Neurobehavior disinhibition in childhood predisposes boys to substance use disorder by young adulthood: direct and mediated etiologic pathways

Abstract

Objective: The development of substance use disorder (SUD) was prospectively investigated in 66 boys having fathers with SUD and 104 boys having fathers with no adult Axis I or II psychiatric disorder. Evaluations were conducted to determine the context in which neurobehavior disinhibition in relation to parental SUD, parental neglect of the child and child’s social maladjustment culminated in a DSM-III-R diagnosis of SUD. Methods: A neurobehavior disinhibition latent trait was derived using indicators of behavior undercontrol, affect dysregulation and executive cognitive functioning in the boys when they were 10–12 and again at 16 years of age. These latter characteristics have been frequently observed in individuals who have a prefrontal cortex disturbance. The data were analyzed to determine whether the score on the neurobehavior disinhibition construct mediates the association between father’s and mother’s SUD and son’s SUD. Results: SUD in the mother and father predicted neurobehavior disinhibition in the son. The neurobehavior disinhibition score in the sons predicted SUD between ages 10–12 and 19. Neurobehavior disinhibition, in conjunction with social maladjustment and drug use frequency, mediated the association between paternal and maternal SUD and son’s SUD. Neurobehavior disinhibition was unrelated to neglect of the child by either the father or mother; however, paternal but not maternal neglect at age 10–12 predicted SUD at age 19. Conclusions: The association of neurobehavior disinhibition in childhood and SUD by young adulthood suggests that a prefrontal cortex dysfunction contributes to SUD liability. The results extend previous findings demonstrating that neurobehavior disinhibition is an important component of the liability to SUD.

Introduction

Externalizing behavior during childhood, manifest as impulsivity, goal impersistence, reactive aggression, and sensation seeking, has been shown in numerous investigations to be associated with an increased risk for adolescent substance use and subsequent diagnosis of substance use disorder (SUD) (Tarter et al., 1999, Brook et al., 1996, Hawkins et al., 1992, Kellam et al., 1983). Among individuals who develop SUD, the severity of behavior undercontrol commonly surpasses the diagnostic thresholds for attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder and conduct disorder and their various comorbid configurations (Biederman et al., 1997, Clark et al., 1999).

Internalizing characteristics, featured by negative affect, irritability, emotional lability, and difficult temperament, are also associated with an increased risk for SUD (Blackson et al., 1999, Chassin et al., 1991, Clark et al., 1997, Tarter et al., 1995). Anxiety disorder, post-traumatic stress disorder and depression disorder, reflecting the clinically diagnosed variants of these latter characteristics, have been similarly observed to heighten the risk for SUD (Clark and Sayette, 1993, Clark et al., 1999, Merikangas et al., 1998). Internalizing and externalizing disturbances are commonly manifest conjointly in high-risk youth, suggesting that the underlying core component of SUD liability is a disturbance in psychological self-regulation (Spear, 2000, Tarter et al., 1999).

Psychological self-regulation is largely subserved by the executive cognitive functions (ECF), consisting of attentional control, abstracting, working memory, strategic problem solving, and self-monitoring goal directed motivation (Barkley, 1997). These capacities are deficient in children who are at high risk for SUD ascertained on the basis of either having an affected parent with SUD (Giancola and Tarter, 1999, Giancola et al., 1996) or evidencing prodromal childhood psychiatric disturbance such as conduct disorder (Moffitt, 1993) or ADHD (Biederman et al., 1997). Notably, youth at high risk for SUD are prone to impulsive aggression, sudden unpredictable mood change, irritability, thrill seeking, and a disproportionate reaction to provocation (Kirillova et al., 2001, Tarter et al., 1995, Waschbusch et al., 2002). These cognitive, behavioral and affective characteristics have been frequently documented in individuals who have a prefrontal cortex (PFC) lesion (Benson, 1993, Fuster, 1989).

It has been recognized for over a century that the cardinal feature of a PFC disturbance is diminished inhibitory control (Young, 1970). Significantly, disinhibitory psychopathology (Gorrenstein and Newman, 1980) and neurobehavior disinhibition (Iacono et al., 2000) have been theorized to characterize the pattern of disturbances integral to SUD risk. Notably, behavior disinhibition, derived as a construct indicated by DSM-IV symptom counts of conduct disorder and ADHD along with measures of substance experimentation and novelty seeking, has been shown to be highly heritable (h²=0.84) (Young et al., 2000). These findings point at the possible mechanisms underlying the covariation between behavior disorders and SUD as well as commonality (common liability) between these disorders and liabilities to SUD consequent to use of different drugs. The importance of diminished self-regulation is further underscored by the finding in a recent study demonstrating that the score on a neurobehavior disinhibition construct (indicated by measures of emotion, behavior and executive cognitive functions), in conjunction with frequency of 30-day substance use, predicted the transition to SUD diagnosis between ages 16 and 19 with 85% accuracy and accounted for 50% of variance on the overall problem density score of the Drug Use Screening Inventory (DUSI-R) (Tarter et al., 2003). In this latter study, the standardized odds ratio of neurobehavior disinhibition (OR=6.83) was substantially larger than the odds ratio for substance use frequency (OR=3.19) for predicting SUD.

Neurophysiological findings also implicate neurobehavior disinhibition as an important contributor of risk for SUD. Attenuated amplitude of the P300 component of the event related potential has been frequently documented in youth and young adults at high risk for SUD (Brigham et al., 1995, Hesselbrock et al., 1993, Iacono et al., 1999). The P300 amplitude—an indicator of neurobehavior disinhibition (Begleiter and Porjesz, 1999)—most strongly reflects frontal-parietal cortical activity (Casey et al., 2001, He et al., 2001, Linden et al., 1999, Mecklinger and Ullsperger, 1995). Notably, reduced P300 amplitude in individuals at high risk for SUD has been linked to a prefrontal disturbance (Bauer et al., 1996, Bauer and Hesselbrock, 2001). In addition, the observation that young adults at high risk for SUD are impaired at performing an antisaccade task (Blekher et al., 2002, Cowley et al., 1994, Iacono, 1998) complements the evidence pertaining to a PFC dysfunction.

Considering the aggregate evidence, it can be concluded that low self-regulation during childhood magnifies the risk for SUD. Importantly, the construct of neurobehavior disinhibition is particularly heuristic for informing about the neurobiological substrate underlying the risk for SUD. Research has not been conducted, however, to elucidate the role of contextual factors which, in conjunction with neurobehavior disinhibition, leads to SUD.This study evaluated the progression to SUD between late childhood (age 10–12) and young adulthood (age 19) focusing on the covariation between individual differences in neurobehavior disinhibition and key environment factors during childhood and adolescence. Manifold environmental factors have been reported to increase the risk for adolescent substance use (Hawkins et al., 1992), although less is known about the factors which are integral to SUD. One factor that appears to have special salience on SUD risk is child neglect (Dunn et al., 2002 for review) which, in its less severe manifestation, is expressed as deficient parental supervision or monitoring of the child. A low level of ongoing parental engagement with the child has been frequently shown to be associated with childhood disruptive behaviors and adolescent substance abuse (Dishion and Loeber, 1985, Dishion and McMahan, 1998, Dishion et al., 2002). Notably, low parental involvement, and its more severe variant manifest as child neglect, mitigates normative socialization, including the acquisition of self-regulation that is ordinarily established concomitant to ongoing synergistic interactions between parents and children (Schore, 1994). A family environment featured by low parental involvement thus magnifies the risk for the psychologically dysregulated child to initiate substance use. In view of the salience of neurobehavior disinhibition in the risk for SUD, and evidence indicating that child neglect is an important contextual factor predisposing to SUD, this investigation was conducted to determine the pattern of covariation of these factors on the development of SUD between late childhood and young adulthood. The conceptual model guiding this investigation is depicted in Fig. 1.