Connecting the dots: Harnessing dual-site transcranial magnetic stimulation to assess the causal influence of medial frontal areas on the motor cortex

Dual-site transcranial magnetic stimulation (TMS) has been widely employed to investigate the influence of cortical structures on the primary motor cortex (M1). Here, we leveraged this technique to probe the causal influence of two key areas of the medial frontal cortex, namely the supplementary motor area (SMA) and the medial orbitofrontal cortex (mOFC), on M1. We show that SMA stimulation facilitates M1 activity across short (6 and 8 ms) and long (12 ms) inter-stimulation intervals, putatively recruiting cortico-cortical and cortico-subcortico-cortical circuits, respectively. Crucially, magnetic resonance imaging revealed that this facilitatory effect depended on a key morphometric feature of SMA: individuals with larger SMA volumes exhibited more facilitation from SMA to M1. Notably, we also provide evidence that the facilitatory effect of SMA stimulation at short intervals did not arise from spinal interactions of volleys descending simultaneously from SMA and M1. On the other hand, mOFC stimulation moderately suppressed M1 activity at both short and long intervals, irrespective of mOFC volume. These results suggest that dual-site TMS is an interesting tool to study the differential influence of SMA and mOFC on M1 activity, paving the way for the multi-modal assessment of these fronto-motor circuits in health and disease. Key pointsO_LIDual-site TMS has been widely employed to investigate effective connectivity between cortical structures and the primary motor cortex (M1). C_LIO_LIHere, we probed the causal influence of the supplementary motor area (SMA) and the medial orbitofrontal cortex (mOFC) on M1 activity. C_LIO_LISMA stimulation facilitates M1 activity at both short and long inter-stimulation intervals; this facilitatory effect is related to SMA volume. C_LIO_LImOFC stimulation moderately suppresses M1 activity, independent of mOFC volume. C_LIO_LIThe findings pave the way for multi-modal assessment of fronto-motor circuits in health and disease. C_LI