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Developing and evaluating behavioural tasks to assess basal ganglia function

Clinch, Susanne 2017. Developing and evaluating behavioural tasks to assess basal ganglia function. PhD Thesis, Cardiff University.
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Abstract

Huntington’s disease (HD) is a primary example of a basal ganglia disorder, from which, medium spiny neurons in the striatum degenerate. As this causes a breakdown in basal ganglia cortico-thalamic circuitry, this leads to a range of symptoms including motor, cognitive and behavioural deficits. One therapeutic option is to replace medium spiny neurons with precursor striatal cells and reconnect the lost circuitry. However, the lack of performance based functional outcome measures for people with HD have made it difficult to assess how the graft affects standards of daily living. Although neuroimaging techniques can be used to quantify the morphological and molecular effects that the intervention has on that brain region, and associated circuitry, an important question still remains, namely whether there has been any effect on functional ability. Using assessments that have high ecological validity, such as dual tasks could be a valuable measure, especially as previous studies suggest that the striatum is required for optimal performance in such tasks. Therefore the focus of this thesis was to design, develop and assess performance based functional tasks that involve the neurocircuity affected in HD; namely the basal ganglia. The aim of the study in Chapter 2 was to select, develop and evaluate motor-cognitive dual task paradigms for use in people with HD. The findings revealed that the Step and Stroop which targeted lower limb function, best distinguished disease stage in HD compared to the other lower limb assessments tested. During this experiment, it became apparent that upper limb assessments for people with HD were particularly limited. Therefore, in Part 2, a new upper limb dual task assessment was developed and called the Clinch token transfer test (C3t). The findings revealed that this was sensitive to disease stage and could provide a useful outcome measure for people with HD in the future. To take the findings from Chapter 2 further, a new, standardised C3t was developed. This version was evaluated, optimised, and then validated in a large group of people gene positive for HD, and in heathy controls. The findings revealed that the C3t significantly correlated with all the Unified Huntington Disease Rating Scale measures, successfully distinguished between all disease stages, and revealed that the performance in this task was also sensitive to the subtle disease symptoms in the early stages of HD. As the Stroop task is commonly used in people with HD, the aim of Chapter 3 was to use immediate early gene expression to identify if the striatum was activated during a rodent analogue of the Stroop task. The findings revealed what could be the first in a series of experiments in that, striatal activation significantly correlated with performance in the congruent and the incongruent versions of this test when compared to cage controls. The findings presented in this thesis support that dual task assessments could have an important role in assessing function in HD, which could translate to performance in tasks that affect the standards of daily living. Importantly, as different dual tasks can result in different levels of dual task interference, this suggests that practice effects could affect how sensitive some dual task paradigms are over others. In addition, selecting outcome measures that are specific to the regions affected in HD, in both clinic and in pre-clinical models, will permit sensitive tracking of neurodegeneration, and could also be used to assess the outcomes of therapies that target this specific neural region.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Funders: REPAIR-HD
Date of First Compliant Deposit: 30 May 2017
Date of Acceptance: 22 May 2017
Last Modified: 02 Dec 2017 02:30
URI: http://orca.cf.ac.uk/id/eprint/100957

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