Stephen M. Malone

Behavioral Disinhibition and the Development of Early-Onset Addiction: Common and Specific Influences

Research on substance use disorders is often compartmentalized, focused on understanding addiction to one substance or substance class at a time. Although this approach has contributed significantly to knowledge about addictions, early-onset substance use disorders appear to share common etiology with each other and with other disorders, traits, behaviors, and endophenotypes associated with behavioral disinhibition. We propose that a common genetic liability to behavioral disinhibition underlies the co-occurrence of these externalizing attributes. This liability is expressed in part through brain mechanisms related to cognitive control, impulsivity, and sensitivity to reward, all of which are maturing during adolescence. During this important transitional period, problem behaviors emerge, including the initiation of substance use. Exposure to various environmental risks further amplifies the risk associated with the common liability, increasing the likelihood of addiction generally. Specific environmental and genetic factors ultimately contribute to the differentiation among externalizing disorders.

Substance use disorders, externalizing psychopathology, and P300 event-related potential amplitude

We hypothesize the existence of an inherited predisposition for a spectrum of behaviors and traits characterized by behavioral disinhibition. This externalizing spectrum includes childhood disruptive disorders, antisocial behavior, substance use disorders, personality traits related to behavioral undercontrol, and the precocious expression of problem behavior. We further hypothesize that a genetically influenced central nervous system diathesis underlies this spectrum and is reflected in reduced P300 amplitude in a visual oddball event-related potential task. A review of evidence bearing on the model is derived from findings from the Minnesota Twin Family Study, a population-based, longitudinal investigation of twin youth. These findings indicate that the collection of attributes related to behavioral disinhibition is familial, heritable, and interrelated. Evidence supporting P3 amplitude reduction (P3-AR) as an index of genetic vulnerability for this externalizing spectrum includes its association with (a) familial risk for substance use and antisocial personality disorders, (b) diagnoses of childhood disruptive disorders and substance use disorders, (c) early onset of undersocialized behavior, and (d) quantitative phenotypes related to externalizing problems. In addition, the development of substance use disorders over a 3-year period is associated with P3-AR measured prior to their expression. These findings suggest that P3-AR indexes one aspect of the genetic diathesis for a spectrum of externalizing problem behavior.

Identifying a multivariate endophenotype for substance use disorders using psychophysiological measures

This investigation examined how reduced amplitude of the P300 event-related potential (elicited from a visual oddball task) can be used together with an electrodermal response modulation measure (indexing the ability to inhibit responsivity to a temporally predictable aversive stimulus) to identify adolescents at especially high risk to develop substance dependence. One hundred and twenty-nine 17-year-old boys were divided into groups characterized as low risk (high amplitude P300 and good electrodermal modulation), high risk (reduced amplitude P300 and poor modulation), or intermediate risk (a high or good score on one measure and a low or poor score on the other). P300 amplitude and electrodermal modulation were uncorrelated. High-risk boys had 4-6 times more alcohol dependence than intermediate or low-risk boys and 2-3 times more nicotine dependence. Performance on an antisaccade eye-tracking task in which participants directed their gaze in a direction opposite to target movement was related to electrodermal modulation but not P300 amplitude. The results from all three psychophysiological measures together suggest that the neural circuits affecting P300 amplitude and electrodermal response modulation are different and that poor electrodermal response modulation may reflect an inhibitory control deficit mediated by the frontal lobes.

Theta and delta band activity explain N2 and P3 ERP component activity in a go/no-go task

OBJECTIVES Recent work indicates that the feedback negativity and P3 components from gambling feedback tasks can be understood as mixtures of functionally distinct processes occurring separately in theta and delta frequency bands. The current study was conducted to assess whether dissociable processes occurring in the theta and delta bands would similarly account for activity underlying N2 and P3 components in a go/no-go task. METHODS The current study measured EEG signals from 66 participants during a go/no-go task, and a time-frequency principal components analysis decomposition approach was used to extract theta and delta measures from condition averages. RESULTS Theta and delta measures separately increased in relation to response inhibition, and were uniquely related to the N2 and P3 components, as predicted. CONCLUSIONS Findings support the view that the theta and delta measures indexed separable processes related to response inhibition, and better indexed the processes underlying N2 and P3 components in this go/no-go task. SIGNIFICANCE Theta and delta measures may index separable functional processes across other common ERP tasks, and may represent an improved target for research relative to standard time-domain components.

Longitudinal associations between depression and substance dependence from adolescence through early adulthood

AIMS The association between depression and substance dependence is poorly understood; examinations of these two disorders over time during key developmental periods can provide insight into how these problems relate to each other. The goal of the present study was to examine longitudinal associations between depression and substance (alcohol and illicit drug) dependence during the period from adolescence through early adulthood. PARTICIPANTS Participants in the Minnesota Twin Family Study, a community-based sample of 1252 youth and their families, were used. Youth were first assessed at age 17; they returned to the study at ages 20 and 24. MEASUREMENTS Major depression and drug and alcohol dependence were assessed via structured interviews. Gender was examined as a possible moderator. FINDINGS The results indicated that both substance dependence and depression showed stability over time--that is, each disorder was associated with increased risk for the same disorder later. Substance dependence between ages 17 and 20 predicted increased risk of depression between ages 20 and 24. These associations did not differ significantly by gender. CONCLUSIONS Substance dependence during late adolescence predicts the subsequent occurrence of major depression.

Genetic and environmental influences on antisocial behavior and alcohol dependence from adolescence to early adulthood

Genetic and environmental influences on symptoms of adult antisocial behavior (AAB) and alcohol dependence at ages 17, 20, and 24 were examined cross-sectionally and longitudinally in 188 monozygotic and 101 dizygotic male twin pairs. A moderate genetic influence on both AAB and alcohol dependence was found at each age, with a substantial proportion of this influence common to the two disorders, suggesting they share susceptibility genes. Biometrical models showed that continuity effects accounted for most of the stable variance in symptoms of both AAB and alcohol dependence, indicating that genetic and environmental effects associated with each of these disorders were similar at each age. Significant cross-lag effects (effects of alcohol dependence contributing to variance in AAB and vice versa) were observed at ages 20 and 24 for both disorders. The largest and theoretically most interesting of these effects indicated that one sixth of the genetic influence on AAB at age 20 was due to genetic effects associated with alcohol dependence at age 17. Thus, alcohol dependence symptoms at age 17 in particular had an effect on antisocial behavior symptoms at age 20, suggesting that alcohol involvement in adolescence may ensnare otherwise desisting youth in persistent antisocial behavior.

The enrichment study of the Minnesota twin family study: Increasing the yield of twin families at high risk for externalizing psychopathology

The Enrichment Study (ES) was designed to extend the Minnesota Twin Family Study (MTFS) by oversampling 11-year-old twins at especially high risk for substance use disorders by virtue of having a childhood disruptive disorder. The sample was ascertained from Minnesota birth records. To identify high-risk twins, we conducted telephone screening interviews for parent-reported symptoms of attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) as well as indications of academic disengagement. Twins who exceeded a predetermined threshold were invited to participate. To facilitate comparison with the previously ascertained MTFS participants, a random sample of 11-year-old twins was also recruited. As part of the ES study, 499 twin pairs, and their parents, visited the University of Minnesota, where each participant completed a clinical interview, psychophysiological evaluation, and thorough assessment of environmental risk. We were highly successful in recruiting at-risk twins; 52% of the screened male twins and 41% of the screened females met criteria for a diagnosis of ADHD, CD, or oppositional defiant disorder (ODD). At the pair level, 63% of the screened pairs had at least one member with a childhood disruptive disorder. This article provides an overview of the study design and includes a review of recent findings using this sample of twins.

Brain electrophysiological endophenotypes for externalizing psychopathology: a multivariate approach.

Abnormalities in electrophysiological measures of stimulus-evoked brain activity (including the P3 event-related potential (ERP) and its associated delta and theta time–frequency (TF) components), and intrinsic, resting state brain activity (including EEG in the beta frequency band) have each been associated with biological vulnerability to a variety of externalizing (EXT) spectrum disorders, such as substance use disorders, conduct disorder, and antisocial behavior. While each of these individual measures has shown promise as an endophenotype for one or more aspects of EXT, we proposed that the power to identify EXT-related genes may be enhanced by using these measures collectively. Thus, we sought to explore a multivariate approach to identifying electrophysiological endophenotypes related to EXT, using measures identified in the literature as promising individual endophenotypes for EXT. Using data from our large twin sample (634 MZ and 335 DZ, male and female same-sex pairs), and fitting multivariate biometric Cholesky models, we found that these measures (1) were heritable, (2) showed significant phenotypic and genetic correlation with a general vulnerability to EXT (which is itself highly heritable), (3) showed modest phenotypic and genetic correlation with each other, and (4) were sensitive to genetic effects that differed as a function of gender. These relationships suggest that these endophenotypes are likely tapping into neurophysiological processes and genes that are both common across them and unique to each—all of which are relevant to a biological vulnerability to EXT psychopathology.

Error rate on the antisaccade task: Heritability and developmental change in performance among preadolescent and late-adolescent female twin youth

We examined heritability of error rate on the antisaccade task among female twin youths. This task appears to be sensitive to prefrontal functioning, providing a measure of individual differences in inhibitory control associated with genetic risk for schizophrenia. The sample consisted of 674 11-year-olds and 616 17-year-olds, comprising the two cohorts of female twins from the Minnesota Twin Family Study, a population-based investigation of substance abuse and related psychopathology. We used biometric model-fitting methods to determine the relative magnitude of genetic and environmental influences on performance. In both age cohorts, the best fitting model contained additive genes and nonshared environment. Despite substantial age-related differences in mean performance levels (effect size = .81), additive genes accounted for greater than half the variance in performance in both age cohorts. These results are consistent with the hypothesis that antisaccade error rate might serve as an endophenotype for behavior disorders reflecting frontal lobe dysfunction or problems with inhibitory control.

Quantitative EEG in obsessive-compulsive disorder

Electroencephalograms (EEGs) were recorded from 13 unmedicated and nondepressed patients with DSM-III-R obsessive-compulsive disorder (OCD) and from 10 age-matched controls. All subjects were also administered the Wechsler Memory Scale Delayed Logical Memory and Delayed Visual Reproduction tests. Quantitative analysis of the EEG revealed lower log absolute power in the delta, beta 1, and beta 2 bandwidths for OCD patients at frontal and right-hemisphere locations. OCD patients displayed greater hemispheric asymmetries in EEG activity based on difference measures of EEG power from homologous electrode pairs, indicative of severe right hemisphere EEG hypoactivity. Standardized measures of hemispheric asymmetry for the beta 2 bandwidth accurately predicted group membership and were correlated both with poorer patient performance on the visual-spatial memory task and better performance on the verbal memory task. OCD patients were significantly impaired on the visual-spatial task, but not on the verbal memory test, relative to controls.