# Presentation: 530809

## P3 Event-Related Potential Amplitude and the Risk for Disinhibitory Behavior Disorders

**W.G. Iacono**
***University of Minnesota***

## Co-Contributors

**Scott Carlson****	****	****	****Irene Elkins**
**Robert Krueger****	****	****Steve Malone**
**Matt McGue ****	****	****	****(& many others)**

**Supported by NIDA & NIAAA**

## Theme of this Address

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

## Undersocialized-Disinhibited Behaviors

**Precocious (before age 15):**
**Cigarette use**
**Alcohol use **
**Police contact**
**Drug use **
**Sexual intercourse**

## 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**

## 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 boys****	****N****MZ****= 411 pairs**
**	****	****N=674 girls   ****	****M****DZ****= 215 pairs**

## Results: Organized to Address Two Questions

**Are these externalizing disorders etiologically distinct with specific behavioral & psychophysiological risk indicators? or **
**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? **

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

## 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**

## Prevalence of Problem Behavior Before Age 15

| Early 
Behavior | Male %
(N=577) | Female %
(N=669) |
| --- | --- | --- |
| Tobacco | 58 | 41 |
| Alcohol | 25 | 20 |
| Police | 13 | 4 |
| Drug | 4 | 6 |
| Sex | 4 | 6 |

## Probability of age-20 diagnosis as a function of the number of early problem behaviors: Male

**Percent**

**Early Behaviors**

**McGue & Iacono, Submitted**

## Probability of age-20 diagnosis as a function of the number of early problem behaviors: Female

**Percent**

**Early Behaviors**

**McGue & Iacono, Submitted**

## Relationship between Early Problem Behavior and Age 20 Externalizing

**McGue & Iacono, Submitted**

## 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**

## 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**

## 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)**

**E**

**C & E**

**E**

**E**

**A & E**

## 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**

## Parental Substance Abuse Predicts Offspring Disorders

| 
Disorder | Parental Alcoholism
(controlling for drug effect, n=246) |  | Parental Drug Dep
(controlling for alcohol effect, n= 92) |  |
| --- | --- | --- | --- | --- |
|  | OR | CI | OR | CI |
| ADHD | 1.78 | .84-3.79 | 3.34 | 1.50-7.45 |
| CD | 2.31 | 1.46-3.66 | 4.09 | 2.41-6.96 |
| ODD | 2.34 | 1.51-3.63 | 1.80 | 1.11-2.93 |
| AAB | 2.60 | 1.30-5.19 | 1.72 | .83-3.56 |
| Nic Dep | 1.95 | 1.24-3.07 | 1.74 | 1.06-2.87 |
| Alc Dep | 2.38 | 1.35-4.19 | 1.93 | 1.11-3.37 |
| Drug Dep | 2.86 | 1.33-6.25 | 2.88 | 1.38-6.05 |

**Parental Substance Abuse Predicts Offspring Disorders**

## 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)**

## Rotating Heads Task of Begleiter et al. (1984)

** **

**Rotating Heads Task of Begleiter et al. (1984)**

**160 Trials**

**80 Trials**

## Pz

**P****z**

**P****3**

**P****4**

## Slide 22

## Reduced P3 Is Associated with High Externalizing

**Reduced P3 Is Associated with High Externalizing**

## 	Is P3 amplitude reduction associated with early problem behaviors?

## Iacono & McGue, Submitted

**Iacono & McGue, Submitted**

## 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**

## Comorbid = Indicated disorder+all others  Pure = Indicated disorder only

***Comorbid***** = Indicated disorder+all others  *****Pure***** = Indicated disorder only**

## Comorbid = Indicated disorder+all others  Pure = Indicated disorder only

## 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 **

## All = May have substance abuse  Without SA = Free of substance abuse

***All***** = May have substance abuse  *****Without SA***** = Free of substance abuse**

## 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**

## All = all offspring  No Ext = no ext. dx at intake  Low risk = no paternal dx

***All *****= all offspring  *****No Ext *****= no ext. dx at intake  *****Low risk***** = no paternal dx**

**Iacono et al., 2002**

## 	(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)**

## 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:**

## 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**

## 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**

## Thank you!

## Slide 38