Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury.

A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (n = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI.

Implantable brain-computer interface for neuroprosthetic-enabled volitional hand grasp restoration in spinal cord injury.

Loss of hand function after cervical spinal cord injury severely impairs functional independence. We describe a method for restoring volitional control of hand grasp in one 21-year-old male subject with complete cervical quadriplegia (C5 American Spinal Injury Association Impairment Scale A) using a portable fully implanted brain-computer interface within the home environment. The brain-computer interface consists of subdural surface electrodes placed over the dominant-hand motor cortex and connects to a transmitter implanted subcutaneously below the clavicle, which allows continuous reading of the electrocorticographic activity. Movement-intent was used to trigger functional electrical stimulation of the dominant hand during an initial 29-weeks laboratory study and subsequently via a mechanical hand orthosis during in-home use. Movement-intent information could be decoded consistently throughout the 29-weeks in-laboratory study with a mean accuracy of 89.0% (range 78-93.3%). Improvements were observed in both the speed and accuracy of various upper extremity tasks, including lifting small objects and transferring objects to specific targets. At-home decoding accuracy during open-loop trials reached an accuracy of 91.3% (range 80-98.95%) and an accuracy of 88.3% (range 77.6-95.5%) during closed-loop trials. Importantly, the temporal stability of both the functional outcomes and decoder metrics were not explored in this study. A fully implanted brain-computer interface can be safely used to reliably decode movement-intent from motor cortex, allowing for accurate volitional control of hand grasp.

Development and deployment of an at-home strength and conditioning program to support a phase I trial in persons with chronic spinal cord injury.

STUDY DESIGN: Nonrandomized clinical trial (NCT02354625). OBJECTIVES: As a part of a Phase I clinical trial to assess the safety of autologous human Schwann cells (ahSC) in persons with chronic spinal cord injury (SCI), participants engaged in a multimodal conditioning program pre- and post-ahSC transplantation. The program included a home-based strength and endurance training program to prevent lack of fitness and posttransplantation detraining from confounding potential ahSC therapeutic effects. This paper describes development, deployment, outcomes, and challenges of the home-based training program. SETTING: University-based laboratory. METHODS: Development phase: two men with paraplegia completed an 8-week laboratory-based 'test' of the home-based program. Deployment phase: the first four (two males, two females) participant cohort of the ahSC trial completed the program at home for 12 weeks pre and 20 weeks post ahSC transplant. RESULTS: Development phase: both participants improved their peak aerobic capacity (VO2peak) (≥17%), peak power output (POpeak) (≥8%), and time to exhaustion (TTE) (≥7%). Deployment phase: pretransplant training minimally increased fitness in the two male participants (≥6% POpeak and ≥9% TTE). The two women had no POpeak changes and slight TTE changes (+2.6 and -1.2%, respectively.) All four participants detrained during the posttransplant recovery period. After posttransplant retraining, all four participants increased TTE (4-24%), three increased VO2peak (≥11%), and two increased POpeak (≥7%). CONCLUSIONS: Home-based strength and condition programs can be effective and successfully included in therapeutic SCI trials. However, development of these programs requires substantial content knowledge and experience.

Imaging characteristics of chronic spinal cord injury identified during screening for a cell transplantation clinical trial.

OBJECTIVEIn cell transplantation trials for spinal cord injury (SCI), quantifiable imaging criteria that serve as inclusion criteria are important in trial design. The authors' institutional experience has demonstrated an overall high rate of screen failures. The authors examined the causes for trial exclusion in a phase I, open-lab clinical trial examining the role of autologous Schwann cell intramedullary transplantation. Specifically, they reviewed the imaging characteristics in people with chronic SCI that excluded applicants from the trial, as this was a common cause of screening failures in their study.METHODSThe authors reviewed MRI records from 152 people with chronic (> 1 year) SCI who volunteered for intralesional Schwann cell transplantation but were deemed ineligible by prospectively defined criteria. Rostral-caudal injury lesion length was measured along the long axis of the spinal cord in the sagittal plane on T2-weighted MRI. Other lesion characteristics, specifically those pertaining to lesion cavity structure resulting in trial exclusion, were recorded.RESULTSImaging records from 152 potential participants with chronic SCI were reviewed, 42 with thoracic-level SCI and 110 with cervical-level SCI. Twenty-three individuals (55%) with thoracic SCI and 70 (64%) with cervical SCI were not enrolled in the trial based on imaging characteristics. For potential participants with thoracic injuries who did not meet the screening criteria for enrollment, the average rostral-caudal sagittal lesion length was 50 mm (SD 41 mm). In applicants with cervical injuries who did not meet the screening criteria for enrollment, the average sagittal lesion length was 34 mm (SD 21 mm).CONCLUSIONSWhile screening people with SCI for participation in a cell transplantation clinical trial, lesion length or volume can exclude potential subjects who appear appropriate candidates based on neurological eligibility criteria. In planning future cell-based therapy trials, the limitations incurred by lesion size should be considered early due to the screening burden and impact on candidate selection.

Long-term recording of electromyographic activity from multiple muscles to monitor physical activity of participants with or without a neurological disorder.

Various portable monitors have been used to quantify physical activity but most rely on detecting limb movement with a sensor rather than measuring muscle activity. Our first goal was to design and validate a portable system for recording surface electromyographic activity (EMG) from eight muscles over 24 h. The modular system includes: (1) preamplifiers that filter and amplify signals; (2) a preprocessor unit for further filtering and amplification, signal offset and power supply modification; (3) a data-logger for analog-to-digital conversion; a flash memory card for data storage and (4) a rechargeable battery. The equipment samples EMG at 1000 Hz, has a resolution of 2.6 µV and records signals up to 10 mV. The built-in analog filters create a bandwidth appropriate for surface EMG. Our second aim was to test the system biologically by recording EMG from able-bodied and spinal cord injured participants. Modifications were made to electrodes for remote preamplifier placement, and to the battery connection after pilot testing. Thereafter, 31 consecutive 24-h EMG recordings were successful. Both the engineering and biological validation of this system establishes it as a valuable tool for measuring physical activity from different muscles in real-world environments whether individuals have an intact or damaged nervous system.

Clinical Outcomes from a Multi-Center Study of Human Neural Stem Cell Transplantation in Chronic Cervical Spinal Cord Injury.

Human neural stem cell transplantation (HuCNS-SC®) is a promising central nervous system (CNS) tissue repair strategy in patients with stable neurological deficits from chronic spinal cord injury (SCI). These immature human neural cells have been demonstrated to survive when transplanted in vivo, extend neural processes, form synaptic contacts, and improve functional outcomes after experimental SCI. A phase II single blind, randomized proof-of-concept study of the safety and efficacy of HuCNS-SC transplantation into the cervical spinal cord was undertaken in patients with chronic C5-7 tetraplegia, 4-24 months post-injury. In Cohort I (n = 6) dose escalation from 15,000,000 to 40,000,000 cells was performed to determine the optimum dose. In Cohort II an additional six participants were transplanted at target dose (40,000,000) and compared with four untreated controls. Within the transplant group, there were nine American Spinal Injury Association Impairment Scale (AIS) B and three AIS A participants with a median age at transplant of 28 years with an average time to transplant post-injury of 1 year. Immunosuppression was continued for 6 months post-transplant, and immunosuppressive blood levels of tacrolimus were achieved and well tolerated. At 1 year post-transplantation, there was no evidence of additional spinal cord damage, new lesions, or syrinx formation on magnetic resonance (MR) imaging. In summary, the incremental dose escalation design established surgical safety, tolerability, and feasibility in Cohort I. Interim analysis of Cohorts I and II demonstrated a trend toward Upper Extremity Motor Score (UEMS) and Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) motor gains in the treated participants, but at a magnitude below the required clinical efficacy threshold set by the sponsor to support further development resulting in early study termination.

Spasms after spinal cord injury show low-frequency intermuscular coherence.

Intermuscular coherence allows the investigation of common input to muscle groups. Although beta-band (15-30 Hz) intermuscular coherence is well understood as originating from the cortex, the source of intermuscular coherence at lower frequencies is still unclear. We used a wearable device that recorded electromyographic (EMG) signals during a 24-h period in four lower limb muscles of seven spinal cord injury patients (American Spinal Cord Injury Association impairment scale: A, 6 subjects; B, 1 subject) while they went about their normal daily life activities. We detected natural spasms occurring during these long-lasting recordings and calculated intermuscular coherence between all six possible combinations of muscle pairs. There was significant intermuscular coherence at low frequencies, between 2 and 13 Hz. The most likely source for this was the spinal cord and its peripheral feedback loops, because the spinal lesions in these patients had interrupted connections to supraspinal structures. This is the first report to demonstrate that the spinal cord is capable of producing low-frequency intermuscular coherence with severely reduced or abolished descending drive. NEW & NOTEWORTHY This is the first report to demonstrate that intermuscular coherence between lower limb muscles at low frequencies can be produced by the spinal cord with severely reduced or abolished descending drive.

Body System Effects of a Multi-Modal Training Program Targeting Chronic, Motor Complete Thoracic Spinal Cord Injury.

The safety and efficacy of pharmacological and cellular transplantation strategies are currently being evaluated in people with spinal cord injury (SCI). In studies of people with chronic SCIs, it is thought that functional recovery will be best achieved when drug or cell therapies are combined with rehabilitation protocols. However, any functional recovery attributed to the therapy may be confounded by the conditioned state of the body and by training-induced effects on neuroplasticity. For this reason, we sought to investigate the effects of a multi-modal training program on several body systems. The training program included body-weight-supported treadmill training for locomotion, circuit resistance training for upper body conditioning, functional electrical stimulation for activation of sublesional muscles, and wheelchair skills training for overall mobility. Eight participants with chronic, thoracic-level, motor-complete SCI completed the 12-week training program. After 12 weeks, upper extremity muscular strength improved significantly for all participants, and some participants experienced improvements in function, which may be explained by increased strength. Neurological function did not change. Changes in pain and spasticity were highly variable between participants. This is the first demonstration of the effect of this combination of four training modalities. However, balancing participant and study-site burden with capturing meaningful outcome measures is also an important consideration.

Understanding therapeutic benefits of overground bionic ambulation: exploratory case series in persons with chronic, complete spinal cord injury.

OBJECTIVE: To explore responses to overground bionic ambulation (OBA) training from an interdisciplinary perspective including key components of neuromuscular activation, exercise conditioning, mobility capacity, and neuropathic pain. DESIGN: Case series. SETTING: Academic research center. PARTICIPANTS: Persons (N=3; 2 men, 1 woman) aged 26 to 38 years with complete spinal cord injury (SCI) (American Spinal Injury Association Impairment Scale grade A) between the levels of T1 and T10 for ≥1 year. INTERVENTION: OBA 3d/wk for 6 weeks. MAIN OUTCOME MEASURES: To obtain a comprehensive understanding of responses to OBA, an array of measures were obtained while walking in the device, including walking speeds and distances, energy expenditure, exercise conditioning effects, and neuromuscular and cortical activity patterns. Changes in spasticity and pain severity related to OBA use were also assessed. RESULTS: With training, participants were able to achieve walking speeds and distances in the OBA device similar to those observed in persons with motor-incomplete SCI (10-m walk speed, .11-.33m/s; 2-min walk distance, 11-33m). The energy expenditure required for OBA was similar to walking in persons without disability (ie, 25%-41% of peak oxygen consumption). Subjects with lower soleus reflex excitability walked longer during training, but there was no change in the level or amount of muscle activity with training. There was no change in cortical activity patterns. Exercise conditioning effects were small or nonexistent. However, all participants reported an average reduction in pain severity over the study period ranging between -1.3 and 1.7 on a 0-to-6 numeric rating scale. CONCLUSIONS: OBA training improved mobility in the OBA device without significant changes in exercise conditioning or in neuromuscular or cortical activity. However, pain severity was reduced and no severe adverse events were encountered during training. OBA therefore opens the possibility to reduce the common consequences of chronic, complete SCI such as reduced functional mobility and neuropathic pain.

An adaptive brain actuated system for augmenting rehabilitation.

For people living with paralysis, restoration of hand function remains the top priority because it leads to independence and improvement in quality of life. In approaches to restore hand and arm function, a goal is to better engage voluntary control and counteract maladaptive brain reorganization that results from non-use. Standard rehabilitation augmented with developments from the study of brain-computer interfaces could provide a combined therapy approach for motor cortex rehabilitation and to alleviate motor impairments. In this paper, an adaptive brain-computer interface system intended for application to control a functional electrical stimulation (FES) device is developed as an experimental test bed for augmenting rehabilitation with a brain-computer interface. The system's performance is improved throughout rehabilitation by passive user feedback and reinforcement learning. By continuously adapting to the user's brain activity, similar adaptive systems could be used to support clinical brain-computer interface neurorehabilitation over multiple days.

Do additional inputs change maximal voluntary motor unit firing rates after spinal cord injury?

BACKGROUND: Motor unit firing frequencies are low during maximal voluntary contractions (MVCs) of human thenar muscles impaired by cervical spinal cord injury (SCI). OBJECTIVE: This study aimed to examine whether thenar motor unit firing frequencies increase when driven by both maximal voluntary drive and other concurrent inputs compared with an MVC alone. METHODS: Motor unit firing rates, force, and surface electromyographic activity (EMG) were compared across 2 contractions: (a) MVC alone and (b) MVC combined with another input (combination contraction). Other inputs (conditions) included vibration, heat, or cold applied to the anterior surface of the forearm, electrical stimulation delivered to the anterior surface of the middle finger, a muscle spasm, or a voluntary contraction of the contralateral thenar muscles against resistance. RESULTS: The maximal firing frequency (n = 68 units), force, and electromyographic activity (n = 92 contraction pairs) were all significantly higher during the combined contractions compared with MVCs alone. There was a 3-way interaction between contraction, condition, and subject for maximal motor unit firing rates, force, and EMG. Thus, combined contraction responses were different for conditions across subjects. Some conditions (eg, a muscle spasm) resulted in more effective and more frequent responses (increases in unit firing frequency, force, EMG in >50% contractions) than others. Recruitment of new units also occurred in combined contractions. CONCLUSIONS: Motoneurons are still responsive to additional afferent inputs from various sources when rate modulation from voluntary drive is limited by SCI. Individuals with SCI may be able to combine inputs to control functional tasks they cannot perform with voluntary drive alone.