The loss of physical activity after a spinal cord injury results in musculoskeletal deterioration and metabolic dysfunction. Rehabilitation often overlooks the importance of physical activity in the paralyzed limbs for systemic metabolic health. There is a need for safe, feasible exercise interventions to increase physical activity levels in the paralyzed limbs of people with chronic paralysis that have severe musculoskeletal loss. The goal of this work is to 1) develop a gene expression signature after a single dose and long term training using a high force exercise in people with an acute spinal cord injury; 2) develop a novel low force exercise intervention using electrical muscle stimulation to limit force production and increase routine physical activity for chronically paralyzed human skeletal muscle; 3) determine the gene expression signature after a single dose of this novel low force exercise in people with long term paralysis; 4) develop a dose estimate of this low force exercise needed to initiate a phenotype transformation of chronically paralyzed skeletal muscle. The major findings of this research are 1) a single dose of high force exercise increases the expression of key regulatory genes needed for the transformation of paralyzed skeletal muscle observed after long term training; 2) our novel low force exercise intervention challenges chronically paralyzed muscle but not non-paralyzed muscle; 3) a single dose of low force exercise increases the expression of key regulatory genes needed to improve skeletal muscle health; 4) a dose of at least 4 days per week of our low force exercise is needed to initiate a phenotype transformation of chronically paralyzed skeletal muscle. Together, this work supports the use of a low force exercise intervention for people with long term spinal cord injury and establish the need for future work assessing effects of our low force exercise on the systemic health and quality of life of people with long term spinal cord injury.

The corticospinal tract (CST), which carries commands from the cerebral cortex to the spinal cord, is vital to fine motor control. Spinal cord injury (SCI) often damages CST axons, causing loss of motor function, most notably in the hands and legs. Our preliminary work in rats suggests that CST circuitry is complex: neurons whose axons project to the lower cervical spinal cord, which directly controls hand function, also send axon collaterals to other locations in the nervous system and may engage parallel motor systems. To inform research into repair of SCI, we therefore aimed to map the entire projection pattern, or “connectome,” of such cervically-projecting CST axons. In this study, we mapped the corticospinal connectome of the Rhesus macaque - an animal model more similar to humans, and therefore more clinically relevant for examining SCI. Comparison of the Rhesus macaque and rat CST connectome, and extrapolation to the human CST connectome, may improve targeting of treatments and rehabilitation after human SCI. To selectively trace cervically-projecting CST motor axons, a virus encoding a Cre-recombinase-dependent tracer (AAV-DIO-gCOMET) was injected into the hand motor cortex, and a virus encoding Cre-recombinase (AAV-Cre) was injected into the C8 level of the spinal cord. In this intersectional approach, the gCOMET virus infects many neurons in the cortex, but gCOMET expression is not turned on unless the nucleus also contains Cre-recombinase, which must be retrogradely transported from axon terminals in the C8 spinal cord. Thus, gCOMET is only expressed in neurons that project to the C8 spinal cord, and it proceeds to fill the entire neuron, including all axon collaterals. Any gCOMET-labeled axon segments observed in other regions of the nervous system are therefore collaterals of cervically-projecting axons. gCOMET-positive axons were immunohistochemically labeled, and axon density was quantified using a fluorescence microscope and Fiji/ImageJ software. Specific regions of interest were chosen for analysis because of their known relevance in motor function in humans, and for comparison to results of a similar study in rats. Results in the first monkey have revealed both similarities and differences between the monkey and rodent CST connectome. Analyses of additional monkeys are ongoing. The final results will provide detailed information about differences between rodent and primate CST, will serve as a baseline for examining changes in the CST connectome after SCI, and will provide guidance for studies targeting treatment and functional recovery after SCI.

Vital autonomic and cardiovascular functions are susceptible to dysfunction after spinal cord injury (SCI), with cardiovascular dysregulation contributing to morbidity and mortality in the SCI population. Autonomic dysreflexia (AD) is a condition that develops after injury to the sixth thoracic spinal segment or higher and is characterized by potentially dangerous and volatile surges in arterial pressure often accompanied with irregular heart rate, headache, sweating, flushing of the skin, and nasal congestion. These symptoms occur in response to abnormal outflow of sympathetic activity from the decentralized spinal cord typically triggered by noxious, yet unperceived nociceptive stimulation beneath the level of lesion. Maladaptive plasticity of primary afferents and spinal interneurons influencing sympathetic preganglionic neurons is known to contribute to the development of AD. However, there are currently no treatments capable of targeting this underlying pathophysiology. The goal of this work was to test pharmacological agents for their potential to modify intraspinal plasticity associated with AD in order to prophylactically prevent the development of this condition altogether. We first tested whether the drug rapamycin (RAP), a well-studied inhibitor of the growth promoting kinase “mammalian target of rapamycin” (mTOR), could prevent aberrant sprouting of primary c-fiber afferents in association with reduced indices of AD severity. Naïve and T4-transected rats undergoing 24/7 cardiovascular monitoring were treated with rapamycin (i.p.) for 4 weeks before tissue collection. RAP attenuated intraspinal mTOR activity after injury, however it also caused toxic weight loss. RAP treated SCI rats developed abnormally high blood pressure both at rest and during colorectal distension (CRD) induced AD, as well as more frequent bouts of spontaneous AD (sAD). These cardiovascular alterations occurred without altered intraspinal c-fiber sprouting. Our finding that rapamycin exacerbates cardiovascular dysfunction after SCI underscores the importance of screening potential pharmacological agents for cardiovascular side effects and suggests that the mTOR pathway plays a limited or dispensable role in c-fiber sprouting after SCI. We next examined the effects of the antinociceptive drug gabapentin (GBP) on AD development. Our previous work demonstrated that a single acute administration of GBP can reduce the severity of AD. The mechanism of action, however, remains unclear. Emerging evidence suggests that GBP may act by blocking de novo synaptogenesis. We investigated whether continuous GBP treatment could attenuate the development of AD by modifying synaptic connectivity between primary afferents and ascending propriospinal neurons. SCI rats were treated with GBP every six hours for four weeks. We found that GBP reduced blood pressure during CRD stimulation and prevented bradycardia typically observed during AD. However, GBP treated rats also had a higher sAD frequency and failed to return to pre-injury body weight. Moreover, SCI reduced the density of putative excitatory (VGLUT2+) and inhibitory (VGAT+) synaptic puncta in the lumbosacral cord, although GBP did not alter these parameters. Our results suggest that continuous GBP treatment alters hemodynamic control after SCI and that decreased synaptic connectivity may contribute to the development of AD. These studies demonstrate the need for further research to better understand the cellular signaling driving maladaptive plasticity after SCI as well as the complex and dynamic changes in intraspinal synaptic connectivity contributing to the development of AD. Moreover, GBP treatment may offer clinical benefit by reducing blood pressure during AD, however the optimal dosage must be identified to avoid undesired side-effects.

After individuals sustain a spinal cord injury, all aspects of their lifestyle must change for them to manage their new life roles. One important area of recovery that is often not addressed during the rehabilitation process is sexual functioning. The purpose of this quantitative study was to examine how doctor communication about sexual health with women who have sustained spinal cord injuries predicts their levels of sexual functioning and sexual self-esteem. The theoretical framework was the sexual health model. Questionnaires were used to gather data from 45 women who had completed rehabilitation from spinal cord injuries. Level of current sexual functioning was measured using the Female Sexual Function Index. Sexual self-esteem was measured using the Multidimensional Sexual Self-Concept Questionnaire. Satisfaction with doctor-patient communication was measured using the Patient Satisfaction Questionnaire and Perceived Self-Efficacy in Patient-Physician Interactions-Sex. Findings from correlation analysis indicated a positive correlation between general satisfaction with doctor-patient communication and confidence to communicate with the doctor about sexual health. Results also indicated a negative correlation between sexual self-esteem and sexual functioning. Findings may be used to improve communication between doctors and patients about sexual health, which may reduce the stigma of talking about sexuality and may promote more holistic treatment for women recovering from spinal cord injuries.

Research has shown that people with physical disabilities are at risk for developing secondary health conditions. Many of these secondary health conditions may be reduced by engaging in physical activity, yet people with physical disabilities are less likely to participate in physical activity. Information gaps remain regarding facilitators and barriers to physical activity. The purpose of this phenomenological study was to understand the experiences with physical activity among adults with a spinal cord injury (SCI). Research questions asked were about exercise experiences, barriers and facilitators, and the role of the natural and social environment. The theoretical framework used was the theory of planned behavior, in which attitudes and perceived advantages and disadvantages to performing a behavior are considered. In-depth interviews were conducted with 10 adults, 18 years of age and older, who have an SCI that requires the use of a wheelchair. Interviews were transcribed verbatim and analyzed thematically by identifying key phrases, determining recurring phrases, and grouping codes into themes. NVivo, a qualitative software, aided in the analysis. The participants in this study faced many obstacles, including physical and social barriers. Despite these barriers, participants recognized the importance of physical activity and identified factors that encouraged exercise. The implications for positive social change from this research include a better understanding among healthcare professionals working with people with disabilities and disability advocates of the experiences people with an SCI have when exercising and the potential to minimize the barriers to physical activity in an effort to reduce related secondary health conditions.

Following spinal cord injury (SCI), bladder management is of primary importance. As an activity of daily living (ADL), it affects community integration and quality of life (QOL). Women with SCI have neurogenic bladders that require self-catheterization, but they are unable to catheterize the native urethra, thus making bladder management physically and emotionally challenging. The purpose of this study was to understand the experiences of women with SCI who undergo urinary diversion surgery for bladder management. Qualitative data were collected using semistructured interviews from 10 women with SCI after urinary diversion surgery for bladder management. Qualitative Nvivo analysis of interview data was based on cognitive adaptation theory, which emphasizes adaptation to life-threatening events. Analysis showed improved quality of life among these 10 women, with improvements in independence, convenience, aesthetics, confidence, and sexuality. The women's lived experiences also showed enhanced privacy, dignity, normalcy, and safety. The lack of awareness in health care workers to offer this procedure was universally highlighted by participants. The social change implications include the need to advocate for women with SCI with bladder management needs who are unaware of this surgery option. Understanding the bladder management needs of women with SCI may help this population make choices for a better quality of life.

Cervical myelopathy is the most common form of spinal cord injury in North America with roughly 19,000 new cases in the US every year. It results from chronic compression of the spinal cord by osteophytes, intervertebral disc herniation, and ossified ligaments. It commonly affects adults over the age of 50 years and causes upper extremity numbness, loss of hand dexterity, gait disturbances, and decreased proprioception. Recent studies imaging studies have shown this injury is highly dependent on the dynamic motion of the spine, often worsening in extreme flexion and extension. Surgical intervention is the accepted mode of treatment with the aim of decompressing the spinal canal and stabilizing the spine. However, 25% of patients have reoccurrence of symptoms indicating that surgical treatments may not be adequately addressing the injury. A main reason for this is little data has been reported on the spinal cord mechanics during cervical spinal motion in either healthy or cervical myelopathy subjects. To address this, we utilized MR imaging and finite element modeling to investigate spinal cord mechanics. As far as we know, we are the first group to obtain in vivo 3 dimensional spinal cord displacement and strain data from human subjects and the first to develop a C2 to T1 FE model of the healthy and cervical myelopathic spine and spinal cord. Utilizing high resolution 3T MR imaging in neutral, flexion, and extension positions we were able to obtain spinal cord displacement and strain fields from both healthy subjects and cervical myelopathy subjects before and after surgical intervention. In healthy subjects, flexion motion of the spine causes the spinal cord to move superiorly and in extension the spinal cord moves inferiorly. During extension, localizations of high principal strain can be seen in healthy subjects at areas of bony impingement and dural buckling. In both flexion and extension, cervical myelopathy subjects exhibited very little spinal cord displacement due to spinal cord compression. Principal strains during flexion and extension were greater in cervical myelopathy patients than healthy patients, specifically at the C4-6 vertebral levels. Surgical treatments for cervical myelopathy did restore spinal cord motion however, not in the same pattern or direction as healthy subjects. Additionally principal strains of the spinal cord were not reduced after surgical intervention. This indicates that surgical interventions are not adequately addressing the altered mechanics of the spinal cord during cervical myelopathy. To determine the how common surgical techniques for cervical myelopathy affect spinal cord mechanics, a FE model of the cervical spine and spinal cord was developed. The spinal cord motion was validated against MR imaging data obtained from normal subjects. Once validated, the model was used to develop a FE model of cervical myelopathy and surgical interventions. The native FE model predicted spinal cord motion well and replicated bony spinal cord impingement and dural buckling seen in healthy subjects. The FE model of cervical myelopathy also replicated spinal cord motion well as compared to MR imaging data of cervical myelopathy. Principal strains obtained from the healthy and cervical myelopathy FE models were similar in flexion however in extension, principal strains were higher at the C3, C6 and C7 levels. This is different than the patterns exhibited in the MR imaging and is most likely due to the percent of spinal cord compression induced in the FE model. Three, C4 to C7 surgical interventions were introduced to the model: anterior discectomy and fusion, anterior discectomy and fusion with laminectomy, and double door laminoplasty. In flexion, all surgical treatments doubled spinal cord principal strains at the C3 level and minimally reduced tensile strain at C4. The majority of strain reduction occurred at C5-7. In extension, all surgical techniques increased principal strains at the C3 and C4 levels. Little or no reduction in principal strains was seen at the C5 and C7 levels. All surgical techniques reduced principal strains at the C6 level. Of the surgical techniques, ACDF tended to reduce spinal cord principal strains the least in both flexion and extension and tended to induce the highest von Mises stresses. Combining the data obtained from MR imaging and FE modeling we can see that cervical myelopathy alters spinal cord mechanics by limiting spinal cord motion and increasing spinal cord strain. Additionally, current surgical techniques are not addressing the change in spinal cord mechanics effectively. Specifically after surgery, and especially with ACDF, spinal cord displacements and strains are being increased and transferred to different sections of the spinal cord. This indicates not only the need and importance of further research in spinal cord mechanics but also the need to improve treatments for cervical myelopathy which adequately restore the spinal cord mechanics.

Paralyzed muscle fatigues more quickly than intact muscle. The reason for this difference is currently unknown. This work will bridge this gap in knowledge by evaluating the predictive abilities of higher-resolution closed-form mathematical models of muscle force and fatigue. Knowledge garnered from this effort will suggest possible mechanisms for the differences in fatiguability of muscle in different states of health. The hypothesis to be tested is that the concept missing from present models, and thus the present understanding of the physiology, is the dynamic behavior of divalent calcium (Ca2+) during induced muscle contraction. If the behavior of Ca2+ can be understood as a Riccati-Bass diffusion process, muscle force and low-frequency fatigue in paralyzed muscle can be more accurately predicted over the time course of response to neuromuscular electrical stimulation. The abilities of existing mathematical models to predict force and low-frequency fatigue are compared to the predictive abilities of new models that include the Riccati-Bass equation. There are several major findings of this study. First, it was found that the structure of the Conaway models better predicts force and low-frequency fatigue than do the Ding models. Second, the cross-bridge friction is the most influential factor in generating force in fresh muscle at frequencies greater than 5 pps. Finally, the calcium leak current is most influential in low-frequency fatigue in paralyzed muscle. It is concluded that the process of muscle fatigue occurs as calcium channel remodeling and inactivation of excitation-contraction coupling from ionic crowding accelerate with every additional contraction.

The current study was designed to test the effectiveness of spinal cord stimulation (SCS) in a retrospective group of 43 failed back surgery syndrome (FBSS) patients. A medical record review was conducted on study participants to capture · relevant presurgical biopsychosocial variables deemed to be of potential prognostic value. In addition, a multidimensional approach to outcome assessment was undertaken along three general domains: general health status, disease specific outcomes, and surgical outcomes. Descriptive statistics of presurgical variables and outcome measurements are provided as well as a model of outcome prediction based on these prognostic variables. Results suggest that the use of neurostimulation may help to reduce low back and/or leg pain in some patients with FBSS; however, a large number of patients reported continuing pain, physical disability, and inability to work despite treatment. The current study calls into question the efficacy of SCS for FBSS. Recommendations for future studies are presented.

Les systèmes neuromodulateurs jouent un rôle essentiel dans la mise en place et dansla régulation des réseaux moteurs spinaux afin d’adapter finement le rythme et le patronlocomoteur aux contraintes internes et externes de l’organisme. Il a été montré que desaltérations du fonctionnement de ces systèmes étaient impliquées dans de nombreusespathologies neurologiques. La sclérose latérale amyotrophique (SLA) est une maladieneurodégénérative caractérisée par la perte des neurones moteurs corticaux et spinaux. Bienque les symptômes de la SLA n’apparaissent qu’à l’âge adulte, de plus en plus d’élémentsamènent à penser que des modifications précoces des réseaux locomoteurs spinaux ont lieudès les stades précoces du développement chez un modèle animal de la SLA, la souris SOD1.C’est dans ce cadre général que nous avons émis l’hypothèse que des altérations précoces dessystèmes neuromodulateurs pourraient intervenir dans la physiopathologie de la SLA. Dansun premier temps, nous avons comparé la modulation monoaminergique des réseaux moteursspinaux en réalisant des enregistrements extracellulaires de l’activité locomotrice générée parla préparation de moelle épinière isolée chez la souris nouveau-née sauvage et SOD1. Nousnous sommes ensuite attachés en combinant des enregistrements électrophysiologiques extraetintracellulaires avec des techniques d’immunohistochimie et de biologie cellulaire à décrirela mise en place et l’évolution avec l’âge des synapses cholinergiques reçues par lesmotoneurones en provenance d’interneurones de la lamina X : les boutons en C. Enfin, nousavons initié une approche (1) comportementale sur le long terme de l’activité motrice dessouris SOD1 et (2) des capacités plastiques des synapses glutamatergiques reçues par lesmotoneurones en culture. L’ensemble de ces travaux, nous a permis de mettre en évidence desaltérations précoces et évolutives des principaux systèmes neuromodulateurs spinaux:cholinergique, dopaminergique et noradrénergique chez les animaux SOD1. Nos résultatsmontrent pour la première fois (1) qu’une dynamique complexe des récepteurs M2 sous lesboutons en C existe et que celle-ci est perturbée chez les souris SOD1 et (2) que lesmotoneurones ne sont pas les seuls neurones à dégénérer dans la moelle de ces animaux maisque les neurones cholinergiques de la lamina X situés dans les segments lombaires L2 sontaussi la cible de processus neurodégénératifs. / Neuromodulatory systems play a crucial role in the establishment and regulation ofspinal motor networks to finely adjust the locomotor rhythm and pattern to the internal andexternal constraints. It is now well admitted that alterations in neuromodulatory functions areinvolved in diverse neurologic disorders. Amyotrophic lateral sclerosis is a neurodegenerativedisease characterized by the specific loss of cortical and spinal motor neurons. A growingbody of evidence now suggests that although ALS syndromes occur in adulthood, alterationscan be detected as early as at the embryonic stages in the spinal cord of the rodent model ofALS, the SOD1 mouse. In this context, we hypothesized that early alterations in the spinalneuromodulatory systems may be involved in the pathophysiology of ALS. To answer thisquestion, in a first step, we compared the monoaminergic modulation of spinal network byrecording extracellularly the fictive locomotion produced in the in vitro spinal cordpreparation form newborn wild-type and SOD1 mice. By combining extra- intracellularrecordings with immunohistochemical and cellular biology technics, we aimed, in a secondstep, to investigate the cholinergic synapses arising onto motoneurons and their neuronalsource, the lamina X interneurons as a function of the mouse age. Finally, we initiated (1) aninnovative behavioural study of mouse motor habits and (2) an analysis of the synapticplasticity of glutamatergic synapses imping on motoneurons in culture. Altogether, our datademonstrated early and progressive changes of the major spinal neuromodulatory systems:cholinergic, dopaminergic and noradrenergic. Our data show for the first time that: (1) M2receptors undergo a complex dynamic under C-bouton that is completely disturbed in SOD1motoneurons and (2) motoneurons are not the only cellular subtype to degenerate in SOD1mice. Indeed, we found evidence that neurodegenerative processes also target lamina Xcholinergic interneurons in the SOD1 spinal cord.