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<p>Using a cross-sectional design, Bandura's (1986) Social Cognitive Theory and Self-Efficacy Theory (1977) were used as a framework to determine whether wheelchairuse self-efficacy and exercise barrier self-efficacy mediate the relationship between wheelchair mobility and leisure-time physical activity (LTPA) in people with spinal cord injury (SCI). Fourty-six manual wheelchair users (76.1 % male), with varying levels of SCI (80.4% paraplegic, 47.8% complete injuries) participated in this study. Participants completed The Wheelchair Skills Test version 4.1 (Wheelchair Skills Test Version 4.1 [WST 4.1],2008) which measured wheelchair mobility, a modified barrier self-efficacy questionnaire (McAuley & Mihalko, 1998) which measured exercise barrier self-efficacy, the Wheelchair Mobility Confidence Scale (WMCS; Rushton & Miller, 2009) which measured wheelchair-use self-efficacy, and the Physical Activity Recall Assessment for people with SCI (PARA-SCI; Martin Ginis, Latimer, Hicks & Craven, 2005) which measured LTPA. It was hypothesized that (1) there would be a positive relationship between wheelchair mobility and LTPA, and (2) wheelchair-use self-efficacy and exercise barrier self-efficacy would mediate this relationship. Using linear regression models, a positive association between wheelchair mobility and LTPA was established (β = .29, p < .05). Exercise barrier self-efficacy was a significant partial mediator, explaining 47.7% ofthe variance in the mobility-LTPA relationship. Wheelchair-use selfefficacy was a non-significant mediator. This thesis has practical and theoretical implications for understanding and improving LTPA participation and represents the first study to determine the relationship between wheelchair mobility, self-efficacy, and LTPA in people living with SCI.</p> / Master of Science (MS)

<p>Body weight supported devices available to enhance locomotor recovery following an incomplete spinal cord injury (SCI) include treadmills with (Lokomat^TM) and without (Manual Treadmill) robotic assistance, and the overground ZeroG^TM system. Cardiovascular and muscular demands of these devices were compared during steady-state locomotion at the <em>same</em> level of body weight support (BWS) in 7 individuals with incomplete SCI (42.6±4.29 years) and matched able-bodied controls (CON). Questionnaires evaluated consumer preference based on walking experience. Oxygen uptake (VO₂), heart rate (HR) and ratings of perceived exertion (RPE) were expressed as percentage of peak values obtained using arm ergometry. Additionally, VO₂ was expressed relative to resting metabolic equivalents (METS). Filtered electromyography (EMG) signals from tibialis anterior (TA), rectus femoris (RF), biceps femoris (BF) and medial gastrocnemius (MG) were normalized to ZeroG^TMstepping. Lokomat^TM sessions were the least demanding in terms of oxygen uptake compared to the Manual Treadmill and ZeroG^TM, and considered the least appropriate device for the SCI group’s current level of function. For SCI, the a) ZeroG^TM required 3.0 METS, 54.7% of VO₂peak, 84.7% of peak HR, b) Manual Treadmill required 2.8 METS, 52.9% of VO₂peak, 80.8% of peak HR and c) Lokomat^TM required 1.7 METS, 30.1% of VO₂peak, 67.3% of peak HR. Central RPEs were 3.8, 3.7, 0.5 and peripheral RPEs were 5.1, 4.1, 0.7 for the ZeroG^TM, Manual Treadmill and Lokomat^TM respectively. For CON, walking required minimal effort (at most 31.5% of VO₂ peak), with ZeroG^TM sessions requiring greater muscle activation. For SCI, muscle activation was higher in treadmill conditions compared to the ZeroG^TM due to increases in TA and BF activity. The Manual Treadmill and ZeroG^TM should be considered progressions following Lokomat^TM training where hip extension can be encouraged using the treadmill and additional components of gait (e.g. balance, torso stability) can be focused on using the ZeroG^TM.</p> / Master of Science (MS)

Several studies have reported that administration of cannabinoid receptor agonists in inflammatory/autoimmune and CNS injury models resulted in significant attenuation of clinical disease. The beneficial effects correlated with the observed reduction of inflammatory mediators and peripheral immune cell infiltration into the site of inflammation. Previous studies from our laboratories demonstrated that administration of cannabinoid type 2 receptor agonist attenuated disease score and improved recovery in two murine models of neuroinflammation; spinal cord injury (SCI) and experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. The goal of the current investigation was to evaluate the mechanisms through which administration of selective cannabinoid-2 receptor (CB2R) agonists modify inflammatory responses and help to improve function in SCI and EAE. In SCI, an acute neuroinflammatory disorder, administration of CB2R agonist at 1 h and 24 h following contusion injury to the cord resulted in improved recovery of motor function and bladder function (the ability to spontaneously void) compared to control animals. Evaluation of inflammatory mediators at 48h demonstrated a dramatic reduction in the expression of the chemokines CXCL9, 10, 11 and cytokines IL-23 and its receptor in CB2R agonist-treated cords. There was also a reduction in the expression of toll-like receptors (TLR1, TLR4, TLR6, and TLR7), which correlated with a decreased number of immunoreactive microglia. Interestingly, at seven days post injury, CB2R agonist-treated injured cords showed a significant reduction in both hematopoietic and myeloid cell infiltration. In EAE, a chronic neuroinflammatory disorder, our laboratories demonstrated previously that administration of a CB2R agonist led to lower disease scores and improved recovery. In this study, we observed reduced numbers of infiltrating hematopoietic and myeloid cells into the spinal cord and brain of CB2 agonist-treated mice. This reduction was observed at the peak of disease (day 17) and the effect was maintained at the chronic stage of disease (day 30). Evaluation of molecules associated with cell migration showed decreased levels of the adhesion molecule VCAM-1 and matrix metalloproteinases MMP-2 and 9 at peak of EAE in treated mice. The decrease in VCAM-1 correlates with our previous observation of decreased leukocyte rolling and adhesion to brain microvasculature. However, the reduction in MMP-2/9 expression suggests that CB2R agonists may also affect leukocyte transmigration into the perivascular space and further infiltration into the CNS parenchyma. This process requires both chemokine cues and the gelatinases MMP2/9. Animals deficient in these MMPs show leukocyte accumulation in the perivascular space and are resistant to EAE. There are no reports in the literature on possible CB2R agonist effects on gelatinases in myeloid cells. Although both MMP-2 and -9 are produced by antigen-presenting cells and act on similar substrates, MMP-9 appears to play a crucial role in EAE. Therefore, we decided to examine the effects of CB2 signaling on MMP-9 expression in myeloid cells, focusing on myeloid bone marrow-derived dendritic cells (BMDC). Activation of bone marrow-derived macrophages, dendritic cells, and primary microglia with the cytokine cocktail TNFα, IL-1ß, IL-6, containing PGE2, which mimicked an inflammatory milieu, resulted in expression of high levels of MMP-9. Treatment with CB2R agonists reduced MMP-9 in all three cell types. Since migration of DC to various sites is required for their activation and for the initiation of adaptive immune responses, we evaluated the effects of CB2R agonists on migration. The reduced levels of MMP-9 correlated with reduced migration of DC to the draining lymph nodes in vivo, as well as reduced migration vitro in the matrigel migration assay. The effect on MMP-9 expression was mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to the AP-1 site in the MMP-9 promoter. We postulate that, by dampening production of MMP-9 and subsequent MMP-9-dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells including DC. / Physiology

Greater than 50% of all spinal cord injuries (SCIs) in humans occur at the cervical level and the biggest desire of quadriplegic patients is recovery of hand and digit function. Several weeks after spinal cord injury, re-organization and re-modeling of spared endogenous pathways occurs and plasticity of both supraspinal and interneuronal networks are believed to mediate functional recovery. Propriospinal interneurons (PNs) are neurons found entirely in the spinal cord with axons projecting to different spinal segments. PNs function by modulating locomotion, integrating supraspinal motor pathways and peripheral sensory afferents. Recent studies have postulated that if PNs are spared following SCI, these neurons can contribute to functional recovery by establishing synaptic connections onto motor neurons. However, to what extent cervical PNs are involved in recovery of reaching behavior is not known. In our first study, we generated a lentiviral vector that permits highly efficient retrograde transport (HiRet) upon uptake at synaptic terminals in order to map supraspinal and interneuronal populations terminating near forelimb motoneurons (MNs) innervating the limb. With this vector, we found neurons labeled within the C3-C4 spinal cord and in the red nucleus, two major populations which are known to modulate forelimb reaching behavior. We also proceeded to use a novel two-viral vector method to specifically label ipsilateral C3-C4 PNs with tetracycline-inducible GFP. Histological analysis showed detailed labeling of somas, dendrites along with axon terminals. Based on this data, we proceeded to determine the contribution of C3-C4 PNs and rubrospinal neurons on forelimb reaching and grasping before and after cervical SCI. In our second study, we have examined a double-infection technique for shutdown of PNs and rubrospinal neurons (RSNs) in adult rats. Adult rats were microinjected with a lentiviral vector expressing tetracycline-inducible inhibitory DREADDs into C6-T1 spinal levels. Adeno-associated viral vectors (AAV2) expressing TetON mixed with GIRK2 were injected into the red nucleus and C3-C4 spinal levels respectively. Rats were tested for deficits in reaching behaviors upon application of doxycycline and clozapine-n-oxide (CNO) administration. No behavioral deficits were observed pre-injury. Rats then received a C5 spinal cord lesion to sever cortical input to forelimb motoneurons and were allowed four weeks to spontaneously recover. Upon re-administration of CNO to activate inhibitory DREADDs, deficits were observed in forelimb reaching. Histological analysis of the C3-C4 spinal cord and red nucleus showed DREADD+ neurons co-expressing GIRK2 in somas and dendrites of PNs and RSNs. PN terminals expressing DREADD were observed near C6-T1 motoneurons and in the brainstem. Control animals did not show substantial deficits with CNO administration. These results indicate both rubro- and propriospinal pathways are necessary for recovery of forelimb reaching. In a separate study, we sought to determine if promoting severed CST sprouting rostral to a C5 lesion near C3-C4 PNs could improve behavioral recovery post SCI. Past studies have examined sprouting and regeneration of corticospinal tract (CST) fibers post-cervical SCI through viral upregulation of key components of the PI3K/Akt/mTOR cascade. We examined the regenerative growth potential of CST fibers that are transduced with AAV2 expressing constituively active Akt3 or STAT3 both separately and in combination (Akt3 + STAT3). We have observed significant increases in CST axonal sprouting and regeneration in Akt3 and Akt3 + STAT3 transduced samples. However, no recovery was observed as animals transduced with viral constitutively active Akt3 displayed an epileptic phenotype. Further, epileptic animals with constitutively active Akt3 were found to have significant cortical neuron cell hypertrophy, activatived astrogliosis, increased dendritic arbors and hemimegencephalitis (HME). These results indicate a new model for examining mechanisms of HME and mTOR hyperactivity-induced epilepsy in adult rodents. / Biomedical Sciences

The rhythmic activity of locomotion is most frequently modeled as a periodic oscillation coordinated by a spinal Central Pattern Generator (CPG) controlling reciprocal activation of flexor and extensor muscles. Expression of locomotion errors in the form of spontaneous deletions in the motor output has been critical in formulating models of CPG network structure governing locomotion in mammals (Lafreniere-Roula et al 2005, Duysens 2006). Deletions are defined as the disappearance of either antagonist or agonist muscles’ activity along with the simultaneous tonic/rhythmic activity of the corresponding agonist or antagonist muscles. The formulation of a two-layer model of the CPG (Rhythm Generator (RG) layer & Pattern Formation (PF) layer) by Rybak et al (2006) stems from observations of such deletions in the fictive locomotion of the decerebrated cat. The RG functions as a clock controlling the temporal activity of the PF layer which controls the firing pattern of motor neuron pools that activate muscles. The deletion episodes are said to be “resetting” if the EMG activity after the deletion does not return after an integer value of the pre-deletion average period. If the motoneuron activity returns in phase with the pre-deletion “clock”, the deletion period is considered to be “non-resetting”. Multiunit Activity (MUA) recorded from a spinalised air-stepping cat was analyzed against its corresponding EMG activity to investigate the role of MUA in rhythmogenicity, specifically whether or not MUA activity may represent the RG layer of the Central Pattern Generator (CPG) model. This hypothesis would predict that MUA activity should be disrupted in phase or amplitude when and only when deletions episodes are re-setting.. Alternatively, MUA activity may reflect PF layer activity. In this case MUA activity should be disrupted in phase or amplitude during each of the deletions episodes. MUA’s spatio-temporal characteristics were compared to that of the EMG activity during the deletion periods for analysis. From the analysis performed, there was a significant proportion (average more than 25%) of the MUA (collected from the lumbar region of the spinal cord of spinalized cat) that were disrupted in phase or amplitude during non-resetting deletions or undisrupted during resetting episodes, indicating that MUA activity is unlikely to represent the RG layer activity during . In addition, MUA oscillation during the period of deletions was unchanged (amplitude or phase) for more than 25% of the deletion episodes, ruling out the possibility that MUA represents the activity of the PF layer. So although MUA has been found to be highly synchronized throughout the lumbar extent during locomotor activity, it does not appear to act as a “clocking” mechanism for the locomotor rhythm. / Bioengineering