Working memory (WM) is the active retention and processing of information over a few seconds and is considered an essential component of cognitive function. The reduced WM capacity is a common feature in many diseases, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment (MCI), and Alzheimer's disease (AD). The theta-gamma neural code is an essential component of memory representations in the multi-item WM. A large body of studies have examined the association between cross-frequency coupling (CFC) across the cerebral cortices and WM performance; electrophysiological data together with the behavioral results showed the associations between CFC and WM performance. The oscillatory entrainment (sensory, non-invasive electrical/magnetic, and invasive electrical) remains the key method to investigate the causal relationship between CFC and WM. The frequency-tuned non-invasive brain stimulation is a promising way to improve WM performance in healthy and non-healthy patients with cognitive impairment. The WM performance is sensitive to the phase and rhythm of externally applied stimulations. CFC-transcranial-alternating current stimulation (CFC-tACS) is a recent approach in neuroscience that could alter cognitive outcomes. The studies that investigated (1) the association between CFC and WM and (2) the brain stimulation protocols that enhanced WM through modulating CFC by the means of the non-invasive brain stimulation techniques have been included in this review. In principle, this review can guide the researchers to identify the most prominent form of CFC associated with WM processing (e.g., theta/gamma phase-amplitude coupling), and to define the previously published studies that manipulate endogenous CFC externally to improve WM. This in turn will pave the path for future studies aimed at investigating the CFC-tACS effect on WM. The CFC-tACS protocols need to be thoroughly studied before they can be considered as therapeutic tools in patients with WM deficits.

Department of Medical Biophysics and Medical Informatics 3rd Faculty of Medicine Charles University Prague Prague Czechia

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