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.
Minzenberg
Michael J
MJ
Department of Psychiatry, University of California, Davis School of Medicine, Sacramento, CA, USA. michael.minzenberg@ucdmc.ucdavis.edu
Watrous
Andrew J
AJ
Yoon
Jong H
JH
Ursu
Stefan
S
Carter
Cameron S
CS
D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001931:Brain Mapping; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D005260:Female; D006801:Humans; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D000077408:Modafinil; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017397:Prefrontal Cortex / Q000502:physiology; D013647:Task Performance and Analysis
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D050484:Norepinephrine Plasma Membrane Transport Proteins; D000077408:Modafinil; D009638:Norepinephrine