The Problem and Potential of TMS' Infinite Parameter Space: A Targeted Review and Road Map Forward

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive, effective, and FDA-approved brain stimulation method. However, rTMS parameter selection remains largely unexplored, with great potential for optimization. In this review, we highlight key studies underlying next generation rTMS therapies, particularly focusing on: (1) rTMS Parameters, (2) rTMS Target Engagement, (3) rTMS Interactions with Endogenous Brain Activity, and (4) Heritable Predisposition to Brain Stimulation Treatments. We performed a targeted review of pre-clinical and clinical rTMS studies. Current evidence suggests that rTMS pattern, intensity, frequency, train duration, intertrain interval, intersession interval, pulse and session number, pulse width, and pulse shape can alter motor excitability, long term potentiation (LTP)-like facilitation, and clinical antidepressant response. Additionally, an emerging theme is how endogenous brain state impacts rTMS response. Researchers have used resting state functional magnetic resonance imaging (rsfMRI) analyses to identify personalized rTMS targets. Electroencephalography (EEG) may measure endogenous alpha rhythms that preferentially respond to personalized stimulation frequencies, or in closed-loop EEG, may be synchronized with endogenous oscillations and even phase to optimize response. Lastly, neuroimaging and genotyping have identified individual predispositions that may underlie rTMS efficacy. We envision next generation rTMS will be delivered using optimized stimulation parameters to rsfMRI-determined targets at intensities determined by energy delivered to the cortex, and frequency personalized and synchronized to endogenous alpha-rhythms. Further research is needed to define the dose-response curve of each parameter on plasticity and clinical response at the group level, to determine how these parameters interact, and to ultimately personalize these parameters.