1. Neurobiology of Schizophrenia Structure, 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 Stress Biological Factors Drug Use
Disease Genes
Viral Infection
Environmental Toxins
Peri-natal/Birth
Complications
TRIGGERS:
Environmental Stress Biological Factors Drug Use SZ
B i o l o g i c a l V u l n e r a b i l i t y
Structure
Biochem
Function
Neurol +
Cognitive
Deficits
Early
Negative
Symptoms
Weak
Positive
Symptoms
Emerging
Psychotic
Symptoms
Age 5 12 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 HC NeuroImage 2005
Areas of significant activation (10-10 voxel-wise corrected for targets vs standards)

44. SZ vs Controls Areas of activation for target processing.
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 fMRIhl
HEALTHY VOLUNTEERS
N=43, group-matched
SCHIZOPHRENIA
N=20

46. Auditory Oddball fMRI Task SZ and 1o Relatives vs Controls

47. IS THE DIFFERENT BRAIN RESPONSE IN PATIENTS RELATED TO GENETIC DIFFERENCES ?
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 Component BOLD activation pattern best separating SZ patients from healthy controls (p<0.006)

50. Extracted fMRI Component What 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

51. Gene Findings Genetic component best explaining activation in the fMRI component (p<0.001).
* * * * * *

52. Schizophrenia Symptoms Were Related to Both fMRI and Genetic Data

53. 2. ERP Auditory Oddball Study

54. P300 Has 2 Major Components
P3b
P3a,

56. The correlation between the target p300 and SNP component = 0
The correlation between the target p300 and SNP component = 0.55 (p<0.0002).

57. BRAIN PROBE TASK SUBJECTS ANALYSIS BRAIN DATA GENE DATA P3a P3b
rs AADC
rs ADRA2A
rs CHRNA7
rs DISC 1
rs CHAT
rs CHRNA7
rs SCARB1
rs GNAO1
rs APOC3
rs CHRM3
PARALLEL ICA
SCHIZOPHRENIA
VS NORMAL CONTROLS
P3a
rs ADRA2A
rs7412 APOE
rs ABCB1
rs TH
rs ABCB1
rs MDH1
rs GNAO1
rs ADRA2A
NORMAL CONTROLS
PARALLEL ICA
rs ADRA2A
rs7412 APOE
rs ABCN1
rs TH
rs ABCB1
rs MDH1
rs GNAO1
rs ADRA2A
P3b

59. Conclusions : “Imaging Genetics”
Aim: to meld genetic & brain imaging findings to elucidate role of genetic variation in neuro-psychiatric disorders, or to associate normal population differences in cognition or behavior with structural/functional brain imaging measures.
Instantiation: Once a potential neuropsychiatric disorder risk gene has been identified, a useful strategy is to explore if normal gene variants have any influence on normal brain structure/function.
This helps provide a context for how altered function at a genetic level may play out at a brain system level (a la Weinberger).

60. THANK YOU !