(PS4-93) Difficulties in Identifying Peak Frequencies of Cross-frequency Phase-amplitude Coupling: Implications for Personalized Frequency Approaches of Tacs in Clinical Studies

Transcranial Alternating Current Stimulation (tACS) is a non-invasive brain stimulation that applies a low-intensity alternating current at specific frequencies to modulate neural oscillations. tACS is gaining popularity as a neuromodulation treatment for psychopathology, making it a prime candidate for personalized intervention. Personalizing stimulation waveforms based on individual endogenous frequencies is one method believed to improve therapeutic effects. However, challenges exist with identifying endogenous frequency, especially for complex stimulation procedures, such as theta-gamma phase-amplitude coupling (PAC) and in participants with psychopathology. This study examines the methodological challenges of identifying personalized stimulation frequencies, using theta-gamma phase-amplitude coupling (PAC) as an example target.

We analyzed EEG data of 67 participants with bipolar disorder (BD), 32 with schizophrenia (SZ), and 48 healthy controls (HC) recorded during a cognitive control task. We conducted wavelet convolution of 3-50 Hz activity, computed standardized coupling coefficients (PACz) between each theta (4-8 Hz) phase and gamma (30-50 Hz) power frequency pair, and visualized the results in a comodulogram for each individual. We used 3 methods to locate the theta-gamma frequency pair with the strongest coupling: visual inspection, global maximum, and local maximum.

Visual inspection successfully identified a peak PACz in 64% of BD, 59% of SZ, and 68% of HC. The global and local maximum methods frequently (53% and 29%, respectively) identified questionable peaks (values close to 0; bordering frequency bands other than theta and gamma). The presence of more than one peak was also a common problem. Modifying wavelet parameters (e.g., wavelet length, cycle numbers) to improve frequency specificity increased the successful identification of peak PACz to 94% of SZ, 83% of BD, and 86% of HC.

Considerable interindividual variability in PAC patterns and attenuations in endogenous theta-gamma coupling pose significant challenges for personalizing stimulation frequencies for tACS. Researchers should use multiple approaches to identify peak coupling frequencies, consider cognitive tasks to drive relevant activity, and be aware of psychopathology that may alter endogenous activity. Currently, tACS is a viable strategy to modulate cognitive function, with multiple opportunities as an adjunctive approach to traditional psychotherapy; however, the dosing and personalization needs to be further investigated before widespread use.