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P3 Event-Related Potential Amplitude and the Risk for Disinhibitory Disorders in Adolescent Boys
William G. Iacono, PhD;
Scott R. Carlson, BA;
Stephen M. Malone, PhD;
Matthew McGue, PhD
Arch Gen Psychiatry. 2002;59:750-757.
ABSTRACT
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Background The children of parents who abuse alcohol typically show reduced amplitude
of the P3 event-related potential wave. We determined if this effect was present
in a population-based sample of older adolescent boys, whether it was associated
with paternal antisocial personality and drug use, and whether it appeared
in youth with childhood externalizing and substance use disorders.
Methods A statewide sample of 502 male youth, identified from Minnesota birth
records as members of twin pairs, had their P3 amplitude measured, using a
visual oddball paradigm when they were approximately 17 years old. Structured
clinical interviews covering attention-deficit/hyperactivity disorder, conduct
disorder, oppositional defiant disorder, antisocial personality disorder,
and substance use disorders were administered in person to the youth and his
parents at the time of the P3 assessment and again to the youth 3 years later.
Results Reduced P3 was associated with disorders and paternal risk for disorders,
reflecting a behavioral disinhibition spectrum that included attention-deficit/hyperactivity
disorder, oppositional defiant disorder, conduct disorder, antisocial personality
disorder, alcoholism, nicotine dependence, and illicit drug abuse and dependence.
Reduced P3 at age 17 predicted the development of substance use disorders
at age 20. Most effect sizes associated with these group differences exceeded
0.70, indicating medium to moderately large group differences. Maternal alcoholism
and substance use during pregnancy were unrelated to P3 amplitude in offspring.
Conclusion Small amplitude P3 may indicate genetic risk for a dimension of disinhibiting
psychiatric disorders, including childhood externalizing, adult antisocial
personality disorder, and substance use disorders.
INTRODUCTION
RESEARCH INDICATES that, compared with the sons of men without alcoholism,
the sons of parents who abuse alcohol show reduced amplitude of the P3 component
of the electrocortical event-related potential,1
supporting the hypothesis of Begleiter et al2
that P3 amplitude has potential as a biological marker for alcoholism risk.
Nevertheless, many relevant issues have not been systematically addressed.
Investigators have most often recruited subjects at risk for alcoholism by
identifying parents in treatment settings and studying their children.2-20
Such samples are likely to represent particularly severe cases of alcoholism,
an ideal place to begin a search for biological markers, but replication in
community samples is needed. Other studies have recruited high-risk subjects
by means of advertisements soliciting volunteer offspring of parents who abuse
alcohol21-25
or by screening undergraduate volunteers for a family history of alcoholism.26-28 Although each source
has its advantages, participants who volunteer in response to advertisements
and undergraduate recruits may be unusual in several important respects and
are not representative of the population of individuals with paternal histories
of alcoholism. To our knowledge, there have not yet been any studies assessing
P3 amplitude in the sons of parents who abuse alcohol ascertained from an
unselected community-based sample representative of subjects with alcoholism
in the general population.
Reduced P3 amplitude is not unique to alcoholics and their children
but has been reported for several related phenotypes. Several important childhood
psychiatric disorders, such as attention-deficit/hyperactivity disorder, oppositional
defiant disorder, and conduct disorder, have been associated with risk for
alcoholism.29-33
These externalizing disorders have also been associated with reduced P3 amplitude.34-39
Moreover, adult subjects with a substance use disorder defined more broadly40-41 or with antisocial personality disorder
(ASPD)24, 42-44
tend to have reduced P3 amplitudes. Consistent with these findings, reduced
P3 amplitude appears to be associated with risk for substance abuse in general,
not just alcoholism,45-46 and
reduced P3 in preadolescence may predict subsequent substance use and alcoholism
in adolescence.6, 23
The results of these and other studies have led to proposals that P3
amplitude is a candidate endophenotype associated with vulnerability to a
broad spectrum of disinhibited psychiatric disorders, including externalizing
psychiatric syndromes and substance abuse.47-48
This makes it imperative to assess relevant psychiatric disorders in studies
using P3 amplitude as a risk indicator, a strategy that has been applied only
selectively in this extensive
literature.3, 11, 13, 17, 38-39,43, 45, 49-50
A third unresolved issue concerns the role of maternal substance use
during pregnancy in relation to P3 amplitude. Studies of P3 amplitude and
alcoholism risk have typically excluded subjects whose mothers had a diagnosed
substance use disorder (for an exception, see Hill et al8).
This strategy, while controlling for effects of maternal alcoholism, does
not necessarily control for any effects of alcohol consumption during pregnancy.
Moreover, given the tendency toward assortative mating, ie, for spouses to
select each other on the basis of shared characteristics, such a strategy
is also likely to bias the samples used. It would thus seem desirable to systematically
assess any effects on P3 amplitude of maternal substance use disorders and
substance use during pregnancy.
In the present investigation, we hypothesized that P3 amplitude findings
observed previously in convenience samples would be evident in a general population
sample. Specifically, we predicted that P3 amplitude reduction in adolescent
youth would be associated with a range of substance and externalizing disorders
and with a history of paternal substance abuse. In addition, we expected P3
amplitude at age 17 to predict the development of substance use disorders
at age 20.
SUBJECTS AND METHODS
SUBJECTS
Participants, aged 16.6 to 18.3 years (mean ± SD, 17.5 ±
0.4 years), consisted of 502 male youth (226 twin pairs and 50 unmatched twins)
from the older cohort of the Minnesota Twin Family Study. All were identified
from birth records as twins born in Minnesota between January 1, 1972, and
December 31, 1978 (a thorough description of the Minnesota Twin Family Study
research design, sample characteristics, and diagnostic procedures can be
found elsewhere51). Three years later, 417
youth (83%) (mean ± SD age, 20.7 ± 0.5 years) returned for a
follow-up assessment. Consistent with the demographics of the state of Minnesota
at the time the boys were born, most (99%) were white. Participants' biological
fathers ranged in age from 32.2 to 66.1 years (mean ± SD, 46.7 ±
5.5 years), and mothers from 33.0 to 59.4 years (mean ± SD, 44.4 ±
4.5 years). All youth and their parents gave written informed assent or consent
as appropriate.
Adolescents were split into psychiatric risk groups depending on their
study intake diagnoses and whether they developed (for the first time) a substance
use disorder between the ages of 17 and 20. To achieve consistency with existing
research on P3 in the sons of parents who abuse alcohol, participants were
also divided into paternal risk groups based on their father's family history,
history of alcohol consumption, and diagnosis. A nonpsychiatric comparison
group was composed of participants free of psychiatric disorders whose fathers
did not have a serious drinking history; antisocial, alcohol, or illicit drug
use disorders; or first-degree male relatives with a history of alcohol-related
problems. Those nonpsychiatric subjects who returned for their follow-up assessment
and were still free of substance use disorders served as the comparison group
for the analysis of the longitudinal data.
ASSESSMENTS
Trained master's and bachelor's level interviewers conducted structured
in-person interviews of mothers, fathers, and their sons independently in
our university laboratory. Adolescents were interviewed with a revised version
of the Diagnostic Interview for Children and Adolescents52
and a modified version of the Composite International Diagnostic Interview53 expanded Substance Abuse Module.54
Mothers were interviewed about their sons, using the parent version of the
Diagnostic Interview for Children and Adolescents, enabling the assignment
of DSM-III-R55 diagnoses
of the youth by combining mother and son interview data, using a "best-estimate"
approach.56 At the follow-up assessment, the
20-year-old men received the Substance Abuse Module and served as sole informants
about themselves.
Fathers and mothers were interviewed about themselves, using the Substance
Abuse Module, and both were interviewed about the father's first-degree male
relatives, using a composite interview derived from the Family History–Research
Diagnostic Criteria57 and Family Informant
Schedule and Criteria.58 In addition, fathers
were given an ASPD interview specially developed for the Minnesota Twin Family
Study.59
Except for a diagnosis of substance abuse, which is based on the presence
of a single symptom, adolescents and their parents were considered to have
a lifetime study diagnosis if all DSM-III-R symptom
criteria were satisfied (definite certainty level) or all criteria but 1 were
satisfied (probable certainty level). Cohen  reliability coefficients
for the various disorders of interest in the present study ranged from 0.71
(oppositional defiant disorder) to more than 0.90 (for ASPD and substance
diagnoses).51
Because we were working with a population-based rather than a treatment
sample, we were concerned about potential false-negative diagnoses stemming
from our participants' possible desire to downplay their drinking problems.
Because quantitative traits can enhance the study of qualitative phenotypes,
serving as a "useful proxy for alcoholism diagnoses,"60(p636)
we examined 2 quantitative measures that are associated with vulnerability
to alcoholism: age at first use of alcohol61-64
and maximum number of drinks consumed in a 24-hour period.60, 65
We combined these 2 measures such that fathers in the most deviant decile
of the distribution on either alcoholism-related phenotype were considered
to have a significant drinking history. This identified 35 "affected" fathers
(with 65 sons in the sample) whose drinking history was considered significant
in the absence of a diagnosis of dependence. If either the father or the mother
reported that any first-degree male relative of the father's had at least
2 drinking problems (from a list including physical fights, loss of friends,
and legal, financial, medical, family, school, or work difficulties) or had
ever been treated for alcoholism, paternal family history was coded as positive.
Ninety-one subjects had a positive history of alcoholism in the father's immediate
family by this measure in the absence of alcohol dependence in the 48 fathers
themselves. These 48 fathers were also in the "affected" group.
PROCEDURES
We used the rotated-heads oddball paradigm2
illustrated in Figure 1. In this
task, subjects watched 240 computerized stimuli consisting of an oval (two
thirds of the trials) or a stylized head (one third of trials) and indicated
by button press on which side of the head its ear appeared. Stimulus duration
was 98 milliseconds, with the intertrial interval varying randomly between
1 and 2 seconds. Subjects were required to maintain their gaze on a fixation
point that appeared in the center of the screen between trials. Subjects performed
several practice trials to ensure they understood the task.
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Figure 1. Schematic representation of the
stimuli used in the rotated-heads task. The oval on the left was presented
on 180 trials and required no response. Each pair of ovals on the right (normal
and rotated) were presented on 40 occasions, and the subject was required
to push a button near his left or right hand to indicate if the ear was on
the right or the left side of the head. For normal heads, the side of the
screen displaying the ear and the side of the head with the ear were the same
(easy condition). For the rotated heads, the side of the screen displaying
the ear and the side of the head with the ear were opposite (hard condition).
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All subjects completed the procedure at the same time of late morning.
Participants sat in a padded high-backed chair, and the Grass Model 12A Neurodata
Acquisition System (West Warwick, RI) was used to record electroencephalographic
and electro-oculographic data filtered at 0.01 to 30 Hz (half-amplitude).
Electroencephalographic data were recorded from 3 parietal locations, 1 on
the midline scalp (Pz) and 1 over each hemisphere (P3 and P4). Linked earlobes
served as reference and an electrode on the right shin as ground. Blinks and
eye movements were recorded with a pair of biopotential electrodes arranged
in a transverse montage, one electrode superior to the eye and the other over
the outer canthus. Impedances were below 5 k for scalp electrodes and
below 10 k for electro-oculographic recordings. For each trial, 2 seconds
of electroencephalographic or electro-oculographic data, including a 500-millisecond
prestimulus baseline, were digitized to 12-bits resolution at a rate of 256
Hz. Target trials were repeated if the subject failed to respond or if the
limits of the analog-to-digital converter were exceeded.
Blinks and other ocular artifacts in the electroencephalographic data
were corrected offline by a computer algorithm.66
We digitally filtered the mean event-related potentials, using a frequency-sampled
finite impulse response low-pass filter with least squares error and a transition
band.67 The cutoff frequency of this zero-phase
filter (attenuation of 3 dB) was approximately 7.56 Hz, and it resulted in
40-dB attenuation of the signal at 11.56 Hz.
Using a computer algorithm, we determined the point of maximum amplitude
in each waveform between 250 and 800 milliseconds. One of several trained
individuals, guided by the characteristics of waveforms recorded at other
electrode locations, monitored the algorithm to ensure that the point chosen
was in fact the P3 wave, defined as the most prominent positive peak in this
time interval. If the waveform in this interval consisted of 2 closely spaced
peaks of approximately equal amplitude, suggesting separate P3a and P3b peaks,68 we selected the second, which would correspond to
P3b.
STATISTICAL ANALYSIS
Analyses consisted of 2-tailed t tests and
analyses of variance, with significance established at P = .05. Effect sizes (Cohen d) were computed, using the SD of the
entire sample (7.79 µV). We assessed associations between P3 amplitude
and measures of alcohol consumption and illicit drug use with Kendall 
rank correlation coefficient, owing to the nonnormal distribution of many
of these measures and because it is superior to Spearman rank correlation
coefficient in cases of tied ranks. In the analysis of paternal risk, hierarchical
linear modeling was used to examine group differences, and a random regression
model was used to calculate odds ratios (ORs) to account for the correlated
nature of the twin data. Such analyses were not applied to the evaluation
of adolescent psychiatric disorders, in which twin pairs were often split
across diagnostic groups. Instead, we reduced the df
for each analysis (by using as the df the number
of twin pairs rather than the number of participants) and recalculated the
appropriate P value. Because in no case did a significant
finding become nonsignificant, we report herein the unadjusted df and P values.
To determine if adolescents with childhood externalizing psychiatric
disorders and substance use disorders had reduced P3, we divided participants
into diagnostic groups and contrasted their P3 amplitude with that of the
comparison subjects. Two different approaches to grouping participants were
taken. One involved assigning subjects to different diagnostic categories
without consideration of any possible comorbid diagnoses. These "comorbid
group" analyses included all participants, and the resulting diagnostic groupings
contain a representative sample of individuals with the diagnosis. The other
grouping strategy involved forming nonoverlapping diagnostic groups of individuals
who had none of the other diagnoses. This "pure group" approach made it possible
to evaluate the effect of having just the designated disorder, because participants
with multiple diagnoses were omitted from the analysis.
To determine if paternal risk was associated with P3 amplitude in offspring,
we separated adolescents into overlapping groups based on 5 paternal characteristics.
We identified as "affected" those fathers diagnosed as having (a) alcoholism
or a sibling or parent with alcoholism, (b) drug abuse or dependence, or (c)
ASPD. Also considered as affected were those fathers (d) with a sibling or
parent with alcoholism or (e) who fell into the most deviant decile of drinking
behavior. These analyses were carried out twice, first considering all the
offspring of fathers with the diagnoses of interest, and then considering
only those offspring who had not themselves developed a substance use disorder.
Although the comparison group of 71 participants was free of individuals
with an externalizing disorder or affected father, 19 of these participants
subsequently developed a substance use disorder at age 20 (another 8 had not
completed their follow-up assessment at the time of this report). These 19
new abusers had significantly smaller P3 amplitude (by 7.12 µV) at age
17 (mean ± SD, 22.76 ± 9.03 µV) than the remainder of
this group (mean ± SD, 29.87 ± 9.20 µV) (t61 = 2.81, P = .007). Using this
still unaffected group of 44 as the control group, all adolescents developing
a substance use disorder between the ages of 17 and 20 who did not already
have such a diagnosis at age 17 were examined to determine if they had smaller
P3 amplitudes at age 17 than the controls.
To simplify the presentation of the data, several preliminary analyses
were carried out. Although 3 recording sites were used, P3 amplitude at the
3 sites was highly correlated (r = 0.87 for Pz-P3
and Pz-P4). In addition, recent evidence indicates that children of parents
who abuse alcohol differ from children of parents who do not abuse alcohol
with respect to P3 amplitude but not its scalp distribution.17
Given these findings, to ease understanding of the results and to facilitate
comparison with the many studies that have reported primarily Pz data, we
analyzed data from Pz only. Because P3 amplitude for the easy and hard conditions
(Figure 1) was also highly correlated
(r = 0.87), we calculated P3 amplitude from the mean
of the easy and hard trials combined. None of the high-risk groups differed
significantly from the comparison participants in P3 latency or in manual
reaction time for correct responses (all t<1.78).
Finally, with 1 exception, performance accuracy (percentage of hits out of
80 target trials) failed to significantly differentiate comparison participants
from any other group. The 1 exception involved the comorbid attention-deficit/hyperactivity
disorder group, which averaged 1 fewer hit (mean, 78.09 hits) than the comparison
group (mean, 79.10 hits) (t112 = 3.34, P<.01). Given these findings of no significant effect
for latency and reaction time and little effect for hit rate, these variables
were not considered further.
RESULTS
ADOLESCENT P3 AMPLITUDE AND PSYCHIATRIC DISORDERS
The results of the P3 analyses are summarized in Table 1 and Figure 2.
All but 3 of the comparisons between the diagnostic groups and controls were
statistically significant. The 3 nonsignificant comparisons involved pure
groups, and 2 involved groups with fewer than 10 subjects. All of the significant
analyses were associated with an effect size of 0.49 or larger (median, 0.73).
Those with externalizing or substance abuse psychiatric disorders differed
little in their P3 amplitude, but collectively their amplitudes were about
6 µV smaller than those of the comparison subjects.
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Table 1. Adolescent P3 Amplitude as a Function of Externalizing the
Substance Use Diagnoses*
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Figure 2. Grand mean event-related potentials
as a function of substance abuse status: waveforms for easy (solid lines)
and hard (dashed lines) trials. A, "High Risk" refers to all participants
with an affected father. "Psychiatric Disorders" refers to the combined group
of adolescents with a diagnosis of attention-deficit/hyperactivity disorder,
oppositional defiant disorder, conduct disorder, nicotine dependence, alcohol
abuse or dependence, or illicit drug abuse or dependence. "Control" refers
to participants with neither an affected father nor a psychiatric disorder.
B, "New Substance Abusers" refers to all participants developing a substance
abuse diagnosis between their initial visit at age 17 and their follow-up
visit at age 20 in the absence of any such diagnosis initially. Some of the
17-year-old control subjects developed a substance diagnosis by age 20; these
individuals were not included in the control group grand means in B.
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To determine whether having a childhood externalizing and a substance
use disorder was associated with having especially small amplitude P3, those
with just one of these types of disorder (n = 167) were compared with those
with both (n = 89). The P3 amplitude of those with both types was 1.9 µV
smaller (mean ± SD, 21.51 ± 6.55 µV) than that of those
with just 1 (mean ± SD, 23.40 ± 7.31 µV), a significant
effect (t254 = 2.03, P = .04).
ADOLESCENT P3 AMPLITUDE AND PATERNAL HISTORY
We assessed the degree of similarity between paternal alcohol dependence
and significant drinking history by means of a tetrachoric correlation, assuming
a normal liability distribution underlying each. The resulting correlation
was highly significant (tetrachoric r = 0.57, P<.001). In addition, we calculated ORs to determine
whether adolescents whose fathers had a significant drinking history were
significantly more likely to have an externalizing disorder than those whose
fathers did not have a psychiatric diagnosis. This was indeed the case for
conduct disorder (OR, 1.93; 95% confidence interval [CI], 1.23-3.05), nicotine
dependence (OR, 2.31; 95% CI, 1.22-4.38), alcohol abuse or dependence (OR,
2.39; 95% CI, 1.39-4.11), and illicit drug abuse or dependence (OR, 3.01;
95% CI, 1.23-7.36).
Moreover, P3 amplitude was reduced among youths whose fathers had a
significant drinking history (n = 182; mean ± SD, 22.26 ± 6.81)
relative to those whose fathers did not (n = 271; mean ± SD, 24.82
± 8.34) (t451 = 3.45, P = .001). Even when subjects whose fathers had a substance use disorder
or ASPD were excluded, those whose fathers had a significant drinking history
had reduced P3 amplitudes (n = 61; mean ± SD, 21.40 ± 6.57)
relative to subjects whose fathers did not (n = 189; mean ± SD, 25.37
± 8.39) (t239 = 3.47, P = .001), yielding an effect size of 0.54.
As Table 2 (and Figure 2A) indicates, in all but 1 instance,
father's diagnosis was associated with reduced P3 amplitude in offspring,
significantly so for half of the group comparisons. The effect sizes range
from 0.39 to 1.00 (median, 0.59), indicating that those with affected fathers
tended to have P3s that were about 4.6 µV smaller than those of comparison
participants.
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Table 2. Adolescent P3 Amplitude as a Function of Paternal History
of Substance Use Disorder and Antisocial Personality Disorder (ASPD)*
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P3 AMPLITUDE AT AGE 17 AND SUBSTANCE ABUSE AT AGE 20
Figure 2B illustrates the
degree to which new substance abusers had smaller P3 amplitudes than controls,
and Table 3 provides P3 values
and corresponding statistics for subjects who were without a substance use
disorder at age 17 but developed one by age 20. The middle columns of the
table examine the same effects when individuals with externalizing psychiatric
disorders at age 17 were removed from the analysis, and the far right columns
examine these effects when adolescents with an affected father were removed
from the analysis. In every comparison but 1, the adolescents who developed
substance use disorders had significantly smaller P3 at age 17 than the comparison
group. The single exception concerned individuals with unaffected fathers
at age 17 who developed illicit drug disorders. Turning to individuals who
had a substance use diagnosis at age 17, these participants had smaller P3s
(by 1.43 µV) than those who became affected between ages 17 and 20.
To formally evaluate this difference, the P3 amplitude of the 148 new substance
abusers (mean ± SD, 23.33 ± 7.30 µV) was compared with
that of the 126 previous abusers (mean ± SD, 21.90 ± 6.45 µV),
revealing a nonsignificant effect (t272
= 1.70, P = .09).
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Table 3. How Adolescent P3 Amplitude at Age 17 Predicts the Development
of Substance Use Disorders Between the Ages of 17 and 20 in Adolescents With
No Substance Use Disorder at Age 17*
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IN UTERO AND MATERNAL EFFECTS
To determine whether maternal use of substances during pregnancy could
account for the P3 effects, P3 amplitude was examined as a function of maternal
substance use during and outside of the mother's pregnancy. The variables
evaluated were any alcohol consumption, regular use of alcohol, average amount
drunk per week, maximum amount drunk in a 24-hour period, any smoking, amount
smoked per day, any use of illicit drugs, and lifetime history of alcohol
dependence, nicotine dependence, and illicit drug abuse or dependence. All
hierarchical linear modeling analyses generated nonsignificant findings (all
F<1.50) and, furthermore, did not suggest that maternal status on these
variables might be associated with reduced P3 amplitude among the adolescent
sons.
SUBSTANCE USE AND P3 AMPLITUDE
Because many participants were already using substances, to evaluate
whether reduced P3 amplitude could reasonably be attributed to use rather
than risk status, correlations were calculated between P3 size and various
substance use measures for those with a substance use disorder (ie, those
included in the groups in the bottom 3 rows of Table 1), those in a familial risk group (the top 3 rows of Table 2), and those who developed a substance
use disorder between the ages of 17 and 20. Measures of substance use included
lifetime number of alcohol intoxications, estimated alcohol consumption in
the preceding year, number of lifetime uses of street drugs, and estimated
daily consumption of tobacco products. The only significant associations were
between P3 amplitude and substance use in the sons of parents who abuse alcohol
and the sons of fathers with ASPD, and only in the groups including sons who
already had developed a substance use disorder. Specifically, amplitude was
inversely correlated with the lifetime numbers of street drug uses and alcohol
intoxications and the estimated amount of alcohol consumed during the past
year in both groups. When the analyses for these groups were repeated using
these measures as covariates, the group differences in P3 amplitude remained
statistically significant.
COMMENT
To our knowledge, the present report is the first study of P3 amplitude
in a population-based sample of adolescent boys. It supports results of prior
studies1 derived from clinic-referred and college
student samples by showing that reduced P3 amplitude is associated with paternal
alcoholism. Our findings also extend this literature in several important
respects. First, the P3 effect in offspring was not limited to those who abuse
alcohol; a father with ASPD was likely to have a son with small amplitude
P3. Second, disinhibiting psychiatric disorders in the youth were associated
with P3 reduction. This was evident in youth with childhood externalizing
disorders and those with substance use disorders, and it was evident in those
with and without comorbid psychiatric disorders. Although not working with
population-based samples or necessarily controlling for possible effects of
comorbid externalizing disorders, other researchers have also found children
with these types of disorders and paternity to have small amplitude P3.34-39,45
Third, reduced P3 recorded in late adolescence was associated with the development
of all types of substance use disorders 3 years later. This was true when
analyses were limited to adolescent boys free of childhood psychiatric disorders
at age 17, and when limited to boys without a paternal history of alcoholism,
illicit drug abuse or dependence, or ASPD. This finding thus complements other
research showing that P3 predicts substance use outcomes in preadolescent
and early adolescent children.6, 15, 23
For all of these various findings, effect sizes were medium to large, with
61% (22/36) of those reported in Table 1, Table 2, and Table 3 exceeding 0.70. Effect sizes of
this approximate magnitude indicate that the overlap between our comparison
and at-risk sample distributions is about 50%. Taken in combination, these
findings are consistent with the hypothesis that reduced P3 in male youth
is associated with vulnerability to a broad spectrum of disinhibiting psychiatric
disorders, including antisocial and addictive disorders.
Because the present study was carried out with high school seniors,
most participants had at least some exposure to psychoactive substances. However,
it is unlikely that substance use per se accounts for the outcome. Offspring
with no substance use diagnosis had reduced amplitude P3 as long as their
fathers had an externalizing diagnosis, and P3 amplitude was uncorrelated
with different measures of nicotine, alcohol, and illicit drug use in most
groups. Substance use was correlated with P3 in 2 groups, the sons of parents
who abuse alcohol and of fathers with ASPD (but only when sons with a substance
use disorder were included in these groups). When the effects of substance
use were controlled for in these analyses, the P3 effects remained significant.
Maternal substance use during pregnancy also seems an unlikely effect on the
findings. Various measures of substance intake during pregnancy were unrelated
to P3 amplitude, as was a lifetime diagnosis of substance disorder in the
mother.
Recent studies have suggested that alcoholism and drug abuse,69-72 as
well as alcoholism and conduct disorder or ASPD,73-77
share a common genetic effect. In addition, factor analyses of the National
Comorbidity Survey data indicated that a single dimension representing externalizing
psychiatric disorders may underlie disorders related to substance use and
antisocial behavior.78-79 The
results of the present study, which indicate that reduced P3 is associated
with disorders and familial risk for disorders reflecting externalizing behavior,
suggest that reduced P3 may be associated with genetic risk for disinhibited
psychiatric disorders generally.
Because diminished P3 amplitude is found in persons with depression80-83 and
schizophrenia,84-86
it cannot be considered a diagnostic marker of externalizing disorders. However,
reduced P3 has not been consistently associated with familial risk for either
depression or schizophrenia, it does not predict the development of these
disorders, and in these disorders it has typically been found using auditory,
not visual, paradigms. These findings leave open the possibility that reduction
in the visual evoked P3 may be a trait marker for externalizing psychiatric
disorders. Recently, reduced P3 coupled with an electrodermal measure of response
inhibition87 was found to identify youth with
much higher rates of alcohol and nicotine dependence than were evident in
youth with only one of these psychophysiological attributes.88
This finding leaves open the possibility that measurement of P3 amplitude
used in conjunction with other measures has the potential to identify a multivariate
endophenotype more specifically associated with externalizing psychiatric
disorders.
Our study has several limitations. Although population-based, our adolescents
were all from twin births. We cannot rule out the possibility that their being
twins limits the generalizability of our findings. Although representative
of the ethnic diversity of the Minnesota population at the time they were
born, they are almost exclusively white. Whether our findings would generalize
to other ethnic groups requires further investigation. We examined only adolescent
boys, all of whom were approximately age 17 at study intake. Findings for
girls and younger youths could be different.
AUTHOR INFORMATION
Submitted for publication March 28, 2001; final revision received October
5, 2001; accepted October 12, 2001.
This study was supported by grants DA 05147 and AA 09367 from the National
Institutes of Health, Bethesda, Md.
Corresponding author: William G. Iacono, PhD, Department of Psychology,
University of Minnesota, 75 East River Rd, Minneapolis, MN 55455 (e-mail: wiacono{at}tfs.psych.umn.edu).
From the Department of Psychology, University of Minnesota, Minneapolis.
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