Neurobiology of schizophrenia

Neurobiology of schizophrenia

1. Neurobiology of Schizophrenia Guide: Dr VS Pal Sir Professor Department of Psychiatry MGMMC and MYH, Indore By- Dr. Priyash Jain

2. Contents Introduction Neurotransmitters and Pathways Genetics Neurodevelopment Neuroimaging Immunology

3. Introduction

4. Introduction In psychosis thought, behaviors, perception and feelings are disordered ; disorganized and disconnected from reality. Schizophrenia is the main psychotic illness. Etiology of schizophrenia is unknown, Genetic predisposition is clear and the role of environmental factors in the development of schizophrenia is evident from the fact that monozygotic twins have approx 50% concordance rates of schizophrenia.

5. Psychosis Delusions Hallucinations Disorganized speech Disorganized behaviour Gross distortions from reality Introduction

6. Symptom domains Positive Negative Cognitive Aggressive Affective Introduction

7. Positive Symptoms Delusions Hallucinations Distortions in language and communications Disorganized speech Disorganized behaviour Introduction

8. Negative Symptoms Alogia Affective blunting Asociality Anhedonia Avolition Introduction

9. Cognitive domains Poor concentration Poor attention Poor performance Poor learning Poor in understanding social cues Introduction

10. Aggressive Symptom domain Assaultiveness Verbally abusive behaviour Frank violence Introduction

11. Affective domain Inability to show expressions Inability to recognize emotions Depressed mood Anxiety Poor self esteem Guilt Suicidal thoughts Introduction

12. Localization of symptom domains

13. Neurotransmitters

14. Neurotransmitters Dopamine Serotonin Glutamate GABA Acetylcholine

15. Dopamine Neurotransmitter Catecholamine Synthesized in brain and kidneys

16. Dopamine receptors- Location D1 – Striatum, renal, mesentric vessels D2 – Striatum, sub stantia niagra , V entral T egmental A rea , pituitary D3– N ucleus A ccumbens , hypothalamus D 4 –Neocort e x , mi d br a in, hi p pocamp u s, medulla, heart & kidney D 5 –Neocort e x , mi d br a in, hi p pocamp u s, medulla

17. Dopamine Pathways A- Nigrostriatal B- Mesolimbic C- Mesocortical D- Tuberoinfundibular E- Thalamic Dopamine pathway

18. Dopamine pathways Mesoli m bi c p a t hw a y Ventral tegmental area to nucleus accumbens Motivation, pleasure and reward Delusions and hallucination

19. Mesolimbic Pathway

20. Mesocortical Pathway V e n t r al t e gmen t al area to prefrontal cortex DLPFC cognition executive functions VMPFC Emotional regulation

21. Mesocortical Pathway Low Dopamine

22. Nigrostriatal pathway S u bstant i a n i gra to basal ganglia Extrapyramidal nervous system Motor movements D e fi c ien c ie s- Bradyk i nes i a Hyperactivity- Hyperkinetic movement disorders

23. 5HT – DA interaction at Nigrostriatal Pathway

24. Tuberoinfundibular pathway Arcuate N ucleus of h y p ot h a l am u s Anterior pituitary Inhibit prolactin release Antipsychotic drugs- increase prolactin – Galactorrhea, amenorrhea

25. 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

26. Serotonin Serotonin receptors present in many brain areas Cortical receptors- excitatory Enhances downstream glutamate release

27. Glutamate Excitatory n e u r o t r a n s mi t t e r Master switch of brain

28. Glutamate Dysfunction Abnormalities in synapse formation during neurodevelopment Genetic abnormalities Deficit in GABA Glutamate hyperactivity Increased Dopamine The major connections between these(PFC, hippocampus, and thalamus) brain regions are glutamatergic, making this neurotransmitter system central to the understanding of the abnormal connectivity in schizophrenia.

29. GABA GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD). There are two isoforms of this enzyme, GAD65 and GAD67. A consistent finding in schizophrenia is the reduction in GAD67 levels in the PFC in schizophrenia.

30. Acetyl choline Cholinergic neurotransmission is integral to cognition and memory, functions that are disrupted in schizophrenia Schizophrenic patients have a much higher incidence of cigarette smoking. Decreased levels of nicotinic and muscarinic receptors are reported in the hippocampus, frontal cortex, thalamus, and striatum in schizophrenia. Decreases in M1 and M4 receptors have been reported in the PFC and striatum in schizophrenia. There is also evidence of reduced expression of nicotinic receptor subunits α7 in the frontal and reduced expression of α4β2 subtypes in the hippocampus in schizophrenia. These findings suggest cholinergic dysfunction in schizophrenia

31. Genetics

32. Genetic Schizophrenia is a highly heritable and polygenic illness. Risk genes, including neuregulin (NRG), dystrobrevin -binding protein 1 (DTNBP1), disrupted in schizophrenia 1 (DISC1 and 2), and regulator of G protein-signaling-4 (RGS 4), have been characterized in human postmortem tissue.

33. Risk for schizophrenia in the relatives of schizophrenic patient

34. Epigenetic Epigenetic regulation of chromatin can occur via several mechanisms such as DNA methylation and posttranslational modifications of histones. There appear to be periods during development when epigenomic changes take place in the human brain. Maternal malnutrition, and viral infections, can lead toabnormal epigenetic changes (hypermethylation) of DNA. The epigenome might serve as a substrate that links environmental exposures, genetic variants, and psychopathology.

35. Neurodevelopment

36. Neurodevelopment PM studies in cortical tissue from schizophrenic individuals found ectopic neurons and abnormal cytoarchitecture in the PFC and entorhinal cortex. These data shows impairment of neuronal migration of these particular cells into the cortex during their critical developmental period (2nd trimester). Interpreted as evidence that schizophrenia is a developmental disorder.

37. Synaptic elimination remains continue upto 3rd decade of life before synaptic density stabilizes at adult levels. Some studies shows schizophrenia as a defect of excessive pruning during adolescence.

38. Synapse Formation

39. Myelination abnormalities This theory originated from structural imaging studies, who found that white matter regions, in addition to grey matter regions, showed volumetric reductions in patients with schizophrenia . Gene expression studies have shown abnormalities in myelination and oligodendrocytes in post-mortem brains of schizophrenia patients. Furthermore, oligodendrocyte numbers appear to be reduced in several post-mortem studies. Myelination abnormalities could be originate from impaired maturation of oligodendrocyte precursor cells, as these have been found to be intact in schizophrenia brains.

40. Neuroimaging

41. Structural Abnormalities V e n t r icle s - In c r eased size of lateral ventricles R educ e d c ort i c al g r a y volume Progressive or static Reduced symmetry – Neurodevelopmental

42. Prefrontal Cortex Anatomical Abnormalities Functional deficits on neuroimaging Symptoms of Schizophrenia mimics – frontal lobotomies and frontal lobe syndrome

43. 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

44. THALAMUS Volume shrinkage Neuronal loss of medial dorsal nuclei Number reduced to 30-45%

45. 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

46. Neural Circuits Early d e v e l o p m e n t a l l e sio n s of d opaminergic tracts Di s turb a nc e s i n con n e ctivity i n di f fer e nt brain regions White matter fibre tracts

47. Immunology

48. Immune system abnormalities Abnormal immune system development may help explain roles of environmental effect such as prenatal hazards, post-pubertal onset, stress, climate, and infections, in addition to genetic effects. Supported by findings of high levels of immune markers in the blood of schizophrenia patients. High levels of immune markers have also been associated with having more severe psychotic symptoms. One study discovered that single-nucleotide polymorphisms (SNP) significantly associated with schizophrenia were located in the major histocompatibility complex region of the genome.

49. Conclusion There is neither a single brain region nor a single neurochemical alteration but several, which have been associated with schizophrenia. The PFC, hippocampus, and thalamus are the regions most often implicated, perhaps in part because these are the regions most studied. At the cellular level, reduced gray matter volumes, reduced size of neurons but without cell loss, and reduced dendritic arborization and spines are the main observations seen in schizophrenia. White matter changes also contribute to connectivity deficits between brain regions implicated in schizophrenia.

50. Reference Kaplan and Sadock's Comprehensive Textbook of Psychiatry, 10 th edition Stahl’s Essential Psychopharmacology 4 th edition