Nicole J. Tester

Long-Term Facilitation of Ventilation in Humans with Chronic Spinal Cord Injury

RATIONALE Intermittent stimulation of the respiratory system with hypoxia causes persistent increases in respiratory motor output (i.e., long-term facilitation) in animals with spinal cord injury. This paradigm, therefore, has been touted as a potential respiratory rehabilitation strategy. OBJECTIVES To determine whether acute (daily) exposure to intermittent hypoxia can also evoke long-term facilitation of ventilation after chronic spinal cord injury in humans, and whether repeated daily exposure to intermittent hypoxia enhances the magnitude of this response. METHODS Eight individuals with incomplete spinal cord injury (>1 yr; cervical [n = 6], thoracic [n = 2]) were exposed to intermittent hypoxia (eight 2-min intervals of 8% oxygen) for 10 days. During all exposures, end-tidal carbon dioxide levels were maintained, on average, 2 mm Hg above resting values. Minute ventilation, tidal volume, and breathing frequency were measured before (baseline), during, and 30 minutes after intermittent hypoxia. Sham protocols consisted of exposure to room air and were administered to a subset of the participants (n = 4). MEASUREMENTS AND MAIN RESULTS Minute ventilation increased significantly for 30 minutes after acute exposure to intermittent hypoxia (P < 0.001), but not after sham exposure. However, the magnitude of ventilatory long-term facilitation was not enhanced over 10 days of intermittent hypoxia exposures. CONCLUSIONS Ventilatory long-term facilitation can be evoked by brief periods of hypoxia in humans with chronic spinal cord injury. Thus, intermittent hypoxia may represent a strategy for inducing respiratory neuroplasticity after declines in respiratory function that are related to neurological impairment. Clinical trial registered with www.clinicaltrials.gov (NCT01272011).

Ventilatory Long-Term Facilitation in Humans

To the Editor: We read with interest the thoughtful editorial written by Iscoe and DiMarco about ventilatory facilitation in spinal cord injury in the January 1, 2014, issue of the Journal (1). The editorial highlighted the results from our recent study, which showed that ventilatory long-term facilitation can be induced in individuals with spinal cord injury (2). The editorial also highlighted some important issues, which will promote future investigations. These include determining the appropriate combination of intermittent hypoxia (i.e., the stimulus most often used to induce ventilatory long-term facilitation) and sustained hypercapnia, and exposure duration, to optimize long-term facilitation. In addition, Iscoe and DiMarco highlighted that intermittent hypoxia has the potential to enhance ventilatory function and improve quality of life. Although we agree with many of the points in the editorial, we are compelled to clarify some of the comments. The authors indicated that the record of long-term facilitation is suspect, which we believe is incorrect. Multiple studies from independent laboratories over the last 40 years have conclusively documented that intermittent hypoxia can lead to long-term facilitation in a multitude of species, including humans (3). The authors also suggested that long-term facilitation in our study lasted for a short time (i.e., 30 min) compared with the duration typically reported in anesthetized laboratory animals. However, the length of time long-term facilitation was sustained in our subjects is unknown, because ventilation was not recorded for longer than 30 minutes (2). A query regarding whether spinal cord injury is necessary to manifest the response was also raised. However, prior studies in humans without spinal cord injury have established that long-term facilitation can be induced under similar conditions. Indeed, we modeled our experimental paradigm based on this published literature (4–7). It is correct that ventilatory long-term facilitation could not be induced in neurologically intact humans initially, because carbon dioxide was not controlled at levels slightly above baseline values (8). However, the seminal paper of Harris and colleagues (5), which employed the appropriate control experiments, clearly showed that ventilatory and genioglossus muscle long-term facilitation were induced after exposure to intermittent hypoxia if carbon dioxide levels were rigorously controlled above baseline values. This finding has been replicated in a number of studies in both healthy individuals (5, 7, 9) and individuals with sleep apnea (4, 6, 7). Indeed, although the findings were not included in the present article, we established that ventilatory long-term facilitation was abolished during the end-recovery period in our subjects with spinal cord injury if carbon dioxide levels were not sustained. The role of carbon dioxide in the manifestation of long-term facilitation in humans also explains Iscoe and DiMarco’s quandary that long-term facilitation was induced in our study, but was absent in the study of Diep and colleagues (10), despite similar stimuli. The manner in which these stimuli were applied varied between investigations. In our present and previous investigations, carbon dioxide was sustained slightly above baseline values throughout the intermittent hypoxia protocol, during both the application of intermittent hypoxia and recovery periods, when ventilatory long-term facilitation typically manifests. In the study by Diep and colleagues (10), carbon dioxide was not maintained during periods of recovery. Consequently, hypocapnia was evident (see Figure 2 in Ref. 10) and ventilatory long-term facilitation was not, as was the case in previous investigations (5, 8). We believe that some of the answers to the mysteries of ventilatory long-term facilitation in humans have been answered, but many questions remain. The fundamental knowledge that has been established by our recent study—namely, that the long-term facilitation can be evoked after chronic spinal cord injury in humans—will allow for subsequent focus on the following questions. What is the combination of intermittent hypoxia and sustained carbon dioxide that evokes the greatest increase in breathing? What other rehabilitation modalities can be combined with intermittent hypoxia? Finally, what are the best outcome measures to determine the impact that ventilatory facilitation has on recovery of respiratory function after spinal cord injury in humans.

Ongoing Walking Recovery 2 Years After Locomotor Training in a Child With Severe Incomplete Spinal Cord Injury

Background and Purpose The authors previously reported on walking recovery in a nonambulatory child with chronic, severe, incomplete cervical spinal cord injury (SCI) after 76 sessions of locomotor training (LT). Although clinical measures did not predict his recovery, reciprocal patterned leg movements developed, affording recovery of independent walking with a reverse rolling walker. The long-term functional limitations and secondary complications often associated with pediatric-onset SCI necessitate continued follow-up of children with SCI. Therefore, the purpose of this case report is to describe this childs walking function and musculoskeletal growth and development during the 2 years since his participation in an LT program and subsequent walking recovery. Case Description Following LT, the child attended elementary school as a full-time ambulator. He was evaluated 1 month (baseline), 1 year, and 2 years after LT. Examination of walking function included measures of walking independence, gait speed and spatiotemporal parameters, gait kinematics, and daily step activity. Growth and development were assessed by tracking his height, weight, incidence of musculoskeletal complications, and gross motor task performance. Outcomes Over the 2 years, the child continued to ambulate independently with a reverse rolling walker, increasing his fastest gait speed. Spatiotemporal and kinematic features of his walking improved, and daily step activity increased. Height and weight remained on their preinjury trajectory and within age-appropriate norms. The child experienced only minor musculoskeletal complications. Additionally, he gained the ability to use reciprocal patterned leg movements during locomotor tasks such as assisted stair climbing and independent tricycle pedaling. Conclusions Two years after recovery of walking, this child with incomplete SCI had maintained and improved his walking function and experienced age-appropriate growth and development.

Arm and leg coordination during treadmill walking in individuals with motor incomplete spinal cord injury: A preliminary study

Arm and leg coordination naturally emerges during walking, but can be affected by stroke or Parkinsons disease. The purpose of this preliminary study was to characterize arm and leg coordination during treadmill walking at self-selected comfortable walking speeds (CWSs) in individuals using arm swing with motor incomplete spinal cord injury (iSCI). Hip and shoulder angle cycle durations and amplitudes, strength of peak correlations between contralateral hip and shoulder joint angle time series, the time shifts at which these peak correlations occur, and associated variability were quantified. Outcomes in individuals with iSCI selecting fast CWSs (range, 1.0-1.3m/s) and speed-matched individuals without neurological injuries are similar. Differences, however, are detected in individuals with iSCI selecting slow CWSs (range, 0.25-0.65 m/s) and may represent compensatory strategies to improve walking balance or forward propulsion. These individuals elicit a 1:1, arm:leg frequency ratio versus the 2:1 ratio observed in non-injured individuals. Shoulder and hip movement patterns, however, are highly reproducible (coordinated) in participants with iSCI, regardless of CWS. This high degree of inter-extremity coordination could reflect an inability to modify a single movement pattern post-iSCI. Combined, these data suggest inter-extremity walking coordination may be altered, but is present after iSCI, and therefore may be regulated, in part, by neural control.

Device use, locomotor training and the presence of arm swing during treadmill walking after spinal cord injury

Study design:Observational, cross-sectional study from a convenience sample with pretest/posttest data from a sample subset.Objectives:Determine the presence of walking-related arm swing after spinal cord injury (SCI), its associated factors and whether arm swing may change after locomotor training (LT).Setting:Malcom Randall VAMC and University of Florida, Gainesville, FL.Methods:Arm movement was assessed during treadmill stepping, pre-LT, in 30 individuals with motor incomplete SCI (iSCI, American Spinal Injury Association Impairment Scale grade C/D, as defined by the International Standards for Neurological Classifications of SCI, with neurological level of impairment at or below C4). Partial body weight support and manual-trainer assistance were provided, as needed, to achieve stepping and allow arm swing. Arm swing presence was compared on the basis of cervical versus thoracic neurological levels of impairment and device type. Leg and arm strength and walking independence were compared between individuals with and without arm swing. Arm swing was reevaluated post-LT in the 21 out of 30 individuals who underwent LT.Results:Of 30 individuals with iSCI, 12 demonstrated arm swing during treadmill stepping, pre-LT. Arm movement was associated with device type, lower extremity motor scores and walking independence. Among the 21 individuals who received LT, only 5 demonstrated arm swing pre-LT. Of the 16 individuals lacking arm swing pre-LT, 8 integrated arm swing post-LT.Conclusion:Devices routinely used for walking post-iSCI appeared associated with arm swing. Post-LT, arm swing presence increased. Therefore, arm swing may be experience dependent. Daily neuromuscular experiences provided to the arms may produce training effects, thereby altering arm swing expression.

Recovery of airway protective behaviors after spinal cord injury

Pulmonary morbidity is high following spinal cord injury and is due, in part, to impairment of airway protective behaviors. These airway protective behaviors include augmented breaths, the cough reflex, and expiration reflexes. Functional recovery of these behaviors has been reported after spinal cord injury. In humans, evidence for functional recovery is restricted to alterations in motor strategy and changes in the frequency of occurrence of these behaviors. In animal models, compensatory alterations in motor strategy have been identified. Crossed descending respiratory motor pathways at the thoracic spinal cord levels exist that are composed of crossed premotor axons, local circuit interneurons, and propriospinal neurons. These pathways can collectively form a substrate that supports maintenance and/or recovery of function, especially after asymmetric spinal cord injury. Local sprouting of premotor axons in the thoracic spinal cord also can occur following chronic spinal cord injury. These mechanisms may contribute to functional resiliency of the cough reflex that has been observed following chronic spinal cord injury in the cat.

Cough following low thoracic hemisection in the cat

A function of the abdominal expiratory muscles is the generation of cough, a critical respiratory defense mechanism that is often disrupted following spinal cord injury. We assessed the effects of a lateral T9/10 hemisection on cough production at 4, 13 and 21 weeks post-injury in cats receiving extensive locomotor training. The magnitudes of esophageal pressure as well as of bilateral rectus abdominis electromyogram activity during cough were not significantly different from pre-injury values at all time points evaluated. The results show that despite considerable interruption of the descending pre-motor drive from the brainstem to the expiratory motoneuron pools, the cough motor system shows a significant function by 4 weeks following incomplete thoracic injury.

Responsiveness of the Neuromuscular Recovery Scale During Outpatient Activity-Dependent Rehabilitation for Spinal Cord Injury:

Background. The Neuromuscular Recovery Scale (NRS) was developed by researchers and clinicians to functionally classify people with spinal cord injury (SCI) by measuring functionally relevant motor tasks without compensation. Previous studies established strong interrater and test-retest reliability and validity of the scale. Objective. To determine responsiveness of the NRS, a version including newly added upper-extremity items, in an outpatient rehabilitation setting. Methods. Assessments using the NRS and 6 other instruments were conducted at enrollment and discharge from a locomotor training program for 72 outpatients with SCI classified as American Spinal Injury Association Impairment Scale grades A to D (International Standards for Neurological Classification of Spinal Cord Injury). Mixed-model t statistics for instruments were calculated and adjusted for confounding factors (eg, sample size, demographic variables) for all patients and subgroups stratified by injury level and/or severity. The resulting adjusted response means (ARMs) and 95% confidence intervals (CIs) were used to determine responsiveness, and significant differences between instruments were identified with pairwise comparisons. Results. The NRS was significantly responsive for SCI outpatients (ARM = 1.05; CI = 0.75-1.35). Changes in motor function were detected across heterogeneous groups. Regardless of injury level or severity, the responsiveness of the NRS was equal to, and often significantly exceeded, the responsiveness of other instruments. Conclusions. The NRS is a responsive measure that detects change in motor function during outpatient neurorehabilitation for SCI. There is potential utility for its application in randomized controlled trials and as a measure of clinical recovery across diverse SCI populations.

Effect of acute intermittent hypoxia treatment on ventilatory load compensation and magnitude estimation of inspiratory resistive loads in an individual with chronic incomplete cervical spinal cord injury

Context: Spinal cord injury (SCI) causes disruption of the efferent input to and afferent input from respiratory muscles, which impairs respiratory motor and sensory functions, respectively. This disturbs the injured individuals ability to respond to ventilatory loads and may alter the respiratory perceptual sensitivity of applied loads. Acute intermittent hypoxia with elevated CO2 (AIH treatment) has been shown to induce ventilatory long-term facilitation in individuals with chronic SCI. This study evaluated the effect of ten days of AIH treatment on ventilatory load compensation and respiratory perceptual sensitivity to inspiratory resistive loads (IRL), in an individual with chronic, incomplete cervical SCI. Methods: Case report and literature review. Findings: We report a case of a 55-year-old female with a C4 chronic, incomplete SCI (American Spinal Injury Association Impairment Scale D). The subject underwent evaluation at four time-points: Baseline, Post Sham, AIH Day 1 and AIH Day 10. Significant improvements in airflow generated in response to applied IRL were found after AIH treatment compared to Baseline. There were no significant changes in the respiratory perceptual sensitivity to applied IRL after AIH treatment. Clinical relevance: Rehabilitative interventions after SCI demand restoration of the respiratory motor function. However, they must also ensure that the respiratory perceptual sensitivity of the injured individual does not hinder their capability to compensate to ventilatory challenges.

Altered Obstacle Negotiation after Low Thoracic Hemisection in the Cat

Following a lateralized spinal cord injury (SCI) in humans, substantial walking recovery occurs; however, deficits persist in adaptive features of locomotion critical for community ambulation, including obstacle negotiation. Normal obstacle negotiation is accomplished by an increase in flexion during swing. If an object is unanticipated or supraspinal input is absent, obstacle negotiation may involve the spinally organized stumbling corrective response. How these voluntary and reflex components are affected following partial SCI is not well studied. This study is the first to characterize recovery of obstacle negotiation following low-thoracic spinal hemisection in the cat. Cats were trained pre- and post-injury to cross a runway with an obstacle. Assessments focused on the hindlimb ipsilateral to the lesion. Pre-injury, cats efficiently cleared an obstacle by increasing knee flexion during swing. Post-injury, obstacle clearance permanently changed. At 2 weeks, when basic overground walking ability been recovered, the hindlimb was dragged over the obstacle (∼90%). Surprisingly, the stumbling corrective response was not elicited until after 2 weeks. Despite a notable increase, between 4 and 8 weeks, in the ability to modify limb trajectory when approaching an obstacle, limb lift during obstacle approach was insufficient during ∼50% of encounters and continued to evoke the stumbling corrective response even at 16 weeks. A post-injury lead limb bias identified during negotiations with complete clearance, suggests a potential training strategy to increase the number of successful clearances. Therefore, following complete severing of half of the spinal cord, the ability to modify ipsilateral hindlimb trajectory shows significant recovery and by 16 weeks permits effective clearing of an obstacle, without contact, ∼50% of the time. Although this suggests plasticity of supporting circuitry, it is insufficient to support consistent clearance. This inconsistency, even at the most chronic time point assessed (16 weeks), is probably a contributing factor to falls reported for people with SCI.