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

Abstract

BackgroundRepetitive 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.MethodsWe performed a targeted review of pre-clinical and clinical rTMS studies.ResultsCurrent 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.ConclusionsWe 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.

Practice makes plasticity: 10-Hz rTMS enhances LTP-like plasticity in musicians and athletes

“…However, with non-invasive brain stimulation, we often see this is not the case. Rather, an inverted U-shape curve indicates a “sweet spot” for much of plasticity induction (Caulfield and Brown, 2022 ). In fact, in many cases, more stimulation may reverse results, such as by doubling iTBS pulse numbers (Gamboa et al, 2010 ).…”

Neuronavigation maximizes accuracy and precision in TMS positioning: Evidence from 11,230 distance, angle, and electric field modeling measurements

“…The most common rTMS protocol is to apply 120% MT stimulation over the left DLPFC, making the typical stimulation intensity range relatively limited. Despite the group-level efficacy of this commonly used intensity, some researchers have pointed out that the dose-response curve of multiple TMS parameters follows an inverted U-shape with peak efficacy in the middle [ 49 ]. Others have suggested that using prospective E-field dosing would help to further reduce the dose variability at the cortical level by taking tissue composition and conductivity into consideration [ 50 ].…”

TMS-Induced Modulation of EEG Functional Connectivity Is Affected by the E-Field Orientation

“…In addition, nTMS parameters, such as stimulation intensity and timing, are usually adjusted based on peripheral functional responses when available, e.g., when stimulating the motor cortex to observe motor evoked potentials (MEPs) through electromyography [ 15 , 16 , 17 , 18 ]. When electroencephalography (EEG) is recorded in a simultaneous coregistration, a more effective nTMS outcome can be obtained by adjusting the stimulation parameters based on the cortico-cortical responses as mapped by nTMS–EEG [ 19 , 20 ].…”