Neuroplastic Effects of Oscillation-locked Brain Stimulation

Introduction: Neurostimulation often evokes neuroplasticity, which holds therapeutic potential for neuropsychiatric disorders. However, it is difficult to ensure reliable plasticity in individual patients, limiting the use of this mechanism in functional neurosurgery. One way of enhancing treatment response may be through personalizing the intervention by increasing the temporal precision of the stimulation. This approach is known as oscillation-locked or phase-locked stimulation and links the stimulation to a certain phase of an endogenous brain rhythm. Targeting the negative peak of a region's typical oscillation, as a time of relative depolarization, could particularly enhance stimulation effects. Thus, we hypothesize that personalized, phase-locked neurostimulation applied at the negative peak of the alpha oscillation may be more optimal for inducing clinically relevant neuroplasticity.

Methods: In this multimodal transcranial magnetic stimulation (TMS)-EEG study, healthy adults received either phase-locked (N = 11) or random-phase (N = 8) TMS to the left dorsolateral prefrontal cortex. During phase-locked TMS, triplet bursts at 50 Hz were delivered during the negative peak of the alpha oscillation (phase angle of 180°). We recorded TMS-evoked potentials (TEPs) to paired-pulse TMS, which induces long-interval intracortical inhibition (LICI) and reflects inhibitory neuroplasticity, before and after phase-locked and random-phase TMS to assess whether these protocols induce different neuroplasticity changes.

Results: Phase locking was successful with a phase angle at stimulation of 175.2° ± 74.9° (M ± SD). LICI of P200 TEP, an EEG metric of cortical inhibitory function, was reduced by phase-locked TMS (mean difference = 1.29 μV, 95% CI [0.67, 1.92]), but this inhibition was increased by random-phase TMS (mean difference = -1.91 μV, 95% CI [-2.66, -1.15]).

Conclusion : Our findings suggest that neuroplasticity is differentially modulated by phase-locked and random-phase stimulation protocols. Phase-locked TMS decreases inhibitory neuroplasticity, which may lead to a higher left frontal excitability state and be beneficial in the treatment of depression. This study lays the foundational neurophysiological groundwork for a plasticity-oriented, temporally precise stimulation approach that can be adapted and leveraged by surgical neuromodulation for neuropsychiatric disorders.