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

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

2. Overview • Introduction • Endophenotypes • P300 amplitude: • Theoretical background • Main findings of P300 addiction research area • The present study • Meta-analytic methods • Results • Conclusion

3. Introduction Endophenotypes: • Endophenotypes (intermediate phenotypes) are “measurable components unseen by the unaided eye along the pathway between disease and distal genotype” (Gottesman & Gould, 2003) • Heritable traits that reflect the actions of genes predisposing an individual to a disorder • 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 Genotype Endophenotype Phenotype

4. Introduction Endophenotypes: Twofundamental criteria forbeinganendophenotype (Gottesman & Gould, 2003): • Itshouldbeassociatedwith the disorder and thus, shouldappear in thosewith the disorder more oftenthanitappears in the generalpopulation. • Itshouldbefound in non-affectedbiologicalrelatives of thosewho have the disorder at a higherratethan in the generalpopulation as well. Disorder Intermediate phenotype Reduced P300 amplitude Genes Unaffected

5. Introduction P300 amplitude: theoretical background • Largepositive-going EEG peak (300 – 800ms after the presentation of stimuli, recognized as requiring a response/demandattention) • Typicallyelicitedbyan “oddball” paradigm • P300 is thought to reflect the mental processesunderlying: • The deployment of attentional resources to anincoming stimulus • The evaluation of the stimulus • The subsequentmemorymechanismsengagedforthat stimulus • Reduced P300 amplitudes: • Ineffecientallocation of attentional resources in processing task relevant cognitiveinformation (deficits in attentionalcontrol)

6. Introduction Main findings of P300 addiction research area: • P300 amplitude reductions have been observed in: • (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: • P300 as a disease marker • P300 as a vulnerability marker

7. Introduction • However: • 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!

8. The present study Major purpose : • 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: • P300 in relation to SUD (Meta-analysis 1) • P300 in relation to a FH+ of substance use (Meta-analysis 2)

9. Method Extensive literature search Criteria for inclusion: • English language • Peer-reviewed • SUD+/FH+ groups • Control groups • Oddball paradigm • Standard 2 stimulus • Novelty oddball • Rotated head task • P300 (P3b) measure • Sufficient statististical information: M, SD, n

10. Method Statisticalmethods: • CMA (Comprehensive Meta-Analysis) • Effect size (ES) statistic Cohen’s d • Formula d = (M1 – M2)/SD • M1 = mean P300 amplitude (Pz) in SUD-/FH- groups • M2 = mean P300 amplitude in SUD+/FH+ groups • SD = pooledstandarddeviation of the twogroups’ P300 amplitude outcomes • Overall ES: rates are pooledusingrandom-effects model • Influence of moderating variables: a priori definedsubgroupanalysis

11. Method A priori defined subgroups Chosen based on their theoretical and methodological significance to SUDs, high-risk samples, and P300 research.

12. Results: Meta-Analysis 1 Overall ES: • d = 0.51 (95% CI = 0.41-0.61, p < .001) • SUD patients have significantly < P300 amplitudes as compared to healthy controles

13. Results: Meta-Analysis 1 Significant Subgroup Analyses: • Substance use status • Source of subject recruitment Qb (1) = 13.12, p < .001 Qb (2) = 8.15, p < .05

14. Results: Meta-Analysis 2 Overall ES: • d = 0.28 (95% CI = 0.15-0.41, p < .001) • FH+ individuals have significantly < P300 amplitudes as compared to low risk controles

15. Results: Meta-Analysis 2 Significant Subgroup Analysis: • Gender Qb (1) = 16.68, p < .001

16. Conclusion Main findings: • 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: • 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

17. Conclusion Future directions: • Additional efforts are needed to obtain a more comprehensive understandig of how P300 amplitude reflect gender differences, SUD, and risk for substance use. • A key challenge would be to precisely identify the brain systems that are involved, and the genes that contribute to these brain-bases differences.

18. Thanks for your attention Any questions?

19. Introduction P300 amplitude: heritability and genetics • Heritabilityestimate of 60% (van Beijsterveldt & van Baal, 2002) Notidenticalforbothgenders (Yoon, Iacono, Malone, & McGue, 2006) • H2 = 0.65 formales • H2 = 0.32 forfemales • Associatedgenes: • 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)

20. Publication bias • Meta-analysis 1: • Evidence of publication bias • Trim & Fill method (Duval & Tweedie) • Corrected ES estimate based on the imputation of 10 hypothetical studies: d = 0.38 (p < .001) • Meta-analysis 2: • No evidence of publication bias