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The purpose of this study was to identify rehabilitative effects and changes in white matter microstructure in people with high-level spinal cord injury following bilateral upper-extremity motor skill training. Five subjects with high-level (C5–C6) spinal cord injury (SCI) performed five visuo-spatial motor training tasks over 12 sessions (2–3 sessions per week). Subjects controlled a two-dimensional cursor with bilateral simultaneous movements of the shoulders using a non-invasive inertial measurement unit-based body-machine interface. Subjects’ upper-body ability was evaluated before the start, in the middle and a day after the completion of training. MR imaging data were acquired before the start and within two days of the completion of training. Subjects learned to use upper-body movements that survived the injury to control the body-machine interface and improved their performance with practice. Motor training increased Manual Muscle Test scores and the isometric force of subjects’ shoulders and upper arms. Moreover, motor training increased fractional anisotropy (FA) values in the cingulum of the left hemisphere by 6.02% on average, indicating localized white matter microstructure changes induced by activity-dependent modulation of axon diameter, myelin thickness or axon number. This body-machine interface may serve as a platform to develop a new generation of assistive-rehabilitative devices that promote the use of, and that re-strengthen, the motor and sensory functions that survived the injury.