Modulatory Effects of Modafinil on Neural Circuits Regulating Emotion and Cognition

Abstract

Modafinil differs from other arousal-enhancing agents in chemical structure, neurochemical profile, and behavioral effects. Most functional neuroimaging studies to date examined the effect of modafinil only on information processing underlying executive cognition, but cognitive enhancers in general have been shown to have pronounced effects on emotional behavior, too. We examined the effect of modafinil on neural circuits underlying affective processing and cognitive functions. Healthy volunteers were enrolled in this double-blinded placebo-controlled trial (100 mg/day for 7 days). They underwent BOLD fMRI while performing an emotion information-processing task that activates the amygdala and two prefrontally dependent cognitive tasks—a working memory (WM) task and a variable attentional control (VAC) task. A clinical assessment that included measurement of blood pressure, heart rate, the Hamilton anxiety scale, and the profile of mood state (POMS) questionnaire was also performed on each test day. BOLD fMRI revealed significantly decreased amygdala reactivity to fearful stimuli on modafinil compared with the placebo condition. During executive cognition tasks, a WM task and a VAC task, modafinil reduced BOLD signal in the prefrontal cortex and anterior cingulate. Although not statistically significant, there were trends for reduced anxiety, for decreased fatigue-inertia and increased vigor-activity, as well as decreased anger-hostility on modafinil. Modafinil in low doses has a unique physiologic profile compared with stimulant drugs: it enhances the efficiency of prefrontal cortical cognitive information processing, while dampening reactivity to threatening stimuli in the amygdala, a brain region implicated in anxiety.

Emotion Dysregulation in Attention Deficit Hyperactivity Disorder

“…Modafinil, which inhibits dopamine and norepinephrine transporters and decreases ϒ-aminobutyric acid also shows promise as a treatment for ADHD (131). In healthy adults, modafinil decreases amygdala activation during the viewing of fearful stimuli and boosts prefrontal cortical activation during executive functions (132). Again, this profile points to a drug with possible benefit for ADHD and associated emotion dysregulation.…”

Effect of Modafinil on Learning and Task-Related Brain Activity in Methamphetamine-Dependent and Healthy Individuals

“…However, discrepancies between behavioral performance and brain activation when examining modafinil are not unique to this study. A prior fMRI study in which modafinil (100 mg) was given daily for 7 days showed no effect of the medication on performance in a test of attentional control, but reduced ACC activation during task performance (Rasetti et al, 2010), also showing a mismatch between behavioral and fMRI effects of modafinil. Moreover, it is important to note that the mixed results found for the cognition-enhancing effects of modafinil on behavior in healthy participants often depend on the particular behavioral task, measures employed, and dosing regimens (Repantis et al, 2010).…”

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

“…There were 178 DRD2 GG/ HTR2A CC subjects, 33 DRD2 GG/HTR2A T carriers, 43 DRD2 T carriers/HTR2A CC, and 11 DRD2 T carriers/ HTR2A T carriers in this sample. The VAC is an eventrelated design task that has been used in several previous investigations (Blasi et al, , 2013aRasetti et al, 2010) to elicit brain activity during three levels of attentional control (low, intermediate, high) (see Supplementary Materials and Methods).…”