Resting state functional connectivity modifications in monoaminergic circuits underpin fatigue development in patients with multiple sclerosis.

Dysregulation of monoaminergic networks might have a role in the pathogenesis of fatigue in multiple sclerosis (MS). We investigated longitudinal changes of resting state (RS) functional connectivity (FC) in monoaminergic networks and their association with the development of fatigue in MS. Eighty-nine MS patients and 49 age- and sex-matched healthy controls (HC) underwent neurological, fatigue, and RS functional MRI assessment at baseline and after a median follow-up of 1.3 years (interquartile range = 1.01-2.01 years). Monoaminergic-related RS FC was estimated with an independent component analysis constrained to PET atlases for dopamine (DA), noradrenaline (NA), and serotonin (5-HT) transporters. At baseline, 24 (27%) MS patients were fatigued (F) and 65 were not fatigued (NF). Of these, 22 (34%) developed fatigue (DEV-FAT) at follow-up and 43 remained not fatigued (NO-FAT). At baseline, F-MS patients showed increased monoaminergic-related RS FC in the caudate nucleus vs NF-MS and in the hippocampal, postcentral, temporal, and occipital cortices vs NF-MS and HC. Moreover, F-MS patients exhibited decreased RS FC in the frontal cortex vs NF-MS and HC, and in the thalamus vs NF-MS. During the follow-up, no RS FC changes were observed in HC. NO-FAT patients showed limited DA-related RS FC modifications, whereas DEV-FAT MS patients showed increased DA-related RS FC in the left hippocampus, significant at time-by-group interaction analysis. In the NA-related network, NO-FAT patients showed decreased RS FC over time in the left superior frontal gyrus. This region showed increased RS FC in both DEV-FAT and F-MS patients; this divergent behavior was significant at time-by-group interaction analysis. Finally, DEV-FAT MS patients presented increased 5-HT-related RS FC in the angular and middle occipital gyri, while this latter region showed decreased 5-HT-related RS FC during the follow-up in F-MS patients. In MS patients, distinct patterns of alterations were observed in monoaminergic networks based on their fatigue status. Fatigue was closely linked to specific changes in the basal ganglia and hippocampal, superior frontal, and middle occipital cortices.

Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial.

BACKGROUND: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings. METHODS: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task). RESULTS: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula. CONCLUSIONS: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements. TRIAL REGISTRATION NUMBER: NCT03679468.

2.5-Year changes of connectivity dynamism are relevant for physical and cognitive deterioration in multiple sclerosis.

BACKGROUND: In MS, functional connectivity (FC) dynamism may influence disease evolution. OBJECTIVES: The objective is to assess time-varying functional connectivity (TVFC) changes over time at 2.5-year follow-up in MS patients according to physical and cognitive worsening. METHODS: We collected 3T magnetic resonance imaging (MRI) for TVFC assessment (performed using sliding-window analysis of centrality) and clinical evaluations at baseline and 2.5-year follow-up from 28 healthy controls and 129 MS patients. Of these, 79 underwent baseline and follow-up neuropsychological assessment. At 2.5 years, physical/cognitive worsening was defined according to disability/neuropsychological score changes. RESULTS: At follow-up, 25/129 (19.3%) MS patients worsened physically and 14/79 (17.7%) worsened cognitively. At baseline, MS patients showed reduced TVFC versus controls. At 2.5-year follow-up, no TVFC changes were detected in controls. Conversely, TVFC decreased over time in parieto-temporal regions in stable MS patients and in default-mode network in worsened MS. In physically worsened MS, basal ganglia TVFC reductions were also found. Reduced TVFC over time in the putamen in physically worsened and reduced TVFC in the precuneus in cognitively worsened were significant versus stable MS. DISCUSSION: At 2.5-year follow-up, default-mode network TVFC reductions were found in worsening MS. Moreover, reduced deep gray matter TVFC characterized physically worsened patients, whereas precuneus involvement characterized cognitively worsened MS patients.

Discovering functional connectivity features characterizing multiple sclerosis phenotypes using explainable artificial intelligence.

Multiple sclerosis (MS) is a neurological condition characterized by severe structural brain damage and by functional reorganization of the main brain networks that try to limit the clinical consequences of structural burden. Resting-state (RS) functional connectivity (FC) abnormalities found in this condition were shown to be variable across different MS phases, according to the severity of clinical manifestations. The article describes a system exploiting machine learning on RS FC matrices to discriminate different MS phenotypes and to identify relevant functional connections for MS stage characterization. To this end, the system exploits some mathematical properties of covariance-based RS FC representation, which can be described by a Riemannian manifold. The classification performance of the proposed framework was significantly above the chance level for all MS phenotypes. Moreover, the proposed system was successful in identifying relevant RS FC alterations contributing to an accurate phenotype classification.

Emerging Perspectives on MRI Application in Multiple Sclerosis: Moving from Pathophysiology to Clinical Practice.

MRI plays a central role in the diagnosis of multiple sclerosis (MS) and in the monitoring of disease course and treatment response. Advanced MRI techniques have shed light on MS biology and facilitated the search for neuroimaging markers that may be applicable in clinical practice. MRI has led to improvements in the accuracy of MS diagnosis and a deeper understanding of disease progression. This has also resulted in a plethora of potential MRI markers, the importance and validity of which remain to be proven. Here, five recent emerging perspectives arising from the use of MRI in MS, from pathophysiology to clinical application, will be discussed. These are the feasibility of noninvasive MRI-based approaches to measure glymphatic function and its impairment; T1-weighted to T2-weighted intensity ratio to quantify myelin content; classification of MS phenotypes based on their MRI features rather than on their clinical features; clinical relevance of gray matter atrophy versus white matter atrophy; and time-varying versus static resting-state functional connectivity in evaluating brain functional organization. These topics are critically discussed, which may guide future applications in the field.

Monoaminergic network abnormalities: a marker for multiple sclerosis-related fatigue and depression.

OBJECTIVE: To investigate monoaminergic network abnormalities in patients with multiple sclerosis (MS) according to their fatigue and depressive status through a positron emission tomography (PET)-based constrained independent component analysis (ICA) on resting state (RS) functional MRI (fMRI). METHODS: In this prospective study, 213 patients with MS (mean age=40.6±12.5 years; 94/119 men/women; 153 relapsing-remitting; 60 progressive) and 62 healthy controls (HCs, mean age=39.0±10.4 years; 30/32 men/women) underwent neurological, fatigue, depression and RS fMRI assessment. Patterns of dopamine, norepinephrine-related and serotonin-related RS functional connectivity (FC) were derived by ICA, constrained to PET atlases for dopamine, norepinephrine and serotonin transporters, obtained in HCs' brain. RESULTS: Compared with HCs, patients with MS showed abnormalities in all three explored monoaminergic networks, mostly with decreased RS FC within PET-guided monoaminergic networks in frontal regions and subcortical areas including the cerebellum and thalamus, and increased RS FC in temporo-parieto-occipital cortical areas, including bilateral precunei.MS-related fatigue was associated with decreased RS FC within the PET-guided dopamine network in the left thalamus and left cerebellum, and with increased RS FC within the PET-guided serotonin network in the left middle occipital gyrus. MS-related depression was associated with more distributed abnormalities involving the three explored monoaminergic networks, resulting in overall reduced RS FC in the frontal lobe, limbic areas and the precuneus. CONCLUSIONS: Patients with MS present diffuse dysregulation in the monoaminergic networks. Specific alterations in these networks were associated with fatigue and depression, providing a pathological marker for these bothersome symptoms and putative targets for their treatment.

Spinal cord lesions and brain grey matter atrophy independently predict clinical worsening in definite multiple sclerosis: a 5-year, multicentre study.

OBJECTIVES: To evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients. METHODS: Baseline 3.0T brain and cervical cord T2-weighted and three-dimensional T1-weighted MRI was acquired in 367 patients with MS (326 relapse-onset and 41 progressive-onset) and 179 healthy controls. Expanded Disability Status Scale (EDSS) score was obtained at baseline and after a median follow-up of 5.1 years (IQR=4.8-5.2). At follow-up, patients were classified as clinically stable/worsened according to EDSS changes. Generalised linear mixed models identified predictors of clinical worsening, evolution to secondary progressive (SP) MS and reaching EDSS=3.0, 4.0 and 6.0 milestones at 5 years. RESULTS: At follow-up, 120/367 (33%) patients with MS worsened clinically; 36/256 (14%) patients with relapsing-remitting evolved to SPMS. Baseline predictors of EDSS worsening were progressive-onset versus relapse-onset MS (standardised beta (ß)=0.97), higher EDSS (ß=0.41), higher cord lesion number (ß=0.41), lower normalised cortical volume (ß=-0.15) and lower cord area (ß=-0.28) (C-index=0.81). Older age (ß=0.86), higher EDSS (ß=1.40) and cord lesion number (ß=0.87) independently predicted SPMS conversion (C-index=0.91). Predictors of reaching EDSS=3.0 after 5 years were higher baseline EDSS (ß=1.49), cord lesion number (ß=1.02) and lower normalised cortical volume (ß=-0.56) (C-index=0.88). Baseline age (ß=0.30), higher EDSS (ß=2.03), higher cord lesion number (ß=0.66) and lower cord area (ß=-0.41) predicted EDSS=4.0 (C-index=0.92). Finally, higher baseline EDSS (ß=1.87) and cord lesion number (ß=0.54) predicted EDSS=6.0 (C-index=0.91). CONCLUSIONS: Spinal cord damage and, to a lesser extent, cortical volume loss helped predicting worse 5-year clinical outcomes in MS.

Resting state effective connectivity abnormalities of the Papez circuit and cognitive performance in multiple sclerosis.

The Papez circuit is central to memory and emotional processes. However, little is known about its involvement in multiple sclerosis (MS). We aimed to investigate abnormalities of resting state (RS) effective connectivity (EC) between regions of the Papez circuit in MS and their relationship with cognitive performances. Sixty-two MS patients and 64 healthy controls (HC) underwent neuropsychological assessment, 3D T1-weighted, and RS functional MRI. RS EC analysis was performed using SPM12 and dynamic causal modeling. RS EC abnormalities were investigated using parametric empirical Bayes models and were correlated with cognitive scores. Compared to HC, MS patients showed (posterior probability > 0.95) higher EC between the right entorhinal cortex and right subiculum, and lower EC from the anterior cingulate cortex (ACC) to the posterior cingulate cortex (PCC), from left to right subiculum, from left anterior thalamus to ACC, and within ACC and PCC. Lower RS EC from the ACC to the PCC correlated with worse global cognitive scores (rho = 0.19; p = 0.03), worse visuospatial memory (rho = 0.19; p = 0.03) and worse semantic fluency (rho = 0.21; p = 0.02). Lower RS EC from the left to the right subiculum correlated with worse verbal memory (rho = 0.20; p = 0.02), lower RS EC within the ACC correlated with worse attention (rho = -0.19; p = 0.04) and more severe brain atrophy (rho = -0.26; p = 0.003). Higher EC from the right entorhinal cortex to right subiculum correlated with worse semantic fluency (rho = 0.21; p = 0.02). In conclusion, MS patients showed altered RS EC within the Papez circuit. Abnormal RS EC involving cingulate cortices and hippocampal formation contributed to explain cognitive deficits.

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.

Cognitive function in primary and secondary progressive multiple sclerosis: A multiparametric magnetic resonance imaging study.

BACKGROUND AND PURPOSE: The differences in cognitive function between primary progressive and secondary progressive multiple sclerosis (MS) remain unclear. We compared cognitive performance between primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), and explored the structural and functional magnetic resonance imaging (MRI) correlates of their cognitive functions. METHODS: Seventy-five healthy controls and 183 MS patients (60 PPMS and 123 SPMS) underwent 3.0-T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological Tests; cognitive domain z-scores were calculated and then averaged to obtain a measure of global cognition. Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter (WM) fractional anisotropy (FA) and mean diffusivity abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated. RESULTS: PPMS and SPMS had similar z-scores in all investigated cognitive domains. Poor global cognitive function was associated with decreased FA of the medial lemniscus (ΔR 2 = 0.11, p = 0.011) and lower normalized gray matter volume (ΔR 2 = 0.29, p < 0.001) in PPMS, and with decreased FA of the fornix (ΔR 2 = 0.35, p < 0.001) and lower normalized WM volume (ΔR 2 = 0.05; p = 0.034) in SPMS. CONCLUSIONS: PPMS and SPMS had similar neuropsychological performance. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different WM tracts, whereas RS FC alterations did not contribute to explaining their global cognitive functioning.

MRI of Transcallosal White Matter Helps to Predict Motor Impairment in Multiple Sclerosis.

Background Altered callosal integrity has been associated with motor deficits in patients with multiple sclerosis (MS), but its contribution to disability has, to the knowledge of the authors, not been investigated by using multiparametric MRI approaches. Purpose To investigate structural and functional interhemispheric MRI substrates of global disability at different milestones and upper limb motor impairment in MS. Materials and Methods In this cross-sectional study, healthy control patients and patients with MS (between January 1, 2008, and December 31, 2016) were retrospectively selected from our hospital database. Clinical assessment included Expanded Disability Status Scale (EDSS), nine-hole peg test, and digital finger tapping test. By using structural and resting-state functional MRI sequences, probabilistic tractography of hand corticospinal tract fibers, and transcallosal fibers between hand-motor cortices (hereafter, referred to as hand-M1), supplementary motor areas (SMAs), premotor cortices (PMCs), and voxel-mirror homotopic connectivity (VMHC) were analyzed. Random forest analyses identified the MRI predictors of clinical disability at different milestones (EDSS scores of 3.0, 4.0, 6.0) and upper limb motor impairment (nine-hole peg test and finger tapping test z scores < healthy control patients 5th percentile). Results One-hundred thirty healthy control patients (median age, 39 years; interquartile range, 31-50 years; 70 women) and 340 patients with MS (median age, 43 years; interquartile range, 33-51 years; 213 women) were studied. EDSS 3.0 predictors (n = 159) were global measures of atrophy and lesions together with damage measures of corticospinal tracts and transcallosal fibers between PMCs and SMAs (accuracy, 86%; P = .001-.01). For EDSS 4.0 (n = 131), similar predictors were found in addition to damage in transcallosal fibers between hand-M1 (accuracy, 89%; P = .001-.049). No MRI predictors were found for EDSS 6.0 (n = 70). Nine-hole peg test (right, n = 161; left, n = 166) and finger tapping test (right, n = 117; left, n = 111) impairments were predicted by damage in transcallosal fibers between SMAs and PMCs (accuracy range, 69%-77%; P = .001-.049). VMHC abnormalities did not explain clinical outcomes. Conclusion Structural, not functional, abnormalities at MRI in transcallosal premotor and motor white matter fibers predicted severity of global disability and upper limb motor impairment in patients with multiple sclerosis. The informative role of such predictors appeared less evident at higher disability levels. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Barkhof and Pontillo in this issue.

Improved Assessment of Longitudinal Spinal Cord Atrophy in Multiple Sclerosis Using a Registration-Based Approach: Relevance for Clinical Studies.

BACKGROUND: Reliable measurements of cervical cord atrophy progression may be useful for monitoring neurodegeneration in multiple sclerosis (MS). PURPOSE: To compare a new, registration-based (Reg) method with two existing methods (active surface [AS] and propagation segmentation [PropSeg]) to measure cord atrophy changes over time in MS. STUDY TYPE: Retrospective. SUBJECTS: Cohort I: Eight healthy controls (HC) and 28 MS patients enrolled at a single institution, and cohort II: 25 HC and 63 MS patients enrolled at three European sites. FIELD STRENGTH/SEQUENCE: 3D T1-weighted gradient echo sequence, acquired at 1.5 T (cohort I) and 3.0 T (cohort II). ASSESSMENT: Percentage cord area changes (PCACs) between baseline and follow-up (cohort I: 2.34 years [interquartile range = 2.00-2.55 years], cohort II: 1.05 years [interquartile range = 1.01-1.18 years]) were evaluated for all subjects using Reg, AS, and PropSeg. Reg included an accurate registration of baseline and follow-up straightened cord images, followed by AS-based optimized cord segmentation. A subset of studies was analyzed twice by two observers. STATISTICAL TESTS: Linear regression models were used to estimate annualized PCAC, and effect sizes expressed as the ratio between the estimated differences and HC error term (P < 0.05). Reproducibility was assessed by linear mixed-effect models. Annualized PCACs were used for sample size calculations (significance: α = 0.05, power: 1 - ß = 0.80). RESULTS: Annualized PCACs and related standard errors (SEs) were lower with Reg than with other methods: PCAC in MS patients at 1.5 T was -1.12% (SE = 0.22) with Reg, -1.32% (SE = 0.30) with AS, and -1.40% (SE = 0.33) with PropSeg, while at 3.0 T PCAC was -0.83% (SE = 0.25) with Reg, -0.92% (SE = 0.32) with AS, and -1.18 (SE = 0.53) with PropSeg. This was reflected in larger effect sizes and lower sample sizes. Intra- and inter-observer agreement range was 0.72-0.91 with AS, and it was >0.96 with Reg. DATA CONCLUSION: The results support the use of the registration method to measure cervical cord atrophy progression in future MS clinical studies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

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.

Resting state network functional connectivity abnormalities in systemic lupus erythematosus: correlations with neuropsychiatric impairment.

Neuropsychiatric manifestations are highly prevalent in systemic lupus erythematosus (SLE)-patients. We aimed to unravel the substrates of these manifestations by investigating abnormalities of resting state (RS) functional connectivity (FC) and their correlations with neuropsychiatric variables in SLE-patients. Thirty-two SLE-patients and 32 age- and sex-matched healthy controls (HC) underwent brain 3T RS fMRI. Neuropsychological assessment was performed for all SLE-patients. The main large-scale cognitive and psychiatric functional networks were derived and between-group comparisons and correlations with neuropsychological measures were performed. Compared to HC, SLE-patients exhibited increased RS FC in the right middle cingulate cortex and decreased RS FC in the left precuneus within default-mode network (DMN). They also showed increased RS FC in the left cerebellar crus I and left posterior cingulate cortex, and decreased RS FC in the left angular gyrus within working-memory networks (WMN). Compared to HC, SLE-patients exhibited increased RS FC in the left insular cortex and decreased RS FC in the right anterior cingulate cortex within salience network (SN), as well as decreased RS FC in the right middle frontal gyrus within executive-control network (ECN). Correlation analysis indicated a maladaptive role for left angular gyrus and cerebellar RS FC abnormalities in WMN, affecting memory and executive functions; and for precuneus and insular abnormalities in DMN and SN for psychiatric symptoms. Cingulate cortex modifications within DMN and SN correlated with better memory and global cognitive performance. Significant RS FC alterations in relevant cognitive and psychiatric networks occur in SLE-patients and participate in the pathophysiology of neuropsychiatric symptoms.

Time-varying connectivity of the precuneus and its association with cognition and depressive symptoms in neuromyelitis optica: A pilot MRI study.

BACKGROUND: The precuneus is involved in cognition and depression; static functional connectivity (SFC) abnormalities of this region have been observed in neuromyelitis optica spectrum disorders (NMOSD). Time-varying functional connectivity (TVC) underpins dynamic variations of brain connectivity. OBJECTIVE: The aim of this study was to explore precuneus SFC and TVC in NMOSD patients and their associations with neuropsychological features. METHODS: This retrospective study includes 27 NMOSD patients and 30 matched healthy controls undergoing resting state functional magnetic resonance imaging (MRI) and a neuropsychological evaluation of cognitive performance and depressive symptoms. A sliding-window correlation analysis using bilateral precuneus as seed region assessed TVC, which was quantified by the standard deviation of connectivity across windows. Mean connectivity indicated SFC. RESULTS: Compared to controls, patients had reduced SFC between precuneus, temporal lobe, putamen and cerebellum, and reduced TVC between precuneus and prefronto-parietal-temporo-occipital cortices and caudate. Patients also had increased intra-precuneal TVC and increased TVC between the precuneus and the temporal cortex. More severe depressive symptoms correlated with increased TVC between the precuneus and the temporal lobe; worse cognitive performance mainly correlated with higher TVC between the precuneus and the parietal lobe. CONCLUSION: TVC rather than SFC of the precuneus correlates with NMOSD neuropsychological features; different TVC abnormalities underlie depressive symptoms and cognitive impairment.

Functional and structural MRI correlates of executive functions in multiple sclerosis.

BACKGROUND: Executive dysfunctions, including difficulties in attention, working memory, planning, and inhibition affect 15%-28% of multiple sclerosis (MS) patients. OBJECTIVES: To investigate structural and functional magnetic resonance imaging (MRI) abnormalities underlying executive function (EF) in MS patients. METHODS: A total 116 MS patients and 65 controls underwent resting-state (RS) and diffusion-weighted sequences and neuropsychological examination, including Wisconsin Card Sorting Test (WCST) to test EF. Brain RS cognitive networks and fractional anisotropy (FA) from a priori selected white matter tracts were derived. Associations of WCST scores with RS functional connectivity (FC) and FA abnormalities were investigated. RESULTS: In MS patients, predictors of working memory/updating were: lower corpus callosum (CC) FA, lower left working-memory network (WMN), right WMN RS FC for worse performance; lower executive control network (ECN), higher default-mode network (DMN), and salience network (SN) RS FC for better performance (R2 = 0.35). Predictors of attention were lower CC genu FA, lower left WMN, and DMN RS FC for worse performance; higher left WMN and ECN RS FC for better performance (R2 = 0.24). Predictors of worse shifting/inhibition were lower CC genu and superior cerebellar peduncle (SCP) FA, lower left WMN RS FC for worse performance; and higher ECN RS FC for better performance (R2 = 0.24). CONCLUSIONS: CC and SCP microstructural damage and RS FC abnormalities in cognitive networks underlie EF frailty in MS.

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis.

BACKGROUND: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. OBJECTIVE: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. METHODS: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). RESULTS: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 (p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC (p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS (p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 (p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability (r = -0.40/-0.62, p < 0.05, corrected). CONCLUSIONS: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.

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.

Clinical correlates of hypothalamic functional changes in migraine patients.

OBJECTIVE: To elucidate the hypothalamic involvement in episodic migraine and investigate the association between hypothalamic resting state functional connectivity changes and migraine patients' clinical characteristics and disease progression over the years. METHODS: Ninety-one patients with episodic migraine and 73 controls underwent interictal resting state functional magnetic resonance imaging. Twenty-three patients and controls were re-examined after a median of 4.5 years. Hypothalamic resting state functional connectivity changes were investigated using a seed-based correlation approach. RESULTS: At baseline, a decreased functional interaction between the hypothalamus and the parahippocampus, cerebellum, temporal, lingual and orbitofrontal gyrus was found in migraine patients versus controls. Increased resting state functional connectivity between the hypothalamus and bilateral orbitofrontal gyrus was demonstrated in migraine patients at follow-up versus baseline. Migraine patients also experienced decreased right hypothalamic resting state functional connectivity with ipsilateral lingual gyrus. A higher migraine attack frequency was associated with decreased hypothalamic-lingual gyrus resting state functional connectivity at baseline, while greater headache impact at follow-up correlated with decreased hypothalamic-orbitofrontal gyrus resting state functional connectivity at baseline. At follow-up, a lower frequency of migraine attacks was associated with higher hypothalamic-orbitofrontal gyrus resting state functional connectivity. CONCLUSIONS: During the interictal phase, the hypothalamus modulates the activity of pain and visual processing areas in episodic migraine patients. The hypothalamic-cortical interplay changes dynamically over time according to patients' clinical features.

Action observation training promotes motor improvement and modulates functional network dynamic connectivity in multiple sclerosis.

We investigated modifications of resting state dynamic functional network connectivity (dFNC) following a 2-week action observation training (AOT) in 46 right-handed healthy controls (HC) and 41 patients with multiple sclerosis (pwMS) and dominant-hand motor impairment, who were randomized to AOT or control (C) training. PwMS had decreased baseline dFNC versus HC. After training, MS groups improved in right upper limb functions, mainly in AOT, and showed dFNC increase (larger in MS-AOT vs MS-C) in sensorimotor and cognitive networks (p range, ⩽0.001-0.01). Both HC groups showed decreased dFNC over time (p range, ⩽0.001-0.01). Clinical improvements following interventions correlated with sensorimotor and cognitive dFNC changes, suggesting their possible role in motor recovery.