Mapping the Causal Roles of Non-Primary Motor Areas in Human Reach Planning and Execution.

Non-primary motor areas, including dorsal premotor cortex (PMd), ventral premotor cortex (PMv), and posterior parietal cortex (PPC), contribute to movement planning, but how these regions differentially shape kinematic features of goal-directed movements, and how this specialization is associated with functional connectivity within the frontoparietal network, remains of interest, particularly in relation to recovery after stroke. We used functional magnetic resonance imaging (fMRI), transcranial magnetic stimulation (TMS), and kinematic assessments to explore how these areas influence reaching performance in neurologically intact adults. Participants performed a goal-directed planar reaching task using the KINARM exoskeleton robot. Brief TMS pulse trains were initiated before movement onset to perturb cortical activity at subthreshold and suprathreshold intensities targeting bilateral PMd, PMv, and dorsomedial superior parietal lobule (SPL) within PPC. Resting-state fMRI quantified functional connectivity among these regions to assess whether connectivity explains stimulation-induced kinematic changes. Relative to the control target within the postcentral sulcus (PCS), subthreshold stimulation of contralateral PMd and PMv reduced reach efficiency and smoothness, while suprathreshold stimulation of contralateral PPC increased deviation error and reduced smoothness. Among ipsilateral targets, PMd showed consistent TMS-induced effects, and was the only target where resting-state connectivity predicted behavioral response. Stronger interhemispheric connectivity in the primary motor cortex and weaker interhemispheric PPC connectivity were associated with greater reductions in straightness and smoothness during subthreshold ipsilateral PMd stimulation. We found that perturbation of premotor and parietal targets led to distinct kinematic effects that varied by site, intensity, and laterality, with premotor stimulation showing the most consistent disruptions at subthreshold intensity and bilateral effects, whereas parietal effects were observed primarily for contralateral stimulation at suprathreshold intensity, and differences in network organization explain variability in behavioral response. Identifying contributions of cortical areas and connectivity patterns may help personalize interventions after stroke. Trial Registration: This study was registered at ClinicalTrials.gov under ID NCT04286516.