Stroke is the leading cause of long-term neurological disability worldwide, signifying the need for viable therapeutic options. Pre-clinical and post-mortem stroke studies have demonstrated that stroke increases the number of newborn progenitor cells (PCs) in the adult brain that can migrate to the site of injury. While there is a positive correlation between increasing neurogenesis and improvements in stroke recovery, methods used to increase PCs and neurogenesis also alter many other forms of plasticity, making it difficult to determine the function of PCs per se. To investigate whether specifically enhancing PC survival is sufficient to improve recovery, the iBax transgenic mouse model was used to remove the pro-apoptotic gene Bax inducibly from nestin-expressing PCs either before or after focal strokes induced by photothrombosis. Increasing PC survival before or after stroke in the iBax mice increased the number of PCs in the peri-infarct region. Interestingly, the majority of the cells that migrated to the peri-infarct region expressed the glial fibrillary acidic protein (GFAP) which is found in astrocytes when Bax was removed prior to stroke, yet when Bax was removed after stroke the majority of the cells expressed doublecortin (DCX) which is expressed in neuroblasts. Irrespective of this significant increase in the different populations of surviving PCs following stroke, there was no change in long-term behavioural deficits on the adhesive removal, horizontal ladder, and cylinder tasks up to 90 days post stroke. Additionally, enhancing PC survival before or after stroke resulted in a significant increase in adult-generated neurons within the dentate gyrus, which was associated with a modest change in spatial learning on the Barnes maze. Together, these experiments suggest strategies that enhance the survival of the PCs by preventing cell death will, by themselves, be insufficient to promote sensorimotor recovery following stroke.

Stroke has the ability to chronically alter both a person’s understanding and or use of language. Aphasia is a term that represents the loss or impairment of language function as a consequence of brain damage caused by a stroke and current data reveal that at least 25% of all strokes result in aphasia. Spouses often play a pivotal role in a stroke patient’s journey towards recovery. For this reason, there is a dire need for increased knowledge regarding spousal psychosocial welfare and increased insight into the experiences of these individual’s altered life situations. This paper considers aphasia, by nature of its deficits, a family disorder. Additionally, the contents of this paper explore the significance of caregiver coping strategies and ongoing caregiver involvement in recovery as a mechanism towards increased well being. Evidence to confirm the effects of stroke on spouses, as well as to support involvement of spouses in speech-language treatment to facilitate living well with aphasia, was obtained through primary and secondary research. Primary research was compiled through a telephone interview with the spouse of a 62-year-old male with aphasia while secondary research was conducted through an extensive literature search from 2000 to 2011. / text

This projects attempts to gain an understanding of the role that perceptions and attitudes to ageing play in the recovery process after stroke. Firstly, a systematic review establishes the current opinion within the literature, and how perceived quality of life and depression interplay during the stroke recovery process. Whilst a relationship is apparent in the literature, the direction of causality remained unclear, in addition to many contributing factors possibly adding the interaction. The reader is introduced to the wider context of stroke, looking at the consequences of stroke and the adjustment process. Whilst older adults add a complexity to formulation and clinical work, they are also the predominant age group who experience stroke. Therefore, the role of the ageing process is introduced, in light of the current literature around stroke and recovery. A journal article then examines the role of attitudes towards ageing and perceptions of quality of life, in older adults after stroke. The relationship between attitudes and perceptions is explored, in relation to depressive symptoms in the sample recruited; using a questionnaire based cross sectional design. The questionnaires used were the Attitudes to Ageing Questionnaire (AAQ), the World Health Organisation Quality of Life, version for Older adults (WHOQOL‐Old) assessment and the New Multidimensional Depression Scale (NMDS). A correlational analysis revealed that positive attitudes toward ageing were associated with greater levels of perceived quality of life, and that both were negatively associated with depression. The findings are discussed in the context of ageing literature and incorporating aspects of loss, in an effort to understand how perceptions and attitudes may be protective factors in the journey of recovery from stroke.

The remapping of cortical networks after stroke is hypothesized to be one of the mechanisms subserving functional recovery. Our understanding of cortical remapping remains limited due to the inability to resolve which cells are active while performing motor tasks with high temporal and spatial specificity. The experiments presented in the first chapter of this thesis evaluate the ability of the inducible Arc-CreERT2:Rosa-YFPf/f model to label cells in the motor cortex activated by a motor-related behaviour. Through the modification of previously published 4-hydroxytamoxifen treatment paradigms, this model can differentiate between animals that performed the rotarod task at two time points and home cage controls. In addition, 65% of cells active at the first behavioural time point are reactivated. Taken together, these data suggest that the Arc-CreERT2:Rosa-YFPf/f model is able to reliably label networks used to perform the same behavioural task at two time points. The second chapter of this thesis details a pilot study in which the Arc-CreERT2:Rosa-ChR2:YFPf/f model was used to test the effect of daily optogenetic stimulation of the contralateral cortex on functional recovery. The results of this chapter suggest that stimulating the contralesional motor cortex may impair functional recovery. Overall, the results of this thesis lay the foundation to use this model to investigate motor networks in both naïve and pathological conditions, such as stroke.

Following unilateral stroke there is significant loss of function in the body side contralateral to the damage and a robust degenerative-regenerative cascade of events in both hemispheres. It is natural to compensate for loss of function by relying more on the less-affected body side to accomplish everyday living tasks (e.g. brushing teeth, drinking coffee). This is accompanied by a “learned disuse” of the impaired side thought to occur due to repeated experience with its ineptness. However, as investigated in these studies, it may also be due to brain changes instigated by experience with the intact body side. The central hypothesis of these dissertation studies is that experience with the intact forelimb, after unilateral sensorimotor cortex (SMC) damage, disrupts functional recovery with the impaired forelimb and interferes with peri-lesion neural plasticity. Following unilateral ischemic lesions, rats were trained on a skilled reaching task with their intact (less-affected) forelimb or received control procedures. The impaired forelimb was then trained and tested on the same skilled reaching task. Intact forelimb experience worsened performance with the impaired forelimb even when initiated at a more delayed time point following lesions. Intact forelimb training also reduced peri-lesion expression of FosB/ΔFosB, a marker of neuronal activation, and caudal forelimb motor map areas compared to animals without intact forelimb training. It was further established that it is focused training of the intact forelimb and not experience with this limb per se, as animals trained with both forelimbs in an alternating fashion did not exhibit this effect. Transections of the corpus callosum blocked the maladaptive effect of intact forelimb experience on impaired forelimb recovery, suggesting a disruptive influence of the intact hemisphere onto the lesion hemisphere that is mediated by experience. Together these dissertation studies provide insight into how experience with the less-affected, intact body side, can influence peri-lesion neural plasticity and recovery of function with the impaired forelimb. The findings from these studies suggest that compensatory use of the less-affected (intact) body side following unilateral brain damage is not advantageous if the ultimate goal is to improve function in the impaired body side. / text

Stroke is a widespread condition, which often leaves survivors with lasting deficits in motor function, however, physical rehabilitation is the only treatment available after the acute period. A large body of preclinical literature suggests dopamine-augmenting drugs, could enhance motor recovery following stroke. Unfortunately, mixed clinical results have prevented the implementation of such treatments, possibly due to the wide variety of G protein-coupled receptors these drugs can activate. Using a mouse photothrombosis stroke model and a battery of motor and sensorimotor behavioural tests, the current study aims to demonstrate proof of principle for the use of D1-class dopamine receptor agonists to enhance poststroke motor recovery and to evaluate the role of aerobic exercise rehabilitation in an asynchronous study design. The effect of light-dark cycle on behavioural outcome (horizontal ladder test, adhesive removal test, cylinder test) and histological outcome (infarct size) in photothrombotic stroke was evaluated in order to optimize the stroke model, but no there was no evidence of differences between strokes occurring during the light or dark period of a mouse’s circadian rhythm. A bioactive, suboptimal dose of D1-agonist dihydrexidine, was determined by evaluating its effect on locomotor activity and its ability to increase expression of immediate early gene c-fos. Using the determined dose, studies evaluating the efficacy of 7-days and 2-days of dihydrexidine administration on poststroke motor recovery, were performed, indicating efficacy of a 7-days, but not of a 2-days, course of treatment. The 7-days dihydrexidine treatment resulted in accelerated recovery as compared to a control group receiving saline. This work demonstrates, for the first time, proof of principle for the use of specific activation of D1-class dopamine receptors to enhance motor recovery following stroke.

This thesis investigates on clinical applicability of a novel sensing technology in the areas of postural steadiness and stroke assessment. The mechanically simple Distributive Tactile Sensing approach is applied to extract motion information from flexible surfaces to identify parameters and disorders of human movement in real time. The thesis reports on the design, implementation and testing of smart platform devices which are developed for discrimination applications through the use of linear and non-linear data interpretation techniques and neural networks for pattern recognition. In the thesis mathematical models of elastic plates, based on finite element and finite difference methods, are developed and described. The models are used to identify constructive parameters of sensing devices by investigating sensitivity and accuracy of Distributive Tactile Sensing surfaces. Two experimental devices have been constructed for the investigation. These are a sensing floor platform for standing applications and a sensing chair for sitting applications. Using a linear approach, the sensing floor platform is developed to detect centre of pressure, an important parameter widely used in the assessment of postural steadiness. It is demonstrated that the locus of centre of pressure can be determined with an average deviation of 1.05mm from that of a commercialised force platform in a balance application test conducted with five healthy volunteers. This amounts to 0.4% of the sensor range. The sensing chair used neural networks for pattern recognition, to identify the level of motor impairment in people with stroke through performing functional reaching task while sitting. The clinical studies with six real stroke survivors have shown the robustness of the sensing technique to deal with a range of possible motion in the reaching task investigated. The work of this thesis demonstrates that the novel Distributive Tactile Sensing approach is suited to clinical and home applications as screening and rehabilitation systems. Mechanical simplicity is a merit of the approach and has potential to lead to versatile low-cost units.

Stroke is the most common serious neurological condition worldwide. Members of the Black population are at an increased risk of suffering a stroke due to several risk factors which are more prevalent in this racial group. The purpose of this qualitative research study is to describe how African-Caribbean stroke survivors, who live in Canada, understand their illness and manage their care during the early recovery period. Eight participants who were of African-Caribbean origin who were living in Canada and recovering from a stroke were interviewed. Results of the study indicate that participants were not knowledgeable about the risk factors for stroke, they did not recognize the warning signs of a stroke as a medical emergency, and they did not always follow treatment regimes recommended by their physicians. Participants in the study described stroke as a catastrophic event, resulting in feelings of intense fear, being out of control, uncertainty, yearning for their old self, and feelings of detachment from their own body. Motivating factors in their recovery from stroke were the support of family, their own individual personal determination, and the acceptance of the illness by the participants. Nurses and physiotherapists were valued by the participants due to the role they played in improving their functional abilities. Participants expressed a desire for nurses to become knowledgeable about the African-Caribbean culture, in order to provide them with education pertaining to diet as well as steps they can take to reduce their risk of having another stroke. Responding to the care needs of this population will require individualized nursing care which considers the influence of culture on how the illness is perceived. / Thesis (Master, Nursing) -- Queen's University, 2010-04-30 09:59:56.286

Stroke is a leading cause of neurological disability, often resulting in long-term motor impairments due to damage to the striatum and/or motor cortex. While both humans and animals show spontaneous recovery following stroke, little is known about how the injury location affects recovery and what causes recovery to plateau. This information is essential in order to improve current rehabilitation practice and develop new therapies to enhance recovery. In this thesis, we used endothelin-1 (ET-1), a potent vasoconstrictor, to produce focal infarcts in the forelimb motor cortex (FMC), the dorsolateral striatum (DLS) or both the FMC and DLS in male Sprague-Dawley rats. In the first experiment, the spontaneous recovery profile of animals was followed over an 8-week period using multiple behavioural tasks assessing motor function and limb preference to identify how recovery varies depending on injury location. Infarct volumes were measured to determine the association between injury and behavioural outcome. All three groups had significant functional impairments on the Montoya staircase, beam traversal, and cylinder tests following stroke, with the combined group having the largest and most persistent impairments. Importantly, spontaneous recovery was not simply dependent on lesion volume but on the lesion location and the behavioural test employed. In the second experiment, we focused on a potential cellular mechanism thought to underlie post-stroke plasticity and functional recovery. In a separate cohort of animals, we assessed how plasticity-limiting perineuronal nets (PNNs) and associated parvalbumin-positive (PV) GABAergic interneurons change following similar ET-1 strokes as in the prior experiment. A significant reduction in the density of PNNs was observed in the perilesional cortex of animals that received a cortical-only or combined stroke but not a striatal-only injury. Although there were no significant differences in the density of PV interneurons between sham and stroked groups, a significant negative correlation existed between cortical infarct volume and the density of PV interneurons in the perilesional cortex. Taken together these results demonstrate that lesion location influences motor recovery and neuroplastic changes following stroke. This supports the idea that a “one size fits all” approach for stroke rehabilitation may not be effective and treatment needs to be individualized to the patient.

abstract: Stroke remains the leading cause of adult disability in developed countries. Most survivors live with residual motor impairments that severely diminish independence and quality of life. After stroke, the only accepted treatment for these patients is motor rehabilitation. However, the amount and kind of rehabilitation required to induce clinically significant improvements in motor function is rarely given due to the constraints of our current health care system. Research reported in this dissertation contributes towards developing adjuvant therapies that may augment the impact of motor rehabilitation and improve functional outcome. These studies have demonstrated reorganization of maps within motor cortex as a function of experience in both healthy and brain-injured animals by using intracortical microstimulation technique. Furthermore, synaptic plasticity has been identified as a key neural mechanism in directing motor map plasticity, evidenced by restoration of movement representations within the spared cortical tissue accompanied by increase in synapse number translating into motor improvement after stroke. There is increasing evidence that brain-derived neurotrophic factor (BDNF) modulates synaptic and morphological plasticity in the developing and mature nervous system. Unfortunately, BDNF itself is a poor candidate because of its short half-life, low penetration through the blood brain barrier, and activating multiple receptor units, p75 and TrkB on the neuronal membrane. In order to circumvent this problem efficacy of two recently developed novel TrkB agonists, LM22A-4 and 7,8-dihydroxyflavone, that actively penetrate the blood brain barrier and enhance functional recovery. Findings from these dissertation studies indicate that administration of these pharmacological compounds, accompanied by motor rehabilitation provide a powerful therapeutic tool for stroke recovery. / Dissertation/Thesis / Ph.D. Neuroscience 2013