State-dependent modulation of interactions of theta and gamma rhythms in working memory

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ABSTRACT Transcranial alternating current stimulation (tACS) is a noninvasive neuromodulation technique that allows for frequency-specific entrainment of brain oscillations. Many cognitive functions are underpinned by oscillatory timing and patterns, and cognitive deficits in neuropsychiatric disorders are associated with disturbances in those patterns. tACS has the potential to synchronize rhythmic activity and mitigate cognitive deficits. However, a major challenge is that the effects of tACS on brain oscillations depend on the current brain state of the individual and on the timing of stimulation relative to the phase of ongoing oscillations. Using a working memory paradigm, we will address this challenge by investigating the state- dependent effects of tACS delivered to the left dorsolateral prefrontal cortex (DLPFC) on theta-gamma cross frequency coupling (tgCFC) and theta fronto-parietal phase synchronization, two EEG markers critical to working memory function. Specifically, in Aim 1, we will test the hypothesis that tACS with theta- nested gamma waveform delivered intermittently during key task epochs with strong tgCFC will improve cross-frequency interactions and frontoparietal phase synchrony during performance of a spatial working memory task, relative to tACS delivered with the same waveform during task-free epochs and sham stimulation. In Aim 2, we will test the hypothesis that closed-loop gamma tACS applied in phase with ongoing theta oscillations will enhance cross-frequency interactions and fronto-parietal phase synchronization relative to open-loop tACS with theta-nested gamma waveform. We will also determine the relationship between tACS-induced change in task performance and change in EEG markers across different stimulation conditions. These studies will help us identify reliable strategies to manipulate cross- frequency interactions between theta and gamma rhythms and to enhance phase synchronization between frontal and parietal regions, which support working memory function. They will also lay the groundwork for potential clinical trials that can test the efficacy of task-locked and closed-loop stimulation paradigms in clinical populations.