High-level Spinal Cord Injury Research Articles

Effects of Robotic Postural Stand Training with Epidural Stimulation on Sitting Postural Control in Individuals with Spinal Cord Injury: A Pilot Study.

(1) Background. High-level spinal cord injury (SCI) disrupts trunk control, leading to an impaired performance of upright postural tasks in sitting and standing. We previously showed that a novel robotic postural stand training with spinal cord epidural stimulation targeted at facilitating standing (Stand-scES) largely improved standing trunk control in individuals with high-level motor complete SCI. Here, we aimed at assessing the effects of robotic postural stand training with Stand-scES on sitting postural control in the same population. (2) Methods. Individuals with cervical (n = 5) or high-thoracic (n = 1) motor complete SCI underwent approximately 80 sessions (1 h/day; 5 days/week) of robotic postural stand training with Stand-scES, which was performed with free hands (i.e., without using handlebars) and included periods of standing with steady trunk control, self-initiated trunk and arm movements, and trunk perturbations. Sitting postural control was assessed on a standard therapy mat, with and without scES targeted at facilitating sitting (Sit-scES), before and after robotic postural stand training. Independent sit time and trunk center of mass (CM) displacement were assessed during a 5 min time window to evaluate steady sitting control. Self-initiated antero-posterior and medial-lateral trunk movements were also attempted from a sitting position, with the goal of covering the largest distance in the respective cardinal directions. Finally, the four Neuromuscular Recovery Scale items focused on sitting trunk control (Sit, Sit-up, Trunk extension in sitting, Reverse sit-up) were assessed. (3) Results. In summary, neither statistically significant differences nor large Effect Size were promoted by robotic postural stand training for the sitting outcomes considered for analysis. (4) Conclusions. The findings of the present study, together with previous observations, may suggest that robotic postural stand training with Stand-scES promoted trunk motor learning that was posture- and/or task-specific and, by itself, was not sufficient to significantly impact sitting postural control.

Acute Intermittent Hypoxia Induces Chemoreflex-Independent Sympathetic Plasticity and Improves Cardiovascular Function in a Rodent Model of Spinal Cord Injury

Background: Cardiovascular complications are one of the leading causes of morbidity and mortality in people with spinal cord injury (SCI). Activation of spinal sympathetic circuitry is critical to offset cardiovascular dysregulation and disease in those with high-level SCI. Acute intermittent hypoxia (AIH) elicits plasticity (i.e., a gradual increase in nerve activity post-AIH exposure) in phrenic and non-phrenic spinal motor circuitry and improves motor function — yet the cardiovascular benefits of AIH after SCI are largely unexplored. Aims: Determine mechanisms (Aim 1) and potential benefits (Aim 2) of AIH-induced sympathetic plasticity post-SCI. Hypothesis: We hypothesized that AIH elicits chemoreflex-dependent sympathetic plasticity and improves cardiovascular function in rats with SCI. Methods: For Aim 1, 40 adult (10-12 weeks) male Wistar rats were subjected to a spinal cord contusion injury (T3, 300 kdyn) and randomly assigned to 5 groups of 8 each: AIH alone, AIH after carotid body denervation (CBX, no peripheral chemoreflex), time control with no intervention (TC), simulated hemorrhage (to mimic AIH-induced hypotension), and AIH plus phenylephrine (to prevent hypotension during hypoxic episodes). Two weeks post-SCI recovery, rats were anesthetized with urethane (~2.1g.kg−1 i.v.) and underwent femoral venous and arterial catheterizations to monitor blood pressure (BP), sample arterial blood gases, and enable intravenous fluid and drug delivery. Additionally, splanchnic sympathetic nerve activity (sSNA) was recorded using a suction electrode at baseline and for up to 90-min following each experimental paradigm. AIH consisted of 10 x 1 min episodes of FiO2 = 0.1 (balanced N2) interspersed with 2 min of FiO2 = 1. Hexamethonium bromide (30 mg.kg−1) was infused to subtract noise levels from each recording, after which rats were euthanized with chloral hydrate. For Aim 2, 19 additional rats were subjected to the same injury model and time post-injury and allocated to 2 groups: AIH ( n = 11) and TC ( n = 8). These rats were instrumented with left-ventricular (LV) and arterial catheters and assessed simultaneously for cardiac and peripheral hemodynamic function at baseline and 90-min post-AIH/TC. Results: Aim 1) When expressed as % change from baseline, sSNA increased at 90-min post-treatment in AIH (93±67%, P = 0.02) and CBX (193±182%, P < 0.001), but not TC rats (50±45%, P = 0.40). Preventing BP reduction during hypoxic episodes with i.v. phenylephrine blocked the increase in sSNA 90-min post-AIH (12±66%, P > 0.99). Mimicking the AIH-induced BP reduction with simulated hemorrhage (10 x 1-min BP reductions of ~20-25 mmHg equal to those during AIH, interspersed by 2-min of euvolemia), increased sSNA 90-min post-intervention (106±86%, P = 0.01). Aim 2) The changes in maximal LV pressure (AIH = 11±8 mmHg vs. TC = 2±5 mmHg, P = 0.05) and mean arterial pressure (AIH = 8±7 mmHg vs. TC = 0±4 mmHg, P = 0.05) were greater at 90-min post-AIH treatment. Conclusions: We conclude that AIH elicits sympathetic plasticity and improves cardiovascular function post-SCI. Since AIH-induced sympathetic plasticity remains in the presence of a bilateral CBX, is replicated by episodic simulated hemorrhage, and is blocked by phenylephrine, AIH-induced sympathetic plasticity is independent of carotid (peripheral) chemoreflex activation, and is closely linked to episodic hypotension. We suggest that AIH-induced sympathetic plasticity arises from episodic reductions in spinal/medullary cardiovascular centers blood flow (and oxygen delivery) post-SCI. International Spinal Research Trust and Natural Sciences, Engineering Research Council of Canada, International Collaboration on Repair Discoveries. 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.

Identification and assessment of Electronic Aids for Daily Living considered essential by persons with high level tetraplegia: a case series

Although assistive technology (AT) is recognized as a basic human right, access to AT, and particularly electronic aids to daily living (EADL), is limited. We aimed to understand how persons with high level spinal cord injury (SCI) prioritize EADL needs and assess satisfaction and efficacy of self-identified EADL. Thus, in this case series, we recruited three participants with C4, C5 or C6 SCI receiving in-patient SCI rehabilitation. Each received dedicated occupational therapy-based assistance in identifying EADL items within an unrestricted envelope of support ($5000 CDN) for use in maximizing physical independence and supporting their return to community-based living. Items identified were categorized by need (emergency/security; home environment control; or virtual access to the outside world). Each participant selected distinct EADL. Evaluation of selected EADL items indicated very high satisfaction. The selected EADL contributed to participants’ returns to employment, community life, or reduced requirements for attendant services. These findings suggest that identification of essential technology should reflect the unique needs of each person and the context in which it will be used. These findings also support use of mainstream technology to meet EADL needs of individuals with limited physical abilities.

Paradoxical breathing during sleep is associated with increased sleep apnea and reduced ventilatory capacities in high-level spinal cord injury.

Sleep-disordered breathing is highly prevalent in individuals with high-level spinal cord injury. In addition, chest mechanics are known to be altered, leading to paradoxical breathing. Here we investigated the interaction between paradoxical breathing and sleep quality in these patients, and its association with measurements of respiratory function, hypercapnic ventilatory response and peak exercise ventilation. Home-based polysomnography was performed in 13 patients with spinal cord injury (C4 to T4) untreated for sleep-disordered breathing. We defined paradoxical breathing as counterphase between thoracic and abdominal movements during slow-wave and rapid eye movement sleep. Sleep quality, pulmonary function, hypercapnic ventilatory responses and peak exercise ventilation were compared between those with and without paradoxical breathing. Half of individuals presented with nocturnal paradoxical breathing. Despite similar age, body mass index, injury level, time since injury, and respiratory function, those with paradoxical breathing had higher apnea-hypopnea index (13 ± 8 versus 5 ± 3 events per hr) and average sleep heart rate (67 ± 12 versus 54 ± 4 bpm; p < 0.05). Moreover, paradoxical breathing was associated with lower hypercapnic ventilatory response (slope: 0.35 ± 0.17 versus 0.96 ± 0.38) and lower peak exercise ventilation (33 ± 4 versus 48 ± 12 L min-1; p < 0.05). Nocturnal respiratory muscle desynchronization could play a role in the pathophysiology of sleep apnea, and could relate to low ventilatory responses to both hypercapnia and exercise in high-level spinal cord injury. Polysomnography may be an important diagnostic tool for these patients for whom therapeutic approaches should be considered to treat this abnormality.

Empowering High-Level Spinal Cord Injury Patients in Daily Tasks With a Hybrid Gaze and FEMG-Controlled Assistive Robotic System.

Individuals with high-level spinal cord injuries often face significant challenges in performing essential daily tasks due to their motor impairments. Consequently, the development of reliable, hands-free human-computer interfaces (HCI) for assistive devices is vital for enhancing their quality of life. However, existing methods, including eye-tracking and facial electromyogram (FEMG) control, have demonstrated limitations in stability and efficiency. To address these shortcomings, this paper presents an innovative hybrid control system that seamlessly integrates gaze and FEMG signals. When deployed as a hybrid HCI, this system has been successfully used to assist individuals with high-level spinal cord injuries in performing activities of daily living (ADLs), including tasks like eating, pouring water, and pick-and-place. Importantly, our experimental results confirm that our hybrid control method expedites the performance in pick-place tasks, achieving an average completion time of 34.3 s, which denotes a 28.8% and 21.8% improvement over pure gaze-based control and pure FEMG-based control, respectively. With practice, participants experienced up to a 44% efficiency improvement using the hybrid control method. This state-of-the-art system offers a highly precise and reliable intention interface, suitable for daily use by individuals with high-level spinal cord injuries, ultimately enhancing their quality of life and independence.

Neuromodulation in Spinal Cord Injury Using Transcutaneous Spinal Stimulation-Mapping for a Blood Pressure Response: A Case Series.

Spinal cord transcutaneous stimulation (scTS) offers a promising approach to enhance cardiovascular regulation in individuals with a high-level spinal cord injury (SCI), addressing the challenges of unstable blood pressure (BP) and the accompanying hypo- and hypertensive events. While scTS offers flexibility in stimulation locations, it also leads to significant variability and lack of validation in stimulation sites utilized by studies. Our study presents findings from a case series involving eight individuals with chronic cervical SCI, examining the hemodynamic effects of scTS applied in different vertebral locations, spanning from high cervical to sacral regions. Stimulation of the lumbosacral vertebrae region (L1/2, S1/2, and also including T11/12) significantly elevated BP, unlike cervical or upper thoracic stimulation. The observed trend, which remained consistent across different participants, highlights the promising role of lumbosacral stimulation in neuromodulating BP.

Permanent pacemaker implantations among patients with spinal cord injury in the United States

Abstract Background Acute spinal cord injury (SCI) is associated with severe cardiovascular complications. Information regarding the need for permanent cardiac pacing in SCI patients is scarce and based on case reports and small case series. We aimed to investigate the extent of permanent pacemaker (PPM) implantation procedures as well as to identify predictors for PPM insertion among SCI patients in a U.S contemporary, nationwide, all-comer registry. Methods Using the National Inpatient Sample (NIS) database, patients hospitalized with a primary diagnosis of SCI in the US between 2016-2019 and underwent PPM implantation were identified. Patients with cardiac implantable electronic device in-situ were excluded. Baseline demographics, clinical characteristics, injury type, in-hospital procedures and outcomes including time to PPM implantation, length of stay and mortality were collected. Outcome analysis performed after propensity score matching (PSM). Predictors of PPM implantation were identified via a multivariable logistic regression model. Results A total of 35880 patients, were hospitalized with a primary diagnosis of SCI during the study period, and 240 (0.7%) received a PPM. Median age of patients receiving PPM was 69 years, 75% were males, and 67% had high level SCI injury (level C1-5). Time to PPM implantation was 9 days (IQR 4-19). PPM implantation was associated with higher rates of cervical spine injuries, traumatic brain injury (TBI), chest and upper limbs injuries, respiratory failure and other signs of severe illness. Longer hospital stay and higher in-hospital mortality rate was observed in patients receiving a PPM. Multivariate analysis identified the following independent risk factors for PPM implantation: cervical SCI [OR 77.07 (11.13-553.42), p&amp;lt;0.001], TBI [OR 3.84(1.59-9.28), p=0.003] and tracheostomy/respiratory ventilation&amp;gt; 96 h [OR 31.766(7.91-127.54), p=&amp;lt;0.001]. Conclusion Cervical SCI, need for tracheostomy and prolonged mechanical ventilation were the strongest predictors for PPM implantation in patients hospitalized for SCI in a nationwide registry.

Unbiased multitissue transcriptomic analysis reveals complex neuroendocrine regulatory networks mediated by spinal cord injury-induced immunodeficiency

BackgroundSpinal cord injury (SCI), which causes loss of sensory and motor function in the body below the level of injury, is a devastating disease of the central nervous system. SCI leads to severe secondary immunosuppression, called SCI-induced immunodeficiency syndrome (SCI-IDS), which is characterized by increased susceptibility to infection and further exacerbates neurological dysfunction. Several studies have suggested that SCI-IDS is an independent risk factor for poor neurological prognosis. SCI-IDS predominantly occurs following injury above the T5 levels and eventually leads to systemic immune failure, possibly via the sympathetic–adrenal medullary axis and the hypothalamic‒pituitary‒adrenal (HPA) axis. However, the mechanism remains unclear.Methods and objectivesThe concentrations of adrenocorticotropic hormone and cortisol in plasma, as well as changes in sympathetic activity (blood pressure and catecholamine levels in plasma), were assessed in rats in the high-level (T3) spinal cord injury (T3-SCI) group and the low-level (T10) spinal cord injury (T10-SCI) group. Second, the differential regulation of the gene network between the sympathetic–adrenal medullary axis and the HPA axis was explored by histology and multitissue transcriptomics, and the neuroendocrine–immune network associated with SCI-IDS was further elucidated.ResultsThe spleen and thymus gland, which are secondary immune organs, were significantly atrophied in rats in the T3-SCI group, and the white pulp of the spleen was significantly atrophied. The level of cortisol, which is mediated by the adrenal glands, was markedly elevated, but norepinephrine levels were markedly decreased. There was no difference in adrenocorticotropic hormone expression between any of the groups. The transcriptome analysis results showed that the downregulated differentially expressed genes (DEGs) in the T3-SCI group were enriched in the GO term immunoregulation, indicating that splenic immune function was markedly impaired after high-level SCI. The upregulated DEGs in the hypothalamus (hub genes: Nod2, Serpine1, Cebpb, Nfkbil1, Ripk2, Zfp36, Traf6, Akap8, Gfer, Cxcl10, Tnfaip3, Icam1, Fcgr2b, Ager, Dusp10, and Mapkapk2) were significantly enriched in inflammatory pathways, and the downregulated genes (hub genes: Grm4, Nmu, P2ry12, rt1-bb1, Oprm1, Zfhx2, Gpr83, and Chrm2) were enriched in pathways related to inhibitory Gi-mediated G protein-coupled receptor (Gi-GPCR) neurons and neuropeptide changes. The upregulated genes in the adrenal glands (hub genes: Ciart, per2, per3, cry1, and cry2) were enriched in cortisol secretion and circadian rhythm changes, and the downregulated genes (hub genes: IL7r, rt1-bb, rt1-bb1, rt1-da, rt1-ba, cd74, cxcr3, vcam1, ccl5, bin1, and IL8) were significantly enriched in MHC-mediated immune responses.ConclusionsTo explore the possible mechanism underlying SCI-IDS, this study assessed the differential regulation of the gene network associated with neuroendocrine immunity after SCI. Progressive neuroinflammation spreads after injury, and neurotransmission through Gi-mediated G protein-coupled receptors in the HPA axis and neuropeptide production by the hypothalamus are inhibited. Disruption of the connection between the hypothalamus and the adrenal glands causes autonomous regulation of the adrenal glands, disturbance of circadian rhythm and finally hypercortisolemia, leading to general suppression of peripheral adaptive immunity. Neuraxial nerve inflammation caused by SCI persists indefinitely, blocking nerve repair; persistent system-wide immunosuppression in the periphery results in increased susceptibility to infection, leading to poor neurological prognosis.

Proinflammatory and Immunomodulatory Gene and Protein Expression Patterns in Spinal Cord and Spleen Following Acute and Chronic High Thoracic Injury.

In addition to paralysis and loss of sensation, high-level spinal cord injury (SCI) causes sympathetic dysfunction that can lead to autonomic dysreflexia (AD) and chronic immune suppression involving splenic leukopenia. Evidence has shown that treatment with either gabapentin or blockade of TNFα mitigates maladaptive plasticity and the underlying hemodynamic dysfunction, spleen atrophy, and immune dysfunction associated with AD. Because significant improvements long term was noted following treatments only during acute stages of recovery, we sought to systematically examine changes in proinflammatory and immunomodulatory cytokines to ascertain the reason. Adult female Wistar rats underwent complete T4 spinal transection before euthanasia at systematic intervals from 3 days to 8 weeks after injury. Using qRT-PCR and meso scale discovery (MSD) assays, the gene and protein expression of TNFα and IFNγ in the spleen, upper thoracic (T4-9) and lumbosacral (L5-S6) spinal cords were analyzed. We found that spleen atrophy occurs in a biphasic manner compared to naïve controls, with significant decreases in the spleen mass noted at 3 days and 8 weeks after injury. Splenic TNFα mRNA and protein levels did not change significantly over time, while IFNγ gene expression dipped acutely with trends for increased protein levels at more chronic time points. TNFα protein increased significantly only in thoracic spinal cord segments from 3 to 14 days post-injury. IFNγ mRNA and protein levels remained unelevated in injured spinal cords over time, with trends for increased protein levels at 2 and 8 weeks in the lumbosacral segments. Novel temporal-spatial cytokine expression profiles reveal that TNFα protein levels are increased solely in upper thoracic segments after high thoracic SCI, while IFNγ remains unaltered. Splenic leukopenia and latent systemic immunosuppression are not associated with altered TNFα or IFNγ expression in the spleen or spinal cord.

Pulse rate variability: An alternative to heart rate variability in adults with spinal cord injury.

Pulse rate variability (PRV) is often used as an alternative to heart rate variability (HRV) to measure psychophysiological function. However, its validity to do so is unclear, especially in adults with spinal cord injury (SCI). This study compared PRV and HRV in adults with higher-level SCI (SCI-H, n = 23), lower-level SCI (SCI-L, n = 22), and able-bodied participants (AB n = 44), in a seated position as a function of performance in a reactivity task (Oxford Sleep Resistance Test: OSLER). PRV and HRV was measured using reflective finger-based photoplethysmography (PPG) and electrocardiography, respectively, at baseline, immediately post-OSLER, and after five-minute recovery. Agreement between PRV and HRV was determined by Bland-Altman analysis and differences between PRV and HRV over time by linear mixed effects model (LMM) analysis. Concurrent validity was assessed through correlation analyses between PRV and HRV. Additional correlation analyses were performed with psychosocial factors. Results indicated insufficient to moderate agreement between PRV and HRV. LMM analyses indicated no differences over time for standard deviation of normal-to-normal intervals and low-frequency power but significant differences for root mean square of successive differences and high frequency power. Nevertheless, PRV and HRV were highly correlated (Median r = .878 (.675-.990)) during all assessment periods suggesting sufficient concurrent validity. Similar correlation patterns were also found for PRV and HRV with psychosocial outcomes. While differences existed, results suggest PRV derived from reflective finger-based PPG is a valid proxy of HRV in tracking psychophysiological function in adults with SCI and could therefore be used as a more accessible monitoring tool.

Woman with agonal breathing.

A 42-year-old healthy woman with cerebral palsy, oriented consciousness, and partial dependence in daily activities at baseline reported gradual decrease in muscle strength in all her limbs for 6 months. The patient became comatose with agonal breathing unexpectedly during the night hours without any warning. Initial clinical presentation showed a very slow respiratory rate of 8 times/min and SpO2 = 92% under non-rebreathing mask covering. Atrial blood gas test revealed hypercapnic respiratory acidosis (pH, 6.9; PCO2 > 200 mmHg). Intubation was performed immediately. Chest radiography showed no active lesions (Figure 1). Her consciousness returned to baseline a few hours after intubation, but she developed quadriplegia. Brain computed tomography showed no obvious lesions. Brain magnetic resonance imaging (MRI) revealed no obvious lesion but incidentally revealed C2 odontoid process fracture with cord indentation (Figure 2). Cervical MRI showed displaced odontoid process fracture with cord compression, causing myelopathy at C2–C4 levels (Figure 3). It is challenging to diagnose spinal cord injury (SCI) in the absence of trauma history.1 Non-traumatic SCI is a rare neurological emergency.2 There are few case reports of spontaneous atraumatic cervical fracture due to tuberculosis or rheumatoid arthritis.3, 4 High-level SCI causes impairment of respiratory muscles and reduces vital capacity and chest wall compliance. It also influences the respiratory drive, leading to hypercapnia.5, 6 SCI is an often forgotten but important cause of central nervous system depression in patients with hypercapnic respiratory failure in emergency settings. We present a case of atraumatic odontoid fracture, resulting in myelopathy and hypercapnic respiratory failure. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Vision-Based Robot Arm Control Interface for Retrieving Objects from the Floor

Approximately half of the patients with spinal cord injuries in Japan have a cervical spinal cord injury. Owing to the trunk dysfunction, patients with high-level spinal cord injuries have particular difficulty when searching for or picking up objects from the floor. Recently, welfare robot arms have been developed to help such individuals increase self-reliance. In this study, we propose an operating system that includes an eye-in-hand system with a touchscreen interface for grasping objects from the floor and delivering them to the individual. In the proposed method, the visual information of the target object is shown on a touchscreen interface. The patient specifies the target position for the robot arm by drawing a line on the target object on the interface. We conducted an experiment to compare the proposed interface with an on-screen joystick to demonstrate the proposed system’s efficiency and its ability to reduce physical burden. The results show that the proposed method is both quicker to use and effectively reduces the physical burden on the user compared to the conventional method.

A clinical case of transient diabetes insipidus with high spinal trauma

BACKGROUND: Diabetes insipidus is characterized by the kidneys inability to absorb water and concentrate urine, which is based on a defect in the synthesis or secretion of vasopressin and is manifested by severe thirst and excretion of large volumes of diluted urine. Data on diabetes insipidus in adults with isolated spinal injury are presented in single works of foreign authors, and no domestic and foreign publications have focused on diabetes insipidus in children. Available publications are descriptions and evaluations of the diseases clinical picture according to clinical and laboratory abnormalities and analyzed therapy in the postoperative period.&#x0D; CLINICAL CASE: This study presents a clinical case of transient diabetes insipidus in a 12-year-old patient with high-level spinal cord injury after shrapnel and explosive trauma. A detailed description of the clinical picture is provided.&#x0D; DISCUSSION: Polyuria, polydipsia, and low urine density were noted on day 14 after surgical correction and stabilization of post-traumatic spinal deformity with spinal cord rupture at the CVICVII level. The condition was considered a transient diabetes insipidus. Clinical and laboratory recovery was achieved on day 12 after surgery thanks to treatment by desmopressin.&#x0D; CONCLUSIONS: This clinical case presents that diabetes insipidus may develop in pediatric patients with isolated spinal injury. Given the insufficient understanding of the causes of this rare disease, differential diagnosis is necessary for pediatric patients with high-level spinal cord injuries associated with polyuria and low urine density. Moreover, treatment with desmopressin should be prescribed appropriately.

High-Level Spinal Cord Injury and the Failure of US Acute Rehabilitation: An Analysis and Commentary.

Acute and long-term morbidity and mortality rates have not changed in the United States for people with high-level spinal cord injury in 40 yrs, neither has the conventional invasive respiratory management for these patients. This is despite a 2006 challenge to institutions for a paradigm shift to avoid or decannulate patients of tracheostomy tubes. Centers in Portugal, Japan, Mexico, and South Korea decannulate high-level patients to up to continuous noninvasive ventilatory support and use mechanical insufflation exsufflation, as we have done and reported since 1990, but there has been no such paradigm shift in US rehabilitation institutions. The quality of life and financial consequences of this are discussed. An example of decannulation of a relatively easy case, after failure to do so during 3 mos of acute rehabilitation, is presented to encourage institutions to begin to learn and apply noninvasive management before decannulating more severe patients with little to no ventilator free breathing ability.

Intravesical injection of botulinum toxin type a may be an effective treatment option for autonomic dysreflexia in patients with high-level spinal cord injury

Objective To evaluate the efficacy of intravesical injection of botulinum toxin type A (BTX-A) for neurogenic detrusor overactivity (DO) in reducing the frequency and severity of autonomic dysreflexia (AD). Design A cross-sectional nonrandomized trial with before (baseline) and after (follow-up) assessments. Setting A single spinal cord injury (SCI) rehabilitation center in China. Participants Twenty-five patients with SCI at or above T6 and a history of AD who underwent urodynamic studies (UDS) before and 3 months after BTX-A injection. Interventions Received bladder injection treatment wtih 200 U BTX-A. Outcome Measures The maximum detrusor pressure(Pdetmax) and voume at first DO(VFIDC), baseline and overall maximum systolic blood pressure (SBP) during UDS, and scores of Incontinence Specific Quality of Life Instrument (IQoL) were recorded before and 3 months after the injection. The change in SBP (ΔSBP) from baseline to maximum SBP during UDS was calculated to assess the severity. The frequency of AD was recorded using ambulatory blood pressure monitoring during a 24 h period before and 3 months after the injection. Results BTX-A injection decreased the Pdetmax and increased the VFIDC and mean urine volume per catheterization increased. The maximum SBP and the ΔSBP during UDS decreased significantly decreased after the injection (151.44 ± 13.92 vs 133.32 ± 9.20 mmHg and 49.44 ± 12.81 vs 33.08 ± 9.11 mmHg respectively, P < 0.05). The frequency of bladder-related ADs (i.e. performed a clean intermittent catheterization or leakage) during a 24-h period significantly decreased from 11.04 ± 1.81–7.88 ± 2.15 (P < 0.001). Conclusions BTX-A decreases the severity of SBP increase and the number of AD episodes 3 months after intravesical injection.

The susceptibility of cardiac arrhythmias after spinal cord crush injury in rats

High-level spinal cord injury (SCI) often interrupts supraspinal regulation of sympathetic input to the heart. Although it is known that dysregulated autonomic control increases the risk for cardiac disorders, the mechanisms mediating SCI-induced arrhythmias are poorly understood. Here, we employed a rat model of complete spinal cord crush injury at the 2nd/3rd thoracic (T2/3) level to investigate cardiac rhythm disorders resulting from SCI. Rats with T9 injury and naïve animals served as two controls. Four weeks after SCI, rats were implanted with a radio-telemetric device for electrocardiogram and blood pressure monitoring. During 24-h recordings, heart rate variability in rats with T2/3 but not T9 injury exhibited a significant reduction in the time domain, and a decrease in power at low frequency but increased power at high frequency in the frequency domain which indicates reduced sympathetic and increased parasympathetic outflow to the heart. Pharmacological blockade of the sympathetic or parasympathetic branches confirmed the imbalance of cardiac autonomic control. Activation of sympatho-vagal input during the induction of autonomic dysreflexia by colorectal distention triggered various severe arrhythmic events in T2/3 injured rats. Meanwhile, intravenous infusion of the β1-adrenergic receptor agonist, dobutamine, caused greater incidence of arrhythmias in rats with T2/3 injury than naïve and T9 injured controls. Together, the results indicate that high-level SCI increases the susceptibility to developing cardiac arrhythmias likely owing to compromised autonomic homeostasis. The T2/3 crush model is appropriate for studying abnormal cardiac electrophysiology resulting from SCI.

Spinal Cord Injury Impairs Lung Immunity in Mice.

Pulmonary infection is a leading cause of morbidity and mortality after spinal cord injury (SCI). Although SCI causes atrophy and dysfunction in primary and secondary lymphoid tissues with a corresponding decrease in the number and function of circulating leukocytes, it is unknown whether this SCI-dependent systemic immune suppression also affects the unique tissue-specific antimicrobial defense mechanisms that protect the lung. In this study, we tested the hypothesis that SCI directly impairs pulmonary immunity and subsequently increases the risk for developing pneumonia. Using mouse models of severe high-level SCI, we find that recruitment of circulating leukocytes and transcriptional control of immune signaling in the lung is impaired after SCI, creating an environment that is permissive for infection. Specifically, we saw a sustained loss of pulmonary leukocytes, a loss of alveolar macrophages at chronic time points postinjury, and a decrease in immune modulatory genes, especially cytokines, needed to eliminate pulmonary infections. Importantly, this injury-dependent impairment of pulmonary antimicrobial defense is only partially overcome by boosting the recruitment of immune cells to the lung with the drug AMD3100, a Food and Drug Administration-approved drug that mobilizes leukocytes and hematopoietic stem cells from bone marrow. Collectively, these data indicate that the immune-suppressive effects of SCI extend to the lung, a unique site of mucosal immunity. Furthermore, preventing lung infection after SCI will likely require novel strategies, beyond the use of orthodox antibiotics, to reverse or block tissue-specific cellular and molecular determinants of pulmonary immune surveillance.

Preserved Cardio‐Inotropic Baroreflex Function Following Optimized Hemodynamic Management in High‐Thoracic Spinal Cord Injury

. Chronic high-level spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, notably impairments to cardiac contractile function and baroreflex control of blood pressure. Recently, our group has demonstrated that hemodynamic management targeting the heart (i.e. dobutamine, DOB), rather than standard vasopressor treatment (i.e. norepinephrine, NE) improves cord oxygenation and mitigates hemorrhage in a porcine model of acute T2 SCI. Yet, the potential long-term cardiovascular benefits of acute cardio-centric hemodynamic management remain elusive.Assess the chronic changes in hemodynamics and baroreflex function associated with acute DOB administration in animals with T2 SCI.17 Yucatan mini-pigs received a T2 weight-drop contusion SCI, with either DOB (2.5 ug/kg/min, n=6), NE (4.25 ug/kg/min, n=6) or no treatment (CON, n=5) starting at 30 mins until 6 hrs post-SCI. Animals were subsequently recovered and housed for 12 weeks post-SCI. During terminal experiments, animals were instrumented with left ventricular (LV), pulmonary artery and femoral artery catheters to assess LV function, cardiac output (Q) and blood pressure, respectively. Linear regression analyses were used to estimate cardiovagal baroreflex (V-BRx) gain from the relationship of pulse interval vs. systolic blood pressure, and "cardio-inotropic" baroreflex (I-BRx) gain from the relationship of LV contractile function (rate of pressure rise for a given end-diastolic volume) vs. diastolic blood pressure during modified Oxford tests.Data are presented as means±SD. At 12 weeks post-SCI, DOB animals had preserved cardiac output (∆Q=+531±471ml/min) and mean arterial pressure (MAP=81±9mmHg), whereas both Q and MAP were lower in CON animals (∆Q=-385±720ml/min, p=0.44; MAP=65±3mmHg, p<0.0037). In contrast, NE-treated animals had uncharacteristic hypertension as indicated by elevations to MAP (NE=88±11 vs. CON=65±3mmHg, p=0.0029), arterial elastance (NE=3.7±0.4 vs. CON=2.7±0.1mmHg/ml, p=0.016) and total peripheral resistance (NE=50.3±4.3 vs. CON:35.7±10.3mmHg/ml/min, p=0.074). I-BRx function also appeared to be improved in DOB (slope=-0.56±0.33ml/s) vs. CON (slope=-0.04±0.05ml/s, p=0.044), while V-BRx gain did not differ between groups.Cardio-centric management appears to optimize cardiovascular hemodynamics more effectively than vasopressor therapy in chronic high-thoracic SCI. Reduced secondary spinal cord damage with DOB therapy may preserve descending sympathetic pathways to the heart, ultimately improving baroreflex control of blood pressure.

Thoracic VGluT2+ Spinal Interneurons Regulate Structural and Functional Plasticity of Sympathetic Networks after High-Level Spinal Cord Injury.

Traumatic spinal cord injury (SCI) above the major spinal sympathetic outflow (T6 level) disinhibits sympathetic neurons from supraspinal control, causing systems-wide "dysautonomia." We recently showed that remarkable structural remodeling and plasticity occurs within spinal sympathetic circuitry, creating abnormal sympathetic reflexes that exacerbate dysautonomia over time. As an example, thoracic VGluT2+ spinal interneurons (SpINs) become structurally and functionally integrated with neurons that comprise the spinal-splenic sympathetic network and immunological dysfunction becomes progressively worse after SCI. To test whether the onset and progression of SCI-induced sympathetic plasticity is neuron activity dependent, we selectively inhibited (or excited) thoracic VGluT2+ interneurons using chemogenetics. New data show that silencing VGluT2+ interneurons in female and male mice with a T3 SCI, using hM4Di designer receptors exclusively activated by designer drugs (Gi DREADDs), blocks structural plasticity and the development of dysautonomia. Specifically, silencing VGluT2+ interneurons prevents the structural remodeling of spinal sympathetic networks that project to lymphoid and endocrine organs, reduces the frequency of spontaneous autonomic dysreflexia (AD), and reduces the severity of experimentally induced AD. Features of SCI-induced structural plasticity can be recapitulated in the intact spinal cord by activating excitatory hM3Dq-DREADDs in VGluT2+ interneurons. Collectively, these data implicate VGluT2+ excitatory SpINs in the onset and propagation of SCI-induced structural plasticity and dysautonomia, and reveal the potential for neuromodulation to block or reduce dysautonomia after severe high-level SCI.SIGNIFICANCE STATEMENT In response to stress or dangerous stimuli, autonomic spinal neurons coordinate a "fight or flight" response marked by increased cardiac output and release of stress hormones. After a spinal cord injury (SCI), normally harmless stimuli like bladder filling can result in a "false" fight or flight response, causing pathological changes throughout the body. We show that progressive hypertension and immune suppression develop after SCI because thoracic excitatory VGluT2+ spinal interneurons (SpINs) provoke structural remodeling in autonomic networks within below-lesion spinal levels. These pathological changes can be prevented in SCI mice or phenocopied in uninjured mice using chemogenetics to selectively manipulate activity in VGluT2+ SpINs. Targeted neuromodulation of SpINs could prevent structural plasticity and subsequent autonomic dysfunction in people with SCI.

Toward rebalancing blood pressure instability after spinal cord injury with spinal cord electrical stimulation: A mini review and critique of the evolving literature.

High-level spinal cord injury commonly leads to blood pressure instability. This manifests clinically as orthostatic hypotension (OH), where blood pressure can drop to the point of loss of consciousness, and autonomic dysreflexia (AD), where systolic blood pressure can climb to over 300 mmHg in response to an unperceived noxious stimulus. These blood pressure fluctuations can occur multiple times a day, contributing to increased vessel shear stress and heightened risk of cardiovascular disease. The pathophysiology of both of these conditions is rooted in impairments in regulation of spinal cord sympathetic preganglionic neurons, which control blood pressure by mediating vascular resistance and catecholamine release. Recently, spinal cord electrical stimulation has provided evidence that it may modulate these blood pressure imbalances. Early proposed mechanisms suggest activation of spinal cord dorsal horn neurons that ultimately act upon the sympathetic preganglionic neuronal pathways. For OH, spinal cord stimulation likely induces local activation of these neurons to generate baseline sympathetic tone and accompanying vasoconstriction. The mechanisms for spinal stimulation regulating AD are less clear, though some suggest it activates inhibitory circuits to dampen the overactive sympathetic response. While questions remain, spinal cord electrical stimulation is an intriguing new modality that may restore blood pressure regulation following spinal cord injury.