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.
Disease Genes
Viral Infection
Environmental Toxins
Peri-natal/Birth
Complications
TRIGGERS: Environmental Stress
Biological Factors
Drug Use
Biological Vulnerability
Structure
Biochem
Function
Age
0
Neurol +
Cognitive
Deficits
5
Premorbid
Early
Negative
Symptoms
Weak
Positive
Symptoms
12
15
Early
Prodrome
Emerging
Psychotic
Symptoms
18
Late
Prodrome
21
GENE  CELL  SYSTEM  BEHAVIOR
Schizophrenia – The Temporal
Lobe
First Psychotic Episode Patients
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•
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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 EventRelated 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
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 ?
P<0.0006
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.
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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).
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*
*
*
*
Schizophrenia Symptoms Were Related to
Both fMRI and Genetic Data
2. ERP Auditory Oddball Study
P300 Has 2 Major Components
P3b
P3a,
Target ERP components (Pz)
n200
-6
n200
-4
-2
uV
0
early p300
2
4
6
late p300
late p300
8
10
12
early p300
average ERP
-200
0
200
400
ms
600
800
1000
The correlation between the target p300
and SNP component = 0.55 (p<0.0002).
BRAIN SUBJECTS
PROBE
ANALYSIS
BRAIN DATA
GENE DATA
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
The paired ERP component responding to novel stimuli
-10
-5
uV
0
5
10
NORMAL
CONTROLS
15
PARALLEL ICA
0
ms 500
1000
P3a
-2
0
2
4
6
P3b
0
ms
500
rs1800545 ADRA2A
rs7412 APOE
rs1128503 ABCB1
rs6578993 TH
rs1045642 ABCB1
rs2278718 MDH1
rs4784642 GNAO1
rs521674 ADRA2A
rs1800545 ADRA2A
rs7412 APOE
rs1128503 ABCN1
rs6578993 TH
rs1045642 ABCB1
rs2278718 MDH1
rs4784642 GNAO1
rs521674 ADRA2A
The paired ERP component reponding to target stimuli
uV
TASK
1000
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 !