Audiology and Speech Pathology - Theses
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ItemMotor speech phenotype of Huntington’s disease: A potential clinical marker in the premanifest phase( 2021)Huntington’s disease (HD) is an inherited neurodegenerative condition caused by a mutation in the HTT gene coding for the protein Huntingtin. The autosomal dominant inheritance nature of HD makes it amenable to diagnostic and predictive genetic testing. HD is characterised by movement disorder, cognitive and psychiatric symptoms. A formal diagnosis of manifest HD is indicated by the phenotypic appearance of unequivocal movement disorder in carriers of expanded HTT gene. Prior to diagnosis of manifest HD, carriers of the expanded HD gene may show subtle changes in their fine motor skills, cognition, behaviour, and speech. The premanifest phase of HD (PreHD) may be an optimal time for introduction of disease-modifying drug trials, based on an assumption that the brain is most receptive to therapeutic changes in that period. Various intervention methods are in development, but one of the challenges in clinical trials, however, is the lack of easily accessible, sensitive and measurable biomarkers to improve onset detection accuracy, provide routine monitoring of disease progression, and evaluate intervention efficacy. The thesis explored the use of acoustic speech as a potential biomarker of HD, by (i) identifying speech symptoms in the premanifest and manifest phases of HD, (ii) examining speech stimuli and digital speech metrics that are sensitive in detecting speech changes in people carrying the expanded HD gene, and (iii) evaluating the reliability and speech metrics of speech across multiple assessment intervals. Speech was analysed perceptually and objectively, and measures of articulatory agility, voice quality, and prosody (speech-timing) were extracted and compared between people with premanifest HD, manifest HD and healthy controls. Speech outcomes were correlated to other clinical measures of motor function, fine motor performance, cognitive abilities and disease burden. A 6-month longitudinal speech investigation was also conducted to evaluate the reliability and stability of speech in PreHD. Findings from experimental studies in the thesis indicated speech differences between PreHD and control groups were audible to expert listeners (i.e., speech pathologists) using perceptual assessment of speech (Chapter 4). Objective acoustic analysis revealed speech differences on measures of articulatory agility and speech-timing between PreHD and healthy controls, but these differences are only observed in speech tasks that required a higher level of cognitive load and motor effort (Chapter 5). Speech tasks and speech metrics shown to be sensitive, reliable, and stable in PreHD and healthy controls were identified in the final chapter of this thesis (Chapter 6). Overall, these studies have explored the potential for acoustic speech measures to be utilised in clinical settings as behavioural markers of disease. The validation of speech as markers requires further research in the field, however, the thesis has provided some data on using speech to monitor disease progression and evaluate treatment efficacy in premanifest and manifest HD.
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ItemExploring the aetiology of child speech and language disorders: Genes, brain and behaviour( 2020)Background Speech and language disorders are exceptionally common, affecting 1 in 20 children, yet we understand little about their aetiology. Advances in genetic analysis and brain imaging have increased our ability to unravel genetic contributions and brain-behaviour explanations for speech and language disorders. This PhD is focused on elucidating gene-brain-behaviour relationships, by refining the speech and language phenotypes of children with genetic and neural pathologies. Aims There were three main aims of the thesis, each forming a sub-study: Study 1. To conduct speech and language phenotyping of individuals and families, to drive targeted sequencing and identification of known and novel genes that cause speech and language disorders; Study 2. To conduct speech and language phenotyping of a cohort of individuals with pathogenic variants in FOXP1, a gene implicated in impaired communication; Study 3. To describe brain-behaviour associations between topography and severity of polymicrogyria (PMG) and speech and language ability. Methods Participants were recruited through research databases, clinical collaborators and online parent support groups. Speech and oral motor function, receptive and expressive language, non-verbal cognition and adaptive behaviour were assessed using a protocol of standardised tests. Clinical history, MRI data (Study 3) and cognitive assessments were analysed to interpret speech and language findings in the context of broader neurodevelopmental phenotypes. Results Study 1. 25 probands with severe or persistent speech disorder were referred to the study and 16 were included in the final analysis. Speech and language were characterised in all probands and 49 family members. DNA samples for these 16 probands were sent for whole exome or whole genome sequencing. Study 2. Speech and language assessments were completed in 29 individuals with pathogenic FOXP1 variants. All verbal individuals had a complex speech phenotype including dysarthria and broader motor planning and programming impairments and 88% had phonological errors. Language impairments affected nearly all participants, though abilities varied across the cohort. Study 3. 52 individuals with PMG were assessed and MRIs analysed. All verbal participants (regardless of their PMG pattern) had dysarthria, which ranged in severity from mild cases with subclinical features only, to more severe cases with no verbal speech. Developmental speech errors and language impairments were frequent, and profiles were more severe in individuals with perisylvian PMG and bilateral distribution of PMG. Discussion This PhD has important clinical implications for diagnosis, prognosis and clinical management of children with severe speech and language disorders. The detailed speech and language phenotyping here can assist clinicians in identifying individuals with severe speech disorders who may warrant genetic testing or brain imaging (e.g. to detect PMG) to elucidate the cause of their speech disorder. Novel information I have provided about the exact nature of speech and language phenotypes will also assist clinicians and families with prognostic counselling, and to understand the implications these conditions have for learning support and educational placement. Results can also be used to inform development of targeted therapy approaches for children with these genetic and neurological conditions. The discovery that very few patients were receiving targeted therapy (e.g. for dysarthria), highlights the urgent need for early referrals for evidence-based speech therapy.