Modafinil Effects on Middle-Frequency Oscillatory Power During Rule Selection in Schizophrenia

Abstract

Control-related cognitive processes such as rule selection are associated with cortical oscillations in the theta, alpha and, beta ranges, and modulated by catecholamine neurotransmission. Thus, a potential strategy for improving cognitive control deficits in schizophrenia would be to use pro-catecholamine pharmacological agents to augment these control-related oscillations. In a double-blind, placebo-controlled (within-subjects) study, we tested the effects of adjunctive single-dose modafinil 200 mg on rule-related 4-30 Hz oscillations in 23 stable schizophrenia patients, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine the power of 4-30 Hz oscillations. Modafinil (relative to placebo) enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with modest effects during rule maintenance. Modafinil treatment in schizophrenia augments middle-frequency cortical oscillatory power associated with rule selection, and may subserve diverse subcomponent processes in proactive cognitive control.

Concordant neurophysiological signatures of cognitive control in humans and rats

“…We tested this possibility with modafinil, a dopamine reuptake inhibitor that has been shown to increase extracellular levels of dopamine [22]. Based on a large literature [42,43], we had predicted that modafinil would dosedependently increase several signals, including N200, ERN, and frontal theta power. Surprisingly, none of these signals were modulated with modafinil in either species, though we observed a trend in stimulus-locked theta power in rats (p = 0.08) that may bear out in future studies.…”

The effect of modafinil on the rat dopamine transporter and dopamine receptors D1–D3 paralleling cognitive enhancement in the radial arm maze

“…Studies using modafinil on memory deficits in schizophrenic patients are quite promising and improvement of short-term verbal memory, verbal WM performance, spatial WM errors (WMEs) and strategy use is furthermore observed in schizophrenics ( Turner et al, 2004a , b ; Scoriels et al, 2012 ). Minzenberg et al (2014) studied modafinil effects in schizophrenia and observed improvement of rule selection and representation. Moreover, modafinil was studied in healthy volunteers and significantly enhanced performance in trials of cognition such as WM, cognitive flexibility, and planning ( Muller et al, 2004 ; Turner et al, 2004a , b ; Finke et al, 2010 ).…”

Modafinil improves attentional performance in healthy, non-sleep deprived humans at doses not inducing hyperarousal across species

“…The mechanism of action underlying this effect remains to be determined however. The pro-cognitive effects of modafinil may arise from its ability to facilitate middle frequency cortical oscillations (theta, alpha, beta) acutely (Minzenberg et al, 2014a, 2014b), or higher frequency cognitive-control related activity (gamma) with sustained treatment (Minzenberg et al, 2016). Further, McKenna and colleagues (McKenna et al, 2013) identified numerous regions underlying 5C-CPT performance using fMRI.…”