Download Schizophrenia as a Brain Disease: Evidence from Biological Measures

Schizophrenia as a Brain Disease: Evidence
from Biological Measures
(Excluding Brain Imaging & Genetics)
Godfrey D. Pearlson
Olin Neuropsychiatry Research Center, Institute of Living HHC, Hartford, CT
Depts. of Psychiatry & Neuroscience, Yale University School of Medicine, New Haven, CT
RSNA
11-2016
Disclosures
• Receive funding from NIMH, NIDA, NHTSA.
• No discussion of products being used for nonFDA approved indications.
• Contact: [email protected]
• This talk is archived on NRC-IOL.org under
“Talks”
Underlying Assumption
……………………AGE-RELATED/DEVELOPMENTAL EFFECTS…………….
…………………………..ENVIRONMENTAL INFLUENCES………………………
GENE  CELL  SYSTEM 
BEHAVIOR
Cell-Cell
Pathology
Normal
Variation,
Or Mutations,
Or CNVs
Molecular
Biology
Neural Circuit
Function
Normal Variation
Endophenotypes
Sensory motor
Integration
SZ
Schizophrenia Endophenotypes
5 broad domains
1. Electrophysiology. Resting state, Evoked
potentials (e.g. N100, P50, P300) and ERO’s.
2. Eye Movement. Smooth pursuit, saccades,
anti-saccades.
3. Cognition. Multiple domains, especially
working memory, set-shifting, executive
functioning, social cognition, memory.
4. Simple Sensory Processing. Visuo-spatial
frequency processing.
5. (NeuroImaging. sMRI, fMRI, DTI etc).
Criteria for an Endophenotype
(After Gottesman; Illness liability markers- not illness markers)
1.
Biological measures associated with an illness.
2.
State- and treatment-independent,
(versus biomarkers).
3.
Heritable (h2) & quantifiable.
4.
Familial co-segregation with the illness.
5. Found in some unaffected close relatives, at a
rate higher than in the general population,
(versus biomarkers).
(Issues of sensitivity vs specificity)
Optimal Endophenotypes
Glahn et al, Biol Psychiatry, 2012
• Joint genetic determination of
endophenotype and disease risk is
fundamental to the endophenotype
concept
• Criteria of Optimal Endophenotype:
– Must be heritable
– Must be genetically correlated with the illness
(pleiotropy)
Familiar Endophenotypes
• Raised fasting plasma glucose in non-diabetic firstdegree relatives of type-2 diabetics.
• Raised serum iron in unaffected relatives of
hemochromatosis patients.
• Abnormal EEG in unaffected relatives of juvenile
myoclonic epilepsy patients.
All of the above clarified mode of inheritance and
ultimately identified risk genes/loci, e.g. Mahtani 1996,
Greenberg 1988, Lalouel 1985).
Assumed Advantages of
Endophenotypes
• Closer to the genotype than the DSM clinical
phenotype.
• Genetically simpler in structure than clinical
phenotype.
• More tractable to genotyping.
• Can assess in unaffected close relatives, as
well as probands.
An In-Depth Look at One
Endophenotype- the Auditory
Oddball P300 Event-Related
Potential (P300 ERP)
Basic Auditory Oddball Paradigm
(
0%
90%
10%
)
10%
One of These Things (Is Not Like The Others)
Patients are ~as quick and accurate as healthy subjects
Bertram & Ernest: J-SSS, 2010
Auditory Oddball, P300 Event-Related
Potential (ERP)
Amplitude
smaller in
SZ.
This Response is There For a
Reason………..
P300 is Conserved in Mammals
P300 as An Endophenotype
BSNIP-1, N=2500
B-SNIP1 Neurocognitive Biomarker Panel
Auditory ERPs
Paired stimuli
Sensory suppression or gating
P50 and N100 ERPs
Oddball
Standards and targets
Working memory updating
Hamm et al. (2012) Psychophysiology
B-SNIP1 Biomarker Panel: ERPs
Auditory ERPs
Paired stimuli
Sensory suppression or gating
P50 and N100 ERPs
Oddball
Standards and targets
Working memory updating
Hamm et al. (2012) Psychophysiology
B-SNIP1: Cognition
BACS
Verbal memory
Processing speed
Reasoning
Working memory
AJP 2013
BSNIP Cognition Familiality
Working Memory is a
Schizophrenia Endophenotype
Glahn et al, Am J Med Genet Part B, 2007
• Working memory locus
of dysfunction in
psychosis (Goldman-Rakic,
1994; Carter et al., 1996; Callicott et
al., 1999; Minzenberg et al., 2009)
• Impairment exists prior
to disease onset and
independent of state
(Niendam et al, 2003; Reichenberg
et al, 2005; Lee & Park 2005)
• Family members exhibit
impairment (Cannon et al.,
h2=0.466,
p=6x10-5; ρ
g=-0.392,
p=0.004
2000; Egan et al., 2001; Glahn et
al., 2003; Almasy et al., 2008;
Calkins et al., 2006)
Eye Tracking Abnormalities
• First biological abnormality recorded in SZ, in
1908, 50 years prior to antipsychotic drug use.
• Rediscovered by Holzman et al., 1974 who
also noted impairment in unaffected relatives.
Eye Tracking Measures
• Gain = speed of eye, relative to speed of target.
• Root mean square error = how closely eye is foviated
on target throughout task. (e.g. if gain [speed]
matches target, but consistently lags behind then gain
is normal but RMS error is reduced).
• Saccades= rapid movement of eye towards a target.
e.g. eye jumps ahead of target (anticipatory saccade)
or falls behind with a ‘catch-up’ saccade.
• Anti-Saccade Task= subjects have to move eyes rapidly
to a specified location on the opposite side of the
visual field from a remembered target.
Pursuit Eye Movements
• Provide stable perception of moving
objects.
• Match eye velocity to object (target)
velocity.
• Mechanisms involved:
– Motion perception
– Sensorimotor transformation
– Cortical motor command
– Controlled by retinal feedback
and
– extraretinal mechanisms:
prediction, anticipation, working
memory, visuo-spatial attention
and transformation, multimodal
visuomotor control
BSNIP-1 Smooth Pursuit
Saccade/Anti-Saccade Errors
Antisaccade
Cognitive control
Inhibition
Errors, latency, accuracy
Sensory Processing Deficits in
Schizophrenia
Visual Spatial Frequency Processing
Deficits
Visual P1 Developmental Aspects
Genotyping Endophenotypes
Biological Pathways Implicated in Common Across AOD,
(P300), Paired Stimulus Processing & Resting EEG
From Mokhtari et al. Schiz Bull 2015.
Parallel ICA
Pearlson, Liu Calhoun 2015
Summary
• Schizophrenia patients show multiple
abnormalities across many biological domains,
in tasks ranging from simple to complex.
• Many of these are strongly heritable, found in
unaffected first-degree relatives, not
attributable to antipsychotic medications, and
already present at illness onset.
• Genotyping these endophenotypes supports
neurodevelopmental origin for SZ.
• Many, if not all EP are not SZ-specific.
Thank You