Spinal cord injury (SCI) is a debilitating condition that can significantly affect an individual's life, causing paralysis, autonomic dysreflexia, and chronic pain. Transspinal stimulation (TSS) is a non-invasive form of neuromodulation that activates the underlying neural circuitries of the spinal cord. Application of TSS can be performed through multiple stimulation protocols, which may vary in the electrodes' size or position as well as stimulation parameters, and which may influence the response of motor functions to the stimulation. Due to the novelty of TSS, it is beneficial to summarize the available evidence to identify the range of parameters that may provide the best outcomes for motor response. The PubMed and Google Scholar databases were searched for studies examining the effects of TSS on limb motor function. A literature search yielded 34 studies for analysis, in which electrode placement and stimulation parameters varied considerably. The stimulation protocols from each study and their impact on limb motor function were summarized. Electrode placement was variable based on the targeted limb. Studies for the upper limbs targeted the cervical enlargement with anatomical placement of the cathode over the cervical vertebral region. In lower-limb studies, the cathode(s) were placed over the thoracic and lumbar vertebral regions, to target the lumbar enlargement. The effects of carrier frequency were inconclusive across the studies. Multisite cathodal placements yielded favorable motor response results compared to single-site placement. This review briefly summarized the current mechanistic evidence of the effect of TSS on motor response after SCI. Our findings indicate that optimization of stimulation parameters will require future randomized controlled studies to independently assess the effects of different stimulation parameters under controlled circumstances.

Two persons with chronic motor complete spinal cord injury (SCI) were implanted with percutaneous spinal cord epidural stimulation (SCES) leads to enable motor control below the injury level (NCT04782947). Through a period of temporary followed by permanent SCES implantation, spinal mapping was conducted primarily to optimize configurations enabling volitional control of movement and training of standing and stepping as a secondary outcome. In both participants, SCES enabled voluntary increased muscle activation and movement below the injury and decreased assistance during exoskeleton-assisted walking. After permanent implantation, both participants voluntarily modulated induced torques but not always in the intended directions. In one participant, percutaneous SCES enabled motor control below the injury one-day following temporary implantation as confirmed by electromyography. The same participant achieved independent standing with minimal upper extremity self-balance assistance, independent stepping in parallel bars and overground ambulation with a walker. SCES via percutaneous leads holds promise for enhancing rehabilitation and enabling motor functions for people with SCI.

Spinal cord injury (SCI) produces paralysis and a unique form of neurogenic disuse osteoporosis that dramatically increases fracture risk at the distal femur and proximal tibia. This bone loss is driven by heightened bone resorption and near-absent bone formation during the acute post-SCI recovery phase and by a more traditional high-turnover osteopenia that emerges more chronically, which is likely influenced by the continual neural impairment and musculoskeletal unloading. These observations have stimulated interest in specialized exercise or activity-based physical therapy (ABPT) modalities (e.g., neuromuscular or functional electrical stimulation cycling, rowing, or resistance training, as well as other standing, walking, or partial weight-bearing interventions) that reload the paralyzed limbs and promote muscle recovery and use-dependent neuroplasticity. However, only sparse and relatively inconsistent evidence supports the ability of these physical rehabilitation regimens to influence bone metabolism or to increase bone mineral density (BMD) at the most fracture-prone sites in persons with severe SCI. This review discusses the pathophysiology and cellular/molecular mechanisms that influence bone loss after SCI, describes studies evaluating bone turnover and BMD responses to ABPTs during acute versus chronic SCI, identifies factors that may impact the bone responses to ABPT, and provides recommendations to optimize ABPTs for bone recovery.

A male with C7 complete tetraplegia participated in 14 weeks of body weight supported treadmill training (BWSTT) combined with spinal cord epidural stimulation (SCES), 4 weeks of no intervention, and two more weeks of BWSTT + SCES. The participant presented with unstable resting seated blood pressure (BP; 131/66 mmHg). After retrospective analysis, resting systolic BP decreased and diastolic BP increased, yielding a safe mean arterial BP. There was a fivefold increase in BWSTT bouts per session, and percentage of body weight support decreased to 69%. BWSTT + SCES safely and effectively regulated resting BP and mitigated symptoms of orthostatic intolerance. These effects were not maintained after 4 weeks without training.

After spinal cord injury (SCI) physical activity levels decrease drastically, leading to numerous secondary health complications. Exoskeleton-assisted walking (EAW) may be one way to improve physical activity for adults with SCI and potentially alleviate secondary health complications. The effects of EAW may be limited, however, since exoskeletons induce passive movement for users who cannot volitionally contribute to walking. Trans-spinal stimulation (TSS) has shown the potential to enable those with even the most severe SCI to actively contribute to movements during EAW. To explore the effects of EAW training on improving secondary health complications in persons with SCI, participants with chronic (n = 8) were enrolled in an EAW program 2–3 times per week for 12 weeks. Anthropometrics (seated and supine waist and abdominal circumferences (WC and AC), body composition assessment (dual exposure x-ray absorptiometry-derived body fat percent, lean mass and total mass for the total body, legs, and trunk), and peak oxygen consumption (VO2 during a 6-minute walk test [6MWT]) were assessed before and after 12 weeks of EAW training. A subset of participants (n = 3) completed EAW training with concurrent TSS, and neuromuscular activity of locomotor muscles was assessed during a 10-m walk test (10MWT) with and without TSS following 12 weeks of EAW training. Upon completion of 12 weeks of training, reductions from baseline (BL) were found in seated WC (−2.2%, P = 0.036), seated AC (−2.9%, P = 0.05), and supine AC (−3.9%, P = 0.017). Percent fat was also reduced from BL for the total body (−1.4%, P = 0.018), leg (−1.3%, P = 0.018), and trunk (−2%, P = 0.036) regions. No effects were found for peak VO2. The addition of TSS for three individuals yielded individualized responses but generally increased knee extensor activity during EAW. Two of three participants who received TSS were also able to initiate more steps without additional assistance from the exoskeleton during a 10MWT. In summary, 12 weeks of EAW training significantly attenuated markers of obesity relevant to cardiometabolic health in eight men with chronic SCI. Changes in VO2 and neuromuscular activity with vs. without TSS were highly individualized and yielded no overall group effects.

ABSTRACT Introduction Spinal cord injury (SCI) produces diminished bone perfusion and bone loss in the paralyzed limbs. Activity-based physical therapy (ABPT) modalities that mobilize and/or reload the paralyzed limbs (e.g., bodyweight-supported treadmill training (BWSTT) and passive-isokinetic bicycle training) transiently promote lower-extremity blood flow (BF). However, it remains unknown whether ABPT alter resting-state bone BF or improve skeletal integrity after SCI. Methods Four-month-old male Sprague-Dawley rats received T9 laminectomy alone (SHAM; n = 13) or T9 laminectomy with severe contusion SCI (n = 48). On postsurgery day 7, SCI rats were stratified to undergo 3 wk of no ABPT, quadrupedal (q)BWSTT, or passive-isokinetic hindlimb bicycle training. Both ABPT regimens involved two 20-min bouts per day, performed 5 d·wk−1. We assessed locomotor recovery, bone turnover with serum assays and histomorphometry, distal femur bone microstructure using in vivo microcomputed tomography, and femur and tibia resting-state bone BF after in vivo microsphere infusion. Results All SCI animals displayed immediate hindlimb paralysis. SCI without ABPT exhibited uncoupled bone turnover and progressive cancellous and cortical bone loss. qBWSTT did not prevent these deficits. In comparison, hindlimb bicycle training suppressed surface-level bone resorption indices without suppressing bone formation indices and produced robust cancellous and cortical bone recovery at the distal femur. No bone BF deficits existed 4 wk after SCI, and neither qBWSTT nor bicycle altered resting-state bone perfusion or locomotor recovery. However, proximal tibia BF correlated with several histomorphometry-derived bone formation and resorption indices at this skeletal site across SCI groups. Conclusions These data indicate that passive-isokinetic bicycle training reversed cancellous and cortical bone loss after severe SCI through antiresorptive and/or bone anabolic actions, independent of locomotor recovery or changes in resting-state bone perfusion.

(1) Background: Resource intensive imaging tools have been employed to examine muscle and bone qualities after spinal cord injury (SCI). We tested the hypothesis that surface neuromuscular electrical stimulation (NMES) amplitude can be used to examine knee extensor muscle quality, distal femur and proximal tibia bone mineral density (BMD) in persons with SCI. (2) Methods: Seventeen persons (2 women) with chronic SCI participated in three weeks of NMES-resistance training twice weekly of 4 sets of 10 repetitions. Participants were classified according to the current amplitude (>100 mA) and the number of repetitions (>70 reps) of leg extension into greater (n = 8; 1 woman; group A) and lower (n = 9; 1 woman; group B) musculoskeletal qualities. Magnetic resonance imaging, dual energy x-ray absorptiometry, isometric peak torque, Modified Ashworth and Penn spasm frequency scales were conducted. (3) Results: In between group comparisons, current amplitude was lower (38–46%) in group A. Whole (27–32%; p = 0.02), absolute (26–33%, p = 0.02) thigh muscle and absolute knee extensor muscle cross-sectional areas (22–33%, p = 0.04) were greater in group A. Right distal femur (24%; p = 0.08) and proximal tibia (29%; p = 0.03) BMDs were lower in group B, and peak isometric torque (p < 0.01), extensor spasticity scorers (p = 0.04) and muscle spasm scores (p = 0.002) were significantly higher in group A. Regression models revealed that amplitude of current, repetitions and body weight can accurately predict musculoskeletal qualities in persons with SCI. (4) Conclusions: Surface NMES amplitude and repetitions of leg extension differentiated between SCI survivors with greater versus lower musculoskeletal qualities. The study may shed the light on the interplay between muscle and bone in persons with SCI.

Bone density decreases rapidly after spinal cord injury (SCI), increasing fracture risk. The most common fracture sites are at the knee (i.e., distal femur or proximal tibia). Despite this high fracture incidence, knee-specific scans for bone density using dual x-ray absorptiometry (DXA) were not available until 2014 and are still not routinely used in clinical practice today. This has made it difficult to determine the rehabilitation efficacy and hindered understanding of the long-term changes in knee areal bone density. The purpose of this investigation was to compare areal bone mineral density values for the knee from both total-body and knee-specific DXA scans in persons with SCI. A total of 20 participants (16 males) >1 yr-post spinal cord injury received two DXA scans; a total-body scan and a knee-specific scan. Standardized methods were used to create regions of interest to determine bone density of four regions - the epiphysis and metaphysis of the distal femur and proximal tibia - from the total-body scan. Linear regressions and Bland-Altman analyses were conducted to determine the correlation (r2) and agreement (mean bias ± 95% level of agreement) respectively between the two scan types for each region. Linear regression analyses showed strong significant (p < 0.001) relationships between the two scan types for the distal femur epiphysis (r2 = 0.88) and metaphysis (r2 = 0.98) and the proximal tibia epiphysis (r2 = 0.88) and metaphysis (r2 = 0.99). The mean bias ± 95% level of agreement were distal femur epiphysis (0.05 ± 0.1 g/cm2) and metaphysis (0.02 ± 0.04 g/cm2); proximal tibia epiphysis (-0.02 ± 0.1 g/cm2) and metaphysis (0.02 ± 0.03 g/cm2). Results suggest knee-specific bone density can be assessed using a total-body DXA scan. This may allow for more comprehensive use of DXA scans which would reduce the burden of multiple site-specific scans for persons with SCI and enable more widespread adoption of knee bone density assessment in this population.

Diminished bone perfusion develops in response to disuse and has been proposed as a mechanism underlying bone loss. Bone blood flow (BF) has not been investigated within the unique context of severe contusion spinal cord injury (SCI), a condition that produces neurogenic bone loss that is precipitated by disuse and other physiological consequences of central nervous system injury. Herein, 4-mo-old male Sprague-Dawley rats received T-9 laminectomy (SHAM) or laminectomy with severe contusion SCI (n = 20/group). Time course assessments of hindlimb bone microstructure and bone perfusion were performed in vivo at 1- and 2-wk postsurgery via microcomputed tomography (microCT) and intracardiac microsphere infusion, respectively, and bone turnover indices were determined via histomorphometry. Both groups exhibited cancellous bone loss beginning in the initial postsurgical week, with cancellous and cortical bone deficits progressing only in SCI thereafter. Trabecular bone deterioration coincided with uncoupled bone turnover after SCI, as indicated by signs of ongoing osteoclast-mediated bone resorption and a near-complete absence of osteoblasts and cancellous bone formation. Bone BF was not different between groups at 1 wk, when both groups displayed bone loss. In comparison, femur and tibia perfusion was 30%-40% lower in SCI versus SHAM at 2 wk, with the most pronounced regional BF deficits occurring at the distal femur. Significant associations existed between distal femur BF and cancellous and cortical bone loss indices. Our data provide the first direct evidence indicating that bone BF deficits develop in response to SCI and temporally coincide with suppressed bone formation and with cancellous and cortical bone deterioration. NEW & NOTEWORTHY We provide the first direct evidence indicating femur and tibia blood flow (BF) deficits exist in conscious (awake) rats after severe contusion spinal cord injury (SCI), with the distal femur displaying the largest BF deficits. Reduced bone perfusion temporally coincided with unopposed bone resorption, as indicated by ongoing osteoclast-mediated bone resorption and a near absence of surface-level bone formation indices, which resulted in severe cancellous and cortical microstructural deterioration after SCI.

The purpose of this article is to highlight the importance of considering sleep-disordered breathing (SDB) as a potential confounder to rehabilitation research interventions in spinal cord injury (SCI). SDB is highly prevalent in SCI, with increased prevalence in individuals with higher and more severe lesions, and the criterion standard treatment with continuous positive airway pressure remains problematic. Despite its high prevalence, SDB is often untested and untreated in individuals with SCI. In individuals without SCI, SDB is known to negatively affect physical function and many of the physiological systems that negatively affect physical rehabilitation in SCI. Thus, owing to the high prevalence, under testing, low treatment adherence, and known negative effect on the physical function, it is contended that underdiagnosed SDB in SCI may be confounding physical rehabilitation research studies in individuals with SCI. Studies investigating the effect of treating SDB and its effect on physical rehabilitation in SCI were unable to be located. Thus, studies investigating the likely integrated relationship among physical rehabilitation, SDB, and proper treatment of SDB in SCI are needed. Owing to rapid growth in both sleep medicine and physical rehabilitation intervention research in SCI, the authors contend it is the appropriate time to begin the conversations and collaborations between these fields. We discuss a general overview of SDB and physical training modalities, as well as how SDB could be affecting these studies.

This review of literature provides the latest evidence involving invasive and non-invasive uses of electrical stimulation therapies that assist in restoring functional abilities and the enhancement of quality of life in those with spinal cord injuries. The review includes neuromuscular electrical stimulation and functional electrical stimulation activities that promote improved body composition changes and increased muscular strength, which have been shown to improve abilities in activities of daily living. Recommendations for optimizing electrical stimulation parameters are also reported. Electrical stimulation is also used to enhance the skills of reaching, grasping, standing, and walking, among other activities of daily living. Additionally, we report on the use of invasive and non-invasive neuromodulation techniques targeting improved mobility, including standing, postural control, and assisted walking. We attempt to summarize the effects of epidural stimulation on cardiovascular performance and provide a mechanistic explanation to the current research findings. Future trends such as the combination of epidural stimulation and exoskeletal-assisted walking are also discussed.

Acute intermittent hypoxia (AIH) is a strategy to improve motor output in humans with neuromotor impairment. A single AIH session increases the amplitude of motor evoked potentials (MEP) in a finger muscle (first dorsal intemsseous), demonstrating enhanced corticospinal neurotransmission. Since AIH elicits phrenic/diaphragm long-term facilitation (LTF) in rodent models, we tested the hypothesis that AIH augments diaphragm MEPs in humans. Eleven healthy adults (7 males, age = 29 +/- 6 years) were tested. Transcranial and cervical magnetic stimulation were used to induce diaphragm MEPs and compound muscle action potentials (CMAP) recorded by surface EMG, respectively. Stimulus-response curves were generated prior to and 30-60 min after AIH. Diaphragm LTF was assessed by measurement of integrated EMG burst amplitude and frequency during eupnoeic breathing before and after AIH. Following baseline measurements, AIH was delivered from an oxygen generator connected to a facemask under poikilocapnic conditions (15 one minute episodes of 9% inspired oxygen with one minute room air intervals). There were no detectable changes in MEP (-1.5 +/- 12.1%, p = 0.96) or CMAP (+0.1 +/- 7.8%, p = 0.97) amplitudes across the stimulus-response curve. At stimulation intensities approximating 50% of the difference between minimum and maximum baseline amplitudes, MEP and CMAP amplitudes were also unchanged (p > 0.05). Further, no AIH effect was observed on diaphragm EMG activity during eupnoea post-AIH > 0.05). We conclude that unlike hand muscles, poikilocapnic AIH does not enhance diaphragm MEPs or produce diaphragm LTF in healthy humans.

After spinal cord injury (SCI) respiratory complications are a leading cause of morbidity and mortality. Acute intermittent hypoxia (AIH) triggers spinal respiratory motor plasticity in rodent models, and repetitive AIH may have the potential to restore breathing capacity in those with SCI. As an initial approach to provide proof of principle for such effects, we tested single-session AIH effects on breathing function in adults with chronic SCI. 17 adults (13 males; 34.1 +/- 14.5 years old; 13 motor complete SCI; >6 months post injury) completed two randomly ordered sessions, AIH versus sham. AIH consisted of 15, 1-min episodes (hypoxia: 10.3% O2; sham: 21% O2) interspersed with room air breathing (1.5 min, 21% oxygen); no attempt was made to regulate arterial CO2 levels. Blood oxygen saturation (SpO2), maximal inspiratory and expiratory pressures (MIP; MEP), forced vital capacity (FVC), and mouth occlusion pressure within 0.1 s (P0.1) were assessed. Outcomes were compared using nonparametric Wilcoxon's tests, or a 2 x 2 ANOVA. Baseline SpO2 was 97.2 +/- 1.3% and was unchanged during sham experiments. During hypoxic episodes, SpO2 decreased to 84.7 +/- 0.9%, and returned to baseline levels during normoxic intervals. Outcomes were unchanged from baseline post-sham. Greater increases in MIP were evident post AIH vs. sham (median values; +10.8 cmH2O vs. -2.6 cmH2O respectively, 95% confidence interval (-18.7) - (-4.3), p = .006) with a moderate Cohen's effect size (0.68). P0.1, MEP and FVC did not change postAIH. A single AIH session increased maximal inspiratory pressure generation, but not other breathing functions in adults with SCI. Reasons may include greater spared innervation to inspiratory versus expiratory muscles or differences in the capacity for AIH-induced plasticity in inspiratory motor neuron pools. Based on our findings, the therapeutic potential of AIH on breathing capacity in people with SCI warrants further investigation.

Spinal interneurons which discharge in phase with the respiratory cycle have been repeatedly described over the last 50 years. These spinal respiratory interneurons are part of a complex propriospinal network that is synaptically coupled with respiratory motoneurons. This article summarizes current knowledge regarding spinal respiratory interneurons and emphasizes chemical, electrical and physiological methods for activating spinal respiratory neural circuits. Collectively, the work reviewed here shows that activating spinal interneurons can have a powerful impact on spinal respiratory motor output, and can even drive rhythmic bursting in respiratory motoneuron pools under certain conditions. We propose that the primary functions of spinal respiratory neurons include 1) shaping the respiratory pattern into the final efferent motor output from the spinal respiratory nerves; 2) coordinating respiratory muscle activation across the spinal neuraxis; 3) coordinating postural, locomotor and respiratory movements, and 4) enabling plasticity of respiratory motor output in health and disease.

Acute intermittent hypoxia (AIH) and task-specific training (TST) synergistically improve motor function after spinal cord injury; however, mechanisms underlying this synergistic relation are unknown. We propose a hypothetical working model of neural network and cellular elements to explain AIH-TST synergy. Our goal is to forecast experiments necessary to advance our understanding and optimize the neurotherapeutic potential of AIH-TST.

After spinal cord injury (SCI), respiratory complications are a leading cause of morbidity and mortality. A novel technique, acute intermittent hypoxia (AIH) triggers spinal motor plasticity, and can increase tidal volume at rest in humans with SCI. Only sparse, inconclusive literature exists about the effects of AIH on maximal effort respiratory maneuvers after SCI. PURPOSE: this pilot study seeks to investigate the effects of AIH on maximal effort respiratory ability in adults with SCI. METHODS: 4 community-dwelling, adult males with SCI completed a single AIH or sham treatment in randomized order, 7+ days apart. AIH consisted of 15, 1 minute periods breathing a hypoxic gas mixture (9-13% oxygen), interspersed with 1.5 minute periods breathing room air. Sham treatments replicated AIH, but used air (21% oxygen) versus hypoxic episodes. Blood oxygen saturation was monitored. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were recorded prior to and 30 minutes after AIH and sham. Pre and post scores for each condition were compared using non-parametric Friedman’s two-way ANOVA by ranks. RESULTS: Baseline blood oxygen saturation averaged 97 ± 2%. During AIH, saturation decreased to an average of 82 ± 3%, then returned to baseline. Blood oxygen saturation remained stable during sham treatments. MIP did not differ at any point on either day (pre-AIH, 90.4 cmH2O +/- 34.33; post-AIH, 99.35 cmH2O +/- 17.6; pre-sham, 98.8 cmH2O +/- 21.3; post-sham, 85.2 cmH2O +/- 17.3; Χ2=6.231, p=.101). MEP did not differ at any point on either day (pre-AIH, 91.2 cmH2O +/- 23.1; post-AIH 93.4 cmH2O +/- 26.8; pre-sham 80 cmH2O +/-25.6; post-sham 85.4 +/- 21.1; Χ2= 2.4, p = .494) Individually, 3 participants increased MIP after AIH, but decreased after sham; the fourth participant increased MEP after AIH, but decreased after sham. CONCLUSION: These pilot study results suggest AIH may affect maximal effort respiratory ability in adults with SCI. Although group means did not differ, individual outcomes varied with AIH improving one outcome in each participant versus sham. Further research is warranted to examine response variations and to determine the therapeutic potential of AIH after SCI. Support: Brooks-PHHP Research Collaboration; Center for Respiratory Research and Rehabilitation at the University of Florida.