Sustained Modafinil Treatment Effects on Control-Related Gamma Oscillatory Power in Schizophrenia

Abstract

Control-related cognitive processes such as rule selection and maintenance are associated with cortical oscillations in the gamma range, and modulated by catecholamine neurotransmission. Control-related gamma power is impaired in schizophrenia, and an understudied treatment target. It remains unknown whether pro-catecholamine pharmacological agents augment control-related gamma oscillations in schizophrenia. We tested the effects of 4-week fixed-dose daily adjunctive modafinil (MOD) 200 mg, in a randomized double-blind, placebo-controlled, parallel-groups design. Twenty-seven stable schizophrenia patients performed a cognitive control task during EEG, at baseline and after 4 weeks of treatment. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4-80 Hz oscillations. The modafinil group (n = 14), relative to placebo group (n = 13), exhibited enhanced oscillatory power associated with high-control rule selection in the gamma range after treatment, with additional effects during rule maintenance in gamma and sub-gamma ranges. MOD-treated patients who exhibited improved task performance with treatment also showed greater treatmentrelated delay period gamma compared with MOD-treated patients without improved performance. This is the first evidence in schizophrenia of augmentation of cognition-related gamma oscillations by an FDA-approved agent with therapeutic potential. Gamma oscillations represent a novel treatment target in this disorder, and modulation of catecholamine signaling may represent a viable strategy at this target.

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.…”

Enhancing Clinical Trials Through Synergistic Gamma Power Analysis

“…Studies involving other neurotransmitters support the notion that the effects of E/I imbalance are more widespread than initially believed. Compounds targeting dopaminergic and norepinephrinergic neurons typically increase evoked gamma power (23,24), indicating that these neurotransmitters can be indirectly surveilled using this measurement technique. Preclinical evidence in rodents also suggests that ASSR also changes in response to cholinergic neurotransmitter modulation (25).…”

Potential Role of Oestrogen Modulation in the Treatment of Neurocognitive Deficits in Schizophrenia

“…Using an alpha-7 nicotinic receptor agonist, Keefe and colleagues [ 19 ] showed significant improvement in performance on the CogState battery [ 20 ] with relatively small effect sizes (Cohen’s d = 0.26), but no significant improvement on the Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery [ 21 ]. Although administration of a generalized attention-enhancing agent (modafinil) with an uncertain mechanism of action elicited enhanced cortical gamma-range oscillatory power [ 22 ], other studies [ 23 ] failed to find significant differences between modafinil treatment and placebo on assays of trained tasks and cognitive measures from the MATRICS battery. Given that cognitive deficits are related to functional impairment, which prevents full recovery, and that no effective pharmacological treatments for cognitive deficits are presently available, there remains an urgent need to identify novel pharmacological treatments to reverse cognitive deficits in people with schizophrenia.…”