Bain total was calculated as the summation of the three different scores.Дiffusion imaging data were pre-processed and analysed with MRtrix3 ( ) and the multi-shell multi-tissue fixel based analysis pipeline (described in detail at ). The three Bain scores are rated from 0-10 with 0 meaning no tremor and 10 extremely severe tremor. The Bain score was used to rate tremor severity observed while writing a standardised sentence (вЂThis is a sample of my best handwritingвЂ™) and drawing an Archimedes spiral on a pre-drawn pattern with the dominant hand ( 22, 23). The SARA is a (semi-) quantitative 40-point scale rating gait, stance, sitting, speech disturbance, finger chase, nose-finger test, fast alternating hand movements, and heel-shin slide. The SARA is a validated MS-specific ataxia scale and thought to provide a comprehensive assessment of cerebellar function. Three different scores were measured for cerebellar dysfunction: cFSS, the scale for the assessment and rating of ataxia (SARA) ( 21) and the Bain score ( 22). Determining which measure of cerebellar function shows the strongest relation to cerebellar pathology, could inform the most adequate measure to monitor cerebellar function in the clinic.ДЄ Neurostatus certified neurologist determined the Kurtzke Expanded Disability Status Scale (EDSS) for all participants as a measure of overall disease disability ( 20). Cerebellar function was assessed using a range of clinical assessment tools, including cerebellar functional system score (cFSS), scale for the assessment and rating of ataxia (SARA), and Bain. In this study we aimed to assess the relationship between the clinical presentation of cerebellar dysfunction and cerebellar pathology using advanced dwMRI and conventional MRI techniques (brain and lesion volumetrics) in MS. We have shown such methods are highly sensitive to axonal loss in people with MS presenting with optic neuritis, revealing with a high specificity, damage to the visual pathways of the brain relevant to the specific neurological presentation of patients ( 19). Advanced dwMRI methods can assess fibre-specific changes in the presence of crossing-fibres and cellular pathologies such as inflammation, demyelination and oedema ( 18). The cerebellum receives nearly 200 million input fibres ( 15) and is known to consist of complex networks with large number of crossing fibres ( 16, 17). Axons are tightly bundled and due to the strong anisotropy of water diffusion within the axolemma, it can be readily interrogated using diffusion-weighted MRI (dwMRI).

Thus, the drive towards personalised treatment requires greater specificity and sensitivity in terms of both pathological and disability markers.Дespite the constellation of pathologies present in the MS brain, irreversible axonal loss is considered to the primary contributor to progressive neurological decline ( 12- 14). This likely reflects a combination of pathologically non-specific imaging markers and complex interactions between focal pathology, and individual disability trajectories. Furthermore, it correlation with clinical disease severity and cerebellar function, measured using EDSS and cerebellar functional system score (cFSS) respectively, is only modest at best ( 10, 11). Despite the importance of cerebellar involvement to general disease progression, MRI indicated cerebellar pathology is often not reliably detectable in patients in the early stages of MS ( 9). Lesions in the white matter, including the cerebellar peduncles ( 7), and cerebellar atrophy ( 8) are common and more severe in patients with progressive disease phenotypes. To improve our knowledge about the role the cerebellum plays in MS, it is important to understand cerebellar damage and its relation to cerebellar function.Д¬erebellar inflammation and neurodegeneration in people with MS are commonly identified using magnetic resonance imaging (MRI). Importantly, involvement of the cerebellum at disease onset is associated with worse prognosis ( 5) and, cerebellar relapses are associated with poorer recovery and earlier onset of progressive disease ( 6). In MS, focal damage to cerebellum and its efferent and afferent pathways lead to a range of highly disabling symptoms such as loss of dexterity, ataxia, dysarthria and tremor ( 2) that have a significant impact on quality of life ( 3, 4).

The cerebellum is an important structure deeply integrated into major networks involved in motor control, cognition and executive control ( 1). The clinical course of MS is highly heterogenous and outcomes are difficult to predict. Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system.

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