The mere mention of Psychiatry evokes an esoteric almost nonmedical aura but it is inevitable specially as we progress that we realize

the biological substrate which has always been there – the brain

The Brain and Behaviour

Joge Los Baños, MD

Functional Neuroanatomy
• Sensory System – process external stimuli • Association Units – integrates sensory input with internal drivers and emotional stimuli • Motor System – manipulates external environment

Sensory Systems
• Somatosensory
(light touch, pressure, pain, temperature, vibration, proprioception)

• • • •

Visual (see) Auditory (hear) Olfactory (smell) Gustatory (taste)

Two Paradigms on the formation of the final synaptic arrangement
1. Genetics and Experience / Nature and Nurture
– – Fiber projection arrangment organized by fixed and diffusible chemical cues modeling and remodeling on the basis of coordinated neural activity (activity-dependent formation of synaptic connectivity)

4.

Presence of highly specialized brain cells that respond exclusively to extremely specific stimuli (cellular localization of specific feature extraction) e.g. “grandmother cell”

Somatotropic organization of the Somatosensory System

Fiber Sorting after entry to spinal cord
1. Synapse within one or two spinal segments 2. Conscious perception of touch, temperature, pain, decussate on entry and ascend through spinothalamic tract
• • Lateral spinothalamic: localized, discrete, acute pain Medial spinothalamic and spinoreticulothalamic : diffuse, chronic pain

3. Conscious perception of touch, proprioception, vibration ascend without immediate decussation through the posterior columns

• All somatosensory fibers project to, and synapse in, the thalamus • The thalamic neurons preserve the somatotropic representation by projecting fibers to the somatosensory cortex

Somatotropic

map

Psychiatric implications
• Reciprocal connections in the somatosensory system specifically fibers that project from and to the thalamus and cortex serve to filter sensory input but in pathological states may underlie psychosomatic syndromes as conversion disorders.

Visual System

Central Visual Pathway
• Once the ganglion cell axons leave the retina, they travel through the optic nerve to the optic chiasm, a partial crossing of the axons. • At the optic chiasm the left and right visual worlds are separated. • After the chiasm, the fibers are called the optic tract. • The optic tract wraps around the cerebral peduncles of the midbrain to get to the lateral geniculate nucleus (LGN). • The LGN is really a part of the thalamus, and remember that nothing gets up to cortex without synapsing in thalamus first • Almost all of the optic tract axons, therefore, synapse in the LGN. • The remaining few branch off to synapse in nuclei of the midbrain: the superior colliculi and the pretectal area.

Central Visual Pathway
• The neurons in the LGN send their axons directly to V1 (primary visual cortex, striate cortex, area 17) via the optic radiations. • This highway of visual information courses through the white matter of the temporal and parietal lobes, and can be very vulnerable to strokes. • Once the axons reach V1, they terminate primarily in a single sub-layer of cortex. • As the signal is transmitted to upper layers of cortex, the information from the two eyes is mixed and binocular vision is created • but in yet another layer the two eyes are still entirely separate. Therefore, if you could label the inputs from a single eye, you would see little pillars of label which line up next to each other and form tiger stripes. These are the ocular dominance stripes. (stereoscopic localization)

Central Visual Pathway
• Primary visual cortex: lines of specific orientation • Secondary visual cortex: particular movements and angles • Inferior temporal Cortex (ITC): shape, form, and color • Posterior parietal Cortex: location, motion, and distance • Left ITC: facial features • Right ITC: complex shapes

Disorders of Visual Perception
• Prosopagnosia (inability to recognize faces) • Apperceptive Visual Agnosia
– (inability to identify and draw from visual cues)

• Associative Visual Agnosia
– (inability to name or use objects despite ability to use them)

• Color agnosia (inability to recognize color) • Color anomia (inability to name color) • Central achromatopsia
– (complete inability to perceive color)

• Anton’s syndrome (inability to acknowledge blindness) • Balint’s syndrome
– (optic ataixa, oculomotor apraxia, simultagnosia)

• Gertmann’s syndrome
– (agraphia, aclaculia, right-left disorientation, finger agnosia)

Auditory System

Auditory Pathway
• The auditory nerve carries the signal into the brainstem and synapses in the cochlear nucleus. • From the cochlear nucleus, auditory information is split into at least two streams • Auditory nerve fibers going to the ventral cochlear nucleus synapse on their target cells with preservation of the timing of the signal to the microsecond. • The ventral cochlear nucleus cells then project to a collection of nuclei in the medulla called the superior olive. • In the superior olive, the minute differences in the timing and loudness of the sound in each ear are compared, and from this you can determine the direction the sound came from. • The superior olive then projects up to the inferior colliculus via a fiber tract called the lateral lemniscus.

Auditory Pathway
• The second stream of information starts in the dorsal cochlear nucleus. • Unlike the exquisitely time-sensitive localization pathway, this stream analyzes the quality of sound. • The dorsal cochlear nucleus, with fairly complex circuitry, picks apart the tiny frequency differences which make "bet" sound different from "bat" and "debt". • This pathway projects directly to the inferior colliculus, also via the lateral lemniscus.

Summary of the Auditory Pathway
• Fibers from the cochlear nuclei and the superior olive (not the inferior) travel up the lateral lemniscus (not the medial) to the inferior colliculus (not the superior), and then to the medial geniculate (not the lateral) in the thalamus which projects to primary auditory cortex, located on the banks of the temporal lobes. • Try remembering the mnemonic, "S-L-I-M" .

Olfactory System
• The axons from all the thousands of cells expressing the same odor receptor converge in the olfactory bulb. Mitral cells in the olfactory bulb send the information about the individual features to other parts of the olfactory system in the brain, which puts together the features into a representation of the odor. • Since most odor molecules have many individual features, the combination of features gives the olfactory system a broad range of odors that it can detect. • Odor information is easily stored in long term memory and has strong connections to emotional memory. • This is possibly due to the olfactory system's close anatomical ties to the limbic system and hippocampus, areas of the brain that have long been known to be involved in emotion and place memory, respectively.

Olfactory Tract and Central Pathways
• Mitral cell axons project to the olfactory cortex via the olfactory tract. • Medial fibers of the tract contact the anterior olfactory nucleus and the septal area. • Some fibers project to the contralateral olfactory bulb via the anterior commissure. • Lateral fibers contact third-order neurons in the primary olfactory cortex (prepyriform and entorhinal areas) directly. • Third-order neurons send projections to the dorsomedial nucleus of the thalamus, the basal forebrain, and the limbic system.

Olfactory Tract and Central Pathways
• The thalamic connections are thought to serve as a conscious mechanism for odor perception, while the amygdala and the entorhinal area are limbic system components and may be involved in the affective components of olfaction. • Investigations of regional cerebral blood flow have demonstrated a significant increase in the amygdaloid nucleus with the introduction of a highly aversive odorant stimulus, and this has been associated with subjective perceived aversiveness.

Olfactory System
• Olfaction is tightly associated with sexual and reproductive responses. • The structures of higher olfactory processing in phylogenetically more primitive animals have evolved in humans into the limbic system, the center of the emotional brain and the gate through which experience is admitted into memory according to emotional significance.

Gustatory
• Discriminate only broad classes of stimuli • Detection and discrimination of foods involve a combination of other senses

Autonomic Sensory System
Unconscious monitoring of basic functions necessary for life: visceral organ activity, blood pressure, cardiac output, blood glucose levels, body temperature

Motor Systems
• Basal Ganglia • Cerebellum • Motor Cortex

Basal Ganglia and Cerebellum

• The basal ganglia and cerebellum are large collections of nuclei that modify movement on a minute-to-minute basis. • Motor cortex sends information to both, and both structures send information right back to cortex via the thalamus. • The output of the cerebellum is excitatory, while the basal ganglia are inhibitory. • The balance between these two systems allows for smooth, coordinated movement, and a disturbance in either system will show up as movement disorders.

Basal ganglia

Basal Ganglia
• a collection of nuclei deep to the white matter of cerebral cortex. • The name includes: caudate, putamen, nucleus accumbens, globus pallidus, substantia nigra, subthalamic nucleus, and historically the claustrum and the amygdala.

Basal Ganglia functions and connections
• The caudate and putamen receive most of the input from cerebral cortex; in this sense they are the doorway into the basal ganglia. • There are some regional differences: for example, medial caudate and nucleus accumbens receive their input from frontal cortex and limbic areas, and are implicated more in thinking and schizophrenia than in moving and motion disorders. • The caudate and putamen are reciprocally interconnected with the substantia nigra, but send most of their output to the globus pallidus

Basal Ganglia functions and connections
The substantia nigra can be divided into two parts:
– substantia nigra pars compacta (SNpc) – substantia nigra pars reticulata (SNpr) – The SNpc receives input from the caudate and putamen, and sends information right back. The SNpr also receives input from the caudate and putamen, but sends it outside the basal ganglia to control head and eye movements. – The SNpc is the more famous of the two, as it produces dopamine, which is critical for normal movement. – The SNpc degenerates in Parkinson's disease.

Basal Ganglia functions and connections
The globus pallidus can also be divided into two parts:
– globus pallidus externa (GPe) – globus pallidus interna (GPi) – Both receive input from the caudate and putamen, and both are in communication with the subthalamic nucleus. – It is the GPi, however, that sends the major inhibitory output from the basal ganglia back to thalamus. – The GPi also sends a few projections to an area of midbrain (the PPPA), presumably to assist in postural control.

Basal Ganglia
• Principal neurotransmitters: ACh, GABA, and dopamine • the overall effect on thalamus is inhibitory • The function of the basal ganglia is often described in terms of a "brake hypothesis" • To sit still, you must put the brakes on all movements except those reflexes that maintain an upright posture. • To move, you must apply a brake to some postural reflexes, and release the brake on voluntary movement.

Basal Ganglia
• In such a complicated system, it is apparent that small disturbances can throw the whole system out of whack, often in unpredictable ways. • The deficits tend to fall into one of two categories:
– the presence of extraneous unwanted movements or – an absence or difficulty with intended movements.

Lesions of the Basal Ganglia
• Parkinson's disease: the slow and steady loss of dopaminergic neurons in SNpc. • The three symptoms usually associated with Parkinson's are tremor, rigidity, and bradykinesia. • The tremor is most apparent at rest. • Rigidity is a result of simultaneous contraction of flexors and extensors, which tends to lock up the limbs. • Bradykinesia, or "slow movement", is a difficulty initiating voluntary movement, as though the brake cannot be released.

Lesions of the Basal Ganglia
• Huntington's disease, or chorea, is a hereditary disease of unwanted movements. • It results from degeneration of the caudate and putamen, and produces continuous dance-like movements of the face and limbs. • A related disorder is hemiballismus, flailing movements of one arm and leg, which is caused by damage (i.e., stroke) of the subthalamic nucleus.

Cerebellum

Inputs and Outputs of the Cerebellum
The cerebellum operates in 3's: 3) there are 3 highways leading in and out of the cerebellum: the peduncles or stalks 5) there are 3 main inputs 7) and there are 3 main outputs from 3 deep nuclei

Inputs and Outputs of the Cerebellum
2) there are 3 highways leading in and out of the cerebellum: the peduncles or stalks
1) inferior 2) middle 3) superior

Inputs and Outputs of the Cerebellum
there are 3 main inputs • • • • • • mossy fibers from the spinocerebellar pathways climbing fibers from the inferior olive more mossy fibers from the pons, which are carrying information from cerebral cortex The mossy fibers from the spinal cord have come up ipsilaterally The fibers coming down from cerebral cortex, however, DO need to cross (the cerebrum is concerned with the opposite side of the body, unlike the cerebellum). These fibers synapse in the pons (hence the huge block of fibers in the cerebral peduncles labeled "corticopontine"), cross, and enter the cerebellum as mossy fibers.

Inputs and Outputs of the Cerebellum
The 3 deep nuclei are: • • • Fastigial - primarily concerned with balance, and sends information mainly to vestibular and reticular nuclei Interposed Dentate The dentate and interposed nuclei are concerned more with voluntary movement, and send axons mainly to thalamus and the red nucleus.

Cerebellum
• The cerebellum is involved in the coordination of movement. • it compares what you thought you were going to do (according to motor cortex) with what is actually happening down in the limbs (according to proprioceptive feedback), and corrects the movement if there is a problem. • The cerebellum is also partly responsible for motor learning e.g. riding a bicycle. • Unlike the cerebrum, which works entirely on a contralateral basis, the cerebellum works ipsilaterally.

Primary Motor System

Basic Motor Pathway
• The motor pathways are pathways which originate in the brain or brainstem and descend down the spinal cord to control the a-motor neurons. • These large neurons in the ventral horns of the spinal cord send their axons out via the spinal roots and directly control the muscles. • The motor pathways can control posture, reflexes, and muscle tone, as well as the conscious voluntary movements that we think of when we hear "motor system".

Basic Motor Pathway
• The most famous pathway is the so called "pyramidal system", which begins with the large pyramidal neurons of the motor cortex, travels through the pyramids of the brainstem, and finally ends on or near the a-motor neurons. • This system is extremely important clinically, as strokes often affect the motor system. Therefore it is crucial to understand the anatomy of the motor pathway.

Apraxia
Three levels: • Limb-kinetic:
– inability to use the contralateral hand

• Ideomotor:
– inability to perform an isolated motor act upon command

• Ideational:
– inability to perform in organized sequence a series of skilled acts

Motor System Pathway

Autonomic Motor System
Parasympathetic: “deactivating” Sympathetic: activating = fight or flight Hypothalamus: controls appetite, rage, temperature, blood pressure, perspiration, sexual drive

Association Systems

Basic Brain Organization
• Brainstem and reticular activating system: arousal and attention • Posterior cortex: perception and language • Frontal cortex: generates programs and executes plans; determines how the brain acts on its knowledge • Korbinian Brodmann: 47 distinct cytoarchitectural areas • Pierre Broca and Karl Wernicke: function localization mapping

• DOMINANT and NON DOMINANT hemispheres: Dominant Hemisphere process information in a sequential, analytic, linear fashion, and efficient at processing language and other symbolic information Non Dominant Hemisphere- process information in a gestalt , holistic, parallel fashion, and is particularly efficient in processing visuospatial information., unconscious processing, Prosody

Language
Three-level processing in language comprehension: 2. Phonological processing (inferior gyrus of frontal lobes) 3. Lexical processing (left temporal lobe) 4. Semantic processing (middle and superior gyri of left temporal lobe) Mirror pathways on both hemisphere: Right = pure language skills Left = prosody

Limbic System

• Papez believed that the experience of emotion was primarily determined by the cingulate cortex and, secondly, by other cortical areas. • Emotional expression was thought to be governed by the hypothalamus. • The cingulate gyrus projects to the hippocampus, and the hippocampus projects to the hypothalamus by way of the bundle of axons called fornix. • Hypothalamic impulses reach the cortex via relay in the anterior thlamic nuclei.

• Emotion is not a function of any specific brain center but of a circuit that involves four basic structures, interconnected through several nervous bundles : the hypothalamus with its mamillary bodies, the anterior thalamic nucleus, the cingulate gyrus and the hippocampus. • This circuit (Papez circuit), acting in an harmonic fashion, is responsible for the central functions of emotion (affect), as well as for its peripheral expressions (symptoms).

• More recently, Paul McLean, accepting the essential bases of Papez proposal, created the denomination limbic system and added new structures to circuit : the orbitofrontal and medialfrontal cortices (prefrontal area), the parahippocampal gyrus and important subcortical groupings like the amygdala, the medial thalamic nucleus, the septal area, prosencephalic basal nuclei (the most anterior area of the brain) and a few brainstem formations.

Limbic System
Structures: Amygdala Cingulate Gyrus Fornix Hippocampus Hypothalamus Olfactory Cortex Thalamus

Amygdala
• If you remember only one word about the amygdala, the word is FEAR. • The amygdala is the nucleus responsible for the lurch you feel in your stomach when you turn around in a dark alley and notice someone following you. • It couples a learned sensory stimulus (man in ski mask in alley = danger) to an adaptive response (fight or flight).

Amygdala
• Inputs: the amygdala must get sensory input, and it must be fairly highly processed input to recognize the elements of a scene that signal danger. The association areas of visual, auditory, and somatosensory cortices are the main inputs to the amygdala.

Amygdala
• Outputs: the amygdala must be able to control the autonomic system, to provoke such an instant sympathetic response. The main outputs of the amygdala are to the hypothalamus and brainstem autonomic centers, including the vagal nuclei and the sympathetic neurons.

Amygdala
• The amygdala is also involved with mood and the conscious emotional response to an event, whether positive or negative. To this end, the amygdala is also extensively interconnected with frontal cortex, mediodorsal thalamus, and the medial striatum.

Memory
• There are at least three different types of memory. • The most short term is working memory. • Working memory is like the RAM of a computer. It is the type of memory that enables you to spit back the last sentence of a conversation when someone accuses you of not listening. • Like the RAM of a computer, it is crucial for performing some common operations in your head: adding numbers, composing a sentence, following directions, etc. • Also like a computer, the space devoted to that operation is recycled as soon as you turn to something else. • It does not become a permanent memory. • Working memory does not require the hippocampus; it is probably a cortical phenomenon.

Hippocampus and Memory
• The second type is what we most commonly associate with "memory". • This is long-term or declarative memory, and is composed of all the facts, figures, and names you have ever learned. • All of your experiences and conscious memory fall into this category. • It is analogous to the hard drive of a computer. • Although no one knows exactly where this enormous database is stored, it is clear that the hippocampus is necessary to file away new memories as they occur.

Hippocampus and Memory
• The third type is procedural memory, and is probably the most durable form of memory. • These are actions, habits, or skills that are learned simply by repetition. • Examples include playing tennis, playing an instrument, solving a puzzle, etc. • The hippocampus is not involved in procedural memory, but it is likely that the cerebellum plays a role in some instances.

Hippocampus and Memory
• Therefore, the hippocampus is critical in laying down declarative memory, but is not necessary for working memory, procedural memory, or memory storage. • Damage to the hippocampus will only affect the formation of new declarative memories.

Prefrontal Area

Prefrontal Area
• This area comprises the entire non-motor anterior region of the frontal lobe. • It underwent a great deal of development during the evolution of mammals. • It is specially large in man and in some species of dolphins. • It does not belong to the traditional limbic circuit, but its intense bi-directional connections with thalamus, amygdala and other subcortical structures, account for the important role it plays in the genesis and, specially, in the expression of affective states.

Prefrontal Area
• When the pre-frontal cortex suffers a lesion, the subject looses his sense of social responsibility as well as the capacity for concentration and abstraction. In some cases, although consciousness and some cognitive functions, like speech, remain intact, the subject can no longer solve problems, even the most elementary ones. • When pre-frontal lobotomy was used for treatment of certain psychiatric disturbances, the patients entered into a stage of "affective buffer", no longer showing any sign of joy, sadness, hope or despair. • In their words or attitudes, no traces of affection could be detected.

Psychiatric Implications
• Four A of schizophrenia = brain functions subserved in part by limbic structures • Reduced gray matter volume (hippocampus, amygdala, parahippocampus) • Decreased frontal lobe activation • Activation of the same areas for spoken language as that in auditory hallucination • Frontal lobe injury impairs executieve functions: motivation, attention, sequencing of actions

Psychiatric Implications
• Frontal lobe injury impairs executive functions: motivation, attention, sequencing of actions • frontal lobe syndrome: slowed thinking, poor judgment, decreased curiosity, social withdrawal, irritability

Neural Development
• Migration to adult sites • Heterotopia (incorrectly placed neurons) • Auditory processing and language:
– Temporally determined perceptual map of phonemes – Nueronal location of specific sounds differ across cultures (difficulty of Japanese to distinguish “la” from “ra”) – Very early experiences may establish the density and fidelity of neural circuits for specific functions

Psychiatric Implications
• nature and nurture • Milieu affects neural development such that a person may either be:
– given an advantage (e.g. musically exposed being better at mathematics and spatial reasoning) – or disadvantaged (e.g. pattern of trauma or fear flood amygdala to be specifically alert to threatening stimuli; or chaos for poor acquisition of complex cognitive skills later)

• Tantalizing basis for development theories • Early experiences primes the basic circuitry for language, emotion, and other advanced behaviours

Neurophysiology and Neurochemistry

Synaptic Transmission
• Synaptic transmission = propagation of nerve impulses from one nerve cell to another. • Neurotransmitter release into synaptic space = nerve impulses transmission • Synapse = junction at which the axon of the presynaptic neuron terminates at some location upon the postsynaptic neuron. • Terminal button = enlarged structure at end of a presynaptic axon, where it is juxtaposed to the postsynaptic neuron • An axon can make contact anywhere along the second neuron:
– on the dendrites (an axodendritic synapse) – on the cell body (an axosomatic synapse) – on the axons (an axo-axonal synapse).

Synaptic Transmission
• The neurotransmitters are a diverse group of chemical compounds ranging from simple amines such as dopamine and amino acids such as gaminobutyrate (GABA), to polypeptides such as the enkephalins. • The mechanisms by which they elicit responses in both presynaptic and postsynaptic neurons are as diverse as the mechanisms employed by growth factor and cytokine receptors.

Presynaptic Components
• voltage gated calcium channels locally raise intracellular Ca concentration and initiates cascade of interaction • neurotransmitter containing vesicles fuse with the presynaptic membrane and undergoes exocytosis • neurotransmitter diffuse into cleft and binds to specific receptors on external membrane of the postsynaptic neuron. • Tansmembrane transporter molecules return free Mono Amine NT to nerve terminals where they are repackaged into vesicles for release or degraded by MAO. (Mao type A metabolize Norepinephrine and Serotonin and its inhibition by Mao
inhibitors is associated with mood elevation. Mao B metabolize Dopamine)

Postsynaptic Components
  Receptors are the site of action of most available psychoactive substances. Principal functions of these receptors- to alter electrical transmembrane potential to either increase or decrease likelihood of triggering an action potential Sensitivity of receptors are due to a. number of receptors present b. affinity of the receptor for the neurotransmitter c. efficiency of translation of both neurotransmitter and receptor into a neuronal message

Postsynaptic Components
 

• G Proteins • Second Messengers
– – – – – Cyclic Nucleotides Calcium Phosphoinositol Metabolites Eicosanoids JAK-STAT

• Protein Kinases

Neurotransmitter Receptors
• Once the molecules of neurotransmitter are released from a cell as the result of the firing of an action potential, they bind to specific receptors on the surface of the postsynaptic cell. • In all cases in which these receptors have been cloned and characterized in detail, it has been shown that there are numerous subtypes of receptor for any given neurotransmitter. • As well as being present on the surfaces of postsynaptic neurons, neurotransmitter receptors are found on presynaptic neurons. • In general, presynaptic neuron receptors act to inhibit further release of neurotransmitter.

Neurotransmitter Receptors
• The vast majority of neurotransmitter receptors belong to a class of proteins known as the serpentine receptors. • This class exhibits a characteristic transmembrane structure: that is, it spans the cell membrane, not once but seven times. • The link between neurotransmitters and intracellular signaling is carried out by association either with G-proteins (small GTP-binding and hydrolyzing proteins) or with protein kinases, or by the receptor itself in the form of a ligand-gated ion channel (for example, the acetylcholine receptor). • One additional characteristic of neurotransmitter receptors is that they are subject to ligand-induced desensitization: That is, they can become unresponsive upon prolonged exposure to their neurotransmitter.

Neurotransmitters
• The molecule is synthesized in the neuron • The molecule is present in the presynaptic neuron and is released on depolarization in physiologically significant amounts • When administered exogenously as a drug, the exogenous molecule mimics the effects of the endogenous neurotransmitter • A mechanism in the neuron or the synaptic cleft acts to remove or deactivate the neurotransmitter

Transmitter Molecule Acetylcholine

Derived From Choline

Site of Synthesis CNS, parasympathetic nerves

Serotonin 5-Hydroxytryptamine (5-HT)

Tryptophan

CNS, chromaffin cells of the gut, enteric cells

GABA Glutamate Aspartate Glycine Histamine Epinephrine synthesis pathway

Glutamate       Histidine

CNS CNS CNS spinal cord hypothalamus

Tyrosine

adrenal medulla, some CNS cells

Norpinephrine synthesis pathway

Tyrosine

CNS, sympathetic nerves

Dopamine synthesis pathway Adenosine ATP Nitric oxide, NO

Tyrosine ATP   Arginine

CNS CNS, periperal nerves sympathetic, sensory and enteric nerves CNS, gastrointestinal tract

Metabolism of Catecholamine Neurotransmitters

Dopaminergic

pathway

• The first is the mesolimbic pathway–the bundle of dopaminergic fibres associated with the reward circuit. • This pathway originates in the ventral tegmental area and innervates several structures of the limbic system, including the nucleus accumbens. • The mesolimbic pathway is important for memory and for motivating behaviours. • By blocking this pathway, antipsychotic drugs reduce the intense emotions caused by conditions such as schizophrenia.

• The mesocortical pathway also originates in the ventral tegmental area, but projects to the frontal cortex and surrounding structures. • Some evidence indicates that a malfunction in this pathway might be the cause of some of the symptoms of schizophrenia, such as hallucinations and disordered thinking. • Medications that block this pathway reduce psychotic delirium, but also reduce the overall activity of the frontal lobes.

• The third, nigrostriatal pathway projects axons from the substantia nigra to the striatum (caudate nucleus and putamen), which is involved in motor control. Degeneration of the neurons in this pathway is associated with the trembling and muscular rigidity symptomatic of Parkinson’s disease.

• A fourth dopaminergic pathway worth mentioning is the tuberoinfundibular pathway, which connects the hypothalamus to the pituitary gland, where it influences the secretion of hormones such as prolactin.

Serotonin
• naturally produced in the Pineal gland which lies deep at the centre of the human brain. • The average adult human possesses only 5 to 10 mg of serotonin, 90 % of which is in the intestine and the rest in blood platelets and the brain.

Involved in the control of
• • • • • • • • • • Appetite Sleep memory and learning temperature regulation Mood Behaviour cardiovascular function muscle contraction endocrine regulation depression

GABA
• Several amino acids have distinct excitatory or inhibitory effects upon the nervous system. The amino acid derivative, g-aminobutyrate, also called 4-aminobutyrate, (GABA) is a well-known inhibitor of presynaptic transmission in the CNS, and also in the retina. The formation of GABA occurs by the decarboxylation of glutamate catalyzed by glutamate decarboxylase (GAD). GAD is present in many nerve endings of the brain as well as in the b-cells of the pancreas. Neurons that secrete GABA are termed GABAergic.

GABA
• GABA exerts its effects by binding to two distinct receptors, GABA-A and GABA-B. The GABA-A receptors form a Cl- channel. The binding of GABA to GABA-A receptors increases the Clconductance of presynaptic neurons. The anxiolytic drugs of the benzodiazepine family exert their soothing effects by potentiating the responses of GABA-A receptors to GABA binding. The GABA-B receptors are coupled to an intracellular G-protein and act by increasing conductance of an associated K+ channel.

Monoamine neurotransamitters
• present in only a small percentage of neurons localized in small nuclei of the brain • have enormous impact on total brain functioning because the diffuse projections of axons from these monoaminergic neurons can affect virtually every brain region.

 

Amino Acids
• Most abundant neurotransmitter    1.  GaBa – major inhibitory N. ( Bzd act on  this mechanism)   2.  Glutamate- major excitatory N.  NMDA is  the most understood receptor of glutamate  and has a role in learning memory and  psychopathology  :  psychosis , Schizophrenia

• and it is possible to conceptualize the brain as reflecting the balance between the excitatory amino acid glutamate, and the inhibitory amino acid g-aminobutyric acid

• all existing drugs for psychiatric conditions act through monoamine or amino acid neurotransmitter systems

Peptides
• A.       Endogenous opiods-      1.  involved in regulation of stress, pain, mood     2.  Endogenous opiods :             enkephalins, endorphins, dynorphins     3. effects of neurotransmission in  hippocampus:                contributes to addiction B.       Substance P      1. Primary neurotransmitter in sensory neurons &            strianigral pathway; associated with mediation             of pain C.       Cholecystokinin       involved in pathophysiology of Schizophrenia,        eating and  movement disorders

Somatostatin    1. growth hormone inhibiting factor    2. implicated in Huntington’s disease, Alzheimer’s    dementia   Vasopressin and Oxytoxin    1. synthesized in the hypothalamus    2. mood regulation   Neuropeptide Y   1.  stimulate appetite   2.  area of interst in Obesity

Nucleotides  Purine adenosine inhibits the release of other  neurotransmitters  and ATP   Gasses       Nitric Oxide  acts as both intraneuronal second  messenger and neurotransmitter.  With  excessive  exposure to glutamate Nitric  Oxide  is metabolized to  toxic free radicals which may injure or kill  cells  through excitotoxicity   Eicosanoids Anandamides             Sigma receptors

Neurotrophic factors
• Growth factors that allow neurons to regenerate their axon are also called neurotrophic factors. NGF (Nerve Growth Factor) is the most widely-known. Recently, other factors have been identified, such as BDNF (Brain-Derived Neurotrophic Factor), CNTF (Ciliary Neurotrophic Factor), GDNF (Glial Cell-line Neurotrophic Factor), and IGF (Insulin Growth Factor), to name only a few.

Neurotransmitters:
• Neurons can also be classified according to the neurotransmitters they contain (e.g., the dopamine neurons of the substantia nigra). • neurotransmitters have defined effects on the activity of neurons, whereas complex brain functions, such as those disturbed in psychiatric disorders, are mediated by the coordinated activity of ensembles of neurons. • effects of neurotransmitters on behavioral, emotional, or cognitive states must be viewed within the context of the neural circuits that they influence.

Genetics and Brain Development
Alterations in gene expression occur both during development and in adulthood and may be the bases for abnormal and normal development, and for abnormal and normal adaptation to stress

The 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. These patterns of activation are mediated by the connections among specific brain structures.

• Every function of the human brain is a consequence of the activity of specific neural circuits. The 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 development the connections of particular neurons are focused by the pruning or elimination of axonal projections to inappropriate targets.

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

Illnesses in the Brain cannot be  viewed in isolation

Population Genetics
provided some of the first objective data that mental illnesses were biological illnesses, thereby 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
• 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 between the neuroendocrine and central nervous systems : 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

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• Pathological alterations in hypothalamic-pituitary-adrenal function have been associated with mood disorders, posttraumatic stress disroder, 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 loss, emotional lability, impairment in concentration and memory Hypothyroidism: fatigue, decreased libido, memory impairment, irritability, suicidal ideation

Psychoneuroimmunology
• Classical conditioning paradigms have been associated with suppression or enhancement of the immune response • Stressful life events can increase susceptibility to infectious diseases • Academic/examination stress in medical students showed decreased natural killer cell activity, T cells, mitogen responses, interferon production, impaired cellular immunity

Psychoneuroimmunology
• Altered CNS function results from a combination of the direct effects of an injurious event on vaiorus cell types and the effects of inflammatory mediators on neurons and supporting cells • Involvement of viral infection during neural development in some cases of schizophrenia • Immune activation may contribute to the pathophysiology of depression

• circadian rhythms are set by 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

Biological Rhythms and Chronobiology

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.