Highlights of main Highlights of main findingsfindings““From genes to brain to From genes to brain to behavior”behavior”

The P300 event-related The P300 event-related brain potential as a brain potential as a neurobiological neurobiological endophenotype for endophenotype for substance use substance use disorders: A meta-disorders: A meta-analysisanalysis

Anja Euser, MSc.Anja Euser, MSc.

Instituut voor PsychologieInstituut voor Psychologie

Erasmus Universiteit RotterdamErasmus Universiteit Rotterdam

Overview

• IntroductionIntroduction• EndophenotypesEndophenotypes• P300 amplitude: P300 amplitude:

• Theoretical backgroundTheoretical background• Main findings of P300 addiction research areaMain findings of P300 addiction research area

• The present studyThe present study

• Meta-analytic methodsMeta-analytic methods

• ResultsResults

• ConclusionConclusion

Introduction

Endophenotypes:Endophenotypes:

• Endophenotypes (intermediate phenotypes) are “measurable Endophenotypes (intermediate phenotypes) are “measurable components unseen by the unaided eye along the pathway between components unseen by the unaided eye along the pathway between disease and distal genotype” (Gottesman & Gould, 2003)disease and distal genotype” (Gottesman & Gould, 2003)

• Heritable traits that reflect the actions of genes predisposing an Heritable traits that reflect the actions of genes predisposing an individual to a disorderindividual to a disorder

• In essence, endophenotypes are at the center of the clinical aspect, 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 phenotype, and the genotype. This is why they can be utilized in the process of unraveling the genetic causes of (psychiatric) illnessesthe process of unraveling the genetic causes of (psychiatric) illnesses

Genotype Endophenotype

Phenotype

Introduction

Endophenotypes:Endophenotypes:

Two fundamental criteria for being an endophenotype (Gottesman & Two fundamental criteria for being an endophenotype (Gottesman & Gould, 2003):Gould, 2003):

1.1. It should be associated with the disorder and thus, should appear in It should be associated with the disorder and thus, should appear in those with the disorder more often than it appears in the general those with the disorder more often than it appears in the general population.population.

2.2. It should be found in non-affected biological relatives of those who 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 have the disorder at a higher rate than in the general population as well.well.

Genes

Intermediate

phenotype

Unaffected

DisorderReduced

P300 amplitude

Introduction

P300 amplitude: theoretical backgroundP300 amplitude: theoretical background

• Large positive-going EEG peak (300 – 800ms after the presentation Large positive-going EEG peak (300 – 800ms after the presentation of stimuli, recognized as requiring a response/demand attention)of stimuli, recognized as requiring a response/demand attention)

• Typically elicited by an “oddball” paradigmTypically elicited by an “oddball” paradigm

• P300 is thought to reflect the mental processes underlying:P300 is thought to reflect the mental processes underlying:• The deployment of attentional resources to an incoming stimulusThe deployment of attentional resources to an incoming stimulus• The evaluation of the stimulusThe evaluation of the stimulus• The subsequent memory mechanisms engaged for that stimulusThe subsequent memory mechanisms engaged for that stimulus

• Reduced P300 amplitudes: Reduced P300 amplitudes: • Ineffecient allocation of attentional resources in processing task Ineffecient allocation of attentional resources in processing task

relevant cognitive information (deficits in attentional control) relevant cognitive information (deficits in attentional control)

Introduction

Main findings of P300 addiction research area:Main findings of P300 addiction research area:

• P300 amplitude reductions have been observed in:P300 amplitude reductions have been observed in:• (Chronic) Alcoholics (Chronic) Alcoholics • Children (and other family members) of alcoholics Children (and other family members) of alcoholics • Individuals who abuse illicit substances Individuals who abuse illicit substances • Children of SUD patientsChildren of SUD patients• Current and ex-smokersCurrent and ex-smokers

• Two lines of research in accordance with the 2 criteria for Two lines of research in accordance with the 2 criteria for an endophenotype:an endophenotype:

• P300 as a disease markerP300 as a disease marker• P300 as a vulnerability markerP300 as a vulnerability marker

Introduction

• However:However:• Findings are not entirely consistent across laboratories!Findings are not entirely consistent across laboratories!• There are many non-significant findings as wellThere are many non-significant findings as well• Inconsistency among studies may be due to differences in Inconsistency among studies may be due to differences in

several sample-, task-, and study characteristicsseveral sample-, task-, and study characteristics

That’s why we need a meta-analysis! That’s why we need a meta-analysis!

The present study

Major purpose :Major purpose :

• Examine whether the P300 amplitude is a disease as well as Examine whether the P300 amplitude is a disease as well as a vulnerability marker for SUD, and hence, whether P300 a vulnerability marker for SUD, and hence, whether P300 fulfils the two important criteria for an endophenotypefulfils the two important criteria for an endophenotype

• Assess potential moderating effects of specific sample-, Assess potential moderating effects of specific sample-, task-, and study variables on P300 outcomes and provide an task-, and study variables on P300 outcomes and provide an empirical basis for future studiesempirical basis for future studies

Two seperate meta-analysis:Two seperate meta-analysis:

1.1. P300 P300 in relation to SUD (in relation to SUD (Meta-analysis 1)Meta-analysis 1)2.2. P300 in relation to a FH+ of substance use (Meta-analysis 2)P300 in relation to a FH+ of substance use (Meta-analysis 2)

Method

Extensive literature searchExtensive literature search

Criteria for inclusion:Criteria for inclusion:

• English languageEnglish language• Peer-reviewedPeer-reviewed• SUD+/FH+ groupsSUD+/FH+ groups• Control groupsControl groups• Oddball paradigmOddball paradigm

• Standard 2 stimulusStandard 2 stimulus• Novelty oddballNovelty oddball• Rotated head taskRotated head task

• P300 (P3b) measureP300 (P3b) measure• Sufficient statististical Sufficient statististical

information: information: MM,, SD SD, , nn

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 meta-analyses (n= 63)

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

M eta-analysis 1: P300 am plitude in relation to SUD (n = 38)

M eta-analysis 2: P300 am plitude in relation to FH+ of substance use (n = 34)

Method

Statistical methods:Statistical methods:

• CMA (Comprehensive Meta-Analysis)CMA (Comprehensive Meta-Analysis)

• Effect size (ES) statistic Cohen’s Effect size (ES) statistic Cohen’s dd

• FormulaFormula d = d = ((MM11 – M – M2)/2)/SDSD• MM1 = mean P300 amplitude (Pz) in SUD-/FH- groups1 = mean P300 amplitude (Pz) in SUD-/FH- groups• MM2 = mean P300 amplitude in SUD+/FH+ groups2 = mean P300 amplitude in SUD+/FH+ groups• SD SD = pooled standard deviation of the two groups’ P300 amplitude = pooled standard deviation of the two groups’ P300 amplitude

outcomesoutcomes

• Overall ES: rates are pooled using random-effects modelOverall ES: rates are pooled using random-effects model

• Influence of moderating variables: a priori defined Influence of moderating variables: a priori defined subgroup analysissubgroup analysis

Method

A priori defined subgroupsA priori defined subgroups

Chosen based on their Chosen based on their theoretical and theoretical and methodological methodological significance to SUDs, significance to SUDs, high-risk samples, and high-risk samples, and P300 research.P300 research.

Results: Meta-Analysis 1

Overall ES:Overall ES:

• dd = 0.51 (95% CI = 0.41-0.61, = 0.51 (95% CI = 0.41-0.61, pp < .001)< .001)

• SUD patients have significantly < SUD patients have significantly < P300 amplitudes as compared to P300 amplitudes as compared to healthy controleshealthy controles

Results: Meta-Analysis 1

Significant Subgroup Analyses:Significant Subgroup Analyses:

1.1. Substance use statusSubstance use status

2.2. Source of subject recruitmentSource of subject recruitment

QQbb (1) = 13.12, (1) = 13.12, pp < .001< .001

QQbb (2) = 8.15, (2) = 8.15, pp < .05< .05

Results: Meta-Analysis 2

Overall ES:Overall ES:

• dd = 0.28 (95% CI = 0.15-0.41, = 0.28 (95% CI = 0.15-0.41, pp < .001)< .001)

• FH+ individuals have significantly < FH+ individuals have significantly < P300 amplitudes as compared to low P300 amplitudes as compared to low risk controlesrisk controles

Results: Meta-Analysis 2

Significant Subgroup Analysis:Significant Subgroup Analysis:

1.1. GenderGenderQQbb (1) = 16.68, (1) = 16.68, pp < .001< .001

Conclusion

Main findings:Main findings:

• P300 amplitude is strongly associated with SUDs and, to P300 amplitude is strongly associated with SUDs and, to a lesser extent, also with a FH+ of substance use.a lesser extent, also with a FH+ of substance use.

• P300 amplitude reduction can be a useful disease and P300 amplitude reduction can be a useful disease and vulnerability marker and a promosing neurobiological vulnerability marker and a promosing neurobiological endophenotype for SUDsendophenotype for SUDs

Other highlights:Other highlights:

1.1. This is only the case in malesThis is only the case in males2.2. P300 amplitude reduction is not specific for alcoholP300 amplitude reduction is not specific for alcohol3.3. The effect is even observable after a prolonged period of The effect is even observable after a prolonged period of

abstinence (state-independent)abstinence (state-independent)4.4. Different P300 effect sizes can be expected in different Different P300 effect sizes can be expected in different

populationspopulations

Conclusion

Future directions:Future directions:

• Additional efforts are needed to obtain a more Additional efforts are needed to obtain a more comprehensive understandig of how P300 amplitude comprehensive understandig of how P300 amplitude reflect gender differences, SUD, and risk for substance reflect gender differences, SUD, and risk for substance use.use.

• A key challenge would be to precisely identify the brain A key challenge would be to precisely identify the brain systems that are involved, and the genes that systems that are involved, and the genes that contribute to these brain-bases differences.contribute to these brain-bases differences.

Thanks for your attention

Any questions?Any questions?

Introduction

P300 amplitude: heritability and geneticsP300 amplitude: heritability and genetics

• Heritability estimate of 60% (van Beijsterveldt & van Baal, Heritability estimate of 60% (van Beijsterveldt & van Baal, 2002)2002)

Not identical for both genders (Yoon, Iacono, Malone, & Not identical for both genders (Yoon, Iacono, Malone, & McGue, 2006)McGue, 2006)

• HH2 2 = 0.65 for males= 0.65 for males• HH2 2 = 0.32 for females= 0.32 for females

• Associated genes:Associated genes:• DRD2 (Taq1 A1 allele) DRD2 (Taq1 A1 allele) (Hill et al., 1998)(Hill et al., 1998)

• DRD3 (Ser9Gly polymorphism) DRD3 (Ser9Gly polymorphism) (Mulert et al., 2006)(Mulert et al., 2006)

• CNR1 gene CNR1 gene (Johnson et al., 1997)(Johnson et al., 1997)

• COMT COMT (Gallinat et al., 2003; Tsai et al., 2003)(Gallinat et al., 2003; Tsai et al., 2003)

Publication bias

Meta-analysis 1:Meta-analysis 1:

• Evidence of publication biasEvidence of publication bias• Trim & Fill method (Duval & Trim & Fill method (Duval &

Tweedie)Tweedie)• Corrected ES estimate based on Corrected ES estimate based on

the imputation of 10 the imputation of 10 hypothetical studies: hypothetical studies: dd = = 0.38 (0.38 (pp < .001) < .001)

Meta-analysis 2:Meta-analysis 2:

• No evidence of publication biasNo evidence of publication bias