Divergent time-varying connectivity of thalamic sub-regions characterizes clinical phenotypes and cognitive status in multiple sclerosis.

We aimed to investigate abnormal time-varying functional connectivity (FC) for thalamic sub-regions in multiple sclerosis (MS) and their clinical, cognitive and MRI correlates. Eighty-nine MS patients (49 relapsing-remitting [RR] MS; 40 progressive [P] MS) and 53 matched healthy controls underwent neurological, neuropsychological and resting state fMRI assessment. Time-varying connectivity (TVC) was quantified using sliding-window seed-voxel correlation analysis. Standard deviation of FC across windows was taken as measure of TVC, while mean connectivity across windows expressed static FC. MS patients showed reduced TVC vs controls between most of thalamic sub-regions and fronto-temporo-occipital regions. At the same time, they showed increased static FC between all thalamic sub-regions and structurally connected cortico-subcortical regions. TVC reduction was mainly driven by RRMS; while PMS exhibited a variable pattern of TVC abnormalities, characterized by reduced TVC between frontal/motor thalamic seeds and default-mode network areas and increased TVC vs controls/RRMS between posterior thalamic sub-regions and occipito-temporo-insular cortices, associated with severity of clinical disability. Compared with controls, both cognitively preserved and impaired patients showed reduced TVC between anterior thalamic sub-regions and frontal cortex. Cognitively impaired patients also showed increased TVC of the right postcentral thalamic sub-region with the cingulate cortex and postcentral gyrus vs both controls and cognitively preserved patients. Divergent patterns of TVC thalamic abnormalities were found between RRMS and PMS patients. TVC reduction in RRMS may represent the attempt of thalamic network to keep with stable connections. Conversely, increased TVC of posterior thalamic sub-regions characterized PMS and cognitively impaired MS, possibly reflecting maladaptive mechanisms.

Differential association of cortical, subcortical and spinal cord damage with multiple sclerosis disability milestones: A multiparametric MRI study.

BACKGROUND: In multiple sclerosis (MS), cortical, subcortical and infratentorial structural damage may have a differential contribution to clinical disability according to disease phases. PURPOSE: To determine the relative contributions of cortical, deep (D) grey matter (GM), cerebellar and cervical cord damage to MS disability milestones. METHODS: Multi-centre 3T brain and cervical cord T2- and three-dimensional (3D) T1-weighted images were acquired from 198 MS patients (139 relapsing-remitting (RR) MS, 59 progressive (P) MS) and 67 healthy controls. Brain/cord lesion burden, cortical thickness (CTh), DGM and cerebellar volumetry and cord cross-sectional area (CSA) were quantified. Random forest analyses identified predictors of expanded disability status scale (EDSS) disability milestones (EDSS = 3.0, 4.0 and 6.0). RESULTS: MS patients had widespread atrophy in all investigated compartments versus controls (p-range: ⩽0.001-0.05). Informative determinants of EDSS = 3.0 were cord CSA, brain lesion volume, frontal CTh and thalamic and cerebellar atrophy (out-of-bag (OOB) accuracy = 0.84, p-range: ⩽0.001-0.05). EDSS = 4.0 was mainly predicted by cerebellar and cord atrophy, frontal and sensorimotor CTh and cord lesion number (OOB accuracy = 0.84, p-range: ⩽0.001-0.04). Cervical cord CSA (p = 0.001) and cord lesion number (p = 0.003) predicted EDSS = 6.0 (OOB accuracy = 0.77). CONCLUSION: Brain lesion burden, cortical and thalamic atrophy were the main determinants of EDSS = 3.0 and 4.0, while cord damage played a major contribution to EDSS = 6.0.

Dynamic Functional Connectivity in the Main Clinical Phenotypes of Multiple Sclerosis.

Introduction: Dynamic functional connectivity (dFC) allows capturing recurring patterns (states) of interaction among functional networks. In this study, we investigated resting state (RS) dFC abnormalities across the different clinical phenotypes of multiple sclerosis (MS) and assessed their correlation with motor and cognitive performances. Methods: RS functional magnetic resonance imaging (fMRI) and 3D T1-weighted MRI data were acquired from 128 MS patients (69 relapsing-remitting [RR] MS, 34 secondary progressive [SP] MS, and 25 primary progressive [PP] MS) and 40 healthy controls (HC). RS fMRI data underwent independent component analysis and sliding-window correlations, to identify recurring dFC states and between-group dFC differences in the main networks. Results: dFC identified three recurring connectivity states: State 1 (frequency of appearance during fMRI acquisition = 57%, low dFC strength), State 2 (frequency = 19%, middle-high dFC strength), and State 3 (frequency = 24%, high sensorimotor and visual dFC strength). Compared to HC, MS (as a whole), RRMS, and PPMS patients exhibited lower State1/State 3 dFC (p = 0.0001, corrected) between sensorimotor, cerebellar, and cognitive networks, and some dFC increments (p = 0.001-0.05, uncorrected) in sensorimotor, visual, default-mode, and frontal/attention networks in States 2 and 3. Similar results were observed in SPMS versus RRMS patients. In MS, dFC decrease in sensorimotor, default-mode, and frontal/attention networks was correlated with worse motor and cognitive performances. Conclusions: MS patients exhibited overall lower dFC, and marginally higher dFC in sensorimotor/cognitive networks in the less-frequent middle/high-connected States. dFC abnormalities became more severe in progressive MS and correlated with motor and cognitive impairment, suggesting the presence of maladaptive mechanisms concomitant with accumulation of damage. Impact statement This is the first study exploring reorganization of dynamic functional connectivity in patients with multiple sclerosis (MS) across the main clinical phenotypes of the disease. Here, we demonstrated abnormalities of connectivity dynamism, which were present at all disease stages, but became more severe in progressive MS and correlated with worse motor and cognitive performances. These findings suggested that progressive MS patients might experience a maladaptive neuronal response to transient loss of dynamic coordination and flexibility among sensory and cognitive brain regions, leading to the progression of clinical impairment.

MRI correlates of clinical disability and hand-motor performance in multiple sclerosis phenotypes.

BACKGROUND: Hand-motor impairment affects a large proportion of multiple sclerosis (MS) patients; however, its substrates are still poorly understood. OBJECTIVES: To investigate the association between global disability, hand-motor impairment, and alterations in motor-relevant structural and functional magnetic resonance imaging (MRI) networks in MS patients with different clinical phenotypes. METHODS: One hundred thirty-four healthy controls (HC) and 364 MS patients (250 relapsing-remitting MS (RRMS) and 114 progressive MS (PMS)) underwent Expanded Disability Status Scale (EDSS) rating, nine-hole peg test (9HPT), and electronic finger tapping rate (EFTR). Structural and resting state (RS) functional MRI scans were used to perform a source-based morphometry on gray matter (GM) components, to analyze white matter (WM) tract diffusivity indices and to perform a RS seed-based approach from the primary motor cortex involved in hand movement (hand-motor cortex). Random forest analyses identified the predictors of clinical impairment. RESULT: In RRMS, global measures of atrophy and lesions together with measures of structural damage of motor-related regions predicted EDSS (out-of-bag (OOB)-R2 = 0.19, p-range = <0.001-0.04), z9HPT (right: OOB-R2 = 0.14; left: OOB-R2 = 0.24, p-range = <0.001-0.03). No RS functional connectivity (FC) abnormalities were identified in RRMS models. In PMS, cerebellar and sensorimotor regions atrophy, cerebellar peduncles integrity and increased RS FC between left hand-motor cortex and right inferior frontal gyrus predicted EDSS (OBB-R2 = 0.16, p-range = 0.02-0.04). CONCLUSION: In RRMS, only measures of structural damage contribute to explain motor impairment, whereas both structural and functional MRI measures predict clinical disability in PMS. A multiparametric MRI approach could be relevant to investigate hand-motor impairment in different MS phenotypes.

Clinical predictivity of thalamic sub-regional connectivity in clinically isolated syndrome: a 7-year study.

Here, we explored trajectories of sub-regional thalamic resting state (RS) functional connectivity (FC) modifications occurring in clinically isolated syndrome (CIS) patients early after their first clinical episode, and assessed their relationship with disability over 7 years. RS fMRI and clinical data were prospectively acquired from 59 CIS patients and 13 healthy controls (HC) over 2 years. A clinical re-assessment was performed in 53 (89%) patients after 7 years. Using a structural connectivity-based atlas, five thalamic sub-regions (frontal, motor, postcentral, occipital, and temporal) were used for seed-based RS FC. Thalamic RS FC abnormalities and their longitudinal changes were correlated with disability. Thirty-nine (66.1%) patients suffered a second clinical relapse, but the median EDSS remained stable over time. At baseline, CIS patients vs HC showed reduced RS FC (p < 0.001, uncorrected) with: (1) frontal cortices, for the whole thalamus, occipital, postcentral, and temporal thalamic sub-regions, (2) occipital cortices, for the occipital thalamic sub-region. In CIS, the longitudinal analysis revealed at year 2 vs baseline: (1) no significant whole-thalamic RS FC changes; (2) reduction of motor, postcentral, and temporal sub-regional RS FC with occipital cortices (p < 0.05, corrected); (3) an increase (p < 0.001, uncorrected) of postcentral and occipital sub-regional thalamic RS FC with frontal cortices, left putamen, and ipsi- and contralateral thalamus, this latter correlating with less severe clinical disability at year 7. Thalamo-cortical disconnections were present in CIS mainly in thalamic sub-regions closer to the third ventricle early after the demyelinating event, evolved in the subsequent 2 years, and were associated with long-term clinical disability.

Longitudinal cortical thinning progression differs across multiple sclerosis phenotypes and is clinically relevant: A multicentre study.

BACKGROUND: Longitudinal evolution of cortical thickness (CTh) in different MS phenotypes has been rarely studied. AIM: To investigate the regional pattern and 1-year progression of cortical thinning in relapsing-remitting (RR) and progressive (P) MS. METHODS: 3T high-resolution T1-weighted magnetic resonance imaging (MRI) was obtained from 86 patients (75 RRMS, 11 PMS) and 34 healthy controls (HC) at three European sites at baseline and 1-year follow-up. Using FreeSurfer, baseline CTh between-group differences, longitudinal CTh changes and their correlations with clinical and MRI variables were assessed. RESULTS: Baseline frontal, parietal and sensorimotor atrophy was found in MS versus HC. Such pattern was driven by RRMS, while PMS showed additional parietal, insular and sensorimotor cortical atrophy versus RRMS. At 1-year versus baseline, additional frontal and temporal cortical thinning was detected in RRMS patients, while a widespread CTh reduction was found in PMS patients (significant at time-by-group interaction vs RRMS). In MS, baseline fronto-parietal atrophy correlated with more severe disability and higher lesion volume. Baseline inferior parietal CTh decrease and 1-year temporal cortical thinning correlated with more severe disability. CONCLUSION: Parieto-temporal baseline CTh abnormalities and thinning pattern over time characterized the main MS clinical phenotypes and were associated with 1-year disability worsening.

Two-year dynamic functional network connectivity in clinically isolated syndrome.

BACKGROUND: The features of functional network connectivity reorganization at the earliest stages of MS have not been investigated yet. OBJECTIVE: To combine static and dynamic analysis of resting state (RS) functional connectivity (FC) to identify mechanisms of clinical dysfunction and recovery occurring in clinically isolated syndrome (CIS) patients. METHODS: RS functional magnetic resonance imaging (fMRI) and clinical data were prospectively acquired from 50 CIS patients and 13 healthy controls (HC) at baseline, month 12 and month 24. Between-group differences and longitudinal evolution of network FC were analysed across 41 functionally relevant networks. RESULTS: At follow-up, 47 patients developed MS. Disability remained stable (and relatively low). CIS and HC exhibited two recurring RS FC states (states 1 and 2, showing low and high internetwork connectivity, respectively). At baseline, patients showed reduced state 2 connectivity strength in the default-mode and cerebellar networks, and no differences in global dynamism versus HC. A selective FC reduction in networks affected by the clinical attack was also detected. At follow-up, increased state 2 connectivity strength and global connectivity dynamism was observed in patients versus HC. CONCLUSION: Longitudinal FC modifications occurring relatively early in the course of multiple sclerosis may represent a protective mechanism contributing to preserve clinical function over time.

Characterizing Rapid Fluctuations of Resting State Functional Connectivity in Demyelinating, Neurodegenerative, and Psychiatric Conditions: From Static to Time-Varying Analysis.

Functional magnetic resonance imaging (fMRI) at resting state (RS) has been widely used to characterize the main brain networks. Functional connectivity (FC) has been mostly assessed assuming that FC is static across the whole fMRI examination. However, FC is highly variable at a very fast time-scale, as demonstrated by neurophysiological techniques. Time-varying functional connectivity (TVC) is a novel approach that allows capturing reoccurring patterns of interaction among functional brain networks. Aim of this review is to provide a description of the methods currently used to assess TVC on RS fMRI data, and to summarize the main results of studies applying TVC in healthy controls and patients with multiple sclerosis (MS). An overview of the main results obtained in neurodegenerative and psychiatric conditions is also provided. The most popular TVC approach is based on the so-called "sliding windows," in which the RS fMRI acquisition is divided in small temporal segments (windows). A window of fixed length is shifted over RS fMRI time courses, and data within each window are used to calculate FC and its variability over time. Sliding windows can be combined with clustering techniques to identify recurring FC states or used to assess global TVC properties of large-scale functional networks or specific brain regions. TVC studies have used heterogeneous methodologies so far. Despite this, similar results have been obtained across investigations. In healthy subjects, the default-mode network (DMN) exhibited the highest degree of connectivity dynamism. In MS patients, abnormal global TVC properties and TVC strengths were found mainly in sensorimotor, DMN and salience networks, and were associated with more severe structural MRI damage and with more severe physical and cognitive disability. Conversely, abnormal TVC measures of the temporal network were correlated with better cognitive performances and less severe fatigue. In patients with neurodegenerative and psychiatric conditions, TVC abnormalities of the DMN, attention and executive networks were associated to more severe clinical manifestations. TVC helps to provide novel insights into fundamental properties of functional networks, and improves the understanding of brain reorganization mechanisms. Future technical advances might help to clarify TVC association with disease prognosis and response to treatment.

Abnormal functional connectivity of thalamic sub-regions contributes to fatigue in multiple sclerosis.

OBJECTIVE: To investigate sub-regional thalamic resting-state (RS) functional connectivity (FC) abnormalities in multiple sclerosis (MS) and their correlation with fatigue and its subcomponents (physical, cognitive, and psychosocial). METHODS: From 122 MS patients and 94 healthy controls, 5 thalamic sub-regions (frontal, motor, postcentral, occipital, temporal) were parcellated based on their cortico-thalamic structural connectivity and used for a seed-based RS FC analysis. Abnormalities of thalamic RS FC in MS patients and their correlation with Modified Fatigue Impact Scale (MFIS) were assessed. RESULTS: Compared to controls and non-fatigued MS ( n = 86), fatigued MS patients ( n = 36) showed thalamic RS FC abnormalities with middle frontal gyrus, sensorimotor network, precuneus, insula, and cerebellum, which correlated with global MFIS. Higher thalamic RS FC with precuneus and lower RS FC with posterior cerebellum correlated with cognitive MFIS. Higher thalamic RS FC with sensorimotor network in frontal-, motor-, and temporal thalamic sub-regions correlated with physical and psychosocial MFIS. Reduced thalamic RS FC with right insula in motor-, postcentral-, and occipital thalamic sub-regions correlated with psychosocial fatigue. CONCLUSION: Regional thalamic RS FC abnormalities with different cortical regions, including the frontal lobe, sensorimotor network, precuneus, insular cortices, and cerebellum contribute to fatigue in MS. Abnormal RS FC of selected thalamo-cortical connections explains different components of fatigue.

Elevated plasma fibrinogen levels in multiple sclerosis patients during relapse.

Fibrinogen is a protein that plays a key role in blood coagulation and thrombosis and it is involved in several inflammatory processes; in multiple sclerosis (MS) may be related with blood-brain barrier (BBB) disruption. We analysed the relationship between plasma fibrinogen levels and the presence of active lesions on magnetic resonance imaging (MRI) during relapses of multiple sclerosis (MS) and clinically isolated syndrome (CIS) patients. METHODS: We collected data of patients admitted to a tertiary-care hospital with relapse of MS and CIS from 2008 to 2013 and we analysed the relation between plasma fibrinogen levels (normal: 200mg/dl-417mg/dl) and the presence of active lesions on brain or spinal MRI. RESULTS: A total of 58 patients were included, 45 (77%) CIS patients, 12 (21%) relapsing-remitting MS (RR-MS) and 1 (2%) active progressive MS (P-MS). 17 patients had high plasma fibrinogen levels (> 417mg/dl). Among total of patients with elevated plasma fibrinogen, 15 (88%) had active lesions on MRI and only 2 (12%) did not have active lesion on MRI (p = 0,013) with a specificity of 95%. All patients with fibrinogen > 417mg/dl were CIS (p = < 0.05). DISCUSSION: We observed that high plasma fibrinogen levels had a high specificity high specificity, but low sensitivity (only 40%) for detection of active lesions on MRI during relapses of MS. These findings support the hypothesis that fibrinogen could play an important role on the development of MS lesions, however, additional studies are needed to confirm these results.

Structural connectivity-defined thalamic subregions have different functional connectivity abnormalities in multiple sclerosis patients: Implications for clinical correlations.

In spite of the well-known importance of thalami in multiple sclerosis (MS), only limited data on whole and subregional thalamic functional connectivity (FC) changes are available. Using diffusion tensor imaging, we performed a structural connectivity based thalamic parcellation and investigated subregional thalamic resting-state (RS) FC alterations and their relationship with clinical/cognitive measures in MS. MRI data from a reference set of healthy controls (HC) were used to parcellate the thalami into five subregions, according to their structural connectivity. For each thalamic subregion, a seed-based RS FC analysis was performed in 187 MS patients and 94 HC. Correlations between thalamic RS FC and clinical/cognitive variables were assessed. Compared to HC, MS patients showed increased intra- and inter-thalamic RS FC for almost all thalamic subregions, and increased RS FC between all thalamic subregions and the left insula. Frontal and motor thalamic subregions also showed reduced RS FC with the caudate nucleus. For the temporal thalamic subregion, we observed reduced RS FC with the ipsilateral thalamus, anterior and middle cingulate cortex, and cerebellum. Compared to cognitively preserved, cognitively impaired MS patients had higher thalamic RS FC with several temporal areas. In MS patients, lower RS FC between thalamic subregions and the caudate and cingulate cortex correlated with worse motor performance, whereas higher RS FC with the insula correlated with better motor performance. The main thalamic subregions have different RS-FC abnormalities in MS patients. Increased thalamic RS FC with the insula may have a compensatory role, whereas increased RS FC with temporal areas, observed in patients with cognitive impairment may reflect maladaptive mechanisms. Hum Brain Mapp 38:6005-6018, 2017. © 2017 Wiley Periodicals, Inc.

Hepatotoxicity after high-dose intravenous methylprednisolone in multiple sclerosis patients.

Hepatotoxicity is a rare adverse event of methylprednisolone that should be considered in clinical practice. In patients at risk, we propose liver function surveillance, by measuring hepatic enzymes concentration 15-30 days after methylprednisolone administration. Additionally, we propose ACTH, dexamethasone, or plasma exchange as alternate treatment options for these patients.

Palatal and Oromandibular Tremor Secondary to Degenerative Olivary Hypertrophy After Ependymoma Surgery.

Palatal tremor (PT) is a rare movement disorder that involves pharynx, tongue, and other facial muscles. Symptomatic PT is due to lesions on the dentate-rubro-olivary pathways. We present an illustrative case of PT due to degenerative olivary hypertrophy after ependymoma surgery.