Transcript Slide 1

The P300 event-related brain
potential as a neurobiological
endophenotype for substance
use disorders: A meta-analysis
Highlights of main findings
“From genes to brain to behavior”
Anja Euser, MSc.
Instituut voor Psychologie
Erasmus Universiteit Rotterdam
Overview
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Introduction
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Endophenotypes
P300 amplitude:
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Theoretical background
Main findings of P300 addiction research area
The present study
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Meta-analytic methods
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Results
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Conclusion
Introduction
Endophenotypes:
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Endophenotypes (intermediate phenotypes) are “measurable components unseen
by the unaided eye along the pathway between disease and distal genotype”
(Gottesman & Gould, 2003)
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Heritable traits that reflect the actions of genes predisposing an individual to a disorder
Genotype
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Endophenotype
Phenotype
In essence, endophenotypes are at the center of the clinical aspect, the phenotype,
and the genotype. This is why they can be utilized in the process of unraveling the
genetic causes of (psychiatric) illnesses
Introduction
Endophenotypes:
Two fundamental criteria for being an endophenotype (Gottesman & Gould, 2003):
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It should be associated with the disorder and thus, should appear in those with
the disorder more often than it appears in the general population.
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It should be found in non-affected biological relatives of those who have the
disorder at a higher rate than in the general population as well.
Disorder
Genes
Intermediate
Reduced
P300
phenotype
amplitude
Unaffected
Introduction
P300 amplitude: theoretical background
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Large positive-going EEG peak (300 – 800ms after the presentation of stimuli,
recognized as requiring a response/demand attention)
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Typically elicited by an “oddball” paradigm
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P300 is thought to reflect the mental processes underlying:
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The deployment of attentional resources to an incoming stimulus
The evaluation of the stimulus
The subsequent memory mechanisms engaged for that stimulus
Reduced P300 amplitudes:
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Ineffecient allocation of attentional resources in processing task relevant
cognitive information (deficits in attentional control)
Introduction
Main findings of P300 addiction research area:
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P300 amplitude reductions have been observed in:
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(Chronic) Alcoholics
Children (and other family members) of alcoholics
Individuals who abuse illicit substances
Children of SUD patients
Current and ex-smokers
Two lines of research in accordance with the 2 criteria for an endophenotype:
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P300 as a disease marker
P300 as a vulnerability marker
Introduction
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However:
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Findings are not entirely consistent across laboratories!
There are many non-significant findings as well
Inconsistency among studies may be due to differences in several sample-,
task-, and study characteristics
That’s why we need a meta-analysis!
The present study
Major purpose :
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Examine whether the P300 amplitude is a disease as well as a
vulnerability marker for SUD, and hence, whether P300 fulfils the two
important criteria for an endophenotype
Assess potential moderating effects of specific sample-, task-, and study
variables on P300 outcomes and provide an empirical basis for future
studies
Two seperate meta-analysis:
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P300 in relation to SUD (Meta-analysis 1)
P300 in relation to a FH+ of substance use (Meta-analysis 2)
Method
Extensive literature search
Criteria for inclusion:
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English language
Peer-reviewed
SUD+/FH+ groups
Control groups
Oddball paradigm
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Standard 2 stimulus
Novelty oddball
Rotated head task
P300 (P3b) measure
Sufficient statististical
information: M, SD, n
Overall result of Pubmed and
Scopus database search; potentially
relevant studies (n = 631)
Full-text analysis: studies retrieved
for detailed evaluation; potentially
appropriate studies (n = 236)
Studies selected for meta-analyses
(n = 81)
Seperate studies with usable
information included in metaanalyses (n = 63)
Meta-analysis 1: P300 amplitude
in relation to SUD
(n = 38)
Excluded (n = 395)
- search overlap
- review or comment
- unrelated to topic
- no human study
- no English language
Excluded (n = 155)
- no oddball paradigm
- no SUD+/FH+ sample
- no suitable control group
- inappropriate P300 (P3b) measure
- duplicate data
Excluded (n = 18)
Insufficient information to
permit effect size calculations
Meta-analysis 2: P300 amplitude
in relation to FH+ of substance use
(n = 34)
Method
Statistical methods:
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CMA (Comprehensive Meta-Analysis)
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Effect size (ES) statistic Cohen’s d
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Formula d = (M1 – M2)/SD
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M1 = mean P300 amplitude (Pz) in SUD-/FH- groups
M2 = mean P300 amplitude in SUD+/FH+ groups
SD = pooled standard deviation of the two groups’ P300 amplitude outcomes
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Overall ES: rates are pooled using random-effects model
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Influence of moderating variables: a priori defined subgroup analysis
Method
A priori defined subgroups
Chosen based on their theoretical
and methodological significance to
SUDs, high-risk samples, and P300
research.
Results: Meta-Analysis 1
Overall ES:
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d = 0.51 (95% CI = 0.41-0.61, p < .001)
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SUD patients have significantly < P300
amplitudes as compared to healthy controles
Results: Meta-Analysis 1
Significant Subgroup Analyses:
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Substance use status
Qb (1) = 13.12, p < .001
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Source of subject recruitment
Qb (2) = 8.15, p < .05
Results: Meta-Analysis 2
Overall ES:
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d = 0.28 (95% CI = 0.15-0.41, p < .001)
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FH+ individuals have significantly < P300
amplitudes as compared to low risk controles
Results: Meta-Analysis 2
Significant Subgroup Analysis:
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Gender
Qb (1) = 16.68, p < .001
Conclusion
Main findings:
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P300 amplitude is strongly associated with SUDs and, to a lesser
extent, also with a FH+ of substance use.
P300 amplitude reduction can be a useful disease and vulnerability
marker and a promosing neurobiological endophenotype for SUDs
Other highlights:
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This is only the case in males
P300 amplitude reduction is not specific for alcohol
The effect is even observable after a prolonged period of abstinence
(state-independent)
Different P300 effect sizes can be expected in different populations
Conclusion
Future directions:
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Additional efforts are needed to obtain a more comprehensive
understandig of how P300 amplitude reflect gender differences, SUD,
and risk for substance use.
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A key challenge would be to precisely identify the brain systems that are
involved, and the genes that contribute to these brain-bases differences.
Thanks for your attention
Any questions?
Introduction
P300 amplitude: heritability and genetics
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Heritability estimate of 60% (van Beijsterveldt & van Baal, 2002)
Not identical for both genders (Yoon, Iacono, Malone, & McGue, 2006)
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H2 = 0.65 for males
H2 = 0.32 for females
Associated genes:
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DRD2 (Taq1 A1 allele) (Hill et al., 1998)
DRD3 (Ser9Gly polymorphism) (Mulert et al., 2006)
CNR1 gene (Johnson et al., 1997)
COMT (Gallinat et al., 2003; Tsai et al., 2003)
Publication bias
Meta-analysis 1:
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Evidence of publication bias
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Trim & Fill method (Duval & Tweedie)
Corrected ES estimate based on the
imputation of 10 hypothetical studies:
d = 0.38 (p < .001)
Meta-analysis 2:
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No evidence of publication bias