Timing-dependent synergies between motor cortex and posterior spinal stimulation in humans.

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. 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.

Intraoperative electrical stimulation of the human dorsal spinal cord reveals a map of arm and hand muscle responses.

Although 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-six people undergoing clinically indicated cervical spine surgery consented to mapping of 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 argue 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 & NOTEWORTHY 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.

Use of the train-of-five bipolar technique to provide reliable, spatially accurate motor cortex identification in asleep patients.

OBJECTIVE: Intraoperative cortical and subcortical mapping techniques have become integral for achieving a maximal safe resection of tumors that are in or near regions of eloquent brain. The recent literature has demonstrated successful motor/language mapping with lower rates of stimulation-induced seizures when using monopolar high-frequency stimulation compared to traditional low-frequency bipolar stimulation mapping. However, monopolar stimulation carries with it disadvantages that include more radiant spread of electrical stimulation and a theoretically higher potential for tissue damage. The authors report on the successful use of bipolar stimulation with a high-frequency train-of-five (TOF) pulse physiology for motor mapping. METHODS: Between 2018 and 2019, 13 patients underwent motor mapping with phase-reversal and both low-frequency and high-frequency bipolar stimulation. A retrospective chart review was conducted to determine the success rate of motor mapping and to acquire intraoperative details. RESULTS: Thirteen patients underwent both high- and low-frequency bipolar motor mapping to aid in tumor resection. Of the lesions treated, 69% were gliomas, and the remainder were metastases. The motor cortex was identified at a significantly greater rate when using high-frequency TOF bipolar stimulation (n = 13) compared to the low-frequency bipolar stimulation (n = 4) (100% vs 31%, respectively; p = 0.0005). Intraoperative seizures and afterdischarges occurred only in the group of patients who underwent low-frequency bipolar stimulation, and none occurred in the TOF group (31% vs 0%, respectively; p = 0.09). CONCLUSIONS: Using a bipolar wand with high-frequency TOF stimulation, the authors achieved a significantly higher rate of successful motor mapping and a low rate of intraoperative seizure compared to traditional low-frequency bipolar stimulation. This preliminary study suggests that high-frequency TOF stimulation provides a reliable additional tool for motor cortex identification in asleep patients.

Timing dependent synergies between motor cortex and posterior spinal stimulation in humans.

Volitional movement requires descending input from 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 dorsal epidural SCS targeted at the sensorimotor interface or anterior epidural SCS 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 with epidural electrodes while muscle responses were 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, 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.

Neurophysiological profiles of responders and nonresponders to hypoglossal nerve stimulation: a single-institution study.

STUDY OBJECTIVES: Hypoglossal nerve stimulation (HGNS) is an effective alternative treatment for obstructive sleep apnea that acts by opening the airway via selective stimulation of nerve fibers that innervate tongue muscles that protrude (genioglossus) and stiffen the tongue (transverse and vertical) while avoiding nerve fibers that innervate tongue muscles that retract the tongue (styloglossus and hyoglossus). There remains a subset of postoperative patients who fail to adequately respond to HGNS, in some cases due to mixed activation of muscles that simultaneously protrude and retract the tongue. This study aims to characterize the relationship between neurophysiological data from individual tongue muscle activation during intraoperative electromyographic recordings and postoperative apnea-hypopnea index responses to HGNS. METHODS: A single-institution review of 46 patients undergoing unilateral HGNS implantation for obstructive sleep apnea. Patients were separated into responders and nonresponders through comparison of pre and postoperative apnea-hypopnea index. Neurophysiological data included electromyographic responses of the genioglossus, styloglossus/hyoglossus, intrinsic/vertical, and hyoglossus (neck) muscles to intraoperative stimulation using unipolar (- to - and o to o) and bipolar (+ to +) settings. RESULTS: The overall treatment success rate was 61% as determined by a postoperative apnea-hypopnea index < 20 events/h with a greater than 50% AHI reduction. We observed no statistically significant relationships between treatment response and individual muscle responses. However, we did note that increasing body mass index was correlated with worse postoperative responses. CONCLUSIONS: Although we noted a significant subgroup of clinical nonresponders to HGNS postoperatively, these patients were not found to exhibit significant inclusion of tongue retractors intraoperatively on neurophysiological analysis. Further research is needed to delineate additional phenotypic factors that may contribute to HGNS treatment responses. CITATION: Wang D, Modik O, Sturm JJ, et al. Neurophysiological profiles of responders and nonresponders to hypoglossal nerve stimulation: a single-institution study. J Clin Sleep Med. 2022;18(5):1327-1333.

Neurophysiological monitoring of tongue muscle activation during hypoglossal nerve stimulation.

OBJECTIVES/HYPOTHESIS: Upper airway stimulation for obstructive sleep apnea (OSA) via implantable hypoglossal nerve stimulation (HGNS) reduces airway obstruction by selectively stimulating nerve fibers that innervate muscles that produce tongue protrusion, while avoiding fibers that produce tongue retraction. This selective stimulation likely depends upon the location, intensity, and type of electrical stimulation delivered. This study investigates the impact of changing stimulation parameters on tongue muscle activation during HGNS using intraoperative nerve integrity monitoring in conjunction with electromyography (EMG). STUDY DESIGN: Prospective case series. METHODS: Ten patients undergoing unilateral HGNS implantation for OSA in a university hospital setting were studied. Data included EMG responses in tongue muscles that produce protrusion (genioglossus), retraction (styloglossus/hyoglossus), and stiffening (transverse/vertical) in response to intraoperative bipolar probe electrical stimulation of lateral and medial branches of the hypoglossal nerve (HGN) and to implantable pulse generator (IPG) unipolar and bipolar settings after placement of the stimulation cuff. RESULTS: Stimulation of medial division HGN branches resulted in EMG responses in genioglossus muscles, but not in styloglossus/hyoglossus muscles, whereas stimulation of the lateral division HGN branches drove responses in styloglossus/hyoglossus muscles. Variable responses in transverse/vertical muscles were observed with stimulation of lateral and medial division branches. After electrode cuff placement, unipolar and bipolar HGN stimulation configurations of IPG resulted in unique patterns of muscle activation. CONCLUSIONS: The relative activation of extrinsic and intrinsic tongue musculature by HGNS is determined by stimulus location, intensity, and type. Intraoperative neurophysiological monitoring of tongue muscle activation enables proper electrode cuff placement and may provide essential data for stimulus optimization. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1836-1843, 2020.

Contralateral Tongue Muscle Activation during Hypoglossal Nerve Stimulation.

OBJECTIVE: The effectiveness of upper airway stimulation via hypoglossal nerve stimulation for obstructive sleep apnea depends upon the pattern of tongue muscle activation produced. This study investigated the nature of contralateral tongue muscle activation by unilateral hypoglossal nerve stimulation using intraoperative nerve integrity monitoring in conjunction with electromyography and explored the relationship between contralateral tongue muscle activation and polysomnographic measures of obstructive sleep apnea severity. STUDY DESIGN: Prospective case series. SETTING: Tertiary care medical center. SUBJECTS AND METHODS: Fifty-one patients underwent unilateral (right) hypoglossal nerve stimulator implantation for obstructive sleep apnea. Neurophysiological data included electromyographic responses in ipsilateral (right) and contralateral (left) genioglossus muscles in response to intraoperative bipolar probe stimulation (0.3 mA) of medial hypoglossal nerve branches. Clinical data included pre- and postoperative apnea-hypopnea indices and oxygen desaturation levels. RESULTS: A subset of patients (20/51, 39%) exhibited electromyographic responses in both the ipsilateral and contralateral genioglossus (bilateral), whereas the remaining patients (31/51, 61%) exhibited electromyographic responses only in the ipsilateral genioglossus (unilateral). The baseline characteristics of bilateral and unilateral responders were similar. Both groups exhibited significant and comparable improvements in apnea-hypopnea index and oxygen desaturations after hypoglossal nerve stimulation. Neither the amplitude nor the latency of contralateral genioglossus responses was predictive of clinical outcomes. CONCLUSION: A subset of patients undergoing unilateral hypoglossal nerve stimulation exhibits activation of contralateral genioglossus muscles. Patients with unilateral and bilateral genioglossus responses exhibit comparable, robust improvements in apnea-hypopnea index and oxygen desaturation levels.

Intraoperative identification of mixed activation profiles during hypoglossal nerve stimulation.

STUDY OBJECTIVES: The effectiveness of hypoglossal nerve stimulation (HGNS) in the treatment of obstructive sleep apnea (OSA) depends on the selective stimulation of nerve fibers that innervate the tongue muscles that produce tongue protrusion (genioglossus) and stiffening (transverse/vertical) while avoiding fibers that innervate muscles that produce tongue retraction (styloglossus/hyoglossus). Postoperative treatment failures can be related to mixed activation of retractor and protrusor muscles, despite intraoperative efforts to identify and avoid nerve fibers that innervate the retractor muscles. This study describes a novel intraoperative protocol that more optimally identifies mixed activation by utilizing an expanded set of stimulation/recording parameters. METHODS: This study was a case series in a university hospital setting of patients undergoing unilateral hypoglossal nerve stimulation implantation for obstructive sleep apnea. Data included electromyographic responses in the genioglossus and styloglossus/hyoglossus to intraoperative stimulation with an implantable pulse generator using unipolar (- - -, o-o) and bipolar (+-+) settings. RESULTS: In a subset of patients (3/55), low-intensity unipolar implantable pulse generator stimulation revealed significant mixed activation of the styloglossus/hyoglossus and genioglossus muscles that was not evident under standard bipolar implantable pulse generator stimulation conditions. Additional surgical dissection and repositioning of the electrode stimulation cuff reduced mixed activation. CONCLUSIONS: A novel intraoperative neurophysiological monitoring protocol was able to detect significant mixed activation during hypoglossal nerve stimulation that was otherwise absent using standard parameters. This enabled successful electrode cuff repositioning and a dramatic reduction of mixed activation.