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Background: Remote objective tests may supplement in-clinic examination to better inform treatment decisions. Previous cross-sectional studies presented objective speech metrics as potential markers of Multiple Sclerosis (MS) disease progression., Objective: To examine the short-term stability and long-term sensitivity of speech metrics to MS progression., Methods: We prospectively recorded speech from people with MS at baseline, six, twelve weeks, and at ten months or longer after baseline (1y+). Only people with a definite diagnosis of MS and without other potential causes of dysarthria were included. Speech tasks comprehended 1) a sustained vowel /a/, 2) saying the days of the week, 3) repeating the non-word pa-ta-ka multiple times as fast as possible, 4) reading the Grandfather Passage, and 5) telling a personal story. We selected speech metrics of interest according to their association with MS presence, correlation with general disability, and short-term metric stability in the absence of disease progression. Selected speech metrics were analysed for short- versus long-term changes in the whole MS cohort and in the clinically stable versus progression subgroups at 1y+., Results: Sixty-nine people with MS participated (76.8 % female, age mean 47.5 ± 11.1 SD, EDSS median 3.5, interquartile range 3.5). Twenty-six unique speech metrics satisfied the suitability criteria. On average, reading rate improved 3.5 % for all people with MS and 6.5 % for slow readers with MS from baseline to the six-week, driven by a reduction in pauses. At 1y+, participants showed a 3.1 % average reduction in vocalization time during the reading task, which was similar in the progression (n = 29) and non-progression (n = 40) groups and thus unrelated to disease progression. Both findings are in the opposite direction of what would be generally expected for deterioration in speech performance and might be attributable to familiarity and training effects. Other speech metrics showed either negligible change or a similar variability between short-term and long-term differences., Conclusion: Most individual long-term changes were small and within short-term variability intervals, irrespective of clinical disease progression. Familiarity and practice effects might have blunted the measurement of change. The present lack of longitudinal sensitivity of speech in MS contradicts previous cross-sectional findings and requires further investigation., Competing Interests: Declaration of competing interest Adam Vogel is Chief Science Officer of Redenlab Inc. Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker's honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. Frederique Boonstra has nothing to disclose. Gustavo Noffs works in scientific development for Redenlab Inc. Helmut Butzkueven has received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL, and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee. Scott Kolbe receives grant income from the National Health and Medical Research Council of Australia and has received honoraria from Novartis, Biogen and Merck Thushara Perera has nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Multiple sclerosis (MS) is a progressive disease that often affects the cerebellum. It is characterised by demyelination, inflammation, and neurodegeneration within the central nervous system. Damage to the cerebellum in MS is associated with increased disability and decreased quality of life. Symptoms include gait and balance problems, motor speech disorder, upper limb dysfunction, and oculomotor difficulties. Monitoring symptoms is crucial for effective management of MS. A combination of clinical, neuroimaging, and task-based measures is generally used to diagnose and monitor MS. This paper reviews the present and new tools used by clinicians and researchers to assess cerebellar impairment in people with MS (pwMS). It also describes recent advances in digital and home-based monitoring for people with MS., (© 2022. The Author(s).)

Neurodegenerative disease often affects speech. Speech acoustics can be used as objective clinical markers of pathology. Previous investigations of pathological speech have primarily compared controls with one specific condition and excluded comorbidities. We broaden the utility of speech markers by examining how multiple acoustic features can delineate diseases. We used supervised machine learning with gradient boosting (CatBoost) to delineate healthy speech from speech of people with multiple sclerosis or Friedreich ataxia. Participants performed a diadochokinetic task where they repeated alternating syllables. We subjected 74 spectral and temporal prosodic features from the speech recordings to machine learning. Results showed that Friedreich ataxia, multiple sclerosis and healthy controls were all identified with high accuracy (over 82%). Twenty-one acoustic features were strong markers of neurodegenerative diseases, falling under the categories of spectral qualia, spectral power, and speech rate. We demonstrated that speech markers can delineate neurodegenerative diseases and distinguish healthy speech from pathological speech with high accuracy. Findings emphasize the importance of examining speech outcomes when assessing indicators of neurodegenerative disease. We propose large-scale initiatives to broaden the scope for differentiating other neurological diseases and affective disorders.

Background: Upper limb tremor is common in people with multiple sclerosis (pwMS) and can affect day to day function, impacting on their tremor related quality of life (tremor-QOL). The Quality of Life in Essential Tremor Questionnaire (QUEST) is a tremor-QOL scale, however it has not been validated for use in pwMS. This is in contrast to the Multiple Sclerosis Impact Scale (MSIS-29), a MS health related QOL (MS-QOL) scale validated in pwMS. The aim of this study was to quantify tremor-QOL in pwMS using both the QUEST and MSIS-29 and establish the convergent validity of the QUEST scale with the MSIS-29., Methods: Data were derived from an existing registered clinical trial studying the efficacy of Botox (onabotulinumtoxinA) compared to placebo in pwMS-related upper limb tremor (ACTRN12617000379314). We determined MS-related disability (Expanded Disability status scale score (EDSS)), tremor severity (Bain and Findley Clinical Tremor Rating Scale (Bain)), cerebellar function (Scale for the Assessment and rating of Ataxia (SARA)), and upper limb manual dexterity (9 Hole Peg Test (9-HPT)). The QUEST and MSIS-29 were used to quantify tremor-QOL and MS-QOL respectively. Convergent validity was investigated by examining the correlation between QUEST and MSIS-29, and the pattern of correlation of the two scales compared to the EDSS, SARA, BAIN and 9-HPT., Results: Our cohort of 57 patients (16 male; 41 female), mean age of 47.6, had moderate MS-related disability with median EDSS score of 5 (IQR = 3.5). Median Bain score was 8, indicating mild tremor severity, which corresponded to mild to moderately poor tremor-QOL given mean Quest Summary Index (QSI) of 45.7. QSI correlated to tremor severity as measured by Bain total score (rs(55) = 0.339, p < 0.01), manual dexterity as measured by 9-HPT (rs(55) = 0.304, p < 0.05), and MS disease activity measured by EDSS (rs(55) = 0.347, p < 0.01). MSIS-29 also showed correlations to EDSS, and 9-HPT, but did not correlate to Bain total score. There was a strong relationship between QSI and MSIS-29 in pwMS (r(55) = 0.709, p < 0.01)., Conclusion: In this cross-sectional study, we found that both the MS-QOL and tremor-QOL of pwMS with upper limb tremor was reduced. We were also the first to demonstrate that tremor-QOL in pwMS with upper limb tremor can be measured using the QUEST, which may be better suited for use in pwMS affected by arm-tremor than the MSIS-29. There is a lack of literature to specifically address tremor-QOL in pwMS, and more research is warranted., (Copyright © 2022. Published by Elsevier B.V.)

Background: Multiple Sclerosis (MS) pathology is likely to disrupt central auditory pathways, thereby affecting an individual's ability to discriminate speech from noise. Despite the importance of speech discrimination in daily communication, it's characterization in the context of MS remains limited. This cross-sectional study evaluated speech discrimination in MS under "real world" conditions where sentences were presented in ecologically valid multi-talker speech or broadband noise at several signal-to-noise ratios (SNRs)., Methods: Pre-recorded Bamford-Kowal-Bench sentences were presented at five signal-to-noise ratios (SNR) in one of two background noises: speech-weighted noise and eight-talker babble. All auditory stimuli were presented via headphones to control (n = 38) and MS listeners with mild (n = 20), moderate (n = 16) and advanced (n = 10) disability. Disability was quantified by the Kurtzke Expanded Disability Status Scale (EDSS) and scored by a neurologist. All participants passed a routine audiometric examination., Results: Despite normal hearing, MS psychometric discrimination curves which model the relationship between signal-to-noise ratio (SNR) and sentence discrimination accuracy in speech-weighted noise and babble did not change in slope (sentences/dB) but shifted to higher SNRs (dB) compared to controls. The magnitude of the shift in the curve systematically increased with greater disability. Furthermore, mixed-effects models identified EDSS score as the most significant predictor of speech discrimination in noise (odds ratio = 0.81; p < 0.001). Neither age, sex, disease phenotype or disease duration were significantly associated with speech discrimination performance in noise. Only MS listeners with advanced disability self-reported audio-attentional difficulty in a questionnaire designed to reflect auditory processing behaviours in daily life., Conclusion: Speech discrimination performance worsened systematically with greater disability, independent of age, sex, education, disease duration or disease phenotype. These results identify novel auditory processing deficits in MS and highlight that speech discrimination tasks may provide a viable non-invasive and sensitive means for disease monitoring in MS., (Copyright © 2020. Published by Elsevier B.V.)

Background and Purpose: Objective measurement of speech has shown promising results to monitor disease state in multiple sclerosis. In this study, we characterize the relationship between disease severity and speech metrics through perceptual (listener based) and objective acoustic analysis. We further look at deviations of acoustic metrics in people with no perceivable dysarthria., Methods: Correlations and regression were calculated between speech measurements and disability scores, brain volume, lesion load and quality of life. Speech measurements were further compared between three subgroups of increasing overall neurological disability: mild (as rated by the Expanded Disability Status Scale ≤2.5), moderate (≥3 and ≤5.5) and severe (≥6)., Results: Clinical speech impairment occurred majorly in people with severe disability. An experimental acoustic composite score differentiated mild from moderate (P < 0.001) and moderate from severe subgroups (P = 0.003), and correlated with overall neurological disability (r = 0.6, P < 0.001), quality of life (r = 0.5, P < 0.001), white matter volume (r = 0.3, P = 0.007) and lesion load (r = 0.3, P = 0.008). Acoustic metrics also correlated with disability scores in people with no perceivable dysarthria., Conclusions: Acoustic analysis offers a valuable insight into the development of speech impairment in multiple sclerosis. These results highlight the potential of automated analysis of speech to assist in monitoring disease progression and treatment response., (© 2020 European Academy of Neurology.)

Speech production relies on motor control and cognitive processing and is linked to cerebellar function. In diseases where the cerebellum is impaired, such as multiple sclerosis (MS), speech abnormalities are common and can be detected by instrumental assessments. However, the potential of speech assessments to be used to monitor cerebellar impairment in MS remains unexplored. The aim of this study is to build an objectively measured speech score that reflects cerebellar function, pathology and quality of life in MS. Eighty-five people with MS and 21 controls participated in the study. Speech was independently assessed through objective acoustic analysis and blind expert listener ratings. Cerebellar function and overall disease disability were measured through validated clinical scores; cerebellar pathology was assessed via magnetic resonance imaging, and validated questionnaires informed quality of life. Selected speech variables were entered in a regression model to predict cerebellar function. The resulting model was condensed into one composite speech score and tested for prediction of abnormal 9-hole peg test (9HPT), and for correlations with the remaining cerebellar scores, imaging measurements and self-assessed quality of life. Slow rate of syllable repetition and increased free speech pause percentage were the strongest predictors of cerebellar impairment, complemented by phonatory instability. Those variables formed the acoustic composite score that accounted for 54% of variation in cerebellar function, correlated with cerebellar white matter volume (r = 0.3, p = 0.017), quality of life (r = 0.5, p < 0.001) and predicted an abnormal 9HPT with 85% accuracy. An objective multi-feature speech metric was highly representative of motor cerebellar impairment in MS.

Background: Tremor is present in almost half of multiple sclerosis (MS) patients. The lack of understanding of its pathophysiology is hampering progress in development of treatments., Objectives: To clarify the structural and functional brain changes associated with the clinical phenotype of upper limb tremor in people with MS., Methods: Fifteen healthy controls (46.1 ± 15.4 years), 27 MS participants without tremor (46.7 ± 11.6 years) and 42 with tremor (46.6 ± 11.5 years) were included. Tremor was quantified using the Bain score (0-10) for overall severity, handwriting and Archimedes spiral drawing. Functional magnetic resonance imaging activations were compared between participants groups during performance of a joystick task designed to isolate tremulous movement. Inflammation and atrophy of cerebello-thalamo-cortical brain structures were quantified., Results: Tremor participants were found to have atrophy of the cerebellum and thalamus, and higher ipsilateral cerebellar lesion load compared to participants without tremor ( p  < 0.020). We found higher ipsilateral activation in the inferior parietal lobule, the premotor cortex and supplementary motor area in MS tremor participants compared to MS participants without tremor during the joystick task. Finally, stronger activation in those areas was associated with lower tremor severity., Conclusion: Subcortical neurodegeneration and inflammation along the cerebello-thalamo-cortical and cortical functional neuroplasticity contribute to the severity of tremor in MS.

Background: Treatment of tremor in MS is an unmet need. OnabotulinumtoxinA (BoNT-A) has shown promising results; however, little is known regarding its effects on the brain. The clinical presentation of tremor MS is shown to depend on subcortical neural damage and cortical neural plasticity. This study aimed to identify effects of onabotulinumtoxinA (BoNT-A) on brain activation in MS and upper-limb tremor using functional MRI., Methods: Forty-three MS participants with tremor were randomized to receive intramuscular injections of placebo (n = 22) or BoNT-A (n = 21). Tremor was quantified using the Bain score (0-10) for severity, handwriting and Archimedes drawing at baseline, 6 weeks and 12 weeks. Functional MRI activation within two previously identified clusters, ipsilateral inferior parietal cortex (IPL) and premotor/supplementary motor cortex (SMC) of compensatory activity, was measured at baseline and 6 weeks., Results: Treatment with BoNT-A resulted in improved handwriting tremor at 6 weeks (p = 0.049) and 12 weeks (p = 0.014), and tremor severity -0.79 (p = 0.007) at 12 weeks. Furthermore, the patients that received BoNT-A showed a reduction in activation within the IPL (p = 0.034), but not in the SMC. The change in IPL activation correlated with the reduction in tremor severity from baseline to 12 weeks (β = 0.608; p = 0.015) in the BoNT-A group. No tremor and fMRI changes were seen in the placebo treated group., Conclusion: We have shown that reduction in MS-tremor severity after intramuscular injection with BoNT-A is associated with changes in brain activity in sensorimotor integration regions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Tremor is a debilitating symptom of Multiple Sclerosis (MS). Little is known about its pathophysiology and treatments are limited. Clinical trials investigating new interventions often rely on subjective clinical rating scales to provide supporting evidence of efficacy., New Method: We present a novel instrument (TREMBAL) which uses electromagnetic motion capture technology to quantify MS tremor. We aim to validate TREMBAL by comparison to clinical ratings using regression modelling with 310 samples of tremor captured from 13 MS participants who performed five different hand exercises during several follow-up visits. Minimum detectable change (MDC) and test-retest reliability were calculated and comparisons were made between MS tremor and data from 12 healthy volunteers., Results: Velocity of the index finger was most congruent with clinical observation. Regression modelling combining different features, sensor configurations, and labelling exercises did not improve results. TREMBAL MDC was 84% of its initial measurement compared to 91% for the clinical rating. Intra-class correlations for test-retest reliability were 0.781 for TREMBAL and 0.703 for clinical ratings. Tremor was lower (p =  0.002) in healthy subjects., Comparison With Existing Methods: Subjective scales have low sensitivity, suffer from ceiling effects, and mitigation against inter-rater variability is challenging. Inertial sensors are ubiquitous, however, their output is nonlinearly related to tremor frequency, compensation is required for gravitational artefacts, and their raw data cannot be intuitively comprehended., Conclusions: TREMBAL, compared with clinical ratings, gave measures in agreement with clinical observation, had marginally lower MDC, and similar test-retest reliability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Importance: Multiple sclerosis produces neurological impairments that are variable in duration, severity and quality. Speech is frequently impaired, resulting in decreased communication skills and quality of life. Advancements in technology now makes it possible to use quantitative acoustic assessment of speech as biomarkers of disease progression., Observations: Four domains of speech have been identified: articulation (slow articulation and imprecise consonants), voice (pitch and loudness instability), respiration (decreased phonatory time and expiratory pressure) and prosody (longer and frequent pauses, deficient loudness control). Studies also explored I) predictive models for diagnosis of MS and of ataxia using speech variables, II) the relationship of dysarthria with cognition and III) very few studies correlated neuroimaging with dysarthria. We could not identify longitudinal studies of speech or dysarthria in Multiple Sclerosis., Conclusion and Relevance: Refinement of objective measures of speech has enhanced our understanding of Multiple Sclerosis-related deficits in cross-sectional analysis while both integrative and longitudinal studies are identified as major gaps. This review highlights the potential for using quantitative acoustic assessments as clinical endpoints for diagnosing, monitoring progression and treatment in disease modifying trials., (Copyright © 2018 Elsevier B.V. All rights reserved.)