Resting-state functional connectivity of anterior and posterior cerebellar lobes is altered in multiple sclerosis.

BACKGROUND: Damage to the cerebellar sensorimotor and cognitive domains may underlie physical and cognitive disability. OBJECTIVE: To investigate resting-state functional connectivity (FC) of sensorimotor and cognitive cerebellum, and clinical correlates in multiple sclerosis (MS). METHODS: A total of 119 patients with MS and 42 healthy subjects underwent multimodal 3T-magnetic resonance imaging (MRI). Patients were evaluated using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Scale. After parcellation of sensorimotor (lobules I-V + VIII) and cognitive cerebellum (lobules VI, VII, IX, X), we calculated cerebellar resting-state FC using a seed-based approach. RESULTS: In patients with MS, the sensorimotor cerebellum showed increased FC mainly with cerebellar, thalamic, and cortical (frontal, parietal, temporal) areas and decreased FC with insular areas; the cognitive cerebellum showed increased FC mainly with thalamic and cortical (temporal-occipital) areas, and decreased FC with frontal-insular areas. Both sensorimotor and cognitive cerebellar FC negatively correlated with disability, and positively with cognitive scores. Cerebellar structural damage only partially influenced results. CONCLUSION: The two neocerebellar circuits showed altered FC with subcortical and cortical areas. The association between increased sensorimotor and cognitive cerebellar FC and low levels of physical and cognitive disability suggests that altered FC might modulate the effects of cerebellar structural damage on clinical condition.

Deep grey matter involvement and altered sensory gating in multiple sclerosis.

BACKGROUND: Somatosensory temporal discrimination threshold (STDT) is altered in multiple sclerosis (MS). In healthy subjects (HS), voluntary movement modulates the STDT through mechanisms of subcortical sensory gating. OBJECTIVE: With neurophysiological and magnetic resonance imaging (MRI) techniques, we investigated sensory gating and sensorimotor integration in MS. METHODS: We recruited 38 relapsing-remitting multiple sclerosis (RR-MS) patients with no-to-mild disability and 33 HS. We tested STDT at rest and during index finger abductions and recorded the movement kinematics. Participants underwent a 3T MRI protocol. RESULTS: Patients exhibited higher STDT values and performed slower finger movements than HS. During voluntary movement, STDT values increased in both groups, albeit to a lesser extent in patients, while the mean angular velocity of finger movements decreased in patients alone. Patients had a smaller volume of the thalamus, pallidum and caudate nucleus, and displayed higher mean diffusivity in the putamen, pallidum and thalamus. STDT correlated with thalamic volume while mean angular velocity correlated with putaminal volume. Changes in mean angular velocity during sensorimotor integration inversely correlated with mean diffusivity in the thalamus and pallidum. Changes in STDT and velocity were associated with fatigue score. CONCLUSION: Altered STDT and sensorimotor integration are related to structural damage in the thalamus and basal ganglia in MS and likely to affect motor performance.

Functional disconnection of thalamic and cerebellar dentate nucleus networks in progressive supranuclear palsy and corticobasal syndrome.

AIM: To assess functional rearrangement following neurodegeneration in the thalamus and dentate nucleus in patients with progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). METHODS: We recruited 19 patients with PSP, 11 with CBS and 14 healthy subjects. All the subjects underwent resting-state (rs) fMRI using a 3T system. Whole brain functional connectivity of the thalamus and dentate nucleus were calculated by means of a seed-based approach with FEAT script in FSL toolbox. Thalamic volume was calculated by means of FIRST, and the dentate area by means of Jim software. RESULTS: Both thalamic volume and dentate area were significantly smaller in PSP and CBS patients than in healthy subjects. No significant difference emerged in thalamic volume between PSP and CBS patients, whereas dentate area was significantly smaller in PSP than in CBS. Thalamic functional connectivity was significantly reduced in both patient groups in various cortical, subcortical and cerebellar areas. By contrast, changes in dentate nucleus functional connectivity differed in PSP and CBS: it decreased in subcortical and prefrontal cortical areas in PSP, but increased asymmetrically in the frontal cortex in CBS. CONCLUSIONS: Evaluating the dentate nucleus size and its functional connectivity may help to differentiate patients with PSP from those with CBS.

Effect on Cognition of Estroprogestins Combined with Interferon Beta in Multiple Sclerosis: Analysis of Secondary Outcomes from a Randomised Controlled Trial.

INTRODUCTION: Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-ß) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. OBJECTIVES: We investigated whether a combination of estroprogestins and IFN-ß can improve cognition in women with MS. METHODS: Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-ß-1a (Rebif®, Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-ß-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon®, MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-ß-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial®, Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24 months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao's Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined 'cognitive impairment'. RESULTS: At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p = 0.03). The risk of developing cognitive impairment over 24 months was lower in group 3 (p = 0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p = 0.03). CONCLUSIONS: This study suggests that the combination of high-dose estroprogestins and IFN-ß may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised. Protocol Number NCT00151801, registered in ClinicalTrials.gov.

Multiple Sclerosis: Changes in Thalamic Resting-State Functional Connectivity Induced by a Home-based Cognitive Rehabilitation Program.

Purpose To investigate thalamic connectivity changes after use of a video game-based cognitive rehabilitation program, as thalamic damage and alterations in thalamocortical functional connectivity (FC) are important factors in cognitive dysfunction in patients with multiple sclerosis (MS). Materials and Methods This prospective study was approved by the local ethical committee. Twenty-four patients with MS and cognitive impairment were randomly assigned to either an intervention or a wait-list group. Patients were evaluated with cognitive tests and 3-T resting-state functional magnetic resonance (MR) imaging at baseline and after an 8-week period. In addition, 11 healthy subjects underwent baseline resting-state functional MR imaging. Patients in the intervention group performed the video game-based cognitive rehabilitation program, while those in the wait-list group served as control subjects. Repeated measures analysis of variance was used to test efficacy of the intervention. The thalamic resting-state network was identified with a seed-based method; both first-level and high-level analyses were performed by using software tools. Results Patients showed lower baseline FC compared with healthy subjects. A significant improvement was seen in results of the Paced Auditory Serial Addition Test and the Stroop Test after 8 weeks of cognitive rehabilitation (F = 6.616, [P = .018] and F = 5.325 [P = .030], respectively). At follow-up, the intervention group had an increased FC in the cingulum, precuneus, and bilateral parietal cortex and a lower FC in the cerebellum and in left prefrontal cortex compared with the wait-list group (P < .05, family-wise error corrected); correlations were found between FC changes in these regions and cognitive improvement (P < .05, family-wise error corrected). Conclusion The results of this study show the relevance of thalamic regulation of the brain networks involved in cognition and suggest that changes in thalamic resting-state network connectivity may represent a functional substrate for cognitive improvement associated with a video game-based cognitive rehabilitation program. (©) RSNA, 2016.

Multiple sclerosis: altered thalamic resting-state functional connectivity and its effect on cognitive function.

PURPOSE: To investigate, by using resting-state (RS) functional magnetic resonance (MR) imaging, thalamocortical functional connectivity (FC) and its correlations with cognitive impairment in multiple sclerosis (MS). MATERIALS AND METHODS: All subjects provided written informed consent; the study protocol was approved by the university institutional review board for this HIPAA-compliant study. Forty-eight patients with relapsing-remitting MS and 24 control subjects underwent multimodal MR imaging, including diffusion-tensor imaging, three-dimensional (3D) T1-weighted imaging, and functional MR imaging at rest and a neuropsychological examination with the Paced Auditory Serial Addition Test (PASAT). Functional MR imaging data were analyzed with tools from FMRIB Software Library, by using the seed-based method to identify the thalamic RS network (RSN). RESULTS: When compared with control subjects, patients showed gray matter and white matter atrophy, as well as diffusion-tensor imaging abnormalities (P < .01). Patients displayed significantly greater synchronization than control subjects in the cerebellum; basal ganglia; hippocampus; cingulum; and temporo-occipital, insular, frontal, and parietal cortices. They also exhibited significantly lower synchronization in the thalamus; cerebellum; cingulum; and insular, prefrontal, and parieto-occipital cortices (cluster level, P < .05, corrected for familywise error [FWE]). In patients, the PASAT score at 3 seconds significantly inversely correlated with the thalamus, cerebellum, and some cortical areas in all cerebral lobes; the PASAT score at 2 seconds significantly correlated, even more strongly, with all the aforementioned regions and, in addition, with the cingulum and the left hippocampus (cluster level, P < .05, corrected for FWE). CONCLUSION: Thalamic RSN is disrupted in MS, and decreased performance in cognitive testing is associated with increased thalamocortical FC, thus suggesting that neuroplasticity changes are unable to compensate for tissue damage and to prevent cognitive dysfunction.