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The supplementary motor area (SMA-proper) plays a key role in the preparation and execution of voluntary movements. Anatomically, SMA-proper is densely reciprocally connected to primary motor cortex (M1), but neuronal coordination within the SMA-M1 network and its modification by external perturbation are not well understood. Here we modulated the SMA-M1 network using MR-navigated multicoil associative transcranial magnetic stimulation in healthy subjects. Changes in corticospinal excitability were assessed by recording motor evoked potential (MEP) amplitude bilaterally in a hand muscle. We found timing-dependent bidirectional Hebbian-like MEP changes during and for at least 30 min after paired associative SMA-M1 stimulation. MEP amplitude increased if SMA stimulation preceded M1 stimulation by 6 ms, but decreased if SMA stimulation lagged M1 stimulation by 15 ms. This associative plasticity in the SMA-M1 network was highly topographically specific because paired associative stimulation of pre-SMA and M1 did not result in any significant MEP change. Furthermore, associative plasticity in the SMA-M1 network was strongly state-dependent because it required priming by near-simultaneous M1 stimulation to occur. We conclude that timing-dependent bidirectional associative plasticity is demonstrated for the first time at the systems level of a human corticocortical neuronal network. The properties of this form of plasticity are fully compatible with spike-timing-dependent plasticity as defined at the cellular level. The necessity of priming may reflect the strong interhemispheric connectivity of the SMA-M1 network. Findings are relevant for better understanding reorganization and potentially therapeutic modification of neuronal coordination in the SMA-M1 network after cerebral lesions such as stroke.

The supplementary motor area (SMA) is important for preparation and execution of voluntary movements and densely anatomically connected with the hand area of primary motor cortex (M1). However, little is known about the effective connectivity between SMA and ipsilateral M1 (SMA → M1). Here, we used paired-coil transcranial magnetic stimulation (pcTMS) to study the SMA → M1 effective connectivity in healthy human subjects. In Experiment 1, we tested the effects of different induced current directions in the SMA and M1, and different intensities of conditioning SMA stimulation. Coil placement over the SMA-proper was verified by MRI-navigation. We found a SMA → M1 facilitatory effect on motor evoked potential (MEP) amplitude that occurred very specifically only with an induced conditioning current directed from the midline towards the targeted SMA, an induced test current in M1 directed antero-medially and sufficient intensity of conditioning SMA stimulation. In Experiment 2, we selected these effective parameters to explore the effects of SMA → M1 on the active MEP amplitude, cortical silent period (CSP) duration, and using a triple-pulse protocol, on short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). None of these measures was affected by conditioning SMA stimulation. Our findings demonstrate that pcTMS identifies predominantly facilitatory connections from SMA-proper to the hand area of the ipsilateral M1. The successful activation of this connection depends on effective SMA-proper stimulation, is state dependent and likely mediated via excitatory interneurons in M1.

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