Measuring Neuroplastic Effects of Oscillation-Locked Transcranial Magnetic Stimulation

About This Grant

PROJECT SUMMARY/ABSTRACT Major depressive disorder (MDD) is an epidemic, evident from its substantial global prevalence and burden, and is driving other major public health issues, including economic consequences. More than 30% of individuals living with MDD demonstrate no response to two or more antidepressant interventions and ultimately exhibit treatment resistance. Transcranial magnetic stimulation (TMS) has emerged as a safe, evidence-based, and non-invasive neuromodulation therapy for treatment-resistant depression. TMS utilizes electromagnetic induction to create an electric current in the brain, depolarizing cortical neurons and eliciting neurophysiological and behavioral effects. TMS works by inducing neuroplasticity, both within the stimulated cortex and its broader connected networks. However, the current efficacy rate of TMS for MDD remains up to 60%. This variability in treatment response may partially result from current clinical TMS approaches failing to incorporate the influence of brain dynamics at the time of stimulation on the neuroplastic effects and therapeutic outcomes. In line with this notion, it may be possible to reliably improve TMS response by enhancing the TMS-induced neuroplasticity through synchronizing the stimulation with ongoing neural activity. An oscillation-locked stimulation protocol delivers stimulation timed to a certain phase of an endogenous neural oscillation, which has been shown to modulate the ongoing brain activity in a more selective manner. Specifically, oscillation-locked stimulation can reliably produce opposing neuroplastic outcomes of potentiation or depression, depending on whether a pulse occurs at a negative-going or positive-going phase of a local oscillatory potential. Initial investigations and my Preliminary Data indicate that this effect is present in the human left dorsolateral prefrontal cortex, a critical hub in circuits governing cognitive and affective functions and the most common clinical TMS target. However, these findings have not been extensively examined, and the impact of oscillation-locked TMS on neuroplasticity has not been fully delineated. I will aim to bridge this knowledge gap by elucidating how precise, oscillation-locked TMS induces local and network neuroplasticity and by examining how these effects vary across the spectrum of depressive severity. My central hypothesis is that the phase of the ongoing oscillatory activity at the time of stimulation will differentially modulate both local (Aim 1) and network (Aim 2) neuroplasticity in adults without psychiatric diagnoses and those with MDD. This study will advance our theoretical understanding of clinically relevant neuroplasticity and investigate the potential of developing a brain state-dependent TMS protocol to effectively modulate relevant brain networks. In addition to completing the proposed research study under the Kirschstein-NRSA Fellowship, I will pursue rigorous clinical and career development activities to fulfill the requirements for my MD and PhD degrees and establish myself as an independent physician-scientist with expertise in neuromodulation.