A single sequence of intermittent hypoxia does not alter stretch reflex excitability in able-bodied individuals.

Spasticity attributable to exaggerated stretch reflex pathways, particularly affecting the ankle plantar flexors, often impairs overground walking in persons with incomplete spinal cord injury. Compelling evidence from rodent models underscores how exposure to acute intermittent hypoxia (AIH) can provide a unique medium to induce spinal plasticity in key inhibitory pathways mediating stretch reflex excitability and potentially affect spasticity. In this study, we quantify the effects of a single exposure to AIH on the stretch reflex in able-bodied individuals. We hypothesized that a single sequence of AIH will increase the stretch reflex excitability of the soleus muscle during ramp-and-hold angular perturbations applied to the ankle joint while participants perform passive and volitionally matched contractions. Our results revealed that a single AIH exposure did not significantly change the stretch reflex excitability during both passive and active matching conditions. Furthermore, we found that able-bodied individuals increased their stretch reflex response from passive to active matching conditions after both sham and AIH exposures. Together, these findings suggest that a single AIH exposure might not engage inhibitory pathways sufficiently to alter stretch reflex responses in able-bodied persons. However, the generalizability of our present findings requires further examination during repetitive exposures to AIH along with potential reflex modulation during functional movements, such as overground walking.

A Research Protocol to Study the Priming Effects of Breathing Low Oxygen on Enhancing Training-Related Gains in Walking Function for Persons With Spinal Cord Injury: The BO2ST Trial.

Brief episodes of low oxygen breathing (therapeutic acute intermittent hypoxia; tAIH) may serve as an effective plasticity-promoting primer to enhance the effects of transcutaneous spinal stimulation-enhanced walking therapy (WALKtSTIM) in persons with chronic (>1 year) spinal cord injury (SCI). Pre-clinical studies in rodents with SCI show that tAIH and WALKtSTIM therapies harness complementary mechanisms of plasticity to maximize walking recovery. Here, we present a multi-site clinical trial protocol designed to examine the influence of tAIH + WALKtSTIM on walking recovery in persons with chronic SCI. We hypothesize that daily (eight sessions, 2 weeks) tAIH + WALKtSTIM will elicit faster, more persistent improvements in walking recovery than either treatment alone. To test our hypothesis, we are conducting a placebo-controlled clinical trial on 60 SCI participants who randomly receive one of three interventions: tAIH + WALKtSTIM; Placebo + WALKtSTIM; and tAIH + WALKtSHAM. Participants receive daily tAIH (fifteen 90-sec episodes at 10% O2 with 60-sec intervals at 21% O2) or daily placebo (fifteen 90-sec episodes at 21% O2 with 60-sec intervals at 21% O2) before a 45-min session of WALKtSTIM or WALKtSHAM. Our primary outcome measures assess walking speed (10-Meter Walk Test), endurance (6-Minute Walk Test), and balance (Timed Up and Go Test). For safety, we also measure pain levels, spasticity, sleep behavior, cognition, and rates of systemic hypertension and autonomic dysreflexia. Assessments occur before, during, and after sessions, as well as at 1, 4, and 8 weeks post-intervention. Results from this study extend our understanding of the functional benefits of tAIH priming by investigating its capacity to boost the neuromodulatory effects of transcutaneous spinal stimulation on restoring walking after SCI. Given that there is no known cure for SCI and no single treatment is sufficient to overcome walking deficits, there is a critical need for combinatorial treatments that accelerate and anchor walking gains in persons with lifelong SCI. Trial Registration: ClinicalTrials.gov, NCT05563103.

A Wearable Mixed Reality Platform to Augment Overground Walking: A Feasibility Study.

Humans routinely modify their walking speed to adapt to functional goals and physical demands. However, damage to the central nervous system (CNS) often results in abnormal modulation of walking speed and increased risk of falls. There is considerable interest in treatment modalities that can provide safe and salient training opportunities, feedback about walking performance, and that may augment less reliable sensory feedback within the CNS after injury or disease. Fully immersive virtual reality technologies show benefits in boosting training-related gains in walking performance; however, they lack views of the real world that may limit functional carryover. Augmented reality and mixed reality head-mount displays (MR-HMD) provide partially immersive environments to extend the virtual reality benefits of interacting with virtual objects but within an unobstructed view of the real world. Despite this potential advantage, the feasibility of using MR-HMD visual feedback to promote goal-directed changes in overground walking speed remains unclear. Thus, we developed and evaluated a novel mixed reality application using the Microsoft HoloLens MR-HMD that provided real-time walking speed targets and augmented visual feedback during overground walking. We tested the application in a group of adults not living with disability and examined if they could use the targets and visual feedback to walk at 85%, 100%, and 115% of each individual's self-selected speed. We examined whether individuals were able to meet each target gait speed and explored differences in accuracy across repeated trials and at the different speeds. Additionally, given the importance of task-specificity to therapeutic interventions, we examined if walking speed adjustment strategies were consistent with those observed during usual overground walking, and if walking with the MR-HMD resulted in increased variability in gait parameters. Overall, participants matched their overground walking speed to the target speed of the MR-HMD visual feedback conditions (all p-values > 0.05). The percent inaccuracy was approximately 5% across all speed matching conditions and remained consistent across walking trials after the first overall walking trial. Walking with the MR-HMD did not result in more variability in walking speed, however, we observed more variability in stride length and time when walking with feedback from the MR-HMD compared to walking without feedback. The findings offer support for mixed reality-based visual feedback as a method to provoke goal-specific changes in overground walking behavior. Further studies are necessary to determine the clinical safety and efficacy of this MR-HMD technology to provide extrinsic sensory feedback in combination with traditional treatments in rehabilitation.

Caffeine Enhances Intermittent Hypoxia-Induced Gains in Walking Function for People with Chronic Spinal Cord Injury.

Incomplete spinal cord injury (iSCI) often results in lifelong walking impairments that limit functional independence. Thus, treatments that trigger enduring improvement in walking after iSCI are in high demand. Breathing brief episodes of low oxygen (i.e., acute intermittent hypoxia, AIH) enhances breathing and walking function in rodents and humans with chronic iSCI. Pre-clinical studies found that AIH also causes the accumulation of extracellular adenosine that undermines AIH-induced functional plasticity. Pharmacologically blocking adenosine A2a receptors (A2aR) prior to AIH resulted in a dramatic improvement in motor facilitation in rodents with iSCI; however, a similar beneficial effect in humans is unclear. Thus, we conducted a double-blind, placebo-controlled, crossover randomized study to test the hypothesis that a non-selective A2aR antagonist (i.e., caffeine) enhances AIH-induced effects on walking function in people with chronic (≥1yr) iSCI. We enrolled 12 participants to receive daily (5 days) caffeine or placebo (4 mg/kg) 30 min before breathing 15, 1.5-min low oxygen (AIH; FIO2 = 0.10) or SHAM (FIO2 = 0.21) episodes with 1-min intervals. We quantified walking function as the change in the 10-meter walk test (speed) and 6-min walk test (endurance) relative to baseline, on Day 5 post-intervention, and on follow-up Days 12 and 19. Participants walked faster (Day 19; p < 0.001) and farther (Day 19; p = 0.012) after caffeine+AIH and the boost in speed persisted more than after placebo+AIH or caffeine+SHAM (Day 19; p < 0.05). These results support our hypothesis that a caffeine pre-treatment to AIH training shows promise as a strategy to augment walking speed in persons with chronic iSCI.

Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease.

We review progress towards greater mechanistic understanding and clinical translation of a strategy to improve respiratory and non-respiratory motor function in people with neuromuscular disorders, therapeutic acute intermittent hypoxia (tAIH). In 2016 and 2020, workshops to create and update a "road map to clinical translation" were held to help guide future research and development of tAIH to restore movement in people living with chronic, incomplete spinal cord injuries. After briefly discussing the pioneering, non-targeted basic research inspiring this novel therapeutic approach, we then summarize workshop recommendations, emphasizing critical knowledge gaps, priorities for future research effort, and steps needed to accelerate progress as we evaluate the potential of tAIH for routine clinical use. Highlighted areas include: 1) greater mechanistic understanding, particularly in non-respiratory motor systems; 2) optimization of tAIH protocols to maximize benefits; 3) identification of combinatorial treatments that amplify plasticity or remove plasticity constraints, including task-specific training; 4) identification of biomarkers for individuals most/least likely to benefit from tAIH; 5) assessment of long-term tAIH safety; and 6) development of a simple, safe and effective device to administer tAIH in clinical and home settings. Finally, we update ongoing clinical trials and recent investigations of tAIH in SCI and other clinical disorders that compromise motor function, including ALS, multiple sclerosis, and stroke.

Daily acute intermittent hypoxia combined with walking practice enhances walking performance but not intralimb motor coordination in persons with chronic incomplete spinal cord injury.

Persons living with incomplete spinal cord injuries (SCI) often struggle to regain independent walking due to deficits in walking mechanics. They often dedicate many weeks of gait training before benefits to emerge, with additional training needed for benefits to persist. Recent studies in humans with SCI found that daily bouts of breathing low oxygen (acute intermittent hypoxia, AIH) prior to locomotor training elicited persistent (weeks) improvement in overground walking speed and endurance. AIH-induced improvements in overground walking may result from changes in control strategies that also enhance intralimb coordination; however, this possibility remains untested. Here, we examined the extent to which daily AIH combined with walking practice (AIH + WALK) improved overground walking performance and intralimb motor coordination in persons with chronic, incomplete SCI. METHODS: We recruited 11 persons with chronic (> 1 year), incomplete SCI to participate in a randomized, double-blind, balanced, crossover study. Participants first received either daily (5 consecutive days) AIH (15, 90-s episodes of 10.0% O2 with 60s intervals at 20.9% O2) or SHAM (15, 90s episodes at 20.9% O2 with 60s intervals at 20.9% O2) followed by 30-min of overground walking practice. They received the second treatment after a minimum 2-week washout period. We quantified overground walking performance, in terms of speed and endurance, using the 10-Meter Walk Test (10MWT) and 6-Minute Walk Test (6MWT), respectively. We quantified intralimb motor coordination using kinematic variability measures of foot trajectory (i.e., endpoint variability, EV) and of inter-joint coupling between the hip and knee, as well as between the knee and ankle joints (i.e., angular coefficient of correspondence, ACC). We compared the changes in walking performance relative to baseline (BL) between daily AIH + WALK and daily SHAM+WALK on treatment day 5 (T5), 1-week follow-up (F1), and 2-weeks follow-up (F2). We also compared these changes between participants who used bilateral walking aids (N = 5) and those who did not. To assess the effects of daily AIH + WALK on intralimb coordination, we compared potential treatment-induced changes in EV and ACC relative to BL at F1 and F2. RESULTS: Participants improved overground walking performance (speed and endurance) after daily AIH + WALK, but not SHAM+WALK. Following daily AIH + WALK, participants decreased their 10MWT time at T5 by 28% (95% CI 0.2-10.1 s, p = 0.04), F1 by 28% (95% CI 1.1-13.5 s, p = 0.01), and F2 by 27% (95% CI 1.4-13.9 s, p = 0.01) relative to BL. The greatest decreases in the 10MWT occurred in participants who used bilateral walking aids (p < 0.05). We also found daily AIH + WALK resulted in an increase in 6MWT distance at T5 by 22% (95% CI 13.3-72.6 m, p = 0.001), F1 by 21% (95% CI 13.1-72.5 m, p = 0.001), and F2 by 16% (95% CI 2.9-62.2 m, p = 0.02). However, measures of EV and ACC during self-selected walking conditions did not change following daily AIH + WALK (all p-values >0.50). CONCLUSIONS: Consistent with prior studies, daily AIH + WALK triggered improvements in walking speed and endurance that persisted for weeks after treatment. Greatest improvements in speed occurred in participants who used bilateral walking aids. No change in EV and ACC may suggest that intralimb motor coordination was not a significant gait training priority during daily AIH + WALK.

Acute intermittent hypoxia boosts spinal plasticity in humans with tetraplegia.

Paired corticospinal-motoneuronal stimulation (PCMS) elicits spinal synaptic plasticity in humans with chronic incomplete cervical spinal cord injury (SCI). Here, we examined whether PCMS-induced plasticity could be potentiated by acute intermittent hypoxia (AIH), a treatment also known to induce spinal synaptic plasticity in humans with chronic incomplete cervical SCI. During PCMS, we used 180 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation over the hand representation of the primary motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the first dorsal interosseous (FDI) muscle ~1-2 ms before the arrival of antidromic potentials elicited in motoneurons by electrical stimulation of the ulnar nerve. During AIH, participants were exposed to brief alternating episodes of hypoxic inspired gas (1 min episodes of 9% O2) and room air (1 min episodes of 20.9% O2). We examined corticospinal function by measuring motor evoked potentials (MEPs) elicited by cortical and subcortical stimulation of corticospinal axons and voluntary motor output in the FDI muscle before and after 30 min of PCMS combined with AIH (PCMS+AIH) or sham AIH (PCMS+sham-AIH). The amplitude of MEPs evoked by magnetic and electrical stimulation increased after both protocols, but most after PCMS+AIH, consistent with the hypothesis that their combined effects arise from spinal plasticity. Both protocols increased electromyographic activity in the FDI muscle to a similar extent. Thus, PCMS effects on spinal synapses of hand motoneurons can be potentiated by AIH. The possibility of different thresholds for physiological vs behavioral gains needs to be considered during combinatorial treatments.

Daily acute intermittent hypoxia to improve walking function in persons with subacute spinal cord injury: a randomized clinical trial study protocol.

BACKGROUND: Restoring community walking remains a highly valued goal for persons recovering from traumatic incomplete spinal cord injury (SCI). Recently, studies report that brief episodes of low-oxygen breathing (acute intermittent hypoxia, AIH) may serve as an effective plasticity-inducing primer that enhances the effects of walking therapy in persons with chronic (> 1 year) SCI. More persistent walking recovery may occur following repetitive (weeks) AIH treatment involving persons with more acute SCI, but this possibility remains unknown. Here we present our clinical trial protocol, designed to examine the distinct influences of repetitive AIH, with and without walking practice, on walking recovery in persons with sub-acute SCI (< 12 months) SCI. Our overarching hypothesis is that daily exposure (10 sessions, 2 weeks) to AIH will enhance walking recovery in ambulatory and non-ambulatory persons with subacute (< 12 months) SCI, presumably by harnessing endogenous mechanisms of plasticity that occur soon after injury. METHODS: To test our hypothesis, we are conducting a randomized, placebo-controlled clinical trial on 85 study participants who we stratify into two groups according to walking ability; those unable to walk (non-ambulatory group) and those able to walk (ambulatory group). The non-ambulatory group receives either daily AIH (15, 90s episodes at 10.0% O2 with 60s intervals at 20.9% O2) or daily SHAM (15, 90s episodes at 20.9% O2 with 60s intervals at 20.9% O2) intervention. The ambulatory group receives either 60-min walking practice (WALK), daily AIH + WALK, or daily SHAM+WALK intervention. Our primary outcome measures assess overground walking speed (10-Meter Walk Test), endurance (6-Minute Walk Test), and balance (Timed Up & Go Test). For safety, we also measure levels of pain, spasticity, systemic hypertension, and autonomic dysreflexia. We record outcome measures at baseline, days 5 and 10, and follow-ups at 1 week, 1 month, 6 months, and 12 months post-treatment. DISCUSSION: The goal of this clinical trial is to reveal the extent to which daily AIH, alone or in combination with task-specific walking practice, safely promotes persistent recovery of walking in persons with traumatic, subacute SCI. Outcomes from this study may provide new insight into ways to enhance walking recovery in persons with SCI. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02632422 . Registered 16 December 2015.

Acute intermittent hypoxia as a potential adjuvant to improve walking following spinal cord injury: evidence, challenges, and future directions.

PURPOSE OF REVIEW: The reacquisition and preservation of walking ability are highly valued goals in spinal cord injury (SCI) rehabilitation. Recurrent episodes of breathing low oxygen (i.e., acute intermittent hypoxia, AIH) is a potential therapy to promote walking recovery after incomplete SCI via endogenous mechanisms of neuroplasticity. Here, we report on the progress of AIH, alone or paired with other treatments, on walking recovery in persons with incomplete SCI. We evaluate the evidence of AIH as a therapy ready for clinical and home use and the real and perceived challenges that may interfere with this possibility. RECENT FINDINGS: Repetitive AIH is a safe and an efficacious treatment to enhance strength, walking speed and endurance, as well as, dynamic balance in persons with chronic, incomplete SCI. SUMMARY: The potential for AIH as a treatment for SCI remains high, but further research is necessary to understand treatment targets and effectiveness in a large cohort of persons with SCI.

Differential deficits in spatial and temporal interlimb coordination during walking in persons with incomplete spinal cord injury.

BACKGROUND: Returning to community walking remains a major challenge for persons with incomplete spinal cord injury (iSCI) due, in part, to impaired interlimb coordination. Here, we examined spatial and temporal features of interlimb coordination during walking and their associations to gait deficits in persons with chronic iSCI. RESEARCH QUESTION: Do deficits in spatial and temporal interlimb coordination correspond differentially to clinical indicators of walking performance in persons with iSCI? METHODS: Sixteen persons with chronic iSCI and eleven able-bodied individuals participated in this study. Participants walked at self-selected gait speeds along an instrumented walkway that recorded left and right step lengths and times. We quantified interlimb coordination in terms of normalized differences between left and right step lengths (spatial asymmetry index) and step times (temporal asymmetry index), as well as, gap and phase coordination indices. We then assessed the extent to which these indices independently associated with clinical measures of walking performance. RESULTS: Participants with iSCI demonstrated greater spatial and temporal asymmetry, as well as, reduced gap and phase interlimb coordination as compared to age-matched controls (p < 0.001). We found no linear relationships between spatial and temporal asymmetry indices (p > 0.05) or between gap and phase coordination indices (p > 0.05). Spatial and temporal asymmetry indices weakly correlated with SCI-FAI composite scores (r2 = 0.26; p = 0.04). However, only spatial asymmetry indices strongly correlated with slower walking speed (r2 = 0.51; p < 0.002). We also found participants who used a hand-held assistive device (walker) demonstrated great spatial asymmetry as compared to those who did not (p < 0.03). SIGNIFICANCE: Differential impairments in spatial and temporal interlimb coordination correspond to overground walking deficits in persons with chronic iSCI. Spatial asymmetry associated with decreased walking speed and increased reliance on hand-held assistive devices. Gait training methods that target well-defined space and time domains of interlimb coordination may enhance overground gait training in persons with iSCI.

A Forward Move: Interfacing Biotechnology and Physical Therapy In and Out of the Classroom.

Ongoing advances and discoveries in biotechnology will require physical therapists to stay informed and contribute to their development and implementation. The extent of our profession's involvement in how physical therapists engage biotechnology is determined by us. In this Perspective article, we advocate the need for our profession to educate clinicians alongside scientists, technologists, and engineers and empower them to collectively think more as codevelopers and less as "siloed" builders and consumers of biotechnology. In particular, we highlight the value of augmenting the physical therapy curricula to provide students with new levels of knowledge about the converging fields of engineering and physical therapy. We present successful examples of how such a concept can occur within physical therapist professional education programs and propose strategies to overcome perceived challenges that may stymie this possibility.

Variability of Leg Kinematics during Overground Walking in Persons with Chronic Incomplete Spinal Cord Injury.

Incomplete spinal cord injury (iSCI) often leads to partial disruption of spinal pathways that are important for motor control of walking. Persons with iSCI present with deficits in walking ability in part because of inconsistent leg kinematics during stepping. Although kinematic variability is important for normal walking, growing evidence indicates that excessive variability may limit walking ability and increase reliance on assistive devices (AD) after iSCI. The purpose of this study was to assess the effects of iSCI-induced impairments on kinematic variability during overground walking. We hypothesized that iSCI results in greater variability of foot and joint displacement during overground walking compared with controls. We further hypothesized that variability is larger in persons with limited walking speed and greater reliance on ADs. To test these hypotheses, iSCI and control subjects walked overground. Kinematic variability was quantified as step-to-step foot placement variability (end-point), and variability in hip-knee, hip-ankle, and knee-ankle joint space (angular coefficient of correspondence [ACC]). We characterized sensitivity of kinematic variability to cadence, auditory cue, and AD. Supporting our hypothesis, persons with iSCI exhibited greater kinematic variability than controls, which scaled with deficits in overground walking speed (p < 0.01). Significant correlation between ACC and end-point variability, and with walking speed, indicates that both are markers of walking performance. Moreover, hip-knee and hip-ankle ACC discriminated AD use, indicating that ACC may capture AD-specific control strategies. We conclude that increased variability of foot and joint displacement are indicative of motor impairment severity and may serve as therapeutic targets to restore walking after iSCI.

Constraints on Stance-Phase Force Production during Overground Walking in Persons with Chronic Incomplete Spinal Cord Injury.

Persons with incomplete spinal cord injury (iSCI) face ongoing struggles with walking, including reduced speed and increased reliance on assistive devices (ADs). The forces underlying body weight support and gait, as measured by ground reaction forces (GRFs), are likely altered after iSCI because of weakness and AD dependence but have not been studied. The purpose of this study was to examine GRF production during overground walking after iSCI, because greater insight into GRF constraints is important for refining therapeutic interventions. Because of reduced and discoordinated motor output after iSCI, we hypothesized that persons with iSCI would exert smaller GRFs and altered GRF modifications to increased cadence compared with able-bodied (AB) persons, especially when using an AD. Fifteen persons with chronic iSCI, stratified into no AD (n = 7) and AD (n = 8) groups, walked across an instrumented walkway at self-selected and fast (115% self-selected) cadences. Fifteen age-matched AB controls walked at their own cadences and iSCI-matched conditions (cadence and AD). Results showed fore-aft GRFs are reduced in persons with iSCI compared with AB controls, with reductions greatest in persons dependent on an AD. When controlling for cadence and AD, propulsive forces were still lower in persons with iSCI. Compared with AB controls, persons with iSCI demonstrated altered GRF modifications to increased cadence. Persons with iSCI exhibit different stance-phase forces compared with AB controls, which are impacted further by AD use and slower walking speed. Minimizing AD use and/or providing propulsive biofeedback during walking could enhance GRF production after iSCI.

Effects of acute intermittent hypoxia on hand use after spinal cord trauma: A preliminary study.

OBJECTIVE: To test the hypothesis that daily acute intermittent hypoxia (AIH) combined with hand opening practice improves hand dexterity, function, and maximum hand opening in persons with chronic, motor-incomplete, cervical spinal cord injury. METHODS: Six participants completed the double-blind, crossover study. Participants received daily (5 consecutive days) AIH (15 episodes per day: 1.5 minutes of fraction of inspired oxygen [FIo2] = 0.09, 1-minute normoxic intervals) followed by 20 repetitions of hand opening practice and normoxia (sham, FIo2 = 0.21) + hand opening practice. Hand dexterity and function were quantified with Box and Block and Jebsen-Taylor hand function tests. We also recorded maximum hand opening using motion analyses and coactivity of extensor digitorum and flexor digitorum superficialis muscles using surface EMG. RESULTS: Daily AIH + hand opening practice improved hand dexterity, function, and maximum hand opening in all participants. AIH + hand opening practice improved Box and Block Test scores vs baseline in 5 participants (p = 0.057) and vs sham + hand opening practice in all 6 participants (p = 0.016). All participants reduced Jebsen-Taylor Hand Function Test (JTHF) time after daily AIH + hand opening practice (-7.2 ± 1.4 seconds) vs baseline; 4 of 6 reduced JTHF time vs sham + hand opening practice (p = 0.078). AIH + hand opening practice improved maximum hand aperture in 5 of 6 participants (8.1 ± 2.7 mm) vs baseline (p = 0.018) and sham + hand opening practice (p = 0.030). In 5 participants, daily AIH-induced changes in hand opening were accompanied by improved EMG coactivity (p = 0.029). CONCLUSIONS: This report suggests the need for further study of AIH as a plasticity "primer" for task-specific training in spinal cord injury rehabilitation. Important clinical questions remain concerning optimal AIH dosage, patient screening, safety, and effect persistence. CLINICALTRIALSGOV IDENTIFIER: NCT01272336.

Neural Stem Cell Therapy and Rehabilitation in the Central Nervous System: Emerging Partnerships.

The goal of regenerative medicine is to restore function through therapy at levels such as the gene, cell, tissue, or organ. For many disorders, however, regenerative medicine approaches in isolation may not be optimally effective. Rehabilitation is a promising adjunct therapy given the beneficial impact that physical activity and other training modalities can offer. Accordingly, "regenerative rehabilitation" is an emerging concentration of study, with the specific goal of improving positive functional outcomes by enhancing tissue restoration following injury. This article focuses on one emerging example of regenerative rehabilitation-namely, the integration of clinically based protocols with stem cell technologies following central nervous system injury. For the purposes of this review, the state of stem cell technologies for the central nervous system is summarized, and a rationale for a synergistic benefit of carefully orchestrated rehabilitation protocols in conjunction with cellular therapies is provided. An overview of practical steps to increase the involvement of physical therapy in regenerative rehabilitation research also is provided.

Neuromechanical principles underlying movement modularity and their implications for rehabilitation.

Neuromechanical principles define the properties and problems that shape neural solutions for movement. Although the theoretical and experimental evidence is debated, we present arguments for consistent structures in motor patterns, i.e., motor modules, that are neuromechanical solutions for movement particular to an individual and shaped by evolutionary, developmental, and learning processes. As a consequence, motor modules may be useful in assessing sensorimotor deficits specific to an individual and define targets for the rational development of novel rehabilitation therapies that enhance neural plasticity and sculpt motor recovery. We propose that motor module organization is disrupted and may be improved by therapy in spinal cord injury, stroke, and Parkinson's disease. Recent studies provide insights into the yet-unknown underlying neural mechanisms of motor modules, motor impairment, and motor learning and may lead to better understanding of the causal nature of modularity and its underlying neural substrates.

Modulation of hand aperture during reaching in persons with incomplete cervical spinal cord injury.

The intact neuromotor system prepares for object grasp by first opening the hand to an aperture that is scaled according to object size and then closing the hand around the object. After cervical spinal cord injury (SCI), hand function is significantly impaired, but the degree to which object-specific hand aperture scaling is affected remains unknown. Here, we hypothesized that persons with incomplete cervical SCI have a reduced maximum hand opening capacity but exhibit novel neuromuscular coordination strategies that permit object-specific hand aperture scaling during reaching. To test this hypothesis, we measured hand kinematics and surface electromyography from seven muscles of the hand and wrist during attempts at maximum hand opening as well as reaching for four balls of different diameters. Our results showed that persons with SCI exhibited significantly reduced maximum hand aperture compared to able-bodied (AB) controls. However, persons with SCI preserved the ability to scale peak hand aperture with ball size during reaching. Persons with SCI also used distinct muscle coordination patterns that included increased co-activity of flexors and extensors at the wrist and hand compared to AB controls. These results suggest that motor planning for aperture modulation is preserved even though execution is limited by constraints on hand opening capacity and altered muscle co-activity. Thus, persons with incomplete cervical SCI may benefit from rehabilitation aimed at increasing hand opening capacity and reducing flexor-extensor co-activity at the wrist and hand.

Neuromuscular constraints on muscle coordination during overground walking in persons with chronic incomplete spinal cord injury.

OBJECTIVE: Incomplete spinal cord injury (iSCI) disrupts motor control and limits the ability to coordinate muscles for overground walking. Inappropriate muscle activity has been proposed as a source of clinically observed walking deficits after iSCI. We hypothesized that persons with iSCI exhibit lower locomotor complexity compared to able-body (AB) controls as reflected by fewer motor modules, as well as, altered module composition and activation. METHODS: Eight persons with iSCI and eight age-matched AB controls walked overground at prescribed cadences. Electromyograms of fourteen single leg muscles were recorded. Non-negative matrix factorization was used to identify the composition and activation of motor modules, which represent groups of consistently co-activated muscles that accounted for 90% of variability in muscle activity. RESULTS: Motor module number, composition, and activation were significantly altered in persons with iSCI as compared to AB controls during overground walking at self-selected cadences. However, there was no significant difference in module number between persons with iSCI and AB controls when cadence and assistive device were matched. CONCLUSIONS: Muscle coordination during overground walking is impaired after chronic iSCI. SIGNIFICANCE: Our results are indicative of neuromuscular constraints on muscle coordination after iSCI. Altered muscle coordination contributes to person-specific gait deficits during overground walking.