumps over myelin segment →next node of ranvier• Transmission of the AP into chemical Neurontransmission:• At synaptic terminus of the axon, AP triggers the release ofneurotransmitters into the synaptic cleft → may act on otherneurons or muscles.• Presynaptic nerve terminals contain voltage-gated Ca channels → locally raise intracellular Ca → cascade of protein-protein and protein- lipid interactions → neurotransmittercontainingsynaptic vesicles fuse with presynaptic membrane→ release contents into synaptic cleft• in muscles: AP → opens voltage-gated Ca channels → triggers the movement of myosin on actin fibers (excitation –contraction coupling)

• SYNAPSES• All or none phenomenon: once an action potential has beentriggered, it is propagated at full strength for the entire length ofthe axon• axon hillock – originates AP, acted upon by excitatory andinhibitory influences• synapse – site at which stimuli are given and received and

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where the finest shadings of neuronal activity are negotiated• components of the synapse:

◦ axon terminal of the presynaptic neuron◦ synaptic cleft◦ dendrite of the postsynaptic neuron

• AP in presynaptic neuron → AP moves down the axon → axon terminal or to other functionally similar regions of the axons (axonal varicosities) → AP causes the release ofneurotransmitter (NT) molecules into the synaptic cleft → NTmolecules diffuse across the synaptic cleft → binds to theirspecific receptors on the external membrane of the dendrite ofthe post synaptic neuron• types: depending on the location of the termination

◦ axosomatic – postsynaptic neuronal cell body◦ axoaxonic – axon◦ axodentritic – dendrite

• gap junctions – electrical synapses that allow the directtransfer of ions between 2 neurons as a form of intraneuronalneurochemical communication• cojoint synapses – have both electrical and chemicalcharacteristics• Only synapses of functional relevance survive into adulthood.• Adult synaptic relationships are constantly remodeled throughincreases and decreases in the size and strength of individualsynapses, also formation of new synapses and elimination ofunnecessary synapses.• Mechanical adhesive properties: mediated by variouscombinations of Ca-dependent cadherin family of adhesionmolecules• Changes in structure: mediated by growth factors – acts onspecific receptors to regulate protein-protein interactions andto modify levels of gene expression• N-methyl-D-aspartate (NMDA) glutamate receptors: essentialto certain forms of long term potentiation (LTP) in w/ccoordinated neuronal activity strengthens certain synapses.• LTP – proposed to be cellular correlate of long term memory• Presynaptic Components• contains the synthetic machinery responsible for the synthesis of all NT except peptide NT, which are synthesizes in the cell body• NT synthesis stimulated by:

◦ influx of Ca ions◦ variations in levels of the 2nd messenger cAMP◦ changes in levels of circulating hormones.

• Once synthesized, NT is packaged into synaptic vesicles (may store a mixture of amine and peptide NT)• Mitochondria: provide energy for synthesis, storage, releaseand degradation of NT• presynaptic membrane contains: ion channels – trigger vesicle release, NT receptors – mediates feedback inhibition of NT synthesis and release, NT transporters – take NT up from the synaptic cleft for recycling or degradation.• NT storage vesicles in the presynaptic terminal fuse with thepresynaptic membrane and release their component into thesynaptic cleft: Exocytosis

◦ Synapsins and Rab3: control the localization ofvesicles◦ synaptotagmin and synaptobrevin: components ofthe vesicle membrane◦ neurexins and syntaxins: components of the plasmamembrane, mediate the fusion of the inner surface ofthe presynaptic membrane◦ synaptophysins: aids in the creation of a pore in thepresynaptic membrane

• Once a monoamine NT such as norE, dopamine, or serotoninhas been released into the synaptic cleft, it acts until it diffusesaway, or moved by reuptake mechanisms• specific presynaptic transmembrane transporter moleculesreturn free monoamine NT to the nerve terminal where they

are:◦ repackaged into vesicles for release in response tosubsequent AP◦ degraded into monoamine oxidases (MAOs)

• transporters – sites of major mechanism of actions of boththerapeutic and illicit drugs

◦ Tricyclic antidepressants – inhibits norE andserotonin reuptake mechanisms◦ Selective serotonin reuptake inhibitors (SSRIs) –detects the inhibition of monoamine reuptakethrough transporters◦ Cocaine – blocks all 3 monoamine transporters

• degradation of recycled biogenic amine NT is principallymediated by MAOs attached to the outer mitochondrialmembrane.• MAOA – metabolizes norE and serotonin• MAOB – metabolizes dopamine• Synapse• synaptic compartment: the space between the pre andpostsynaptic membranes. Contains a mixture of NT with thegreatest influence on thought and behavior• NT are available to act on specific receptors and to initiate orinhibit the generation of AP on postsynaptic cell

◦ amino acids: glutamate, GABA, glycine, aspartate,homocysteate◦ biogenic amines: norE, serotonin, dopamine, epi,acetylcholine, histamine◦ neuropeptides: vasopressin, oxytocin, enkephalins,endorphins, substance P, neurontensin, etc..◦ nucleotides: adenosine, cAMP◦ gases: NO, CO, NH3, prostaglandin

• synaptic cleft of cholinergic synapses harbours acetylcholinesterase, which inactivates aCh by cleaving it intoacetate and choline• concentrations of NT are in the synaptic left regulated by

◦ feedback inhibition of transmitter release◦ reuptake into the presynaptic terminal by transporter

molecules• Postsynaptic Components• Receptors – sites of action of many of the psychotherapeuticand psychoactive drugs• function: alter the electrical transmembrane potential - eitherto increase or to decrease the likelihood of triggering an AP• once the threshold of the action potential is reached at theaxon hillock, the all-or-none action potential is initiated by theopening of voltage-gated Na channels – there virtually nochance for modification of the impulse• response to a constant NT:

◦ supersensitivity – greater than usual◦ subsenisitivity – less than usual

• sensitivity of a receptor may be due to:◦ number of receptors present◦ affinity of the receptor for the NT◦ efficiency with which the binding of the NT to thereceptor is translated into an intraneuronal msg.

• 2 types of NT receptors:◦ seven-transmembrane-domain receptors: requires Gproteins to open channels.◦ ligand-gated ion channels: the channels is anintegral part of the complex that binds the ligand

• intracytoplasmic loop◦ 1st-smallest◦ 2nd- fairly large◦ 3rd- largest

• tyrosine kinase receptors – does not cause changes inmembrane potential. Has extracellular ligand-bindingcomponent, single transmembrane domain, and intracellulartyrosine kinase – which phosphorylates both itself and other

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cytoplasmic proteins → triggers a cascade of intracellularphosphorylations → changes in gene expression.• Tyrosine kinase receptors bind growth factors and mediate the plasticity of synaptic associations

◦ Nerve growth factor (NGF)◦ Brain-derived neurotropic factor (BDNF)

• Postsynaptic cells are also regulated by circulating hormones(thyroid hormone, steroids) – hormones diffuse through themembrane → bind to cytoplasmic receptors → translocated into the nucleus → regulate gene expression

G Proteins -family of guanisine triphosphate (GTP)-binding proteins withsimilar structures -interact with members of the very large family of seven transmembrane-domain receptors of w/c the adrenergic receptor is a prototype -consist of 3 smaller proteins, alpha, beta and gamma subunits -when an intact G protein binds to a receptor, the receptorassumes a state w/ a high affinity for the neurotransmittermolecule, triggering the replacement of GDP with GTP on thealpha subunit, thereby destabilizing the associations among the neurotransmitter, the receptor and the G protein -GTP associated alpha subunit is the active fragment involved in activating or inhibiting a particular effector molecule -alpha subunit has the ability to convert GTP to GDP -activity of GTP-associated alpha subunit is stopped when GTP is converted to GDPa) alphas subunit-stimulation of adenyl cyclase activityb)alpha1 subunit-inhibition of adenyl cyclase activityc)alphao subunit-stimulation of phosphoinositol 2nd messengersystem

SECOND MESSENGERS1. Cyclic Nucleotides (cAMP and cGMP)*cAMP-produced from ATP by the enzyme adenyl cyclase-binds to CREBPa) Gs protein-stinulates activity of adenyl cyclaseb) G1 Protein-inhibits the activity of adenyl cyclase

2. Calcium (IP3 and DAG)-stimulates formation of NO and may trigger excitotoxic cellular damage

3. Phosphoinositol Metabolites-receptor-activated enzyme phospholipase C convertsmembrane lipid (phosphatidylinjositol 4,5-biphosphate) into IP3and DAGa) IP3- cause the release of calcium from intraneuronal storesb) DAG-activate a specific protein kinase4. Eicosanoids6. Gases7. JAK-STAT-receptor for cytokines

Protein Kinases- catalyze the transfer of the terminal phosphate group of ATPonto protein moleculesTyrosine kinases-activated by growth factors binding to specifictransmembrane receptors*lithium therapy has been shown to reduce the activity of protein kinase in concert with its salutary effects on bipolar disorder

NEUROTRANSMITTERSCriteria1. The Molecule is synthesized in the neuron2. The molecule is present in the presynaptic neuron and is

released on depolarization in physiologically significant amounts.3. When administered exogenously as a drug, the exogenousmolecule mimics the effects of the endogenous neurotransmitter.4. A mechanism in the neurons or the synaptic cleft acts toremove or deactivate the neurotransmitter

3. Major Types1. Biogenic amines -the best known and most understoodneurotransmitters because they were the first to be discovered -constitute the neurotransmitter substance in only a smallpercentage of neurons - synthesized in a discrete nucleus of neurons from which axons project widely throughout the brain and spinal cord - exert a disproportionate influence on the activity of the brain,and they are of central importance to the pharmacological therapy of thought, mood, and anxiety disorders

*Dopamine, norepinephrine, and epinephrine are products of the catecholamine synthetic pathway

*Serotonin, acetylcholine, and histamine are derived from distinct precursors

2. Amino acids- late to be discovered- present in upward of 70 percent of neurons- two major amino acid neurotransmitters are GABA andglutamateGABA- inhibitory amino acidGlutamate-excitatory amino acid

3. Peptides -As many as 300 peptide neurotransmitters may be in the human brain- short protein consisting of fewer than 100 amino acids-made in the neuronal cell body by the transcription andtranslation of a genetic message-stored in synaptic vesicles and are released from the axonterminals-activity is terminated by the action of enzymes, peptidases,which cleave the peptides between specific amino acid residues

BIOGENIC AMINESa) Dopamine*Primary and alternative pathways for the formation ofcatecholamines:(1) tyrosine hydroxylase(2) aromatic amino acid decarboxylase(3) dopamine-I2-hydroxylase(4) phenylethanolamine-N-methyltransferase(5) nonspecific N-methyltransferase in lung and folate-dependentN-methyltransferase in brain(6) catechol-forming enzyme

**actions of dopamine are terminated by 2 general routes1. can be taken back up into the presynaptic neuron and recycled as a neurotransmitter( reuptake mechanism)- Reuptake occurs by the passage of the dopamine molecule from the synaptic space, through the presynaptic dopamine transporter, into the intracellular space, where it is packaged into vesicles

2. dopamine can be metabolized- 2 major enzymes involved are monoamine oxidase (MAO) and, less importantly, catechol-O-methyltransferase (COMT)a) MAO is localized on the outer mitochondrial membrane,

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principally in the presynaptic terminal, where it acts on dopamine that has been taken up into the presynaptic terminal but not yetrepackaged into vesiclesb) COMT is a soluble enzyme localized in the cytoplasm of thepostsynaptic cell and of glial cells and, possibly also, extracellularly

Dopamine Receptors*D1 and D5 receptors-stimulate the formulation of cAMP byactivating the stimulatory G protein, Gs*D2, D3, and D4 receptorsD2 receptor-inhibits the formation of cAMP by activating theinhibitory G protein, Gi, and some data indicate that the D3 and D4 receptors act similarly-prominent in the striatum (caudate nucleus and putamen)D3 receptor-concentrated in the nucleus accumbensD4 receptor-concentrated in the frontal cortex**D2 receptors-associated with a greatly reduced risk ofdevelopment of parkinsonian side effects and tardive dyskinesia-not only do they treat the positive symptoms of schizophrenia,effectively treated by pure D2 receptor antagonists (psychosis,hallucinations, agitation), they also improve the negativesymptoms of schizophrenia (blunted affect, ambivalence,catatonia)*Amphetamines cause the release of dopamine, and cocaineblocks the uptake of dopamine- increase the amount of dopamine present in the synapse*Cocaine and methamphetamine (Desoxyn) are among the most addicting substances*dopaminergic systems may be particularly involved in the brain's so-called reward or pleasure-seeking system, and this involvement may explain the high addiction potential of cocaine* dopamine transporter can be blocked by bupropion (Wellbutrin)- transporter is the portal of entry of the neurotoxinmethylphenyltetrahydropyridine (MPTP), which may causeparkinsonism by killing the nigral dopaminergic neurons

Dopamine and PsychopathologyDopamine may be involved in:a)mood disordersb) depression and high in maniac) schizophrenia

3 Most Important Dopaminergic Tracts1. nigrostriatal tract- projects from its cell bodies in the substantia nigra to the corpus striatum-when the D2 receptors at the end of this tract are blocked byclassic antipsychotic drugs, Parkinsonian side effects emerge- In Parkinson's disease the nigrostriatal tract degenerates,resulting in the motor symptoms of the disease- may somehow be involved with the control of mood

2. mesolimbic-mesocortical tract- projects from its cell bodies in the ventral tegmental area (VTA), which lies adjacent to the substantia nigra, to most areas of the cerebral cortex, and to the limbic system - tract may be involved in mediating the antipsychotic effectsof antipsychotic drugs

3. tuberoinfundibular tract- cell bodies of the are in the arcuate nucleus and the periventricular area of the hypothalamus, project to the infundibulum and the anterior pituitary- dopamine acts as a release-inhibiting factor in the tract byinhibiting the release of prolactin from the anterior pituitary

-patients who take dopamine receptor antagonists often haveroughly threefold elevated prolactin levels because theblockade of dopamine receptors in the tract eliminates theinhibitory effect of dopamine

b) Norepinephrine and Epinephrine-catecholamines- norepinephrine system and the epinephrine system are alsoreferred to as the noradrenergic system and the adrenergicsystem, respectively.-receptors are referred to simply as adrenergic receptors* major concentration of noradrenergic (and adrenergic) cellbodies that project upward in the brain is in the compact locusceruleus in the pons-axons of these neurons project through the medial forebrainbundle to the cerebral cortex, the limbic system, thethalamus, and the hypothalamus*catecholamines are synthesized from tyrosine, and the rate limiting enzyme is tyrosine hydroxylase-In neurons that release norepinephrine, the enzyme dopamine β-hydroxylase converts dopamine to norepinephrine-neurons that release dopamine lack this enzyme- In neurons that release epinephrine, the enzymephenylethanolamine-N-methyltransferase (PNMT) convertsnorepinephrine into epinephrine*Neurons that release either dopamine or norepinephrine do not have PNMTpsychiatric drugs that are most associated with norepinephrine:· classic antidepressant drugs· tricyclic drugs· MAO inhibitors (MAOIs)· venlafaxine (Effexor), mirtazapine (Remeron), bupropion, and nefazodone (Serzone)*tricyclic drugs, venlafaxine, bupropion, and nefazodone, block the reuptake of norepinephrine (and serotonin) into the presynaptic neuron, and the MAOIs block the catabolism of norepinephrine (and serotonin)

Norepinephrine and Psychopathology-biogenic amine hypothesis of mood disorders was based on the observation that the tricyclic drugs and the MAOIs are effective in alleviating the symptoms of depression

c) Serotoninmajor site of serotonergic cell bodies*upper pons and the midbrain specifically, the median and dorsal raphe nuclei and, to a lesser extent, the caudal locus ceruleus, the area postrema, and the interpeduncular area-these neurons project to the basal ganglia, the limbic system, and the cerebral cortex

Serotonin and Drugs-tricyclic drugs and the MAOIs, respectively, block the uptake and the metabolism of serotonin and norepinephrine, thus increasing the concentration of both neurotransmitters in the synaptic cleft-Fluoxetine is one of the selective serotonin reuptake inhibitors (SSRIs) that are used in the treatment of depression-Other drugs in that class include paroxetine (Paxil), sertraline(Zoloft), fluvoxamine (Luvox), and citalopram (Celexa), all of which are usually associated with minimal adverse effects, especially in comparison with the tricyclic drugs and the MAOIs

Serotonin and Psychopathology*principal association of serotonin is with depression, assuggested in the biogenic amine hypothesis of mood disorders

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-this hypothesis is simply that depression is associated with too little serotonin and that mania is associated with too muchserotonin* permissive hypothesis postulates that low levels of serotonin permit abnormal levels of norepinephrine to cause depression or mania

PEPTIDE NEUROTRANSMITTERSa) Endogenous Opiods- analgesic and psychological effects

b) Substance P- primary neurotransmitter in most primary afferent sensory neurons and in the striatonigral pathway -most prominently associated with mediation of the perception of pain.-Abnormalities affecting substance P have been hypothesized for Huntington's disease, dementia of the Alzheimer's type, and mood disorders

c) Neurotensin- involved in the pathophysiology ofschizophrenia, mostly because of its coexistence with dopamine in some axon terminals-preliminary reports suggest that neurotensin-related peptides or drugs have beneficial effects for some psychotic symptoms

d) Cholecystokinin- involved in the pathophysiology of schizophrenia. CCK has also been implicated in the pathophysiologies of eating disorders and movement disorders-causes anxiety and triggers panic attacks in people with panicdisorder

e) Somatostatin- also known as growth hormone-inhibiting factor-implicated in Huntington's disease and dementia of theAlzheimer's type

f) Vasopressin and Oxytocin- involved in the regulation of mood and most recently, social behaviour are both synthesized in the hypothalamus and are released inthe posterior pituitary

g) Neuropeptide Y- stimulate the appetite, and development of neuropeptide Y receptor antagonists is an active area of interest for obesity researchers

AMINO ACID NEUROTRANSMITTERSa) Glycine- synthesized primarily from serine by the actions ofserine trans-hydroxymethylase and I2-glycerate dehydrogenase, both of which are rate limiting

b) Histamine- Neurons that release histamine as theirneurotransmitter are located in the hypothalamus and project to the cerebral cortex, the limbic system, and the thalamus- H1-receptor stimulation increases the production of IP3 and DAG-H2 stimulation increases the production of cAMP-H3 receptor may regulate vascular tone*blockade of H1 receptors is the mechanism of action for allergy medications and is partly the mechanism for commonly observed side effects (e.g., sedation, weight gain, and hypotension) of some psychotropic drugs

c) AcetylcholineCNS Cholinergic Tracts-group of cholinergic neurons in the nucleus basalis of Meynertprojects to the cerebral cortex and the limbic system-additional cholinergic neurons in the reticular system project tothe cerebral cortex, the limbic system, the hypothalamus, and the thalamus

*Some patients with dementia of the Alzheimer's type or Downsyndrome appear to have specific degeneration of the neurons in the nucleus basalis of Meynert

Cholinergic Receptorsa) Muscarinic- antagonized by atropine and by theanticholinergic drugsb) Nicotinic- ligand-gated ion channels that havethe receptor site directly on the ion channel itself* most common use of anticholinergic drugs in psychiatry is intreatment of the motor abnormalities caused by the use ofclassic antipsychotic drugs (e.g., haloperidol)* Drugs that increase cholinergic activity by blocking breakdownby acetylcholinesterase (e.g., donepezil [Aricept]) have beenshown to be effective in the treatment of dementia of theAlzheimer's type

Acetylcholine and Psychopathology*most common association with acetylcholine is dementia of the Alzheimer's type and other dementias

d) GABA- found almost exclusively in the CNS, and it does notcross the blood-brain barrier- highest concentrations in the midbrain and diencephalon, withlower amounts in the cerebral hemispheres, the pons, and themedulla-synthesized from glutamate by the rate-limiting enzyme glutamic acid decarboxylase (GAD), which requires pyridoxine (vitamin B6) as a cofactor-primary neurotransmitter in intrinsic neurons that function as local mediators for the inhibitory feedback loops-commonly coexists with biogenic amine neurotransmitters,glycine, and peptide neurotransmitters, including somatostatin,NPY, CCK, substance P, and vasoactive intestinal peptide (VIP)* thought to suppress seizure activity, anxiety, and mania,considerable effort has been devoted to synthesizing drugs that potentiate GABA activity** focused on its potential role in the pathophysiology of anxietydisorders

e) Glutamate- synthesized from glucose and glutamine inpresynaptic neuron terminals and is stored in synaptic vesicles- primary neurotransmitter in cerebellar granule cells, the striatum,the cells of the hippocampal molecular layer and entorhinal cortex, the pyramidal cells of the cortex, and the thalamocortical andcorticostriatal projections-release is stimulated by nicotine** major pathophysiological conditions currently associated withthe glutamate systems are excitotoxicity and schizophrenia**Excitotoxicity relates to the hypothesis that excessive stimulationof glutamate receptors leads to prolonged and excessiveintraneuronal concentrations of calcium and NO

f) other neurotransmitters1) NUCLEOTIDES

- purine adenosine inhibits the release of other neurotransmitters and ATP

2) NEUROTROPHIC FACTORS - growth factors that allow neurons to regenerate their axon - bind to the tyrosine kinase receptors

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- release happen during unstimulated resting conditions - NGF (Nerve Growth Factor): is the most widely-known - CNTF (Ciliary Neurotrophic Factor) - GDNF (Glial Cell-line Neurotrophic Factor) - IGF (Insulin Growth Factor)

3) GASES - Nitric Oxide: acts as both intraneuronal second messenger and neurotransmitter; excessive exposure to glutamate shall cause NO to be metabolized to toxic free radicals which may injure or kill cells through excitotoxicity

4) EICOSANOIDS - metabolites of arachidonic acid, prostaglandins, prostacyclins, thromboxane, and leukotrienes

5) ENDOCANNABINOIDS - cannabinoids: active ingredients in marijuana - anandamides: generally exhibit pharmacological effects that are less potent (lowering intraocular pressure, decreasing activity level, and relieving pain)

6) SIGMA RECEPTORS - receptor site binds pentazocine (Talwin) and haloperidol

Chemical neurotransmission -process involving the release of a neurotransmitter by one neuron and the binding of theneurotransmitter molecule to a receptor on another neuron.

affected by most drugs used in psychiatry Older antipsychotics, (not the serotonindopamineantagonists)-believed to exert their effects mainly by blockingdopamine type 2 (D2) receptors antidepressants-increase the amount of serotonin or norepinephrine, orboth, in the synaptic cleft benzodiazepine anxiolytics- exert their effects on the GABAA receptors that arelinked to chloride ion channels

Neuromodulators- modulates the response of a neuron to a neurotransmitter- modulatory effect may be present for a longer time- substance may have an effect on a neuron over a long periodof time, and that effect may be more involved with fine tuning thanwith activating or directly inhibiting the generation of an actionpotential

Neurohormone- released into the bloodstream rather than into theextraneuronal space in the brain-once in the bloodstream, the neurohormone can then diffuseinto the extraneuronal space and have its effects on neurons

NEUROGENETICS

alterations in gene expression - occur both during development and in adulthood and may be the bases for: (1) abnormal and normal development, and (2) for abnormal and normal adaptation to stress normal affective, cognitive, and behavioral processes that are disturbed in different psychiatric disorders - arise because of specific patterns of activation in networks of neurons that are distributed through the

central nervous system → patterns of activation: mediated by the connections among specific brain structures

every function of the human brain is a consequence of the activity of specific neural circuits - circuits form as a result of several developmental processes

In early development, some axons initially produce an excessive number of axon branches or collaterals and thus contact a broader set of targets than are present in the adult brain.

During later part of the development, the connections of particular neurons are focused by the pruning or elimination of axonal projections to inappropriate targets.

role of any brain region or group of neurons in the production of specific behaviors or in the pathophysiology of a given neuropsychiatric disorder - must be considered within the context of the neural circuits connecting those neurons with other brain regions

POPULATION GENETICS - provided some of the first objective data that mental illnesses were biological illnesses→helping to destigmatize these human conditions - application of molecular neurobiological tools: led to the ability to study specific genetic linkages among individuals and groups of individuals - application lead to the identification of a specific gene or genes as causative agents for specific mental disorders

PSYCHONEUROENDOCRINOLOGY - refers to the structural and functional relations between the hormonal system and the central nervous system (CNS) and the behaviors that modulate and arise from both

Endocrine disorders are frequently associated with secondary psychiatric symptoms (e.g. depression)

A significant percentage of patients suffering from psychiatric syndromes display regular patterns of endocrine dysfunction

The interactions b/w the neuroendocrine and central nervous sys.:

psychiatric symptoms that accompany some hormonal disorders (e.g., depression in Cushing's syndrome)

in the identification of disorders wherein neuroendocrine regulation is utilized as potential markers for state or trait variables in psychiatric conditions

Pathological alterations in hypothalamic-pituitary-adrenal function have been associated with mood disorders, posttraumatic stress disorder, Alzheimer’s dementia, substance use disorders

Insulin: depression common in DM Hypothalamic-Pituitary-Gonadal Axis

Testosterone: increased violence and aggression, mood improvement, sexual desire

Estrogen: mood enhancement Increased Prolactin: depression,

decreased libido, stress intolerance, anxiety, increased irritability

Hypothalamic-Pituitary-Thyroid axis Neuronal excitability, behaviour,

neurotransmitter regulation Hyperthyroidism: fatigue, irritability,

insomnia, anxiety, restlessness, weight

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loss, emotional lability, impairment in concentration and memory

Hypothyroidism: fatigue, decreased libido, memory impairment, irritability, suicidal ideation

II. PSYCHONEUROIMMUNOLOGY - nervous system and the immune system represent two networks within the body → each contains a massive diversity of cell types and uses a large pharmacopoeia of chemical signals

classical conditioning paradigms → associated with suppression or enhancement of the immune response

stressful life events → ↑ susceptibility to infectious diseases

academic/examination stress in medical students showed ↓ natural killer cell activity, T cells,

mitogen responses, interferon production, and impaired cellular immunity

altered CNS function results from a combination of: direct effects of an injurious event on

various cell types, and effects of inflammatory mediators on

neurons and supporting cells viral infection during neural development

-in some cases of schizophrenia immune activation

-may contribute to the pathophysiology of depression

III. BIOLOGICAL RHYTHMS and CHRONOBIOLOGY

circadian biological rhythms are set by both internal and external forces,

generally called zeitgebers (time givers, time clues, synchronizers)

zeitgebers principally emanating from pontine reticular

formation and suprachiasmatic nuclei of the hypothalamus

Phase advance or Phase delay Depression is the most commonly associated symptom in

biological rhythm disruption

CONCLUSION Understanding the neurobiological bases for psychiatric disorders requires an appreciation of the major principles governing the functional organization and connections in the human brain.

DOCTOR-PATIENT (PX) RELATIONSHIPPx are most tolerant of the therapeutic limitations of medicinewhen there is mutual respect between both parties.

Rapport- harmonious responsiveness that promotes the dev’t of a constructive therapeutic relationship- implies understanding and trust

Biopsychosocial model1) Biological system – the anatomical, structural and molecular substrates of disease and its effects on px’s biological functioning2) Psychological system – the effects of psychodynamic factors, motivation and personality on the experience of and reaction to illness

3) Social system – cultural, environmental, and familial influences on the expression and experience of illness

*The model does not treat medical illness as a direct result of a person’s psychological or sociocultural make up – instead promotes a more comprehensive understanding of dse and txt.

Beyond the Biopsychosocial modelThis model offers no guidance on when and which psychosocial factors are important – MD left with the impression that they must know everything about the px – will focus instead on physical pathology and the use of biological,physical interventions

ADVANTAGES DISADVANTAGES Applicable to chronic conditions

Not applicable to acute conditions

Provides a conceptual framework for disparate information

Not a template for practicing med or txting individual pxs

Reminds the MD that there can be more impt. Issues beyond purely biological

Can’t be a substitute for a relationship that reflects warmth, genuine concern and mutual trust

Spirituality – influences on a person’s mental and physical health Illness Behaviour- sick role, role that society ascribes

Models of interaction - Guides - One is not intrinsically superior over the other - May be used from all four for a single px visit - Difficulties most likely to arise w/ the MD who is rigidly fixed.

PATERNALISTIC MODEL - MD knows best - Px is expected to comply without question

INFORMATIVE MODEL - All available data is freely given but the choice is left wholly up to the px

INTERPRETIVE MODEL - MD who come to know their px better amd make recommendations that take into account the unique characteristics of the individual patient

DELIBERATIVE MODEL - MD act as a friend or counsellor

TRANSFERANCE AND COUNTERTRANSFERANCE - Originating in psychoanalytical theory

Transference - Unconsciously attributing to their MD aspects of important past relationship

COUNTERTRANSFERENCE - Is when MD unconsciously ascribes motives or attributes to px that comes from MD’s past relationships

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PSYCHIARTIRC VERSUS MEDICAL SURGICAL INTERVIEWS 3 FXNS of medical interview: 1) assess the nature of the problem 2) develop and maintain therapeutic relationship 3) communicate information and implement a txt These fxns are exactly the same as those psychiatric and

surgical interviews Also universal are predominant coping mechanisms, both

adaptive and maladaptive – must anticpated by the MD for tx to be effective

2 major technical goals of psychiatric interviews: 1) Recognition of the psychological determinants of behaviour 2) Symptom Classification

STRATEGIES IN DEV’T OF RAPPORT 1. putting pxs and interviewers at ease 2. finding px’s pain and expressing compassion 3. evaluating px’s insight and becoming an ally 4. showing expertise 5. establishing authority as physicians and therapists 6. balancing the roles of emphatic listener, expert and authority

BEGINNING THE INTERVIEW Provides a powerful first impression; can affect the way

the remainder of the interview proceedings.

THE INTERVIEW PROPER Content - topics or subjects Process - what occurs non verbally between doctor and patient

- what is happening in the interview beneath the surface - involves feelings and reactions that are unacknowledged or unconscious → body language, trivial remarks, and apparently casual aides

SPECIFIC TECHNIQUES Common Interview Techniques: 1. Establish rapport as early in the interview as possible. 2. Determine the patient’s chief complaint. 3. Use the chief complaint to develop a provisional differential diagnosis. 4. Rule the various diagnostic possibilities out or in by using focused and detailed questions. 5. Follow up on vague or obscure replies with enough persistence to accurately determine the answer to the question. 6. Let the patient talk freely enough to observe how tightly the thoughts are connected. 7. Use a mixture of open-ended and close-ended questions. 8. Don’t be afraid to ask about topics that you or the patient may find difficult or embarrassing. 9. Ask about suicidal thoughts. 10. Give the patient a chance to ask questions at the end of the interview. 11. Conclude the initial interview by conveying a sense of confidence and, if possible, of hope.

In an ideal interview: 1. Open-ended questioning 2. Becoming more specific 3. Closes with detailed direct questioning

1. Open-ended vs. Close-ended questions 2. Reflection MD repeats to the Px, in a supportive manner, something

that the Px has said 3. Facilitation

MD helps Px continue in the interview by providing both verbal and nonverbal cues that encourage Px to keep talking

4. Silence May be constructive and in certain situations, may allow

Px to contemplate, cry, or just sit in an accepting, supportive environment in which the MD makes it clear that not every moment must be filled with talk

5. Confrontation Meant to point out to a Px something that the MD thinks

the Px is not paying attention to, is missing, or is in some way denying

6. Clarification MD attempts to get details from Px about what they have

already said 7. Interpretation Used when a MD states something about the Px’s

behavior or thinking that the Px may not be aware of 8. Summation MD can take a moment and briefly summarize what a Px

has said thus far 9. Explanation MD explains treatment plans to Px in easily

understandable language and allow Px to respond and ask questions

10. Transition Allow MD to convey the idea that enough information has

been obtained on one subject, that MD’s 11. Self-Revelation Limited, discreet self-disclosure by MDs may be useful in

certain situations, and MDs should feel at ease and communicate a sense of self-comfort

12. Positive Reinforcement allows Px to feel comfortable telling the MD anything, even

about such things as noncompliance with Tx 13. Reassurance Truthful reassurance of a Px can lead to increased trust

and compliance and can be experienced as an empathic response of a concerned MD

14. Advice To be effective and to be perceived as empathic rather

than inappropriate or intrusive, the advice should be given only after Px are allowed to talk freely about their problems so that MDs can have adequate information based from which to make suggestions

15. Ending the Interview MDs want Pxs to leave an interview feeling understood

and respected and believing that all the pertinent and important info has been conveyed to an informed, empathic listener

COMPLIANCE Also known as adherence Degree to which a Px carries out the clinical

recommendations of a treating MD Compliance increases when:

MD has characteristics as enthusiasm and nonpunitive attitude

Px have older doctors with more experience

Increased amount of time spent talking to the Px

Short waiting room time Increased frequency of visits

Other strategies to improve compliance include asking the Px:

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To describe what they believe is wrong with them and what should be done

What they understand to be the reaons for the MD’s recommendations

What they see as the risks and benefits of following prescribed Tx

Common errors of Pxs: not taking medications for as long as

they should

not taking the proper amount of their medication each day

it would be helpful to print the instructions on a piece of paper and ask the Px to read them back

ask the Px specifically and in what amounts the medication is to be taken

Some Px deliberately change the Tx regimen not showing up for appointments taking medications in a manner different

from the recommended MD must negotiate a compromise with the Px They must specify together what they can expect

from each other

Some factors in Px compliance issues: MD-Px relationship or MD-Px match

One of the most important factors Compliance decreases when MD and Px have

different priorities and beliefs, different styles of communication, and different medical expectations

Compliance increases when MD explains to the Px the value of a particular Tx outcome, and emphasizes that following the recommendation will produce this outcome; also when Px know the names and effects of each drug they are taking

Px’s subjective feelings of distress or illness as opposed to MD’s often objective medical estimates of the disease and required therapy

Px who believe they are ill tend toward compliance

Asymptomatic Px are at greater risk for noncompliance

*Please refer to the table at the back for common reasons for noncompliance with medication

SPECIFIC ISSUES IN PSYCHIATRY

Fees MD must openly discuss payment of fees

Confidentiality Psychiatrists should discuss the extent and limitations of

confidentiality with Pxs so that Pxs are clear about what can and cannot remain confidential

The Px must give permission for the use of medical records:

who has access to the Px’s medical records

information required by insurance companies

degree to which the Px’s case will be used for teaching purposes

Supervision It is both commonplace and necessary for doctors in

training to receive supervision from experienced MDs

Missed Appointments and Length of Sessions The Px needs to be informed about the MD’s policies for

missed appointments and length of sessions The Px must know in advance to make an informed

decision about whether to accept the MD’s policy or choose another MD

Availability of Doctor Once a Px enters into a contract to receive care from a

particular MD, that MD is responsible for having a mechanism in place for providing emergency service outside scheduled appointment times

Follow-Up Pxs must be assured that regardless of what occurs in the

course of a particular MD-Px relationship, their care will be ongoing

Problem Patients and Special Interview Situations Problem Px: difficult to work with; engage in power

struggles, are demanding or uncooperative Histrionic Patients Have a dramatic, emotional, and impressionalistic style Dependent Patients Need an inordinate amount of attention and yet never

seem reassured Demanding Patients Have a difficult time delaying gratification and demand that

their discomfort be eliminated immediately Narcissistic Patients act as though they are superior to everyone around them

including the doctor Isolated Patients do not appear to need/want to make contact w/ other

people intimate contact with doctor is viewed with distaste some receive the pyschiatric diagnosis of schizoid

personality withdrawn, absorbed in a world of fantasy and unable to

talk about their feelings doctors should treat these px’s with much respect for their

privacy as possible and should not expect them to respond to the doctor’s concern in kind

Obsessive Patients orderly, punctual and so concerned with detail that they

often don’t see the larger picture Help-Rejecting Complainer appear to communicate only through a long litany of

complaints and disappointments Manipulative Patients have antisocial personality traits Patients from Different Cultures and Backgrounds difference in race, nationality, religion and other significant

cultural differnces bet the px & doctor can impair communication, interfere in establishing rapport, & harbor misunderstanding

Stresses on the Physician a) required for the practice of medicine: (1) vast amt of knowledge & skills, (2) capacity to balance compassionate concern with dispassionate objectivity, (3) wish to relieve pain w/ ability to make painful decisions, (4) desire to cure & control w/ an acceptance of one’s human limitations

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b) learning to balance this interrelated aspects of physician role is essential to allow the doctor to cope productively w/n daily work that involves illness, pain, sadness, suffering, & death c) lack of balance results to a physician feeling overwhelmed & depressed d) a sense of futility & failure can begin to permeate a physician’s attitude, setting the stage for frustration & anger w/ one’s profession, pxs, & self e) many people drawn to medicine are: perfectionistic, demanding of themselves, attentive to details – qualities are adaptive, probably necessary but need to be balance w/ self-knowledge, humility, humor, & kindness

Character & Qualities of the Physicians Imperturability Ability to maintain extreme calm

& steadiness Presence of Mind Self-control in an emergency or

embarrassing situation so that one can say or do the right thing

Clear Judgment Ability to make an informed opinion that is intelligible& free of ambiguity

Ability to Endure Frustration

Capacity to remain firm & deal w/ insecurity & dissatisfaction

Infinite Patience Unlimited ability to bear pain or trial calmly

Charity towards others To be generous & helpful, especially toward the needy & suffering

The search for absolute truth

To investigate facts & pursue reality

Composure Calmness of mind, bearing & appearance

Bravery Capacity to face or endure event w/ courage

Tenacity To be persistent in attaining goal or adhering to something valued

Idealism Forming standards & ideals & living under their influence

Equanimity Ability to handle stressful situations w/ an undisturbed, even temper

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