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

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

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

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

GENE  CELL  SYSTEM  BEHAVIOR

Schizophrenia – The Temporal Lobe

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

Auditory Hallucinations & Temporal Lobe

Identifying Small Fibers: The Arcuate Fasciculus

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

The Dopamine Hypothesis and Schizophrenia

D2 receptor occupancy and symptom response

IN-VIVO DA RELEASE

Multiple Dopamine Receptors

Dopamine and other Neurotransmitters

GENE  CELL  SYSTEM  BEHAVIOR

Basic Auditory Oddball Paradigm 80% 10% 10%

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

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

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

P3 FACTS

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.

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

1. fMRI Auditory Oddball Study

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)

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.

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

Auditory Oddball fMRI Task SZ and 1o Relatives vs Controls

IS THE DIFFERENT BRAIN RESPONSE IN PATIENTS RELATED TO GENETIC DIFFERENCES ? HEALTHY PATIENTS

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

Extracted fMRI Component BOLD activation pattern best separating SZ patients from healthy controls (p<0.006)

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

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

Schizophrenia Symptoms Were Related to Both fMRI and Genetic Data

2. ERP Auditory Oddball Study

P300 Has 2 Major Components P3b P3a,

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

BRAIN PROBE TASK SUBJECTS ANALYSIS BRAIN DATA GENE DATA P3a P3b rs1466163 AADC rs 2429511 ADRA2A rs3087454 CHRNA7 rs821616 DISC 1 rs 885834 CHAT rs1355920 CHRNA7 rs4765623 SCARB1 rs4784642 GNAO1 rs 2071521 APOC3 rs7520974 CHRM3 PARALLEL ICA SCHIZOPHRENIA VS NORMAL CONTROLS P3a rs1800545 ADRA2A rs7412 APOE rs1128503 ABCB1 rs6578993 TH rs1045642 ABCB1 rs2278718 MDH1 rs4784642 GNAO1 rs521674 ADRA2A NORMAL CONTROLS PARALLEL ICA rs1800545 ADRA2A rs7412 APOE rs1128503 ABCN1 rs6578993 TH rs1045642 ABCB1 rs2278718 MDH1 rs4784642 GNAO1 rs521674 ADRA2A P3b

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).

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