Oscillatory impact of Transcranial Magnetic Stimulation at very weak-intensity on the primary motor cortex: A TMS-EEG study in the human brain

BackgroundVery weak transcranial magnetic stimulation (TMS, 10 mT, [~]0.05-10 V/m) has been explored in animal models showcasing potential for effective neuromodulation. However, the physiological effects of these type of pulsed fields remain rather unexplored in humans. ObjectiveWe here aimed to characterize the neural effects of very weak TMS pulsed fields ([~]6V/m, [~]6% of the resting motor threshold, rMT) and explore their ability to evoke and/or modulate local oscillatory activity generated on human primary motor regions. MethodsNeuronavigated TMS was employed in a cohort of healthy participants (n=18) to deliver single pulses and short bursts of rhythmic (20 Hz) TMS at very weak intensity and at conventional levels (here referred as high intensity) usually employed in human applications ([~]113V/m, [~]77% rMT), to the left primary motor cortex (M1). In parallel, their potential to evoke brain activity such as Transcranial Evoked Potentials (TEPs), and to entrain or modulate local ongoing oscillations was explored with scalp EEG recordings. ResultsBoth, single TMS pulses and 4-pulse rhythmic TMS beta (20 Hz) bursts delivered at conventional intensity elicited consistent Transcranial Evoked Potentials (TEPs) and beta-synchronized Event Related Spectral Perturbations (ERSP) around the left M1 area. Most interestingly, very-weak-intensity TMS modulated in this same area oscillatory activity at a mu-alpha frequency (7-13 Hz) only for rhythmic TMS bursts time-locked to -the troughs of the local ongoing beta oscillations. ConclusionsOur data provide first time support for the modulation of oscillatory signals with TMS delivered at an unprecedentedly weak intensity on the human primary motor cortex. This evidence enriches current knowledge on the impact of weak pulsed magnetic fields in humans, paving the way for future neurotherapeutics with a new generation of portable and autonomous low-intensity multichannel TMS devices. HIGHLIGHTSO_LIVery weak-intensity 20Hz TMS rhythmic patterns evoked significant mu-alpha central activity (7-13Hz) when bursts were aligned with the troughs of local ongoing beta oscillatory activity. C_LIO_LIConventional high-intensity single pulse and 20Hz TMS patterns elicited consistent TMS evoked potentials (TEP) and beta-synchronized local changes of Event Related Spectral Perturbations (ERSPs) in the left M1. C_LIO_LIFulfilling established criteria of TMS entrainment, the effects driven by high-intensity stimulation on M1 were TMS pattern- and oscillation-phase-dependent. Differences featured by very weak vs. conventional intensity TMS on entrained oscillatory activity suggests these two modalities operate on distinct physiological mechanisms. C_LI