Neurobiology of Schizophrenia Structure, Function

1. Neurobiology of SchizophreniaStructure, Function Godfrey D. Pearlson, M.D. Neuropsychiatry Research Center Institute of Living Yale University School of Medicine

2. Figure 1. Right and left cerebral hemisphere of the same Down Syndrome brain. Note its globular configuration and steeply sloping occipital pole. In this brain, the superior temporal gyrus is small bilaterally. Photographs courtesy of Yakovlev collection, AFIP

3. Figure 2. Schizophrenia. Lateral aspect of left hemisphere showing deviations of the temporal sulcogyral pattern.

5. Environmental StressBiological FactorsDrug Use Disease Genes Viral Infection Environmental Toxins Peri-natal/Birth Complications TRIGGERS: SZ B i o l o g i c a l V u l n e r a b i l i t y Neurol + Cognitive Deficits Early Negative Symptoms Emerging Psychotic Symptoms Structure Biochem Function Weak Positive Symptoms Age 0 12 5 15 18 21 Early Prodrome Late Prodrome Premorbid

6. GENE  CELL  SYSTEM  BEHAVIOR

7. Schizophrenia – The Temporal Lobe

15. First Psychotic Episode Patients • No confounds of chronic illness • Can compare schizophrenia patients with those with affective (mood) disorder (AFF) psychosis (85% to 90% manic psychosis) • Similar findings in unaffected 10 relatives

16. Auditory Hallucinations & Temporal Lobe

17. Identifying Small Fibers: The Arcuate Fasciculus

19. Symptoms suggestive of frontal lobe dysfunction • Emotional dullness • Impaired judgment • Poor initiative, motivation, drive • Lack of insight • Difficulty in planning • Impaired problem-solving/abstract reasoning • Decreased concern for personal hygiene • Social withdrawal

24. The Dopamine Hypothesis and Schizophrenia

30. D2 receptor occupancy and symptom response

31. IN-VIVO DA RELEASE

32. Multiple Dopamine Receptors

33. Dopamine and other Neurotransmitters

34. GENE  CELL  SYSTEM  BEHAVIOR

35. Basic Auditory Oddball Paradigm 80% 10% 10%

36. One of These Things (Is Not Like The Others)Patients are as quick and accurate as healthy subjects

37. Auditory Oddball, P300 Event-Related Potential (ERP) Amplitude smaller in SZ.

38. This Response is There For a Reason……….. NSD performance in schizophrenia vs healthy controls

39. P3 FACTS

40. Auditory Oddball P3 • Activates multiple cortical regions. • Pattern shows strong heritability. • Abnormal in many SZ patients, (but not specifically abnormal in SZ). --SZ patients can perform the task well. --A well-recognized endophenotype. --Minimally influenced by illness stage or by antipsychotic medication.

41. P300 Manifests Both As An fMRI Activation Pattern And As An ERP

42. 1. fMRI Auditory Oddball Study

43. Kiehl et al. N=100 Study of AO Task in HCNeuroImage 2005 Areas of significant activation (10-10 voxel-wise corrected for targets vs standards)

44. SZvs Controls Controls N=18 Schizophrenia N=18 Areas of activation for target processing. Schizophrenia patients exhibit less activation in multiple areas All illuminated voxels are at p<0.001, corrected for multiple comparisons.

45. Auditory Oddball Task with fMRI hl HEALTHY VOLUNTEERS N=43, group-matched SCHIZOPHRENIA N=20

46. Auditory Oddball fMRI TaskSZ and 1o Relatives vs Controls

47. IS THE DIFFERENT BRAIN RESPONSE IN PATIENTS RELATED TO GENETIC DIFFERENCES ? P<0.0006 HEALTHY PATIENTS

48. We Typed 326 SNPs from 222 Genes, on an Illumina Chip Collaboration with Gualberto Ruano Liu et al. Human Brain Mapping in press

49. Extracted fMRI ComponentBOLD activation pattern best separating SZ patients from healthy controls (p<0.006)

50. Extracted fMRI ComponentWhat regional fMRI BOLD activation pattern best separated SZ patients from healthy control subjects? (p<0.006) Negative Differences. • Superior frontal gyrus BA6 • Medial frontal gyrus BA6 • Superior temporal gyrus BA38 Positive Differences. • Lingual gyrus BA 18, 17 • Precuneus BA 7, 19 • Cuneus BA 17, 18, 19 • Superior parietal lobule BA 7 • Fusiform gyrus BA 18, 19 • Post central gyrus BA 5, 7 • Interior occipital gyrus BA 17, 18