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Neurobiology of Schizophrenia

DR GANESH INGOLE RESIDENT PSYCHIATRY

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• Introduction• Neuro-imaging• Neuro-chemical Abnormalities• Genetics and Neurodevelopment

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INTRODUCTION

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Schizophrenia

• Psychosis– Delusions– Hallucinations– Disorganized speech– Disorganized behaviour– Gross distortions from reality

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Schizophrenia

• Symptom domains– Positive– Negative– Cognitive– Aggressive– Affective

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Schizophrenia

• Positive Symptoms– Delusions– Hallucinations– Distortions in language and communications– Disorganized speech– Disorganized behaviour

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Schizophrenia

• Negative Symptoms– Alogia– Affective blunting– Asociality– Anhedonia– Avolition

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Schizophrenia

• Cognitive domains– Poor concentration– Poor attention– Poor performance– Poor learning – Poor in understanding social cues

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Schizophrenia

• Aggressive Symptom domain– Assaultiveness– Verbally abusive behaviour– Frank violence

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Schizophrenia

• Affective domain– Inability to show expressions– Inability to recognize emotions– Depressed mood– Anxiety– Poor self esteem– Guilt – Suicidal thoughts

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Localization of symptom domains

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NEUROIMAGING

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Structural Abnormalities

• Ventricles- Increased size of lateral ventricles

• Reduced cortical gray volume

• Progressive or static• Reduced symmetry

– Neurodevelopmental

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Prefrontal Cortex

• Anatomical Abnormalities• Functional deficits on neuroimaging• Symptoms of Schizophrenia mimics –

frontal lobotomies and frontal lobe syndrome

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LIMBIC SYSTEM• PM findings and MRI -

decrease in the size of the limbic system including the amygdala, the hippocampus, and the parahippocampal gyrus

• Hippocampus is small, functionally abnormal and has disorganised neurons

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THALAMUS

• Volume shrinkage • Neuronal loss of

medial dorsal nuclei• Number reduced to

30-45%

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Basal ganglia and Cerebellum

• Involved in motor control of movements• Schizophrenia causes odd movements,

gait, facial grimacing• Cell loss and shrinkage in volume• Increase in number of D2 receptors

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Neural Circuits

• Early developmental lesions of dopaminergic tracts

• Disturbances in connectivity in different brain regions

• White matter fibre tracts

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SPECT & PET

• To test DA hyperactivity hypothesis

• Sgnificant, mild elevation in D2 receptor density

• Increase in DA transmission in response to amphetamine challange

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Information Processing in Schizophrenia- DLPFC

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Inappropriate Information Processing

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Neutral Stimuli

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NEUROCHEMICAL ABNORMALITIES

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Neurotransmiters

• Dopamine• Serotonin• Glutamate• Noradrenaline

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Dopamine

• Neurotransmitter • Catecholamine• Synthesized in brain and kidneys

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Dopamine receptors-Location

D1 – Striatum, renal, mesentric vessle

D2 – Striatum, sub.niagra, VTA, pituitary

D3– NA, hypothalamus

D4– Neocortex, midbrain, hippocampus, medulla, heart & kidney

D5– Neocortex, midbrain, hippocampus, medulla

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Dopamine Pathways

• A- Nigrostriatal• B- Mesolimbic• C- Mesocortical• D- Tuberoinfundibular• E- Thalamic Dopamine

pathway

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Dopamine pathways

• Mesolimbic pathway– Ventral tegmental area

of the brainstem to nucleus accumbens in the ventral striatum

– Motivation, pleasure, and reward

– Psychosis, such as delusions and hallucinations

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Mesolimbic Pathway

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Mesolimbic Pathway• Positive, Aggressive symptoms and drug abuse ?to counter negative Symptoms

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Mesocortical Pathway

• Ventral tegmental area to prefrontal cortex

• DLPFC– cognition and

executive functions• VMPFC

– Emotional regulation

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Mesocortical Pathway

• Low Dopamine

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Mesocortical Pathway-VMPFC

•Low Dopamine

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Mesocortical dopamine Hypothesis

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Nigrostriatal pathway

• Substantia nigra to basal ganglia

• Extrapyramidal nervous system

• Motor movements• Deficiencies-

Bradykinesia• Hyperactivity-

Hyperkinetic movement disorders

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5HT – DA interaction at Nigro-striatal Pathway

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Tuberoinfundibular pathway

• Arcuate N of hypothalamus

• Anterior pituitary• Inhibit prolactin

release• Antipsychotic drugs-

increase prolactin– Galactorrhea,

amenorrhea

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Thalamic dopamine pathway

• Arise from multiple sites– Periaqueductal gray matter– Ventral mesencephalon– Hypothalamic nuclei– Lateral parabrachial nucleus• Sleep and arousal mechanisms • Gating info passing through thalamus to the

cortex and other brain areas• Schizophrenia- Normal

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Serotonin

• Serotonin receptors present in many brain areas

• Cortical receptors- excitatory• Enhances downstream glutamate release

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5HT2A Receptors Decreases DA Release

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5HT2A Receptors Decreases DA Release

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Blocking 5HT2A Receptors Increase DA Release

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Cortical 5HT1A Receptors

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Cortical 5HT1A Receptors

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Nigral &Striatal 5HT2A decrease DA release

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Nigral &Striatal 5HT2A decrease DA release

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Raphe 5HT1A Increase DA release

Serotonin binding at raphe nucleus inhibits serotonin release

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Raphe 5HT1A Increase DA release

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Glutamate

• Excitatory neurotransmitter

• Master switch of brain

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Glutamate Dysfunction

• Abnormalities in synapse formation during neurodevelopment

• Genetic abnormalities• Dysconnectivity- Parvalbumin–containig

GABA interneurons• Deficit in GABA• Glutamate hyperactivity• Increased Dopamine

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Glutamate Dysfunction

•Normal Receptors

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Glutamate Dysfunction

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Glutamate Pathways in Brain

• A- Cortico-brainstem• B- Cortico-striatal• C- Hippocampal-striatal• D- Thalamo-cortical• E- Cortico-thalamic• F-Cortico-

cortical(direct)• E- Cortico-

cortical(Indirect)

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Cortico- brainstem • Cortical Pyramidal neurons

to brainstem• Raphe for serotonin• VTA and substantia nigra for

dopamine• Locus coeruleus for

norepinephrine• Key regulator• Direct innervation to other

pathways- excitatory• Indirect- Inhibitory

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Cortico-brainstem Pathway

• Communicates with Mesolimbic pathway in VTA

• Hypoactive NMDA receptors

• Excess Glutamate• Excess DA NA

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NMDA Receptor Hypofunction- Negative Symptoms

• Hypoactive NMDA receptors

• Cortico-brainstem –Overactive

• Excess Glutamate at VTA• Excess stimulation of

braistem pyramidal neurons

• Inhibition of Mesocortical DA neurons

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Cortico-striatal

• Cortical pyramidal neurons to striatal complex

• Cortico-striatal– Dorsal striatum• Cortico-accumbens- nucleus accumbens• Both terminate in GABA neurons of globus

pallidus

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Hippocampal- Accumbens

• Hippocampus to nucleus accumbens• Terminate into GABA neurons• In turn project into Globus pallidus

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NMDA Receptor Hypofunction- Positive Symptoms

• Glutamate at ventral Hippocampus

• Binds to NMDA receptors on GABAeric interneurons

• Pyramidal Glutamate receptors to Nucleus accumbens

• Inhibits Glutamate release at VTA- Normal GABA to Globus pallidus

• Normal DA

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NMDA Receptor Hypofunction- Positive Symptoms

• NMDA receptors hypoactive

• Glutamatergic pathway to NA overactive

• Excess stimulation of GABAergic neurons VTA

• Decreased GABA from Globus Pallidus

• Disinhibition of Mesolimbic pathway

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Thalamo-cortical

• Thalamus to cortex• Process sensory information

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Cortico-Thalamic

• Cortex to Thalamus• Modulates reaction of neurons to sensory

info

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Cortico-cortical

• Direct– Excitatory – Pyramidal neurons excite directly each other

• Indirect– Inhibitory– Through GABA interneurons

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Norepinephrine

• Noradrenergic projections from locus coeruleus to cortex

• A1 receptors on Glutametargic neurons

• Glutamate release in brainstem

• Releases GABA• Inhibits DA release

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Cortical Alpha 1 Receptors

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GENETICS AND NEURODEVELOPMENT

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Genetics

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Subtle Molecular Abnormalities

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Stress Diathesis Model

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Neurodevelopment

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Multiple Susceptibility-1

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Multiple Susceptibility-2

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Genes Causing Abnormal Synaptogenesis

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Synapse Formation

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References• Benjamin James Sadock, Virginia Alcott Sadock,

Pedro Ruiz,2007,Schizophrenia,Synopsis of Psychiatry,11th edition,300-323

• Stephen M Stahl, Psychosis and scizophrenia, Antipsychotic agents, Stahl’s Essential Psychopharmacology, 4th edition, 79-236

• Anissa AD, Olivier G, Integrating the Neurobiology of Schizophrenia

• JN Vyas, Shree Ram Ghimire, Schizophrenia:Neurobiology, Textbook of postgraduate Psychiatry, 3rd edition,237-246

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THANK YOU