Renato Docimo

Distributed changes in default-mode resting-state connectivity in multiple sclerosis.

Background: The default-mode network (DMN) has been increasingly recognized as relevant to cognitive status. Objectives: To explore DMN changes in patients with relapsing–remitting (RR) multiple sclerosis (MS) and to relate these to the cognitive status. Methods: Eighteen cognitively impaired (CI) and eighteen cognitively preserved (CP) RRMS patients and eighteen healthy controls (HCs), matched for age, sex and education, underwent neuropsychological evaluation and anatomical and resting-state functional MRI (rs-fMRI). DMN functional connectivity was evaluated from rs-fMRI data via independent component analysis. T2 lesion load (LL) was computed by a semi-automatic method and global and local atrophy was estimated by SIENAX and SPM8 voxel-based morphometry analyses from 3D-T1 images. Results: When the whole group of RRMS patients was compared with HCs, DMN connectivity was significantly weaker in the anterior cingulate cortex, whereas it was significantly weaker in the core but stronger at the periphery of the posterior cingulate cortex. These findings were more evident in CP than CI patients. Observed DMN changes did not correlate with global atrophy or T2-LL, but were locally associated with regional grey matter loss. Conclusion: Relapsing–remitting multiple sclerosis patients show a consistent dysfunction of DMN at the level of the anterior node. DMN distribution changes in the posterior node may reflect a possible compensatory effect on cognitive performance.

Visual resting-state network in relapsing-remitting MS with and without previous optic neuritis

Objective: To investigate functional connectivity of the visual resting-state network (V-RSN) in normal-sighted relapsing-remitting multiple sclerosis (RRMS) patients with and without previous optic neuritis (ON). Methods: Thirty normal-sighted RRMS patients, 16 without (nON-MS) and 14 with (ON-MS) previous ON, and 15 age- and sex-matched healthy controls (HCs) underwent a neuro-ophthalmologic evaluation, including automated perimetry and retinal nerve fiber layer (RNFL) measurement, as well as an MRI protocol, including structural and resting-state fMRI (RS-fMRI) sequences. Functional connectivity of the V-RSN was evaluated by independent component analysis (ICA). Regional gray matter atrophy was assessed by voxel-based morphometry (VBM). A correlation analysis was performed between RS-fMRI results and clinical, neuro-ophthalmologic, and structural MRI variables. Results: Compared to HCs, patients with RRMS showed a reduced functional connectivity in the peristriate visual cortex, bilaterally. Compared to nON-MS, ON-MS patients revealed a region of stronger functional connectivity in the extrastriate cortex, at the level of right lateral middle occipital gyrus, as well as a region of reduced functional connectivity at the level of right inferior peristriate cortex. These latter changes correlated with the number of previous ON. All detected V-RSN changes did not colocalize with regional gray matter atrophy. Conclusions: Normal-sighted RRMS patients show a significant functional disconnection in the V-RSN. RRMS patients recovered from a previous ON show a complex reorganization of the V-RSN, including an increased functional connectivity at the level of extrastriate visual areas.

Fatigue in multiple sclerosis: The contribution of occult white matter damage

Background: A functional cortico-subcortical disconnection has been recognized in fatigued multiple sclerosis (MS) patients. Normal appearing white matter (NAWM) damage might contribute to the abovementioned disconnectivity. Objectives: To assess the relationship between fatigue and microstructural NAWM damage in relapsing-remitting (RR) MS. Methods: Sixty RRMS patients and 29 healthy controls (HC) underwent a magnetic resonance imaging (MRI) protocol including diffusion tensor imaging (DTI). Patients with a mean Fatigue Severity Scale (FSS) score ⩾ 4 were considered fatigued (fatigued MS (F-MS)). Tract-based spatial statistics were applied for voxel-wise analysis of DTI indices. A correlation analysis was performed between FSS score and DTI indices in the entire MS group. Results: Thirty MS patients were F-MS. Compared to HC, F-MS patients showed a more extensive NAWM damage than not fatigued MS (NF-MS) patients, with additional damage in the following tracts: frontal and occipital juxtacortical fibers, external capsule, uncinate fasciculus, forceps minor, superior longitudinal fasciculus, cingulum, and pons. No differences were found between F-MS and NF-MS patients. Fatigue severity correlated to DTI abnormalities of corona radiata, cingulum, corpus callosum, forceps minor, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, thalamus and anterior thalamic radiation, cerebral peduncle, and midbrain. Conclusions: Fatigue is associated to a widespread microstructural NAWM damage, particularly in associative tracts connected to frontal lobes.

Default mode network changes in multiple sclerosis: a link between depression and cognitive impairment?

In multiple sclerosis (MS), depression is a common disorder whose pathophysiology is still debated. To gain insights into the pathophysiology of depression in MS, resting‐state (RS) functional connectivity (FC) changes of the default mode network (DMN), salience network (SN) and executive control network (ECN) were assessed in a group of depressed MS (D‐MS) patients and in appropriately matched control groups.

Anxiety in Multiple Sclerosis: Psychometric properties of the State-Trait Anxiety Inventory

The aims of the present study were to examine psychometric properties of the Spielberger State‐Trait Anxiety Inventory (STAI‐Y‐1 and STAI‐Y‐2, respectively) in a Multiple Sclerosis (MS) population and to identify a cut‐off score to detect those MS patients with high level of state and/or trait anxiety who could be more vulnerable to development of depression and/or cognitive defects.

Fatigue in multiple sclerosis: The contribution of resting-state functional connectivity reorganization

Objectives: To investigate resting-state functional connectivity (RS-FC) of the default-mode network (DMN) and of sensorimotor network (SMN) network in relapsing remitting (RR) multiple sclerosis (MS) patients with fatigue (F) and without fatigue(NF). Methods: In all, 59 RRMS patients and 29 healthy controls (HC) underwent magnetic resonance imaging (MRI) protocol including resting-state fMRI (RS-fMRI). Functional connectivity of the DMN and SMN was evaluated by independent component analysis (ICA). A linear regression analysis was performed to explore whether fatigue was mainly driven by changes observed in the DMN or in the SMN. Regional gray matter atrophy was assessed by voxel-based morphometry (VBM). Results: Compared to HC, F-MS patients showed a stronger RS-FC in the posterior cingulate cortex (PCC) and a reduced RS-FC in the anterior cingulated cortex (ACC) of the DMN. F-MS patients, compared to NF-MS patients, revealed (1) an increased RS-FC in the PCC and a reduced RS-FC in the ACC of the DMN and (2) an increased RS-FC in the primary motor cortex and in the supplementary motor cortex of the SMN. The regression analysis suggested that fatigue is mainly driven by RS-FC changes of the DMN. Conclusions: Fatigue in RRMS is mainly associated to a functional rearrangement of non-motor RS networks.

A simple measure of cognitive reserve is relevant for cognitive performance in MS patients

Cognitive reserve (CR) contributes to preserve cognition despite brain damage. This theory has been applied to multiple sclerosis (MS) to explain the partial relationship between cognition and MRI markers of brain pathology. Our aim was to determine the relationship between two measures of CR and cognition in MS. One hundred and forty-seven MS patients were enrolled. Cognition was assessed using the Rao’s Brief Repeatable Battery and the Stroop Test. CR was measured as the vocabulary subtest of the WAIS-R score (VOC) and the number of years of formal education (EDU). Regression analysis included raw score data on each neuropsychological (NP) test as dependent variables and demographic/clinical parameters, VOC, and EDU as independent predictors. A binary logistic regression analysis including clinical/CR parameters as covariates and absence/presence of cognitive deficits as dependent variables was performed too. VOC, but not EDU, was strongly correlated with performances at all ten NP tests. EDU was correlated with executive performances. The binary logistic regression showed that only the Expanded Disability Status Scale (EDSS) and VOC were independently correlated with the presence/absence of CD. The lower the VOC and/or the higher the EDSS, the higher the frequency of CD. In conclusion, our study supports the relevance of CR in subtending cognitive performances and the presence of CD in MS patients.

Neuroimaging in Multiple Sclerosis

Magnetic Resonance Imaging (MRI) is the principal neuroimaging technique applied to Multiple Sclerosis (MS). Since the early 1990s, conventional MRI (c-MRI) has become a fundamental tool for MS diagnosis, management and research (Miller DH, Grossman RI, Reingold SC, McFarland HF (1998) The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1(121):3–24). The distinctive features of c-MRI are its high sensitivity to focal white matter (WM) lesions as well as to infraclinical disease activity which is characterized by the appearance of new lesions in the absence of signs and/or symptoms of clinical relapse. In acknowledging these properties, MS diagnostic criteria have implemented specific c-MRI criteria, so that this technique has been chosen as the main paraclinical tool for supporting and reaching MS diagnosis (McDonald WI, Compston A, Edan G, et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127; Polman CH, Reingold SC, Edan G, et al (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 58:840–846; Polman CH, Reingold SC, Banwell B, et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302). More recently, non-conventional MRI (nc-MRI) techniques have allowed researchers to investigate in vivo the pathophysiology of MS. These techniques have been able to confirm, or even anticipate, results of neuropathological studies showing the presence of diffuse microscopic damage outside focal WM lesions, including normal-appearing WM (NAWM) and gray matter (GM). nc-MRI-derived metrics have also prompted considerable interest since it has been shown that they correlate better with clinical disability scores than those deriving from c-MRI-derived. Finally, functional MRI (fMRI), the most recent and advanced nc-MRI technique, has made it possible to investigate mechanisms of cortical neuroplasticity in MS, reporting very promising results.