Cognitive control is a rubric that incorporates multiple cognitive mechanisms that organisms use to effectively enable adaptive behavior (e.g., planning, updating representations of goals, of attentional biases or of action; inhibitory control of pre-potent responses; (Miller and Cohen 2001
)); individually, multiple components of cognitive control are impaired in a variety of psychiatric disorders, including ADHD and substance abuse/dependence, and these effects will be described in more detail here.
A lack of cognitive control over behavior is likely to directly underpin the impulsive behavior that is a cardinal feature of ADHD and substance abuse/dependence. In naturalistic settings, children with ADHD exhibit difficulty suppressing situationally-inappropriate behavior, and it is the consequences of these control failures that lead to the disruptive behaviors that characterize the disorder and contribute to the scholastic deficits. Furthermore, addictive disorders critically include a failure of effective, voluntary control over reward-directed behavior (Jentsch and Taylor 1999
Because multiple dimensions of psychological dysfunction are found in these disorders, it does not immediately follow that the impulsive behavioral patterns in ADHD and substance abuse stem from an empirically-measurable lack of cognitive control; direct investigation of this possibility, using laboratory measures, is necessary. A variety of tests have been used to evaluate the ability to stop or change responses in these clinical populations, and together, these different experimental tasks have provided convergent evidence for a substantial deficit in response inhibition in ADHD and substance abuse. One dimension of cognitive control that has been the focus of considerable study is response inhibition. Response inhibition encompasses the ability to adaptively suppress behavior when environmental contingencies demand it. Laboratory measures of response inhibition normally involve the establishment of a response that becomes the default (“pre-potent”) response. Each of the empirically-validated tasks (see ) incorporates situational requirements for inhibiting, stopping, delaying or modifying the pre-potent response. The nature of control exerted over the pre-potent response can vary widely (e.g. stopping an ongoing behavior, inhibiting responding when reward is no longer delivered, eliminating inappropriate or excessive responding, or inhibiting responses to a previously rewarded stimulus); additionally, the cognitive processes response control may vary, as well (e.g. motor inhibition, ability to bridge a delay, ability to shift responding to new stimuli, ability to weigh magnitude of reward effectively). Importantly, the measures are not suggested to index a singular, invariant construct, but they do all appear to be procedures that allow one to quantify aspects of neural systems dysfunction that occurs in ADHD and substance abuse/dependence.
Common tasks used for the assessment of cognitive control of behavior, including response inhibition
Neuroimaging studies have revealed a common pattern of brain dysfunction that extends beyond anatomical and functional abnormalities in ventrolateral prefrontal cortex. Molecular imaging studies have demonstrated that both ADHD and substance-dependent individuals have altered dopaminergic function and production, particularly in striatal regions (Ernst et al. 1998
; Heinz et al. 2005
; Ludolph et al. 2008
; Martinez et al. 2007
). Beyond these dopaminergic alterations, both disorders show a consistent pattern of lower gray matter density in prefrontal regions (Matochik et al. 2003
; Semrud-Clikeman et al. 2006
) and striatal areas (Castellanos et al. 1994
; Jacobsen et al. 2001
). Functional imaging has also demonstrated hypoactivation of the anterior cingulate when performing a response inhibition task in both ADHD and substance dependent individuals (Hester and Garavan 2004
; Leland et al. 2008
). Together, these data indicate a shared neural dysfunction and dysregulation that may contribute to the shared behavioral deficits, indicative of a parallel neuronal pathway. Although the relationship between these functional, anatomical and biochemical alterations is not well understood, the fact that similarities exist beyond the behavioral output substantiates the claim that a shared neural pathway exists between ADHD and substance abuse.
Amongst neuropsychiatric disorders, ADHD is somewhat unique in that the available pharmacological treatments, while not without side effects, are remarkably effective at controlling symptomatology (Arnsten 2006b
; Biederman et al. 2006
). Additionally, methylphenidate and atomoxetine lessen deficits of inhibitory control in ADHD when given at therapeutically effective doses (Aron et al. 2003
; Chamberlain et al. 2007
; Scheres et al. 2003
; Tannock et al. 1989
). Pre-clinical studies have provided clues as to the neurotransmitter systems that mediate its effects on response inhibition measures. Methylphenidate and amphetamine (both of which non-selectively increase monoamine output in brain) have mixed effects on response inhibition tasks in rats that vary depending upon dose, route of administration and procedure (Cardinal et al. 2000
; Cole and Robbins 1987
; Eagle et al. 2007
; Richards et al. 1999
). On the other hand, atomoxetine, a selective norepinephrine reuptake inhibitor, appears to consistently improve response inhibition in a variety of pre-clinical measures (Robinson et al. 2007
; Seu et al. 2008
). Selective norepinephrine transporter inhibitors differ from traditional stimulant treatments in that stimulants increase extracellular dopamine levels in the striatum, while atomoxetine does not (Bymaster et al. 2002
). Notably, however, both stimulants and atomoxetine both increase dopamine and norepinephrine in prefrontal regions (Berridge et al. 2006
; Bymaster et al. 2002
). These similar prefrontal monoaminergic effects of different drug classes suggest a critical role of prefrontal dopamine and norepinephrine in regulating and recruiting the neural systems that are believed to be critical for inhibiting behavior.
What is less clear, however, is the relationship between early, effective treatment of symptoms of ADHD and later risk for substance abuse disorders. Pre-clinical studies have suggested that developmentally-early treatment with stimulant medications used to treat ADHD reduce sensitivity to addictive drugs in adulthood (Andersen et al. 2002
; Mague et al. 2005
), but see also (Brandon et al. 2003
). These results are seemingly congruent with recent prospective studies indicating that early methylphenidate treatment in ADHD does not increase, and may actually decrease, risk for substance use disorders (Biederman et al. 2008
; Mannuzza et al. 2008
). Because of the potential reductions in substance abuse risk associated with effective treatment of ADHD, it is of empirical interest to further determine whether clinical improvement in treated patients tracks along with effective modulation of the deficits in response inhibition (Nigg et al. 2006
); if that were the case, it would strengthen support for the idea that the relationship between ADHD and substance abuse depends upon an aberrant response inhibition mechanism.
Virtually nothing is known about the pharmacological regulation of response inhibition deficits in substance abuse. Theoretically, effective treatments for ADHD may be expected to accomplish this effect; however, the abuse liability of methylphenidate and amphetamine make them practically problematic in the treatment of substance abuse. On the other hand, atomoxetine lacks abuse liability (Michelson et al. 2003
), but its effects on response inhibition have not yet been evaluated and/or reported in substance abuse. If effective at modulating these deficits in substance-dependent persons, atomoxetine would represent an important tool in determining whether agents that lessen response inhibition deficits could be expected to enable voluntary cessation of drug intake, as is hypothesized by earlier models (Jentsch and Taylor 1999
What are the implications of this common pattern of neurophysiological and response inhibition impairments in the two disorders? Some of the potential relationships are exhibited in . First, and most simplistically, the co-morbidity of the two disorders may explain the concordance of neural and behavioral phenotypes. Second, ADHD, and its corresponding neural and behavioral traits, is a risk factor for addiction, leading to an over-representation of ADHD-like phenotypes in stimulant-dependent subjects. Third, chronic intake of psychostimulants may directly change the function of the orbitofrontal cortex in a manner that mimics neural and behavioral aspects of ADHD. Studies in animal models are particularly helpful in disambiguating the directionality of these sorts of associations present in clinical populations.
Figure 2 This hypothetical model graphically represents the concept that poor response inhibition, mediated by genetically-determined alterations in forebrain catecholamine transmission, is a risk factor for both ADHD and substance abuse. The abuse of illicit (more ...)