MRI indices of functional recovery following intracerebral implantation of a human neural stem cell line in a pre-clinical model of ischaemic stroke

Stem cell therapy for ischaemic stroke is an emerging field in light of an increasing number of patients surviving with permanent disability. Several allogenic and autologous cells types are now in clinical trials with preliminary evidence of safety. Some clinical studies have reported functional improvements in some patients. After initial safety evaluation in a Phase 1 study, the conditionally immortalised human neural stem cell line CTX0E03 is currently in a Phase 2 clinical trial (PISCES-II). Previous pre-clinical studies conducted by ReNeuron Ltd, showed evidence of functional recovery in the Bilateral Asymmetry test up to 6 weeks following transplantation into rodent brain, 4 weeks after middle cerebral artery occlusion. Resting-state fMRI is increasingly used to investigate brain function in health and disease, and may also act as a predictor of recovery due to known network changes in the post-stroke recovery period. Resting-state methods have also been applied to non-human primates and rodents which have been found to have analogous resting-state networks to humans. The sensorimotor resting-state network of rodents is impaired following experimental focal ischaemia of the middle cerebral artery territory. However, the effects of stem cell implantation on brain functional networks has not previously been investigated. Prior studies assessed sensorimotor function following sub-cortical implantation of CTX0E03 cells in the rodent post-stroke brain but with no MRI assessments of functional improvements. This thesis presents research on the effect of sub-cortical implantation of CTX0E03 cells on the resting- state sensorimotor network and sensorimotor deficits in the rat following experimental stroke, using protocols based on previous work with this cell line. The work in this thesis identified functional tests of appropriate sensitivity for long-term dysfunction suitable for this laboratory, and investigated non-invasive monitoring of physiological variables required to optimize BOLD signal stability within a high-field MRI scanner. Following experimental stroke, rats demonstrated expected sensorimotor dysfunction and changes in the resting-state sensorimotor network. CTX0E03 cells did not improve post-stroke functional outcome (compared to previous studies) and with no changes in resting-state sensorimotor network activity. However, in control animals, we observed changes in functional networks due to the stereotaxic procedure. This illustrates the sensitivity of resting-state fMRI to stereotaxic procedures. We hypothesise that the damage caused by cell or vehicle implantation may have prevented functional and network recovery which has not been previously identified due to the application of different functional tests. The findings in this thesis represent one of few pre-clinical studies in resting-state fMRI network changes post-stroke and the only to date applying this technique to evaluate functional outcomes following a clinically applicable human neural stem cell treatment for ischaemic stroke. It was found that injury caused by stereotaxic injection should be taken into account when assessing the effectiveness of treatment.

Validation of the Flexibility of Responses to Self-Critical Thoughts Scale (FoReST) in a clinical population

Background: The Flexibility of Responses to Self-Critical Thoughts Scale (FoReST) is a questionnaire that was developed to assess whether people can be psychologically flexible when experiencing critical thoughts about themselves. This measure could have important application for evaluating third wave therapies such as Acceptance and Commitment Therapy (ACT) and Compassion Focused therapy (CFT). This study investigated the validity (concurrent, predictive and incremental), internal consistency and factor structure of the FoReST in a sample of people experiencing mental health difficulties. Method: A total of 132 individuals attending Primary Care and Community Mental Health Teams within NHS Greater Glasgow and Clyde (NHS GGC) and Psychological Therapy Teams within NHS Lanarkshire participated in this study. Participants completed a battery of assessments that included the FoReST and related measures of similar constructs (psychological flexibility, self-compassion and self-criticism) and measures of mental health and well-being. A cross-sectional correlational design was used. Results: An Exploratory factor analysis described an interpretable 2-factor structure within the items of the FoReST: unworkable action and experiential avoidance. The FoReST demonstrated good internal consistency ( = .89). Concurrent validity was supported through moderate to strong correlations with similar measures and moderate correlations with other mental health and well-being outcomes. Conclusions: The FoReST appears to be a valid assessment measure for using with individuals experiencing mental health difficulties. This new measure will be of use for practitioners using ACT, CFT and those integrating both, to help monitor the process of change in flexibility and self-critical thinking across therapy. Further longitudinal studies are required to assess the test-retest reliability of the FoReST.