Skip to main content

Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory

  • A. Cubillo (a1), A. B. Smith (a1), N. Barrett (a1), V. Giampietro (a2), M. Brammer (a2), A. Simmons (a2) (a3) (a4) and K. Rubia (a1)...

The catecholamine reuptake inhibitors methylphenidate (MPH) and atomoxetine (ATX) are the most common treatments for attention deficit hyperactivity disorder (ADHD). This study compares the neurofunctional modulation and normalization effects of acute doses of MPH and ATX within medication-naive ADHD boys during working memory (WM).


A total of 20 medication-naive ADHD boys underwent functional magnetic resonance imaging during a parametric WM n-back task three times, under a single clinical dose of either MPH, ATX or placebo in a randomized, double-blind, placebo-controlled, cross-over design. To test for normalization effects, brain activations in ADHD under each drug condition were compared with that of 20 age-matched healthy control boys.


Relative to healthy boys, ADHD boys under placebo showed impaired performance only under high WM load together with significant underactivation in the bilateral dorsolateral prefrontal cortex (DLPFC). Both drugs normalized the performance deficits relative to controls. ATX significantly enhanced right DLPFC activation relative to MPH within patients, and significantly normalized its underactivation relative to controls. MPH, by contrast, both relative to placebo and ATX, as well as relative to controls, upregulated the left inferior frontal cortex (IFC), but only during 2-back. Both drugs enhanced fronto-temporo-striatal activation in ADHD relative to control boys and deactivated the default-mode network, which were negatively associated with the reduced DLPFC activation and performance deficits, suggesting compensation effects.


The study shows both shared and drug-specific effects. ATX upregulated and normalized right DLPFC underactivation, while MPH upregulated left IFC activation, suggesting drug-specific laterality effects on prefrontal regions mediating WM.

Corresponding author
* Address for correspondence: K. Rubia, Ph.D., Department of Child and Adolescent Psychiatry/SGDP, P046, Institute of Psychiatry, 16 De Crespigny Park, London SE5 8AF, UK. (Email:
Hide All
APA (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, Text Revision. American Psychiatric Association: Washington, DC.
Baddeley A (1996). The fractionation of working memory. Proceedings of the National Academy of Sciences USA 93, 1346813472.
Brain Image Analysis Unit (2011). XBAM ( Accessed 24 April 2012.
Brammer MJ, Bullmore ET, Simmons A, Williams SC, Grasby PM, Howard RJ, Woodruff PW, Rabe-Hesketh S (1997). Generic brain activation mapping in functional magnetic resonance imaging: a nonparametric approach. Magnetic Resonance Imaging 15, 763770.
Bridgett DJ, Walker ME (2006). Intellectual functioning in adults with ADHD: a meta-analytic examination of full scale IQ differences between adults with and without ADHD. Psychological Assessment 18, 114.
Bullmore E, Long C, Suckling J, Fadili J, Calvert G, Zelaya F, Carpenter TA, Brammer M (2001). Colored noise and computational inference in neurophysiological (fMRI) time series analysis: resampling methods in time and wavelet domains. Human Brain Mapping 12, 6178.
Bullmore ET, Brammer MJ, Rabe-Hesketh S, Curtis VA, Morris RG, Williams SC, Sharma T, McGuire PK (1999). Methods for diagnosis and treatment of stimulus-correlated motion in generic brain activation studies using fMRI. Human Brain Mapping 7, 3848.
Bunge SA, Wright SB (2007). Neurodevelopmental changes in working memory and cognitive control. Current Opinion in Neurobiology 17, 243250.
Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002). Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27, 699711.
Chamberlain SR, Del Campo N, Dowson J, Muller U, Clark L, Robbins TW, Sahakian BJ (2007). Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder. Biological Psychiatry 62, 977984.
Chamberlain SR, Hampshire A, Muller U, Rubia K, Del Campo N, Craig K, Regenthal R, Suckling J, Roiser JP, Grant JE, Bullmore ET, Robbins TW, Sahakian BJ (2009). Atomoxetine modulates right inferior frontal activation during inhibitory control: a pharmacological functional magnetic resonance imaging study. Biological Psychiatry 65, 550555.
Chan YP, Swanson JM, Soldin SS, Thiessen JJ, Macleod SM, Logan W (1983). Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid. Pediatrics 72, 5659.
Christakou A, Murphy CM, Chantiluke K, Cubillo AI, Smith AB, Giampietro V, Daly E, Ecker C, Robertson D; MRC AIMS consortium, Murphy DG, Rubia K (2013). Disorder-specific functional abnormalities during sustained attention in youth with attention deficit hyperactivity disorder (ADHD) and with autism. Molecular Psychiatry 18, 236244.
Conners CK, Sitarenios G, Parker JDA, Epstein JN (1998). Revision and restandardization of the Conners Teacher Rating Scale (CTRS-R): factor structure, reliability, and criterion validity. Journal of Abnormal Child Psychology 26, 279291.
Crone EA, Wendelken C, Donohue S, van Leijenhorst L, Bunge SA (2006). Neurocognitive development of the ability to manipulate information in working memory. Proceedings of the National Academy of Sciences USA 103, 93159320.
Cubillo A, Halari R, Smith A, Taylor E, Rubia K (2012 a). A review of fronto-striatal and frontocortical brain abnormalities in children and adults with attention deficit hyperactivity disorder (ADHD) and new evidence for dysfunction in adults with ADHD during motivation and attention. Cortex 48, 194215.
Cubillo A, Smith AB, Barrett N, Giampietro V, Brammer MJ, Simmons A, Rubia K (2012 b). Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys. Cerebral Cortex. Published online 9 10 2012 . doi:10.1093/cercor/bhs296.
Dennis M, Francis DJ, Cirino PT, Schachar R, Barnes MA, Fletcher JM (2009). Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders. Journal of the International Neuropsychological Society 15, 331343.
Epstein JN, Casey BJ, Tonev ST, Davidson MC, Reiss AL, Garrett A, Hinshaw SP, Greenhill LL, Glover G, Shafritz KM, Vitolo A, Kotler LA, Jarrett MA, Spicer J (2007). ADHD- and medication-related brain activation effects in concordantly affected parent–child dyads with ADHD. Journal of Child Psychology and Psychiatry 48, 899913.
Evans SH, Anastasio EJ (1968). Misuse of analysis of covariance when treatment effect and covariate are confounded. Psychological Bulletin 69, 225234.
Flor-Henry P (1986). Observations, reflections and speculations on the cerebral determinants of mood and on the bilaterally asymmetrical distributions of the major neurotransmitter systems. Acta Neurologica Scandinavica (Suppl.) 109, 7589.
Gallezot JD, Weinzimmer D, Nabulsi N, Lin SF, Fowles K, Sandiego C, McCarthy TJ, Maguire RP, Carson RE, Ding YS (2011). Evaluation of [11C]MRB for assessment of occupancy of norepinephrine transporters: studies with atomoxetine in non-human primates. Neuroimage 56, 268279.
Gamo NJ, Wang M, Arnsten AF (2010). Methylphenidate and atomoxetine enhance prefrontal function through α 2-adrenergic and dopamine D1 receptors. Journal of the American Academy of Child and Adolescent Psychiatry 49, 10111023.
Gau SS, Shang CY (2010). Executive functions as endophenotypes in ADHD: evidence from the Cambridge Neuropsychological Test Battery (CANTAB). Journal of Child Psychology and Psychiatry 51, 838849.
Ginestet CE, Simmons A (2011). Statistical parametric network analysis of functional connectivity dynamics during a working memory task. Neuroimage 55, 688704.
Glick SD, Ross DA, Hough LB (1982). Lateral asymmetry of neurotransmitters in human brain. Brain Research 234, 5363.
Goldberg D, Murray R (eds) (2002). Maudsley Handbook of Practical Psychiatry. Oxford University Press: Oxford.
Goldberg MC, Mostofsky SH, Cutting LE, Mahone EM, Astor BC, Denckla MB, Landa RJ (2005). Subtle executive impairment in children with autism and children with ADHD. Journal of Autism and Developmental Disorders 35, 279293.
Goodman R, Scott S (1999). Comparing the Strengths and Difficulties Questionnaire and the Child Behavior Checklist: is small beautiful? Journal of Abnormal Child Psychology 27, 1724.
Graf H, Abler B, Freudenmann R, Beschoner P, Schaeffeler E, Spitzer M, Schwab M, Gron G (2011). Neural correlates of error monitoring modulated by atomoxetine in healthy volunteers. Biological Psychiatry 69, 890897.
Greenhill LL, Swanson JM, Vitiello B, Davies M, Clevenger W, Wu M, Arnold LE, Abikoff HB, Bukstein OG, Conners CK, Elliott GR, Hechtman L, Hinshaw SP, Hoza B, Jensen PS, Kraemer HC, March JS, Newcorn JH, Severe JB, Wells K, Wigal T (2001). Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial. Journal of the American Academy of Child and Adolescent Psychiatry 40, 180187.
Hannestad J, Gallezot JD, Planeta-Wilson B, Lin SF, Williams WA, van Dyck CH, Malison RT, Carson RE, Ding YS (2010). Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo . Biological Psychiatry 68, 854860.
Hart H, Radua J, Mataix-Cols D, Rubia K (2012). Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD). Neuroscience and Biobehavioral Reviews 36, 22482256.
Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (2013). Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects. JAMA Psychiatry 70, 185198.
Hazell PL, Kohn MR, Dickson R, Walton RJ, Granger RE, van Wyk GW (2010). Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis. Journal of Attention Disorders 15, 674683.
Klein C, Wendling K, Huettner P, Ruder H, Peper M (2006). Intra-subject variability in attention-deficit hyperactivity disorder. Biological Psychiatry 60, 10881097.
Kobel M, Bechtel N, Weber P, Specht K, Klarhofer M, Scheffler K, Opwis K, Penner IK (2009). Effects of methylphenidate on working memory functioning in children with attention deficit/hyperactivity disorder. European Journal of Paediatric Neurology 13, 516523.
Lancaster JL, Rainey LH, Summerlin JL, Freitas CS, Fox PT, Evans AC, Toga AW, Mazziotta JC (1997). Automated labeling of the human brain: a preliminary report on the development and evaluation of a forward-transform method. Human Brain Mapping 5, 238242.
Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, Kochunov PV, Nickerson D, Mikiten SA, Fox PT (2000). Automated Talairach atlas labels for functional brain mapping. Human Brain Mapping 10, 120131.
Landau SM, Lal R, O'Neil JP, Baker S, Jagust WJ (2009). Striatal dopamine and working memory. Cerebral Cortex 19, 445454.
Liddle EB, Hollis C, Batty MJ, Groom MJ, Totman JJ, Liotti M, Scerif G, Liddle PF (2010). Task-related default mode network modulation and inhibitory control in ADHD: effects of motivation and methylphenidate. Journal of Child Psychology and Psychiatry 52, 761771.
Lijffijt M, Kenemans JL, ter Wal A, Quik EH, Kemner C, Westenberg H, Verbaten MN, van Engeland H (2006). Dose-related effect of methylphenidate on stopping and changing in children with attention-deficit/hyperactivity disorder. European Psychiatry 21, 544547.
Marquand AF, De Simoni S, O'Daly OG, Williams SC, Mourao-Miranda J, Mehta MA (2011). Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers. Neuropsychopharmacology 36, 12371247.
Martinussen R, Hayden J, Hogg-Johnson S, Tannock R (2005). A meta-analysis of working memory impairments in children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 44, 377384.
Matthews JN, Altman DG (1996). Statistics notes. Interaction 2: compare effect sizes not P values. British Medical Journal 313, 808.
Merikangas KR, He JP, Brody D, Fisher PW, Bourdon K, Koretz DS (2010). Prevalence and treatment of mental disorders among US children in the 2001–2004 NHANES. Pediatrics 125, 7581.
Miller G, Chapman J (2001). Misunderstanding analysis of covariance. Journal of Abnormal Psychology 110, 4048.
Modi N, Lindemulder B, Gupta S (2000). Single- and multiple-dose pharmacokinetics of an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl) formulation. Journal of Clinical Pharmacology 40, 379388.
Montoya A, Hervas A, Cardo E, Artigas J, Mardomingo MJ, Alda JA, Gastaminza X, Garcia-Polavieja MJ, Gilaberte I, Escobar R (2009). Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment-naive children and adolescents with attention deficit/hyperactivity disorder. Current Medical Research and Opinion 25, 27452754.
Nakao T, Radua J, Rubia K, Mataix-Cols D (2011). Gray matter volume abnormalities in ADHD and the effects of stimulant medication: voxel-based meta-analysis. American Journal of Psychiatry 168, 11541163.
National Institute for Heath and Clinical Excellence (2008). Attention deficit hyperactivity disorder: diagnosis and management of ADHD in children, young people and adults ( Accessed 24 April 2012.
Owen AM, McMillan KM, Laird AR, Bullmore E (2005). N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Human Brain Mapping 25, 4659.
Pasini A, Paloscia C, Alessandrelli R, Porfirio MC, Curatolo P (2007). Attention and executive functions profile in drug naive ADHD subtypes. Brain and Development 29, 400408.
Prehn-Kristensen A, Krauel K, Hinrichs H, Fischer J, Malecki U, Schuetze H, Wolff S, Jansen O, Duezel E, Baving L (2011). Methylphenidate does not improve interference control during a working memory task in young patients with attention-deficit hyperactivity disorder. Brain Research 1388, 5668.
Rhodes SM, Park J, Seth S, Coghill DR (2011). A comprehensive investigation of memory impairment in attention deficit hyperactivity disorder and oppositional defiant disorder. Journal of Child Psychology and Psychiatry 53, 128137.
Rommelse NN, Altink ME, Oosterlaan J, Buschgens CJ, Buitelaar J, Sergeant JA (2008). Support for an independent familial segregation of executive and intelligence endophenotypes in ADHD families. Psychological Medicine 38, 15951606.
Rubia K (2011). ‘Cool’ inferior fronto-striatal dysfunction in attention-deficit hyperactivity disorder (ADHD) versus ‘hot’ ventromedial orbitofronto-limbic dysfunction in conduct disorder: a review. Biological Psychiatry 69, e69e87.
Rubia K (2012). Functional brain imaging across development. European Child and Adolescent Psychiatry. Published online 24 06 2012 . doi:10.1007/s00787-012-0291-8.
Rubia K, Halari R, Christakou A, Taylor E (2009 a). Impulsiveness as a timing disturbance: neurocognitive abnormalities in attention-deficit hyperactivity disorder during temporal processes and normalization with methylphenidate. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 364, 19191931.
Rubia K, Halari R, Cubillo A, Mohammad AM, Brammer M, Taylor E (2011 a). Methylphenidate normalises fronto-striatal underactivation during interference inhibition in medication-naive children with attention-deficit hyperactivity disorder. Neuropsychopharmacology 36, 15751586.
Rubia K, Halari R, Cubillo A, Mohammad M, Taylor E (2009 b). Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naive children with ADHD during a Rewarded Continuous Performance Task. Neuropharmacology 57, 640652.
Rubia K, Halari R, Mohammad AM, Taylor E, Brammer M (2011 b). Methylphenidate normalises fronto-cingulate underactivation during error processing in attention-deficit hyperactivity disorder. Biological Psychiatry 70, 255262.
Rutter M, Bailey A, Berument S, LeCouteur A, Lord C, Pickles A (eds) (2003). Social Communication Questionnaire (SCQ). Western Psychological Services: Los Angeles.
Sauer J-M, Ponsler GD, Mattiuz EL, Long AJ, Witcher JW, Thomasson HR, Desante KA (2003). Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism. Drug Metabolism and Disposition 31, 98107.
Shafritz KM, Marchione KE, Gore JC, Shaywitz SE, Shaywitz BA (2004). The effects of methylphenidate on neural systems of attention in attention deficit hyperactivity disorder. American Journal of Psychiatry 161, 19901997.
Sheridan MA, Hinshaw S, D'Esposito M (2010). Stimulant medication and prefrontal functional connectivity during working memory in ADHD: a preliminary report. Journal of Attention Disorders 14, 6978.
Silk T, Vance A, Rinehart N, Egan G, O'Boyle M, Bradshaw JL, Cunnington R (2005). Fronto-parietal activation in attention-deficit hyperactivity disorder, combined type: functional magnetic resonance imaging study. British Journal of Psychiatry 187, 282283.
Simmons A, Moore E, Williams SC (1999). Quality control for functional magnetic resonance imaging using automated data analysis and Shewhart charting. Magnetic Resonance in Medicine 41, 12741278.
Toplak M, Jain U, Rosemary T (2008). Executive and motivational processes in adolescents with attention-deficit-hyperactivity disorder (ADHD). Behavioural and Brain Functions 1, 8.
Tucker DM, Williamson PA (1984). Asymmetric neural control systems in human self-regulation. Psychological Review 91, 185215.
Vaidya CJ, Austin G, Kirkorian G, Ridlehuber HW, Desmond JE, Glover GH, Gabrieli JDE (1998). Selective effects of methylphenidate in attention deficit hyperactivity disorder: a functional magnetic resonance study. Proceedings of the National Academy of Sciences USA 95, 1449414499.
Valera EM, Brown A, Biederman J, Faraone SV, Makris N, Monuteaux MC, Whitfield-Gabrieli S, Vitulano M, Schiller M, Seidman LJ (2010). Sex differences in the functional neuroanatomy of working memory in adults with ADHD. American Journal of Psychiatry 167, 8794.
Vance A, Silk TJ, Casey M, Rinehart NJ, Bradshaw JL, Bellgrove MA, Cunnington R (2007). Right parietal dysfunction in children with attention deficit hyperactivity disorder, combined type: a functional MRI study. Molecular Psychiatry 12, 826832.
Volkow ND, Wang GJ, Fowler JS, Gatley SJ, Logan J, Ding YS, Hitzemann R, Pappas N (1998). Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. American Journal of Psychiatry 155, 13251331.
Wechsler D (1999). Wechsler Abbreviated Scale of Intelligence. Psychological Corp.: San Antonio, TX.
Wechsler D (2004). Wechsler Intelligence Scale for Children, 4th edn. Psychological Corp.: London, UK.
Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF (2005). Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biological Psychiatry 57, 13361346.
Witcher JW, Long A, Smith B, Sauer JM, Heilgenstein J, Wilens T, Spencer T, Biederman J (2003). Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology 13, 5363.
Wong CG, Stevens MC (2012). The effects of stimulant medication on working memory functional connectivity in attention-deficit/hyperactivity disorder. Biological Psychiatry 71, 458466.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Full text views

Total number of HTML views: 11
Total number of PDF views: 89 *
Loading metrics...

Abstract views

Total abstract views: 712 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 19th November 2017. This data will be updated every 24 hours.