Neurobiology of Schizophrenia Structure, Function
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Transcript of Neurobiology of Schizophrenia Structure, Function
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Neurobiology of Schizophrenia Structure, Function
Godfrey D. Pearlson, M.D.
Neuropsychiatry Research Center
Institute of Living
Yale University School of Medicine
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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
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Figure 2.Schizophrenia. Lateral aspect of left hemisphere showingdeviations of the temporal sulcogyral pattern.
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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:
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GENE CELL SYSTEM BEHAVIOR
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Schizophrenia – The Temporal Lobe
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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
First Psychotic Episode Patients
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Auditory Hallucinations & Temporal Lobe
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Identifying Small Fibers: The Arcuate Fasciculus
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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
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The Dopamine Hypothesis and Schizophrenia
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D2 receptor occupancy and symptom response
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IN-VIVO DA RELEASE
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Multiple Dopamine Receptors
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Dopamine and other Neurotransmitters
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GENE CELL SYSTEM BEHAVIOR
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Basic Auditory Oddball Paradigm
80% 10% 10%
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One of These Things (Is Not Like The Others)
Patients are as quick and accurate as healthy subjects
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Auditory Oddball, P300 Event-Related Potential (ERP)
Amplitude smaller in SZ.
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This Response is There For a Reason………..
NSD performance in schizophrenia vs healthy controls
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P3 FACTS
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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.
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P300 Manifests Both As An fMRI Activation Pattern And As An ERP
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1. fMRI Auditory Oddball Study
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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)
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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
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Auditory Oddball Task with fMRI
hl
HEALTHY VOLUNTEERS N=43, group-matched
SCHIZOPHRENIA N=20
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Auditory Oddball fMRI TaskSZ and 1o Relatives vs Controls
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IS THE DIFFERENT BRAIN RESPONSE IN PATIENTS RELATED TO GENETIC
DIFFERENCES ?
PATIENTSHEALTHY
P<0.0006
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We Typed 326 SNPs from 222 Genes, on an Illumina Chip
Collaboration with Gualberto Ruano Liu et al. Human Brain Mapping in press
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Extracted fMRI ComponentBOLD activation pattern best separating SZ patients from healthy controls (p<0.006)
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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
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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
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2. ERP Auditory Oddball Study
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P300 Has 2 Major Components
P3a,
P3b
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-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
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The correlation between the target p300 and SNP component = 0.55 (p<0.0002).
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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
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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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THANK YOU !