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Its pathomechanism remains to be established. Neurodegenerative lesion models provide an unequalled opportunity to explore the neural correlates of apraxia of speech, which is present in a subset of patients diagnosed with non-semantic variants of primary progressive aphasia. The normalized pairwise variability index, an acoustic measure of speech motor programming, has shown high sensitivity and specificity for apraxia of speech in cross-sectional studies. Here, we aimed to examine the strength of the pairwise variability index and overall word duration (i.e. articulation rate) as markers of progressive motor programming deficits in primary progressive aphasia with apraxia of speech. Seventy-nine individuals diagnosed with primary progressive aphasia (39 with non-fluent variant and 40 with logopenic variant) and 40 matched healthy controls participated. Patients were followed-up annually (range 1\u20136 years, median number of visits = 2). All participants completed a speech assessment task and a high-resolution MRI. Our analyses investigated trajectories of speech production (e.g. pairwise variablity index and word duration) and associations with cortical atrophy in the patients. At first presentation, word duration differentiated the nonfluent and logopenic cases statistically, but the range of scores overlapped substantially across groups. Longitudinally, we observed progressive deterioration in pairwise variability index and word duration specific to the non-fluent group only. The pairwise variability index showed particularly strong associations with progressive atrophy in speech motor programming brain regions. Of novelty, our results uncovered a key role of the right frontal gyrus in underpinning speech motor programming changes in non-fluent cases, highlighting the importance of right-brain regions in responding to progressive neurological changes in the speech motor network. Taken together, our findings validate the use of a new metric, the pairwise variability index, as a robust marker of apraxia of speech in contrast to more generic measures of speaking rate. Sensitive\/specific neuroimaging biomarkers of the emergence and progression of speech impairments will be useful to inform theories of the pathomechanisms underpinning impaired speech motor control. Our findings justify developing more sensitive measures of rhythmic temporal control of speech that may enable confident detection of emerging speech disturbances and more sensitive tracking of intervention-related changes for pharmacological, neuromodulatory and behavioural interventions. A more reliable detection of speech disturbances has relevance for patient care, with predominance of progressive apraxia of speech a high-risk factor for later diagnosis of progressive supranuclear palsy or corticobasal degeneration.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab205","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T14:46:52Z","timestamp":1630594012000},"source":"Crossref","is-referenced-by-count":19,"title":["Brain changes underlying progression of speech motor programming impairment"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0485-8090","authenticated-orcid":false,"given":"Ramon","family":"Landin-Romero","sequence":"first","affiliation":[{"name":"School of Psychology, The University of Sydney, Sydney, NSW, Australia"},{"name":"Brain & Mind Centre, The University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng T","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Psychology, The University of Sydney, Sydney, NSW, Australia"},{"name":"Brain & Mind Centre, The University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope A","family":"Monroe","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Higashiyama","sequence":"additional","affiliation":[{"name":"School of Psychology, The University of Sydney, Sydney, NSW, Australia"},{"name":"Brain & Mind Centre, The University of Sydney, Sydney, NSW, Australia"},{"name":"Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian E","family":"Leyton","sequence":"additional","affiliation":[{"name":"Brain & Mind Centre, The University of Sydney, Sydney, NSW, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R","family":"Hodges","sequence":"additional","affiliation":[{"name":"Brain & Mind Centre, The University of Sydney, Sydney, NSW, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Piguet","sequence":"additional","affiliation":[{"name":"School of Psychology, The University of Sydney, Sydney, NSW, Australia"},{"name":"Brain & Mind Centre, The University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirrie J","family":"Ballard","sequence":"additional","affiliation":[{"name":"Brain & Mind Centre, The University of Sydney, Sydney, NSW, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,2]]},"reference":[{"key":"2021091617284902800_fcab205-B1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/9781444317251.ch6","volume-title":"The handbook of phonetic sciences","author":"Ackermann","year":"2010"},{"key":"2021091617284902800_fcab205-B2","doi-asserted-by":"crossref","DOI":"10.7551\/mitpress\/10471.001.0001","volume-title":"Neural control of speech","author":"Guenther","year":"2016"},{"issue":"2","key":"2021091617284902800_fcab205-B3","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S0149-7634(01)00068-9","article-title":"Neural pathways underlying vocal control","volume":"26","author":"Jurgens","year":"2002","journal-title":"Neurosci Biobehav 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