The dorsal premotor cortex (PMd) plays an import role in action control, sensorimotor integration and motor recovery. Animal studies and human data have demonstrated direct connections between ipsilateral PMd and primary motor cortex hand area (M1(HAND)). In this study we adopted a multimodal approach combining highly focal dual-site TMS (dsTMS) and diffusion tensor imaging (DTI) to probe ipsilateral effective and structural connectivity between PMd and M1(HAND) in humans. A suprathreshold test stimulus (TS) was applied to left M1(HAND) producing a motor evoked potential (MEP) and a subsequent conditioning stimulus (CS) to ipsilateral rostromedial PMd at short latencies ranging from of 0.8 to 2.0 ms. At an interstimulus interval of 1.2 ms, dsTMS of the left M1(HAND) and PMd facilitated MEP amplitudes relative to unconditioned TMS of M1(HAND). This PMd to M1(HAND) facilitation was absent during voluntary contraction of the target muscle. During a two-choice reaction time task, PMd-M1(HAND) facilitation was only observed when dsTMS was given 125 ms after presentation of the cue and subjects responded with their right hand, but not for left hand responses. Our results reveal a short-latency PMd to M1(HAND) connection which modulates excitability of ipsilateral M1(HAND) in a task and effector specific manner. DTI revealed that individual increases in PMd to M1(HAND) facilitation were correlated with fractional anisotropy and axial diffusivity in the juxtacortical white matter underlying the caudal portion of the left superior frontal gyrus. This finding shows that the functional strength of this connection from medial PMd to M1(HAND) has a microstructural correlate in the underlying subcortical white matter. This novel dsTMS paradigm can be used to non-invasively probe effective PMd to M1(HAND) connectivity in healthy individuals and patients with impaired hand function.
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