Research examining the potential effects of stimulant exposure in childhood on subsequent development of substance use disorder (SUD) have focused on differences in the brain reward system as a function of risk.
Methods:
18 drug naïve children ages 7 to 12 years (11 High Risk [ADHD + ODD/CD]; 7 Low Risk [ADHD only]), underwent fMRI scans before and after treatment with mixed amphetamine salts, extended release (MAS-XR). We examined correlations between clinical ratings and fMRI activation at baseline and following treatment as a function of risk status.
Results:
High Risk children had higher activation than Low Risk children at baseline during both the Reward and Surprising Non-Reward conditions. Treatment produced strong differential effects on brain activation pertinent to group and reward outcome.
Conclusions:
Findings support the hypothesized role of reward mechanisms in SUD risk, and suggest that stimulant treatment may have differential effects on reward processing in relation to SUD risk.
AchenbachT.EdelbrockC. (1991). Manual for the CBCL and 1991 profile. University of Vermont.
2.
AnsquerS.Belin-RauscentA.DugastE.DuranT.BenatruI.MarA.HouetoJ. L.BelinD. (2014). Atomoxetine decreases vulnerability to develop compulsivity in high impulsive rats. Biological Psychiatry, 75(10), 825–832.
3.
BarkleyR. A.FischerM.SmallishL.FletcherK. (2003). Does the treatment of attention-deficit/hyperactivity disorder with stimulants contribute to drug use/abuse? A 13-year prospective study. Pediatrics, 111(1), 97–109.
4.
BenningfieldM.BlackfordJ.EllsworhtM.Samanez- LarkinG.MartinP.CowanR.ZaldD. (2014). Caudate response to reward anticipation associated with delay discounting behavior in healthy youth. Developmental Cognitive Neuroscience, 7, 43–52. https://doi.org/10.1016/j.dcn.2013.10.009
5.
BiedermanJ.MonuteauxM.SpencerT.WilensT.MacphersonH.FaraoneS. (2008). Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: A naturalistic controlled 10-year follow-up study. The American Journal of Psychiatry, 165(5), 597–603.
6.
BiedermanJ.WilensT.MickE.SpencerT.FaraoneS. (1999). Pharmacotherapy of attention-deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics, 104(2), e20.
7.
BjorkJ.PardiniD. (2015). Who are those “risk-taking adolescents”? Individual differences in developmental neuroimaging research. Developmental Cognitive Neuroscience, 11, 56–64.
8.
BoileauI.DagherA.LeytonM.GunnR. N.BakerG. B.DiksicM.BenkelfatC. (2006). Modeling sensitization to stimulants in humans: An [11C]raclopride/positron emission tomography study in healthy men. Archives of General Psychiatry, 63(12), 1386–1395.
9.
BuchelC.PetersJ.BanaschewskiT.BokdeA. L.BrombergU.ConrodP. J.FlorH.PapadopoulosD.GaravanH.GowlandP.HeinzA.WalterH.IttermannB.MannK.MartinotJ. L.Paillère-MartinotM. L.NeesF.PausT.PausovaZ.. . . & KnutsonB. (2017). Blunted ventral striatal responses to anticipated rewards foreshadow problematic drug use in novelty-seeking adolescents. Nature Communications, 8, 14140.
10.
CalipariE. S.JonesS. R. (2014). Sensitized nucleus accumbens dopamine terminal responses to methylphenidate and dopamine transporter releasers after intermittent-access self-administration. Neuropharmacology, 82, 1–10.
11.
CampezM.RaikerJ. S.LittleK.AltszulerA. R.MerrillB. M.MacpheeF. L.GnagyE. M.GreinerA. R.MusserE. D.ColesE. K.PelhamW. E. (2022). An evaluation of the effect of methylphenidate on working memory, time perception, and choice impulsivity in children with ADHD. Experimental and Clinical Psychopharmacology, 30(2), 209–219. https://doi.org/10.1037/pha0000446.
12.
CarverC. S.WhiteT. L. (1994). Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: The BIS/BAS scales. Journal of Personality and Social Psychology, 67(2), 319.
13.
CoolsR.BarkerR. A.SahakianB. J.RobbinsT. W. (2003). L-Dopa medication remediates cognitive inflexibility, but increases impulsivity in patients with Parkinson’s disease. Neuropsychologia, 41(11), 1431–1441.
14.
CrowleyT. J.DalwaniM. S.Mikulich-GilbertsonS. K.DuY. P.LejuezC. W.RaymondK. M.BanichM. T. (2010). Risky decisions and their consequences: Neural processing by boys with antisocial substance disorder. PLoS One, 5, e12835.
15.
CzerniakS. M.SikogluE. M.KingJ. A.KennedyD. N.MickE.FrazierJ.MooreC. M. (2013). Areas of the brain modulated by single-dose methylphenidate treatment in youth with ADHD during task-based fMRI: A systematic review. Harvard Review of Psychiatry, 21(3), 151–162.
16.
DuPaulG. J.PowerT. J.AnastopoulosA. D.ReidR. (2016). ADHD rating scale-5 for children and adolescents: Checklists, norms, and clinical interpretation. The Guilford Press.
17.
FaraoneS. V.RostainA. L.MontanoC. B.MasonO.AntshelK. M.NewcornJ. H. (2020). Systematic review: Nonmedical use of prescription stimulants: Risk factors, outcomes, and risk reduction strategies. Journal of the American Academy of Child & Adolescent Psychiatry, 59(1), 100–112. https://doi.org/10.1016/j.jaac.2019.06.012
GoldsteinR.VolkowN. (2011). Dysfunction of the prefrontal cortex in addiction: Neuroimaging findings and clinical implications. Nature Reviews Neuroscience, 12(11), 652–669.
20.
GrimmO.van RooijD.HoogmanM.KleinM.BuitelaarJ.FrankeB.ReifA.PlichtaM. M. (2021). Transdiagnostic neuroimaging of reward system in ADHD and comorbid disorders. Neurosceince and Biobehavioral Reviews, 128, 165–181. https://doi.org/10.1016/j.neubiorev.2021.06.025
21.
GroenmanA.JanssenT.OosterlaanJ. (2017). Childhood psychiatric disorders as risk factor for subsequent substance abuse: A meta-analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 56(7), 556–569. https://doi.org/10.1016/j.jaac.2017.05.004
22.
HartyS. C.IvanovI.NewcornJ.HalperinJ. (2011). The impact of conduct disorder and stimulant medication on later substance use in an ethnically diverse sample of individuals with attention-deficit/hyperactivity disorder in childhood. Journal of Child and Adolescent Psychopharmacology, 21(4), 331–339.
23.
HawesS.WallerR.ByrdA.BjorkJ.DickA.SutherlandM.RiedelM.TobiaM. J.ThomsonN.LairdA. R.GonzalezR. (2021). Reward processing in children with disruptive behavior disorders and callous-unemotional traits in the ABCD study. The American Journal of Psychiatry, 178(4), 333–342. https://doi.org/10.1176/appi.ajp.2020.19101092
24.
HeZ.LiS.MoL.ZhengZ.LiY.LiH.ZhangD. (2023). The VLPFC-engaged voluntary emotion regulation: Combined TMS-fMRI evidence for the neural circuit of cognitive reappraisal. The Journal of Neuroscience, 43(34), 6046–6060.
25.
HenryD. J.WhiteF. J. (1991). Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens. Journal of Pharmacology and Experimental Therapeutics, 258, 882–890.
26.
HumphreysK. L.EngT.LeeS. (2013). Stimulant medication and substance use outcomes: A meta-analysis. JAMA Psychiatry, 70(7), 740–749.
27.
IvanovI.BjorkJ.BlairR. J.NewcornJ. (2022). Sensitization-based risk for substance abuse in vulnerable individuals with ADHD: Review and re-examination of evidence. Neuroscience and Biobehavioral Reviews, 135, 104575.
28.
IvanovI.LiuX.ShulzK.FanJ.LondonE.FristonK.HalperinJ.NewcornJ. (2012). Activation of the motivation and behavioral inhibition systems and vulnerability for substance abuse in drug naïve youth. Psychiatry Research, Neuroimaging, 201(2), 128–135.
29.
IvanovI.ParvazM.VelthorstE.SandinS.GanG.SpechlerP.AlbaughM. D.ChaaraniB.MackeyS.BanaschewskiT.BokdeA. L. W.BrombergU.BüchelC.QuinlanE. B.DesrivièresS.FlorH.GrigisA.GowlandP.HeinzA.. . . & GaravanH. (2021). Substance use initiation in drug naïve adolescents – possible predictors and consequences from a large cohort naturalistic study. Journal of the American Academy of Child and Adolescent Psychiatry, 60(5), 623–636. https://doi.org/10.1016/j.jaac.2020.08.443
30.
IvanovI.SchulzK.LiX.NewcornJ. (2019). Reward processing in drug-naïve youth with various levels of risk for substance use disorders. special issue on adolescent substance use disorders: A Pilot Study. The Journal of Child and Adolescent Psychopharmacology, 29(7), 516–525.
31.
IvanovI.SchulzK.LondonE.NewcornJ. (2008). Inhibitory control deficits in childhood and risk for substance use disorders: A Review. The American Journal of Drug and Alcohol Abuse, 34(3), 239–258.
32.
JohnstoneT.Ores-WalshK. S.GreischarL. L.AlexanderA. L.FoxA. S.DavidsonR. J.OakesT. R. (2006). Motion correction and the use of motion covariates in multiple-subject fMRI analysis. Human Brain Mapping, 27(10), 779–788.
33.
JordanC. J.HarveyR.BaskinB.DwoskinL.KantakK. (2014). Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments. Drug and Alcohol Dependence, 140, 25–32.
34.
JosephJ.LiuX.JiangY.LynamD.KellyT. (2009). Neural correlates of emotional reactivity in sensation seeking. Psychological Science, 20(2), 215–223. https://doi.org/10.1111/j.1467-9280.2009.02283.x
35.
KaufmanJ.BirmaherB.BrentD.RaoU.FlynnC.MoreciP.WilliamsonD.RyanN. (1997). Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry, 36(7), 980–988.
36.
Kearny-RamosT.DowdleL.LenchD.MithoeferO.DevriesW.GeorgeM.AntonR.HanlonC. (2018). Transdiagnostic effects of ventromedial prefrontal cortex transcaranial magnetic stimulation on cue reactivity. Biological Psychiatry. Cognitive Neuroscience and Neuroimaging, 3(7), 599–609. https://doi.org/10.1016/j.bpsc.2018.03.016
37.
KirbyK. N. (2009). One-year temporal stability of delay-discount rates. Psychonomic Bulletin & Review, 16, 457–462.
38.
LambertN. M. (2005). The contribution of childhood ADHD, conduct problems, and stimulant treatment to adolescent and adult tobacco and psychoactive substance abuse. Ethical Human Psychology and Psychiatry, 7(3), 197–221.
39.
LambertN. M.HartsoughC. S. (1998). Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-ADHD participants. Journal of Learning Disabilities, 31(6), 533–544.
40.
LambertN. M.McLeodM.SchenkS. (2006). Subjective responses to initial experience with cocaine: An exploration of the incentive-sensitization theory of drug abuse. Addiction, 101(5), 713–725.
41.
LoneyJ.KramerJ. R.SalisburyH. (2002). Medicated vs. unmedicated ADHD children: Adult involvement with legal and illegal drugs. In JensenP. S.CooperJ. R. (Eds.), Attention deficit hyperactivity disorder. State of the science best practices. Civic Research Institute.
42.
MahmoodO. M.GoldenbergD.ThayerR.MiglioriniR.SimmonsA. N.TapertS. F. (2013). Adolescents’ fMRI activation to a response inhibition task predicts future substance use. Addictive Behaviors, 38(1), 1435–1441.
43.
McTeagueL.HuemerJ.CarreonD.JiangY.EickhoffS.EtkinsA. (2017). Identification of common neural circuit disruptions in cognitive control across psychiatric disorders. The American Journal of Psychiatry, 174(7), 676–685. https://doi.org/10.1176/appi.ajp.2017.16040400
44.
MolinaB. S.HinshawS.ArnoldE.SwansonJ.PelhamW. E.HechtmanL.HozaB.EpsteinJ. N.WigalT.AbikoffH. B.GreenhillL. L.JensenP. S.WellsK. C.VitielloB.GibbonsR. D.HowardA.HouckP. R.HurK.LuB., . . . MTA Cooperative Group. (2013). Adolescent substance use in the multimodal treatment study of attention-deficit/hyperactivity disorder (ADHD) (MTA) as a function of childhood ADHD, random assignment to childhood treatments, and subsequent medication. Journal of the American Academy of Child and Adolescent Psychiatry, 52(3), 250–263.
45.
MolinaB. S.HowardA.SwansonJ.StehliA.MitchellJ.KennedyT.EpsteinJ.ArnoldE.HetchmanL.VitielloB.HozaB. (2018). Substance use through adolescence into early adulthood after childhood-diagnosed ADHD: Findings from the MTA longitudinal study. Journal of Child Psychology and Psychiatry, 59(6), 692–702.
46.
NestbyP.VanderschurenL. J.De VriesT. J. (1997). Ethanol, like psychostimulants and mor- phine, causes long-lasting hyperreactivity of dopamine and acetylcholine neurons of rat nucleus accumbens: Possible role in behavioural sensitization. Psychopharmacology, 133, 69–76.
47.
NormanA. L.PulidoC.SquegliaL. M.SpadoniA. D.PaulusM. P.TapertS. F. (2011). Neural activation during inhibition predicts initiation of substance use in adolescence. Drug and Alcohol Dependence, 119(3), 216–223.
48.
O’DaleyO. G.JoyceD.TracyD. K.AzimA.StephanK. E.MurrayR. M.ShergillS. S. (2014). Amphetamine sensitization alters reward processing in the human striatum and amygdala. PLoS One, 9(4), e93955. https://doi.org/10.1371/journal.pone.0093955
49.
PierceR. C.KalivasP. W. (1997). A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Research Reviews, 25, 192–216.
50.
PingaultJ. B.CoteS.GaleraC.GenoliniC.FalissardB.VitaroF.TremblayR. E. (2013). Childhood trajectories of inattention, hyperactivity and oppositional behaviors and prediction of substance abuse/dependence: A 15-year longitudinal population-based study. Molecular Psychiatry, 18(7), 806–812. https://doi.org/10.1038/mp.2012.87
51.
PlichtaM. M.ScheresA. (2014). 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. Neuroscience and Biobehavioral Reviews, 38, 125–134.
52.
RobinsonT. E.BerridgeK. C. (1993). The neural basis of drug craving: An incentive-sensitization theory of addiction. Brain Research Reviews, 18, 247–291.
53.
RubiaK.HalariR.CubilloA.MohammadA. M.BrammerM.TaylorE. (2009). Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task. Neuropharmacology, 57(7–8), 640–652. https://doi.org/10.1016/j.neuropharm.2009.08.013
54.
SilversJ.InselC.PowersA.FranzP.HelionC.MartinR.WeberJ.MischelW.CaseyB. J.OchnerK. (2017). vlPFC-vmPFC-amygdala interactions underlie age-related differences in cognitive regulation of emotion. Cerebral Cortex, 27(7), 3502–3514.
55.
SlobodinO.van de GlindG.FranckJ.BergerI.YachinN.IvanovI.van den BrinkW. (2015). The role of different aspects of impulsivity as independent risk factors for substance use disorders in patients with ADHD: A review. Current Drug Abuse Reviews, 8(2), 119–133.
56.
SmithA.TaylorE.BrammerM.TooneB.RubiaK. (2006). Task-specific hypoactivation in prefrontal and temporoparietal brain regions during motor inhibition and task switching in medication-naive children and adolescents with attention deficit hyperactivity disorder. The American Journal of Psychiatry, 163(6), 1044–1051.
57.
SpechlerP. A.AllgaierN.ChaaraniB.WhelanR.WattsR.OrrC.AlbaughM. D.D’AlbertoN.HigginsS. T.HudsonK. E.MackeyS.PotterA.BanaschewskiT.BokdeA. L. W.BrombergU.BüchelC.CattrellA.ConrodP. J.DesrivièresS.. . . & GaravanH. (2018). The initiation of cannabis use in adolescence is predicted by sex-specific psychosocial and neurobiological features. The European Journal of Neuroscience, 50(3), 2346–2356. https://doi.org/10.1111/ejn.13989
58.
StangerS.EltonA.RyanS.JamesA.BudneyA.KiltonC. (2013). Neuroeconomics and adolescent substance abuse: Individual differences in neural networks and delay discounting. Journal of the American Academy of Child and Adolescent Psychiatry, 52(7), 747–755.e6.
SteevesT. D.MiyasakiJ.ZurowskiM.LangA. E.PellecchiaG.Van EimerenT.RusjanP.HouleS.StrafellaA. P. (2009). Increased striatal dopamine release in Parkinsonian patients with pathological gambling: A [11C] raclopride PET study. Brain, 132(Pt 5), 1376–1385. https://doi.org/10.1093/brain/awp054
61.
Substance Abuse and Mental Health Services Administration. (2009). Results from the 2008 National Survey on Drug Use and Health: National Findings. NSDUH Series H-36, HHS Publication No. (SMA) 09-4434. Office of Applied Studies.
62.
TegelbeckersJ.KanowskiM.KrauelK.HaynesJ. D.BreitlingC.FlechtnerH. H.KahntT. (2018). Orbitofrontal signaling of future reward is associated with hyperactivity in attention-deficit/hyperactivity disorder. The Journal of Neuroscience, 38(30), 6779–6786.
63.
TomkoR.PrisciandaroJ.Kutty-FallsS.MagidV. (2016). The structure of the UPPS-R-child impulsivity scale and its relations with substance use outcomes among treatment-seeking adolescents. Drug and Alcohol Dependence, 161, 276–283.
64.
VolkowN. D.KoobG. F.McLellanA. T. (2016). Neurobiologic advances from the brain disease model of addiction. The New England Journal of Medicine, 374, 363–371. https://doi.org/10.1056/NEJMra1511480
65.
von RheinD.CoolsR.ZweirsM.van der SchaafM.FrankeB.LumanM.OosterlaanJ.HeslenfeldD. J.HoekstraP. J.HartmanC. A.FaraoneS. V.van RooijD.van DongenE. V.LojowskaM.MennesM.BuitelaarJ. (2015). Increased neural responses to reward in adolescents and young adults with attention-deficit/hyperactivity disorder and their unaffected siblings. Journal of the American Academy of Child & Adolescent Psychiatry, 54(5), 394–402.
66.
WechslerD. (1999). Wechsler abbreviated scale of intelligence (WASI). Harcourt Assessment, Inc.
67.
WetherillR. R.SquegliaL. M.YangT. T.TapertS. F. (2013). A longitudinal examination of adolescent response inhibition: Neural differences before and after the initiation of heavy drinking. Psychopharmacology (Berl), 230(4), 663–671.
68.
WhelanR.WattsR.OrrC. A.AlthoffR. R.ArtigesE.BanaschewskiT.BarkerG. J.BokdeA. L.BüchelC.CarvalhoF. M.ConrodP. J.FlorH.Fauth-BühlerM.FrouinV.GallinatJ.GanG.GowlandP.HeinzA.IttermannB.. . . & GaravanH. (2014). Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature, 512(7513), 185–189.
69.
WhiteF. J.KalivasP. W. (1998). Neuroadaptations involved in amphetamine and cocaine addiction. Drug and Alcohol Dependence, 51, 141–153.
70.
WhiteS. F.PopeK.SinclairS.FowlerK. A.BrislinS. J.WilliamsW. C.PineD. S.BlairRJ. (2013) Disrupted Expected Value and Prediction Error Signaling in Youths with Disruptive Behavior Disorders during a Passive Avoidance Task. Am J Psychiatry, 170(3), 315–23.
71.
WhitesideS. P.LynamD. R. (2003). Understanding the role of impulsivity and externalizing psychopathology in alcohol abuse: Application of the UPPS impulsive behavior scale. Experimental and Clinical Psychopharmacology, 11(3), 210–217.
72.
WilensT. E. (2006). Attention deficit hyperactivity disorder and substance use disorders. The American Journal of Psychiatry, 163, 2059–2063.
73.
ZhangR.AloiJ.BajajS.Bashford-LargoJ.LukoffJ.SchwartzA.ElowskyJ.DobbertinM.BlairK.BlairJ. (2021). Dysfunction in differential reward-punishment responsiveness in conduct disorder relates to severity of callous-unemotional traits but not irritability. Psychological Medicine, 53(5), 1870–1880. https://doi.org/10.1017/S0033291721003500
74.
ZulaufC.SprichS.SafrenS.WilensT. E. (2014). The complicated relationship between attention deficit/hyperactivity disorder and substance use disorders. Current Psychiatry Reports, 16(3), 436. https://doi.org/10.1007/s11920-013-0436-6
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
