Acute intermittent hypoxia increases maximal motor unit discharge rates in people with chronic incomplete spinal cord injury.

Acute intermittent hypoxia (AIH) is an emerging technique for enhancing neuroplasticity and motor function in respiratory and limb musculature. Thus far, AIH-induced improvements in strength have been reported for upper and lower limb muscles after chronic incomplete cervical spinal cord injury (iSCI), but the underlying mechanisms have been elusive. We used high-density surface EMG (HDsEMG) to determine if motor unit discharge behaviour is altered after 15 × 60 s exposures to 9% inspired oxygen, interspersed with 21% inspired oxygen (AIH), compared to breathing only 21% air (SHAM). We recorded HDsEMG from the biceps and triceps brachii of seven individuals with iSCI during maximal elbow flexion and extension contractions, and motor unit spike trains were identified using convolutive blind source separation. After AIH, elbow flexion and extension torque increased by 54% and 59% from baseline (P = 0.003), respectively, whereas there was no change after SHAM. Across muscles, motor unit discharge rates increased by ∼4 pulses per second (P = 0.002) during maximal efforts, from before to after AIH. These results suggest that excitability and/or activation of spinal motoneurons is augmented after AIH, providing a mechanism to explain AIH-induced increases in voluntary strength. Pending validation, AIH may be helpful in conjunction with other therapies to enhance rehabilitation outcomes after incomplete spinal cord injury, due to these enhancements in motor unit function and strength. KEY POINTS: Acute intermittent hypoxia (AIH) causes increases in muscular strength and neuroplasticity in people living with chronic incomplete spinal cord injury (SCI), but how it affects motor unit discharge rates is unknown. Motor unit spike times were identified from high-density surface electromyograms during maximal voluntary contractions and tracked from before to after AIH. Motor unit discharge rates were increased following AIH. These findings suggest that AIH can facilitate motoneuron function in people with incomplete SCI.

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.

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.

Precise quantification of the time course of voluntary activation capacity following Botulinum toxin injections in the biceps brachii muscles of chronic stroke survivors.

BACKGROUND: Spasticity is a key motor impairment that affects many hemispheric stroke survivors. Intramuscular botulinum toxin (BT) injections are used widely to clinically manage spasticity-related symptoms in stroke survivors by chemically denervating muscle fibers from their associated motor neurons. In this study, we sought to understand how BT affects muscle activation, motor unit composition and voluntary force generating capacity over a time period of 3 months. Our purpose was to characterize the time course of functional changes in voluntary muscle activity in stroke survivors who are undergoing BT therapy as part of their physician-prescribed clinical plan. METHOD: Our assessment of the effects of BT was based on the quantification of surface electromyogram (sEMG) recordings in the biceps brachii (BB), an upper arm muscle and of voluntary contraction force. We report here on voluntary force and sEMG responses during isometric elbow contractions across consecutive recording sessions, spread over 12 weeks in three segments, starting with a preliminary session performed just prior to the BT injection. At predetermined time points, we conducted additional clinical assessments and we also recorded from the contralateral limbs of our stroke cohort. Eight subjects were studied for approximately 86 experimental recording sessions on both stroke-affected and contralateral sides. RESULTS: We recorded an initial reduction in force and sEMG in all subjects, followed by a trajectory with a progressive return to baseline over a maximum of 12 weeks, although the minimum sEMG and minimum force were not always recorded at the same time point. Three participants were able to complete only one to two segments. Slope values of the sEMG-force relations were also found to vary across the different time segments. While sEMG-force slopes provide assessments of force generation capacity of the BT injected muscle, amplitude histograms from novel sEMG recordings during the voluntary tasks provide additional insights about differential actions of BT on the overall motor unit (MU) population over time. CONCLUSIONS: The results of our study indicate that there are potential short term as well as long term decrements in muscle control and activation properties after BT administration on the affected side of chronic stroke survivors. Muscle activation levels as recorded using sEMG, did not routinely return to baseline even at three months' post injection. The concurrent clinical measures also did not follow the same time course, nor did they provide the same resolution as our experimental measures. It follows that even 12 weeks after intramuscular BT injections muscle recovery may not be complete, and may thereby contribute to pre-existing paresis.

Concurrent Infection of a Young Tourist by Hookworm and Strongyloides Stercoralis During Low Budget Travel in Southeast Asia.

Strongyloidiasis and hookworm infections are neglected helminth diseases widespread in tropical and subtropical areas. In humans, particularly in immunocompromised patients infections potentially may lead to the life-threatening clinical conditions involving the respiratory as well as gastrointestinal systems. The increased number of tourists travelling to tropical regions is associated with more frequent infection with parasites such as Strongyloides and hookworm. The infection takes place when filariform larvae penetrate the skin exposed to soil, than migrate through the lungs and finally reach the intestine. Travelers are often not aware of how they could get infected. Physicians may suspect strongyloidiasis and hookworm infections in tourists with diarrhea returning from endemic areas, especially when an elevated eosinophilia is observed. In the literature there are many reports about the presence of parasites in indigenous communities, but very few are available regarding travelers. This paper describes a dual infection with hookworm and Strongyloides stercoralis in a young female tourist returning from Southeast Asia. To our knowledge, this is the first report of hookworm and Strongyloides stercoralis infection in a tourist from Europe, acquired in an endemic area.

How a diverse research ecosystem has generated new rehabilitation technologies: Review of NIDILRR's Rehabilitation Engineering Research Centers.

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a "total approach to rehabilitation", combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970's, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program.

Anomalous EMG-force relations during low-force isometric tasks in hemiparetic stroke survivors.

Hemispheric brain injury resulting from a stroke is often accompanied by muscle weakness in contralateral limbs. In neurologically intact subjects, appropriate motoneuronal recruitment and rate modulation are utilized to optimize muscle force production. In the present study, we sought to determine whether weakness in an affected hand muscle in stroke survivors is partially attributable to alterations in the control of muscle activation. Specifically, our goal was to characterize whether the surface EMG amplitude was systematically larger as a function of (low) force in paretic hand muscles as compared to contralateral muscles in the same subject. We tested a multifunctional muscle, the first dorsal interosseous (FDI), in multiple directions about the second metacarpophalangeal joint in ten hemiparetic and six neurologically intact subjects. In six of the ten stroke subjects, the EMG-force slope was significantly greater on the affected side as compared to the contralateral side, as well as compared to neurologically intact subjects. An unexpected set of results was a nonlinear relation between recorded EMG and generated force commonly observed in the paretic FDI, even at very low-force levels. We discuss possible experimental as well as physiological factors that may contribute to an increased EMG-force slope, concluding that changes in motor unit (MU) control are the most likely reasons for the observed changes.

Disturbances of motor unit rate modulation are prevalent in muscles of spastic-paretic stroke survivors.

Stroke survivors often exhibit abnormally low motor unit firing rates during voluntary muscle activation. Our purpose was to assess the prevalence of saturation in motor unit firing rates in the spastic-paretic biceps brachii muscle of stroke survivors. To achieve this objective, we recorded the incidence and duration of impaired lower- and higher-threshold motor unit firing rate modulation in spastic-paretic, contralateral, and healthy control muscle during increases in isometric force generated by the elbow flexor muscles. Impaired firing was considered to have occurred when firing rate became constant (i.e., saturated), despite increasing force. The duration of impaired firing rate modulation in the lower-threshold unit was longer for spastic-paretic (3.9 ± 2.2 s) than for contralateral (1.4 ± 0.9 s; P < 0.001) and control (1.1 ± 1.0 s; P = 0.005) muscles. The duration of impaired firing rate modulation in the higher-threshold unit was also longer for the spastic-paretic (1.7 ± 1.6 s) than contralateral (0.3 ± 0.3 s; P = 0.007) and control (0.1 ± 0.2 s; P = 0.009) muscles. This impaired firing rate of the lower-threshold unit arose, despite an increase in the overall descending command, as shown by the recruitment of the higher-threshold unit during the time that the lower-threshold unit was saturating, and by the continuous increase in averages of the rectified EMG of the biceps brachii muscle throughout the rising phase of the contraction. These results suggest that impairments in firing rate modulation are prevalent in motor units of spastic-paretic muscle, even when the overall descending command to the muscle is increasing.

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.

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.

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.

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.

Differentiation between the contributions of shortening reaction and stretch-induced inhibition to rigidity in Parkinson's disease.

Parkinsonian rigidity is characterized by an increased resistance of a joint to externally imposed motion that remains uniform with changing joint angle. Two candidate mechanisms are proposed for the uniformity of rigidity, involving neural-mediated excitation of shortening muscles, i.e., shortening reaction (SR), or inhibition of stretched muscles, i.e., stretch-induced inhibition (SII). To date, no study has addressed the roles of these two phenomena in rigidity. The purpose of this study was to differentiate these two phenomena, and to quantify the potential contribution of each to wrist joint moment in 17 patients with parkinsonian rigidity, in both Off- and On-medication states. Joint position, torque, and EMGs of selected muscles were collected during externally imposed flexion and extension motions. Moments of shortened and stretched muscles were estimated using a biomechanical model. Slopes of the estimated torque-angle curve were calculated for shortened and stretched muscles, separately. A mixed model ANOVA was performed to compare the contribution between the two mechanisms. During flexion, slopes were significantly (P = 0.003) smaller for SR than for SII, whereas during extension, slopes for SII were significantly (P = 0.003) smaller. Results showed that both SR and SII contributed to rigidity. Which mechanism predominates appeared to be associated with the direction of movement. The findings provide new insights into the biomechanical underpinnings of this common symptom in Parkinson's disease.

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.

Origins of spontaneous firing of motor units in the spastic-paretic biceps brachii muscle of stroke survivors.

One potential expression of altered motoneuron excitability following a hemispheric stroke is the spontaneous unit firing (SUF) of motor units at rest. The elements contributing to this altered excitability could be spinal descending pathways, spinal interneuronal networks, afferent feedback, or intrinsic motoneuron properties. Our purpose was to examine the characteristics of spontaneous discharge in spastic-paretic and contralateral muscles of hemiparetic stroke survivors, to determine which of these mechanisms might contribute. To achieve this objective, we examined the statistics of spontaneous discharge of individual motor units and we conducted a coherence analyses on spontaneously firing motor unit pairs. The presence of significant coherence between units might indicate a common driving source of excitation to multiple motoneurons from descending pathways or regional interneurons, whereas a consistent lack of coherence might favor an intrinsic cellular mechanism of hyperexcitability. Spontaneous firing of motor units (i.e., ongoing discharge in the absence of an ongoing stimulus) was observed to a greater degree in spastic-paretic muscles (following 83.2 ± 16.7% of ramp contractions) than that in contralateral muscles (following just 14.1 ± 10.5% of ramp contractions; P < 0.001) and was not observed at all in healthy control muscle. The average firing rates of the spontaneously firing units were 8.4 ± 1.8 pulses/s (pps) in spastic-paretic muscle and 9.6 ± 2.2 pps in contralateral muscle (P < 0.001). In 37 instances (n = 63 pairs), we observed spontaneous discharge of two or more motor units simultaneously in spastic-paretic muscle. Seventy percent of the dually firing motor unit pairs exhibited significant coherence (P < 0.001) in the 0- to 4-Hz bandwidth (average peak coherence: 0.14 ± 0.13; range: 0.01-0.75) and 22% of pairs exhibited significant coherence (P < 0.001) in the 15- to 30-Hz bandwidth (average peak coherence: 0.07 ± 0.06; range: 0.01-0.31). We suggest that the spontaneous firing was likely not attributable solely to enhanced intrinsic motoneuron activation, but attributable, at least in part, to a low-level excitatory synaptic input to the resting spastic-paretic motoneuron pool, possibly from regional or supraspinal centers.

Quantification of the effects of an alpha-2 adrenergic agonist on reflex properties in spinal cord injury using a system identification technique.

BACKGROUND: Despite numerous investigations, the impact of tizanidine, an anti-spastic medication, on changes in reflex and muscle mechanical properties in spasticity remains unclear. This study was designed to help us understand the mechanisms of action of tizanidine on spasticity in spinal cord injured subjects with incomplete injury, by quantifying the effects of a single dose of tizanidine on ankle muscle intrinsic and reflex components. METHODS: A series of perturbations was applied to the spastic ankle joint of twenty-one spinal cord injured subjects, and the resulting torques were recorded. A parallel-cascade system identification method was used to separate intrinsic and reflex torques, and to identify the contribution of these components to dynamic ankle stiffness at different ankle positions, while subjects remained relaxed. RESULTS: Following administration of a single oral dose of Tizanidine, stretch evoked joint torque at the ankle decreased significantly (p < 0.001) The peak-torque was reduced between 15% and 60% among the spinal cord injured subjects, and the average reduction was 25%. Using systems identification techniques, we found that this reduced torque could be attributed largely to a reduced reflex response, without measurable change in the muscle contribution. Reflex stiffness decreased significantly across a range of joint angles (p < 0.001) after using tizanidine. In contrast, there were no significant changes in intrinsic muscle stiffness after the administration of tizanidine. CONCLUSIONS: Our findings demonstrate that tizanidine acts to reduce reflex mechanical responses substantially, without inducing comparable changes in intrinsic muscle properties in individuals with spinal cord injury. Thus, the pre-post difference in joint mechanical properties can be attributed to reflex changes alone. From a practical standpoint, use of a single "test" dose of Tizanidine may help clinicians decide whether the drug can helpful in controlling symptoms in particular subjects.

Altered nerve excitability properties after stroke are potentially associated with reduced neuromuscular activation.

OBJECTIVE: To determine limb differences in motor axon excitability properties in stroke survivors and their relation to maximal electromyographic (EMG) activity. METHODS: The median nerve was stimulated to record compound muscle action potentials (CMAP) from the abductor pollicis brevis (APB) in 28 stroke subjects (57.3 ± 7.5 y) and 24 controls (56.7 ± 9.3 y). RESULTS: Paretic limb axons differed significantly from non-paretic limb axons including (1) smaller superexcitability and subexcitability, (2) higher threshold during subthreshold depolarizing currents, (3) greater accommodation (S3) to hyperpolarization, and (4) a larger stimulus-response slope. There were smaller differences between the paretic and control limbs. Responses in the paretic limb were reproduced in a model by a 5.6 mV hyperpolarizing shift in the activation voltage of Ih (the current activated by hyperpolarization), together with an 11.8% decrease in nodal Na+ conductance or a 0.9 mV depolarizing shift in the Na+ activation voltage. Subjects with larger deficits in APB maximal voluntary EMG had larger limb differences in excitability properties. CONCLUSIONS: Stroke leads to altered modulation of Ih and altered Na+ channel properties that may be partially attributed to a reduction in neuromuscular activation. SIGNIFICANCE: Plastic changes occur in the axon node and internode that likely influence axon excitability.