Christopher Mandigo

Precise movement requires integrating descending motor control with sensory feedback. Sensory networks interact strongly with descending motor circuits within the spinal cord. We targeted this interaction by pairing stimulation of the motor cortex with coordinated stimulation of the cervical spinal cord. We used separate non-invasive and epidural experiments to test the hypothesis that the strongest muscle response would occur when paired brain and spinal cord stimuli simultaneously converge within the spinal cord. For non-invasive experiments, we measured arm and hand muscle motor evoked potentials (MEPs) in response to transcranial magnetic stimulation (TMS) and transcutaneous spinal cord stimulation (TSCS) in 16 individuals with chronic spinal cord injury (SCI) and 15 uninjured individuals. We compared this noninvasive approach to intraoperative paired stimulation experiments using dorsal epidural electrodes in 38 individuals undergoing surgery for cervical myelopathy. We observed augmented muscle responses to suprathreshold TMS when subthreshold TSCS stimuli were timed to converge synchronously in the spinal cord. At convergent timing, target muscle MEPs increased by 11.0% overall (13.3% in people with SCI, 6.2% in uninjured individuals) compared to non-convergent time intervals. Facilitation correlated with TSCS intensity, with intensity close to movement threshold being most effective. Facilitation did not correlate with SCI level or severity, indicating spared circuits were sufficient for this effect. Noninvasive pairing produced less facilitation compared to intraoperative (epidural) pairing. Thus, sensorimotor interactions in the cervical spinal spinal cord can be targeted with paired stimulation in health and after SCI. Highlights Electrical stimulation of spinal sensory circuits can augment cortical motor evoked potentials, but only when they are timed to arrive synchronously in the spinal cord. Facilitation was at least as large in people with spinal cord injury compared with uninjured controls, suggesting that the necessary circuits for this facilitation were spared by injury. The magnitude of facilitation with noninvasive facilitation was smaller than the facilitation effect observed with epidural stimulation during elective spinal surgery, but they both rely on precisely timed interactions. Facilitation of hand and arm muscle responses correlated with the transcutaneous spinal stimulation intensity, suggesting that the magnitude of the pairing effect can be improved. Pairing was effective both in uninjured participants and those with SCI, independently of injury level, severity, or chronicity.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. image Key points: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain‐ or spinal‐only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

Electrical stimulation of the brain and spinal cord can strengthen sensorimotor circuits and improve movement through associative plasticity. Current paired stimulation paradigms target the motor system alone or sensorimotor connections in cortex. We developed a paired stimulation approach in rats that targets sensory and motor connections in the cervical spinal cord. Since the circuits necessary for paired stimulation are conserved between species, we hypothesized that paired stimulation of motor cortex and posterior cervical spinal cord in humans would produce synergistic muscle responses but only when stimulation is properly timed. In 59 individuals undergoing clinically indicated cervical spine surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord with epidural electrodes while muscle responses were recorded in arm and leg muscles. Spinal electrodes were placed over either the posterior or anterior spinal cord, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and posterior, but not anterior, spinal cord stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred when descending motor and spinal afferent stimuli were timed to converge in the cervical spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, paired stimulation effects were present regardless of the severity of myelopathy as measured by clinical signs or spinal cord imaging. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. Significance Statement Pairs of stimuli that alter nervous system function typically target the motor system alone or the sensorimotor convergence in cortex. In humans undergoing clinically indicated surgery we tested a paired brain and spinal cord stimulation paradigm that we developed in rats to target sensorimotor convergence in the cervical spinal cord. Arm and hand muscle responses to paired stimulation were six times larger than brain or spinal cord stimulation alone and more selective to the targeted muscles when applied to the posterior but not anterior spinal cord. The paired stimulation effect was independent of the degree of myelopathy, suggesting that it could be applied as therapy in people affected by spinal cord injury.

A map of muscle responses to cervical epidural stimulation during clinically indicated surgery revealed strongest activation when stimulating laterally compared to midline and revealed differences to be weaker than expected across different segments. In contrast, waveform shapes and latencies were most similar when stimulating midline and laterally, indicating activation of overlapping circuitry. Thus, a map of the cervical spinal cord reveals organization and may help guide stimulation to activate arm and hand muscles strongly and selectively.

While epidural stimulation of the lumbar spinal cord has emerged as a powerful modality for recovery of movement, how it should be targeted to the cervical spinal cord to activate arm and hand muscles is not well-understood, particularly in humans. We sought to map muscle responses to posterior epidural cervical spinal cord stimulation in humans. We hypothesized that lateral stimulation over the dorsal root entry zone would be most effective, and responses would be strongest in the muscles innervated by the stimulated segment. Twenty-five people undergoing clinically indicated cervical spine surgery were consented to map motor responses. During surgery, stimulation was performed in midline and lateral positions at multiple exposed segments; six arm and three leg muscles were recorded on each side of the body. Across all segments and muscles tested, lateral stimulation produced stronger muscle responses than midline despite similar latency and shape of responses. Muscles innervated at a cervical segment had the largest responses from stimulation at that segment, but responses were also observed in muscles innervated at other cervical segments and in leg muscles. The cervical responses were clustered in rostral (C4-C6) and caudal (C7-T1) cervical segments. Strong responses to lateral stimulation are likely due to the proximity of stimulation to afferent axons. Small changes in response sizes to stimulation of adjacent cervical segments argues for local circuit integration, and distant muscle responses suggest activation of long propriospinal connections. This map can help guide cervical stimulation to improve arm and hand function. New and noteworthy A map of muscle responses to cervical epidural stimulation during clinically indicated surgery revealed strongest activation when stimulating laterally compared to midline, and differences to be weaker than expected across different segments. In contrast, waveform shapes and latencies were most similar when stimulating midline and laterally indicating activation of overlapping circuitry. Thus, a map of the cervical spinal cord reveals organization and may help guide stimulation to activate arm and hand muscles strongly and selectively. Graphical abstract