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.

Acute intermittent hypoxia enhances strength, and modulates spatial distribution of muscle activation in persons with chronic incomplete spinal cord injury.

Acute intermittent hypoxia (AIH) is an emerging technique for facilitating neural plasticity in individuals with chronic incomplete spinal cord injury (iSCI). A single sequence of AIH enhances hand grip strength and ankle plantarflexion torque, but underlying mechanisms are not yet clear. We sought to examine how AIH-induced changes in magnitude and spatial distribution of the electromyogram (EMG) of the biceps and triceps brachii contributes to improved strength. Seven individuals with iSCI visited the laboratory on two occasions, and received either AIH or Sham AIH intervention in a randomized order. AIH consisted of 15 brief (∼60s) periods of low oxygen (fraction of inspired O2 = 0.09) alternating with 60s of normoxia, whereas Sham AIH consisted of repeated exposures to normoxic air. High-density surface EMG of biceps and triceps brachii was recorded during maximal elbow flexion and extension. We then generated spatial maps which distinguished active muscle regions prior to and 60 min after AIH or Sham AIH. After an AIH sequence, elbow flexion and extension forces increased by 91.7 ± 88.4% and 51.7 ± 57.8% from baseline, respectively, whereas there was no difference after Sham AIH. Changes in strength were associated with an altered spatial distribution of EMG and increased root mean squared EMG amplitude in both biceps and triceps brachii muscles. These data suggest that altered motor unit activation profiles may underlie improved volitional strength after a single dose of AIH and warrant further investigation using single motor unit analysis techniques to further elucidate mechanisms of AIH-induced plasticity.

Anodal transcutaneous DC stimulation enhances learning of dynamic balance control during walking in humans with spinal cord injury.

Deficits in locomotor function, including impairments in walking speed and balance, are major problems for many individuals with incomplete spinal cord injury (iSCI). However, it remains unclear which type of training paradigms are more effective in improving balance, particularly dynamic balance, in individuals with iSCI. The purpose of this study was to determine whether anodal transcutaneous spinal direct current stimulation (tsDCS) can facilitate learning of balance control during walking in individuals with iSCI. Fifteen individuals with iSCI participated in this study and were tested in two sessions (i.e., tsDCS and sham conditions). Each session consisted of 1 min of treadmill walking without stimulation or perturbation (baseline), 10 min of walking with either anodal tsDCS or sham stimulation, paired with bilateral pelvis perturbation (adaptation), and finally 2 min of walking without stimulation and perturbation (post-adaptation). The outcome measures were the dynamic balance, assessed using the minimal margin of stability (MoS), and electromyography of leg muscles. Participants demonstrated a smaller MoS during the late adaptation period for the anodal tsDCS condition compared to sham (p = 0.041), and this MoS intended to retain during the early post-adaptation period (p = 0.05). In addition, muscle activity of hip abductors was greater for the anodal tsDCS condition compared to sham during the late adaptation period and post-adaptation period (p < 0.05). Results from this study suggest that anodal tsDCS may modulate motor adaptation to pelvis perturbation and facilitate learning of dynamic balance control in individuals with iSCI.

A New Definition of Poststroke Spasticity and the Interference of Spasticity With Motor Recovery From Acute to Chronic Stages.

The relationship of poststroke spasticity and motor recovery can be confusing. "True" motor recovery refers to return of motor behaviors to prestroke state with the same end-effectors and temporo-spatial pattern. This requires neural recovery and repair, and presumably occurs mainly in the acute and subacute stages. However, according to the International Classification of Functioning, Disability and Health, motor recovery after stroke is also defined as "improvement in performance of functional tasks," i.e., functional recovery, which is mainly mediated by compensatory mechanisms. Therefore, stroke survivors can execute motor tasks in spite of disordered motor control and the presence of spasticity. Spasticity interferes with execution of normal motor behaviors ("true" motor recovery), throughout the evolution of stroke from acute to chronic stages. Spasticity reduction does not affect functional recovery in the acute and subacute stages; however, appropriate management of spasticity could lead to improvement of motor function, that is, functional recovery, during the chronic stage of stroke. We assert that spasticity results from upregulation of medial cortico-reticulo-spinal pathways that are disinhibited due to damage of the motor cortex or corticobulbar pathways. Spasticity emerges as a manifestation of maladaptive plasticity in the early stages of recovery and can persist into the chronic stage. It coexists and shares similar pathophysiological processes with related motor impairments, such as abnormal force control, muscle coactivation and motor synergies, and diffuse interlimb muscle activation. Accordingly, we propose a new definition of spasticity to better account for its pathophysiology and the complex nuances of different definitions of motor recovery.

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.

Varied movement errors drive learning of dynamic balance control during walking in people with incomplete spinal cord injury: a pilot study.

The purpose of this study was to determine whether the application of a varied pelvis perturbation force would improve dynamic balance control and gait stability of people with incomplete spinal cord injury (iSCI). Fourteen participants with iSCI completed the test in two conditions, i.e., walking paired with pelvis perturbation force and treadmill walking only, with 1-week interval in between. The order of the testing condition was randomized across participants. For the pelvis pertubation condition, subjects walked on a treadmill with no force for 1 min, with a varied pelvis perturbation force that was bilaterally applied in the medial-lateral direction for 10 min, without force for 1 min, and then with the perturbation for another 10 min after a sitting break. For the treadmill only condition, a protocol that was similar to the perturbation condition was used but no force was applied. Margin of stability (MoS), weight shifting, and other spatiotemporal gait parameters were calculated. Compared to treadmill training only, participants showed significant smaller MoS and double-leg support time after treadmill walking with pelvis perturbation. In addition, participants showed significantly greater improvements in overground walking speed after treadmill walking with pelvis perturbation than treadmill only (p = 0.021). Results from this study suggest that applying a varied pelvis perturbation force during treadmill walking could improve dynamic balance control in people with iSCI, which could be transferred to overground walking. These findings may be used to develop a new intervention to improve balance and walking function in people with iSCI.

In-Vivo Study of Passive Musculotendon Mechanics in Chronic Hemispheric Stroke Survivors.

We characterized the passive mechanical properties of the affected and contralateral musculotendon units in 9 chronic stroke survivors as well as in 6 neurologically-intact controls. Using a position-controlled motor, we precisely indented the distal tendon of the biceps brachii to a 20 mm depth from skin, recording both its sagittal motion using ultrasound movies and the compression force at the tip of the indenter. Length changes of 8 equally-spaced features along the aponeurosis axis were quantified using a pixel-tracking protocol. We report that, on the aggregate and with respect to contralateral and control, respectively, the affected side initiates feature motion at a shorter indentation distance by 61% and 50%, travels further by 15% and 9%, at a lower rate of 28% and 15%, and is stiffer by 40% and 57%. In an extended analysis including the spatial location of the 8 designated features, we report that in contrast to the contralateral and control muscles, the affected musculotendon unit does not strain measurably within the imaging window. These results confirm that chronic stroke-induced spasticity changes musculotendon unit passive mechanics, causing it to not strain under stretch. The mechanisms responsible for altered passive mechanics may lie within extracellular matrix fibrosis.

Motor Adaptation to Weight Shifting Assistance Transfers to Overground Walking in People with Spinal Cord Injury.

BACKGROUND: Locomotor training has been used to improve walking function in people with incomplete spinal cord injury (iSCI), but functional gains are relatively small for some patients, which may be due to the lack of weight shifting training. OBJECTIVE: To determine whether applying a pelvis assistance force in the coronal plane during walking would improve weight shifting and stepping in people with iSCI. DESIGN: Repeated measures study. SETTING: Rehabilitation hospital. PARTICIPANTS: Seventeen people with iSCI. INTERVENTIONS: A controlled assistance force was bilaterally applied to the pelvis in the medial-lateral direction to facilitate weight shifting, which gradually increased during the course of treadmill walking. MAIN OUTCOME MEASURES: Weight shifting, step length, margin of stability, and muscle activities of the weaker leg were used to quantify gait performance. The spatial-temporal gait parameters during overground walking were collected pre, post, and 10 minutes after treadmill training. RESULTS: During treadmill walking, participants significantly improved weight shifting (ie, center of mass [CoM] lateral distance reduced from 0.16 ± 0.06 m to 0.12 ± 0.07 m, P = .012), and increased step length (from 0.35 ± 0.08 m to 0.37 ± 0.09 m, P = .037) on the stronger side when the force was applied, which were partially retained (ie, CoM distance was 0.14 ± 0.06, P = .019, and step length was 0.37 ± 0.09 m, P = .005) during the late postadaptation period when the force was removed. In addition, weight shifting and step length on the weaker side during overground walking also improved (support base reduced from 0.13 ± 0.06 m to 0.12 ± 0.06 m, P = .042, and step length increased from 0.48 ± 0.12 m to 0.51 ± 0.09 m, P = .045) after treadmill training. CONCLUSIONS: Applying pelvis assistance during treadmill walking may facilitate weight shifting and improve step length in people with SCI, which may partially transfer to overground walking. LEVEL OF EVIDENCE: III.

Re-evaluation of EMG-torque relation in chronic stroke using linear electrode array EMG recordings.

The objective was to re-evaluate the controversial reports of EMG-torque relation between impaired and non-impaired sides using linear electrode array EMG recordings. Ten subjects with chronic stroke performed a series of submaximal isometric elbow flexion tasks. A 20-channel linear array was used to record surface EMG of the biceps brachii muscles from both impaired and non-impaired sides. M-wave recordings for bilateral biceps brachii muscles were also made. Distribution of the slope of the EMG-torque relations for the individual channels showed a quasi-symmetrical "M" shaped pattern. The lowest value corresponded to the innervation zone (IZ) location. The highest value from the slope curve for each side was selected for comparison to minimize the effect of electrode placement and IZ asymmetry. The slope was greater on the impaired side in 4 of 10 subjects. There were a weak correlation between slope ratio and strength ratio and a moderate to high correlation between slope ratio and M-wave ratio between two sides. These findings suggest that the EMG-torque relations are likely mediated and influenced by multiple factors. Our findings emphasize the importance of electrode placement and suggest the primary role of peripheral adaptive changes in the EMG-torque relations in chronic stroke.

Ascending vestibular drive is asymmetrically distributed to the inferior oblique motoneuron pools in a subset of hemispheric stroke survivors.

OBJECTIVE: Aberrant vestibular nuclear function is proposed to be a principle driver of limb muscle spasticity after stroke. Although spasticity does not manifest in ocular muscles, we sought to determine whether altered cortical modulation of ascending vestibuloocular pathways post-stroke could impact the excitability of ocular motoneurons. METHODS: Nineteen chronic stroke survivors, aged 49-68 yrs. were enrolled. Vestibular evoked myogenic potentials (VEMPs) were recorded from the inferior oblique muscles of the eye using surface EMG electrodes. We assessed the impact of ascending otolith pathways on eye muscle activity and evaluated the relationship between otolith-ocular function and the severity of spasticity. RESULTS: VEMP responses were recorded bilaterally in 14/19 subjects. Response magnitude on the affected side was significantly larger than on the spared side. In a subset of subjects, there was a strong relationship between affected response amplitude and the severity of limb spasticity, as estimated using a standard clinical scale. CONCLUSIONS: This study suggests that alterations in ascending vestibular drive to ocular motoneurons contribute to post-stroke spasticity in a subset of spastic stroke subjects. We speculate this imbalance is a consequence of the unilateral disruption of inhibitory corticobulbar projections to the vestibular nuclei. SIGNIFICANCE: This study potentially sheds light on the underlying mechanisms of post-stroke spasticity.

Estimation of musculotendon kinematics under controlled tendon indentation.

The effects of tendon indentation on musculotendon unit mechanics have been left largely unexplored. Tendon indentation is however routinely used in the tendon reflex exam to diagnose the state of reflex pathways. Because muscle mechanoreceptors are sensitive to mechanical changes of the musculotendon unit, this gap in knowledge could potentially impact our understanding of these neurological exams. Accordingly, we have used ultrasound (US) imaging to compare the effects of tendon indentation with the effects angular rotation of the elbow in six neurologically intact individuals. We used sagittal ultrasound movies of the biceps brachii to compare length changes induced by each of these perturbations. Length changes were quantified using a pixel-tracking protocol. Our results show that a 20mm indentation of the distal tendon is broadly equivalent to a 15° elbow rotation. We also show that within the imaging window the strain differences between the two stretching protocols are statistically insignificant. Finally, we show that there exists a significant linear relationship between the two stretching techniques and that this relationship spans a large rotational angle to indentation depth. We have used a novel tendon probe to administer controlled tendon indentations as a way to characterize musculotendon kinematics. Using this probe, we confirm that tendon indentation can be physiologically equated with joint rotation, and can thus be used as an input for muscle stretching protocols. Furthermore, this is potentially a simpler and more practical alternative to externally imposed angular joint motion.

Interdisciplinary concepts for design and implementation of mixed reality interactive neurorehabilitation systems for stroke.

Interactive neurorehabilitation (INR) systems provide therapy that can evaluate and deliver feedback on a patient's movement computationally. There are currently many approaches to INR design and implementation, without a clear indication of which methods to utilize best. This article presents key interactive computing, motor learning, and media arts concepts utilized by an interdisciplinary group to develop adaptive, mixed reality INR systems for upper extremity therapy of patients with stroke. Two INR systems are used as examples to show how the concepts can be applied within: (1) a small-scale INR clinical study that achieved integrated improvement of movement quality and functionality through continuously supervised therapy and (2) a pilot study that achieved improvement of clinical scores with minimal supervision. The notion is proposed that some of the successful approaches developed and tested within these systems can form the basis of a scalable design methodology for other INR systems. A coherent approach to INR design is needed to facilitate the use of the systems by physical therapists, increase the number of successful INR studies, and generate rich clinical data that can inform the development of best practices for use of INR in physical therapy.

Activation deficit correlates with weakness in chronic stroke: evidence from evoked and voluntary EMG recordings.

OBJECTIVE: To use evoked (M-wave) and voluntary (during maximal voluntary contraction (MVC)) EMG recordings to estimate the voluntary activation level in chronic stroke. METHODS: Nine chronic hemiparetic stroke subjects participated in the experiment. M-wave (EMGM-wave) and MVC (EMGMVC) EMG values of the biceps brachii muscles were recorded. RESULTS: Peak torque was significantly smaller on the impaired than non-impaired side. EMGM-wave was also significantly smaller on the impaired than non-impaired side. However, the normalized EMGM-wave/TorqueMVC ratio was not significantly different between two sides. In contrast, both absolute EMGMVC and normalized EMGMVC/TorqueMVC were smaller on the impaired than non-impaired side. The voluntary activation level, EMGMVC/M-wave, was also smaller on the impaired than non-impaired side. The voluntary activation level on the impaired side was highly correlated with weakness (R=0.72), but very low (R=0.32) on the non-impaired side. CONCLUSION: Collectively, our findings suggest that both peripheral and central factors contribute to post-stroke weakness, but activation deficit correlates most closely with weakness as estimated from maximum voluntary torque generation. SIGNIFICANCE: These findings serve to highlight the potential benefit from high-intensity exercises to enhance central activation for facilitation of motor recovery.

Quantifying the deep tendon reflex using varying tendon indentation depths: applications to spasticity.

The deep tendon reflex (DTR) is often utilized to characterize the neuromuscular health of individuals because it is cheap, quick to implement, and requires limited equipment. However, DTR assessment is unreliable and assessor-dependent improve the reliability of the DTR assessment, we devised a novel standardization procedure. Our approach is based on the hypothesis that the neuromuscular state of a muscle changes systematically with respect to the indentation depth of its tendon. We tested the hypothesis by progressively indenting the biceps tendons on each side of nine hemiplegic stroke survivors to different depths, and then superimposing a series of brief controlled taps at each indentation depth to elicit a reflex response. Our results show that there exists a unique indentation depth at which reflex responses are consistently recorded (termed the Reflex Threshold) with increasing amplitude along increasing indentation depth. We further show that the reflex threshold depth is systematically smaller on the affected side of stroke survivors and that it is negatively correlated with the Modified Ashworth Score (VAF 70%). Our procedure also enables measurement of passive mechanical properties at the indentation location. In conclusion, our study shows that controlling for the indentation depth of the tendon of a muscle alters its reflex response predictably. Our novel device and method could be used to estimate neuromuscular changes in muscle (e.g., spasticity). Although some refinement is needed, this method opens the door to more reliable quantification of the DTR.

Reducing Abnormal Muscle Coactivation After Stroke Using a Myoelectric-Computer Interface: A Pilot Study.

Background A significant factor in impaired movement caused by stroke is the inability to activate muscles independently. Although the pathophysiology behind this abnormal coactivation is not clear, reducing the coactivation could improve overall arm function. A myoelectric computer interface (MCI), which maps electromyographic signals to cursor movement, could be used as a treatment to help retrain muscle activation patterns. Objective To investigate the use of MCI training to reduce abnormal muscle coactivation in chronic stroke survivors. Methods A total of 5 healthy participants and 5 stroke survivors with hemiparesis participated in multiple sessions of MCI training. The level of arm impairment in stroke survivors was assessed using the upper-extremity portion of the Fugl-Meyer Motor Assessment (FMA-UE). Participants performed isometric activations of up to 5 muscles. Activation of each muscle was mapped to different directions of cursor movement. The MCI specifically targeted 1 pair of muscles in each participant for reduction of coactivation. Results Both healthy participants and stroke survivors learned to reduce abnormal coactivation of the targeted muscles with MCI training. Out of 5 stroke survivors, 3 exhibited objective reduction in arm impairment as well (improvement in FMA-UE of 3 points in each of these patients). Conclusions These results suggest that the MCI was an effective tool in directly retraining muscle activation patterns following stroke.

Simultaneous characterizations of reflex and nonreflex dynamic and static changes in spastic hemiparesis.

This study characterizes tonic and phasic stretch reflex and stiffness and viscosity changes associated with spastic hemiparesis. Perturbations were applied to the ankle of 27 hemiparetic and 36 healthy subjects under relaxed or active contracting conditions. A nonlinear delay differential equation model characterized phasic and tonic stretch reflex gains, elastic stiffness, and viscous damping. Tendon reflex was characterized with reflex gain and threshold. Reflexively, tonic reflex gain was increased in spastic ankles at rest (P < 0.038) and was not regulated with muscle contraction, indicating impaired tonic stretch reflex. Phasic-reflex gain in spastic plantar flexors was higher and increased faster with plantar flexor contraction (P < 0.012) than controls (P < 0.023) and higher in dorsi-flexors at lower torques (P < 0.038), primarily because of its increase at rest (P = 0.045), indicating exaggerated phasic stretch reflex especially in more spastic plantar flexors, which showed higher phasic stretch reflex gain than dorsi-flexors (P < 0.032). Spasticity was associated with increased tendon reflex gain (P = 0.002) and decreased threshold (P < 0.001). Mechanically, stiffness in spastic ankles was higher than that in controls across plantar flexion/dorsi-flexion torque levels (P < 0.032), and the more spastic plantar flexors were stiffer than dorsi-flexors at comparable torques (P < 0.031). Increased stiffness in spastic ankles was mainly due to passive stiffness increase (P < 0.001), indicating increased connective tissues/shortened fascicles. Viscous damping in spastic ankles was increased across the plantar flexion torque levels and at lower dorsi-flexion torques, reflecting increased passive viscous damping (P = 0.033). The more spastic plantar flexors showed higher viscous damping than dorsi-flexors at comparable torque levels (P < 0.047). Simultaneous characterizations of reflex and nonreflex changes in spastic hemiparesis may help to evaluate and treat them more effectively.

Spasticity, weakness, force variability, and sustained spontaneous motor unit discharges of resting spastic-paretic biceps brachii muscles in chronic stroke.

INTRODUCTION: The purpose of our study was to examine relations among spasticity, weakness, force variability, and sustained spontaneous motor unit discharges in spastic-paretic biceps brachii muscles in chronic stroke. METHODS: Ten chronic stroke subjects produced submaximal isometric elbow flexion force on impaired and non-impaired sides. Intramuscular EMG (iEMG) was recorded from biceps and triceps brachii muscles. RESULTS: We observed sustained spontaneous motor unit discharges in resting biceps on iEMG. Spontaneous discharges increased after voluntary activation only on the impaired side. The impaired side had greater matching errors and greater fluctuations in isometric force. Spontaneous discharges were not related functionally to spasticity, force variability, or weakness. However, greater strength on the impaired side correlated with less force variability. CONCLUSION: Weakness rather than spasticity is a main factor interfering with voluntary force control in paretic-spastic biceps brachii muscles in chronic stroke.

Myoelectric computer interfaces to reduce co-contraction after stroke.

A significant factor in impaired motor function caused by stroke is the inability to activate muscles independently. While the pathophysiology behind this co-contraction, sometimes called abnormal muscle synergy, is not clear, reducing the co-contraction could improve overall arm function. This pilot study describes the use of a myoelectric-computer interface (MCI) to retrain arm muscle activation and reduce co-contraction. We found that both healthy subjects and stroke survivors with hemiparesis learned to reduce co-contraction with MCI training. Three out of five stroke survivors experienced some improvement in arm function as well. These results suggest that MCIs could provide a novel, relatively inexpensive paradigm for stroke rehabilitation.

Contribution of intrinsic properties and synaptic inputs to motoneuron discharge patterns: a simulation study.

Motoneuron discharge patterns reflect the interaction of synaptic inputs with intrinsic conductances. Recent work has focused on the contribution of conductances mediating persistent inward currents (PICs), which amplify and prolong the effects of synaptic inputs on motoneuron discharge. Certain features of human motor unit discharge are thought to reflect a relatively stereotyped activation of PICs by excitatory synaptic inputs; these features include rate saturation and de-recruitment at a lower level of net excitation than that required for recruitment. However, PIC activation is also influenced by the pattern and spatial distribution of inhibitory inputs that are activated concurrently with excitatory inputs. To estimate the potential contributions of PIC activation and synaptic input patterns to motor unit discharge patterns, we examined the responses of a set of cable motoneuron models to different patterns of excitatory and inhibitory inputs. The models were first tuned to approximate the current- and voltage-clamp responses of low- and medium-threshold spinal motoneurons studied in decerebrate cats and then driven with different patterns of excitatory and inhibitory inputs. The responses of the models to excitatory inputs reproduced a number of features of human motor unit discharge. However, the pattern of rate modulation was strongly influenced by the temporal and spatial pattern of concurrent inhibitory inputs. Thus, even though PIC activation is likely to exert a strong influence on firing rate modulation, PIC activation in combination with different patterns of excitatory and inhibitory synaptic inputs can produce a wide variety of motor unit discharge patterns.

Riluzole decreases flexion withdrawal reflex but not voluntary ankle torque in human chronic spinal cord injury.

The objectives of this study were to probe the contribution of spinal neuron persistent sodium conductances to reflex hyperexcitability in human chronic spinal cord injury. The intrinsic excitability of spinal neurons provides a novel target for medical intervention. Studies in animal models have shown that persistent inward currents, such as persistent sodium currents, profoundly influence neuronal excitability, and recovery of persistent inward currents in spinal neurons of animals with spinal cord injury routinely coincides with the appearance of spastic reflexes. Pharmacologically, this neuronal excitability can be decreased by agents that reduce persistent inward currents, such as the selective persistent sodium current inhibitor riluzole. We were able to recruit seven subjects with chronic incomplete spinal cord injury who were not concurrently taking antispasticity medications into the study. Reflex responses (flexion withdrawal and H-reflexes) and volitional strength (isometric maximum voluntary contractions) were tested at the ankle before and after placebo-controlled, double-blinded oral administration of riluzole (50 mg). Riluzole significantly decreased the peak ankle dorsiflexion torque component of the flexion withdrawal reflex. Peak maximum voluntary torque in both dorsiflexion and plantarflexion directions was not significantly changed. Average dorsiflexion torque sustained during the 5-s isometric maximum voluntary contraction, however, increased significantly. There was no effect, however, on the monosynaptic plantar and dorsiflexor H-reflex responses. Overall, these results demonstrate a contribution of persistent sodium conductances to polysynaptic reflex excitability in human chronic spinal cord injury without a significant role in maximum strength production. These results suggest that intrinsic spinal cellular excitability could be a target for managing chronic spinal cord injury hyperreflexia impairments without causing a significant loss in volitional strength.