Stroke rehabilitation is to train the motor function of a patients limb. In this process, functional assessment is of importance, and it is primarily based on a patients task performance. The context of the rehabilitation discussed in this thesis is such that functional assessment is conducted through a computer system and the Internet. In particular, a patient performs the task at home in a haptic virtual environment, and the task performance is transmitted to the therapist over the Internet. One problem with this approach to functional assessment is that a patients mind state is little known to the therapist. This immediately leads to one question, that is, whether an elevated mind state will have some significant effect on the patients task performance? If so, this approach can result in a considerable error. The overall objective of this thesis study was to generate an answer to the aforementioned question. The study focused on a patients elevated fatigue state. The specific objectives of the study include: (i) developing a haptic virtual environment prototype system for functional assessment, (ii) developing a physiological-based inference system for fatigue state, and (iii) performing an experiment to generate knowledge regarding the fatigue effect on task performance. With a limited resource in recruiting patients in the experiment, the study conducted few experiments on patients but mostly on healthy subjects. The study has concluded: (1) the proposed haptic virtual environment system is effective for the wrist coordination task and is likely promising to other tasks, (2) the accuracy of proposed fatigue inference system achieves 89.54%, for two levels of fatigue state, which is promising, (3) the elevated fatigue state significantly affects task performance in the context of wrist coordination task, and (4) the accuracy of the individual-based inference approach is significantly higher than that of the group-based inference approach. The main contributions of the thesis are (1) generation of the new knowledge regarding the fatigue effect on task performance in the context of home-based rehabilitation, (2) provision of the new fatigue inference system with the highest accuracy in comparison with the existing approaches in literature, and (3) generation of the new knowledge regarding the difference between the individual-based inference and group-based inference approaches.

This qualitative study investigated the experiences of family caregivers who cared for a stroke survivor throughout weekend passes from an in-patient rehabilitation facility. Following a Husserlian phenomenological perspective, I interviewed 15 family caregivers of stroke survivors on two separate occasions: within one week after their first scheduled weekend pass, and again two weeks after their final transition home. Interviews followed a semi-structured interview guide, and were audio recorded. Interviews were transcribed verbatim, and analyzed using the principles outlined by Giorgi (1997). Analysis of the caregivers’ descriptions of their experiences led to five themes: (i) Caregivers feel overwhelmed throughout the weekend pass, (ii) Access to supportive resources influences caregiving experiences, (iii) Caregivers adjust to the weekend pass throughout its subsequent use, (iv) Caregivers feel a responsibility and a need to be included by health professionals in the care of their family stroke survivor, and (v) Caregivers describe the weekend pass as a means towards recovery. This study has implications for future health services. By appropriately training and supporting caregivers throughout the weekend pass health care professionals can increase the positive experiences of caregivers, and optimize the opportunity to prepare caregivers and stroke survivors for the eventual transition home.

Transient Receptor Potential ‘Melastatin’ 7 (TRPM7) is a ubiquitously expressed, non-selective divalent cation channel implicated in diverse cellular functions including actomyosin cytoskeletal remodeling, magnesium homeostasis, and anoxic neuronal death. The present study investigates the role of TRPM7 in modulating neuronal morphology and regulating neuronal cytoskeletal dynamics after anoxia. Overexpression of GFP-tagged TRPM7 in neuronal cultures caused a stunted morphology with fewer neurite branches than controls, suggesting that TRPM7 regulates the neuronal cytoskeleton during dendritic outgrowth. I have discovered that TRPM7 may regulate morphology via activation of cofilin-1 (an actin binding protein). I found that TRPM7-dependent cofilin activation during anoxia mediated neuronal death. Overall my work reveals a novel link between anoxia-induced TRPM7 activity and cofilin activation, which likely contributes to neurodegeneration after ischemia.

This qualitative study investigated the experiences of family caregivers who cared for a stroke survivor throughout weekend passes from an in-patient rehabilitation facility. Following a Husserlian phenomenological perspective, I interviewed 15 family caregivers of stroke survivors on two separate occasions: within one week after their first scheduled weekend pass, and again two weeks after their final transition home. Interviews followed a semi-structured interview guide, and were audio recorded. Interviews were transcribed verbatim, and analyzed using the principles outlined by Giorgi (1997). Analysis of the caregivers’ descriptions of their experiences led to five themes: (i) Caregivers feel overwhelmed throughout the weekend pass, (ii) Access to supportive resources influences caregiving experiences, (iii) Caregivers adjust to the weekend pass throughout its subsequent use, (iv) Caregivers feel a responsibility and a need to be included by health professionals in the care of their family stroke survivor, and (v) Caregivers describe the weekend pass as a means towards recovery. This study has implications for future health services. By appropriately training and supporting caregivers throughout the weekend pass health care professionals can increase the positive experiences of caregivers, and optimize the opportunity to prepare caregivers and stroke survivors for the eventual transition home.

Transient Receptor Potential ‘Melastatin’ 7 (TRPM7) is a ubiquitously expressed, non-selective divalent cation channel implicated in diverse cellular functions including actomyosin cytoskeletal remodeling, magnesium homeostasis, and anoxic neuronal death. The present study investigates the role of TRPM7 in modulating neuronal morphology and regulating neuronal cytoskeletal dynamics after anoxia. Overexpression of GFP-tagged TRPM7 in neuronal cultures caused a stunted morphology with fewer neurite branches than controls, suggesting that TRPM7 regulates the neuronal cytoskeleton during dendritic outgrowth. I have discovered that TRPM7 may regulate morphology via activation of cofilin-1 (an actin binding protein). I found that TRPM7-dependent cofilin activation during anoxia mediated neuronal death. Overall my work reveals a novel link between anoxia-induced TRPM7 activity and cofilin activation, which likely contributes to neurodegeneration after ischemia.

The goal of my thesis was to elucidate the impact of protein-energy malnutrition (PEM, a condition commonly found in aging stroke patients) on outcomes from global ischemia. I first examined the hypothesis that PEM will impair working memory in the adult gerbil as measured in the T-maze. Gerbils were fed an adequate (12.5%) or low protein (2%; PEM) diet for 6wk. Stringent assessment of T-maze performance indicated an improvement with PEM although I was unable to reconcile whether this was increased motivation for the food reward or enhanced working memory.<p> The second hypothesis tested was PEM will decrease expression of plasticity-associated hippocampal mRNA and protein expression following global ischemia in the gerbil. The plasticity markers brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (trkB), and growth-associated protein-43 (GAP-43) were examined in the CA1 hippocampal region post-ischemia. PEM induced in gerbils for 4wk did not alter the global ischemia-induced decrease in CA1 neurons. Ischemia resulted in increased CA1 pyramidal expression of BDNF and trkB mRNA at 1, 3, and 7d post-ischemia and increased trkB protein expression at 3 and 7d. PEM further elevated the increased trkB protein detected at 7d in the fibres. Ischemia resulted in increased GAP-43 protein at 3 and 7d post-ischemia with PEM increasing this expression at 3d in the CA3 and hilar regions in addition to CA1. These findings suggest an increased stress-response and/or hyperexcitability state in the hippocampus of malnourished ischemic animals.<p> Since the reliability of the gerbil model of global ischemia has come into question, the third part of my thesis tested the hypothesis that the influence of pre-existing PEM on global ischemia-induced hippocampal injury can be reliably studied with the 2-vessel occlusion rat model. The impact of PEM on CA1 neuronal death and dendritic damage was examined. Rats received protein adequate (18%) or deficient (2%; PEM) diet for 7-8d prior to global ischemia. PEM did not worsen the decrease in CA1 neurons and dendrites observed at 7d post-ischemia. Importantly, I found that PEM altered blood glucose and acid-base balance during surgery and caused brief hypothermia post-surgically, factors which are important for consistent brain injury.<p> Taken together, these findings reveal (i) that nutritional care, although frequently ignored, can have robust effects on recovery mechanisms after brain ischemia; and (ii) the challenges of studying pre-existing PEM in an established rodent model of stroke.

The goal of my thesis was to elucidate the impact of protein-energy malnutrition (PEM, a condition commonly found in aging stroke patients) on outcomes from global ischemia. I first examined the hypothesis that PEM will impair working memory in the adult gerbil as measured in the T-maze. Gerbils were fed an adequate (12.5%) or low protein (2%; PEM) diet for 6wk. Stringent assessment of T-maze performance indicated an improvement with PEM although I was unable to reconcile whether this was increased motivation for the food reward or enhanced working memory.<p> The second hypothesis tested was PEM will decrease expression of plasticity-associated hippocampal mRNA and protein expression following global ischemia in the gerbil. The plasticity markers brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (trkB), and growth-associated protein-43 (GAP-43) were examined in the CA1 hippocampal region post-ischemia. PEM induced in gerbils for 4wk did not alter the global ischemia-induced decrease in CA1 neurons. Ischemia resulted in increased CA1 pyramidal expression of BDNF and trkB mRNA at 1, 3, and 7d post-ischemia and increased trkB protein expression at 3 and 7d. PEM further elevated the increased trkB protein detected at 7d in the fibres. Ischemia resulted in increased GAP-43 protein at 3 and 7d post-ischemia with PEM increasing this expression at 3d in the CA3 and hilar regions in addition to CA1. These findings suggest an increased stress-response and/or hyperexcitability state in the hippocampus of malnourished ischemic animals.<p> Since the reliability of the gerbil model of global ischemia has come into question, the third part of my thesis tested the hypothesis that the influence of pre-existing PEM on global ischemia-induced hippocampal injury can be reliably studied with the 2-vessel occlusion rat model. The impact of PEM on CA1 neuronal death and dendritic damage was examined. Rats received protein adequate (18%) or deficient (2%; PEM) diet for 7-8d prior to global ischemia. PEM did not worsen the decrease in CA1 neurons and dendrites observed at 7d post-ischemia. Importantly, I found that PEM altered blood glucose and acid-base balance during surgery and caused brief hypothermia post-surgically, factors which are important for consistent brain injury.<p> Taken together, these findings reveal (i) that nutritional care, although frequently ignored, can have robust effects on recovery mechanisms after brain ischemia; and (ii) the challenges of studying pre-existing PEM in an established rodent model of stroke.

In contrast to cardiac rehabilitation (CR) programs, traditional stroke rehabilitation aims to maximize functional independence and does not have a strong focus on exercise training and risk factor modification. Given the parallels between stroke and heart disease in cardiovascular etiology and risk factors, CR may be suited to supplement stroke rehabilitation by providing opportunities to enhance fitness and manage stroke risk factors. The aim of this work was to 1) examine the use of a non-adapted CR program of care with individuals with stroke and/or transient ischemic attack (TIA) through a retrospective database review, 2) using a prospective trial, determine the feasibility and effects of an adapted CR program for people with mild to moderate impairment from stroke, and 3) explore characteristics related to degree of program response in aerobic and functional capacity through secondary data analysis. The results from Study 1 demonstrated that traditional CR is an underutilized service for individuals with stroke or TIA, yet improvements in aerobic fitness were comparable to their non-stroke counterparts. In Study 2, adapted CR was feasible for individuals with a range of stroke-related disability and effective in increasing aerobic capacity. The anticipated carry over to improved walking capacity was not observed. There were no changes in health-related quality of life or stroke risk factors. Study 3 identified subgroups of participants who improved or declined in aerobic and ambulatory capacity after the adapted CR program. There were no differences in baseline characteristics, indices of time, intensity or volume of exercise performed across the response subgroups. In summary, given the parallels between stroke and heart disease, the needs of the stroke population and dearth of community-based exercise programming available for them, the CR model of care may be applied for individuals with stroke to provide opportunities for exercise training and risk factor modification.

The neuroprotective effects of AF4, a flavonoid-enriched extract derived from the peel of Northern Spy apples (containing quercetin-3-O-glucoside, quercetin-3-O-galactoside, quercetin-3-O-rhamnoside, quercetin-3-O-rutinoside, epicatechin, and cyanidin-3-O-galactoside) were examined by assessing neuronal loss and motor impairment resulting from hypoxic-ischemic (HI) brain injury in adult C57BL/6 mice. Relative to vehicle treatment (water, 10mL/kg/day), oral administration of AF4 (50 mg/kg/day) for 3 days reduces HI-induced neuronal loss in the striatum and hippocampus, motor impairments, and reduces the ability of LPS to stimulate the production of TNF-alpha in whole blood. Pretreatment with AF4 (1 ug/mL) decreased the death of mouse primary cortical neurons subjected to oxygen glucose deprivation (12 hours) in comparison to vehicle (DMSO) or the same concentration of quercetin or its metabolites. Taken together these findings indicate that AF4 reduces HI-induced brain injury and motor deficits by increasing the resistance of vulnerable neurons to ischemic cell death and decreasing the production of inflammatory cytokines.

Damage to motor areas of the brain, caused by stroke, can produce devastating motor deficits, including aberrant control of force. After stroke, reorganization of the brain’s motor system has been identified as one of the fundamental mechanisms involved in recovery of motor control after stroke. Yet, few studies have investigated how force production and modulation are encoded in the brain after stroke and how this relates to motor outcome. Thus, the purpose of this study was to (1) understand how past neuroimaging literature has contributed to establishing common patterns of brain reorganization during both relative and absolute force production after stroke, (2) examine how brain function is reorganized during force production and modulation in individuals with stroke, and (3) relate this task-related reorganization of brain function to the amount of paretic arm use after stroke. In the second chapter, we systematically reviewed all relevant literature examining brain activation during force production after stroke. The following chapters (chapters 3 and 4) applied functional magnetic resonance imaging (fMRI) to examine the neural correlates of force production and modulation after stroke. Chapter 2 supports differences in task-related brain activation dependent on features of stroke, such as severity and chronicity, as well as influence of rehabilitation. In addition, results suggest that activation of common motor areas of the brain during force production can be identified in relation to functional outcome after stroke. Results from the subsequent two chapters (3 and 4), demonstrate that brain function reorganizes in terms of absolute, and not relative force production after stroke. Specifically, stroke participants exhibit greater activation of motor areas than healthy controls when matched for absolute force production. Moreover, there is a relationship between paretic arm usage and brain activation, where stroke participants having less paretic arm use, as measured using wrist accelerometers, exhibit higher brain activation. Results of this thesis suggest that during absolute force production, brain activation may approach near maximal levels in stroke participants at lower forces than healthy controls. Furthermore, this effect may be amplified even further in subjects with less paretic arm usage, as increased activation in motor areas occurs in participants with less arm use after stroke. Ultimately, the results from this thesis will contribute to research relevant to brain reorganization in individuals with stroke and may lead to the development of new, beneficial therapeutic interventions that optimize brain reorganization and improve functional recovery after stroke.