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The white matter is highly vascularised by the cerebral venous system. In this paper, we describe a unique blood oxygen-level dependent (BOLD) signal within the white matter using functional MRI and spatial independent components analysis. The signal is characterized by a narrow peak frequency band between 0.05 and 0.1 Hz. Hypercapnia, induced transient increases in white matter venous BOLD that disrupted the oscillation indicative of a vasocontractile mechanism. Comparison of the white matter venous BOLD oscillations between 14 healthy subjects and 18 people with perivenular inflammation due to multiple sclerosis (MS), revealed loss of power in the white matter venous BOLD signal in the peak frequency band (patients = 6.70 ± 0.94 dB/Hz vs. controls = 7.64 ± 0.71 dB/Hz; p = 0.006). In MS, lower power was associated with greater levels of neuroinflammatory activity (R = -0.64, p = 0.006). Using a signal modeling technique, we assessed the anatomical distribution of white matter venous BOLD signal abnormalities and detected reduced power in the periventricular white matter, a region of known venous damage in MS. These results demonstrate a novel link between neuroinflammation and vascular physiological dysfunction in the cerebral white matter, and could indicate enduring loss of vascular compliance associated with imperfect repair of blood-brain barrier damage after resolution of acute neuroinflammation.

BackgroundCerebellar damage is common in people with multiple sclerosis (pwMS) and is associated with worse progression and relapse recovery. Studies into the importance of the cerebellum in pwMS are hampered by limited understanding of cerebellar damage and its relation to cerebellar function in pwMS.ObjectiveExamine axonal loss, as a primary driver of progressive neurological decline, in the cerebellum using advanced diffusion MRI and compare axonal loss with cerebellar dysfunction in pwMSMethodsWe recruited 55 pwMS and 14 healthy controls. Clinical assessments included scale for the assessment and rating of ataxia (SARA), and Bain tremor ratings. Subjects underwent FLAIR, T1-weighted and diffusion MRI. Cerebellar grey and white matter and lesion volume were calculated. Cerebellar axonal loss was examined with fibre-specific markers. Fibre density and cross-section (FDC) accounts for microscopic and macroscopic changes in a fibre bundle.ResultsLoss of cerebellar FDC was associated with increased SARA (r=-0.42, pConclusionFibre-specific measures of cerebellar pathology could provide a functionally relevant marker of cerebellar damage in MS. Future trials using fibre-specific markers are needed to further characterize cerebellar pathology in pwMS and understand its significance in disease progression.

Endpoint-to-endpoint fibre bundle connectivity estimated using spherical deconvolution & streamlines tractography in diffusion MRI may be excessive in the presence of pathologies that involve truncation of axons within the white matter. Here we propose a simple modification to an existing method that directly quantifies and corrects for this over-estimation.

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., Highlights • Fibre density is reduced in lesions and normal-appearing white matter in MS • Fibre density detects white matter pathology in regions of crossing fibres • Loss of fibre density and cross-section selectively evident in visual pathways of optic neuritis patients.

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.

The white matter is highly vascularised by the cerebral venous system. The neuroinflammatory disease multiple sclerosis is associated with infiltration of peripheral immune cells into the brain via these vessels. Understanding venous pathophysiology in multiple sclerosis is thus critical for understanding early disease aetiology. In this paper, we describe a unique blood oxygen-level dependent (BOLD) signal within the white matter using functional MRI and spatial independent components analysis, a blind signal source separation method. The signal was characterised by a narrow peak frequency band between 0.05 and 0.1 Hz. Hypercapnia (transient breath holds), known to alter venous calibre in cortex, induced transient increases in white matter BOLD that disrupted the oscillation indicative of a vasodilatory/contractile mechanism. Comparison of the white matter BOLD oscillations between age and sex matched groups of 18 multiple sclerosis and 14 healthy participants revealed a loss of power in the white matter BOLD signal in the peak frequency band (patients = 6.70±0.94 dB/Hz vs controls = 7.64±0.71 dB/Hz; p=0.006). In multiple sclerosis patients, lower power was associated with greater levels of neuroinflammatory activity (R=−0.64, p=0.006) but not neurodegenerative disease markers. Using a signal modelling technique, we assessed the anatomical distribution of white matter BOLD signal abnormalities and detected reduced power in the periventricular white matter, a region of known venous damage in multiple sclerosis patients. These results demonstrate a novel link between neuroinflammation and vascular physiological dysfunction in the cerebral white matter, and could indicate enduring loss of vascular compliance associated with imperfect repair of blood-brain barrier damage after resolution of acute neuroinflammation.

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.

Executive dysfunction has been demonstrated among premutation (PM) carriers (55-199 CGG repeats) of the Fragile X mental retardation 1 (FMR1) gene. Further, alterations to neural activation patterns have been reported during memory and comparison based functional magnetic resonance imaging (fMRI) tasks in these carriers. For the first time, the relationships between fMRI neural activation during an interleaved ocular motor prosaccade/antisaccade paradigm, and concurrent task performance (saccade measures of latency, accuracy and error rate) in PM females were examined. Although no differences were found in whole brain activation patterns, regions of interest (ROI) analyses revealed reduced activation in the right ventrolateral prefrontal cortex (VLPFC) during antisaccade trials for PM females. Further, a series of divergent and group specific relationships were found between ROI activation and saccade measures. Specifically, for control females, activation within the right VLPFC and supramarginal gyrus correlated negatively with antisaccade latencies, while for PM females, activation within these regions was found to negatively correlate with antisaccade accuracy and error rate (right VLPFC only). For control females, activation within frontal and supplementary eye fields and bilateral intraparietal sulci correlated with prosaccade latency and accuracy; however, no significant prosaccade correlations were found for PM females. This exploratory study extends previous reports of altered prefrontal neural engagement in PM carriers, and clearly demonstrates dissociation between control and PM females in the transformation of neural activation into overt measures of executive dysfunction. Hum Brain Mapp 38:1056-1067, 2017. © 2016 Wiley Periodicals, Inc.