Modanfinil 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.