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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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In the citing paper
“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
In the citing paper
“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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BackgroundEffects of modafinil and methylphenidate on visual attention capacity: a TVA-based study
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BackgroundResultInfluentialDodds, C. M., Muller, U., Clark, L., van Loon, A., Cools, R., & Robbins, T. W. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1153-08.2008 · Cited by 113
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“Indeed, it has been proposed that MPH may act relatively selectively to enhance executive functioning (Mehta et al., 2000; Elliott et al., 1997).”
BackgroundWhen we enhance cognition with Adderall, do we sacrifice creativity? A preliminary study
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“A similar, though less extreme, pattern has been found in studies of the effects of methylphenidate and amphetamine on executive functions, including working memory (Mattay et al. 2000, 2003; Mehta et al. 2000) and inhibitory control (DeWit et al. 2002).”
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“Stimulant medications have been shown to enhance performance on a variety of neuropsychological measures (Aman, Roberts, & Pennington, 1998) and improve working memory (Mehta et al., 2000), perhaps masking deficits in the group with ADHD.”
BackgroundNeuroethical issues in cognitive enhancement
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“In accordance, it is not uncommon for PCEs to improve performance primarily or exclusively in individuals with greater impairment (Mehta et al., 2000).”
BackgroundSelf-citationPreferences for Enhancement Pharmaceuticals: The Reluctance to Enhance Fundamental Traits
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Pharmacological Enhancement of Memory and Executive Functioning in Laboratory Animals
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“In addition, there are numerous reports on healthy individuals with a low baseline score for a certain function that respond favourable to agonistic manipulation, whereas individuals with high-baseline scores do not (de Wit et al, 2002; Mehta et al, 2000).”
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“By contrast, methylphenidate typically improves the prefrontal performance to novel tasks in normal volunteers (Elliott et al, 1997; Mehta et al, 2000), supporting the concept that patients show increased susceptibility to the disorganizing effects of prefrontal hyperdopaminergia following…”
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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).”
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BackgroundMethylphenidate Increases Cortical Excitability via Activation of Alpha-2 Noradrenergic Receptors
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“Moreover, MPH improves WM performance in healthy subjects (Elliot et al, 1997; Mehta et al, 2000) and several studies have shown that MPH increases overall speed and accuracy of attentional process in normal adults (Strauss et al, 1984; Solanto, 1998).”
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“The results indicated that the online storage and retrieval of information from posterior cortical association systems were influenced by noradrenergic modulation, through MPH, of the posterior parietal cortex, whereas inhibition of previously successful selections was influenced by dopaminergic modulation of DLPFC [6…”
BackgroundInfluentialThe pharmacology of human working memory
Ellis, K. A., & Nathan, P. J. (2001) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145701002541 · Cited by 100
“Mehta et al. (2000) also studied spatial working-memory performance following methylphenidate administration.”
BackgroundResultThe effects of methylphenidate on whole brain intrinsic functional connectivity
Mueller, S., Costa, A. C. L., Keeser, D., Pogarell, O. M., Berman, A., Coates, U., Reiser, M. F., Riedel, M. J., Möller, H., Ettinger, U., et al. (2014) · Human Brain Mapping · doi:10.1002/hbm.22557 · Cited by 103
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“placebo) in brain activations associated with performance of this task have been observed in the dorsolateral prefrontal cortex and posterior parietal cortex (67).”
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“Similarly, methylphenidate— originally developed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD)—has been shown to improve spatial working memory and planning in healthy adults (Elliott et al., 1997; Mehta et al., 2000).”
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“Mehta and colleagues found that methylphenidate improved spatial self-ordered pointing in healthy adults, accompanied by a reduction in task-related activity in dorsolateral prefrontal cortex (Mehta et al. 2000).”
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“…to a task-related activity refinement in the posterior parietal cortex and dorsolateral prefrontal cortex, especially on the left hemisphere, (Mehta et al., 2000); the former locus seems to relate to online organization and storage of information and the latter to their active manipulation…”
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“MPH-induced increases in these neurotransmitter levels are believed to enhance aspects of cognitive processing, including WM (Mehta et al., 2000).”
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“These results are consistent with the view that MPH enhanced the efficiency of processing in all subjects (Swanson et al. 2011), in agreement with previous research (Mehta et al. 2000; Volkow et al. 2008; Marquand et al. 2011; Tomasi et al. 2011).”
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“MPH-induced increases in these neurotransmitter levels are believed to reduce over activity and enhance aspects of cognitive processing, including WM (Mehta et al., 2000).”
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“It is true, however, that these stimulants improve blood flow to the frontal and parietal lobes and thus improve attention and alertness ( Mehta et al., 2000 ).”
BackgroundDopamine, Paranormal Belief, and the Detection of Meaningful Stimuli
Krummenacher, P., Möhr, C., Haker, H., & Brugger, P. (2009) · Journal of Cognitive Neuroscience · doi:10.1162/jocn.2009.21313 · Cited by 79
“…1997; Arnsten, Cai, Steere, & Goldman-Rakic, 1995; Williams & Goldman-Rakic, 1995; Arnsten, Cai, Murphy, & Goldman-Rakic, 1994) and humans (Mehta et al., 2000) that with respect to a specific task or task demands (e.g., Floresco & Magyar, 2006) dopaminergic actions might follow the…”
BackgroundInfluentialPharmacogenetic Treatments for Drug Addiction: Cocaine, Amphetamine and Methamphetamine
Haile, C. N., Kosten, T. R., & Kosten, T. A. (2009) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990902825447 · Cited by 76
Marquand, A. F., O’Daly, O., Simoni, S. D., Alsop, D. C., Maguire, R. P., Williams, S., Zelaya, F. O., & Mehta, M. A. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.01.058 · Cited by 70
“…study the effects of MPH and ATX on task networks associated with response inhibition (Chamberlain et al., 2009; Vaidya et al., 1998), error monitoring (Graf et al., 2011; Rubia et al., 2011), reversal learning (Dodds et al., 2008) and working memory (Mehta et al., 2000; Schweitzer et al., 2004).”
BackgroundInfluentialSelf-citationTraumatic brain injury alters the functional brain network mediating working memory
Kasahara, M., Menon, D. K., Salmond, C. H., Outtrim, J. G., Tavares, J. V. T., Carpenter, T. A., Pickard, J. D., Sahakian, B. J., & Stamatakis, E. A. (2011) · Brain Injury · doi:10.3109/02699052.2011.608210 · Cited by 75
“The agent enhances spatial working memory in healthy participants, especially in those who perform less well [41], and improves working memory and visuospatial attentional task performance in TBI patients [42].”
BackgroundSelf-citationSánchez-Carrión, R., Vendrell, P., Junqué, C., Fernández‐Espejo, D., Falcón, C., Bargalló, N., Roig-Rovira, T., Cantallops, A. E., & Bernabeu, M. (2008) · Journal of Neurotrauma · doi:10.1089/neu.2007.0417 · Cited by 73
“We found a significant negative correlation between prefrontal activity and performance in our control group, this being consistent with previous reports (Mattay et al., 2000; Mehta et al., 2000; Otten and Rugg, 2001; Daselaar et al., 2004; Hampson et al., 2006).”
Working Memory Capacity Predicts Effects of Methylphenidate on Reversal Learning
van der Schaaf, M. E., Fallon, S. J., ter Huurne, N., Buitelaar, J. K., & Cools, R. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.100 · Cited by 73
Positron Emission Tomography in Schizophrenia: A New Perspective
Patel, N., Vyas, N. S., Puri, B. K., Nijran, K. S., & AL-NAHHAS, A. M. (2010) · Journal of Nuclear Medicine · doi:10.2967/jnumed.109.066076 · Cited by 71
“Thus, prefrontal function, dopamine D1 activation, and basal activity are related (66,67).”
BackgroundArmstrong, I. T., & Munoz, D. P. (2003) · Experimental Brain Research · doi:10.1007/s00221-003-1569-3 · Cited by 71
Trends in Psychiatry and Psychotherapy
(2020) · Trends in Psychiatry and Psychotherapy · doi:10.47626/2237-6089 · Cited by 70
Neuroethics of Cognitive Enhancement
Turner, D. C., & Sahakian, B. J. (2006) · BioSocieties · doi:10.1017/s1745855205040044 · Cited by 71
Self-citationCaffeine and Cognition in Functional Magnetic Resonance Imaging
Koppelstaetter, F., Poeppel, T. D., Siedentopf, C., Ischebeck, A. K., Kolbitsch, C., Mottaghy, F. M., Felber, S. R., Jaschke, W. R., & Krause, B. J. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1417 · Cited by 69
“could demonstrate beneficial effects of methylphenidate (a reuptake inhibitor of dopamine and noradrenaline) on a spatial working memory test by modulating regions in the dorsolateral, prefrontal, and posterior parietal cortex [42].”
The Nonmedical Use of Prescription Stimulants Among Dental and Dental Hygiene Students
McNiel, A. D., Muzzin, K. B., DeWald, J. P., McCann, A. L., Schneiderman, E. D., Scofield, J. C., & Campbell, P. R. (2011) · Journal of Dental Education · doi:10.1002/j.0022-0337.2011.75.3.tb05050.x · Cited by 69
“Studies have found that low doses of stimulants focus attention and improve executive function in both normal and ADD subjects.(7,8) MPH has also been shown to relieve chronic fatigue syndrome and depression.”
BackgroundMethylphenidate Effects on Neural Activity During Response Inhibition in Healthy Humans
Costa, A. C. L., Riedel, M. J., Pogarell, O. M., Menzel-Zelnitschek, F., Schwarz, M., Reiser, M. F., Möller, H., Rubia, K., Meindl, T., & Ettinger, U. (2012) · Cerebral Cortex · doi:10.1093/cercor/bhs107 · Cited by 70
Volkow, N. D., Tomasi, D. G., Wang, G., Telang, F., Fowler, J. S., Wang, R. L., Logan, J., Wong, C., Jayne, M. C., & Swanson, J. M. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.01.003 · Cited by 69
“Specifically, and on the basis of prior imaging studies that showed that stimulant drugs, which increase DA, markedly decreased brain activation during a cognitive task (Mehta et al., 2000; Volkow et al., 2008b), we hypothesized that striatal DA increases with SD would be associated with decreased activation to the VA…”
Huijbregts, S. C. J., de Sonneville, L. M. J., van Spronsen, F. J., Berends, I. E., Licht, R., Verkerk, P. H., & Sergeant, J. A. (2003) · Neuropsychology · doi:10.1037/0894-4105.17.3.369 · Cited by 69
“…and noradrenergic) modulation through the dorsolateral PFC (DLPFC) are those involved in on-line manipulation and monitoring of cognitive representations within working memory (WM; Arnsten, 1998; Luciana & Collins, 1997; McDowell, Whyte, & D’Esposito, 1998; Mehta et al., 2000; Robbins, 2000).”
BackgroundMethylphenidate Improves HIV-1-Associated Cognitive Slowing
Hinkin, C. H., Castellon, S. A., Hardy, D. J., Farinpour, R., Newton, T. F., & Singer, E. J. (2001) · Journal of Neuropsychiatry · doi:10.1176/jnp.13.2.248 · Cited by 68
Functional imaging of cognition in Parkinson's disease
Carbon, M., & Marié, R. (2003) · Current Opinion in Neurology · doi:10.1097/01.wco.0000084225.82329.3c · Cited by 68
Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition
Rasetti, R., Mattay, V. S., Stankevich, B., Skjei, K., Blasi, G., Sambataro, F., Arrillaga-Romany, I. C., Goldberg, T. E., Callicott, J. H., Apud, J. A., et al. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.83 · Cited by 83
“…by catecholaminergic neurons and is similar to the results of numerous neuroimaging studies in the literature involving catecholaminergic effects (eg, Apud et al, 2007; Cools et al, 2002; Cools and Robbins, 2004; Gibbs and D’Esposito, 2005, 2006; Mattay et al, 2002, 2003; Mehta et al, 2000).”
ResultA Review of US Army Research Contributing to Cognitive Enhancement in Military Contexts
Brunyé, T. T., Brou, R. J., Doty, T. J., Gregory, F. D., Hussey, E. K., Lieberman, H. R., Loverro, K. L., Mezzacappa, E. S., Neumeier, W. H., Patton, D. J., et al. (2020) · Journal of Cognitive Enhancement · doi:10.1007/s41465-020-00167-3 · Cited by 78
Repantis, D., Bovy, L., Ohla, K., Kühn, S., & Dresler, M. (2020) · Psychopharmacology · doi:10.1007/s00213-020-05691-w · Cited by 75
“It has been shown previously that stimulant effects on healthy individuals might depend on baseline performance as measured by intelligence scores and working memory capacity (Mehta et al. 2000; Randall et al. 2005).”
BackgroundWorking Memory Brain Activation Following Severe Traumatic Brain Injury
Newsome, M. R., Scheibel, R. S., Steinberg, J. L., Troyanskaya, M., Sharma, R. G., Rauch, R. A., Li, X., & Levin, H. S. (2007) · Cortex · doi:10.1016/s0010-9452(08)70448-9 · Cited by 68
Kuypers, K. P. C., & Ramaekers, J. G. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0321-7 · Cited by 65
“Other researches studying the effects of methylphenidate on spatial memory performance, however, have shown memory performance improvement in young healthy volunteers (Elliott et al. 1997; Mehta et al. 2000).”
BackgroundKambeitz, J., Romanos, M., & Ettinger, U. (2014) · The Pharmacogenomics Journal · doi:10.1038/tpj.2013.9 · Cited by 64
Grizenko, N., Bhat, M., Schwartz, G. J., Ter-Stepanian, M., & Joober, R. (2006) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0606 · Cited by 64
Impaired awareness of movement disorders in Parkinson’s disease
Amanzio, M., Monteverdi, S., Giordano, A., Soliveri, P., Filippi, P., & Geminiani, G. C. (2009) · Brain and Cognition · doi:10.1016/j.bandc.2009.10.011 · Cited by 63
“These differences could be explained by the fact that the dopaminergic effects on behavioral and cognitive functions depend on the baseline level of performance (Kimberg, D’Esposito, & Farah, 1997; Mattay et al., 2000; Mehta et al., 2000).”
BackgroundMehta, M. A., Calloway, P., & Sahakian, B. J. (2000) · Journal of Psychopharmacology · doi:10.1177/026988110001400314 · Cited by 63
Self-citationClassics in Chemical Neuroscience: Methylphenidate
Wenthur, C. J. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00199 · Cited by 69
Mehta, M. A., Hinton, E. C., Montgomery, A. J., Bantick, R. A., & Grasby, P. M. (2005) · Journal of Psychopharmacology · doi:10.1177/0269881105048889 · Cited by 61
Self-citationChavanon, M., Wacker, J., & Stemmler, G. (2013) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2013.00117 · Cited by 64
Neto, B. A. D., Lapis, A. A. M., Bernd, A. B., & Russowsky, D. (2009) · Tetrahedron · doi:10.1016/j.tet.2009.01.081 · Cited by 62
Ni, H., Shang, C., Gau, S. S., Lin, Y., Huang, H., & Yang, L.-K. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713000357 · Cited by 63
“…the association of IR-methylphenidate with improving SWM in adults with ADHD, consistent with findings in healthy adults (Elliott et al., 1997; Mehta et al., 2000; Clatworthy et al., 2009) and in uncontrolled (Kempton et al., 1999; Barnett et al., 2001) and controlled (Bedard et al., 2004;…”
InfluentialSemrud‐Clikeman, M., Pliszka, S. R., & Mario Liotti, A. (2008) · Neuropsychology · doi:10.1037/0894-4105.22.3.329 · Cited by 64
Mehta, M. A. (2003) · NeuroImage · doi:10.1016/j.neuroimage.2003.08.007 · Cited by 60
“Although we have provided some evidence for the latter, the former hypothesis was not supported, despite greater numbers of volunteers than previous studies, using different drugs in which modulatory effects in the PFC were shown (e.g., Mattay et al., 2000; Mehta et al., 2000).”
MethodResultSelf-citationPsychometric schizotypy modulates levodopa effects on lateralized lexical decision performance
Möhr, C., Krummenacher, P., Landis, T., Sándor, P. S., Fathi, M., & Brugger, P. (2004) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2004.08.006 · Cited by 58
Methylphenidate Effects on Prefrontal Functioning During Attentional-Capture and Response Inhibition
Pauls, A. M., O'Daly, O. G., Rubia, K., Riedel, W. J., Williams, S. C. R., & Mehta, M. A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.03.028 · Cited by 57
Self-citationAtomoxetine facilitates attentional set shifting in adolescent rats
Cain, R. E., Wasserman, M. C., Waterhouse, B. D., & McGaughy, J. A. (2011) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2011.04.003 · Cited by 55
“, 2008) or improve cognition in normal subjects (Berridge & Waterhouse, 2003; Chamberlain et al., 2008; Mehta et al., 2000).”
Lou, H. C., Nowak, M., & Kjær, T. W. (2005) · Progress in brain research · doi:10.1016/s0079-6123(05)50014-1 · Cited by 60
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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