Abstract
Cognitive control regulates cognitive and emotional systems to facilitate goal-directed behavior in the context of task-irrelevant distractors. Cognitive control deficits contribute to residual functional impairments across psychiatric disorders and represent a promising novel treatment target. Translational evidence suggests that modafinil may enhance performance in executive functions; however, differential effects on regulatory control in cognitive and emotional domains have not been examined. The present pre-registered randomized-controlled pharmacological fMRI trial examined differential effects of modafinil (single-dose, 200 mg) on cognitive and emotional conflict processing. To further separate objective cognitive enhancing effects from subjective performance perception, a metacognitive paradigm was employed. Results indicated that modafinil specifically enhanced cognitive conflict performance and concomitantly increased activation in the inferior frontal gyrus and its functional communication with the dorsomedial prefrontal cortex. Exploratory analysis further revealed modafinil-enhanced basolateral amygdala reactivity to cognitive conflict, with stronger reactivity being associated with higher cognitive conflict performance. Whereas modafinil enhanced cognitive performance in the metacognitive paradigm, confidence indices remained unaffected. Overall, the present results suggest that modafinil has the potential to enhance cognitive conflict processing while leaving emotional conflict processing unaffected. On the neural level modafinil enhanced the recruitment of a network engaged in general conflict and regulatory control processes, whereas effects on the amygdala may reflect improved arousal-mediated attention processes for conflicting information. The pattern of cognitive enhancing effects in the absence of effects on affective processing suggests a promising potential to enhance cognitive control in clinical populations.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Botvinick MM, Braver TS, Barch DM, Carter CS, Cohen JD. Conflict monitoring and cognitive control. Psychological Rev. 2001;108:624.
Egner T. Multiple conflict-driven control mechanisms in the human brain. Trends Cogn Sci. 2008;12:374–80.
McTeague LM, Goodkind MS, Etkin A. Transdiagnostic impairment of cognitive control in mental illness. J Psychiatr Res. 2016;83:37–46.
Clark L, Blackwell AD, Aron AR, Turner DC, Dowson J, Robbins TW. et al. Association between response inhibition and working memory in adult ADHD: a link to right frontal cortex pathology?. Biol Psychiatry. 2007;61:1395–401.
Aron AR, Dowson JH, Sahakian BJ, Robbins TW. Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2003;54:1465–8.
Dalley JW, Everitt BJ, Robbins TW. Impulsivity, compulsivity, and top-down cognitive control. Neuron. 2011;69:680–94.
Rock P, Roiser J, Riedel W, Blackwell A. Cognitive impairment in depression: a systematic review and meta-analysis. Psychological Med. 2014;44:2029–40.
Schumann G, Binder EB, Holte A, de Kloet ER, Oedegaard KJ, Robbins TW. et al. Stratified medicine for mental disorders. Eur Neuropsychopharmacol. 2014;24:5–50.
Kaser M, Deakin JB, Michael A, Zapata C, Bansal R, Ryan D, et al. Modafinil improves episodic memory and working memory cognition in patients with remitted depression: a double-blind, randomized, placebo-controlled study. Biol Psychiatry: Cogn Neurosci Neuroimaging. 2017;2:115–22.
Bora E, Harrison BJ, Yücel M, Pantelis C. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychological Med. 2013;43:2017–26.
Hasselbalch BJ, Knorr U, Kessing LV. Cognitive impairment in the remitted state of unipolar depressive disorder: a systematic review. J Affect Disord. 2011;134:20–31.
Niendam TA, Laird AR, Ray KL, Dean YM, Glahn DC, Carter CS. Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions. Cogn, Affect, Behav Neurosci. 2012;12:241–68.
Sahakian BJ, Morein-Zamir S. Pharmacological cognitive enhancement: treatment of neuropsychiatric disorders and lifestyle use by healthy people. Lancet Psychiatry. 2015;2:357–62.
Aron AR, Robbins TW, Poldrack RA. Inhibition and the right inferior frontal cortex. Trends Cogn Sci. 2004;8:170–7.
Aron AR, Robbins TW, Poldrack RA. Inhibition and the right inferior frontal cortex: one decade on. Trends Cogn Sci. 2014;18:177–85.
Etkin A, Egner T, Peraza DM, Kandel ER, Hirsch J. Resolving emotional conflict: a role for the rostral anterior cingulate cortex in modulating activity in the amygdala. Neuron .2006;51:871–82.
Egner T, Etkin A, Gale S, Hirsch J. Dissociable neural systems resolve conflict from emotional versus nonemotional distracters. Cereb Cortex. 2007;18:1475–84.
Feng C, Becker B, Huang W, Wu X, Eickhoff SB, Chen T. Neural substrates of the emotion-word and emotional counting Stroop tasks in healthy and clinical populations: a meta-analysis of functional brain imaging studies. NeuroImage. 2018;173:258–74.
Cai W, Ryali S, Chen T, Li C-SR, Menon V. Dissociable roles of right inferior frontal cortex and anterior insula in inhibitory control: evidence from intrinsic and task-related functional parcellation, connectivity, and response profile analyses across multiple datasets. J Neurosci. 2014;34:14652–67.
Bos DJ, Oranje B, Achterberg M, Vlaskamp C, Ambrosino S, de Reus MA, et al. Structural and functional connectivity in children and adolescents with and without attention deficit/hyperactivity disorder. J Child Psychol Psychiatry. 2017;58:810–8.
Chamberlain SR, Hampshire A, Müller U, Rubia K, Del Campo N, Craig K, et al. Atomoxetine modulates right inferior frontal activation during inhibitory control: a pharmacological functional magnetic resonance imaging study. Biol Psychiatry. 2009;65:550–5.
Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology. 2008;33:1477–502.
Deroche-Gamonet V, Darnaudery M, Bruins-Slot L, Piat F, Le Moal M, Piazza P. Study of the addictive potential of modafinil in naive and cocaine-experienced rats. Psychopharmacology. 2002;161:387–95.
Müller U, Rowe J, Rittman T, Lewis C, Robbins T, Sahakian B. Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. Neuropharmacology. 2013;64:490–5.
Dolder PC, Müller F, Schmid Y, Borgwardt SJ, Liechti ME. Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects. Psychopharmacology. 2018;235:467–79.
Nguyen TL, Tian YH, You IJ, Lee SY, Jang CG. Modafinil‐induced conditioned place preference via dopaminergic system in mice. Synapse. 2011;65:733–41.
de Saint Hilaire Z, Orosco M, Rouch C, Blanc G, Nicolaidis S. Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport. 2001;12:3533–7.
Dawson N, Thompson RJ, McVie A, Thomson DM, Morris BJ, Pratt JA. Modafinil reverses phencyclidine-induced deficits in cognitive flexibility, cerebral metabolism, and functional brain connectivity. Schizophrenia Bull. 2010;38:457–74.
Ferraro L, Fuxe K, Agnati L, Tanganelli S, Tomasini MC, Antonelli T. Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat. Synapse. 2005;55:230–41.
Scoriels L, Jones PB, Sahakian B. Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain. Neuropharmacology. 2013;64:168–84.
Battleday RM, Brem A-K. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: a systematic review. Eur Neuropsychopharmacol. 2015;25:1865–81.
Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology. 2003;165:260–9.
Schmaal L, Goudriaan AE, Joos L, Krüse AM, Dom G, van den Brink W, et al. Modafinil modulates resting-state functional network connectivity and cognitive control in alcohol-dependent patients. Biol Psychiatry. 2013;73:789–95.
Franke AG, Gränsmark P, Agricola A, Schühle K, Rommel T, Sebastian A, et al. Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: a double-blind, randomised controlled trial. Eur Neuropsychopharmacol. 2017;27:248–60.
Rattray B, Martin K, Hewitt A, Cooper G, McDonald W. Effect of acute modafinil ingestion on cognitive and physical performance following mental exertion. Hum Psychopharmacol. 2019;34:1–9.
Randall DC, Viswanath A, Bharania P, Elsabagh SM, Hartley DE, Shneerson JM, et al. Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived? J Clin Psychopharmacol. 2005;25:175–9.
Taneja I, Haman K, Shelton RC, Robertson D. A randomized, double-blind, crossover trial of modafinil on mood. J Clin Psychopharmacol. 2007;27:76–8.
Rasetti R, Mattay VS, Stankevich B, Skjei K, Blasi G, Sambataro F, et al. Modulatory effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacology. 2010;35:2101–9.
Schmidt A, Müller F, Dolder PC, Schmid Y, Zanchi D, Liechti ME, et al. Comparative effects of methylphenidate, modafinil, and MDMA on response inhibition neural networks in healthy subjects. Int J Neuropsychopharmacol. 2017;20:712–20.
Fournier JC, Chase HW, Greenberg T, Etkin A, Almeida JR, Stiffler R, et al. Neuroticism and individual differences in neural function in unmedicated major depression: findings from the EMBARC Study. Biol Psychiatry: Cogn Neurosci Neuroimaging. 2017;2:138–48.
Etkin A, Schatzberg AF. Common abnormalities and disorder-specific compensation during implicit regulation of emotional processing in generalized anxiety and major depressive disorders. Am J Psychiatry. 2011;168:968–78.
Ilieva I, Boland J, Farah MJ. Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Neuropharmacology. 2013;64:496–505.
Allen M, Frank D, Schwarzkopf DS, Fardo F, Winston JS, Hauser TU, et al. Unexpected arousal modulates the influence of sensory noise on confidence. Elife. 2016;5:1–17.
Rycroft N, Hutton S, Clowry O, Groomsbridge C, Sierakowski A, Rusted J. Non-cholinergic modulation of antisaccade performance: a modafinil-nicotine comparison. Psychopharmacology. 2007;195:245–53.
Cservenka A, Stroup ML, Etkin A, Nagel BJ. The effects of age, sex, and hormones on emotional conflict-related brain response during adolescence. Brain Cognition. 2015;99:135–50.
Zhao Z, Yao S, Li K, Sindermann C, Zhou F, Zhao W, et al. Real-time functional connectivity-informed neurofeedback of amygdala-frontal pathways reduces anxiety. Psychother Psychosom. 2019;88:5–15.
Wong YN, King SP, Simcoe D, Gorman S, Laughton W, McCormick GC, et al. Open‐label, single‐dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol. 1999;39:281–8.
Müller U, Steffenhagen N, Regenthal R, Bublak P. Effects of modafinil on working memory processes in humans. Psychopharmacology. 2004;177:161–9.
Xu X, Li J, Chen Z, Kendrick KM, Becker B. Oxytocin reduces top-down control of attention by increasing bottom-up attention allocation to social but not non-social stimuli—a randomized controlled trial. Psychoneuroendocrinology. 2019;108:62–9.
Fleming SM, Weil RS, Nagy Z, Dolan RJ, Rees G. Relating introspective accuracy to individual differences in brain structure. Science. 2010;329:1541–3.
Maniscalco B, Lau H. A signal detection theoretic approach for estimating metacognitive sensitivity from confidence ratings. Conscious Cognition. 2012;21:422–30.
Brett M, Anton J-L, Valabregue R, Poline J-B. Region of interest analysis using an SPM toolbox. 8th International Conference on Functional Mapping of the Human Brain, Vol. 16, Abstract 497 (Sendai, Japan, 2002).
Fan L, Li H, Zhuo J, Zhang Y, Wang J, Chen L, et al. The human brainnetome atlas: a new brain atlas based on connectional architecture. Cereb Cortex. 2016;26:3508–26.
Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, et al. A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage. 2005;25:1325–35.
McLaren DG, Ries ML, Xu G, Johnson SC. A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches. Neuroimage. 2012;61:1277–86.
Song S, Zilverstand A, Song H, Uquillas FdO, Wang Y, Xie C, et al. The influence of emotional interference on cognitive control: a meta-analysis of neuroimaging studies using the emotional Stroop task. Sci Rep. 2017;7:1–9.
Patterson TK, Lenartowicz A, Berkman ET, Ji D, Poldrack RA, Knowlton BJ. Putting the brakes on the brakes: negative emotion disrupts cognitive control network functioning and alters subsequent stopping ability. Exp Brain Res. 2016;234:3107–18.
Schulz KP, Clerkin SM, Halperin JM, Newcorn JH, Tang CY, Fan J. Dissociable neural effects of stimulus valence and preceding context during the inhibition of responses to emotional faces. Hum Brain Mapp. 2009;30:2821–33.
Schmaal L, Goudriaan A, Joos L, Dom G, Pattij T, van den Brink W, et al. Neural substrates of impulsive decision making modulated by modafinil in alcohol-dependent patients. Psychological Med. 2014;44:2787–98.
Chamberlain SR, Müller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ. Neurochemical modulation of response inhibition and probabilistic learning in humans. Science. 2006;311:861–3.
Bensmann W, Zink N, Arning L, Beste C, Stock A-K. The presynaptic regulation of dopamine and norepinephrine synthesis has dissociable effects on different kinds of cognitive conflicts. Mol Neurobiol. 2019:56:8087–100.
Horga G, Maia TV, Wang P, Wang Z, Marsh R, Peterson B. Adaptation to conflict via context-driven anticipatory signals in the dorsomedial prefrontal cortex. J Neurosci. 2011;31:16208–16.
Taren AA, Venkatraman V, Huettel SA. A parallel functional topography between medial and lateral prefrontal cortex: evidence and implications for cognitive control. J Neurosci. 2011;31:5026–31.
De Wit S, Kosaki Y, Balleine BW, Dickinson A. Dorsomedial prefrontal cortex resolves response conflict in rats. J Neurosci. 2006;26:5224–9.
Chen T, Becker B, Camilleri J, Wang L, Yu S, Eickhoff SB, et al. A domain-general brain network underlying emotional and cognitive interference processing: evidence from coordinate-based and functional connectivity meta-analyses. Brain Struct Funct. 2018;223:3813–40.
Becker B, Mihov Y, Scheele D, Kendrick KM, Feinstein JS, Matusch A, et al. Fear processing and social networking in the absence of a functional amygdala. Biol Psychiatry. 2012;72:70–7.
LeDoux J. The amygdala. Curr Biol. 2007;17:868–74.
Holland PC, Gallagher M. Amygdala circuitry in attentional and representational processes. Trends Cogn Sci. 1999;3:65–73.
Pagliaccio D, Pine DS, Leibenluft E, Monte OD, Averbeck BB, Costa VD. Cross-species convergence in pupillary response: understanding human anxiety via non-human primate amygdala lesion. Soc Cogn Affect Neurosci. 2019;14:591–9.
Jones BE, Moore RY. Ascending projections of the locus coeruleus in the rat. II. Autoradiographic Study Brain Res. 1977;127:23–53.
Liang K, Juler RG, McGaugh JL. Modulating effects of posttraining epinephrine on memory: involvement of the amygdala noradrenergic system. Brain Res. 1986;368:125–33.
Buffalari DM, Grace AA. Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of α-2 and β receptor activation. J Neurosci. 2007;27:12358–66.
Conradi H, Ormel J, De Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychological Med. 2011;41:1165–74.
Taylor SF, Liberzon I. Neural correlates of emotion regulation in psychopathology. Trends Cogn Sci. 2007;11:413–8.
Zhou F, Zimmermann K, Xin F, Scheele D, Dau W, Banger M, et al. Shifted balance of dorsal versus ventral striatal communication with frontal reward and regulatory regions in cannabis‐dependent males. Hum Brain Mapp. 2018;39:5062–73.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Li, J., Yang, X., Zhou, F. et al. Modafinil enhances cognitive, but not emotional conflict processing via enhanced inferior frontal gyrus activation and its communication with the dorsomedial prefrontal cortex. Neuropsychopharmacol. 45, 1026–1033 (2020). https://doi.org/10.1038/s41386-020-0625-z
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41386-020-0625-z


