Feasibility of Manual Teach-and-Replay and Continuous Impedance Shaping for Robotic Locomotor Training Following Spinal Cord Injury

Robotic gait training is an emerging technique for retraining walking ability following spinal cord injury (SCI). A key challenge in this training is determining an appropriate stepping trajectory and level of assistance for each patient, since patients have a wide range of sizes and impairment levels. Here, we demonstrate how a lightweight yet powerful robot can record subject-specific, trainer-induced leg trajectories during manually assisted stepping, then immediately replay those trajectories. Replay of the subject-specific trajectories reduced the effort required by the trainer during manual assistance, yet still generated similar patterns of muscle activation for six subjects with a chronic SCI. We also demonstrate how the impedance of the robot can be adjusted on a step-by-step basis with an error-based, learning law. This impedance-shaping algorithm adapted the robot's impedance so that the robot assisted only in the regions of the step trajectory where the subject consistently exhibited errors. The result was that the subjects stepped with greater variability, while still maintaining a physiologic gait pattern. These results are further steps toward tailoring robotic gait training to the needs of individual patients

Case study: persistent recovery of hand movement and tactile sensation in peripheral nerve injury using targeted transcutaneous spinal cord stimulation

Peripheral nerve injury can lead to chronic pain, paralysis, and loss of sensation, severely affecting quality of life. Spinal cord stimulation has been used in the clinic to provide pain relief arising from peripheral nerve injuries, however, its ability to restore function after peripheral nerve injury have not been explored. Neuromodulation of the spinal cord through transcutaneous spinal cord stimulation (tSCS), when paired with activity-based training, has shown promising results towards restoring volitional limb control in people with spinal cord injury. We show, for the first time, the effectiveness of targeted tSCS in restoring strength (407% increase from 1.79 ± 1.24 N to up to 7.3 ± 0.93 N) and significantly increasing hand dexterity in an individual with paralysis due to a peripheral nerve injury (PNI). Furthermore, this is the first study to document a persisting 3-point improvement during clinical assessment of tactile sensation in peripheral injury after receiving 6 weeks of tSCS. Lastly, the motor and sensory gains persisted for several months after stimulation was received, suggesting tSCS may lead to long-lasting benefits, even in PNI. Non-invasive spinal cord stimulation shows tremendous promise as a safe and effective therapeutic approach with broad applications in functional recovery after debilitating injuries

Vestibulospinal and Corticospinal Modulation of Lumbosacral Network Excitability in Human Subjects

As part of a project aimed to develop a novel, non-invasive techniques for comprehensive assessment of supraspinal-spinal connectivity in humans, the present study sought to explore the convergence of descending vestibulospinal and corticospinal pathways onto lumbosacral motor pools. Transcutaneous electrical spinal stimulation-evoked motor potentials were recorded from knee and ankle flexors and extensors in resting neurologically intact participants. Descending influences on lumbosacral motor neurons were studied using galvanic vestibular (GVS) or transcranial magnetic stimulation (TMS) to elicit descending vestibulospinal or corticospinal volleys, respectively. Facilitatory conditioning effects of descending corticospinal volleys were manifested by a significant increase of spinally evoked motor potentials in recorded knee and ankle muscles bilaterally, and were observed at the 10–30 ms conditioning-test intervals (CTIs); whereas, facilitatory conditioning effects of vestibulospinal volleys manifested at longer latencies (CTIs of 90 and 110 ms), and lasted up to 250 ms. TMS mediated volleys revealed the conditioning effects at both short and long latencies, suggestive of both direct and indirect influence. In contrast, vestibulospinally mediated conditioning effects occurred at longer latencies, consistent with this pathway’s known anatomical and functional interfaces with other descending systems including the reticulospinal pathway and, suggestively, propriospinal interneurons. Our work demonstrates the utility and sensitivity of transcutaneous spinal stimulation in human neurophysiological studies as a technique for quantitative characterization of excitatory conditioning effects in multiple lumbosacral motor pools, obtained through descending pathways. This characterization becomes critical in understanding the neuroplasticity in the central nervous system during motor learning and neurological recovery

A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group

Role of chemical composition and redox modification of poorly soluble nanomaterials on their ability to enhance allergic airway sensitisation in mice

BACKGROUND: Engineered nanoparticles (NPs) have been shown to enhance allergic airways disease in mice. However, the influence of the different physicochemical properties of these particles on their adjuvant properties is largely unknown. Here we investigate the effects of chemical composition and redox activity of poorly soluble NPs on their adjuvant potency in a mouse model of airway hypersensitivity. RESULTS: NPs of roughly similar sizes with different chemical composition and redox activity, including CeO2, Zr-doped CeO2, Co3O4, Fe-doped Co3O4(using Fe2O3 or Fe3O4) and TiO2 NPs, all showed adjuvant activity. OVA induced immune responses following intranasal exposure of BALB/c mice to 0.02% OVA in combination with 200 μg NPs during sensitization (on day 1, 3, 6 and 8) and 0.5% OVA only during challenge (day 22, 23 and 24) were more pronounced compared to the same OVA treatment regime without NPs. Changes in OVA-specific IgE and IgG1 plasma levels, differential cell count and cytokines in bronchoalveolar lavage fluid (BALF), and histopathological detection of mucosa cell metaplasia and eosinophil density in the conducting airways were observed. Adjuvant activity of the CeO2 NPs was primarily mediated via the Th2 response, while that of the Co3O4 NPs was characterised by no or less marked increases in IgE plasma levels, BALF IL-4 and IL-5 concentrations and percentages of eosinophils in BALF and more pronounced increases in BALF IL-6 concentrations and percentages of lymphocytes in BALF. Co-exposure to Co3O4 NPs with OVA and subsequent OVA challenge also induced perivascular and peribronchiolar lymphoid cell accumulation and formation of ectopic lymphoid tissue in lungs. Responses to OVA combined with various NPs were not affected by the amount of doping or redox activity of the NPs. CONCLUSIONS: The findings indicate that chemical composition of NPs influences both the relative potency of NPs to exacerbate allergic airway sensitization and the type of immune response. However, no relation between the acellular redox activity and the observed adjuvant activity of the different NPs was found. Further research is needed to pinpoint the precise physiological properties of NPs and biological mechanisms determining adjuvant activity in order to facilitate a safe-by-design approach to NP development

Normalization of Blood Pressure With Spinal Cord Epidural Stimulation After Severe Spinal Cord Injury

Chronic low blood pressure and orthostatic hypotension remain challenging clinical issues after severe spinal cord injury (SCI), affecting health, rehabilitation, and quality of life. We previously reported that targeted lumbosacral spinal cord epidural stimulation (scES) could promote stand and step functions and restore voluntary movement in patients with chronic motor complete SCI. This study addresses the effects of targeted scES for cardiovascular function (CV-scES) in individuals with severe SCI who suffer from chronic hypotension. We tested the hypothesis that CV-scES can increase resting blood pressure and attenuate chronic hypotension in individuals with chronic cervical SCI. Four research participants with chronic cervical SCI received an implant of a 16-electrode array on the dura (L1–S1 cord segments, T11–L1 vertebrae). Individual-specific CV-scES configurations (anode and cathode electrode selection, voltage, frequency, and pulse width) were identified to maintain systolic blood pressure within targeted normative ranges without skeletal muscle activity of the lower extremities as assessed by electromyography. These individuals completed five 2-h sessions using CV-scES in an upright, seated position during measurement of blood pressure and heart rate. Noninvasive continuous blood pressure was measured from a finger cuff by plethysmograph technique. For each research participant there were statistically significant increases in mean arterial pressure in response to CV-scES that was maintained within normative ranges. This result was reproducible over the five sessions with concomitant decreases or no changes in heart rate using individual-specific CV-scES that was modulated with modest amplitude changes throughout the session. Our study shows that stimulating dorsal lumbosacral spinal cord can effectively and safely activate mechanisms to elevate blood pressures to normal ranges from a chronic hypotensive state in humans with severe SCI with individual-specific CV-scES

Trainer variability during step training after spinal cord injury: Implications for robotic gait-training device design.

Robotic devices are being developed to automate repetitive aspects of walking retraining after neurological injuries, in part because they might improve the consistency and quality of training. However, it is unclear how inconsistent manual training actually is or whether stepping quality depends strongly on the trainers' manual skill. The objective of this study was to quantify trainer variability of manual skill during step training using body-weight support on a treadmill and assess factors of trainer skill. We attached a sensorized orthosis to one leg of each patient with spinal cord injury and measured the shank kinematics and forces exerted by different trainers during six training sessions. An expert trainer rated the trainers' skill level based on videotape recordings. Between-trainer force variability was substantial, about two times greater than within-trainer variability. Trainer skill rating correlated strongly with two gait features: better knee extension during stance and fewer episodes of toe dragging. Better knee extension correlated directly with larger knee horizontal assistance force, but better toe clearance did not correlate with larger ankle push-up force; rather, it correlated with better knee and hip extension. These results are useful to inform robotic gait-training design