1. P3 Event-Related Potential Amplitude and the Risk for Disinhibitory Behavior Disorders W.G. Iacono University of Minnesota

2. Co-Contributors Scott CarlsonIrene Elkins Robert KruegerSteve Malone Matt McGue (& many others) Supported by NIDA & NIAAA

3. Theme of this Address 1.Behavioral disinhibition is expressed through a spectrum of related psychiatric disorders, personality traits, and undersocialized behaviors with a common etiology 2.Genetically influenced CNS diathesis underlies this spectrum 3.Reduced P3 event-related potential amplitude indexes the genetic diathesis

4. Undersocialized-Disinhibited Behaviors Precocious (before age 15): –Cigarette use –Alcohol use –Police contact –Drug use –Sexual intercourse

5. Externalizing Disorders Childhood –Attention deficit disorder (ADHD) –Oppositional defiant disorder (ODD) –Conduct disorder (CD) Adulthood –Antisocial personality disorder (ASPD) Conduct disorder Adult antisocial behavior (AAB) Substance Use Disorders –Nicotine dependence –Alcohol abuse and dependence –Illicit drug abuse and dependence

6. MTFS Participant Description MN statewide sample of twins identified from birth records -17% refuse Day-long assessment at intake & at three-year follow-up intervals 17 Year Old Intake (N=1,252) N=578 boysN MZ = 411 pairs N=674 girls M DZ = 215 pairs

7. Results: Organized to Address Two Questions 1.Are these externalizing disorders etiologically distinct with specific behavioral & psychophysiological risk indicators? or 2.Are the disorders part of a spectrum in which risk is nonspecific, with each indicator conferring a general increase in risk distributed across all of the disorders?

8. Are different types of early onset problem behavior risk indicators for specific disorders or for externalizing generally?

9. Early Problem Behavior Index (Score ranges from 0 to 5) Count of the following before age 15: –Smoked –Tried alcohol without parental permission –Had contact with police –Used illicit drugs –Had sexual intercourse Behaviors occur together (average tetra- choric correlation =.59) McGue & Iacono, Submitted

10. Prevalence of Problem Behavior Before Age 15 Early Behavior Male % (N=577) Female % (N=669) Tobacco5841 Alcohol2520 Police134 Drug46 Sex46

11. Probability of age-20 diagnosis as a function of the number of early problem behaviors: Male Percent Early Behaviors McGue & Iacono, Submitted

12. Probability of age-20 diagnosis as a function of the number of early problem behaviors: Female Percent Early Behaviors McGue & Iacono, Submitted

13. Relationship between Early Problem Behavior and Age 20 Externalizing McGue & Iacono, Submitted

14. Krueger et al. (2002) Proposed a hierarchical model consisting of: –Generalized externalizing factor –Specific factors that account for distinctions among disorders Model derived from 17-year old twin data

15. Factor Loadings of Externalizing Indicators Externalizing (Disinhibitory) Psychopathology Adolescent/ Adult Antisocial Conduct Disorder Alcohol Dependence Drug Dependence (Low) Constraint Krueger et al. (2002).78.58.71.63.47

16. Genetic and Environmental Contributions to Externalizing Adolescent/ Adult Antisocial Conduct Disorder Alcohol Dependence Drug Dependence (Low) Constraint Externalizing Psychopathology Heritable (81%) Non-heritable (19%) Specific Genetic (A) and Environmental Factors (C&E) Krueger et al. (2002) EC & EEEA & E

17. Do SUD parents tend to have children with SUDs or children with a full range of externalizing disorder? Question asked separately for: Alcohol dependent parents controlling for parental drug dependence Drug dependent parents controlling for alcohol dependence

18. Disorder Parental Alcoholism (controlling for drug effect, n=246) Parental Drug Dep (controlling for alcohol effect, n= 92) ORCIORCI ADHD1.78.84-3.793.341.50-7.45 CD2.311.46-3.664.092.41-6.96 ODD2.341.51-3.631.801.11-2.93 AAB2.601.30-5.191.72.83-3.56 Nic Dep1.951.24-3.071.741.06-2.87 Alc Dep2.381.35-4.191.931.11-3.37 Drug Dep2.861.33-6.252.881.38-6.05 Parental Substance Abuse Predicts Offspring Disorders

19. Background: P3 Amplitude Reduced P3 amplitude is associated with alcoholism risk (Begleiter et al., '84; Polich et al., '94; Hill et al., ’99; Iacono et al.,’02) –Putative endophenotype Individual differences in P3 amplitude are heritable (e.g., van Beijsterveldt et al., ’01; Katsanis et al., 1997: h 2 =.79) Reduced P3 amplitude is observed in other externalizing disorders –Smoking (Anokhin et al., '00; Carlson et al., ‘98) –Drug abuse (e.g., Biggins et al., '97; Branchey et al., '93; Carlson et al., ‘98) –CD/ASPD (e.g., Bauer et al., '94, '99; Carlson et al., ‘98)

20. Normal Rotated LeftRightNo Response Rotating Heads Task of Begleiter et al. (1984) 160 Trials 80 Trials

21. PzPz P3P3 P4P4

23. Reduced P3 Is Associated with High Externalizing

24. Is P3 amplitude reduction associated with early problem behaviors?

25. Iacono & McGue, Submitted

26. P3 Amplitude Reduction and Externalizing Disorders Each of the following two slides plots amplitude reduction effect sizes associated with externalizing: –Separately for boys and girls –Separately for "pure" and comorbid groups –Using a comparison group composed of adolescents with no externalizing disorder or affected father

27. Comorbid = Indicated disorder+all others Pure = Indicated disorder only

29. P3 Amplitude Reduction and Paternal Risk The following slide plots amplitude reduction effect sizes associated with paternal risk: –Separately for all children and those without a substance use disorder at 17

30. All = May have substance abuse Without SA = Free of substance abuse

31. Do those who develop substance abuse for the first time at age 20 have reduced P3 at age 17? Examine P3 amplitude at age 17 for all new cases at 20, new cases that were free of externalizing disorder at 17, and new cases with no affected father Comparison group now excludes new cases developing between 17-20

32. All = all offspring No Ext = no ext. dx at intake Low risk = no paternal dx Iacono et al., 2002

33. (Especially) Low risk control participants who developed a substance use disorder at age 20 (N=19) had smaller P3 at age 17 compared to controls who did not (N=44) t(61)=2.81, p<.01)

34. Summary and Conclusions Different types of problem behavior present before age 15 are nonspecific indicators of risk for externalizing disorders at age 20 Different types of parental SUD confer nonspecific familial risk for offspring externalizing Externalizing disorders load strongly on a latent externalizing factor that is highly heritable P3 findings support the existence of a shared genetic vulnerability for behavioral disinhibition, specifically:

35. P3 Amplitude Summary Reduced P3 is associated with precocious expression of problem behavior Reduced P3 is associated with all externalizing disorders, even in “pure” non- comorbid cases Reduced P3-amplitude identifies spectrum risk: –Those with small P3 express the full range of externalizing disorders –Children of affected fathers have reduced P3 –SUD developing at age 20 is associated with reduced P3 at 17

36. The P3 Endophenotype Reduced P3 is not an “alcoholism endophenotype” Lack of specificity of P3 effect to different externalizing disorders is an etiologic clue, not a problem Reduced P3 may be specific to genetic risk for externalizing E.g., although schizophrenia and depression associated with reduced P3 Auditory, not visual P3 (Ford, '99) State not trait (Mathalon et al., '00) Familial specificity in externalizing Carlson et al. poster Nature of P3 effect requires additional research

37. Thank you!