Spinal cord injury (SCI) is a debilitating condition that disrupts the communication between the brain and the spinal cord. Several studies have sought to determine how to revive dormant spinal circuits caudal to the lesion to restore movements in paralyzed patients. So far, recovery levels in human patients have been modest at best. In contrast, animal models of SCI exhibit more recovery of lost function. Recovery of lost function could arise from structural changes in spinal circuits following spinal cord injury. Previous work from our lab has identified dI3 interneurons as a spinal neuron population central to the recovery of locomotor function in spinalized mice. We seek to determine the changes in the circuitry of dI3 interneurons and motoneurons following SCI in adult mice. After a complete transection of the spinal cord at T9-T11 level in transgenic Isl1:YFP mice and subsequent treadmill training at various time points of recovery following surgery, we examined changes in three key circuits involving dI3 interneurons and motoneurons: 1) Sensory inputs from proprioceptive and cutaneous afferents, 2) GABAergic inputs onto sensory afferents (GABApre), 3) Central excitatory glutamatergic synapses from spinal neurons onto dI3 INs and motoneurons. Furthermore, we examined the possible role of treadmill training on changes in synaptic connectivity to dI3 interneurons and motoneurons. Our data suggests that sensory inputs from the periphery labelled by VGLUT1⁺ to dI3 interneurons decrease transiently or only at later stages after injury, whereas levels of VGLUT1⁺ remain the same for motoneurons after injury. Levels of central excitatory inputs labelled by VGLUT2⁺ to dI3 INs and MNs may show transient increases but fall below levels seen in sham-operated mice after a period of time. Levels of GABApre boutons onto the VGLUT1⁺ sensory afferents that project onto to dI3 INs and MNs can rise shortly after SCI, but those increases do not persist. However, levels of these GABApre boutons onto VGLUT1⁺ inputs never fell below levels observed in sham-operated mice. For some synaptic inputs studied, levels were higher in spinal cord-injured animals that received treadmill training, but these increases were observed only at some time points. Changes in spinal circuitry could be maladaptive. For example, spasticity is a common consequence of SCI, disrupting motor function and resulting in significant discomfort. Spasticity may arise from maladaptive changes in spinal circuits. Current models of hindlimb spasticity are lacking, hindering the study of mechanisms or treatments of spasticity. Therefore, we have generated a novel mouse model of SCI-related spasticity that utilizes optogenetics to activate a subset of cutaneous VGLUT2⁺ sensory afferents to produce reliable incidences of hindlimb spasticity. To examine the efficacy of this optogenetic spasticity model, a T9-T10 complete transection injury was performed in Isl1-Vglut2ᒼᵃᵗᒼʰ mice, followed by the implantation of EMG electrodes into the left and right gastrocnemius and tibialis anterior muscles. Beginning at 9 days post-injury, EMG recordings were performed during episodic optogenetic stimulation. During each recording session, an optic fiber coupled to a 470nm wavelength LED was used to deliver light pulses to the palmar surface of each hindpaw. The results of these recordings demonstrated significant increases in the amplitude of EMG responses to the light stimulus from 2 weeks post-injury to 5 weeks post-injury, indicating hyperreflexia. Interestingly, this hyperreflexia was significantly greater in the female cohort in comparison to the males. Incidences of prolonged involuntary muscle contraction and clonus were also detected through EMG and visual observation during the testing period, supporting the presence of spasticity. Overall, the results in my thesis suggest remodelling of spinal circuits involving spinal interneurons that have previously been implicated in the recovery of locomotor function after spinal cord injury in mice. In addition, we have developed an optogenetic mouse model that appears to reliably elicit spasticity in SCI mice and may be valuable for the study of SCI-related limb spasticity mechanisms due to the maladaptive changes within the spinal cord.

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Thesis advisor: Mary E. Duffy / Ten people with tetraplegic spinal cord injuries participated in a nurse-coached exercise intervention/single subject design study over a period of six months. Four pieces of exercise equipment were used: the RT300S Functional Electrical Stimulation Bike, the VIta Glide, the NuStep TRS 4000, and the Easy Stand Evolv Glider. Measurement of variables of the Manual Muscle Test (MMT), Catz-Itzkovich Spinal Cord Independence Measures (CI-SCIM), and Moorong Self-Efficacy Scale (MSES) were collected at baseline, at three months into the exercise intervention, and at six months (at the conclusion of the intervention). Results were determined by visual analysis of graphs, in keeping with single subject design methods, and statistical analysis of combined data. Of those muscles that demonstrated some strength at baseline, 75% experienced increased strength at three and/or six months into the intervention. Of those muscles that demonstrated no strength at baseline and that were adjacent to muscles that demonstrated some strength at baseline, 66% were found to have increased strength at three and/or six months. Nine of ten participants experienced upward trends in CI-SCIM scores overall (p<.0001). The results of the subscales of Self-Care (p<.0001) and Mobility (p<.0001) indicated statistically significant changes over time. The subscale Respiratory and Sphincter Management was not statistically significant (p>.05). Visual analysis of graphs demonstrated that each of ten participants experienced strong improvements in self-efficacy scores from baseline to three months and from three months to six months into the intervention. R-ANOVA (p<.0001) confirmed statistical significance across ten participants. The Sheehy Spinal Cord Injury Functional Improvement Via Exercise (SCI-FIVE) Model was constructed prior to the study and validated throughout the course of the study. The results of the study validated all components of the Model and demonstrated increased muscle strength, increased self-efficacy, and improved quality of life for the ten study participants who participated in a nurse-coached exercise intervention for people with tetraplegic spinal cord injuries. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.

Within recent literature, internal locus of control (LOC) has been correlated with self-efficacy and improved coping after injury. Service connection (SC) has been linked to well-being after trauma. Level of injury has been associated with physical ability and limitations. This study examines how depression and QOL are associated with LOC and SC for veterans diagnosed with spinal cord injury (SCI). It was hypothesized that internal LOC and SC would correlate with higher QOL and decreased depression. Participants included 58 veterans, 30 diagnosed with paraplegia and 28 with quadriplegia. Measures included a demographics questionnaire, the Rotter's Internal-External Scale of LOC, the Diener's Satisfaction with Life Scale, and the Center for Epidemiological Studies - Depression Scale. Medical records were reviewed for SC. Generalized linear model regressions were run using LOC, SC and level of injury to estimate QOL and depression. Locus of control was a significant predictor of QOL, F=2.961, p=.045, while SC approached significance at F=2.082, p=.077. Locus of control approached significance as a predictor for depression, F=1.977, p=.083 level. Level of injury was not a significant factor for either outcome variable. Follow-up analyses including time since injury (TSI) indicated that the interaction of LOC and TSI was a significant predictor for QOL, F=5.320, p=0.013, and the interaction of SC and TSI was a significant predictor for depression, F=9.800, p=0.002. A significant correlation was found between depression and QOL, r=-.472, p=.000. A significant correlation was found between LOC and TSI, r=-.277, p=.018. Results indicate that internal LOC, SC, and increased TSI are positively associated with improved QOL and lower depression. The negative correlation between LOC and TSI indicates that LOC may be a mutable personality factor that adjusts from being external to internal to improve coping after disability, or those with an internal LOC are more consistent with treatment over time. The negative correlation between depression and QOL indicates that participants endorsing depression perceive having a lower QOL. These findings have important implications for health psychology, as they indicate that increasing internal LOC and access to health care over time can promote lower depression and higher QOL for SCI patients.

Spinal cord injury (SCI) is a debilitating condition accompanied by motor and sensory deficits and a reduced quality of life. Current treatment options are limited and are associated with variable efficacy and a risk of adverse effects. The pathophysiology of SCI is initiated by a primary mechanical insult to the spinal cord, followed by a complex series of deleterious events known as secondary injury. Secondary injury processes include free radical formation, glutamate excitotoxicity, inflammation and cell death. Apoptotic cell death in particular plays a key role in the secondary injury processes and exacerbates tissue degradation and loss of function. The role of Fas-mediated apoptosis in SCI pathophysiology is poorly defined in the literature to date. Correlative evidence suggests that this form of cell death is delayed and occurs in white matter adjacent to sites of primary damage. The cellular and temporal mechanisms of Fas-mediated apoptosis following experimental SCI were evaluated using a clinically relevant clip compression SCI model in the rat. Furthermore, therapeutic manipulation of Fas activation using a soluble form of the Fas receptor (sFasR) was carried out to establish the efficacy and clinical relevance of targeting this aspect of secondary injury. This work shows that Fas-mediated apoptosis is an important contributor to secondary SCI pathology. Oligodendrocytes are targeted by this form of cell death in a delayed fashion post-injury, providing an opportunity for therapeutic intervention. Intrathecal administration of sFasR following SCI reduced post-traumatic apoptosis, improved cell survival, enhanced tissue preservation and resulted in an improved motor recovery. Administration of sFasR was effectively delayed by up to 24 hours post-injury, however a shorter delay of 8 hours post-injury was most efficacious. A surprising result emerged from this work. Delayed intrathecal administration of IgG following SCI showed significant efficacy in both cellular and tissue level outcomes, as well as at the functional level. Fas-mediated apoptosis is an important aspect of secondary SCI pathophysiology and is an attractive therapeutic target. The beneficial outcomes of manipulating Fas activation using sFasR provide further evidence for this. Future work will refine this treatment strategy, bringing it into the SCI patient population.

Injury to the spinal cord results in the disruption of signal transmission between the brain and distal targets. It often presents with the loss of motor function and sensory perception below the level of injury. There are many obstacles following injury that must be overcome in order to encourage axon regeneration and improve functional recovery. A combinatorial approach is necessary to combat physical and chemical barriers to recovery. The fluid filled cyst that forms in the majority of spinal cord injuries presents a physical barrier that we treat with our electrospun bridges. We implanted our bridges into female Long Evans Hooded rats following a complete transection. Using a molecular fusogen, polyethylene glycol, known to seal damaged membranes in conjunction with our bridges, we were able to increase functional recovery compared to animals treated with a bridge and saline. In Chapter 1, we introduce spinal cord anatomy, the pathological classifications, axon pathology, and our therapeutic strategy. Chapter 2 details the materials and methods. Chapter 3 examines previous uses of polyethylene glycol as a molecular fusogen, previous studies utilizing it in spinal cord injury, and our strategy of fusing damaged axons to improve functional recovery. Finally in Chapter 4, I discuss our behavioral results, compare histology, and detail the future of our research including protocol improvements and future combination therapies that include PEG to improve outcome.

Injury to the spinal cord results in partial or complete loss of sensory perception and motor function. After spinal cord injury (SCI), damaged tissue dies and a cavity will form. This cavity prevents the regeneration of tissue and any functional recovery. One way to address the cavity is the insertion of an electrospun scaffold that our lab has created. This provides a substrate for regenerating tissue to grow on, and it is thought that reestablishing the blood supply within the scaffold will allow cells necessary for regeneration to thrive. This could ultimately lead to meaningful recovery for patients who have suffered SCI. Full spinal cord transections were performed on rats, and the scaffolds were inserted into the lesion site. Two different types of scaffold were tested to see if altering the fiber size in the scaffolds produced more blood vessels, and ultimately better regeneration of tissue.

Magister Scientiae (Physiotherapy) - MSc(Physio) / A traumatic spinal cord injury (TSCI) often occurs unexpectedly and causes considerable disability. This condition requires specialized care that is delivered in a time sensitive manner. Data on the incidence, causes, mortality and injury characteristics of TSCI are important for gauging demand for health care and social support services. Unfortunately data on the incidence and causes, as well as functioning such as participation and integration into society, of TSCI are sparse in developing countries such as Tanzania. The overall aim of this study is to determine the incidence, causes, mortality and injury characteristics of TSCI, and to explore the challenges experienced with community reintegration after injury in Tanzania. Both quantitative and qualitative research paradigms were used. The quantitative phase of the study was conducted at Kilimanjaro Christian Medical Centre (KCMC), a referral and teaching hospital in northern Tanzania. The study population was all patients admitted to KCMC with a TSCI from 1 January 2011 to 31 December 2015 (five year period). Quantitative data were collected retrospectively using a data extraction sheet designed by the International Spinal Cord Society which consisted of the following sections: participants’ characteristics (for example age, gender, duration of hospital stay, causes of injury and vertebral injuries) and injury characteristics (location of injury and completeness of injury). Differences between groups (stratified by year) was analysed using both descriptive and inferential statistics. The population for the qualitative phase was based on those included in the quantitative phase. Purposive sampling was used to select adults (over the age of 18 years) with TSCI who were managed at KCMC. Qualitative data were collected by means of individual, semi-structured interviews, and lasted until theoretical saturation was achieved. Thematic analysis was used to derive themes (categories) explaining the latent perceptions of community reintegration and its influences.

Philosophiae Doctor - PhD / Spinal cord injury (SCI) is a devastating condition often affecting young and healthy individuals around the world. This debilitating condition not only creates enormous physical and emotional suffering to individuals but also is a significant financial burden to families and society at large and it affects quality of life. Successful community reintegration following spinal cord injury is considered an important goal of rehabilitation as this has been positively associated with self-esteem, life satisfaction and quality of life. The overall aim of the study was to design a community reintegration programme for individuals who sustained a traumatic spinal cord injury (TSCI) in the Cape Metropolitan Area. The design of this study was a mixed method design including four phases. The first phase of the study was to determine the base line information regarding reintegration into communities after sustaining a TSCI and included 108 participants. Data was collected by use of self-administered/interview administered questionnaire. The results of this phase demonstrated that community reintegration of individuals who sustained a traumatic spinal cord injury was relatively low and employment was found to be a statistically significant variable influencing community reintegration following the injury. The second phase of the study aimed to gain a deeper understanding of how employment and other factors influence reintegration into communities after the injury.

Foi realizado estudo experimental com ratos Wistar Albinos, com o objetivo de avaliar diferentes modelos de estudo da lesão da medula espinhal. Os controles foram formados pelos grupos Anestesia, Divulsionamento dos tecidos moles pré-vertebrais e Laminectomia. Os grupos para estudo da lesão da medula espinhal foram formados por animais nos quais o segmento vertebral localizado entre T10 e L1 foi submetido à secção total da medula espinhal, secção parcial (hemissecção), secção total precedida da aplicação local de anestésico e compressão vertebral. Os animais foram avaliados 2 e 24 horas após a realização dos procedimentos, por meio da Escala de Avaliação Locomotora, Teste do Campo Aberto, Teste de Retirada da Cauda, Teste da Placa Quente e Teste do Pinçamento da Pata (reflexos segmentares e supra-segmentares) e também por métodos histológicos, utilizando-se as colorações de Níssl, HematoxHina-Eosina e Glees. Foi observado que as escalas de avaliação locomotora utilizadas foram menos sensíveis à detecção de mudanças funcionais nos animais se comparadas com os testes de comportamento sensório-motores. O teste Exploração no Plano Vertical foi o mais sensível para detectar deficiências sensório-motoras nos diferentes grupos experimentais. Por esse método detectamos uma diminuição da capacidade de exploração do plano vertical nos animais 24 horas após os procedimentos. O teste de função reflexa mais sensível à detecção de deficiências sensório-motoras nos animais após trauma raquimedular leve, moderado e grave, foi o Teste da Placa Quente. Portanto, este estudo demonstrou que, além das Escalas de Avaliação Locomotora, o Teste do Campo Aberto e o Teste da Placa Quente são de utilização fácil, simples, barata, reprodutível e quantitativa, com sensibilidade para detectar deficiências funcionais em animais que tenham sofrido trauma raquimedular leve, moderado ou grave. A análise histológica em segmentos da medula espinhal abrangendo o sítio da lesão permitiu a avaliação da lesão e correlação entre a lesão sensitiva e motora. / An experimental study was carried out using Wistar Albine rats, aiming at an evaluation of different models for the study of spinal injury. Controls included the following groups: Anesthesia, Divulsion of the soft prevertebral tissues and Laminectomy. Groups for the study of spinal injury were composed by animals whose vertebral segment between T10 and L1 was submitted to Total Section of the Spinal cord, Partial Section (hemissection), Total Section Preceded of Application of Local Anesthetic and Vertebral Compression. Animals were evaluated, 2 and 24 hours after the experimental procedures, by means of the Locomotor Evaluation Scale, Open Field Test, Tail Flick Test, Hot Plate Test and Paw Nippering Test (segmentary and suprasegmentary reflex), as well as by means of histological methods using Níssl, Hematoxilin-Eosin and Glees Stainning. lt was observed that the Locomotor Evaluation Scales so far used were less sensitive to detection of functional changes in animals when compared with the sensorio-motor behaviour tests. The vertical Plain Exploration Test was the most sensitive for detection of sensorio-motor deficiences in different experimental groups. By means of this method we could detect a decrease in the ability to explore the Vertical Plain in the animals of 24 hours. The more sensitive reflex function test to detect sensorio-motor deficiences of animals, following light, moderate or severe spinal cord injury, was the Hot Plate Test. Therefore, this study showed that, in addition to the locomotor Evaluation scales, the Open Field Test and Hot Plate Test are of easy, simple, cheap, reproducible and quantitative utilization, showing enough sensitivity to detect functional deficiences in animals previously submitted to light, moderate or severe spinal cord injury. Histological analysis of spinal cord segments which enclosed the injured site allowed the evaluation of the injury and the relationship between sensitive and motor lesions.