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 showingdeviations of the temporal sulcogyral pattern.

Environmental StressBiological FactorsDrug Use

StructureBiochemFunction

Neurol +CognitiveDeficits

EarlyNegativeSymptoms

WeakPositiveSymptoms

EmergingPsychoticSymptoms

B i o l o g i c a l V u l n e r a b i l i t y

Age5 12 15 180 21

Premorbid EarlyProdrome

LateProdrome

Disease GenesViral InfectionEnvironmental Toxins

Peri-natal/BirthComplications

TRIGGERS:

GENE CELL SYSTEM BEHAVIOR

Schizophrenia – The Temporal Lobe

• 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

First Psychotic Episode Patients

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. Schizophrenia patients exhibit less activation in multiple areas All illuminated voxels are at p<0.001, corrected for multiple comparisons.

Controls N=18 Schizophrenia N=18

Auditory Oddball Task with fMRI

hl

HEALTHY VOLUNTEERS N=43, group-matched

SCHIZOPHRENIA N=20

Auditory Oddball fMRI TaskSZ and 1o Relatives vs Controls

IS THE DIFFERENT BRAIN RESPONSE IN PATIENTS RELATED TO GENETIC

DIFFERENCES ?

PATIENTSHEALTHY

P<0.0006

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 ComponentBOLD 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

P3a,

P3b

-200 0 200 400 600 800 1000

-6

-4

-2

0

2

4

6

8

10

12

ms

uV

Target ERP components (Pz)

n200

average ERP

late p300

early p300

n200

early p300

late p300

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

rs1466163 AADCrs 2429511 ADRA2A rs3087454 CHRNA7rs821616 DISC 1 rs 885834 CHATrs1355920 CHRNA7 rs4765623 SCARB1 rs4784642 GNAO1 rs 2071521 APOC3 rs7520974 CHRM3

SCHIZOPHRENIA VS NORMAL

CONTROLS

NORMAL CONTROLS

PARALLEL ICA

PARALLEL ICA

rs1800545 ADRA2Ars7412 APOErs1128503 ABCN1rs6578993 THrs1045642 ABCB1rs2278718 MDH1rs4784642 GNAO1rs521674 ADRA2A

rs1800545 ADRA2Ars7412 APOErs1128503 ABCB1rs6578993 THrs1045642 ABCB1rs2278718 MDH1rs4784642 GNAO1rs521674 ADRA2A

TASK BRAIN PROBE

SUBJECTS ANALYSIS BRAIN DATA GENE DATA

The paired ERP component responding to novel stimuli

0 500 1000

-10

-5

0

5

10

15ms

uV

P3a

0 500 1000

-2

0

2

4

6

The paired ERP component reponding to target stimuli

ms

uV

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).

THANK YOU !