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

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

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 NMZ= 411 pairs

N=674 girls MDZ= 215 pairs

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?

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

0

20

40

60

80

100

0 1 2 3 4+

N ic D ep

A lc A b /D ep

D ru g A b /D ep

A S P D

Percent

Early Behaviors

McGue & Iacono, Submitted

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

0

20

40

60

80

100

0 1 2 3 4+

N ic D ep

A lc A b /D ep

D ru g A b /D ep

A S P D

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

ConductDisorder

AlcoholDependence

DrugDependence

(Low)Constraint

Krueger et al. (2002)

.78 .58 .71 .63

.47

Genetic and Environmental Contributions to Externalizing

Adolescent/Adult

Antisocial

ConductDisorder

AlcoholDependence

DrugDependence

(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

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: h2=.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)

Normal

Rotated

Left RightNo Response

 

Rotating Heads Task of Begleiter et al. (1984)

160 Trials

80 Trials

PzP3 P4

Reduced P3 Is Associated with High Externalizing

Is P3 amplitude reduction associated with early problem behaviors?

0 1 2 3 4 5

Problem Behavior Index

20

21

22

23

24

25

26

27

28

29

30

P3

Am

pli

tud

e (u

v)

WomenMen

P3 AMPLITUDE AND PROBLEM BEHAVIOR

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

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

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

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)

15

20

25

30

GroupP

3 A

mp

litu

de

uv

Unaffected New

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!