Radiology - Research Publications
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ItemOptic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes(PUBLIC LIBRARY SCIENCE, 2013-12-26)BACKGROUND: Early markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS). OBJECTIVES: To assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months. METHODS: Thirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction. RESULTS: Affected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (Ļ = -0.519, p = 0.001) and 12 months (Ļ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated. CONCLUSIONS: These results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.
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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)ā=ā8.5 (7.8-8.9) years]. RESULTS: In total, 25 (69%) patients converted to MS and had greater baseline lesion volume (pā=ā0.008) and number (pā=ā0.03)than CIS patients. Over the initial 12 months, new lesions (pā=ā0.0001), retinal nerve fibre layer thinning (pā=ā0.04) and ventricular enlargement (pā=ā0.03) 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 (Ļā=ā-0.67, pā=ā0.001). 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 AvailableObjective speech marker correlates with clinical scores in non-dysarthric MS(SAGE PUBLICATIONS LTD, 2017-10-01)Background: Reduction of brain volume occurs in clinically active disease and correlates with progressive disability in multiple Sclerosis (MS). Although dysarthria is highly prevalent in MS, it only becomes clinically relevant in advanced stages of the disease. The relationship between early sub-clinical markers of dysarthria and overall disease severity is poorly understood. Aim: To examine the relationship between an objective marker of speech performance and validated clinical scores for disease severity in non-dysarthric subjects with relapsing-remitting and secondary progressive MS. Method: An experienced neurologist scored patients according to the Expanded Disability Status Scale (EDSS) and the Scale for the Assessment and Rating of Ataxia (SARA). Acoustic analysis was used to investigate the diadochokinetic speed in āas fast as possibleā repetition of the meaningless word /pa/ta/ka/. Brain images were acquired using 3 Tesla magnetic resonance. Images were automatically segmented using FreeSurfer (5.7) to determine volumes for whole brain (excluding ventricules) and cerebellum. Lesions were automatically segmented by the lesion prediction algorithm as implemented in the Lesion Segmentation Tool version 2.0.15 for SPM (Statistical Parametric Mapping software). Statistical correlations were processed in SPSS (v 23.0) controlling for age. After adjustment for multiple comparisons, a p< 0.01 was considered for statistical significance. Results: We assessed 35 MS patients with normal speech (i.e. SARA speech sub-score 0-1; age=47.7Ā±12years; disease duration=13.2Ā±8.4). Diadochokinetic rate (mean=5.63Ā±0.83 syllables per second) directly correlated with EDSS (Spearman's rho=0.454, 2-tailed p=0.007; median EDSS=3.5, interquartile range=3.5) and SARA (rho=0.515, p=0.002; SARA median=9, interquartile range 11.975), but not with whole brain volume (p=0.022), lesion load (p=0.032) or cerebellar volume (p=0.037). Conclusion: Changes in acoustic markers can be detected before overt dysarthria in MS and reflect overall disease severity. Larger and longitudinal studies are needed to understand if those markers can help monitoring disease progression.
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ItemNo Preview AvailablePathophysiology of MS tremor: an fMRI study(SAGE PUBLICATIONS LTD, 2017-10)
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ItemNo Preview AvailableSubclinical speech signs correlate with MS disease severity and differentiates patients with and without clinical cerebellar dysfunction(SAGE PUBLICATIONS LTD, 2017-10-01)Background: Dysarthria is highly prevalent in Multiple Sclerosis (MS). The relationship between dysarthria, MS disease severity and other cerebellar manifestations (such as tremor) is poorly understood. Aim: To examine the relationship between objective markers of speech, disease severity and upper limb tremor in relapsing-remitting and secondary progressive MS. Method: An experienced neurologist determined A) the presence of upper limb tremor, B) the Expanded Disability Status Scale (EDSS) score and C) the degree of dysarthria (from 0, no disturbance to 4, unintelligible). We used acoustic analysis to investigate 4 speech domains: 1) stability of vocal pitch, in sustained utterance of the vowel /a/; 2) stability of loudness, in the same sustained vowel; 3) diadochokinetic speed, in fast repetition of the meaningless word /pa/ta/ka/ and 4) maximum speed of vocal tract movement (i.e. change in pharynx and mouth cavity shape), measured through change in the second formant frequency in the word āalwaysā, from reading of the āGrandfather Passageā. After adjustment for multiple comparisons, a p< 0.0125 was considered for statistical significance. Results: We assessed 24 MS patients with upper limb tremor (47.2Ā±12.3years, 75% female, EDSS=3.7Ā±1.6) and 24 matched patients without tremor (51.2Ā±10.7years, 75% female, EDSS=3.6Ā±1.7). Clinical dysarthria (median=0, mean=0.375Ā±0.76) moderately correlated with EDSS scores (Spearman's rho =.586, p< .001) and with syllable repetition rates (/pa/ta/ka/ rho=.561, p< .001), marginally correlated with speed of tract movement (rho=.363, p=.012), pitch stability (rho=.37, p=.011), loudness stability (rho=.37, p=.01) but not with upper limb tremor presence (p=.039). Only /pa/ta/ka/ rate correlated with EDSS (rho=.529, p< .001) and speed of tract movement differentiated tremor and non-tremor groups (2-tailed t-test p=0.002, rho=.418). Conclusion: Acoustic speech measurements correlate with MS disease severity and can differentiate overt cerebellar dysfunction. Further study is needed to understand the significance of this relationship longitudinally.
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ItemNo Preview AvailableObjective analysis of speech correlates with disease severity in Multiple Sclerosis and differentiates groups with and without upper limb tremor(SAGE PUBLICATIONS LTD, 2017-11-01)Background: Dysarthria is highly prevalent in Multiple Sclerosis. The relationship between dysarthria, MS disease severity and other cerebellar manifestations (such as tremor) is poorly understood. Objective: To examine the relationship between objective markers of speech, disease severity and upper limb tremor in relapsing-remitting and secondary progressive Multiple Sclerosis. Design Methods: An experienced neurologist determined A) the presence of upper limb tremor, B) the Expanded Disability Status Scale (EDSS) score and C) the degree of dysarthria (from 0, no disturbance to 4, unintelligible). Through acoustic analysis of speech, we investigated: 1) stability of vocal pitch, in sustained utterance of the vowel /a/; 2) stability of loudness, in the same sustained vowel; 3) diadochokinetic speed, in fast repetition of the meaningless word /pa/ta/ka/ and 4) maximum speed of vocal tract movement (i.e. change in pharynx and mouth cavity shape), measured in the word āalwaysā (from a standard reading passage). After adjustment for multiple comparisons, p<0.0125 was considered for statistical significance. Results: We assessed 24 participants with Multiple Sclerosis and upper limb tremor (47.2Ā±12.3years, 75% female, EDSS=3.7Ā±1.6) and 24 matched patients with Multiple Sclerosis without tremor (51.2Ā±10.7years, 75% female, EDSS=3.6Ā±1.7). Clinical dysarthria scores (median=0, mean=0.375Ā±0.76) correlated with all acoustic variables measured: diadochokinetic speed Spearmanās rho=.561 (p<.001); pitch stability rho=.37 (p=.011); loudness stability rho=.37 (p=.01); and maximum speed of vocal tract movement rho=.363 (p=.012). Diadochokinetic speed strongly correlated with EDSS (rho=.529, p<.001). Speed of vocal tract movement correlated with tremor and differentiated tremor and non-tremor groups (2-tailed t-test p=0.002, rho=.418). Conclusions: In a typically non-to-mildly dysarthric cohort, acoustic speech measurements correlate with disease severity and can differentiate overt cerebellar dysfunction in Multiple Sclerosis. Further study is needed to understand the significance of this relationship longitudinally.
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ItemNo Preview AvailablePathophysiology of MS tremor: an fMRI study(SAGE PUBLICATIONS LTD, 2017-11)
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ItemNo Preview AvailableValidation of the tremor biomechanics analysis laboratory (TREMBAL) software in MS tremor(SAGE PUBLICATIONS LTD, 2016-09-01)Type: Poster Abstract Category: Clinical aspects of MS - Clinical assessment tools Background: Tremor in MS (MST) is difficult to treat and the development of new interventions is limited by the absence of universal measuring systems. At present, therapeutic outcomes are measured by a variety of clinical rating scales that are subjective and lack sufficient sensitivity. With increasing use of interventional treatments such as Botulinum toxin injections or Deep Brain Stimulation for MST, it has become critical to develop precise measurement instruments. Objective: To clinically validate the TREMBAL software in MST. Methods: TREMBAL (Bionics Institute, Melbourne, Australia) utilises an electromagnetic motion tracker (Ascension, Vermont, US) to acquire absolute displacements and rotations of a tremulous body part. Tremor was recorded bilaterally from four locations (second phalanx of the middle finger, wrist dorsum, forearm and upper arm) in five positions (hands resting on lap, arms outstretched in front, finger-nose, batwing static and batwing action). Tremor exercises were video recorded (GoPro Hero3, GoPro Inc., San Mateo, California) and rated by two experts using the 5-point Unified Tremor Rating Assessment (UTRA) scale where 0=no tremor and 4=severe. TREMBAL tremor displacements (measured in units of millimetres) were averaged and log transformed to match the distribution of clinical ratings. Data were pooled across exercises. Congruence between TREMBAL measures and mean clinical ratings was explored using regression analysis and PearsonĀ“s correlation. Results: We assessed ten MST patients over 6 months and rated 200 videos. The median pooled UTRA score was 0.5 (interquartile range 0, 1.5). The average TREMBAL recorded tremor displacement was 1.65 mm (standard deviation 2.1). A strong correlation between UTRA scores and log transformed TREMBAL displacement was found, r = 0.749, p< 0.001. Conclusions: TREMBAL measurements are highly accurate when compared to clinical measurements. While other objective tremor measures exist, only a few have been benchmarked specifically against MST clinical ratings. The validation of an objective, 3 dimensional tremor measurement system provides real-time tremor severity measurements for clinicians and can be applied in clinical trials of putative therapies for MST.
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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 (pā=ā 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.