A pilot study by Schwippel and colleagues marks the first application of individualized closed-loop transcranial alternating current stimulation (tACS) for depression, potentially enhancing therapeutic outcomes. Transcranial electrical stimulation (tES) has been explored for depression since the 1960s, offering advantages like enhanced safety, reduced costs, and suitability for home use compared to transcranial magnetic stimulation (TMS). However, unlike electroconvulsive therapy (ECT) and TMS, tES has not been cleared by the FDA for depression, possibly due to lower efficacy compared to standard pharmacological treatments and negative findings from multicenter clinical trials.
Individualized tACS Approach
While most tES research for depression involves transcranial direct current stimulation (tDCS), this study investigated biphasic electrical currents (tACS). Both tDCS and tACS apply subthreshold electrical stimuli, but tACS involves oscillating modulation of resting neural membrane potentials matched to the brain’s neural activity. The investigators previously demonstrated that a single tACS session at an individualized frequency matched to a person's resting state alpha (8–12 Hz) frequency could reduce this activity compared to placebo. Individual alpha peak frequency (IAF) has been proposed as a biomarker for depression, potentially guiding treatment allocation.
Study Design and Findings
In this pilot study, the researchers individually adjusted the tACS frequency to each participant’s IAF daily and triggered IAF tACS during heightened alpha activity, effectively “closing the loop” with tES neuromodulation. By targeting and modulating each participant’s alpha frequency cortical oscillations in the prefrontal cortex across repeated sessions, they aimed to reduce neural oscillatory activity via homeostatic mechanisms. Over the 5-day intervention, there was an overall reduction in alpha frequency brain activity, associated with mood improvement following treatment. This triggering of brain stimulation via continuous online monitoring has shown rapid and sustained mood improvement in deep brain stimulation for depression.
Future Research Directions
While these findings suggest that “closing the loop” may improve tES antidepressant effects, several issues need further investigation. It remains unclear which aspects of the tES parameter space benefit from real-time monitoring and individualized adjustment. While alpha has shown promise, other frequency bands like frontal theta (4–8 Hz) may yield more favorable neuromodulatory effects. Phase-locking the tACS stimulus in-phase or anti-phase to ongoing brain activity may further facilitate entrainment or enhance the brain’s homeostatic response to stimulation. Furthermore, it is not clear whether a closed-loop stimulus ought to match the selected frequency target or endeavor to shift the frequency to a higher or lower value.
Safety and Efficacy Considerations
Beyond parameter optimization, the safety of multiple, repeated treatments must be addressed, particularly concerning unintended effects from alterations of alpha or other frequency-specific source generators. Alpha is linked to memory and attention, with broad relevance to cognition and behavior. It is important to determine whether the antidepressant effects of closed-loop tACS are comparable to other stimulation modalities, especially tDCS, which has been extensively studied in sham-controlled clinical trials.
The study by Schwippel and colleagues serves as an interesting initial exploration of a new individualized tES intervention, potentially showing enhanced therapeutic outcomes for depression. Further exploration of this technique for depression and other potential clinical indications is warranted.
