Neurobiology of schizophrenia
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This document provides an overview of the neurobiology of schizophrenia. It discusses several key areas: - Neuroimaging studies have found structural abnormalities in brain areas like the prefrontal cortex, limbic system, thalamus, and basal ganglia. Functional neuroimaging also shows abnormal activity patterns. - Neurochemical abnormalities have been found involving the neurotransmitters dopamine, serotonin, glutamate, and norepinephrine. The dopamine and glutamate systems in particular are implicated in the positive and negative symptoms. - Genetics and neurodevelopmental factors are believed to play a role through subtle molecular abnormalities and disrupted synapse formation during critical periods of brain development.
Neurobiology of schizophrenia
- 1. Neurobiology of Schizophrenia DR GANESH INGOLE RESIDENT PSYCHIATRY 1
- 2. • Introduction • Neuro-imaging • Neuro-chemical Abnormalities • Genetics and Neurodevelopment 2
- 4. Schizophrenia • Psychosis – Delusions – Hallucinations – Disorganized speech – Disorganized behaviour – Gross distortions from reality 4
- 5. Schizophrenia • Symptom domains – Positive – Negative – Cognitive – Aggressive – Affective 5
- 6. Schizophrenia • Positive Symptoms – Delusions – Hallucinations – Distortions in language and communications – Disorganized speech – Disorganized behaviour 6
- 7. Schizophrenia • Negative Symptoms – Alogia – Affective blunting – Asociality – Anhedonia – Avolition 7
- 8. Schizophrenia • Cognitive domains – Poor concentration – Poor attention – Poor performance – Poor learning – Poor in understanding social cues 8
- 9. Schizophrenia • Aggressive Symptom domain – Assaultiveness – Verbally abusive behaviour – Frank violence 9
- 10. Schizophrenia • Affective domain – Inability to show expressions – Inability to recognize emotions – Depressed mood – Anxiety – Poor self esteem – Guilt – Suicidal thoughts 10
- 11. Localization of symptom domains 11
- 12. NEUROIMAGING 12
- 13. Structural Abnormalities • Ventricles- Increased size of lateral ventricles • Reduced cortical gray volume • Progressive or static • Reduced symmetry – Neurodevelopmental 13
- 14. Prefrontal Cortex • Anatomical Abnormalities • Functional deficits on neuroimaging • Symptoms of Schizophrenia mimics – frontal lobotomies and frontal lobe syndrome 14
- 15. 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 15
- 16. THALAMUS • Volume shrinkage • Neuronal loss of medial dorsal nuclei • Number reduced to 30-45% 16
- 17. 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 17
- 18. Neural Circuits • Early developmental lesions of dopaminergic tracts • Disturbances in connectivity in different brain regions • White matter fibre tracts 18
- 19. SPECT & PET • To test DA hyperactivity hypothesis • Sgnificant, mild elevation in D2 receptor density • Increase in DA transmission in response to amphetamine challange 19
- 20. Information Processing in Schizophrenia- DLPFC 20
- 24. Neurotransmiters • Dopamine • Serotonin • Glutamate • Noradrenaline 24
- 25. Dopamine • Neurotransmitter • Catecholamine • Synthesized in brain and kidneys 25
- 26. 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 31
- 27. Dopamine Pathways • A- Nigrostriatal • B- Mesolimbic • C- Mesocortical • D- Tuberoinfundibular • E- Thalamic Dopamine pathway 32
- 28. 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 33
- 30. Mesolimbic Pathway • Positive, Aggressive symptoms and drug abuse ?to counter negative Symptoms 35
- 31. Mesocortical Pathway • Ventral tegmental area to prefrontal cortex • DLPFC – cognition and executive functions • VMPFC – Emotional regulation 36
- 32. Mesocortical Pathway • Low Dopamine 37
- 35. Nigrostriatal pathway • Substantia nigra to basal ganglia • Extrapyramidal nervous system • Motor movements • Deficiencies- Bradykinesia • Hyperactivity- Hyperkinetic movement disorders 40
- 36. 41
- 37. 5HT – DA interaction at Nigro- striatal Pathway 43
- 38. Tuberoinfundibular pathway • Arcuate N of hypothalamus • Anterior pituitary • Inhibit prolactin release • Antipsychotic drugs- increase prolactin – Galactorrhea, amenorrhea 44
- 39. 45
- 40. 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 46
- 41. Serotonin • Serotonin receptors present in many brain areas • Cortical receptors- excitatory • Enhances downstream glutamate release 48
- 42. 5HT2A Receptors Decreases DA Release 49
- 43. 5HT2A Receptors Decreases DA Release 50
- 44. Blocking 5HT2A Receptors Increase DA Release 51
- 47. Nigral &Striatal 5HT2A decrease DA release 54
- 48. Nigral &Striatal 5HT2A decrease DA release 55
- 49. Raphe 5HT1A Increase DA release Serotonin binding at raphe nucleus inhibits serotonin release 56
- 50. Raphe 5HT1A Increase DA release 57
- 51. Glutamate • Excitatory neurotransmitter • Master switch of brain 58
- 52. Glutamate Dysfunction • Abnormalities in synapse formation during neurodevelopment • Genetic abnormalities • Dysconnectivity- Parvalbumin–containig GABA interneurons • Deficit in GABA • Glutamate hyperactivity • Increased Dopamine 65
- 55. 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) 68
- 56. 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 70
- 57. Cortico-brainstem Pathway • Communicates with Mesolimbic pathway in VTA • Hypoactive NMDA receptors • Excess Glutamate • Excess DA NA 71
- 58. 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 72
- 59. Cortico-striatal • Cortical pyramidal neurons to striatal complex • Cortico-striatal– Dorsal striatum • Cortico-accumbens- nucleus accumbens • Both terminate in GABA neurons of globus pallidus 73
- 60. Hippocampal- Accumbens • Hippocampus to nucleus accumbens • Terminate into GABA neurons • In turn project into Globus pallidus 76
- 61. 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 77
- 62. 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 78
- 63. Thalamo-cortical • Thalamus to cortex • Process sensory information 79
- 64. Cortico-Thalamic • Cortex to Thalamus • Modulates reaction of neurons to sensory info 80
- 65. Cortico-cortical • Direct – Excitatory – Pyramidal neurons excite directly each other • Indirect – Inhibitory – Through GABA interneurons 81
- 66. Norepinephrine 82 • Noradrenergic projections from locus coeruleus to cortex • A1 receptors on Glutametargic neurons • Glutamate release in brainstem • Releases GABA • Inhibits DA release
- 67. Cortical Alpha 1 Receptors 83
- 69. Genetics 91
- 77. 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,237-246 100
- 78. THANK YOU 101