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Modafinil enhances alerting-related brain activity in attention networks

Abstract

Rationale

Modafinil is a wake-promoting agent and has been reported to be effective in improving attention in patients with attentional disturbance. However, neural substrates underlying the modafinil effects on attention are not fully understood.

Objectives

We employed a functional magnetic resonance imaging (fMRI) study with the attention network test (ANT) task in healthy adults and examined which networks of attention are mainly affected by modafinil and which neural substrates are responsible for the drug effects.

Methods

We used a randomized placebo-controlled within-subjects cross-over design. Twenty-three healthy adults participated in two series of an fMRI study, taking either a placebo or modafinil. The participants performed the ANT task, which is designed to measure three distinct attentional networks, alerting, orienting, and executive control, during the fMRI scanning. The effects of modafinil on behavioral performance and regional brain activity were analyzed.

Results

We found that modafinil enhanced alerting performance and showed greater alerting network activity in the left middle and inferior occipital gyri as compared with the placebo. The brain activations in the occipital regions were positively correlated with alerting performance.

Conclusions

Modafinil enhanced alerting performance and increased activation in the occipital lobe in the alerting network possibly relevant to noradrenergic activity during the ANT task. The present study may provide a rationale for the treatment of patients with distinct symptoms of impaired attention.

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References

  • Abdullaev Y, Posner MI, Nunnally R, Dishion TJ (2010) Functional MRI evidence for inefficient attentional control in adolescent chronic cannabis abuse. Behav Brain Res 215:45–57. doi:10.1016/j.bbr.2010.06.023

    Article  PubMed  Google Scholar 

  • Backes V, Kellermann T, Voss B, KrÓ“mer J, Depner C, Schneider F, Habel U (2011) Neural correlates of the attention network test in schizophrenia. Eur Arch Psychiatry Clin Neurosci 261(Supple 2):S155–S160. doi:10.1007/s00406-011-0264-9

    Article  PubMed  Google Scholar 

  • Beck AT, Steer RA, Brown GK (1996) Manual for the Beck Depression Inventory, 2nd edn. Pearson, Texas

    Google Scholar 

  • Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33–84. doi:10.1016/S0165-0173(03)00143-7

    Article  PubMed  Google Scholar 

  • Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218. doi:10.1111/j.2044-8341.1974.tb02285.x

    Article  Google Scholar 

  • Caviola L, Faber NS (2015) Pills or push-ups? Effectiveness and public perception of pharmacological and non-pharmacological cognitive enhancement. Front Psychol 6:1852. doi:10.3389/fpsyg.2015.01852

    Article  PubMed  PubMed Central  Google Scholar 

  • Conen S, Theunissen EL, Vermeeren A, van Ruitenbeek P, Stiers P, Mehta MA, Toennes SW, Ramaekers JG (2013) The role of P-glycoprotein in CNS antihistamine effects. Psychopharmacology 229:9–19. doi:10.1007/s00213-013-3075-z

    Article  CAS  PubMed  Google Scholar 

  • Corbetta M, Shulman GL (2002) Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci 3:201–215. doi:10.1038/nrn755

    Article  CAS  PubMed  Google Scholar 

  • Coull JT, Nobre AC, Frith CD (2001) The noradrenergic α2 agonist clonidine modulates behavioural and neuroanatomical correlates of human attentional orienting and alerting. Cereb Cortex 11:73–84. doi:10.1093/cercor/11.1.73

    Article  CAS  PubMed  Google Scholar 

  • del Campo N, Fryer TD, Hong YT, Smith R, Brichard L, Acosta-Cabronero J, Chamberlain SR, Tait R, Izquierdo D, Regenthal R, Dowson J, Suckling J, Baron JC, Aigbirhio FI, Robbins TW, Sahakian BJ, Müller U (2013) A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment. Brain 136:3252–3270. doi:10.1093/brain/awt263

    Article  PubMed  PubMed Central  Google Scholar 

  • Devoto P, Flore G (2006) On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons? Curr Neuropharmacol 4:115–125. doi:10.2174/157015906776359559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devoto P, Flore G, Pira L, Longu G, Gessa GL (2004) Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex. Eur J Pharmacol 487:105–111. doi:10.1016/j.ejphar.2004.01.018

    Article  CAS  PubMed  Google Scholar 

  • Fan J, McCandliss BD, Sommer T, Raz A, Posner MI (2002) Testing the efficiency and independence of attentional networks. J Cogn Neurosci 14:340–347. doi:10.1162/089892902317361886

    Article  PubMed  Google Scholar 

  • Fan J, McCandliss BD, Fossella J, Flombaum JI, Posner MI (2005) The activation of attentional networks. NeuroImage 26:471–479. doi:10.1016/j.neuroimage.2005.02.004

    Article  PubMed  Google Scholar 

  • 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. doi:10.1016/S0893-133X(98)00085-2

    Article  CAS  PubMed  Google Scholar 

  • Ferraro L, Fuxe K, Tanganelli S, Fernandez M, Rambert FA, Antonelli T (2000) Amplification of cortical serotonin release: a further neurochemical action of the vigilance-promoting drug modafinil. Neuropharmacology 39:1974–1983. doi:10.1016/S0028-3908(00)00019-8

    Article  CAS  PubMed  Google Scholar 

  • Green AE, Munafò MR, DeYoung CG, Fossella JA, Fan J, Gray JR (2008) Using genetic data in cognitive neuroscience: from growing pains to genuine insights. Nat Rev Neurosci 9:710–720. doi:10.1038/nrn2461

    Article  CAS  PubMed  Google Scholar 

  • Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:50–55. doi:10.1111/j.2044-8341.1959.tb00467.x

    Article  CAS  PubMed  Google Scholar 

  • Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62. doi:10.1136/jnnp.23.1.56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hart CL, Haney M, Vosburg SK, Comer SD, Gunderson E, Foltin RW (2006) Modafinil attenuates disruptions in cognitive performance during simulated night-shift work. Neuropsychopharmacology 31:1526–1536. doi:10.1038/sj.npp.1300991

    Article  CAS  PubMed  Google Scholar 

  • Ikeda Y, Koeda M, Kim W, Tateno A, Okubo Y, Suzuki H (2012) Caffeine’s effects on attentional networks in healthy subjects: a pharmacological functional magnetic resonance imaging study. J Nippon Med Sch 79:318–319. doi:10.1272/jnms.79.318

    Article  PubMed  Google Scholar 

  • Ishizuka T, Murotani T, Yamatodani A (2010) Modafinil activates the histaminergic system through the orexinergic neurons. Neurosci Lett 483:193–196. doi:10.1016/j.neulet.2010.08.005

    Article  CAS  PubMed  Google Scholar 

  • Johns MW (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14:540–545

    Article  CAS  PubMed  Google Scholar 

  • Johnson KA, Robertson IH, Barry E, Mulligan A, Dáibhis A, Daly M, Watchorn A, Gill M, Bellgrove MA (2008) Impaired conflict resolution and alerting in children with ADHD: evidence from the attention network test (ANT). J Child Psychol Psychiatry 49:1339–1347. doi:10.1111/j.1469-7610.2008.01936.x

    Article  PubMed  Google Scholar 

  • Kim W, Tateno A, Arakawa R, Sakayori T, Ikeda Y, Suzuki H, Okubo Y (2014) In vivo activity of modafinil on dopamine transporter measured with positron emission tomography and [18F]FE-PE2I. Int J Neuropsychopharmacol 17:697–703. doi:10.1017/S1461145713001612

    Article  CAS  PubMed  Google Scholar 

  • Kratz O, Studer P, Baack J, Malcherek S, Erbe K, Moll GH, Heinrich H (2012) Differential effects of methylphenidate and atomoxetine on attentional processes in children with ADHD: an event-related potential study using the attention network test. Prog Neuro-Psychopharmacol Biol Psychiatry 37:81–89. doi:10.1016/j.pnpbp.2011.12.008

    Article  CAS  Google Scholar 

  • 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. doi:10.1016/0006-8993(92)91713-O

    Article  CAS  PubMed  Google Scholar 

  • Liu K, Sun G, Li B, Jiang Q, Yang X, Li M, Li L, Qian S, Zhao L, Zhou Z, von Deneen KM, Liu Y (2013) The impact of passive hyperthermia on human attention networks: an fMRI study. Behav Brain Res 243:220–230. doi:10.1016/j.bbr.2013.01.013

    Article  PubMed  Google Scholar 

  • Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, Johnson R, Livni E, Spencer TJ, Bonab AA, Miler GM, Fischman AJ (2006) Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther 319:561–569. doi:10.1124/jpet.106.106583

    Article  CAS  PubMed  Google Scholar 

  • Marchant NL, Kamel F, Echlin K, Grice J, Lewis M, Rusted JM (2009) Modafinil improves rapid shifts of attention. Psychopharmacology 202:487–495. doi:10.1007/s00213-008-1395-1

    Article  CAS  PubMed  Google Scholar 

  • McNair DM, Lorr M, Droppleman LF (1971) Manual for the Profile of Mood States. Educational and Industrial Testing Service, California

  • Mereu M, Bonci A, Newman AH, Tanda G (2013) The neurobiology of modafinil as an enhancer of cognitive performance and a potential treatment for substance use disorders. Psychopharmacology 229:415–434. doi:10.1007/s00213-013-3232-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Millan MJ, Agid Y, Brüne M, Bullmore ET, Carter CS, Clayton NS, Connor R, Davis S, Deakin B, DeRubeis RJ, Dubois B, Geyer MA, Goodwin GM, Gorwood P, Jay TM, Joëls M, Mansuy IM, Meyer-Lindenberg A, Murphy D, Rolls E, Saletu B, Spedding M, Sweeney J, Whittington M, Young LJ (2012) Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov 11:141–168. doi:10.1038/nrd3628

    Article  CAS  PubMed  Google Scholar 

  • Minzenberg MJ, Carter CS (2008) Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 33:1477–1502. doi:10.1038/sj.npp.1301534

    Article  CAS  PubMed  Google Scholar 

  • Minzenberg MJ, Watrous AJ, Yoon JH, Ursu S, Carter CS (2008) Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI. Science 322:1700–1702. doi:10.1126/science.1164908

    Article  CAS  PubMed  Google Scholar 

  • Murillo-Rodríguez E, Haro R, Palomero-Rivero M, Millán-Aldaco D, Drucker-Colín R (2007) Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increased wakefulness in rats. Behav Brain Res 176:353–357. doi:10.1016/j.bbr.2006.10.016

    Article  PubMed  Google Scholar 

  • Muto V, Shaffii-Le Bourdiec A, Matarazzo L, Foret A, Mascetti L, Jaspar M, Vandewalle G, Phillips C, Degueldre C, Balteau E, Luxen A, Collette F, Maquet P (2012) Influence of acute sleep loss on the neural correlates of alerting, orientating and executive attention components. J Sleep Res 21:648–658. doi:10.1111/j.1365-2869.2012.01020.x

    Article  PubMed  Google Scholar 

  • Oberlin BG, Alford JL, Marrocco RT (2005) Normal attention orienting but abnormal stimulus alerting and conflict effect in combined subtype of ADHD. Behav Brain Res 165:1–11. doi:10.1016/j.bbr.2005.06.041

    Article  PubMed  Google Scholar 

  • Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113. doi:10.1016/0028-3932(71)90067-4

    Article  CAS  PubMed  Google Scholar 

  • Peñaloza RA, Sarkar U, Claman DM, Omachi TA (2013) Trends in on-label and off-label modafinil use in a nationally representative sample. JAMA Intern Med 173:704–706. doi:10.1001/jamainternmed.2013.2807

    Article  PubMed  Google Scholar 

  • Pironti VA, Lai MC, Müller U, Dodds CM, Suckling J, Bullmore ET, Sahakian BJ (2014) Neuroanatomical abnormalities and cognitive impairments are shared by adults with attention-deficit/hyperactivity disorder and their unaffected first-degree relatives. Biol Psychiatry 76:639–647. doi:10.1016/j.biopsych.2013.09.025

    Article  PubMed  PubMed Central  Google Scholar 

  • Posner MI, Petersen SE (1990) The attention system of the human brain. Annu Rev Neurosci 13:25–42. doi:10.1146/annurev.neuro.13.1.25

    Article  CAS  PubMed  Google Scholar 

  • Posner MI, Rothbart MK (2007) Research on attention networks as a model for the integration of psychological science. Annu Rev Psychol 58:1–23. doi:10.1146/annurev.psych.58.110405.085516

    Article  PubMed  Google Scholar 

  • Pringle A, Browning M, Parsons E, Cowen PJ, Harmer CJ (2013) Early markers of cognitive enhancement: developing an implicit measure of cognitive performance. Psychopharmacology 230:631–638. doi:10.1007/s00213-013-3186-6

    Article  CAS  PubMed  Google Scholar 

  • Qu WM, Huang ZL, Xu XH, Matsumoto N, Urade Y (2008) Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. J Neurosci 28:8462–8469. doi:10.1523/JNEUROSCI.1819-08.2008

    Article  CAS  PubMed  Google Scholar 

  • Randall DC, Shneerson JM, Plaha KK, File SE (2003) Modafinil affects mood, but not cognitive function, in healthy young volunteers. Hum Psychopharmacol 18:163–173. doi:10.1002/hup.456

    Article  CAS  PubMed  Google Scholar 

  • Randall DC, Shneerson JM, File SE (2005) Cognitive effects of modafinil in student volunteers may depend on IQ. Pharmacol Biochem Behav 82:133–139. doi:10.1016/j.pbb.2005.07.019

    Article  CAS  PubMed  Google Scholar 

  • Rasetti R, Mattay VS, Stankevich B, Skjei K, Blasi G, Sambataro F, Arrillaga-Romany IC, Goldberg TE, Callicott JH, Apud JA, Weinberger DR (2010) Modulatory effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacology 35:2101–2109. doi:10.1038/npp.2010.83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Repantis D, Schlattmann P, Laisney O, Heuser I (2010) Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review. Pharmacol Res 62:187–206. doi:10.1016/j.phrs.2010.04.002

    Article  CAS  PubMed  Google Scholar 

  • Robertson P Jr, Hellriegel ET (2003) Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet 42:123–137. doi:10.2165/00003088-200342020-00002

    Article  CAS  PubMed  Google Scholar 

  • Rugino T (2007) A review of modafinil film-coated tablets for attention-deficit/hyperactivity disorder in children and adolescents. Neuropsychiatr Dis Treat 3:293–301

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sarter M, Givens B, Bruno JP (2001) The cognitive neuroscience of sustained attention: where top-down meets bottom-up. Brain Res Brain Res Rev 35:146–160. doi:10.1016/S0165-0173(01)00044-3

    Article  CAS  PubMed  Google Scholar 

  • Schneider M, Retz W, Coogan A, Thome J, Rösler M (2006) Anatomical and functional brain imaging in adult attention-deficit/hyperactivity disorder (ADHD)—a neurological view. Eur Arch Psychiatry Clin Neurosci 256:i32–i41. doi:10.1007/s00406-006-1005-3

    Article  PubMed  Google Scholar 

  • Schou M, Pike VW, Sóvágó J, Gulyás B, Gallagher PT, Dobson DR, Walter MW, Rudyk H, Farde L, Halldin C (2007) Synthesis of 11C-labelled (R)-OHDMI and CFMME and their evaluation as candidate radioligands for imaging central norepinephrine transporters with PET. Bioorg Med Chem 15:616–625. doi:10.1016/j.bmc.2006.10.065

    Article  CAS  PubMed  Google Scholar 

  • Schulz S, Arning L, Pinnow M, Epplen JT, Beste C (2012) N-methyl-d-aspartate receptor 2B subunit (GRIN2B) gene variation is associated with alerting, but not with orienting and conflicting in the attention network test. Neuropharmacology 63:259–265. doi:10.1016/j.neuropharm.2012.02.024

    Article  CAS  PubMed  Google Scholar 

  • Shih MC, Hoexter MQ, de Andrade LAF, Bressan RA (2006) Parkinson’s disease and dopamine transporter neuroimaging—a critical review. Sao Paulo Med J 124:168–175. doi:10.1590/S1516-31802006000300014

    Article  PubMed  Google Scholar 

  • Spielberger CD (1983) Manual for the State-Trait Anxiety Inventory, STAI-form Y. Consulting Psychologists Press, California

    Google Scholar 

  • Sturm W, Willmes K (2001) On the functional neuroanatomy of intrinsic and phasic alertness. NeuroImage 14:S76–S84. doi:10.1006/nimg.2001.0839

    Article  CAS  PubMed  Google Scholar 

  • Theunissen EL, Elvira Jde L, van den Bergh D, Ramaekers JG (2009) Comparing the stimulant effects of the H1-antagonist fexofenadine with 2 psychostimulants, modafinil and methylphenidate. J Clin Psychopharmacol 29:439–443. doi:10.1097/JCP.0b013e3181b3b5f3

    Article  CAS  PubMed  Google Scholar 

  • Thiel CM, Zilles K, Fink GR (2004) Cerebral correlates of alerting, orienting and reorienting of visuospatial attention: an event-related fMRI study. NeuroImage 21:318–328. doi:10.1016/j.neuroimage.2003.08.044

    Article  PubMed  Google Scholar 

  • Thienel R, Voss B, Kellermann T, Reske M, Halfter S, Sheldrick AJ, Radenbach K, Habel U, Shah NJ, Schall U, Kircher T (2009) Nicotinic antagonist effects on functional attention networks. Int J Neuropsychopharmacol 12:1295–1305. doi:10.1017/S1461145709990551

    Article  CAS  PubMed  Google Scholar 

  • Thimm M, Kircher T, Kellermann T, Markov V, Krach S, Jansen A, Zerres K, Eggermann T, Stöcker T, Shah NJ, Nöthen MM, Rietschel M, Witt SH, Mathiak K, Krug A (2011) Effects of a CACNA1C genotype on attention networks in healthy individuals. Psychol Med 41:1551–1561. doi:10.1017/S0033291710002217

    Article  CAS  PubMed  Google Scholar 

  • Tohid H, Faizan M, Faizan U (2015) Alterations of the occipital lobe in schizophrenia. Neurosciences (Riyadh) 20:213–224. doi:10.17712/nsj.2015.3.20140757

    Article  Google Scholar 

  • Turner D (2006) A review of the use of modafinil for attention-deficit hyperactivity disorder. Expert Rev Neurother 6:455–468. doi:10.1586/14737175.6.4.455

    Article  CAS  PubMed  Google Scholar 

  • Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ (2004) Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology 29:1363–1373. doi:10.1038/sj.npp.1300457

    Article  CAS  PubMed  Google Scholar 

  • Valentini V, Cacciapaglia F, Frau R, Di Chiara G (2006) Differential α2-mediated inhibition of dopamine and noradrenaline release in the parietal and occipital cortex following noradrenaline transporter blockade. J Neurochem 98:113–121. doi:10.1111/j.1471-4159.2006.03851.x

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Fowler JS, Logan J, Alexoff D, Zhu W, Telang F, Wang GJ, Jayne M, Hooker JM, Wong C, Hubbard B, Carter P, Warner D, King P, Shea C, Xu Y, Muench L, Apelskog-Torres K (2009) Effects of modafinil on dopamine an dopamine transporters in the male human brain: clinical implications. JAMA 301:1148–1154. doi:10.1001/jama.2009.351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vossel S, Geng JJ, Fink GR (2014) Dorsal and ventral attention systems: distinct neural circuits but collaborative roles. Neuroscientist 20:150–159. doi:10.1177/1073858413494269

    Article  PubMed  PubMed Central  Google Scholar 

  • Wisor J (2013) Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions. Front Neurol 4:139. doi:10.3389/fneur.2013.00139

    Article  PubMed  PubMed Central  Google Scholar 

  • Zheng J, Qin B, Dang C, Ye W, Chen Z, Yu L (2012) Alertness network in patients with temporal love epilepsy: a fMRI study. Epilepsy Res 100:67–73. doi:10.1016/j.eplepsyres.2012.01.006

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are entirely responsible for the scientific content of this paper. We are thankful to the Clinical Imaging Center for Healthcare, Nippon Medical School, for their support. In particular, we thank Koji Nagaya, Megumi Hongo, Koji Kanaya, Masaya Suda, and Minoru Sakurai for their technical assistance with the MRI examinations and Michiyo Tamura for research assistance. We also thank Chieko Kishi and Yumiko Fukano for help as clinical research coordinators and Arndt Gerz for his English editing of the manuscript. This work was partially supported by a Grant-in-Aid for Scientific Research (B) (24791237 to Y.I.) from the Japan Society for the Promotion of Science, Japan, and a Ministry of Education, Culture, Sports, Science and Technology-Supported Program for the Strategic Research Foundation at Private Universities, 2008–2012, Japan (S0801035 to H.S.).

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Ikeda, Y., Funayama, T., Tateno, A. et al. Modafinil enhances alerting-related brain activity in attention networks. Psychopharmacology 234, 2077–2089 (2017). https://doi.org/10.1007/s00213-017-4614-9

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