AN ABSTRACT OF THE THESIS OF Elizabeth Dawn Grisley, for the Master’s degree in Cellular and Molecular Systemic Physiology, presented on November 6th, 2015, at Southern Illinois University Carbondale. TITLE: INFLUENCE OF DIET AND STROKE ON EXPRESSION OF GENES THAT MODULATE INFLAMMATION AND NEURONAL REMODELING IN THE ADULT AND AGED MALE RAT CEREBRAL CORTEX MAJOR PROFESSOR: Dr. Joseph L. Cheatwood Nearly 800,000 Americans are stricken by ischemic stroke each year. Other than care with post stroke rehabilitation there are no specific treatments for improving functional recovery. To improve the recovery of stroke patients we are investigating anti-inflammatory, anti-apoptotic, and neuronal remodeling pathways. Estrogen receptor activators are known to be neuroprotective by initiating pathways through ERβ and ERα. The bioactive soy isoflavones, daidzein and genistein, do bind to these estrogen receptors. However, this binding alone is not sufficient to explain the ability of soy-based diets and purified isoflavones to reduce inflammation and improve neuroprotection and recovery after stroke. Herein, we focused on the Pparg, Arg-1, 14-3-3ε, Sirt1, Gap43, Synaptophysin, Sod-1, Bcl-xl, Bcl-2, and the Rtn4(Nogo-A) pathways to test the hypothesis that diets containing soy isoflavones and/or soy protein isolate will reduce inflammation and promote the expression of neuronal plasticity markers following stroke in adult and aged rats via these mechanisms. Adult and aged male Hooded Long Evans rats were fed a semi-purified diet of either 1) sodium caseinate (CAS), 2) sodium caseinate plus the isoflavones daidzein and genistein (CAS+ISO), or 3) soy protein isolate (SPI) for two weeks prior to middle cerebral artery occlusion (MCAO). Permanent unilateral MCAO was performed and tissue was collected from both hemispheres at Day 0 (no stroke) and Day +3. Rats were maintained on their assigned diet throughout the experiment. RNA was extracted and cDNA synthesized for qPCR reaction. All data were normalized to Gapdh via the ΔΔCt method. qPCR analyses of the contralateral and ipsilateral brain tissue at 3 days after stroke resulted in upregulation of Sod-1, Sirt1, 14-3-3ε, Bcl-xl, Bcl-2, Gap43, Syp and Rtn4(Nogo-A) mRNA expression in the contralateral hemisphere. Only Pparg and Arg1 mRNA were found to be upregulated in the ipsilateral hemisphere. Through the upregulation of Pparg mRNA expression in the ipsilateral cortex we have established that the anti-inflammatory pathway is being initiated in our model. However it has been activated by a greater degree with the SPI treatment not the isoflavones daidzein and genistein alone as previously thought. It is unclear if the daidzein and genistein are working concurrently with one or more of the compounds found in the SPI treatment or if one or more additional compounds in the SPI has been the true activator. Since the tissue analyzed in this project was from animals that exhibited significant post stroke behavioral outcomes in a previous experiment we believed the influence of compensatory sprouting from the contralesional hemisphere was modulating the improvement of growth and anti-inflammatory factors to the injured ipsilateral hemisphere. Extensive research is still needed to confirm the source of activation in the PPARG pathway with the SPI treatment, the time and age points that transcriptional expression of our selected genes will activate or influence translational and/or post-translational effects and how the ischemic hemisphere is benefitting from compensatory sprouting from the contralateral hemisphere in this ischemic stroke model. By continuing in the directions mentioned above the mechanism by which isoflavones significantly improve post-stroke behavioral outcomes may be revealed.

A carotid atherosclerotic plaque represents a nidus of inflammation mere centimetres below the blood-brain barrier. This inflammation, along with associated regions of microcalcification, are histopathological features of atheroma at risk of rupture (so-called “vulnerable plaques”) that trigger thromboembolic stroke. While conventional clinical imaging simply measures the degree of vessel stenosis, it is a crude measure that reveals little of the metabolic processes affecting plaque vulnerability. Our research demonstrates the utility of positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF), measuring inflammation and microcalcification respectively, to identify culprit carotid atheroma in vivo, and establish how these processes influence plaque vulnerability. Furthermore, for stroke care it is the downstream thromboembolic effects upon the brain that are key. While proinflammatory conditions may increase the risk of stroke, the relationship between atheroma inflammation and the peri-infarct inflammatory response following a stroke remains poorly defined. Our work demonstrates how inflammatory activity in symptomatic carotid atheroma, measured using PET, influences both chronic small vessel disease and the evolution of lesion volume in the post-stroke period. Using metabolic imaging we can both identify vulnerable atheroma in vivo and demonstrate how these processes affect infarct evolution. We show that whilst inflammation is a generalised process, microcalcification is a focal process that may represent a point of maximum vulnerability. These results also reveal the complexity of the atheroma-brain interaction that may simultaneously trigger events while also influencing stroke evolution in the early recovery period. This has important implications for understanding pathophysiology of both atherosclerosis and stroke evolution, advancing drug-discovery, and potential clinical applications to minimise the impact from this devastating disease.

Introduction: There is a growing literature base focusing on the correlates and predictors of psychological distress following stroke. However, there is still limited understanding regarding the physical, cognitive and psychosocial variables that may increase an individual’s vulnerability to experiencing post stroke psychological distress. This thesis had two aims: 1) to review the evidence relating to functional impairment and depression post stroke, in order to identify any differences in this relationship at different stages of recovery, or over time, and 2) to explore whether perceived social support and perceived control moderate the relationship between cognitive impairment and psychological distress following stroke. Methods: A systematic review of the literature was conducted to investigate any potential differences in the relationship between functional impairment and depression post stroke. Quality criteria were applied to the included studies and the results were discussed in relation to these. A cross-sectional study was conducted to address the second aim of this portfolio. Participants completed three self-report questionnaires and a clinician administered measure. Statistical analysis was utilised to explore the relationships between cognitive impairment, perceived social support, perceived control and psychological distress following stroke. Results: The results of the systematic review were inconclusive. It was not possible to identify any definitive differences in the relationship between functional impairment and depression post stroke, at different time points or with regard to change over time. With regard to the cross-sectional study, none of the independent variables (cognitive impairment, perceived social support and perceived control) were found to be significantly related to psychological distress following stroke. Conclusions: The results of the systematic review highlight the need for methodologically robust, longitudinal studies to investigate differences in the relationship between functional impairment and depression during different stages of recovery and potential change over time in this relationship. Further research into the cognitive and psychosocial correlates and predictors of psychological distress are required in order to identify, and provide timely intervention to, those that are most likely to experience psychological distress following stroke.

L’objet de cette thèse est de présenter les spécificités épidémiologiques, étiologiques et thérapeutiques de la pathologie neurovasculaire dans la population noire spécifique que constitue la population martiniquaise. En 1998, l’étude ERMANCIA I a permis de mettre en évidence une surincidence des accidents vasculaires cérébraux (AVC) en Martinique d’environ 40% par rapport à la métropole avec une haute prévalence de l’hypertension artérielle et du diabète. Ces résultats ont participé à la création en 2003 de la 1ère unité neurovasculaire aux Antilles. Le suivi à 5 ans des patients ERMANCIA I a révélé que la moitié était décédée et que 50% des survivants présentaient une démence vasculaire (soit le double des cohortes métropolitaines), probablement favorisé par une microangiopathie cérébrale sous-jacente souvent sévère amplifiant l’impact cognitif de l’AVC. Ce suivi a également permis d’identifier les faiblesses de la prévention secondaire en Martinique avec près de 80% des hypertendus qui restent mal équilibrés justifiant la création en 2006 d’un réseau de prévention. L’efficacité de ce réseau a été évaluée montrant un taux élevé de bon contrôle tensionnel (74% vs 39%, p=0,01) et une morbi-mortalité vasculaire moindre à 2,5 ans (8,3% vs 24%, p<0,001) que chez les patients contrôles. En 2012, ERMANCIA II a permis de révéler une diminution majeure (en moyenne 30%) de l’incidence des AVC dans la population martiniquaise et de la mortalité à 1 mois pour les patients ≤55 ans (20% vs 8%, p=0,03) probablement en raison d’une meilleure implémentation des mesures de prévention primaire et de la prise en charge en UNV respectivement. Nos données ont également permis de décrire certaines spécificités étiologiques des AVC chez les Martiniquais : grande fréquence de l’athérome intracrânien (pour lequel nous apportons des arguments en faveur d’une nouvelle classification), infarctus choroïdiens antérieurs dont nous décrivons le profil évolutif particulier, infarctus lacunaires multiples sévères. Deux étiologies plus « classiques » comme la drépanocytose et les IC sur morsure de serpent sont devenues anecdotiques. En revanche, une dysplasie carotidienne focale, étiologie déjà décrite mais supposée rare , pourrait être responsable d’un tiers des infarctus carotidiens d’origine indéterminée chez les Afro-Caribéens ≤55 ans exposant à un risque élevé de récidive sous traitement antiagrégant (28% à 14 mois), contre aucun pour les patients traités par endartériectomie. Sur le plan thérapeutique, nos résultats sont en faveur d’un surrisque hémorragique de la thrombolyse standard chez les patients martiniquais les plus âgés, probablement en rapport avec un cumul de lésions microangiopathiques plus important. En l’absence de neuroradiologie interventionnelle en Martinique, nos travaux montrent que certains patients avec occlusion artérielle proximale résistante à la thrombolyse IV standard peuvent bénéficier d’un complément de thrombolytique (0,1mg/Kg de tenecteplase). Une étude randomisée est prévue afin de mieux mesurer le potentiel thérapeutique de cette stratégie. Pour conclure, l’intérêt de ces données est que la population martiniquaise partage très probablement beaucoup de ses « particularités » avec d’autres populations noires encore peu décrites et pour lesquelles l’occidentalisation progressive du mode de vie risque d’accentuer le fardeau représenté par les AVC. / Our work presented herein aimed to describe the epidemiological, etiological and therapeutic features of the stroke pathology in the Martinican Afro-Caribbean population. In 1998, the first population-based epidemiological study, ERMANCIA I, showed a 40% greater firstever stroke incidence in Martinique compared to those observed in continental France, with a high prevalence of hypertension and diabetes. These results contributed to the creation, in 2003, of the first stroke unit in the Caribbean area. In the 5_year follow-up study, we found that half of the patients had died and that 50% of survivors were affected from vascular dementia (twice compared with continental French cohorts): this figure was probably favored by severe underlying cerebral microangiopathy that amplified the cognitive impact of stroke. We also identified a failure in the secondary prevention in Martinique, certified by nearly 80% of hypertensive patients still insufficiently controlled. As a result, in 2006, we developed a well-structured stroke prevention network. The efficiency of this network was attested by the high rate of good blood pressure control (74% vs. 39%, p=0.01) and the reduced vascular morbidity and mortality rate (8.3% vs. 24%, p <0.001) after a 30-month period of activity, in comparison with control “historic” patients. In 2012, ERMANCIA II study revealed a 30% reduction of first-ever stroke incidence and a reduced mortality rate at 1 month for patients ≤55 years (8% vs. 20%, p = 0.03), compared to these observed in ERMANCIA I, likely due to improvement of primary stroke prevention and the best stroke unit management at the acute phase, respectively. Based on our etiological data, we underline: 1) the relatively high frequency of symptomatic intracranial atherosclerosis, for which we propose a new definition; 2) the clinic-radiological features of stroke in the anterior choroidal artery; 3) the atypical picture of “malignant” multilacunar syndrome. On the other hand, stroke due to sickle cell disease or “trigonocephale” snakebite were only anecdotal. However, we found that carotid-bulb atypical fibromuscular dysplasia (CAFD), a very unusual previously described cause of stroke, could be responsible for up to the third of carotidterritory stroke of so-called undetermined etiology among patients ≤55 years. In addition, the relatively high rate of recurrence under antiplatelet (28% at 14 months), was dramatically reduced by endarterectomy in patients with CAFD. From a therapeutic point of view, our results showed an excess rate of post-thrombolysis symptomatic intracerebral hemorrhages in older patients, a figure probably linked to the severe underlying hypertension-triggered cerebral microangiopathy. Owing to the lack of neurointerventionnal option in Martinique, we tested a new therapeutic strategy in patients with a proximal arterial occlusion not responsive to standard IV thrombolysis, consisting in an additional administration of IV tenecteplase, 0.1mg/kg. Our preliminary results were promising, leading us to plan a randomized study. Finally, most of the characteristics of stroke in this Afro-Caribbean population are probably shared by the majority of black people. Thus, our results could have a universal impact in the understanding of stroke burden in blacks.

Abstract The purpose of the study was to describe the experiences of home-dwelling stroke patients and their relatives about coping and to identify possible similarities and differences in these experiences. The research data were collected by interviewing 18 stroke patients and 20 relatives. The data were analysed using the phenomenological method. Based on the data, the stroke patients were divided into six groups with different coping strategies: flexible coping, realistic adjustment, recollection of losses, aspiration to work, denial of illness and submission to problems. Persons showing flexible coping live a full life. Meaningful activities and interpersonal relations promote coping, while problems due to the illness impair it. Persons showing realistic adjustment have modified their life styles to suit their resources. Coping is promoted by satisfaction with life and impaired by incidental periods of lack of energy. Persons who prefer to recollect losses draw energy from their past lives. Coping is promoted by interpersonal rehabilitation and impaired by a lack of meaningful activities. Persons showing aspiration to work seek for meaningful activities similar to salaried employment. Coping is promoted by humour and impaired by a lack of activity. Persons showing denial of illness attribute their problems to causes other than the disorder in brain circulation. Coping is promoted by stability of life and impaired by a fear of changes. Persons showing submission to problems tend to dwell on the losses due to their illness. Coping is promoted by contacts with children and impaired by depression. The relatives showed five coping strategies: re-orientation, confidence, escape, persistence and abandonment. Persons showing re-orientation had modified their strategies to be compatible with their life situation. Coping is promoted by hobbies and social relations and impaired by a lack of connections between rehabilitation and home life. Persons showing confidence see both good and bad points in their life situation. The need to re-consider one's life values is good, while the need to give up plans for the future is bad. People who escape tend to live either in the past or in the future. Coping is promoted by the learning of new roles and impaired by living on the patient's condition. Persistence is shown by people who only modify their strategies when forced to do so. Coping is promoted by planning of the future and impaired by disappointments at the medical and nursing personnel and the rehabilitation system. People who show abandonment are dissatisfied with their life situation. They have few chances to alter the situation and often have poor health. The patients' and relatives' experiences showed both similarities and differences. The patients and relatives had similar experiences of their own situation, treatment and rehabilitation, interpersonal relations and expectations, but the patients had more fears about their life situation than the relatives, while the relatives felt more responsibility for the coping at home. The patients' experiences generally focused on themselves, while the relatives' experiences were more abstract and encompassing. The patients and relatives who coped poorly felt that their whole life was filled by the illness, while for those who coped well it was only one experience among the others. The coping strategies of a patient and a relative who lived in the same household were mutually interdependent, and should therefore be viewed together. The findings may help us to understand the everyday home life of stroke patients and their relatives. They can be utilised while developing the nursing practice and rehabilitation.

Post-stroke depression (PSD) is highly prevalent and has a significant impact on stroke patients’ recovery. The systematic review aimed to build on previous review evidence to investigate the effectiveness of psychosocial interventions on reducing depression levels post-stroke. Multiple electronic databases were searched using a combination of keywords related to depression, stroke and psychosocial interventions. Randomised controlled trials investigating the effect of psychosocial interventions on depression levels for adult stroke patients were included. Methodological quality of included studies was assessed using criteria developed by the authors. Sixteen studies were included, four of which found a significant benefit of psychosocial interventions over control conditions on mood. While the results suggest some psychosocial interventions may be effective in reducing depression post-stroke; confidence in these findings is limited due to methodological limitations within studies. The review identified a number of methodological limitations across all included studies which may explain why previous research has not found any benefit of psychosocial interventions for PSD. Therefore, the evidence base is currently insufficient and further research which utilises a robust methodology is needed before any reliable conclusions can be drawn regarding the effectiveness of psychosocial interventions for PSD. The empirical study aimed to explore participants’ experiences of an Interpersonal Psychotherapy (IPT) assessment and formulation post-stroke to investigate the acceptability of using this model with patients experiencing PSD and indicate if more detailed quantitative research is justified. Ten participants with post-stroke depression (PSD) received two assessment appointments with a Clinical Psychologist, generating an IPT formulation of their difficulties. Participants subsequently took part in a semi-structured interview about their experience of this process. The results of these interviews were transcribed and analysed using Framework Analysis. Participants were seen to link their difficulties post-stroke to three of the four IPT interpersonal focus areas; interpersonal disputes, role transitions and grief loss. Overall, participants found an IPT assessment and formulation to be acceptable and identified benefits of the sessions including: altering their viewpoint, increasing acceptance of impaired functioning, reducing frustration, increasing positive feelings and leading to improvements in their social support. IPT may therefore be a suitable intervention for PSD and further robust, quantitative research is justifiable. Results suggest acceptance and an altered viewpoint are common following an IPT assessment and formulation; therefore future IPT research should measure changes in these variables alongside mood and behaviour.

Spontaneous (non-traumatic) intracerebral haemorrhage accounts for ~10% of all strokes in Western populations. Investigations may identify intracerebral haemorrhage (ICH) as ‘secondary’ to underlying causes such as tumours or aneurysms, but ~80% of ICHs which have no apparent underlying cause (so-called ‘primary’ ICH) tend to be attributed to small vessel vasculopathies such as arteriolosclerosis or cerebral amyloid angiopathy (CAA), on the basis of an adult’s risk factors and clinical and radiographic features of the ICH. The commonly accepted hypothesis is that CAA contributes to lobar ICH and arteriolosclerosis causes non-lobar ICH. In the following thesis, I set out to explore whether (a) the baseline demographic, clinical features and apolipoprotein E genotype of adults with lobar and non-lobar ICH differ, (b) the prognosis of adults with lobar and non-lobar ICH differ and (c) the neuroimaging correlates of small vessel disease in adults with lobar and non-lobar ICH differ since this might provide clues to the vasculopathies underlying lobar and non-lobar ICH. I explored (d) the strength of the association between CAA and ICH by systematically reviewing neuropathological case control studies and (e) the radiological and pathological features of lobar ICH to examine the nature of CAA in persons with lobar ICH and whether any computed tomography (CT) features of ICH are associated with CAA-related lobar ICH. I set up a prospective, community-based inception cohort study of adults with ICH in South East Scotland. Adults with spontaneous primary definite ICH had the opportunity to consent to participate in the Lothian Study of IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN), an ethically-approved, prospective community-based research study examining the causes of ICH using apolipoprotein E genotyping, brain MRI and research autopsy in case of death. Of 128 adults with first-ever spontaneous primary definite ICH diagnosed during 2010- 2011, age and pre-morbid hypertension did not differ by ICH location but a history of dementia was more common in adults with lobar ICH. The proportion of adults with one or more non-lobar brain microbleed (BMB) was significantly higher in adults with non-lobar ICH but I did not find any other differences in the severity or distribution of other neuroimaging correlates of small vessel disease between lobar and non-lobar ICH. The apolipoprotein e4 allele was more common in participants with lobar ICH in comparison to those with non-lobar ICH but the frequency of the e2 allele did not differ by ICH location. Adults with lobar ICH were significantly more likely to survive one year after their ICH in comparison to those with non-lobar ICH after adjustment for other known predictors of outcome. From a systematic review of neuropathological case control studies of CAA and ICH, stratified by ICH location, I found a significant association between CAA and lobar ICH but not with ICH in other locations. I examined the radiological and pathological features of 33 adults with first-ever lobar ICH. The presence of CAA or vasculopathy and the severity of CAA in a lobe affected by ICH was concordant with that of the corresponding contralateral unaffected lobe. Capillary CAA was associated with severe CAA. Subarachnoid extension of the ICH tended to be more frequent in those with CAA-related strictly lobar ICH. Having explored the incidence, risk factors and prognosis of lobar and non-lobar ICH, in future work I would aim to establish the strength of the association between CAA and ICH in different brain locations in a neuropathological case control study. Future work should examine the radiopathological features of lobar ICH in a larger cohort and the coexistence of other small vessel diseases, in particular arteriolosclerosis in persons with ICH.

Most drugs come with unwanted, and perhaps harmful, side-effects. Depending on the size of the treatment benefit such harms may be tolerable. In acute stroke, treatment with aspirin and treatment with alteplase have both proven to be effective in reducing the odds of death or dependency in follow-up. However, in both cases, treated patients are subject to a greater risk of haemorrhage – a serious side-effect which could result in early death or greater dependency. Current treatment licenses are restricted so as to avoid treating those with certain traits or risk factors associated with bleeding. It is plausible however that a weighted combination of all these factors would achieve better discrimination than an informal assessment of each individual risk factor. This has the potential to help target treatment to those most likely to benefit and avoid treating those at greater risk from harm. This thesis will therefore: (i) explore how predictions of harm and benefit are currently made; (ii) seek to make improvements by adopting more rigorous methodological approaches in model development; and (iii) investigate how the predicted risk of harm and treatment benefit could be used to strike an optimal balance. Statistical prediction is not an exact science. Before clinical utility can be established it is essential that the performance of any prediction method be assessed at the point of application. A prediction method must attain certain desirable properties to be of any use, namely: good discrimination – which quantifies how well the prediction method can separate events from non-events; and good calibration – which measures how close the obtained predicted risks match the observed. A comparison of informal predictions made by clinicians and formal predictions made by clinical prediction models is presented using a prospective observational study of stroke patients seen at a single centre hospital in Edinburgh. These results suggest that both prediction methods achieve similar discrimination. A stratified framework based on predicted risks obtained from clinical prediction models is considered using data from large randomised trials. First, with three of the largest aspirin trials it is shown that there is no evidence to suggest that the benefit of aspirin on reducing six month death or dependency varies with the predicted risk of benefit or with the predicted risk of harm. Second, using data from the third International Stroke Trial (IST3) a similar question is posed of the effect of alteplase and the predicted risk of symptomatic intracranial haemorrhage. It was found that this relationship corresponded strongly with the relationship associated with stratifying patients according to their predicted risk of death or dependency in the absence of treatment: those at the highest predicted risk from either event stand to experience the largest absolute benefit from alteplase with no indication of harm amongst those at lower predicted risk. It is concluded that prediction models for harmful side-effects based on simple clinical variables measured at baseline in randomised trials appear to offer little use in targeting treatments. Better separation between harmful events like bleeding and overall poor outcomes is required. This may be possible through the identification of novel (bio)markers unique to haemorrhage post treatment.

Since a significantly greater percentage of body weight is supported by the non-paretic limb following stroke, a greater amount of fatigue may be present during daily activities. This may affect the ability of these individuals to maintain a stable upright posture. The presence of falls following a stroke has been attributed in part to this asymmetrical stance post-stroke. Therefore the purpose of this study was to assess the effect of quadriceps muscle fatigue on bi-pedal posture in individuals who had a stroke and an age-matched control group. Although individuals after stroke displayed greater postural sway under the paretic limb than the non-paretic limb or control subjects, results of this study show that sustaining an isometric knee extension of the non-paretic limb induces changes in postural control for individuals after stroke, but that these changes do not markedly differ from those of healthy age-matched controls.

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.