Effects of modafinil on working memory processes in humans

RationaleModafinil 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.ObjectivesThe 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.MethodsSixteen 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.ResultsModafinil 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.ConclusionsIn 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.

[1]  M. Eysenck.  Attention And Arousal, Cognition And Performance , 1982 .

[2]  F. Rambert,et al.  Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating effect of modafinil; studies with experimental animals. , 1990, European journal of pharmacology.

[3]  E. Weiller,et al.  Antagonism by modafinil of the psychomotor and cognitive impairment induced by sleep-deprivation in 12 healthy volunteers , 1991, European Psychiatry.

[4]  M. Jouvet,et al.  Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat , 1992, Brain Research.

[5]  J. Baranski,et al.  Modafinil, d‐amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature , 1995, Journal of sleep research.

[6]  D. Batejat,et al.  Disrupted Sleep-Wake Rhythm and Performance: Advantages of Modafinil , 1995 .

[7]  Andrew P. Smith,et al.  Noradrenaline and attention lapses , 1996, Nature.

[8]  J. Fuster.  Memory in the cerebral cortex : an empirical approach to neural networks in the human and nonhuman primate , 1996 .

[9]  P. Goldman-Rakic.  Regional and cellular fractionation of working memory. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Baranski,et al.  Self‐monitoring cognitive performance during sleep deprivation: effects of modafinil, d‐amphetamine and placebo , 2003, Journal of sleep research.

[11]  K. Mcclellan,et al.  Modafinil : A Review of its Pharmacology and Clinical Efficacy in the Management of Narcolepsy. , 1998, CNS drugs.

[12]  T. Robbins.  Homology in behavioural pharmacology: an approach to animal models of human cognition. , 1998, Behavioural pharmacology.

[13]  P. Rabbitt,et al.  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 , 1998, Journal of the International Neuropsychological Society.

[14]  A. Arnsten.  Catecholamine modulation of prefrontal cortical cognitive function , 1998, Trends in Cognitive Sciences.

[15]  B. Do,et al.  High-performance liquid chromatographic determination of modafinil and its two metabolites in human plasma using solid-phase extraction. , 1998, Journal of chromatography. B, Biomedical sciences and applications.

[16]  P. Barraud,et al.  Effects of modafinil on attentional processes during 60 hours of sleep deprivation , 1998 .

[17]  S. Pollmann,et al.  D1- Versus D2-Receptor Modulation of Visuospatial Working Memory in Humans , 1998, The Journal of Neuroscience.

[18]  J. Baranski,et al.  Modafinil During 64 Hr of Sleep Deprivation: Dose-Related Effects on Fatigue, Alertness, and Cognitive Performance , 1998 .

[19]  B. Postle,et al.  Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  P. Jäkälä,et al.  Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans , 1999, Neuropsychopharmacology.

[21]  Y. Wong,et al.  Open‐Label, Single‐Dose Pharmacokinetic Study of Modafinil Tablets: Influence of Age and Gender in Normal Subjects , 1999, Journal of clinical pharmacology.

[22]  K. Fuxe,et al.  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 , 1999, Neuropsychopharmacology.

[23]  G. Aston-Jones,et al.  Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system , 1999, The Journal of comparative neurology.

[24]  E. Bullmore,et al.  Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil , 1999, Journal of sleep research.

[25]  B. Postle,et al.  Maintenance versus Manipulation of Information Held in Working Memory: An Event-Related fMRI Study , 1999, Brain and Cognition.

[26]  T. Robbins,et al.  Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease , 1999, Psychopharmacology.

[27]  Jonathan D. Cohen,et al.  Role of locus coeruleus in attention and behavioral flexibility , 1999, Biological Psychiatry.

[28]  Y. Wong,et al.  A Double‐Blind, Placebo‐Controlled, Ascending‐Dose Evaluation of the Pharmacokinetics and Tolerability of Modafinil Tablets in Healthy Male Volunteers , 1999, Journal of clinical pharmacology.

[29]  Richard Coppola,et al.  Effects of Dextroamphetamine on Cognitive Performance and Cortical Activation , 2000, NeuroImage.

[30]  T. Schubert,et al.  Differential Demands on Working Memory for Guiding a Simple Action Sequence: Evidence from Closed-head-injured Subjects , 2000, Journal of clinical and experimental neuropsychology.

[31]  C. Saper,et al.  Hypothalamic Arousal Regions Are Activated during Modafinil-Induced Wakefulness , 2000, The Journal of Neuroscience.

[32]  D. Jasinski.  An evaluation of the abuse potential of modafinil using methylphenidate as a reference , 2000, Journal of psychopharmacology.

[33]  Christian Guilleminault,et al.  Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy , 2000, Neurology.

[34]  J. Caldwell,et al.  A double-blind, placebo-controlled investigation of the efficacy of modafinil for sustaining the alertness and performance of aviators: a helicopter simulator study , 2000, Psychopharmacology.

[35]  T. Robbins,et al.  Chemical neuromodulation of frontal-executive functions in humans and other animals , 2000, Experimental Brain Research.

[36]  J. Russo,et al.  Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. , 2000, Journal of child and adolescent psychopharmacology.

[37]  P. Nathan,et al.  The pharmacology of human working memory. , 2001, The international journal of neuropsychopharmacology.

[38]  T. Rugino,et al.  Effects of modafinil in children with attention-deficit/hyperactivity disorder: an open-label study. , 2001, Journal of the American Academy of Child and Adolescent Psychiatry.

[39]  I. Sora,et al.  Dopaminergic Role in Stimulant-Induced Wakefulness , 2001, The Journal of Neuroscience.

[40]  T. Balkin,et al.  Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine , 2001, Psychopharmacology.

[41]  A. Célérier,et al.  First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice , 2001, Neuroreport.

[42]  H. Freund,et al.  Effects of pallidal deep brain stimulation and levodopa treatment on reaction-time performance in Parkinson’s disease , 2002, Experimental Brain Research.

[43]  Trevor W. Robbins,et al.  Neurochemical modulation of prefrontal cortical function in humans and animals. , 2002 .

[44]  J. Sutcliffe,et al.  The hypocretins: Setting the arousal threshold , 2002, Nature Reviews Neuroscience.

[45]  W. Poewe,et al.  Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. , 2002, Sleep.

[46]  Sharon L. Thompson-Schill,et al.  Models of Functional Organization of the Lateral Prefrontal Cortex in Verbal Working Memory: Evidence in Favor of the Process Model , 2002, Journal of Cognitive Neuroscience.

[47]  Danielle C. Turner,et al.  Cognitive enhancing effects of modafinil in healthy volunteers , 2002, Psychopharmacology.

[48]  H. Nagaraja,et al.  Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study , 2002, Journal of neurology, neurosurgery, and psychiatry.

[49]  D. V. Cramon,et al.  Manipulation of working memory information is impaired in Parkinson's disease and related to working memory capacity. , 2002, Neuropsychology.

[50]  Tyrone D. Cannon,et al.  Maintenance and Manipulation in Spatial Working Memory: Dissociations in the Prefrontal Cortex , 2002, NeuroImage.

[51]  D. Moroz,et al.  Modafinil--medical considerations for use in sustained operations. , 2003, Aviation, space, and environmental medicine.

[52]  R. Fieve,et al.  Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. , 2003, The Journal of clinical psychiatry.

[53]  S. Nishino.  The hypocretin/orexin system in health and disease , 2003, Biological Psychiatry.

[54]  M. Thorpy,et al.  Initiating treatment with modafinil for control of excessive daytime sleepiness in patients switching from methylphenidate: an open-label safety study assessing three strategies , 2003, Psychopharmacology.

[55]  J. Stradling,et al.  Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy , 2003, Neuromuscular Disorders.

[56]  T. Robbins,et al.  Cognitive Impairments in Early Parkinson's Disease Are Accompanied by Reductions in Activity in Frontostriatal Neural Circuitry , 2003, The Journal of Neuroscience.

[57]  Danielle C. Turner,et al.  Subdissociative Dose Ketamine Produces a Deficit in Manipulation but not Maintenance of the Contents of Working Memory , 2003, Neuropsychopharmacology.

[58]  S. File,et al.  Modafinil affects mood, but not cognitive function, in healthy young volunteers , 2003, Human psychopharmacology.

[59]  N. Feldman,et al.  Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy , 2003, Psychopharmacology.

[60]  Roshan Cools,et al.  Using executive heterogeneity to explore the nature of working memory deficits in Parkinson’s disease , 2003, Neuropsychologia.

[61]  Danielle C. Turner,et al.  Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder , 2004, Biological Psychiatry.

[62]  U. Müller,et al.  Noradrenergic blockade and numeric working memory in humans , 2005, Journal of psychopharmacology.

[63]  B. Sahakian,et al.  Contrasting effects of clonidine and diazepam on tests of working memory and planning , 1995, Psychopharmacology.