Chronic Cervical Spinal Cord Injury Research Articles

Combined therapeutic acute intermittent hypercapnic hypoxia and exercise-based respiratory training improve breathing after chronic cervical spinal cord injury

Therapeutic acute intermittent hypoxia (tAIH) is simple, safe, and effective means of inducing respiratory motor plasticity and improving breathing in rodent models of acute cervical spinal cord injury (SCI). Unfortunately, tAIH effects on breathing function are less effective with chronic injury. On the other hand, tAIH restores non-respiratory (limb) motor function with chronic SCI, but only when combined with task specific training (TST). The effcacy of combined tAIH and respiratory TST on breathing ability in rodent models (or humans) with chronic SCI has not been investigated. Here, we explore the potential for tAIH and respiratory TST to increase breathing ability; we further differentiate automatic vs. volitional TST, since the ability to sustain independent breathing is dependent on automatic (and not volitional) breathing function, which relies on distinct neural pathways. Physical exercise increases breathing automatically in direct proportion to metabolic rate, regulating arterial blood gases by a mechanism independent of chemoreceptor feedback (i.e. “exercise hyperpnea”). Thus, in ongoing studies, we are exploring treadmill training as a form of task-specific respiratory training in rats with chronic cervical SCI. We focus on a refined tAIH protocol that combines hypoxia with hypercapnia during each episode (therapeutic acute intermittent hypercapnic hypoxia; or tAIHH), since preliminary data suggests that tAIHH is a more potent stimulus to respiratory motor plasticity vs. tAIH alone. Adult Sprague-Dawley rats with chronic C2 spinal cord hemisection were treated with either 4 weeks of either tAIHH (10, 5-min episodes of 10.5% O2, 4% inspired CO2) combined with treadmill exercise (30 min total run time, 30 cm/sec) or tAIHH alone. Breathing function was assessed in awake, freely moving rats using whole-body plethysmography. In preliminary analyses, breathing capacity (i.e., minute ventilation in response to maximal chemoreflex activation) was increased in chronically injured rats treated with daily tAIHH paired with treadmill training relative to rats treated with tAIHH alone (120.7mL/min/100g vs. 98.7mL/min/100g; p=0.0018). Similar improvements in breathing function were not observed with tAIHH alone. These are the first studies to investigate the therapeutic effcacy of combined tAIH and exercise-based respiratory training targeting automatic breathing. These initial results indicate that, similar to non-respiratory motor systems, pairing tAIHH with respiratory TST improves breathing function in rodents with chronic cervical SCI. Supported by: Craig H. Neilsen Foundation (SCIRP891379), and the McKnight Brain Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prolonged intermittent hypoxia differentially regulates phrenic motor neuron serotonin receptor expression in rats following chronic cervical spinal cord injury

Low-dose (< 2 h/day), acute intermittent hypoxia (AIH) elicits multiple forms of serotonin-dependent phrenic motor plasticity and is emerging as a promising therapeutic strategy to restore respiratory and non-respiratory motor function after spinal cord injury (SCI). In contrast, high-dose (> 8 h/day), chronic intermittent hypoxia (CIH) undermines some forms of serotonin-dependent phrenic motor plasticity and elicits pathology. CIH is a hallmark of sleep disordered breathing, which is highly prevalent in individuals with cervical SCI. Interestingly, AIH and CIH preconditioning differentially impact phrenic motor plasticity. Although mechanisms of AIH-induced plasticity in the phrenic motor system are well-described in naïve rats, we know little concerning how these mechanisms are affected by chronic SCI or intermittent hypoxia preconditioning. Thus, in a rat model of chronic, incomplete cervical SCI (lateral spinal hemisection at C2 (C2Hx), we assessed serotonin type 2 A, 2B and 7 receptor expression in and near phrenic motor neurons and compared: 1) intact vs. chronically injured rats; and 2) the impact of preconditioning with varied “doses” of intermittent hypoxia (IH). While there were no effects of chronic injury or intermittent hypoxia alone, CIH affected multiple receptors in rats with chronic C2Hx. Specifically, CIH preconditioning (8 h/day; 28 days) increased serotonin 2 A and 7 receptor expression exclusively in rats with chronic C2Hx. Understanding the complex, context-specific interactions between chronic SCI and CIH and how this ultimately impacts phrenic motor plasticity is important as we leverage AIH-induced motor plasticity to restore breathing and other non-respiratory motor functions in people with chronic SCI.

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury

High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury (though this effect depended on the anesthetic regimen used during recording), while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.

Participation and autonomy, independence in activities of daily living and upper extremity functioning in individuals with spinal cord injury

Improvements in care and rehabilitation have resulted in a higher proportion of people living with spinal cord injury (SCI), which calls for an increased focus on participation and autonomy. This observational cross-sectional study investigated the impact of SCI on autonomy and how it correlates to activity performance and upper extremity functioning. A total of 25 adults (mean age 58 years) with chronic cervical or thoracic SCI were included. Self-perceived autonomy was measured with Impact on Participation and Autonomy questionnaire, independence in activities of daily living (ADL) with Spinal Cord Independence Measure, upper extremity functioning with Action Research Arm Test (ARAT) and kinematic measures of the drinking task. The results showed that most participants perceived injury-related restrictions in outdoor autonomy (80%), family role (76%), and in indoor autonomy (72%). Independence in self-care (r = 0.72), mobility (r = 0.59) and upper extremity kinematics of movement time (r = 0.63) and smoothness (r = 0.49) were correlated to indoors autonomy. Social life autonomy was correlated to self-care (r = 0.50) and ARAT (r = 0.41). In conclusion, autonomy was perceived restricted after SCI in several major life areas and correlated with independence in ADL and upper extremity functioning. The aspects of autonomy should be considered more in goal setting and clinical decision-making.

Soluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: a first-in-human and randomised clinical trial

Spinal cord injury (SCI) causes neural disconnection and persistent neurological deficits, so axon sprouting and plasticity might promote recovery. Soluble Nogo-Receptor-Fc decoy (AXER-204) blocks inhibitors of axon growth and promotes recovery of motor function after SCI in animals. This first-in-human and randomised trial sought to determine primarily the safety and pharmacokinetics of AXER-204 in individuals with chronic SCI, and secondarily its effect on recovery. We conducted a two-part study in adults (aged 18-65 years) with chronic (>1 year) cervical traumatic SCI at six rehabilitation centres in the USA. In part 1, AXER-204 was delivered open label as single intrathecal doses of 3 mg, 30 mg, 90 mg, or 200 mg, with primary outcomes of safety and pharmacokinetics. Part 2 was a randomised, parallel, double-blind comparison of six intrathecal doses of 200 mg AXER-204 over 104 days versus placebo. Participants were randomly allocated (1:1) by investigators using a central electronic system, stratified in blocks of four by American Spinal Injury Association Impairment Scale grade and receipt of AXER-204 in part 1. All investigators and patients were masked to treatment allocation until at least day 169. The part 2 primary objectives were safety and pharmacokinetics, with a key secondary objective to assess change in International Standards for Neurological Classification of SCI (ISNCSCI) Upper Extremity Motor Score (UEMS) at day 169 for all enrolled participants. This trial is registered with ClinicalTrials.gov, NCT03989440, and is completed. We treated 24 participants in part 1 (six per dose; 18 men, six women), and 27 participants in part 2 (13 placebo, 14 AXER-204; 23 men, four women), between June 20, 2019, and June 21, 2022. There were no deaths and no discontinuations from the study due to an adverse event in part 1 and 2. In part 2, treatment-related adverse events were of similar incidence in AXER-204 and placebo groups (ten [71%] vs nine [69%]). Headache was the most common treatment-related adverse event (five [21%] in part 1, 11 [41%] in part 2). In part 1, AXER-204 reached mean maximal CSF concentration 1 day after dosing with 200 mg of 412 000 ng/mL (SD 129 000), exceeding those concentrations that were efficacious in animal studies. In part 2, mean changes from baseline to day 169 in ISNCSCI UEMS were 1·5 (SD 3·3) for AXER-204 and 0·9 (2·3) for placebo (mean difference 0·54, 95% CI -1·48 to 2·55; p=0·59). This study delivers the first, to our knowledge, clinical trial of a rationally designed pharmacological treatment intended to promote neural repair in chronic SCI. AXER-204 appeared safe and reached target CSF concentrations; exploratory biomarker results were consistent with target engagement and synaptic stabilisation. Post-hoc subgroup analyses suggest that future trials could investigate efficacy in patients with moderately severe SCI without prior AXER-204 exposure. Wings for Life Foundation, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, National Institute on Drug Abuse, and ReNetX Bio.

Testing a Novel Wearable Device for Motor Recovery of the Elbow Extensor Triceps Brachii in Chronic Spinal Cord Injury.

After corticospinal tract damage, reticulospinal connections to motoneurons strengthen preferentially to flexor muscles. This could contribute to the disproportionately poor recovery of extensors often seen after spinal cord injury (SCI) and stroke. In this study, we paired electrical stimulation over the triceps muscle with auditory clicks, using a wearable device to deliver stimuli over a prolonged period of time. Healthy human volunteers wore the stimulation device for ∼6 h and a variety of electrophysiological assessments were used to measure changes in triceps motor output. In contrast to previous results in the biceps muscle, paired stimulation: (1) did not increase the StartReact effect; (2) did not decrease the suppression of responses to transcranial magnetic brain stimulation (TMS) following a loud sound; (3) did not enhance muscle responses elicited by a TMS coil oriented to induce anterior-posterior current. In a second study, chronic cervical SCI survivors wore the stimulation device for ∼4 h every day for four weeks; this was compared with a four-week period without wearing the device. Functional and electrophysiological assessments were repeated at week 0, week 4, and week 8. No significant changes were observed in electrophysiological assessments after paired stimulation. Functional measurements such as maximal force and variability and speed of trajectories made during a planar reaching task also remained unchanged. Our results suggest that the triceps muscle shows less potential for plasticity than biceps; pairing clicks with muscle stimulation does not seem beneficial in enhancing triceps recovery after SCI.

Safety and Feasibility of Cervical and Thoracic Transcutaneous Spinal Cord Stimulation to Improve Hand Motor Function in Children With Chronic Spinal Cord Injury

ObjectiveIn adults with cervical spinal cord injury (SCI), transcutaneous spinal stimulation (scTS) has improved upper extremity strength and control. This novel noninvasive neurotherapeutic approach combined with training may modulate the inherent developmental plasticity of children with SCI, providing even greater improvements than training or stimulation alone. Because children with SCI represent a vulnerable population, we first must establish the safety and feasibility of any potential novel therapeutic approach. The objectives of this pilot study were to determine the safety, feasibility, and proof of principle of cervical and thoracic scTS for short-term effect on upper extremity strength in children with SCI. Materials and MethodsIn this nonrandomized, within-subject repeated measure design, seven participants with chronic cervical SCI performed upper extremity motor tasks without and with cervical (C3–C4 and C6–C7) and thoracic (T10–T11) site scTS. Safety and feasibility of using cervical and thoracic sites scTS were determined by the frequency count of anticipated and unanticipated risks (eg, pain, numbness). Proof-of-principle concept was tested via change in force production during hand motor tasks. ResultsAll seven participants tolerated cervical and thoracic scTS across the three days, with a wide range of stimulation intensities (cervical sites = 20–70 mA and thoracic site = 25–190 mA). Skin redness at the stimulation sites was observed in four of 21 assessments (19%) and dissipated in a few hours. No episode of autonomic dysreflexia was observed or reported. Hemodynamic parameters (systolic blood pressure and heart rate) remained within stable limits (p > 0.05) throughout the assessment time points at baseline, with scTS, and after the experiment. Hand-grip and wrist-extension strength increased (p < 0.05) with scTS. ConclusionsWe indicated that short-term application of scTS via two cervical and one thoracic site is safe and feasible in children with SCI and resulted in immediate improvements in hand-grip and wrist-extension strength in the presence of scTS. Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT04032990.

Daily low dose ampakine treatment causes a sustained increase in diaphragm activation following chronic cervical spinal cord injury

Cervical spinal cord injuries (SCIs) result in significant and long-lasting respiratory compromise, leading to morbidity and mortality in the SCI patient population. There is a critical need to develop therapies to counter this respiratory insufficiency. Ampakines are positive allosteric modulators of AMPA receptors that have been shown to alleviate respiratory depression following neuromuscular disorders or opioid use. We have recently shown that low dose (5mg/kg) ampakines can stimulate diaphragm muscle activation and increase overall ventilation at acute and sub-acute timepoints post C2 spinal hemisection injury in rats. Our next step in the translation pathway is to transition to a repeated daily ampakine exposure paradigm after a chronic SCI, as part of a rehabilitation approach. Previous studies in hippocampal slices have shown that repeated dosing with ampakines can support long term potentiation mechanisms and upregulate neuroplasticity related genes. In the present study, we hypothesized that daily treatment with ampakines in chronically injured rats will cause a sustained increase in diaphragm motor output following a high cervical SCI. Over the period of 8-12 weeks after C2 spinal hemisection injury, rats received daily intra-peritoneal injections of ampakine CX717 (5 mg/kg, n=8; 4M, 4F) or CX1739 (5 mg/kg, n=8; 4M, 4F) or vehicle (2-hydroxypropyl-beta-cyclodextrin; HPCD; n=8; 4M, 4F). Ventilation was measured using whole body plethysmography and diaphragm electromyogram (EMG) was assessed using in-dwelling muscle electrodes. Recordings were conducted at 8-, 10- and 12-weeks post injury. The acute response to intravenous ampakine administration was also assessed at the chronically injured timepoint of 8 weeks. Both CX717 and CX1739 were effective at stimulating ipsilateral diaphragm muscle activity (51 ± 12% and 32 ± 5% increase, respectively; p=0.002) and tidal volume (19 ± 7% and 25 ± 7% respectively; p=0.002) as compared to the HPCD group (EMG: 4 ± 3%, tidal volume: -3 ± 5%) at 8 weeks post C2 hemisection. The effect of CX717 treatment was sustained up to 15 minutes where as CX1739 returned close to baseline by 15 minutes. With daily ampakine treatment, we observed a progressive increase (treatment effect: p=0.009) in ipsilateral diaphragm EMG output during eupneic breathing at the 10- and 12-week time points in both the CX717 (13 ± 5%, 18 ± 7% respectively) and CX1739 (9 ± 4%, 17 ± 7% respectively) treated groups as compared to the EMG output at the onset of the daily ampakine therapy. No change in EMG output was observed in the daily HPCD group (-2 ± 3%, -0.5 ± 5% respectively). There was no impact of daily ampakine treatment on respiratory rate, which may indicate that the drug is acting on spinal motoneurons (vs. a medullary mechanism). Our data indicates that daily treatment with ampakines is a promising therapy to stimulate long-lasting neuroplastic changes in respiratory circuits to promote functional recovery following SCI. 1R01HL139708-01A1 (DDF), 1 R01 HL153140-01 (DDF), Craig Neilsen Foundation Fellowship (SR) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Combined acute intermittent hypoxia and task specific training with hypercapnia improve breathing capacity after chronic cervical spinal cord injury

Therapeutic acute intermittent hypoxia (tAIH) is simple, safe, and effective means of inducing respiratory motor plasticity and improving breathing in rodent models of acute cervical spinal cord injury (SCI). Unfortunately, tAIH effects on breathing function are less effective with chronic injury. On the other hand, tAIH restores non-respiratory (limb) motor function with chronic SCI, but only when combined with task specific training (TST). The efficacy of combined tAIH and respiratory TST on breathing ability in rodent models (or humans) with chronic SCI has not been investigated. Here, we explore the potential for tAIH and respiratory TST to increase breathing ability; we further differentiate automatic vs. volitional TST, since the ability to sustain independent breathing is dependent on automatic (and not volitional) breathing function, which relies on distinct neural pathways. Hypercapnia is a powerful respiratory stimulant, increasing breathing via (automatic) chemoreceptor feedback, independent of voluntary control. Thus, we explore the impact of 7 days of tAIH (10, 5-min episodes of 10.5% O2) combined with automatic, hypercapnia-induced TST (30 min, 9% inspired CO2) on breathing in unanesthetized rats with chronic (7-8 weeks) C2 spinal hemisection. In preliminary analyses, breathing capacity (i.e., ventilatory response to maximal chemoreflex activation) increased following treatment with daily AIH combined with hypercapnia (i.e., respiratory TST) in rats with chronic C2 hemisection (~17% increase). Similar improvements in breathing function were not observed with tAIH or respiratory TST alone. These are the first studies to investigate the therapeutic efficacy of combined tAIH and respiratory TST targeting automatic breathing. These initial results indicate that, similar to non-respiratory motor systems, pairing tAIH with TST improves breathing function in rodents with chronic cervical SCI. Craig H. Neilsen Foundation (SCIRP891379), NIH HL147554, and the McKnight Brain Institute This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Increased paired stimuli enhance corticospinal-motoneuronal plasticity in humans with spinal cord injury.

Paired corticospinal-motoneuronal stimulation (PCMS) has been used to enhance corticospinal excitability and functional outcomes in humans with spinal cord injury (SCI). Here, we examined the effect of increasing the number of paired pulses on PCMS-induced plasticity. During PCMS, corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the hand 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. We tested motor-evoked potentials (MEPs) elicited by TMS over the hand motor cortex and electrical stimulation at the cervicomedullary junction (CMEPs) in the FDI muscle before and after 180 paired pulses (PCMS-180) followed up by another 180 paired pulses (PCMS-360) in humans with and without chronic incomplete cervical SCI. The nine-hole-peg-test (9HPT) was measured before and after PCMS paired pulses in individuals with SCI. We found that the size of MEPs and CMEPs increased after PCMS-180 in both groups compared with baseline and further increased after PCMS-360 in participants with SCI, suggesting a spinal origin for these effects. Notably, in people with SCI, the time to complete the 9HPT decreased after PCMS-180 and further decreased after PCMS-360 compared with baseline but not when the 9HPT was repeated overtime. Our findings demonstrate that increasing the number of PCMS paired pulses potentiates corticospinal excitability and voluntary motor output after SCI, likely through spinal plasticity. This proof-of-principle study suggests that increasing the PCMS dose represents a strategy to boost voluntary motor output after SCI.NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation (PCMS) has been used to enhance corticospinal excitability and functional outcomes in humans with spinal cord injury (SCI). Here, we demonstrate that 360 paired pulses resulted in larger increases in motor-evoked potential size in a hand muscle and in a better ability to complete the nine-hold-peg-test compared with 180 paired pulses in people with SCI. This proof-of-principle study suggests that increasing the PCMS dose represents a strategy to boost motor output after SCI.

Developing guiding principles for technology-based rehabilitation program by engaging people with motor incomplete tetraplegia

BackgroundTechnology-aided rehabilitation is well established in the field of neurologic rehabilitation. Despite the widespread availability, the development of technology-based interventions that incorporate perspectives of the people who will use them is lacking.ObjectivesThis qualitative study aims to understand how people with chronic motor incomplete cervical spinal cord injury view rehabilitation technology to improve upper extremity function and neuromuscular recovery to inform future intervention development.MethodsSeven participants with chronic upper extremity impairment due to spinal cord injury/dysfunction trialed five rehabilitation technology devices. After a 30–45 min trial for each device, participants engaged in a semi-structured interview. Interviews were analyzed using a qualitative approach to explore the experience using and understand features that support motivation to use of rehabilitation technology.ResultsQualitative analysis revealed three major themes: (1) devices must be flexible to meet diverse needs; (2) intervention protocols must be individualized to address unique needs and contexts of users; (3) intervention protocols should be developed and updated by a skilled clinician. These themes and subthemes were used to describe guiding principles to inform future intervention design.ConclusionThe experiences of people with cervical spinal cord injury can be elicited as part of the intervention design process to systematically develop protocols for future feasibility trials. The findings from this study can be used to inform the development of technology-aided rehabilitation programs to improve upper extremity function in people with chronic motor incomplete tetraplegia.Clinical trials registration number: NCT04000256

Tetraplegia is associated with increased hypoxic ventilatory response during nonrapid eye movement sleep

People with cervical spinal cord injury (SCI) are likely to experience chronic intermittent hypoxia while sleeping. The physiological effects of intermittent hypoxia on the respiratory system during spontaneous sleep in individuals with chronic cervical SCI are unknown. We hypothesized that individuals with cervical SCI would demonstrate higher short‐ and long‐term ventilatory responses to acute intermittent hypoxia (AIH) exposure than individuals with thoracic SCI during sleep. Twenty participants (10 with cervical SCI [9 male] and 10 with thoracic SCI [6 male]) underwent an AIH and sham protocol during sleep. During the AIH protocol, each participant experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2) and 40% carbon dioxide (CO2) to achieve an oxygen saturation of less than 90%. This was followed by two breaths of 100% oxygen (O2). Measurements were collected before, during, and 40 min after the AIH protocol to obtain ventilatory data. During the sham protocol, participants breathed room air for the same amount of time that elapsed during the AIH protocol and at approximately the same time of night. Hypoxic ventilatory response (HVR) during the AIH protocol was significantly higher in participants with cervical SCI than those with thoracic SCI. There was no significant difference in minute ventilation (V .E.), tidal volume (V .T.), or respiratory frequency (f) during the recovery period after AIH in cervical SCI compared to thoracic SCI groups. Individuals with cervical SCI demonstrated a significant short‐term increase in HVR compared to thoracic SCI. However, there was no evidence of ventilatory long‐term facilitation following AIH in either group.

Effects of Remote Ischemic Conditioning on Hand Engagement in individuals with Spinal cord Injury (RICHES): protocol for a pilot crossover study

​​​​​​ Background: Most spinal cord injuries (SCI) are not full transections, indicating that residual nerve circuits are retained. Rehabilitation interventions have been shown to beneficially reorganize motor pathways in the brain, corticospinal tract, and at the spinal level. However, rehabilitation training require a large number of repetitions, and intervention effects may be absent or show transient retention. Therefore, the need remains for an effective approach to synergistically improve the amount and duration of neuroplasticity in combination with other interventions. Remote ischemic conditioning (RIC) demonstrates several potential advantages as a candidate for such an approach. Therefore, we propose a protocol to investigate RIC coupled with physical training to promote neuroplasticity in hand muscles. Methods: This will be a prospective randomized-order crossover trial to be performed in eight able-bodied participants and eight participants with chronic cervical SCI. Patients will participate in two experimental sessions consisting of either active or sham RIC preceding a bout of pinch movement exercise. Serial evaluations will be conducted at baseline, after RIC, immediately after pinch exercise, and follow up 15-minutes later. The primary outcome is the change in corticospinal excitability (primarily measured by the motor evoked potential of abductor pollicis brevis muscle). Secondary outcomes will include maximal volitional pinch force, and inflammatory biomarkers. To ensure safety, we will monitor tolerability and hemodynamic responses during RIC. Discussion: This protocol will be the first to test RIC in people with cervical SCI and to investigate whether RIC alters corticospinal excitability. By sharing the details of our protocol, we hope other interested researchers will seek to investigate similar approaches - depending on overlap with the current study and mutual sharing of participant-level data, this could increase the sample size, power, and generalizability of the analysis and results. Trial registration:ClinicalTrial.gov, ID: NCT03851302; Date of registration: February 22, 2019.

Multisite Transcutaneous Spinal Stimulation for Walking and Autonomic Recovery in Motor-Incomplete Tetraplegia: A Single-Subject Design.

ObjectiveThis study investigated the effect of cervical and lumbar transcutaneous spinal cord stimulation (tSCS) combined with intensive training to improve walking and autonomic function after chronic spinal cord injury (SCI).MethodsTwo 64-year-old men with chronic motor incomplete cervical SCI participated in this single-subject design study. They each underwent 2 months of intensive locomotor training and 2 months of multisite cervical and lumbosacral tSCS paired with intensive locomotor training.ResultsThe improvement in 6-Minute Walk Test distance after 2 months of tSCS with intensive training was threefold greater than after locomotor training alone. Both participants improved balance ability measured by the Berg Balance Scale and increased their ability to engage in daily home exercises. Gait analysis demonstrated increased step length for each individual. Both participants experienced improved sensation and bowel function, and 1 participant eliminated the need for intermittent catheterization after the stimulation phase of the study.ConclusionThese results suggest that noninvasive spinal cord stimulation might promote recovery of locomotor and autonomic functions beyond traditional gait training in people with chronic incomplete cervical SCI.ImpactMultisite transcutaneous spinal stimulation may induce neuroplasticity of the spinal networks and confer functional benefits following chronic cervical SCI.

Controversies in cervical spine trauma: The role of timing of surgical decompression and the use of methylprednisolone sodium succinate in spinal cord injury. A narrative and updated systematic review

Traumatic spinal cord injuries (SCIs) have devastating physical, social, and financial consequences for both patients and their families. SCIs most frequently occur at the cervical spine level, and these injuries are particularly prone to causing debilitating functional impairments. Unfortunately, no effective neuroregenerative therapeutic approaches capable of reversing lost neurologic and functional impairments exist, resulting in a large number of patients living with the persistent disability caused by a chronic cervical SCI. Over the past decades, a multitude of nonpharmacologic and pharmacologic neuroprotective strategies have been intensely investigated, including the timing of surgical decompression and the role of methylprednisolone sodium succinate (MPSS) in patients with acute SCI. These strategies have been the source of vibrant debate surrounding their potential risks and benefits. Our aim in this combined narrative and updated systematic review is to provide an assessment on the timing of surgical decompression as well as the role of high-dose MPSS treatment in patients with traumatic SCIs, with a special emphasis on the cervically injured subpopulation. Based on the current literature, there is strong evidence to support early surgical decompression within 24 h of injury to promote enhanced neurologic recovery. Meanwhile, moderate evidence supports the early initiation of a 24-h high-dose MPSS treatment within 8 h of injury, particularly in patients with a cervical SCI.

Posteroanterior Cervical Transcutaneous Spinal Cord Stimulation: Interactions with Cortical and Peripheral Nerve Stimulation

Transcutaneous spinal cord stimulation (TSCS) has demonstrated potential to beneficially modulate spinal cord motor and autonomic circuitry. We are interested in pairing cervical TSCS with other forms of nervous system stimulation to enhance synaptic plasticity in circuits serving hand function. We use a novel configuration for cervical TSCS in which the anode is placed anteriorly over ~C4–C5 and the cathode posteriorly over ~T2–T4. We measured the effects of single pulses of TSCS paired with single pulses of motor cortex or median nerve stimulation timed to arrive at the cervical spinal cord at varying intervals. In 13 participants with and 15 participants without chronic cervical spinal cord injury, we observed that subthreshold TSCS facilitates hand muscle responses to motor cortex stimulation, with a tendency toward greater facilitation when TSCS is timed to arrive at cervical synapses simultaneously or up to 10 milliseconds after cortical stimulus arrival. Single pulses of subthreshold TSCS had no effect on the amplitudes of median H-reflex responses or F-wave responses. These findings support a model in which TSCS paired with appropriately timed cortical stimulation has the potential to facilitate convergent transmission between descending motor circuits, segmental afferents, and spinal motor neurons serving the hand. Studies with larger numbers of participants and repetitively paired cortical and spinal stimulation are needed.

Comparative effectiveness of multisession transcranial direct current stimulation and peripheral nerve somatosensory stimulation for enhancing corticospinal excitability and improving hand function in individuals with chronic cervical spinal cord injury

Comparative effectiveness of multisession transcranial direct current stimulation and peripheral nerve somatosensory stimulation for enhancing corticospinal excitability and improving hand function in individuals with chronic cervical spinal cord injury

Abnormal changes in motor cortical maps in humans with spinal cord injury.

The functional role of motor cortical reorganization following spinal cord injury (SCI) remains largely unknown. Here, we tested motor maps in a hand muscle at rest and during voluntary contraction of the hand with and without voluntary contraction of a proximal arm muscle. Motor map area in participants with SCI decreased during hand voluntary contraction and further decreased during additional contraction of a proximal arm muscle compared with rest. In contrast, motor map area in controls increased during the same motor tasks. Participants with SCI with more severe sensory deficits in the hand showed larger decreases in motor map area. Ten minutes of hand muscle-tendon vibration increased the motor map area during voluntary contraction in SCI participants. These novel findings suggest that abnormal changes in motor cortical maps during voluntary contraction after SCI can be reshaped by sensory input, knowledge that can have implications for rehabilitation. Motor cortical representations reorganize following cervical spinal cord injury (SCI). The functional role of this reorganization remains largely unknown. Using neuronavigated transcranial magnetic stimulation, we examined motor cortical maps during voluntary contraction in humans with chronic cervical SCI and age-matched controls. We constructed motor maps in the first dorsal interosseous (FDI) muscle at rest and during voluntary contraction of the FDI with and without voluntary contraction of the biceps brachi (BB). The role of sensory input into this reorganization was examined by muscle-tendon vibration. We found that, at rest, motor maps were larger in SCI (22.3cm2 ) compared with control (12.6cm2 , P<0.001) participants. Motor map area increased during voluntary contraction of the FDI (120.7%) and further increased during contraction of the BB (143.9%) compared with rest in control subjects; however, motor map area decreased during voluntary contraction of the FDI (69.5%) and further decreased during contraction of the BB (55.5%) in individuals with SCI. SCI participants with larger decreases in map area during voluntary contraction of the FDI were those with larger sensory deficits in the hand and 10min of hand muscle-tendon vibration increased motor map area. These results provide the first evidence of abnormal changes in motor cortical maps in humans with chronic SCI during voluntary contraction, suggesting that sensory input can help to reshape this reorganization.

Modeling chronic cervical spinal cord injury in aged rats for cell therapy studies

With an expanding elderly population, an increasing number of older adults will experience spinal cord injury (SCI) and might be candidates for cell-based therapies, yet there is a paucity of research in this age group. The objective of the present study was to analyze how aged rats tolerate behavioral testing, surgical procedures, post-operative complications, intra-spinal cell transplantation and immunosuppression, and to examine the effectiveness of human iPSC-derived Neural Progenitor Cells (IMR90-hiPSC-NPCs) in a model of SCI. We performed behavioral tests in rats before and after inducing cervical hemi-contusions at C4 level with a fourth-generation Ohio State University Injury Device. Four weeks later, we injected IMR90-hiPSC-NPCs in animals that were immunosuppressed by daily cyclosporine injection. Four weeks after injection we analyzed locomotor behavior and mortality, and histologically assessed the survival of transplanted human NPCs. As rats aged, their success at completing behavioral tests decreased. In addition, we observed high mortality rates during behavioral training (41.2%), after cervical injury (63.2%) and after cell injection (50%). Histological analysis revealed that injected cells survived and remained at and around the grafted site and did not cause tumors. No locomotor improvement was observed in animals four weeks after IMR90-hiPSC-NPC transplantation. Our results show that elderly rats are highly vulnerable to interventions, and thus large groups of animals must be initially established to study the potential efficacy of cell-based therapies in age-related chronic myelopathies.

Operant Conditioning of the Motor Evoked Potentials for Sensorimotor Rehabilitation

<h3>Research Objectives</h3> The corticospinal pathway and its plasticity are essential in sensorimotor function recovery after neuromuscular injuries. To determine if operant up-conditioning of the motor evoked potential (MEP) elicited by transcranial magnetic stimulation (TMS) can increase corticospinal excitability and enhance sensorimotor rehabilitation, we are testing this neuromodulation approach in three different ongoing subprojects. We hypothesized that MEP up-conditioning can improve corticospinal activation of the targeted muscle and thereby improve functions in which that muscle participates. <h3>Design</h3> Each subproject utilizes operant MEP up-conditioning methodology. Standard MEP conditioning protocol consists of 6 baseline and 24 conditioning sessions (3/week, 30-45 min each). In each session, 250 single-pulse MEPs are elicited using TMS with or without operant conditioning (i.e., feedback on performance). Before and after conditioning, electrophysiological, kinematic, and functional assessments are performed. <h3>Setting</h3> Controlled laboratory. <h3>Participants</h3> Volunteers with chronic incomplete spinal cord injury (SCI), or with early-stage knee osteoarthritis (OA). <h3>Interventions</h3> See Design. <h3>Main Outcome Measures</h3> Target muscle MEP size, EMG, kinematics. <h3>Results</h3> Dorsiflexor MEP conditioning in people with chronic incomplete SCI: We hypothesize up-conditioning of the tibialis anterior (TA) MEP induces CNS plasticity that affects TA activation and improves locomotion. Initial studies found up-conditioning can increase TA MEP size and improve locomotion. Our current work aims to characterize cortical and corticospinal mechanisms of changes in MEP, locomotor EMG, and kinematics. Forearm extensor MEP conditioning in people with SCI: We hypothesize that corticospinal excitability for the wrist extensors can be increased through MEP conditioning and that it will help improve forearm motor function. Initial results support such possibilities in individuals with chronic incomplete cervical SCI. Quadriceps MEP conditioning in people with knee OA: We hypothesize that up-conditioning can increase quadriceps MEP size and improve quadriceps activation in individuals with early-stage knee OA. We are developing a protocol to examine the effects of MEP up-conditioning on quadriceps activation and function. <h3>Conclusions</h3> These projects will facilitate the dissemination of MEP conditioning as a neurorehabilitation tool to enhance functional recovery after neuromuscular injuries. <h3>Author(s) Disclosures</h3> Authors listed have no conflicts of interest to declare.