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

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 treatment-related 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.