Modafinil Shifts Human Locus Coeruleus to Low-Tonic, High-Phasic Activity During Functional MRI

Models of cognitive control posit a key modulatory role for the pontine locus coeruleus–norepinephrine (LC-NE) system. In nonhuman primates, phasic LC-NE activity confers adaptive adjustments in cortical gain in task-relevant brain networks, and in performance, on a trial-by-trial basis. This model has remained untested in humans. We used the pharmacological agent modafinil to promote low-tonic/high-phasic LC-NE activity in healthy humans performing a cognitive control task during event-related functional magnetic resonance imaging (fMRI). Modafanil administration was associated with decreased task-independent, tonic LC activity, increased task-related LC and prefrontal cortex (PFC) activity, and enhanced LC-PFC functional connectivity. These results confirm in humans the role of the LC-NE system in PFC function and cognitive control and suggest a mechanism for therapeutic action of procognitive noradrenergic agents.

[1]  D. Gitelman,et al.  The spatial attention network interacts with limbic and monoaminergic systems to modulate motivation-induced attention shifts. , 2008, Cerebral cortex.

[2]  M. Minzenberg,et al.  Modafinil: A Review of Neurochemical Actions and Effects on Cognition , 2008, Neuropsychopharmacology.

[3]  J. Bueller,et al.  Reduced Brainstem Inhibition during Anticipated Pelvic Visceral Pain Correlates with Enhanced Brain Response to the Visceral Stimulus in Women with Irritable Bowel Syndrome , 2008, The Journal of Neuroscience.

[4]  Thomas E. Hazy,et al.  Towards an executive without a homunculus: computational models of the prefrontal cortex/basal ganglia system , 2007, Philosophical Transactions of the Royal Society B: Biological Sciences.

[5]  T. Robbins,et al.  Differential regulation of fronto-executive function by the monoamines and acetylcholine. , 2007, Cerebral cortex.

[6]  A. Arnsten,et al.  Adrenergic pharmacology and cognition: focus on the prefrontal cortex. , 2007, Pharmacology & therapeutics.

[7]  Trevor W. Robbins,et al.  Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol , 2007, Psychopharmacology.

[8]  T. Spencer,et al.  Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro , 2006, Journal of Pharmacology and Experimental Therapeutics.

[9]  Evelyne Balteau,et al.  The Locus Ceruleus Is Involved in the Successful Retrieval of Emotional Memories in Humans , 2006, The Journal of Neuroscience.

[10]  S. Sara,et al.  Network reset: a simplified overarching theory of locus coeruleus noradrenaline function , 2005, Trends in Neurosciences.

[11]  Jonathan D. Cohen,et al.  An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. , 2005, Annual review of neuroscience.

[12]  Cameron S Carter,et al.  Cognitive control involved in overcoming prepotent response tendencies and switching between tasks. , 2005, Cerebral cortex.

[13]  C. Bradshaw,et al.  Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers , 2005, Psychopharmacology.

[14]  Luke Clark,et al.  Modafinil Improves Cognition and Attentional Set Shifting in Patients with Chronic Schizophrenia , 2004, Neuropsychopharmacology.

[15]  Philip Holmes,et al.  The Influence of Spike Rate and Stimulus Duration on Noradrenergic Neurons , 2004, Journal of Computational Neuroscience.

[16]  U. Müller,et al.  Effects of modafinil on working memory processes in humans , 2004, Psychopharmacology.

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

[18]  Nikos K Logothetis,et al.  Interpreting the BOLD signal. , 2004, Annual review of physiology.

[19]  Carson C. Chow,et al.  Frequency-dependent synchrony in locus ceruleus: Role of electrotonic coupling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Nicolaidis,et al.  Variations in extracellular monoamines in the prefrontal cortex and medial hypothalamus after modafinil administration: a microdialysis study in rats , 2001, Neuroreport.

[21]  Karl J. Friston,et al.  Noradrenergically Mediated Plasticity in a Human Attentional Neuronal Network , 1999, NeuroImage.

[22]  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.

[23]  D. Robinson,et al.  Slow oscillations as a probe of the dynamics of the locus coeruleus-frontal cortex interaction in anesthetized rats , 1997, Journal of Physiology-Paris.

[24]  M. Ishimatsu,et al.  Synchronous Activity in Locus Coeruleus Results from Dendritic Interactions in Pericoerulear Regions , 1996, The Journal of Neuroscience.

[25]  G. Aston-Jones,et al.  Extranuclear dendrites of locus coeruleus neurons: activation by glutamate and modulation of activity by alpha adrenoceptors. , 1995, Journal of neurophysiology.

[26]  G Chouvet,et al.  Serotonin selectively attenuates glutamate-evoked activation of noradrenergic locus coeruleus neurons , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  G. Chiara,et al.  Blockade of the Noradrenaline Carrier Increases Extracellular Dopamine Concentrations in the Prefrontal Cortex: Evidence that Dopamine Is Taken up In Vivo by Noradrenergic Terminals , 1990, Journal of neurochemistry.

[28]  G. Aghajanian,et al.  alpha 2-adrenoceptor-mediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo. , 1982, Science.

[29]  K. G. Baker,et al.  The human locus coeruleus complex: an immunohistochemical and three dimensional reconstruction study , 2004, Experimental Brain Research.

[30]  Evian Gordon,et al.  A Direct Brainstem–amygdala–cortical Dalarmt System for Subliminal Signals of Fear , 2004 .

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

[32]  E. Miller,et al.  An integrative theory of prefrontal cortex function. , 2001, Annual review of neuroscience.