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Methylphenidate Enhances Working Memory by Modulating Discrete Frontal and Parietal Lobe Regions in the Human Brain
Open accessAbstract
The indirect catecholamine agonist methylphenidate (Ritalin) is the drug treatment of choice in attention deficit/hyperactivity disorder (AD/HD), one of the most common behavioral disorders of childhood (DSM-IV), although symptoms may persist into adulthood. Methylphenidate can enhance cognitive performance in adults and children diagnosed with AD/HD (Kempton et al., 1999; Riordan et al., 1999) and also in normal human volunteers on tasks sensitive to frontal lobe damage, including aspects of spatial working memory (SWM) performance (Elliott et al., 1997). The present study investigated changes in regional cerebral blood flow (rCBF) induced by methylphenidate during performance of a self-ordered SWM task to define the neuroanatomical loci of the beneficial effect of the drug. The results show that the methylphenidate-induced improvements in working memory performance occur with task-related reductions in rCBF in the dorsolateral prefrontal cortex and posterior parietal cortex. The beneficial effects of methylphenidate on working memory were greatest in the subjects with lower baseline working memory capacity. This is to our knowledge the first demonstration of a localization of a drug-induced improvement in SWM performance in humans and has relevance for understanding the treatment of AD/HD.
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“Indeed, imaging studies have shown that methylphenidate enhances the efficiency of PFC activity both in healthy college students (Mehta et al., 2000) and in subjects with ADHD (Bush et al., 2008).”
From Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders (2011) · cites this paper as Mehta et al., 2000
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“Research additionally shows that ADHD is associated with decreased activity in frontal brain areas and increased activity in posterior (parietal and occipital) brain areas (Durston, 2003), and that MPH affects not only frontal but also posterior areas (Mehta et al., 2000).”
From Implementation Intentions Facilitate Response Inhibition in Children with ADHD (2008) · cites this paper as Mehta et al., 2000
In the citing paper
“Based on accumulating evidence that effects of methylphenidate and related drugs on cognition are baseline performance-dependent (Kimberg et al., 1997; Mattay et al., 2000; Mehta et al., 2000; Gibbs and D’Esposito, 2005; Tipper et al., 2005; Finke et al., 2010), changes in sustained attention following methylphenidate were assessed as a function of baseline A’ scores, independent of group.”
From A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment (2013) · cites this paper as Mehta et al., 2000
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“The effects of methylphenidate and related stimulant drugs in healthy individuals have been shown to be baseline-dependent; i.e. those subjects with relatively low performance levels exhibit greater benefit after the drug (Naylor et al., 1985; Rogers et al., 1999; Mehta et al., 2000; Turner et al., 2003; Clatworthy et al., 2009).”
From A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment (2013) · cites this paper as Mehta et al., 2000
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BackgroundCognitive dysfunction in Parkinson's disease: the role of frontostriatal circuitry
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Self-citationCatecholamine Influences on Dorsolateral Prefrontal Cortical Networks
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Self-citationUnder the curve: Critical issues for elucidating D1 receptor function in working memory
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“Prompted by the results of previous studies (Kimberg, D’Esposito, & Farah, 1997; Mehta et al., 2000b), baseline digit span scores were correlated with the change in the errors on the selfordered spatial WM task.”
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The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers
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“For example, performance on the TOL planning task and the test of spatial working memory is significantly impaired by the dopamine D2 receptor antagonist sulpiride (Mehta et al. 1999) and improved by the indirect agonist methylphenidate (Elliott et al. 1997; Mehta et al. 2000).”
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“Several studies have assessed the effect of MPH or d-AMP on tasks examining various aspects of working memory (Sahakian and Owen 1992; Oken et al. 1995; Elliott et al. 1997; Mehta et al. 2000; Barch and Carter 2005; Silber et al. 2006; Clatworthy et al. 2009) (see Table 1).”
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“The drug generally increases activity, arousal, and talkativeness and improves mood, memory and planning (Elliott et al., 1997; Mehta et al., 2000a,b).”
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“In the Mehta et al. (2000) study the beneficial effect of methylphenidate was predicted by the basal working memory scores according to a simple test of digit span; those subjects with relatively low scores exhibited the best improvements on the spatial working memory test.”
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“Stimulant medication has been found to improve working memory performance by modulating discrete frontal and parietal lobe regions in the human brain (Mehta et al., 2000).”
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“, 2002); and the Token Search task used here has been used to detect increases in spatial working memory in children with attentiondeficit/hyperactivity disorder following a low dose of methylphenidate (Mehta et al., 2000).”
MethodSelf-citationFunctional connectivity of frontal cortex in healthy and ADHD children reflected in EEG coherence
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“modulating frontostriatal brain systems (Mehta et al. 2000), with therapeutic effects thought to rely on its ability to block dopamine and norepinephrine transporters (Solanto 2002).”
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“…Vol. 70, No. 5, 1099–1111 0022-006X/02/$5.00 DOI: 10.1037//0022-006X.70.5.1099 1099 stimulants enhance performance on neuropsychological measures (Aman, Roberts, & Pennington, 1998; Swanson, McBurnett, Wigal, & Pfiffner, 1993) and improve working memory via frontal circuitry (Mehta et al., 2000).”
BackgroundInfluentialde Jongh, R., Bolt, I. L. L. E., Schermer, M., & Olivier, B. (2008) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2007.12.001 · Cited by 198
“Also, subjects with lower baseline working memory capacity showed the greatest improvement in spatial working memory after methylphenidate administration (Mehta et al., 2000).”
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“…there is evidence from other neurotransmitter systems that effects of pharmacological stimulation depend on initial performance (Mattay et al, 2000; Mehta et al, 2000) and since we only had a tendency for behavioral effects of nicotine on reorienting, we performed a further ANOVA including the…”
BackgroundNon-pharmacological cognitive enhancement
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“Low performing healthy controls also benefit from increased dopamine transmission, which is manifested in improved cognitive performance and increased prefrontal cortical activity [43].”
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Insights into the Role of Dopamine Receptor Systems in Learning and Memory
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“As noted in the Introduction, a great deal of animal and human literature supports the hypothesis that intact function of the dopamine system is important for optimal spatial working memory function (Brozoski et al., 1979; Clark et al., 1986; Luciana et al., 1992, 1998; Arnsten et al., 1994; Sawaguchi and Goldman-Raki…”
BackgroundCognitive effects of methylphenidate in healthy volunteers: a review of single dose studies
Linssen, A. M. W., Sambeth, A., Vuurman, E. F. P. M., & Riedel, W. J. (2014) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713001594 · Cited by 159
“MPH enhances performance in normal controls most notably on tasks measuring speed of processing or working memory (Agay et al., 2010; Elliott et al., 1997; Kollins et al., 1998; Linssen et al., 2011; Mehta et al., 2000).”
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“Response control is improved by methylphenidate (MPH) by enhancing frontal-lobe functioning (Mehta et al., 2000; Vaijdya et al., 1998), an effect that presumably involves a deficit associated with striato-frontal dopaminergic projections in AD/HD (e.g., Brandon, Marinelli, & White, 2003; Krause,…”
BackgroundObjective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people
Ilieva, I. P., Boland, J. R., & Farah, M. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.07.021 · Cited by 171
“Several studies have found that participants who perform worse than average when on placebo are more likely to be enhanced by stimulants (Farah et al., 2008; de Wit et al., 2000, 2002; Mattay et al., 2000; Mehta et al., 2000).”
The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex
Spencer, R. C., Devilbiss, D. M., & Berridge, C. W. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.09.013 · Cited by 164
“However, additional evidence indicates that clinically-relevant doses of psychostimulants exert a more complex pattern of actions on frontostriatal activity that are task, region, and hemisphere-dependent (13,71-74).”
Romer, D., Betancourt, L. M., Brodsky, N. L., Giannetta, J. M., Yang, W., & Hurt, H. (2011) · Developmental Science · doi:10.1111/j.1467-7687.2011.01061.x · Cited by 160
Ilieva, I. P., Hook, C. J., & Farah, M. J. (2015) · Journal of Cognitive Neuroscience · doi:10.1162/jocn_a_00776 · Cited by 166
Characteristic neurocognitive profile associated with adult attention-deficit/hyperactivity disorder
McLean, A., Dowson, J., Toone, B., Young, S., Bazanis, E., Robbins, T., & Sahakian, B. (2004) · Psychological Medicine · doi:10.1017/s0033291703001296 · Cited by 142
“Some of these assessments have previously been employed to examine performance in separate groups of treated and untreated children diagnosed with ADHD (Kempton et al. 1999; Barnett et al. 2001) and to assess the effects of stimulant medication in a single case of adult ADHD (Mehta et al. 2000a).”
BackgroundMethodSelf-citationBedard, A.-C., Martinussen, R., Ickowicz, A., & Tannock, R. (2004) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200403000-00006 · Cited by 149
Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate
Engert, V., & Pruessner, J. (2008) · Current Neuropharmacology · doi:10.2174/157015908787386069 · Cited by 146
“Typical positive performance effects in healthy adults following single oral MPH doses include the improvement of vigilance, reaction time and working memory [8, 11, 13, 36].”
BackgroundInfluentialGIBBS, S. E. B., & D'ESPOSITO, M. (2005) · Cognitive, Affective, & Behavioral Neuroscience · doi:10.3758/cabn.5.2.212 · Cited by 145
“Subjects with low working memory capacity, as measured by a span task, show improvements in PFC-dependent tasks with low doses of the D2 dopamine agonist bromocriptine (Kimberg, D’Esposito, & Farah, 1997) or the nonselective dopamine agonist methylphenidate (Mehta et al., 2000), whereas their high-span counterparts ar…”
BackgroundMethodResultInfluentialChamberlain, S. R., Robbins, T. W., Winder-Rhodes, S., Müller, U., Sahakian, B. J., Blackwell, A. D., & Barnett, J. H. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.08.019 · Cited by 178
Self-citationRussell, V. A. (2002) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00425-9 · Cited by 167
Responding to requests from adult patients for neuroenhancements
Larriviere, D., Williams, M. A., Rizzo, M., & Bonnie, R. J. (2009) · Neurology · doi:10.1212/wnl.0b013e3181beecfe · Cited by 140
Schweitzer, J. B., Lee, D. O., Hanford, R. B., Zink, C. F., Ely, T. D., Tagamets, M. A., Hoffman, J. M., Grafton, S. T., & Kilts, C. D. (2004) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.07.011 · Cited by 135
“…a ( e S t b C s P F d t a p r m g n . n the cerebellar vermis both in ADHD participants (Anderson et l 2002; Schweitzer et al 2003) and normal control participants Mehta et al 2000; Volkow et al 1997), most likely by enhancing xtracellular concentrations of norepinephrine (Kuczenski and egal 2001).”
BackgroundInfluentialAudiffren, M. F., Tomporowski, P. D., & Zagrodnik, J. (2009) · Acta Psychologica · doi:10.1016/j.actpsy.2009.06.008 · Cited by 137
The use of methylphenidate among students: the future of enhancement?
Outram, S. M. (2010) · Journal of Medical Ethics · doi:10.1136/jme.2009.034421 · Cited by 132
“For example, Mehta has reported evidence for an improvement in spatial working memory in healthy adults.(18) Similar findings concerning spatial working memory improvement have been found by Elliott et al(19) However, Mehta’s study has suggested that benefits for spatial working memory are proportional to baseline abi…”
BackgroundBerridge, C. W., & Devilbiss, D. M. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.06.023 · Cited by 160
“Consistent with these observations, imaging studies demonstrate that cognition-enhancing doses of stimulants increase task-related activity in the PFC of normal and ADHD subjects whereas cognition-impairing doses suppress activity within the PFC (16,72,73).”
ResultSullivan, R. M., & Brake, W. G. (2003) · Behavioural Brain Research · doi:10.1016/j.bbr.2003.09.015 · Cited by 128
“Such executive functions are known to be improved in humans by DA receptor agonists (Muller et al., 1998), and methylphenidate induces similar effects in both normal adults (Mehta et al., 2000) and in children with ADHD (Kempton et al., 1999).”
Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder
Turner, D. C., Blackwell, A. D., Dowson, J. H., McLean, A., & Sahakian, B. J. (2005) · Psychopharmacology · doi:10.1007/s00213-004-1993-5 · Cited by 127
“It has also been shown that the dorsolateral prefrontal cortex is activated by the SWM test but not the SSP task (Owen et al. 1996), and that the same region is a site involved in the modulatory effects of methylphenidate on SWM performance in healthy young volunteers (Mehta et al. 2000b).”
BackgroundResultInfluentialSelf-citationCognitive effects of modafinil in student volunteers may depend on IQ
Randall, D. C., Shneerson, J. M., & File, S. E. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.07.019 · Cited by 127
“Similarly, Mehta et al. (2000) noted that the positive effects of methylphenidate (40 mg) on spatial working memory performance were greatest in those volunteers with lower baseline working memory capacity.”
Cognitive effects of the dopamine receptor agonist pergolide
Kimberg, D. Y., & D’Esposito, M. (2003) · Neuropsychologia · doi:10.1016/s0028-3932(02)00317-2 · Cited by 130
“The interaction between the working memory capacity in a particular individual, and the effects of the dopaminergic agonist on cognitive performance has now been observed with two different dopaminergic agonists, across three studies[15,19,42] .”
BackgroundResultInfluentialThe likelihood of cognitive enhancement
LYNCH, G. S., Palmer, L. C., & Gall, C. M. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2010.12.024 · Cited by 128
“…in the firing thresholds of neurons (excitability), rhythmic patterns of activity within forebrain, or themagnitude of the excitatory drive from subcortex; e.g., one study shows that Ritalin modulates the net activity of frontal and parietal cortical regions in the human brain (Mehta et al., 2000).”
InfluentialYarkoni, T., & Braver, T. S. (2010) · Plenum series on human exceptionality · doi:10.1007/978-1-4419-1210-7_6 · Cited by 145
“An alternative multivariate technique used in a number of WM/EC studies involving individual differences (e.g., Caplan, McIntosh, & De Rosa, 2007; DellaMaggiore et al., 2000; Grady et al., 1998) is Partial Least Squares (PLS; McIntosh, Bookstein, Haxby, & Grady, 1996; McIntosh & Lobaugh, 2004).”
BackgroundMethodResultInfluentialDissociable effects of self-reported daily sleep duration on high-level cognitive abilities
Wild, C. J., Nichols, E. S., Battista, M. E., Stojanoski, B., & Owen, A. M. (2018) · Sleep · doi:10.1093/sleep/zsy182 · Cited by 123
Self-citationConverging Cognitive Enhancements
Sandberg, A., & Bostrom, N. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1382.015 · Cited by 125
Methylphenidate Decreased the Amount of Glucose Needed by the Brain to Perform a Cognitive Task
Volkow, N. D., Fowler, J. S., Wang, G.-J., Telang, F., Logan, J., Wong, C., Ma, J., Pradhan, K., Benveniste, H., & Swanson, J. M. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002017 · Cited by 117
“Similar results were reported for MP effects on CBF; decreases in task related activation but no changes with the control condition[9].”
ResultGoldstein, R. Z., Woicik, P. A., Maloney, T., Tomasi, D. G., Alia‐Klein, N., Shan, J., Honorio, J., Samaras, D., Wang, R., Telang, F., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1011455107 · Cited by 121
“These whole-brain analyses also revealed correlations between drug use and the dorsolateral PFC, caudate, and inferior parietal lobule (Table 1).”
BackgroundInfluentialKuczenski, R. T., & Segal, D. S. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2004.12.036 · Cited by 121
Karatekin, C. (2004) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2004.t01-1-00285.x · Cited by 124
Sahakian, B. J., Brühl, A. B., Cook, J. L., Killikelly, C., Savulich, G., Piercy, T., Hafizi, S., Pérez, J., Fernández-Egea, E., Suckling, J., et al. (2015) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2014.0214 · Cited by 121
Self-citationPlanning ability in Parkinson's disease is influenced by the COMT val 158 met polymorphism
Foltynie, T., Goldberg, T. E., Lewis, S. J. G., Blackwell, A. D., Kolachana, B. S., Weinberger, D. R., Robbins, T. W., & Barker, R. A. (2004) · Movement Disorders · doi:10.1002/mds.20118 · Cited by 122
Self-citationCoull, J. T., Hwang, H. J., Leyton, M., & Dagher, A. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1258-12.2012 · Cited by 119
Voelker, P., Sheese, B. E., Rothbart, M. K., & Posner, M. I. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.05.059 · Cited by 119
Carr, D. B., Andrews, G. D., Glen, W. B., & Lavı́n, A. (2007) · The Journal of Physiology · doi:10.1113/jphysiol.2007.141671 · Cited by 119
“Administration of the psychostimulant methylphenidate produces an enhancement in working memory performance in human subjects (Elliott et al. 1997; Mehta et al. 2000).”
BackgroundOades, R. D., Sadile, A. G., Sagvolden, T., Viggiano, D., Zuddas, A., Devoto, P., Aase, H., Johansen, E. B., Ruocco, L. A., & Russell, V. A. (2005) · Developmental Science · doi:10.1111/j.1467-7687.2005.00399.x · Cited by 122
“Decreased metabolism was associated with better cognition (Mehta et al. 2000).”
Backgrounddel Campo, N., Fryer, T. D., Hong, Y. T., Smith, R., Brichard, L., Acosta-Cabronero, J., Chamberlain, S. R., Tait, R., Izquierdo, D., Regenthal, R., et al. (2013) · Brain · doi:10.1093/brain/awt263 · Cited by 113
“…related stimulant drugs in healthy individuals have been shown to be baseline-dependent; i.e. those subjects with relatively low performance levels exhibit greater benefit after the drug (Naylor et al., 1985; Rogers et al., 1999; Mehta et al., 2000; Turner et al., 2003; Clatworthy et al., 2009).”
BackgroundResultInfluentialSelf-citation
Metadata
- Authors
- Mehta, M. A., Owen, A. M., Sahakian, B. J., Mavaddat, N., Pickard, J. D., & Robbins, T. W.
- Affiliations
- University of Cambridge (GB)
- MRC Cognition and Brain Sciences Unit (GB)
- Addenbrooke's Hospital (GB)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2000-03-15
- Volume
- 20
- Issue
- 6
- Pages
- RC65-RC65
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6772505
- OpenAlex
- W2170595219
- Cited by
- 608
- References
- 31
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 16 · 2023: 8 · 2022: 9 · 2021: 14 · 2020: 26 · 2019: 21 · 2018: 13 · 2017: 15 · 2016: 27 · 2015: 29 · 2014: 26 · 2013: 34 · 2012: 42
- FWCI
- 11.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- methylphenidate, working memory, spatial working memory, attention deficit hyperactivity disorder, regional cerebral blood flow, dorsolateral prefrontal cortex, posterior parietal cortex, catecholamine agonists, working memory capacity
- MeSH terms
- Adult, Central Nervous System Stimulants, Cerebrovascular Circulation, Frontal Lobe, Humans, Functional Laterality, Male, Memory, Short-Term, Methylphenidate, Parietal Lobe, Tomography, Emission-Computed, Adrenergic Uptake Inhibitors, Dopamine Uptake Inhibitors
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