Improvement of spasticity following intermittent theta burst stimulation in multiple sclerosis is associated with modulation of resting-state functional connectivity of the primary motor cortices.

BACKGROUND: Intermittent theta burst stimulation (iTBS) of the primary motor cortex improves transiently lower limbs spasticity in multiple sclerosis (MS). However, the cerebral mechanisms underlying this effect have never been investigated. OBJECTIVE: To assess whether modulation of spasticity induced by iTBS is underlined by functional reorganization of the primary motor cortices. METHODS: A total of 17 patients with MS suffering from lower limbs spasticity were randomized to receive real iTBS or sham iTBS during the first half of a 5-week indoor rehabilitation programme. Spasticity was assessed using the Modified Ashworth Scale and the Visual Analogue Scale at baseline, after the stimulation session and at the end of the rehabilitation programme. Resting-state functional magnetic resonance imaging (fMRI) was performed at the three time points, and brain functional networks topology was analysed using graph-theoretical approach. RESULTS: At the end of stimulation, improvement of spasticity was greater in real iTBS group than in sham iTBS group ( p = 0.026). iTBS had a significant effect on the balance of the connectivity degree between the stimulated and the homologous primary motor cortex ( p = 0.005). Changes in inter-hemispheric balance were correlated with improvement of spasticity (rho = 0.56, p = 0.015). CONCLUSION: This longitudinal resting-state fMRI study evidences that functional reorganization of the primary motor cortices may underlie the effect of iTBS on spasticity in MS.

Depletion of brain functional connectivity enhancement leads to disability progression in multiple sclerosis: A longitudinal resting-state fMRI study.

BACKGROUND: The compensatory effect of brain functional connectivity enhancement in relapsing-remitting multiple sclerosis (RRMS) remains controversial. OBJECTIVE: To characterize the relationships between brain functional connectivity changes and disability progression in RRMS. METHODS: Long-range connectivity, short-range connectivity, and density of connections were assessed using graph theoretical analysis of resting-state functional magnetic resonance imaging (fMRI) data acquired in 38 RRMS patients (disease duration: 120 ± 32 months) and 24 controls. All subjects were explored at baseline and all patients and six controls 2 years later. RESULTS: At baseline, levels of long-range and short-range brain functional connectivity were higher in patients compared to controls. During the follow-up, decrease in connections' density was inversely correlated with disability progression. Post-hoc analysis evidenced differential evolution of brain functional connectivity metrics in patients according to their level of disability at baseline: while patients with lowest disability at baseline experienced an increase in all connectivity metrics during the follow-up, patients with higher disability at baseline showed a decrease in the connectivity metrics. In these patients, decrease in the connectivity metrics was associated with disability progression. CONCLUSION: The study provides two main findings: (1) brain functional connectivity enhancement decreases during the disease course after reaching a maximal level, and (2) decrease in brain functional connectivity enhancement participates in disability progression.

Voxelwise analysis of conventional magnetic resonance imaging to predict future disability in early relapsing-remitting multiple sclerosis.

BACKGROUND: The ability of conventional magnetic resonance imaging (MRI) to predict subsequent physical disability and cognitive deterioration after a clinically isolated syndrome (CIS) is weak. OBJECTIVES: We aimed to investigate whether conventional MRI changes over 1 year could predict cognitive and physical disability 5 years later in CIS. We performed analyses using a global approach (T(2) lesion load, number of T(2) lesions), but also a topographic approach. METHODS: This study included 38 patients with a CIS. At inclusion, 10 out of 38 patients fulfilled the 2010 revised McDonald's criteria for the diagnosis of multiple sclerosis. Expanded Disability Status Scale (EDSS) evaluation was performed at baseline, year 1 and year 5, and cognitive evaluation at baseline and year 5. T(2)-weighted MRI was performed at baseline and year 1. We used voxelwise analysis to analyse the predictive value of lesions location for subsequent disability. RESULTS: Using the global approach, no correlation was found between MRI and clinical data. The occurrence or growth of new lesions in the brainstem was correlated with EDSS changes over the 5 years of follow-up. The occurrence or growth of new lesions in cerebellum, thalami, corpus callosum and frontal lobes over 1 year was correlated with cognitive impairment at 5 years. CONCLUSION: The assessment of lesion location at the first stage of multiple sclerosis may be of value to predict future clinical disability.

Assessing brain connectivity at rest is clinically relevant in early multiple sclerosis.

OBJECTIVE: The present study aims to determine the clinical counterpart of brain resting-state networks reorganization recently evidenced in early multiple sclerosis. METHODS: Thirteen patients with early relapsing-remitting multiple sclerosis and 14 matched healthy controls were included in a resting state functional MRI study performed at 3 T. Data were analyzed using group spatial Independent Component Analysis using concatenation approach (FSL 4.1.3) and double regression analyses (SPM5) to extract local and global levels of connectivity inside various resting state networks (RSNs). Differences in global levels of connectivity of each network between patients and controls were assessed using Mann-Whitney U-test. In patients, relationship between clinical data (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Score - MSFC) and global RSN connectivity were assessed using Spearman rank correlation. RESULTS: Independent component analysis provided eight consistent neuronal networks involved in motor, sensory and cognitive processes. For seven RSNs, the global level of connectivity was significantly increased in patients compared with controls. No significant decrease in RSN connectivity was found in early multiple sclerosis patients. MSFC values were negatively correlated with increased RSN connectivity within the dorsal frontoparietal network (r = -0.811, p = 0.001), the right ventral frontoparietal network (r = - 0.587, p = 0.045) and the prefronto-insular network (r = -0.615, p = 0.033). CONCLUSIONS: This study demonstrates that resting state networks reorganization is strongly associated with disability in early multiple sclerosis. These findings suggest that resting state functional MRI may represent a promising surrogate marker of disease burden.

Intrathecal synthesis of IgM measured after a first demyelinating event suggestive of multiple sclerosis is associated with subsequent MRI brain lesion accrual.

BACKGROUND: Previous studies have demonstrated that intrathecal synthesis of IgM is observed in multiple sclerosis (MS) and correlates with a worse disease course. These results suggest that IgM participates in the formation of MS lesions. OBJECTIVE: The aim of the present study was to assess the potential association between the level of intrathecal synthesis of IgM measured after a clinically isolated syndrome (CIS) and the subsequent formation of brain lesions. METHODS: Fifty seven patients with a CIS and a high risk developing MS were enrolled in a longitudinal study. Examination of cerebrospinal fluid was performed after the CIS and included measures of intrathecal IgM and IgG synthesis. Patients were assessed with the same 1.5 Tesla magnetic resonance imaging (MRI) system at baseline and after a mean follow-up period of 49 months (range 36-60). Spearman Rank correlation was used to assess the potential correlations between levels of intrathecal immunoglobulin synthesis and MRI data. RESULTS: The level of intrathecal IgM synthesis was correlated with the number of gadolinium-enhancing lesions at baseline (p = 0.01) and with accrual of brain lesions during the follow-up period (p = 0.02). By taking into account brain sub-regions, we demonstrated that the level of intrathecal IgM synthesis was only correlated with the increased number of lesions in the periventricular regions (p = 0.004). The level of intrathecal IgG synthesis was not correlated with any MRI data. CONCLUSION: The present longitudinal study demonstrates that the level of intrathecal IgM synthesis measured after a CIS is associated with subsequent lesion accrual during the first years of MS. This result emphasizes the involvement of IgM in plaque formation.

In vivo quantification of brain injury in adult Niemann-Pick Disease Type C.

Development of surrogate markers is necessary to assess the potential efficacy of new therapeutics in Niemann-Pick Disease Type C (NP-C). In the present study, magnetization transfer ratio (MTR) imaging, a quantitative MRI imaging technique sensitive to subtle brain microstructural changes, was applied in two patients suffering from adult NP-C. Statistical mapping analysis was performed to compare each patient's MTR maps with those of a group of 34 healthy controls to quantify and localize the extent of brain injury of each patient. Using this method, pathological changes were evidenced in the cerebellum, the thalami and the lenticular nuclei in both patients and also in the fronto-temporal cortices in the patient with the worse functional deficit. In addition, white matter changes were located in the midbrain, the cerebellum and the fronto-temporal lobes in the patient with the higher level of disability and in only one limited periventricular white matter region in the other patient. A 6-month follow-up was performed in the patient with the lower functional deficit and evidenced significant extension of grey matter (GM) and white matter (WM) injuries during the following period (14% of increased injury for GM and 53% for WM). This study demonstrates that significant brain injury related to clinical deficit can be assessed in vivo in adult NP-C using MTR imaging. Although preliminary, these findings suggest that MTR imaging may be a relevant candidate for the development of biomarker in NP-C.

Frequency of cognitive impairment dramatically increases during the first 5 years of multiple sclerosis.

Previous studies have demonstrated that cognitive impairment is already present in patients suffering from a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). However, little is known about the course of cognitive impairment after the occurrence of a CIS. In order to characterise the early evolution of cognitive impairment, the authors assessed during a 5-year follow-up period a group of 24 CIS patients with high risk of developing MS. Longitudinal neuropsychological assessment was performed at two time points (baseline and year 5) in patients and controls (baseline and year 1). At year 5, 54% of patients showed cognitive impairment against 29% at baseline. Multiple regression models showed that patients with a higher T(2) lesion load at baseline had a higher cognitive impairment at year 5. This longitudinal study performed in CIS patients showed that the frequency of cognitive impairment increases dramatically during the first 5 years following a CIS and that the cognitive status at year 5 was predictable by conventional MRI parameters recorded at baseline.

Cognitive impairment at the onset of multiple sclerosis: relationship to lesion location.

The impact of lesion location on cognitive functioning was assessed in a group of 97 patients with a clinically isolated syndrome. Using the Brief Repeatable Battery, we evidenced that 24% of patients showed at least one abnormal test, 20% at least two and 15% at least three. Verbal learning performances were inversely associated with presence of lesions in Broca's area, in the right frontal lobe and in the splenium while spatial learning performances were inversely correlated to the presence of lesions in the deep white matter. No associations were evidenced between lesion location and performance of tasks exploring attention and executive functions.

Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging.

The aim of the study was to assess the prevalence, the distribution and the impact on disability of grey matter (GM) pathology in early multiple sclerosis. Eighty-eight patients with a clinically isolated syndrome with a high risk developing multiple sclerosis were included in the study. Forty-four healthy controls constituted the normative population. An optimized statistical mapping analysis was performed to compare each subject's GM Magnetization Transfer Ratio (MTR) imaging maps with those of the whole group of controls. The statistical threshold of significant GM MTR decrease was determined as the maximum p value (p<0.05 FDR) for which no significant cluster survived when comparing each control to the whole control population. Using this threshold, 51% of patients showed GM abnormalities compared to controls. Locally, 37% of patients presented abnormalities inside the limbic cortex, 34% in the temporal cortex, 32% in the deep grey matter, 30% in the cerebellum, 30% in the frontal cortex, 26% in the occipital cortex and 19% in the parietal cortex. Stepwise regression analysis evidenced significant association (p = 0.002) between EDSS and both GM pathology (p = 0.028) and T2 white matter lesions load (p = 0.019). In the present study, we evidenced that individual analysis of GM MTR map allowed demonstrating that GM pathology is highly heterogeneous across patients at the early stage of MS and partly underlies irreversible disability.

Occurrence of neuronal dysfunction during the first 5 years of multiple sclerosis is associated with cognitive deterioration.

Brain neuronal injury is present in patients suffering from multiple sclerosis (MS) from the earliest stage of the disease; however, the functional counterpart of early neuronal injury is largely unknown. The goal of this study was to assess the potential impact of early neuronal dysfunction affecting white matter (WM), grey matter (GM), or the cerebellum on cognitive deterioration and/or EDSS progression during the first 5 years of MS. Magnetic resonance spectroscopic (MRS) examinations and neuropsychological assessments were performed in 23 patients included after the first clinical attack of MS and 24 healthy controls. The same protocol was performed in patients after a follow-up of 5 years. Metabolic neuronal function was assessed in WM (splenium of corpus callosum), GM (dorsal posterior cingulate cortex), and the cerebellum by evaluating N-acetylaspartate (NAA) levels. During follow-up, 39% of patients showed cognitive deterioration and 43% showed a deterioration in their EDSS. Patients with cognitive deterioration had greater NAA level reductions during follow-up in the cerebellum (p = 0.003) and WM (p = 0.02) compared to patients without cognitive deterioration. In addition, patients with cognitive deterioration had higher progression of T2 lesion load (T2LL) during the follow-up period compared to patients without cognitive deterioration (p = 0.03). No differences between patients with and without EDSS progression in terms of NAA levels or T2LL were observed. The present longitudinal study found evidence that, during the first 5 years of MS, cognitive deterioration is associated with the progression of neuronal dysfunction and tissue injury as assessed by MRS and T2LL, respectively.