Radiology - Research Publications
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ItemEarly imaging predictors of longer term multiple sclerosis risk and severity in acute optic neuritis(SAGE PUBLICATIONS INC, 2019)BACKGROUND: Biomarkers are urgently required for predicting the likely progression of multiple sclerosis (MS) at the earliest stages of the disease to aid in personalised therapy. OBJECTIVE: We aimed to examine early brain volumetric and microstructural changes and retinal nerve fibre layer thinning as predictors of longer term MS severity in patients with clinically isolated syndromes (CIS). METHODS: Lesion metrics, brain and regional atrophy, diffusion fractional anisotropy and retinal nerve fibre layer thickness were prospectively assessed in 36 patients with CIS over the first 12 months after presentation and compared with clinical outcomes at longer term follow-up [median (IQR) = 8.5 (7.8-8.9) years]. RESULTS: In total, 25 (69%) patients converted to MS and had greater baseline lesion volume (p = 0.008) and number (p = 0.03)than CIS patients. Over the initial 12 months, new lesions (p = 0.0001), retinal nerve fibre layer thinning (p = 0.04) and ventricular enlargement (p = 0.03) were greater in MS than CIS patients. In MS patients, final Expanded Disability Status Scale score correlated with retinal nerve fibre layer thinning over the first 12 months (ρ = -0.67, p = 0.001). CONCLUSIONS: Additional to lesion metrics, early measurements of fractional anisotropy and retinal nerve fibre layer thinning are informative about longer term clinical outcomes in CIS.
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ItemNovel Functional MRI Task for Studying the Neural Correlates of Upper Limb Tremor(FRONTIERS MEDIA SA, 2018-07-02)Introduction: Tremor of the upper limbs is a disabling symptom that is present during several neurological disorders and is currently without treatment. Functional MRI (fMRI) is an essential tool to investigate the pathophysiology of tremor and aid the development of treatment options. However, no adequately or standardized protocols for fMRI exists at present. Here we present a novel, online available fMRI task that could be used to assess the in vivo pathology of tremor. Objective: This study aims to validate the tremor-evoking potential of the fMRI task in a small group of tremor patients outside the scanner and assess the reproducibility of the fMRI task related activation in healthy controls. Methods: Twelve HCs were scanned at two time points (baseline and after 6-weeks). There were two runs of multi-band fMRI and the tasks included a "brick-breaker" joystick game. The game consisted of three conditions designed to control for most of the activation related to performing the task by contrasting the conditions: WATCH (look at the game without moving joystick), MOVE (rhythmic left/right movement of joystick without game), and PLAY (playing the game). Task fMRI was analyzed using FSL FEAT to determine clusters of activation during the different conditions. Maximum activation within the clusters was used to assess the ability to control for task related activation and reproducibility. Four tremor patients have been included to test ecological and construct validity of the joystick task by assessing tremor frequencies captured by the joystick. Results: In HCs the game activated areas corresponding to motor, attention and visual areas. Most areas of activation by our game showed moderate to good reproducibility (intraclass correlation coefficient (ICC) 0.531-0.906) with only inferior parietal lobe activation showing poor reproducibility (ICC 0.446). Furthermore, the joystick captured significantly more tremulous movement in tremor patients compared to HCs (p = 0.01) during PLAY, but not during MOVE. Conclusion: Validation of our novel task confirmed tremor-evoking potential and reproducibility analyses yielded acceptable results to continue further investigations into the pathophysiology of tremor. The use of this technique in studies with tremor patient will no doubt provide significant insights into the treatment options.
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ItemNo Preview AvailableValidation of a precision tremor measurement system for multiple sclerosis(ELSEVIER SCIENCE BV, 2019-01-01)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.
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ItemNo Preview AvailableWhat speech can tell us: A systematic review of dysarthria characteristics in Multiple Sclerosis(ELSEVIER SCIENCE BV, 2018-12)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.
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ItemParallel Changes in Structural and Functional Measures of Optic Nerve Myelination after Optic Neuritis(PUBLIC LIBRARY SCIENCE, 2015-05-28)INTRODUCTION: Visual evoked potential (VEP) latency prolongation and optic nerve lesion length after acute optic neuritis (ON) corresponds to the degree of demyelination, while subsequent recovery of latency may represent optic nerve remyelination. We aimed to investigate the relationship between multifocal VEP (mfVEP) latency and optic nerve lesion length after acute ON. METHODS: Thirty acute ON patients were studied at 1, 3, 6 and 12 months using mfVEP and at 1 and 12 months with optic nerve MRI. LogMAR and low contrast visual acuity were documented. By one month, the mfVEP amplitude had recovered sufficiently for latency to be measured in 23 (76.7%) patients with seven patients having no recordable mfVEP in more than 66% of segments in at least one test. Only data from these 23 patients was analysed further. RESULTS: Both latency and lesion length showed significant recovery during the follow-up period. Lesion length and mfVEP latency were highly correlated at 1 (r = 0.94, p = <0.0001) and 12 months (r = 0.75, p < 0.001). Both measures demonstrated a similar trend of recovery. Speed of latency recovery was faster in the early follow-up period while lesion length shortening remained relatively constant. At 1 month, latency delay was worse by 1.76 ms for additional 1mm of lesion length while at 12 months, 1mm of lesion length accounted for 1.94 ms of latency delay. CONCLUSION: A strong association between two putative measures of demyelination in early and chronic ON was found. Parallel recovery of both measures could reflect optic nerve remyelination.
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ItemTremor in multiple sclerosis is associated with cerebello-thalamic pathology(SPRINGER WIEN, 2017-12)Tremor in people with multiple sclerosis (MS) is a frequent and debilitating symptom with a relatively poorly understood pathophysiology. To determine the relationship between clinical tremor severity and structural magnetic resonance imaging parameters. Eleven patients with clinically definite MS and right-sided upper limb tremor were studied. Tremor severity was assessed using the Bain score (overall severity, writing, and Archimedes spiral drawing). Cerebellar dysfunction was assessed using the Scale for the Assessment and Rating of Ataxia. Dystonia was assessed using the Global Dystonia Scale adapted for upper limb. For all subjects, volume was calculated for the thalamus from T1-weighted volumetric scans using Freesurfer. Superior cerebellar peduncle (SCP) cross-sectional areas were measured manually. The presence of lesions was visually determined and the lesion volumes were calculated by the lesion growth algorithm as implemented in the Lesion Segmentation Toolbox. Right thalamic volume negatively correlated with Bain tremor severity score (ρ = - 0.65, p = 0.03). Left thalamic volume negatively correlated with general Bain tremor severity score (ρ = - 0.65, p = 0.03) and the Bain writing score (ρ = - 0.65, p = 0.03). Right SCP area negatively correlated with Bain writing score (ρ = - 0.69, p = 0.02). Finally, Bain Archimedes score was significantly higher in patients with lesions in the contralateral thalamus. Whole brain lesion load showed no relationship with tremor severity. These results implicate degeneration of key structures within the cerebello-thalamic pathway as pathological substrates for tremor in MS patients.
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ItemTechnologies for Advanced Gait and Balance Assessments in People with Multiple Sclerosis(FRONTIERS MEDIA SA, 2018-02-02)Subtle gait and balance dysfunction is a precursor to loss of mobility in multiple sclerosis (MS). Biomechanical assessments using advanced gait and balance analysis technologies can identify these subtle changes and could be used to predict mobility loss early in the disease. This update critically evaluates advanced gait and balance analysis technologies and their applicability to identifying early lower limb dysfunction in people with MS. Non-wearable (motion capture systems, force platforms, and sensor-embedded walkways) and wearable (pressure and inertial sensors) biomechanical analysis systems have been developed to provide quantitative gait and balance assessments. Non-wearable systems are highly accurate, reliable and provide detailed outcomes, but require cumbersome and expensive equipment. Wearable systems provide less detail but can be used in community settings and can provide real-time feedback to patients and clinicians. Biomechanical analysis using advanced gait and balance analysis technologies can identify changes in gait and balance in early MS and consequently have the potential to significantly improve monitoring of mobility changes in MS.
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ItemFibre-specific white matter changes in multiple sclerosis patients with optic neuritis(ELSEVIER SCI LTD, 2018)Long term irreversible disability in multiple sclerosis (MS) is thought to be primarily driven by axonal degeneration. Axonal degeneration leads to degenerative atrophy, therefore early markers of axonal degeneration are required to predict clinical disability and treatment efficacy. Given that additional pathologies such as inflammation, demyelination and oedema are also present in MS, it is essential to develop axonal markers that are not confounded by these processes. The present study investigated a novel method for measuring axonal degeneration in MS based on high angular resolution diffusion magnetic resonance imaging. Unlike standard methods, this novel method involved advanced acquisition and modelling for improved axonal sensitivity and specificity. Recent work has developed analytical methods, two novel axonal markers, fibre density and cross-section, that can be estimated for each fibre direction in each voxel (termed a "fixel"). This technique, termed fixel-based analysis, thus simultaneously estimates axonal density and white matter atrophy from specific white matter tracts. Diffusion-weighted imaging datasets were acquired for 17 patients with a history of acute unilateral optic neuritis (35.3 ± 10.2 years, 11 females) and 14 healthy controls (32.7 ± 4.8 years, 8 females) on a 3 T scanner. Fibre density values were compared to standard diffusion tensor imaging parameters (fractional anisotropy and mean diffusivity) in lesions and normal appearing white matter. Group comparisons were performed for each fixel to assess putative differences in fibre density and fibre cross-section. Fibre density was observed to have a comparable sensitivity to fractional anisotropy for detecting white matter pathology in MS, but was not affected by crossing axonal fibres. Whole brain fixel-based analysis revealed significant reductions in fibre density and fibre cross-section in the inferior fronto-occipital fasciculus (including the optic radiations) of patients compared to controls. We interpret this result to indicate that this fixel-based approach is able to detect early loss of fibre density and cross-section in the optic radiations in MS patients with a history of optic neuritis. Fibre-specific markers of axonal degeneration should be investigated further for use in early stage therapeutic trials, or to monitor axonal injury in early stage MS.