1. Highlights of main findings “From genes to brain to behavior” The P300 event-related brain potential as a neurobiological endophenotype for substance use disorders: A meta-analysis Anja Euser, MSc. Instituut voor Psychologie Erasmus Universiteit Rotterdam

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

4. Introduction Endophenotypes: Two fundamental criteria for being an endophenotype (Gottesman & Gould, 2003): 1. 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. 2. 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. Genes Intermediate phenotype Unaffected Disorder Reduced P300 amplitude

5. Introduction P300 amplitude: theoretical background Large positive-going EEG peak (300 – 800ms after the presentation of stimuli, recognized as requiring a response/demand attention) Large positive-going EEG peak (300 – 800ms after the presentation of stimuli, recognized as requiring a response/demand attention) Typically elicited by an “oddball” paradigm Typically 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 stimulus The deployment of attentional resources to an incoming stimulus The evaluation of the stimulus The evaluation of the stimulus The subsequent memory mechanisms engaged for that stimulus The subsequent memory mechanisms engaged for that stimulus Reduced P300 amplitudes: Reduced P300 amplitudes: Ineffecient allocation of attentional resources in processing task relevant cognitive information (deficits in attentional control) Ineffecient allocation of attentional resources in processing task relevant cognitive information (deficits in attentional control)

6. Introduction 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 patients Children of SUD patients Current and ex-smokers Current and ex-smokers Two lines of research in accordance with the 2 criteria for an endophenotype: Two lines of research in accordance with the 2 criteria for an endophenotype: P300 as a disease marker P300 as a disease marker P300 as a vulnerability marker P300 as a vulnerability marker

7. Introduction However: However: Findings are not entirely consistent across laboratories! Findings are not entirely consistent across laboratories! There are many non-significant findings as well There are many non-significant findings as well Inconsistency among studies may be due to differences in several sample-, task-, and study characteristics 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 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 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: 1. P300 in relation to SUD (Meta-analysis 1) 2. P300 in relation to a FH+ of substance use (Meta-analysis 2)

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

10. Method Statistical methods: CMA (Comprehensive Meta-Analysis) CMA (Comprehensive Meta-Analysis) Effect size (ES) statistic Cohen’s d Effect size (ES) statistic Cohen’s d Formula d = (M1 – M2)/SD Formula d = (M1 – M2)/SD M1 = mean P300 amplitude (Pz) in SUD-/FH- groups M1 = mean P300 amplitude (Pz) in SUD-/FH- groups M2 = mean P300 amplitude in SUD+/FH+ groups M2 = mean P300 amplitude in SUD+/FH+ groups SD = pooled standard deviation of the two groups’ P300 amplitude outcomes SD = pooled standard deviation of the two groups’ P300 amplitude outcomes Overall ES: rates are pooled using random-effects model Overall ES: rates are pooled using random-effects model Influence of moderating variables: a priori defined subgroup analysis Influence of moderating variables: a priori defined subgroup analysis

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) d = 0.51 (95% CI = 0.41-0.61, p <.001) SUD patients have significantly < P300 amplitudes as compared to healthy controles SUD patients have significantly < P300 amplitudes as compared to healthy controles

13. Results: Meta-Analysis 1 Significant Subgroup Analyses: 1. Substance use status 2. 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) d = 0.28 (95% CI = 0.15-0.41, p <.001) FH+ individuals have significantly < P300 amplitudes as compared to low risk controles FH+ individuals have significantly < P300 amplitudes as compared to low risk controles

15. Results: Meta-Analysis 2 Significant Subgroup Analysis: 1. 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 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 P300 amplitude reduction can be a useful disease and vulnerability marker and a promosing neurobiological endophenotype for SUDs Other highlights: 1. This is only the case in males 2. P300 amplitude reduction is not specific for alcohol 3. The effect is even observable after a prolonged period of abstinence (state-independent) 4. 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. 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. 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 Heritability estimate of 60% (van Beijsterveldt & van Baal, 2002) Heritability estimate of 60% (van Beijsterveldt & van Baal, 2002) Not identical for both genders (Yoon, Iacono, Malone, & McGue, 2006) H 2 = 0.65 for males H 2 = 0.65 for males H 2 = 0.32 for females H 2 = 0.32 for females Associated genes: Associated genes: DRD2 (Taq1 A1 allele) (Hill et al., 1998) DRD2 (Taq1 A1 allele) (Hill et al., 1998) DRD3 (Ser9Gly polymorphism) (Mulert et al., 2006) DRD3 (Ser9Gly polymorphism) (Mulert et al., 2006) CNR1 gene (Johnson et al., 1997) CNR1 gene (Johnson et al., 1997) COMT (Gallinat et al., 2003; Tsai et al., 2003) COMT (Gallinat et al., 2003; Tsai et al., 2003)

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