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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.

OBJECTIVE: To investigate the factors influencing enlarged perivascular space (EPVS) characteristics at the onset of acute ischemic stroke (AIS), and whether the PVS characteristics can predict later post-stroke epilepsy (PSE). METHODS: A total of 312 patients with AIS were identified, of whom 58/312 (18.6%) developed PSE. Twenty healthy participants were included as the control group. The number of PVS in the basal ganglia (BG), centrum semiovale (CS), and midbrain (MB) was manually calculated on T2 -weighted MRI. The scores and asymmetry index (AI) of EPVS in each region were compared among the enrolled participants. Other potential risk factors for PSE were also analyzed, including NIHSS at admission and stroke etiologies. RESULTS: The EPVS scores were significantly higher in the bilateral BG and CS of AIS patients compared to those of the control group (both p < 0.01). No statistical differences in EPVS scores in BG, CS, and MB were obtained between the PSE group and the nonepilepsy AIS group (all p > 0.01). However, markedly different AI scores in CS were found between the PSE group and the nonepilepsy AIS group (p = 0.004). Multivariable analysis showed that high asymmetry index of EPVS (AI≥0.2) in CS was an independent predictor for PSE (OR = 3.7, 95% confidence interval 1.5-9.1, p = 0.004). CONCLUSIONS: Asymmetric distribution of EPVS in CS may be an independent risk factor and a novel imaging biomarker for the development of PSE. Further studies to understand the mechanisms of this association and confirmation with larger patient populations are warranted.

Preclinical studies of remote degeneration have largely focused on brain changes over the first few days or weeks after stroke. Accumulating evidence suggests that neurodegeneration occurs in other brain regions remote to the site of infarction for months and even years following ischaemic stroke. Brain atrophy appears to be driven by both axonal degeneration and widespread brain inflammation. The evolution and duration of these changes are increasingly being described in human studies, using advanced brain imaging techniques. Here, we sought to investigate long-term structural brain changes in a model of mild focal ischaemic stroke following injection of endothlin-1 in adult Long-Evans rats (n = 14) compared with sham animals (n = 10), over a clinically relevant time-frame of 48 weeks. Serial structural and diffusion-weighted MRI data were used to assess dynamic volume and white matter trajectories. We observed dynamic regional brain volume changes over the 48 weeks, reflecting both normal changes with age in sham animals and neurodegeneration in regions connected to the infarct following ischaemia. Ipsilesional cortical volume loss peaked at 24 weeks but was less prominent at 36 and 48 weeks. We found significantly reduced fractional anisotropy in both ipsi- and contralesional motor cortex and cingulum bundle regions of infarcted rats (P < 0.05) from 4 to 36 weeks, suggesting ongoing white matter degeneration in tracts connected to but distant from the stroke. We conclude that there is evidence of significant cortical atrophy and white matter degeneration up to 48 weeks following infarct, consistent with enduring, pervasive stroke-related degeneration.

Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "Fixel-Based Analysis" (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities.Copyright © 2021

OBJECTIVE: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to

PURPOSE: Quantitative susceptibility mapping (QSM) is a novel MR technique that allows mapping of tissue susceptibility values from MR phase images. QSM is an ill-conditioned inverse problem, and although several methods have been proposed in the field, in the presence of a wide range of susceptibility sources, streaking artifacts appear around high susceptibility regions and contaminate the whole QSM map. QSMART is a post-processing pipeline that uses two-stage parallel inversion to reduce the streaking artifacts and remove banding artifact at the cortical surface and around the vasculature. METHOD: Tissue and vein susceptibility values were separately estimated by generating a mask of vasculature driven from the magnitude data using a Frangi filter. Spatially dependent filtering was used for the background field removal step and the two susceptibility estimates were combined in the final QSM map. QSMART was compared to RESHARP/iLSQR and V-SHARP/iLSQR inversion in a numerical phantom, 7T in vivo single and multiple-orientation scans, 9.4T ex vivo mouse data, and 4.7T in vivo rat brain with induced focal ischemia. RESULTS: Spatially dependent filtering showed better suppression of phase artifacts near cortex compared to RESHARP and V-SHARP, while preserving voxels located within regions of interest without brain edge erosion. QSMART showed successful reduction of streaking artifacts as well as improved contrast between different brain tissues compared to the QSM maps obtained by RESHARP/iLSQR and V-SHARP/iLSQR. CONCLUSION: QSMART can reduce QSM artifacts to enable more robust estimation of susceptibility values in vivo and ex vivo.

INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP. METHODS AND ANALYSIS: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures. ETHICS AND DISSEMINATION: The study was approved by the Alfred Health Ethics Committee (594/20). Each

Objective: To objectively describe cerebellar mediated speech function using a multiparameter index that reflects pathology and quality of life in MS. Background: Cerebellar function plays a role in cognitive processing and motor control and is important for speech production. Multiple sclerosis (MS) can result in impaired cerebellar function, leading to speech deficits. These deficits can be detected by instrumental measurement. Speech as a marker of cerebellar impairment but is not well described. Method: The speech and clinical features of 85 people with MS (plus 21 matched controls) were assessed using objective acoustic analysis, validated questionnaires of quality of life and disease severity using the Scale for the Assessment and rating of Ataxia. Magnetic resonance imaging was used to measure cerebellar pathology. A regression model with eight speech variables were used to predict cerebellar function. A composite speech score was developed from the model and tested for prediction of fine motor function using the 9-hole peg test (9HPT), for correlations with imaging outcomes and self-assessed quality of life. Results: Speech timing metrics (eg. slow rate of syllable repetition, increased proportion of silence) were the strongest predictors of cerebellar impairment, alongside phonatory instability. The acoustic composite score accounted for 54% of variation in cerebellar dysfunction, was associated 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. Conclusion: Motor cerebellar impairment in MS was reflected in an objective multi-feature speech metric.

PURPOSE: Parameter mapping in sodium MRI data is challenging due to inherently low SNR and spatial resolution, prompting the need to employ robust models and estimation techniques. This work aims to develop a continuum model of sodium T2* -decay to overcome the limitations of the commonly employed bi-exponential models. Estimates of mean T2* -decay and fast component fraction in tissue are emergent from the inferred continuum model. METHODS: A closed-form continuum model was derived assuming a gamma distribution of T2* components. Sodium MRI was performed on four healthy human subjects and a phantom consisting of closely packed vials filled with an aqueous solution of varying sodium and agarose concentrations. The continuum model was applied to the phantom and in vivo human multi-echo 7T data. Parameter maps by voxelwise model-fitting were obtained. RESULTS: The continuum model demonstrated comparable estimation performance to the bi-exponential model. The parameter maps provided improved contrast between tissue structures. The fast component fraction, an indicator of the heterogeneity of localised sodium motion regimes in tissue, was zero in CSF and high in WM structures. CONCLUSIONS: The continuum distribution model provides high quality, high contrast parameter maps, and informative voxelwise estimates of the relative weighting between fast and slow decay components.

Cognitive dysfunction can be identified in patients with clinically isolated syndromes suggestive of multiple sclerosis using ocular motor testing. This study aimed to identify the functional neural correlates of cognitive dysfunction in patients with clinically isolated syndrome using MRI. Eighteen patients with clinically isolated syndrome and 17 healthy controls were recruited. Subjects underwent standard neurological and neuropsychological testing. Subjects also underwent functional MRI (fMRI) during a cognitive ocular motor task, involving pro-saccade (direct gaze towards target) and anti-saccade (direct gaze away from target) trials. Ocular motor performance variables (averaged response time and error rate) were calculated for each subject. Patients showed a trend towards a greater rate of anti-saccade errors (p = 0.09) compared to controls. Compared to controls, patients exhibited increased activation in the right postcentral, right supramarginal gyrus, and the right parietal operculum during the anti-saccade>pro-saccade contrast. This study demonstrated that changes in functional organisation of cognitive brain networks is associated with subtle cognitive changes in patients with clinically isolated syndrome.

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

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 “as fast as possible” 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=47.7±12years; disease duration=13.2±8.4). Diadochokinetic rate (mean=5.63±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 bef

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 “always”, from reading of the “Grandfather Passage”. After adjustment for multiple comparisons, a p< 0.0125 was considered for statistical significance. Results: We assessed 24 MS patients with upper limb tremor (47.2±12.3years, 75% female, EDSS=3.7±1.6) and 24 matched patients without tremor (51.2±10.7years, 75% female, EDSS=3.6±1.7). Clinical dysarthria (median=0, mean=0.375±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 ce

DNA methylation of the Fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary has been associated with executive dysfunction in female carriers of a FMR1 premutation (PM: 55-199 CGG repeats), whereas neuroanatomical changes have been associated with executive dysfunction in PM males. To our knowledge, this study for the first time examined the inter-relationships between executive function, neuroanatomical structure and molecular measures (DNA methylation and FMR1 mRNA levels in blood) in PM and control (<44 CGG repeats) females. In the PM group, FMR1 intron 1 methylation was positively associated with executive function and cortical thickness in middle and superior frontal gyri, and left inferior parietal gyrus. By contrast, in the control group, FMR1 intron 1 methylation was negatively associated with cortical thickness of the left middle frontal gyrus and superior frontal gyri. No significant associations were revealed for either group between FMR1 mRNA and neuroanatomical structure or executive function. In the PM group, the lack of any significant association between FMR1 mRNA levels and phenotypic measures found in this study suggests that either FMR1 expression is not well conserved between tissues, or that FMR1 intron 1 methylation is linked to neuroanatomical and cognitive phenotype in PM females via a different mechanism.

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.

Inhalant misuse is common during adolescence, with ongoing chronic misuse associated with neurobiological and cognitive abnormalities. While human imaging studies consistently report white matter abnormalities among long-term inhalant users, longitudinal studies have been lacking with limited data available regarding the progressive nature of such abnormalities, including the potential for recovery following periods of sustained abstinence. We exposed adolescent male Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (3,000 ppm) for 1 hour/day, 3 times/week for 8 weeks to model abuse patterns observed in adolescent and young adult human users. This dosing regimen resulted in a significant retardation in weight gain during the exposure period (p<0.05). In parallel, we performed longitudinal magnetic resonance imaging (T₂-weighted) and diffusion tensor imaging prior to exposure, and after 4 and 8 weeks, to examine the integrity of white matter tracts, including the anterior commissure and corpus callosum. We also conducted imaging after 8 weeks of abstinence to assess for potential recovery. Chronic intermittent toluene exposure during adolescence and early adulthood resulted in white matter abnormalities, including a decrease in axial (p<0.05) and radial (p<0.05) diffusivity. These abnormalities appeared region-specific, occurring in the anterior commissure but not the corpus callosum and were not present until after at least 4 weeks of exposure. Toluene-induced effects on both body weight and white matter parameters recovered following abstinence. Behaviourally, we observed a progressive decrease in rearing activity following toluene exposure but no difference in motor function, suggesting cognitive function may be more sensitive to the effects of toluene. Furthermore, deficits in rearing were present by 4 weeks suggesting that toluene may affect behaviour prior to detectable white matter abnormalities. Consequently, exposure to inhalants that co