Normal movement execution requires proper coupling of motor and sensory activation. An increasing body of literature supports the idea that incorporation of sensory stimulation into motor rehabilitation practices increases its effectiveness. Paired associative stimulation (PAS) studies, in which afferent and efferent pathways are activated in tandem, have brought attention to the importance of well-timed stimulation rather than non-associative (i.e., open-loop) activation. In patients with tetraplegia resulting from spinal cord injury (SCI), varying degrees of upper limb function may remain and could be harnessed for rehabilitation. Incorporating associative sensory stimulation coupled with self-paced motor training would be a means for supplementing sensory deficits and improving functional outcomes. In a motor rehabilitation setting, it seems plausible that sensory feedback stimulation in response to volitional movement execution (to the extent possible), which is not utilized in most PAS protocols, would produce greater benefits. This capability is developed and tested in the present study by implementing a brain-computer interface (BCI) to apply sensory stimulation synchronized with movement execution through the detection of movement intent in real time from electroencephalography (EEG). The results demonstrate that accurate sensory stimulation application in response to movement intent is feasible in SCI patients with chronic motor deficit and often precedes the onset of movement, which is deemed optimal by PAS investigations that do not involve a volitional movement task.

La spasticité et la douleur neuropathique sont deux symptômes apparaissant fréquemment après une lésion médullaire. La spasticité est définie comme une augmentation du tonus musculaire qui provoque des contractures, tandis que la douleur neuropathique se caractérise par des sensations douloureuses survenant suite à une lésion du système nerveux.Ces deux symptômes résultent en partie d’une désinhibition des réseaux neuronaux sous-lésionnels lié à une diminution de l’expression du cotransporteur potassium-chlorure type 2 (KCC2). Pour être efficace,l’inhibition nécessite l’action de cette protéine qui extrait les ions chlorure des neurones.L’objectif de la présente thèse est donc d’identifier des médicaments capables d’activer KCC2 afin de restaurer l’inhibition dans le but de traiter la spasticité et la douleur neuropathique.Dans un premier temps, nos résultats ont montré que l’activation de récepteurs sérotoninergiques 5-HT2A avec le TCB-2 rétablit l’expression de KCC2 dans la corne dorsale après une lésion médullaire ou névrectomie. Or le TCB-2 réduit seulement la douleur neuropathique après la lésion spinale.Par la suite, nous avons identifié la prochlorperazine comme une molécule augmentant l’activité de KCC2. Si la prochlorperazine est efficace contre la spasticité, elle a néanmoins un effet plus modeste envers l’allodynie mécanique suite à une lésion médullaire.Enfin, nous avons démontré que la diminution de KCC2,ainsi que l’hyperexcitabilité des motoneurones suite à la lésion, dépendent de l’activation des calpaïnes.Cette thèse valide KCC2 comme une cible thérapeutique dans le traitement de la spasticité et la douleur neuropathique suite à une lésion médullaire. / Spasticity and neuropathic pain are two symptoms that arise frequently after a spinal cord injury. Spasticity is defined as an increase of the muscle tone contributing to cramps, whereas neuropathic pain consists of painful responses caused by a damaged nervous system. Both symptoms arise, in part, due to a loss of inhibition in the sublesional neural networks, linked to a downregulation of the expression of potassium-chloride cotransporter type 2 (KCC2). For inhibition to be efficient, the action of this protein, which extrudes chloride ions from neurons, is needed.The objective of this thesis is, therefore, to identify drugs capable of activating KCC2 to recover inhibition with the objective of treating spasticity and neuropathic pain.First, our results have proven that the activation of serotonin receptors 5-HT2A with TCB-2 restores KCC2 expression in the dorsal horn after a spinal cord or peripheral nerve injury. However, TCB-2 reduces neuropathic pain after a spinal cord injury exclusively.In the next stage of the work, we have identified prochlorperazine as an enhancer of KCC2 activity. Prochlorperazine is efficient against spasticity, although it only showed a modest reduction of mechanical hyperalgesia in animals with a spinal cord injury.Lastly, we have proven that KCC2 downregulation and motoneuron hyperexcitability after a spinal cord injury depend on the overactivation of calpains.This thesis validates KCC2 as a druggable target to treat spasticity and neuropathic pain after spinal cord injury.

Cortical representations are plastic and are allocated based on the proportional use or disuse of a pathway. A steady stream of sensory input maintains the integrity of cortical networks; while in contrast, alterations in afferent activation promote sensorimotor reorganization. After an incomplete spinal cord injury (SCI), damage to the ascending and/or descending pathways induces widespread modifications to the sensorimotor system. Strengthening these spared sensorimotor pathways may be therapeutic by promoting functional recovery after injury. Using a technique called transcranial magnetic stimulation (TMS), we show that the leg motor cortex is facilitated by peripheral sensory inputs via disinhibition and potentiation of excitatory intracortical circuits. Hence, in addition to its crucial role in sensory perception, excitation from peripheral sensory afferents can reinforce muscle activity by engaging, and possibly shaping, the activity of the human motor cortex. After SCI, the amount of excitation produced by afferent stimulation reaching the motor cortex is expectantly reduced and delayed. This reduction of sensory inflow to the motor cortex may contribute to our findings that cortical inhibition is down-regulated after SCI, and this compensation may aid in the recruitment of excitatory networks in the motor cortex as a result of the damage to its output neurons. By repeatedly pairing sensory inputs from a peripheral nerve in the leg with direct cortical activation by TMS, in an intervention called paired associative stimulation, we show that the motor system can be potentiated in both uninjured individuals and after SCI. In the uninjured subjects, we show that in order to produce associative facilitation, the time window required for coincident activation of the motor cortex by TMS and peripheral sensory inputs is not as narrow as previously thought (~100 vs. ~20 ms), likely due to the persistent activation of cortical neurons following activation by TMS. The potential to condition the nervous system with convergent afferent and cortical inputs suggests that paired associative stimulation may serve as a priming tool for motor plasticity and rehabilitation following SCI.

<p>The World Health Organisation estimates that the majority of the disabled population resides in the developing world, but most of the research on outcomes of patients originates from the developed world. In the light of the differences in healthcare structures and function, especially rehabilitation between settings and countries, it is imperative to have an understanding of the&nbsp / functioning of patients at discharge with the objective of measuring the level at which outcomes are met. The aim of this study was therefore to determine the process of rehabilitation and the&nbsp / outcome of patients following in-patient rehabilitation at a facility in the Western Cape. A quantitative research design was employed to address the objectives. Self-administered&nbsp / questionnaires were developed to collate information pertaining to the demographic-, socioeconomic- and medical profile of patients and data extraction sheets collected information relating&nbsp / to the process of rehabilitation and the impairment status of patients on admission. With regards to activity and participation, a longitudinal study design was used, which utilised standardised&nbsp / outcomes measures. The sample consisted of all patients with stroke and spinal cord injury admitted within a three-month period, and all ethical principles relating to research on human&nbsp / subjects, as stipulated in the Helsinki Declaration were adhered to during data collection, with ethical clearance obtained from relevant authorities. The SAS and the Microsoft Excel Package&nbsp / 2007 were used to analyse the quantitative data elements. Descriptive statistics using frequencies, percentages, ranges, means, and standard deviations and inferential statistics using&nbsp / chi-square, student T-tests and correlation tests, for determining the predictors of functional outcome, were calculated. There were 175 patients, whereof 82 were patients with stroke and 93&nbsp / with spinal cord injury, with 143 (76 presenting with spinal cord injury and 67 with stroke) meeting the inclusion criteria on admission. The mean age of those with spinal cord injury and stroke&nbsp / was 34.14 and 52.95 years. Most of the patients with spinal cord injuries were single (73.68%), whereas the majority (53.73%) of patients with strokes were married at the time of injury. All&nbsp / patients were managed by the doctor and the nurse, with most of the patients receiving physiotherapy, occupational therapy and social assistance from the social worker. With regards to recreational activities, 46.87% of patients with spinal cord injury and 39.39% of those with stroke attended the learn to swim programme, and 29.68% of patients with spinal cord injury attended the wheelchair basketball sessions. The mean length of hospital stay for patients with spinal cord injury and stroke was 73.11 and 51. 62 days, with most of the spinal cord injured patients&nbsp / (80.26%) and stroke patients (82.08%) discharged home without follow-up rehabilitation. The most prevalent impairments on admission of the spinal cord injury cohort were muscle&nbsp / weakness (75.0%), bladder incontinence (71.1%) and reduced sensation (69.7%), whereas patients with stroke presented mostly with muscle paralysis (80.6%), abnormal tone (76.1%) and aphasia (50.8%). Functional limitations experienced by the participants included, mobility, stair climbing and transfers. The participants experienced participation restrictions in the following&nbsp / domains, leisure activities and employment. A clinical significant improvement was noted in execution of functional task of patients with spinal cord injury (p&lt / 0.0001) and stroke (p&lt / 0.0001)&nbsp / between admission and discharge. A significant statistical change was also detected for the participation elements of both stroke and spinal cord injury cohorts. Functional ability on&nbsp / admission was found to be a predictor of functional outcome of the stroke diagnostic group at discharge, whereas the multiple&nbsp / redictor model of functional outcome of the spinal cord injured cohort at discharge was significant with remaining variables of functional outcome score on admission (p&lt / 0.0001) and bladder -and bowel impairment(s) (p=0.0247). The study findings suggest that despite the significant change in activity and participation, most of the patients were discharged home without further follow-up for rehabilitation, irrespective of the activity&nbsp / limitations and participation restrictions still experienced at the time of discharge. The latter finding&nbsp / questions the duration of the length of hospital stay, which does not allow patients to be independent in all meaningful activities and participatory actions and roles by the end of inpatient rehabilitation. The study findings could assist authorities to adapt the existing rehabilitation&nbsp / programme and referral process . </p>

Traumatic spinal cord injury (SCI) is a devastating condition for which there is no effective clinical treatment. Neuroprotective molecules that minimize tissue loss have shown promising results; however systemic delivery may limit in vivo benefits due to short systemic half-life and minimal passage across the blood-spinal cord barrier. To overcome these limitations, an injectable intrathecal delivery vehicle comprised of hyaluronan and methylcellulose (HAMC) was developed, and previously demonstrated to be safe and biocompatible intrathecally. Here, HAMC was determined to persist in the intrathecal space for between 4-7 d in vivo, indicating it as an optimal delivery system for neuroprotective agents to reduce tissue degeneration after SCI. HAMC was then investigated as an in vivo delivery system for two neuroprotective proteins: erythropoietin (EPO) and fibroblast growth factor 2 (FGF2). Both proteins demonstrated a diffusive release profile in vitro and maintained significant bioactivity during release. When EPO was delivered intrathecally with HAMC to the injured spinal cord, reduced cavitation in the tissue and significantly improved neuron counts were observed relative to the conventional delivery strategies of intraperitoneal and intrathecal bolus. When FGF2 was delivered intrathecally from HAMC, therapeutic concentrations penetrated into the injured spinal cord tissue for up to 6 h. Poly(ethylene glycol) modification of FGF2 significantly increased the amount of protein that diffused into the tissue when delivered similarly. Because FGF2 is a known angiogenic agent, dynamic computed tomography was developed for small animal serial assessment of spinal cord hemodynamics. Following SCI and treatment with FGF2 from HAMC, moderate improvement of spinal cord blood flow and a reduction in permeability were observed up to 7 d post-injury, suggesting that early delivery of neuroprotective agents can have lasting effects on tissue recovery. Importantly, the entirety of this work demonstrates that HAMC is an effective short-term delivery system for neuroprotective agents by improving tissue outcomes following traumatic SCI.

Traumatic spinal cord injury (SCI) is a devastating condition for which there is no effective clinical treatment. Neuroprotective molecules that minimize tissue loss have shown promising results; however systemic delivery may limit in vivo benefits due to short systemic half-life and minimal passage across the blood-spinal cord barrier. To overcome these limitations, an injectable intrathecal delivery vehicle comprised of hyaluronan and methylcellulose (HAMC) was developed, and previously demonstrated to be safe and biocompatible intrathecally. Here, HAMC was determined to persist in the intrathecal space for between 4-7 d in vivo, indicating it as an optimal delivery system for neuroprotective agents to reduce tissue degeneration after SCI. HAMC was then investigated as an in vivo delivery system for two neuroprotective proteins: erythropoietin (EPO) and fibroblast growth factor 2 (FGF2). Both proteins demonstrated a diffusive release profile in vitro and maintained significant bioactivity during release. When EPO was delivered intrathecally with HAMC to the injured spinal cord, reduced cavitation in the tissue and significantly improved neuron counts were observed relative to the conventional delivery strategies of intraperitoneal and intrathecal bolus. When FGF2 was delivered intrathecally from HAMC, therapeutic concentrations penetrated into the injured spinal cord tissue for up to 6 h. Poly(ethylene glycol) modification of FGF2 significantly increased the amount of protein that diffused into the tissue when delivered similarly. Because FGF2 is a known angiogenic agent, dynamic computed tomography was developed for small animal serial assessment of spinal cord hemodynamics. Following SCI and treatment with FGF2 from HAMC, moderate improvement of spinal cord blood flow and a reduction in permeability were observed up to 7 d post-injury, suggesting that early delivery of neuroprotective agents can have lasting effects on tissue recovery. Importantly, the entirety of this work demonstrates that HAMC is an effective short-term delivery system for neuroprotective agents by improving tissue outcomes following traumatic SCI.

An increasing number of people with disabilities are choosing to become parents. However, several official goverment reports and other evidence points to the fact that parents with disabilities sometimes experience negative bias and distrust of their capacities as parents. The aim of this study is to describe and analyse aspects of parenthood in the families including parents with disabilities and/or chronic illness, as well as to illuminate concepts of an thoughts on parenthood and disability in these families. This is a qualitative interview study, complemented with structured diaries and network maps. The impairments or chronic illness of the parents in the eleven families of the study are cerebral palsy, spinal cord injury and multiple sclerosis. The different areas of the study are: the parents' reflections on becoming parents, the impact of the surrounding environment on the family, the effects of impairment or chronic illness in the family's everyday life and the parents' reflections on children and parenthood. The parents first and foremost describe their families as like any other families, but at the same time describe the special circumstances they live under. They work to handle the possibilities of negative consequences for the children with different strategies. The parents describe what they regard as the special experiences and knowledge that their children acquire which will benefit them as adults. The study recognises some dichotomous concepts relevant to different areas of family life in families with disabilities. The feeling the parents express of living in a world of double standpoints can be understood as ambivalence or in terms of embrace of paradox.

Chondroitin sulfate proteoglycans (CSPGs) are one major class of axon growth inhibitors that are upregulated and accumulated around the lesion site after spinal cord injury (SCI), and result in regenerative failure. To overcome CSPG-mediated inhibition, digestion of CSPGs with chondroitinase ABC (chABC) has been explored and it has shown promising results. chABC digests glycosaminoglycan chains on CSPGs and can thereby enhance axonal regeneration and promote functional recovery when delivered at the site of injury. However, chABC has a crucial limitation; it is thermally unstable and loses its enzymatic activity rapidly at 37 ºC. Therefore, it necessitates the use of repeated injections or local infusions with a pump for days to weeks to provide fresh chABC to retain its enzymatic activity. Maintaining these infusion systems is invasive and clinically problematic. In this dissertation, three studies are reported that demonstrate our strategy to overcome current limitations of using chABC and develop a delivery system for facilitating chABC treatment after SCI: First, we enhanced the thermostability of chABC by adding trehalose, a protein stabilizer, and developed a system for its sustained local delivery in vivo. Enzymatic activity was assayed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and dimethylmethylene blue (DMMB), and conformational change of the enzyme was measured via circular dichroism (CD) with and without trehalose. When stabilized with trehalose, chABC remained enzymatically active at 37 ºC for up to 4 weeks in vitro. We developed a lipid microtube-agarose hydrogel delivery system for a sustained release and showed that chABC released from the delivery system is still functionally active and slowly released over 2 weeks in vitro. Second, the hydrogel-microtube system was used to locally deliver chABC over two weeks at the lesion site following a dorsal over hemisection injury at T10. The scaffold consisting of hydrogel and chABC loaded lipid microtubes was implanted at the top of the lesion site immediately following injury. To determine effectiveness of topical delivery of thermostabilized chABC, animal groups treated with single injection or gel scaffold implantation of chABC and penicillinase (P'ase) were included as controls. Two weeks after surgery, the functionality of released chABC and the cellular responses were examined by immunohistological analysis with 3B3, CS-56, GFAP and Wisteria floribunda agglutinin (WFA). The results demonstrated that thermostabilized chABC was successfully delivered slowly and locally without the need for an indwelling catheter by using the hydrogel-microtube delivery system in vivo. The results demonstrated that released chABC from the gel scaffold effectively digested CSPGs, and therefore, there were significant differences in CSPG digestion at the lesion site between groups treated with chABC loaded microtube-hydrogel scaffolds and controls. Third, a long term in vivo study (45 days) was conducted to examine axonal sprouting/regeneration and functional recovery with both a single treatment each of microtube loaded chABC or Neurotrophin-3 (NT-3), and a combination of them by using the hydrogel-microtube delivery system. Over the long term study period, the treated animals showed significant improvement in locomotor function and more sprouting of cholera toxin B subunit (CTB)-positive ascending dorsal column fibers and 5-HT serotonergic fibers around the lesion site. We demonstrated that this significant improvement of chABC thermostability facilitates the development of a minimally invasive method for sustained, local delivery of chABC that is potentially a useful and effective approach for treating SCI. In addition to that, we demonstrated that combinatorial therapy with chABC and neurotrophic factors could provide a synergistic effect on axonal regrowth and functional recovery after SCI.

The debilitating effects of spinal cord injury can be attributed to a lack of regeneration in the central nervous system. Identification of growth-promoting pathways, particularly ones that can be controlled by small molecules, could provide significant advancements in regenerative science and lead to potential treatments for spinal cord injury. The biological investigations of neuroregenerative small molecules, specifically the natural products clovanemagnolol and vinaxanthone, have been expanded to a whole organism context using the nematode Caenorhabditis elegans (C. elegans) as a tool for these studies. A straightforward assay using C. elegans was developed to screen for compounds that promote neuronal outgrowth in vivo. This outgrowth assay was then used to guide the design of chemically edited analogs of clovanemagnolol that maintained biological activity while possessing structures amenable to further modification for mechanism of action studies. Pull-down experiments using affinity reagents synthesized from a neuroactive structural derivative, clovanebisphenol, and the C. elegans proteome combined with mass spectrometry-based protein identification and genetic recapitulation using mutant C. elegans identified the putative protein target of the small molecule as a kinesin light chain, KLC-1. Furthermore, the small molecule-promoted regeneration of injured neurons in vivo was studied using laser microsurgery to cut specific axons in C. elegans followed by treatment with a library of analogs of the growth-promoting natural product vinaxanthone. Enhanced axonal regeneration was observed following small molecule treatment and the results were used to determine the structure-activity relationship of vinaxanthone, which may guide future development of potential drug candidates for the treatment of spinal cord injury. / text

This study investigated a series of independent unassisted and device-assisted transfers from a wheelchair to vehicle mock-up and vice versa while simultaneously capturing kinematic, kinetic and electromyographic (EMG) data of impaired volunteers. The study provides a venue for observation and evaluation of upper extremity (UE) joint stresses, muscular force and functional demands associated with transfers in persons with spinal cord injury (SCI) to ultimately prevent UE injury, minimize excessive stress, preserve functionality and limit pain. If people with SCI lose function of their UEs, due to pain and/or degeneration, they must then rely on others for everyday tasks. Five paraplegic males from the Tampa Bay area were recruited to take part in the study. Participants were asked to perform a series of transfers using 4 commercially available devices or mock-ups of that device as well as an unassisted transfer, which permitted the use of no assistive device. Three data types were captured: kinematic data using motion capture, kinetic data using force transducers which were integrated into the vehicle mock-up and EMG of 5 bilateral muscle groups. Data collection took approximately 4 hours per subject. Forces occurring during the unassisted transfers were found to be the highest. This is also supported by the EMG data. Performing level transfers lessened stresses at the UE versus non-level transfers. The highest moments of the UEs were found at the shoulders with high variability between subjects. It was also found that body mass index (BMI) had an affect on a subjects ability to perform transfers. Ultimately this study found that using an assistive device is better than not using an assistive device. This is proven by EMG and force data, which were both found to be less with the use of an assistive device as opposed to transferring independently with no assistance. Performing level transfers, maintaining ones body mass and staying active are all factors that will limit stresses at the UEs during wheelchair transfers to and from a vehicle.