Attention-Deficit/Hyperactivity Disorder (ADHD) and Substance Use Disorder (SUD) often co-occur and are associated with treatment resistance. Both disorders are characterized by similar reward-processing deficits with decreased striatal responses to reward anticipation, though literature is inconsistent. It is unclear whether substance misuse exaggerates reward-processing deficits observed in ADHD. The aim of this study was to examine substance misuse effects on reward-processing in ADHD. Functional MRI data in a Monetary Incentive Delay (MID) task from a multi-site study were compared across ADHD groups with and without substance misuse (ADHD + SM and ADHD-only, respectively) and healthy controls (n = 40/group, 74 males and 46 females, aged 13.7–25.9 years). Substance misuse was defined as misuse of alcohol, nicotine, or drugs. Groups were matched with presence/absence of parental SUD to avoid interference with SUD trait effects. Compared to ADHD-only and controls, ADHD + SM showed hyperactivation in putamen during reward anticipation. Compared to controls, the ADHD groups showed hypoactivation in motor/sensory cortices and hyperactivation in frontal pole and OFC during reward outcome. ADHD + SM also showed hyperactivation in frontal pole during neutral outcome. Moreover, ADHD + SM patients showed higher callous-unemotional (CU) traits that were positively correlated with putamen responses to reward anticipation. Our results show distinct condition-independent neural activation profile for ADHD + SM compared to ADHD-only and controls. Effects of comorbid substance misuse and variability of its prevalence across ADHD studies might have contributed to inconsistencies in ADHD literature. Contrasted with findings for reward-processing in SUD literature, results potentially suggest distinct underlying mechanisms for SUD subgroups with different characteristics, like antisocial/psychopathic traits.
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Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: A meta-analysis of follow-up studies. Psychol Med. 2006;36:159–65.
Polanczyk G, Rohde LA. Epidemiology of attention-deficit/hyperactivity disorder across the lifespan. Curr Opin Psychiatry. 2007;20:386–92.
Molina BSG, Pelham WE. Attention-deficit/hyperactivity disorder and risk of substance use disorder: developmental considerations, potential pathways, and opportunities for research. Annu Rev Clin Psychol. 2014;10:607–39.
Lee SS, Humphreys KL, Flory K, Liu R, Glass K. Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: a meta-analytic review. Clin Psychol Rev. 2011;31:328–41.
Ilbegi S, Groenman AP, Schellekens A, Hartman CA, Hoekstra PJ, Franke B, et al. Substance use and nicotine dependence in persistent, remittent, and late-onset ADHD: a 10-year longitudinal study from childhood to young adulthood. J Neurodev Disord. 2018;10:1–8.
Biederman J, Wilens T, Mick E, Milberger S, Spencer TJ, Faraone SV. Psychoactive substance use disorders in adults with attention deficit hyperactivity disorder (ADHD): effects of ADHD and psychiatric comorbidity. Am J Psychiatry. 1995;152:1652–8.
Sizoo B, van den Brink W, Koeter M, van Eenige MG, van Wijngaarden-Cremers P, van der Gaag RJ. Treatment seeking adults with autism or ADHD and co-morbid Substance Use Disorder: Prevalence, risk factors and functional disability. Drug Alcohol Depend. 2010;107:44–50.
Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson B, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur. Neuropsychopharmacol. 2011;21:655–79.
Wilens TE. Impact of ADHD and its treatment on substance abuse in adults. J Clin Psychiatry. 2004;65:38–45.
Castells X, Ramos-Quiroga JA, Rigau D, Bosch R, Nogueira M, Vidal X, et al. Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression analysis. CNS Drugs. 2011;25:157–69.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Publication; 2013.
Faraone SV, Asherson P, Banaschewski T, Biederman J, Buitelaar JK, Ramos-Quiroga JA, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Prim. 2015;1:15020.
Coffey SF, Gudleski GD, Saladin ME, Brady KT. Impulsivity and rapid discounting of delayed hypothetical rewards in cocaine-dependent individuals. Exp Clin Psychopharmacol. 2003;11:18–25.
DL Von, Bassani DG, Fuchs SC, Szobot CM, Pechansky F. Impulsivity, age of first alcohol use and substance use disorders among male adolescents: a population based case—control study. Addiction. 2008;1198–205. https://doi.org/10.1111/j.1360-0443.2008.02223.x.
Adisetiyo V, Gray KM. Neuroimaging the neural correlates of increased risk for substance use disorders in attention-deficit/hyperactivity disorder—A systematic review. Am. J. Addict. 2017;26:99–111.
Zuckerman M Sensation seeking (psychology revivals): beyond the optimal level of arousal. Psychology Press; 2014.
Haber SN, Knutson B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology. 2010;35:4–26.
Galvan A. Adolescent development of the reward system. Front Hum Neurosci. 2010;4:6.
Greven CU, Bralten J, Mennes M, O’Dwyer L, van Hulzen KJ, Rommelse N, et al. Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings. JAMA Psychiatry. 2015;1–10. https://doi.org/10.1001/jamapsychiatry.2014.3162.
Shaw P, De Rossi P, Watson B, Wharton A, Greenstein D, Raznahan A, et al. Mapping the development of the basal ganglia in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2014;53:780–9.
Plichta MM, Scheres A. Ventral-striatal responsiveness during reward anticipation in ADHD and its relation to trait impulsivity in the healthy population: a meta-analytic review of the fMRI literature. Neurosci Biobehav Rev. 2014;38:125–34.
van Hulst BM, de Zeeuw P, Bos DJ, Rijks Y, Neggers SF, Durston S, et al. Children with ADHD symptoms show decreased activity in ventral striatum during the anticipation of reward, irrespective of ADHD diagnosis. J Child Psychol Psychiatry Allied Discip. 2017;58:206–14.
Hägele C, Schlagenhauf F, Rapp M, Sterzer P, Beck A, Bermpohl F, et al. Dimensional psychiatry: Reward dysfunction and depressive mood across psychiatric disorders. Psychopharmacology (Berl). 2015;232:331–41.
von Rhein D, Cools R, Zwiers MP, van der Schaaf M, Franke B, Luman M, et al. Increased neural responses to reward in adolescents and young adults with attention-deficit/hyperactivity disorder and their unaffected siblings. J Am Acad Child Adolesc Psychiatry. 2015;54:394–402.
Paloyelis Y, Mehta MA, Faraone SV, Asherson P, Kuntsi J. Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51:722–32.
Scheres A, Milham MP, Knutson B, Castellanos FX. Ventral striatal hyporesponsiveness during reward anticipation in attention-deficit/hyperactivity disorder. Biol Psychiatry. 2007;61:720–4.
Luijten M, Schellekens AF, Kühn S, Machielse MWJ, Sescousse G. Disruption of reward processing in addiction. JAMA Psychiatry. 2017;74:387.
Schouw MLJ, De Ruiter MB, Kaag AM, van den Brink W, Lindauer RJL, Reneman L, et al. Dopaminergic dysfunction in abstinent dexamphetamine users: Results from a pharmacological fMRI study using a reward anticipation task and a methylphenidate challenge. Drug Alcohol Depend. 2013;130:52–60.
Peters J, Bromberg U, Schneider S, Brassen S, Menz M, Banaschewski T, et al. Lower ventral striatal activation during reward anticipation in adolescent smokers. Am J Psychiatry. 2011;168:540–9.
Cope LM, Martz ME, Hardee JE, Zucker RA, Heitzeg MM. Reward activation in childhood predicts adolescent substance use initiation in a high-risk sample. Drug Alcohol Depend. 2019;194:318–25.
Dallery J, Locey ML. Effects of acute and chronic nicotine on impulsive choice in rats. Behav pharmacol. 2000; 15–23.
Eppolito AK, France CP, Gerak LR. Effects of acute and chronic morphine on delay discounting in pigeons. J Exp Anal Behav. 2013;99:277–89.
Groman SM, Lee B, Seu E, James AS, Feiler K, Mandelkern MA, et al. Dysregulation of D2-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure. J Neurosci. 2012;32:5843–52.
Paine TA, Dringenberg HC, Olmstead MC. Effects of chronic cocaine on impulsivity: relation to cortical serotonin mechanisms. Behav Brain Res. 2003;147:135–47.
Liu S, Heitz RP, Bradberry CW. A touch screen based stop signal response task in rhesus monkeys for studying impulsivity associated with chronic cocaine self-administration. J Neurosci Methods. 2009;177:67–72.
Kolokotroni KZ, Rodgers RJ, Harrison AA. Effects of chronic nicotine, nicotine withdrawal and subsequent nicotine challenges on behavioural inhibition in rats. Psychopharmacology (Berl). 2012;219:453–68.
Setlow B, Mendez IA, Mitchell MR, Simon NW. Effects of chronic administration of drugs of abuse on impulsive choice (delay discounting) in animal models. Behav Pharmacol. 2009;20:380–9.
Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ. High impulsivity predicts the switch to compulsive cocaine-taking. Science. 2008;320:1352–5.
Ortal S, van de Glind G, Johan F, Itai B, Nir Y, Iliyan I, et al. The role of different aspects of impulsivity as independent risk factors for substance use disorders in patients with ADHD: a review. Curr. Drug Abuse Rev. 2015;8:119–33.
Edwards AC, Kendler KS. Twin study of the relationship between adolescent attention-deficit/hyperactivity disorder and adult alcohol dependence. J Stud Alcohol Drugs. 2012;73:185–94.
Blair RJR. The neurobiology of psychopathic traits in youths. Nat. Rev. Neurosci. 2013;14:786–99.
Frick PJ, Moffitt TE. A proposal to the DSM-V childhood disorders and the ADHD and disruptive behavior disorders work groups to include a specifier to the diagnosis of conduct disorder based on the presence of callous-unemotional traits. Washington, DC. Am Psychiatr Assoc. 2010;1–36.
von Rhein D, Mennes M, van Ewijk H, Groenman AP, Zwiers MP, Oosterlaan J, et al. The NeuroIMAGE study: a prospective phenotypic, cognitive, genetic and MRI study in children with attention-deficit/hyperactivity disorder. Design and descriptives. Eur Child Adolesc Psychiatry. 2014. https://doi.org/10.1007/s00787-014-0573-4.
Kaufman J, Birmaher B, Brent D, Rao UMA, Flynn C, Moreci P, et al. Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36:980–8.
Conners CK, Sitarenios G, Parker JDA, Epstein JN. Revision and restandardization of the conners teacher rating scale (CTRS-R): factor structure. Reliability Criterion Val. 1998;26:279–91.
Conners CK, Erhardt D, Epstein JN, Parker JDA, Sitarenios G, Sparrow E. Self-ratings of ADHD symptoms in adults I: Factor structure and normative data. J Atten Disord. 1999;3:141–51.
Loeber R, Wung P, Keenan K, Giroux B, Stouthamer-Loeber M, Van Kammen WB, et al. Developmental pathways in disruptive child behavior. Dev Psychopathol. 1993;5:103–33.
Elliott DS, Huizinga D, Ageton SS Explaining delinquency and drugs use. Beverly Hills, CA: Sage.; 1985.
Schippers GM, Broekman TG, Buchholz A, Koeter MWJ. Van Den Brink W. Measurements in the Addictions for Triage and Evaluation (MATE): An instrument based on the World Health Organization family of international classifications. Addiction. 2010;105:862–71.
Saunders JB, Aasland OG, Babor TF, De La Fuente JR, Grant M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction. 1993;88:791–804.
Gavin DR, Ross HE, Skinner HA. Diagnostic validity of the DAST in the assessment of DSM-III drug disorders. Br J Addict. 1989;84:301–7.
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom K-O. The Fagerström test for nicotine dependence: a revision of the fagerstrom tolerance questionnaire. Br. J. Addict. 2018;86:1119–27.
Sobell LC, Brown J, Leo GI, Sobell MB. The reliability of the alcohol timeline followback when administered by telephone and by computer. Drug Alcohol Depend. 1996;42:49–54.
RStudio Team. RStudio: Integrated Development for R. 2019. Boston, MA: RStudio, Inc. http://www.rstudio.com/.
Ho DE, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw. 2011;42. https://doi.org/10.18637/jss.v042.i08.
Kimonis ER, Frick PJ, Skeem JL, Marsee MA, Cruise K, Munoz LC, et al. Assessing callous-unemotional traits in adolescent offenders: validation of the Inventory of Callous-Unemotional Traits. Int J Law Psychiatry. 2008;31:241–52.
Byrd Amy L, Kahn Rachel E, Pardini DA. A validation of the inventory of callous-unemotional traits in a community sample of young adult males. J Psychopathol Behav Assess. 2014;35:1–26.
Gow RV, Vallee-Tourangeau F, Crawford MA, Taylor E, Ghebremeskel K, Bueno AA, et al. Omega-3 fatty acids are inversely related to callous and unemotional traits in adolescent boys with attention de fi cit hyperactivity disorder. Prostaglandins Leukot Essent Fat Acids. 2013;88:411–8.
Hoogman M, Aarts E, Zwiers M, Slaats-Willemse D, Naber M, Onnink M, et al. Nitric oxide synthase genotype modulation of impulsivity and ventral striatal activity in adult ADHD patients and healthy comparison subjects. Am J Psychiatry. 2011;168:1099–106.
Knutson B, Fong GW, Adams CM, Varner JL, Hommer D. Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport. 2001;12:3683–7.
Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23:S208–19.
Jenkinson M, Beckmann CF, Behrens TEJ, Woolrich MW, Smith SM. FSL. Neuroimage. 2012;62:782–90.
Smith SS, Newman JP. Alcohol and drug abuse-dependence disorders in psychopathic and nonpsychopathic criminal offenders. J. Abnorm. Psychol. 1990;99:430–9.
Boehler CN, Hopf JM, Krebs RM, Stoppel CM, Schoenfeld MA, Heinze HJ, et al. Task-load-dependent activation of dopaminergic midbrain areas in the absence of reward. 2011;31:4955–61.
Schultz W. Updating dopamine reward signals. Curr Opin Neurobiol. 2013;23:229–38.
Cservenka A, Courtney KE, Ghahremani DG, Hutchison KE, Ray LA. Development, initial testing and challenges of an ecologically valid reward prediction error FMRI task for alcoholism. Alcohol Alcohol. 2017;52:617–24.
Fiorillo CD, Tobler PN, Schultz W. Discrete coding of reward probability and uncertainty by dopamine neurons. Science. 2003;299:1898–902.
Linnet J. Neurobiological underpinnings of reward anticipation and outcome evaluation in gambling disorder. Front Behav Neurosci. 2014;8:1898–902.
Cao Z, Bennett M, Orr C, Icke I, Banaschewski T, Barker GJ, et al. Mapping adolescent reward anticipation, receipt, and prediction error during the monetary incentive delay task. Hum Brain Mapp. 2019;40:262–83.
Stalnaker TA, Liu T, Takahashi YK, Schoenbaum G. Orbitofrontal neurons signal reward predictions, not reward prediction errors. Neurobiol Learn Mem. 2018;153:137–43.
Goldstein RZ, Volkow ND. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. 2011;12:652–69.
Filbey FM, Dunlop J, Myers US. Neural effects of positive and negative incentives during marijuana withdrawal. PloS one. 2013;8.
Just AL, Meng C, Smith DG, Bullmore ET, Robbins TW, Ersche KD, et al. Effects of familial risk and stimulant drug use on the anticipation of monetary reward: an fMRI study. Transl Psychiatry. 2019;9.
Yau WYW, Zubieta JK, Weiland BJ, Samudra PG, Zucker RA, Heitzeg MM, et al. Nucleus accumbens response to incentive stimuli anticipation in children of alcoholics: relationships with precursive behavioral risk and lifetime alcohol use. J Neurosci. 2012;32:2544–51.
Tervo-clemmens B, Quach A, Calabro FJ, Foran W, Luna B. NeuroImage meta-analysis and review of functional neuroimaging differences underlying adolescent vulnerability to substance use. Neuroimage. 2020;209:116476.
Cloninger CR, Sigvardsson S, Bohman M. Childhood personality predicts alcohol abuse in young adults. Alcohol Clin Exp Res. 1988;12:494–505.
Hansen WB, Flay BR, Weber MD, Johnson CA, Graham JW. Evidence for two paths of alcohol use onset in adolescents. Addict Behav. 1989;14:399–408.
Fitzgerald HE, Ellis DA, Sanford K, Zucker RA, Bingham CR. Other evidence for at least two alcoholisms II: Life course variation in antisociality and heterogeneity of alcoholic outcome. Dev Psychopathol. 2009;8:831.
Murray L, Waller R, Hyde LW. A systematic review examining the link between psychopathic personality traits, antisocial behavior, and neural reactivity during reward and loss processing. Personal Disord Theory, Res Treat. 2018;9:497–509.
Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Benning SD, Li R, et al. Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits. Nat Neurosci. 2010;13:419–21.
Bjork JM, Chen G, Hommer DW. Psychopathic tendencies and mesolimbic recruitment by cues for instrumental and passively obtained rewards. Biol Psychol. 2012;89:408–15.
Tuithof M, ten Have M, van den Brink W, Vollebergh W, de Graaf R. The role of conduct disorder in the association between ADHD and alcohol use (disorder). Results from the Netherlands Mental Health Survey and Incidence Study-2. Drug Alcohol Depend. 2012;123:115–21.
Bjork JM, Knutson B, Hommer DW. Incentive-elicited striatal activation in adolescent children of alcoholics. Addiction. 2008;103:1308–19.
Slobodin O, Davidovitch M. Gender differences in objective and subjective measures of ADHD among clinic-referred children. Front Hum Neurosci. 2019;13:1–14.
Wu CC, Samanez-Larkin GR, Katovich K, Knutson B. Affective traits link to reliable neural markers of incentive anticipation. Neuroimage. 2014;84:279–89.
Tobler PN, Fiorillo CD, Schultz W. Adaptive coding of reward value by dopamine neurons. Science. 2005;307:1642–5.
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Paraskevopoulou, M., van Rooij, D., Batalla, A. et al. Effects of substance misuse on reward-processing in patients with attention-deficit/hyperactivity disorder. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00896-1