Modafinil is a well-tolerated psychostimulant drug with low addictive potential that is used to treat patients with narcolepsy or attention deficit disorders and to enhance vigilance in sleep-deprived military personal. So far, understanding of the cognitive enhancing effects of modafinil and the relevant neurobiological mechanisms are incomplete.
The aim of this study was to investigate the effects of modafinil on working memory processes in humans and how they are related to noradrenergic stimulation of the prefrontal cortex.
Sixteen healthy volunteers (aged 20–29 years) received either modafinil 200 mg or placebo using a double blind crossover design. Two computerized working memory tasks were administered, a numeric manipulation task that requires short-term maintenance of digit-sequences and different degrees of manipulation as well as delayed matching task that assesses maintenance of visuo-spatial information over varying delay lengths. The battery was supplemented by standardized paper pencil tasks of attentional functions.
Modafinil significantly reduced error rates in the long delay condition of the visuo-spatial task and in the manipulation conditions, but not in the maintenance condition of the numeric task. Analyses of reaction times showed no speed-accuracy trade-off. Attentional control tasks (letter cancellation, trail-making, catch trials) were not affected by modafinil.
In healthy volunteers without sleep deprivation modafinil has subtle stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks, especially in lower performing subjects. Overlapping attentional and working memory processes have to be considered when studying the noradrenergic modulation of the prefrontal cortex.
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Arnsten AFT (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cognit Sci 2:436–447
Arnsten AFT, Robbins TW (2002) Neurochemical modulation of prefrontal function in humans and animals. In: Stuss DT, Knight RT (eds) Principles of frontal lobe function. Oxford University, New York, pp 51–84
Aston-Jones G, Rajkowski J, Cohen J (1999) Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 46:1309–1320
Baranski JV, Pigeau RA (1997) Self-monitoring cognitive performance during sleep deprivation: effects of modafinil, d-amphetamine and placebo. J Sleep Res 6:84–91
Baranski JV, Cian C, Esquivie D, Pigeau RA, Raphel C (1998) Modafinil during 64 hr of sleep deprivation: dose-related effects on fatigue, alertness, and cognitive performance. Mol Psychol 10:173–193
Barde LH, Thompson-Schill SL (2002) Models of functional organization of the lateral prefrontal cortex in verbal working memory: evidence in favor of the process model. J Cognit Neurosci 14:1054–1063
Becker PM, Schwartz JR, Feldman NT, Hughes RJ (2004) Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy. Psychopharmacology 171:133–139
Bensimon G, Benoit D, Lacomblez L, Weiller E et al. (1991) Antagonism by modafinil of the psychomotor and cognitive impairment induced by sleep-deprivation in 12 healthy volunteers. Eur Psychiatry 6:93–97
Béracochéa D, Cagnard B, Célérier A, le Merrer J, Pérès M, Piérard C (2001) First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice. Neuroreport 12:375–378
Bublak P, Schubert T, Matthes-von Cramon G, von Cramon Y (2000) Differential demands on working memory for guiding a simple action sequence: evidence from closed-head-injured subjects. J Clin Exp Neuropsychol 22:176–190
Bublak P, Müller U, Grön G, Reuter M, von Cramon DY (2002) Difficult manipulation of working memory information is impaired in Parkinson’s disease and related to working memory capacity. Neuropsychology 16:577–590
Buguet A, Moroz DE, Radomski MW (2003) Modafinil: medical considerations for use in sustained operations. Aviat Space Environ Med 74:659–663
Burnat P, Robles F, Do B (1998) High-performance liquid chromatographic determination of modafinil and its two metabolites in human plasma using solid-phase extraction. J Chromatogr B 706:295–304
Caldwell JA Jr, Caldwell JL, Smythe NK III, Hall KK (2000) A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study. Psychopharmacology 150:272–282
Coull JT, Middleton HC, Robbins TW, Sahakian BJ (1995) Contrasting effects of clonidine and diazepam on tests of working memory and planning. Psychopharmacology 120:311–321
DeBattista C, Doghramji K, Menza MA, Rosenthal MH, Fieve RR, Modafinil in Depression Study Group (2003) Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 64:1057–1064
Duteil J, Rambert FA, Pessonnier J, Hermant JF, Gombert R, Assous E (1990) Central alpha1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. Eur J Pharmacol 180:49–58
D’Esposito M, Postle BR, Ballard D, Lease J (1999) Maintenance versus manipulation of information held in working memory: an event-related fMRI study. Brain Cognit 41:66–86
Ellis KA, Nathan PJ (2001) The pharmacology of human working memory. Int J Neuropsychopharmacol 4:299–313
Ellis CM, Monk C, Simmons A, Lemmens G, Williams SC, Brammer M, Bullmore E, Parkes JD (1999) Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome: actions of modafinil. J Sleep Res 8:85–93
Eysenck MW (1982) Attention and arousal: cognition and performance. Springer, Berlin
Ferraro L, Antonelli T, Tanganelli S, O’Connor WT, Perez de la Mora M, Mendez-Franco J, Rambert FA, Fuxe K (1999) The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade. Neuropsychopharmacology 20:346–356
Fuster JM (1995) Memory in the cerebral cortex: an empirical approach to neural networks in the human brain and nonhuman primate. MIT Press, Cambridge
Glahn DC, Kim J, Cohen MS, Poutanen VP, Therman S, Bava S, Van Erp TG, Manninen M, Huttunen M, Lonnqvist J, Standertskjold-Nordenstam CG, Cannon TD (2002) Maintenance and manipulation in spatial working memory: dissociations in the prefrontal cortex. Neuroimage 17:201–213
Goldman-Rakic PS (1996) Regional and cellular fractionation of working memory. Proc Natl Acad Sci USA 93:13473–13480
Gruber O, Bublak P, von Cramon DY (1999) The neural correlates of working memory components: a functional magnetic resonance imaging study at 3 Tesla [abstract]. J Cognit Neurosci 11:32–33
Honey RA, Turner DC, Honey GD, Sharar SR, Kumaran D, Pomarol-Clotet E, McKenna P, Sahakian BJ, Robbins TW, Fletcher PC (2003) Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory. Neuropsychopharmacology 28:2037–2044
Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, van Den Pol AN (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415:145–159
Högl B, Saletu M, Brandauer E, Glatzl S, Frauscher B, Seppi K, Ulmer H, Wenning G, Poewe W (2002) Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 25:905–909
Jäkälä P, Riekkinen M, Sirviö J, Koivisto E, Kejonen K, Vanhanen M, Riekkinen P Jr (1999) Guanfacine, but not clonidine, improves planning and working memory performance in humans. Neuropsychopharmacology 20:460–470
Jasinski DR (2000) An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol 14:53–60
Lagarde D, Batejat D (1995) Disrupted sleep-wake rhythm and performance: advantages of modafinil. Mol Psychol 7:165–191
Lewis SJ, Cools R, Robbins TW, Dove A, Barker RA, Owen AM (2003a) Using executive heterogeneity to explore the nature of working memory deficits in Parkinson’s disease. Neuropsychologia 41:645–654
Lewis SJ, Dove A, Robbins TW, Barker RA, Owen AM (2003b) Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry. J Neurosci 23:6351–6356
Lin JS, Roussel B, Akaoka H, Fort P, Debilly G, Jouvet M (1992) Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain Res 591:319–326
Mattay VS, Callicott JH, Bertolino A, Heaton I, Frank JA, Coppola R, Berman KF, Goldberg TE, Weinberger DR (2000) Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage 12:268–275
McClellan KJ, Spencer CM (1998) Modafinil: a review of its pharmacology and clinical efficacy in the management of narcolepsy. CNS Drugs 9:311–324
Mehta MA, Sahakian BJ, McKenna PJ, Robbins TW (1999) Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease. Psychopharmacology 146:162–174
Mehta MA, Swainson R, Ogilvie AD, Sahakian J, Robbins TW (2001) Improved short-term spatial memory but impaired reversal learning following the dopamine D(2) agonist bromocriptine in human volunteers. Psychopharmacology 159:10–20
Müller U (2002) Die katecholaminerge Modulation präfrontaler kognitiver Funktionen beim Menschen (MPI Series in Cognitive Neuroscience 26). Max-Planck-Institut für neuropsychologische Forschung, Leipzig
Müller U, von Cramon DY, Pollmann S (1998) D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 18:2720–2728
Müller U, Mottweiler E, Bublak P (2004) Noradrenergic blockade and numeric working memory in humans. J Psychopharmacol (in press)
Nishino S (2003) The hypocretin/orexin system in health and disease. Biol Psychiatry 54:87–95
Pigeau R, Naitoh P, Buguet A, McCann C, Baranski J, Taylor M, Thompson M, Mack II (1995) Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature. J Sleep Res 4:212–228
Postle BR, Berger JS, D’Esposito M (1999) Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance. Proc Natl Acad Sci USA 96:12959–12964
Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN (2002) Efficacy and safety of modafinil (provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 72:179–183
Randall DC, Shneerson JM, Plaha KK, File SE (2003) Modafinil affects mood, but not cognitive function, in healthy young volunteers. Hum Psychopharmacol Clin Exp 18:163–173
Robbins TW (1998) Homology in behavioural pharmacology: an approach to animal models of human cognition. Behav Pharmacol 9:509–519
Robbins TW (2000) Chemical neuromodulation of frontal-executive functions in humans and other animals. Exp Brain Res 133:130–138
Robbins TW, James M, Owen AM, Sahakian BJ, Lawrence AD, McInnes L, Rabbitt PM (1998) A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: implications for theories of executive functioning and cognitive aging. Cambridge neuropsychological test automated battery. J Int Neuropsychol Soc 4:474–490
Rugino TA, Copley TC (2001) Effects of modafinil in children with attention-deficit/hyperactivity disorder: an open-label study. J Am Acad Child Adolesc Psychiatry 40:230–235
Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS, Saper CB (2000) Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 20:8620–8628
Schubert T, Volkmann J, Müller U, Sturm V, Voges J, Freund HJ, Von Cramon DY (2002) Effects of pallidal deep brain stimulation and levodopa treatment on reaction-time performance in Parkinson’s disease. Exp Brain Res 144:8–16
Smith A, Nutt D (1996) Noradrenaline and attention lapses. Nature 380:291
Stivalet P, Esquivie D, Barraud PA, Leifflen D, Raphel C (1998) Effects of modafinil on attentional processes during 60 hours of sleep deprivation. Hum Psychopharmacol Clin Exp 13:501–507
Sutcliffe JG, de Lecea L (2002) The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3:339–349
Talbot K, Stradling J, Crosby J, Hilton-Jones D (2003) Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy. Neuromuscul Disord 13:357–364
Taylor FB, Russo J (2000) Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. J Child Adolesc Psychopharmacol 10:311–320
Thorpy MJ, Schwartz JR, Kovacevic-Ristanovic R, Hayduk R (2003) Initiating treatment with modafinil for control of excessive daytime sleepiness in patients switching from methylphenidate: an open-label safety study assessing three strategies. Psychopharmacology 167:380–385
Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ (2003) Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology 165:260–269
Turner DC, Clark L, Dowson J, Robbins T, Sahakian B (2004) Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 55:1031–1040
US Modafinil in Narcolepsy Multicenter Study Group (2000) Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 54:1166–1175
Wesensten NJ, Belenky G, Kautz MA, Thorne DR, Reichardt RM, Balkin TJ (2002) Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology 159:238–247
Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM (2001) Dopaminergic role in stimulant-induced wakefulness. J Neurosci 21:1787–1794
Wong YN, King SP, Simcoe D, Gorman S, Laughton W, McCormick GC, Grebow P (1999) Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol 39:281–288
The authors are indebted to Dr. Luke Clark and an anonymous reviewer for comments on an earlier version of this paper, to Sandra Brattge and Bettina Johst for programming the delayed matching task, to Anke Pitzmaus for laboratory assistance and to all volunteers for participation. The study was supported by the Max Planck Society and the Alexander von Humboldt-Foundation (Feodor Lynen-Fellowship awarded to U.M.).
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Müller, U., Steffenhagen, N., Regenthal, R. et al. Effects of modafinil on working memory processes in humans. Psychopharmacology 177, 161–169 (2004). https://doi.org/10.1007/s00213-004-1926-3
- Working memory