Probing the orientation specificity of excitatory and inhibitory circuitries in the primary motor cortex with multi-channel TMS

Background The electric field orientation is a crucial parameter for optimizing the excitation of neuronal tissue in transcranial magnetic stimulation (TMS). Yet, the effects of stimulus orientation on the short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) paradigms are poorly known, mainly due to significant technical challenges in manipulating the TMS-induced stimulus orientation within milliseconds. Objective Our aim is to assess the effect of the TMS-induced stimulus orientation on the SICI and ICF paradigms and search for the optimal orientations to maximize the facilitation and suppression of the motor evoked potentials (MEP). Methods We applied paired-pulse multi-channel TMS in healthy subjects to generate SICI and ICF with conditioning and test pulses in the same, opposite, and perpendicular orientations to each other. The conditioning- and test-stimulus intensities were 80% and 110% of the resting motor threshold, respectively. Results Both SICI and ICF were significantly affected by the conditioning- and test-stimulus orientation. MEP suppression and facilitation were strongest with both pulses delivered in the same direction. SICI with a 2.5-ms and ICF with a 6.0-ms interstimulus interval (ISI) were more sensitive to changes in stimulus orientation compared with SICI at 0.5- and ICF at 8.0-ms ISIs, respectively. Conclusion Our findings provide evidence that SICI and ICF at specific ISIs are mediated by distinct mechanisms. Such mechanisms exhibit a preferential orientation depending on the anatomical and morphological arrangement of inhibitory and excitatory neuronal populations. We also demonstrate that the SICI and ICF can be maximized by adjusting the TMS-induced electric field orientation. ### Competing Interest Statement J.O.N. has received unrelated consulting fees from Nexstim Plc, and R.J.I. is an advisor and a minority shareholder of the company. J.O.N., L.M.K., and R.J.I. are inventors on patent applications on mTMS technology. The other authors declare no conflict of interest.