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.

Enhanced motor learning and motor savings after acute intermittent hypoxia are associated with a reduction in metabolic cost.

Breathing mild bouts of low oxygen air (i.e. acute intermittent hypoxia, AIH) has been shown to improve locomotor function in humans after a spinal cord injury. How AIH-induced gains in motor performance are achieved remains unclear. We examined the hypothesis that AIH augments motor learning and motor retention during a locomotor adaptation task. We further hypothesized that gains in motor learning and retention will be associated with reductions in net metabolic power, consistent with the acquisition of energetically favourable mechanics. Thirty healthy individuals were randomly allocated into either a control group or an AIH group. We utilized a split-belt treadmill to characterize adaptations to an unexpected belt speed perturbation of equal magnitude during an initial exposure and a second exposure. Adaptation was characterized by changes in spatiotemporal step asymmetry, anterior-posterior force asymmetry, and net metabolic power. While both groups adapted by reducing spatial asymmetry, only the AIH group achieved significant reductions in double support time asymmetry and propulsive force asymmetry during both the initial and the second exposures to the belt speed perturbation. Net metabolic power was also significantly lower in the AIH group, with significant reductions from the initial perturbation exposure to the second. These results provide the first evidence that AIH mediates improvements in both motor learning and retention. Further, our results suggest that reductions in net metabolic power continue to be optimized upon subsequent learning and are driven by more energetically favourable temporal coordination strategies. Our observation that AIH facilitates motor learning and retention can be leveraged to design rehabilitation interventions that promote functional recovery. KEY POINTS: Brief exposures to low oxygen air, known as acute intermittent hypoxia (AIH), improves locomotor function in humans after a spinal cord injury, but it remains unclear how gains in motor performance are achieved. In this study, we tested the hypothesis that AIH induces enhancements in motor learning and retention by quantifying changes in interlimb coordination, anterior-posterior force symmetry and metabolic cost during a locomotor adaptation task. We show the first evidence that AIH improves both motor learning and savings of newly learned temporal interlimb coordination strategies and force asymmetry compared to untreated individuals. We further demonstrate that AIH elicits greater reductions in metabolic cost during motor learning that continues to be optimized upon subsequent learning. Our findings suggest that AIH-induced gains in locomotor performance are facilitated by enhancements in motor learning and retention of more energetically favourable coordination strategies.

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.

Targeted Neuromodulation of Abnormal Interhemispheric Connectivity to Promote Neural Plasticity and Recovery of Arm Function after Stroke: A Randomized Crossover Clinical Trial Study Protocol.

Background: Despite intensive rehabilitation efforts, most stroke survivors have persistent functional disability of the paretic arm and hand. These motor impairments may be due in part to maladaptive changes in structural and functional connections between brain regions. The following early stage clinical trial study protocol describes a noninvasive brain stimulation approach to target transcallosally mediated interhemispheric connections between the ipsi- and contralesional motor cortices (iM1 and cM1) using corticocortical paired associative stimulation (ihPAS). This clinical trial aims to characterize ihPAS-induced modulation of interhemispheric connectivity and the effect on motor skill performance and learning in chronic stroke survivors. Methods/Design: A repeated-measures, cross-over design study will recruit 20 individuals post-stroke with chronic mild-moderate paretic arm impairment. Each participant will complete an active ihPAS and control ihPAS session. Assessments of cortical excitability and motor skill performance will be conducted prior to and at four time points following the ihPAS intervention. The primary outcome measures will be: TMS-evoked interhemispheric motor connectivity, corticomotor excitability, and response time on a modified serial reaction time task. Discussion/Conclusion: The findings from this single-site early stage clinical trial will provide foundational results to inform the design of larger-scale, multisite clinical trials to evaluate the therapeutic potential of ihPAS-based neuromodulation for upper limb recovery after stroke. This trial is registered with NCT02465034.

Evidence of impaired neuromuscular responses in the support leg to a destabilizing swing phase perturbation in hemiparetic gait.

The neuromuscular mechanisms that underlie post-stroke impairment in reactive balance control during gait are not fully understood. Previous research has described altered muscle activations in the paretic leg in response to postural perturbations from static positions. Additionally, attenuation of interlimb reflexes after stroke has been reported. Our goal was to characterize post-stroke changes to neuromuscular responses in the stance leg following a swing phase perturbation during gait. We hypothesized that, following a trip, altered timing, sequence, and magnitudes of perturbation-induced activations would emerge in the paretic and nonparetic support legs of stroke survivors compared to healthy control subjects. The swing foot was interrupted, while subjects walked on a treadmill. In healthy subjects, a sequence of perturbation-induced activations emerged in the contralateral stance leg with mean onset latencies of 87-147 ms. The earliest latencies occurred in the hamstrings and hip abductor and adductors. The hamstrings, the adductor magnus, and the gastrocnemius dominated the relative balance of perturbation-induced activations. The sequence and balance of activations were largely preserved after stroke. However, onset latencies were significantly delayed across most muscles in both paretic and nonparetic stance legs. The shortest latencies observed suggest the involvement of interlimb reflexes with supraspinal pathways. The preservation of the sequence and balance of activations may point to a centrally programmed postural response that is preserved after stroke, while post-stroke delays may suggest longer transmission times for interlimb reflexes.

Intermittent Hypoxia-Induced Enhancements in Corticospinal Excitability Predict Gains in Motor Learning and Metabolic Efficiency.

Acute intermittent hypoxia (AIH) enhances human motor function after incomplete spinal cord injury. Although the underlying mechanisms in humans are unknown, emerging evidence indicates that AIH facilitates corticospinal excitability to the upper limb. However, the functional relevance of this plasticity remains unexplored, and it is unclear whether similar plasticity can be induced for lower limb motor areas. We recently demonstrated that AIH improves motor learning and metabolic efficiency during split-belt walking. Thus, we hypothesized that AIH increases lower limb excitability and that these enhancements would predict the magnitude of motor learning and the corresponding reductions in net metabolic power. We assessed tibialis anterior (TA) excitability using transcranial magnetic stimulation and quantified changes in spatiotemporal asymmetries and net metabolic power in response to split-belt speed perturbations. We show that AIH enhances TA excitability, and that the magnitude of this facilitation positively correlates with greater spatiotemporal adaptation. Notably, we demonstrate a novel association between increased excitability and reduced net metabolic power during motor learning and savings. Together, our results suggest that AIH-induced gains in excitability predict both the magnitude of motor learning and the associated metabolic efficiency. Determining indices of AIH-induced improvements in motor performance is critical for optimizing its therapeutic reach.

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.

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.

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.

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.

Contralesional Hemisphere Regulation of Transcranial Magnetic Stimulation-Induced Kinetic Coupling in the Poststroke Lower Limb.

BACKGROUND: The neural constraints underlying hemiparetic gait dysfunction are associated with abnormal kinetic outflow and altered muscle synergy structure. Recent evidence from our lab implicates the lesioned hemisphere in mediating the expression of abnormally coupled hip adduction and knee extension synergy, suggesting a role of cortical networks in the regulation of lower limb motor outflow poststroke. The potential contribution of contralesional hemisphere (CON-H) in regulating paretic leg kinetics is unknown. The purpose of this study is to characterize the effect of CON-H activation on aberrant across-joint kinetic coupling of the ipsilateral lower-extremity muscles poststroke. METHODS: Amplitude-matched adductor longus motor-evoked potentials were elicited using single pulse transcranial magnetic stimulation (TMS) of the lesioned (L-H) and CON-Hs during an isometric adductor torque matching task from 11 stroke participants. For 10 control participants, TMS of the contralateral and ipsilateral hemisphere were given during the same task. TMS-induced torques were characterized at the hip and knee joints to determine the differential regulation of abnormal kinetic synergies by each motor cortices. The TMS-induced ratio of knee extension/hip adduction torques was quantified during 40 and 20% of maximum adduction torque. FINDINGS: For both the 40 and 20% target adduction tasks, we find that contralesional stimulation significantly reduced but did not eliminate the TMS-induced ratio of knee extension/hip adduction torques for the stroke group (p = 0.0468, p = 0.0396). In contrast, the controls did not present a significantly different TMS-evoked torque following stimulation (p = 0.923) of the hemisphere ipsilateral to the test leg. INTERPRETATION: The reduced expression of abnormal across-joint kinetic coupling suggests that the CON-H may contribute an adaptive role in lower limb control poststroke. Future study of neuromodulation paradigms that leverage adaptive CON-H activation may yield clinically relevant gains in lower limb motor function poststroke.

Downregulating Aberrant Motor Evoked Potential Synergies of the Lower Extremity Post Stroke During TMS of the Contralesional Hemisphere.

BACKGROUND: Growing evidence demonstrates unique synergistic signatures in the lower limb (LL) post-stroke, with specific across-plane and across-joint representations. While the inhibitory role of the ipsilateral hemisphere in the upper limb (UL) has been widely reported, examination of the contralesional hemisphere (CON-H) in modulating LL expressions of synergies following stroke is lacking. OBJECTIVE: We hypothesize that stimulation of lesioned and contralesional motor cortices will differentially regulate paretic LL motor outflow. We propose a novel TMS paradigm to identify synergistic motor evoked potential (MEP) patterns across multiple muscles. METHODS: Amplitude and background activation matched adductor MEPs were elicited using single pulse TMS of L-H and CON-H (control ipsilateral) during an adductor torque matching task from 11 stroke and 10 control participants. Associated MEPs of key synergistic muscles were simultaneously observed. RESULTS: By quantifying CON-H/L-H MEP ratios, we characterized a significant targeted inhibition of aberrant MEP coupling between ADD and VM (p = 0.0078) and VL (p = 0.047) exclusive to the stroke group (p = 0.028) that was muscle dependent (p = 0.039). We find TA inhibition in both groups following ipsilateral hemisphere stimulation (p = 0.0014; p = 0.015). CONCLUSION: We argue that ipsilaterally mediated attenuation of abnormal synergistic activations post stroke may reflect an adaptive intracortical inhibition. The predominance of sub 3ms interhemispheric MEP latency differences implicates LL ipsilateral corticomotor projections. These findings provide insight into the association between CON-H reorganization and post-stroke LL recovery. While a prevailing view of driving L-H disinhibition for UL recovery seems expedient, presuming analogous LL neuromodulation may require further examination for rehabilitation. This study provides a step toward this goal.

Tuning of robotic therapy controllers for stroke gait: Using isometrically constrained EMG modular structures.

The development of EMG based controllers for automated gait orthosis is a promising intervention for post-stroke gait rehabilitation and assistive device applications. However, the integration of stroke specific modular neuromuscular patterns for the design of active gait assistance controller is largely unexplored. To this end, this work presents preliminary evidence of the associated variability between lower limb muscle activation patterns underlying discrete isometric control objectives and the analogous dynamic subtask during treadmill gait using matrix factorization algorithms. We find that common muscle coordination patterns underlying both isometric and dynamic gait submovements can be used to reconstruct relevant spatio-temporal patterns for healthy locomotion. We propose that synergies extracted isometrically may be sufficient to tune adaptive controller assistance for disruptive linkages in the EMG control signal to impact gait dysfunction.

Evaluation of lower limb cross planar kinetic connectivity signatures post-stroke.

Following stroke, aberrant three dimensional multijoint gait impairments emerge that present in kinematic asymmetries such as circumduction. A precise pattern of cross-planar coordination may underlie abnormal hemiparetic gait as several studies have underscored distinctive neural couplings between medio-lateral control and sagittal plane progression during walking. Here we investigate potential neuromechanical constraints governing abnormal multijoint coordination post-stroke. 15 chronic monohemispheric stroke patients and 10 healthy subjects were recruited. Coupled torque production patterns were assessed using a volitional isometric torque generation task where subjects matched torque targets for a primary joint in 4 directions while receiving visual feedback of the magnitude and direction of the torque. Secondary torques at other lower limb joints were recorded without subject feedback. We find that common features of cross-planar connectivity in stroke subjects include statistically significant frontal to sagittal plane kinetic coupling that overlay a common sagittal plane coupling in healthy subjects. Such coupling is independent of proximal or distal joint control and limb biomechanics. Principal component analysis of the stroke aggregate kinetic signature reveals unique abnormal frontal plane coupling features that explain a larger percentage of the total torque coupling variance. This study supports the idea that coupled cross-planar kinetic outflow between the lower limb joints uniquely emerges during pathological control of frontal plane degrees of freedom resulting in a generalized extension of the limb. It remains to be seen if a pattern of lower limb motor outflow that is centrally mediated contributes to abnormal hemiparetic gait.