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

Objective: Electric-field orientation is crucial for optimizing neuronal excitation in transcranial magnetic stimulation (TMS). Yet, the stimulus orientation effects on short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are poorly understood due to technical challenges in manipulating the TMS-induced stimulus orientation within milliseconds. We aimed to assess the orientation sensitivity of SICI and ICF paradigms and identify optimal orientations for motor evoked potential (MEP) facilitation and suppression. Methods: We applied paired-pulse multi-channel TMS to 12 healthy subjects with conditioning and test stimuli in the same, opposite, and perpendicular orientations to each other at four interstimulus intervals (ISI) to generate refractoriness, SICI, and ICF. Results: MEP modulation was affected by the conditioning- and test-stimulus orientation, being strongest when both pulses were in the same direction. MEP modulation with 2.5-ms and 6.0-ms ISIs were more sensitive to orientation changes than 0.5- and 8.0-ms ISIs. Conclusion: SICI and ICF orientation sensitivity exhibit a complex dependence on the conditioning stimulus orientation, which might be explained by anatomical and morphological arrangements of inhibitory and excitatory neuronal populations. Significance: Distinct mechanisms mediating SICI and ICF are sensitive to stimulus orientation at specific ISIs, describing a structural–functional relationship that maximizes each effect at the cortical level.