Neurophysiology of Schizophrenia
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Neurophysiology of Schizophrenia
Dr. Shivan A.C. Mahabir
DM. Psychiatry
Part 1 Year 1
17 April, 2012
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Schizophrenia
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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%
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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.
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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
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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.
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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.
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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).
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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.
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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).
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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.
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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).
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Stress-Diathesis Model
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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.