neurophysiology of schizophrenia

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Neurophysiology of Schizophrenia

Dr. Shivan A.C. Mahabir

DM. Psychiatry

Part 1 Year 1

17 April, 2012



Schizophrenia



Genetics

The most likely explanation for the unusual genetic transmission of

schizophrenia—

its high frequency of 1% and its partial penetrance—

is thatthe illness is polygenic, involving in any given case perhaps as many as 3

to 10 genes. As with other polygenic diseases, such as diabetes and

hypertension, it is possible that one or all of the critical genes are simply

allelic variations—polymorphisms—of genes, each one of which by itself

would not cause disease. Rather it is the combination of allelic

polymorphisms in the context of a specific genetic background that is critical

for the disease.

DEGREE OF RELATION

(% OF GENES SHARED)

LIFETIME RISK OF

DEVELOPING SCHIZOPHRENIA

MONOZYGOTIC TWIN (100%) 48%

1ST DEGREE (50% ) 6% - 17%

2ND DEGREE (25%) 2%- 6%

3RD DEGREE (12.5% ) 2%

GENERAL POPULATION (0%) 1%



Anatomical Changes Early in the disease there is a reduction in the blood flow to the

left globus pallidus suggestive of a disturbance in the system thatconnects the basal ganglia to the frontal lobes.

Second, there appears to be a disturbance in the frontal lobesthemselves since blood flow does not increase during tests of frontallobe function involving working memory, as it does in normal

subjects.

Third, the cortex of the medial temporal lobe is thinner and theanterior portion of the hippocampus is smaller than in normalpeople, especially on the left side, consistent with a defect inmemory.

Finally, the lateral and third ventricles are enlarged and there iswidening of the sulci, especially in the thinner temporal lobe and inthe frontal lobe, reflecting a reduction in the volume of this lobe aswell.



Neurotransmitters

DOPAMINE: Dopaminergic neurons are not randomly distributed in the brain

but are organized into four major systems: thetuberoinfundibular, nigrostriatal, mesolimbic, andmesocortical systems.

The dopaminergic nigro str iatal system contr ibutes to the

symptoms of Parkinso n disease., EPSE, tardive

dyskinesia.

The dopaminergic mesolimbic system has its origin in cell bodies in the ventral tegmental area, which is medial and superior to the substantia nigra. These cells project to the

mesial components of the limbic system: the nucleusaccumbens, the ventral striatum, the nuclei of the striaterminalis, parts of the amygdala and hippocampus, the lateralseptal nuclei, the entorhinal cortex, the mesial frontal cortex,and the anterior cingulate cortex. It has a role in emotions andmemory.

Carlsson proposed that the positive symptoms of



Neurotransmitters Among the projections of the mesolimbic system, those to the

nucleus accumbens are thought to be particularly importantbecause of the extensive connections of this nucleus to thelimbic system. The nucleus accumbens receives and integratesinputs from the amygdala, hippocampus, entorhinal area,anterior cingulate area, and parts of the temporal lobe.

The mesolimbic dopaminergic projection to the nucleus

accumbens is thought to modulate these inputs and therebyinfluence the output of the nucleus accumbens to its targetregions: the ventral pallidum, septum, hypothalamus, anterior cingulate area, and frontal lobes. As we have seen, some of theinput sources, in particular the hippocampus, and some of theoutput targets, such as the cingulate cortex and the frontal

lobes are thought to be disturbed in schizophrenia. Overactivemodulation of the integration of the inputs to the nucleusaccumbens and of the output from it could contribute topositive symptoms of schizophrenia.



Neurotransmitters

Daniel Weinberger postulated that two dopaminergic

systems are disturbed in different ways in schizophrenia.

First, an increase in activity in the mesolimbic pathway

(perhaps through the D2 and D3 receptors and particularly

through the D4 receptors) would account for the positive

symptoms. Second, decreased activity of the mesocortical connections

in the prefrontal cortex would account for the negative

symptoms.

Weinberger proposes that activity in the mesocortical

pathway to the prefrontal cortex normally inhibits themesolimbic pathway by feedback inhibition and that the

primary defect in schizophrenia is a reduction in this

activity, which leads to disinhibition and overactivity in the

mesolimbic pathway.



Neurotransmitters

GLUTAMATE:

N -methyl-D-aspartate (NMDA) receptors are present

on the dopaminergic axon terminals in the prefrontal

cortex and enhance dopamine release from the

terminals. Psychosis may be caused by inhibiting

dopamine release eg PCP (mesocortical pathway)

In contrast, at the dopaminergic terminals in the

nucleus accumbens PCP increases dopaminerelease and inhibits reuptake (mesolimbic

pathway).



Neurotransmitters

GAMMA AMINO BUTYRIC ACID (GABA): Abnormalities of GABA activity in schizophrenia have

been consistently shown in the last ten years.

Schizophrenia is associated with both decreased

numbers and abnormalities in the distribution of

GABAergic neurons in the cortex, particularly in thecortical laminae (Kaplan & Sadock, 1995).

The precise role GABA plays in the pathogenesis of

schizophrenia is not entirely clear. GABA appears to

have an effect on regulation of dopamine levels in thebrain, so it's possible that the GABA-dopamine

interaction is responsible for some symptoms of the

disease.



Neurotransmitters

ACETYLCHOLINE: Strong support for a role of the muscarinic cholinergic

system in schizophrenia comes from post-mortem and

brain-imaging studies.

Several post-mortem studies have consistently shown a

significant decrease of muscarinic receptor density in

different brain regions that are considered to be of

crucial importance in the pathophysiology of

schizophrenia eg. frontal cortex, basal ganglia and

hippocampus. These results include significant decreases in specific

subtypes of the muscarinic receptor (in particular M1).



Neurotransmitters

SEROTONIN Though serotonin does appear to have a role in

schizophrenia, the assumption that it is directly

responsible is still in question. Many have now theorized

that increased levels of serotonin in the prefrontal

cortex will result in lower dopamine levels in the area.These reduced dopamine levels, which may be

responsible for the negative symptoms of

schizophrenia, appear to lead to increased levels of

dopamine in secondary dopaminergic systems. Theincreased dopamine levels are most likely

responsible for the positive symptoms of

schizophrenia.



Neurotransmitters

NOREPINEPHRINE: The raised levels of norepinephrine in schizophrenia are

no longer in doubt. What norepinephrine's role is,

however, what part its reward system plays, and to what

extent it modulates dopamine levels is still under

question.

It is proposed that schizophrenia may be related to a

defect in the noradrenergic reward system.

Hyperactivity of the system would produce raised

norepinephrine levels, which creates a state of heightened autonomic arousal. They have observed

this state throughout all phases of the psychosis

(Hemmings & Hemmings, 1978).



Stress-Diathesis Model



References

1. Towards a muscarinic hypothesis of schizophrenia-TJ Raedler, FP Bymaster, R Tandon, D Copolov

and B Dean.

2. Principles of Neural Science. 4th edition. Eric

Kandel.3. Kaplan, H.I., & Sadock, B.J. (Eds.).

(1995). Comprehensive Textbook of

Psychiatry. Baltimore, MD: Williams & Wilkins.

neurophysiology of schizophrenia

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