Immunomodulators and immunosuppressants for progressive multiple sclerosis: a network meta-analysis.

BACKGROUND: In recent years a broader range of immunomodulatory and immunosuppressive treatment options have emerged for people with progressive forms of multiple sclerosis (PMS). While consensus supports these options as reducing relapses, their relative benefit and safety profiles remain unclear due to a lack of direct comparison trials. OBJECTIVES: To compare through network meta-analysis the efficacy and safety of alemtuzumab, azathioprine, cladribine, cyclophosphamide, daclizumab, dimethylfumarate, diroximel fumarate, fingolimod, fludarabine, glatiramer acetate, immunoglobulins, interferon beta 1-a and beta 1-b, interferon beta-1b (Betaferon), interferon beta-1a (Avonex, Rebif), laquinimod, leflunomide, methotrexate, minocycline, mitoxantrone, mycophenolate mofetil, natalizumab, ocrelizumab, ofatumumab, ozanimod, pegylated interferon beta-1a, ponesimod, rituximab, siponimod, corticosteroids, and teriflunomide for PMS. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase up to August 2022, as well as ClinicalTrials.gov and the WHO ICTRP. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more treatments as monotherapy, compared to placebo or to another active agent, for use in adults with PMS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We performed data synthesis by pair-wise and network meta-analysis. We assessed the certainty of the body of evidence according to GRADE. MAIN RESULTS: We included 23 studies involving a total of 10,167 participants. The most frequent (39% of studies) reason for a rating of high risk of bias was sponsor role in study authorship and data management and analysis. Other concerns were performance, attrition, and selective reporting bias, with 8.7% of studies at high risk of bias for all three of these domains. The common comparator for network analysis was placebo. Relapses over 12 months: assessed in one study (318 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 24 months: assessed in six studies (1622 participants). The number of people with clinical relapses is probably trivially reduced with rituximab (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.19 to 1.95; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Relapses over 36 months: assessed in four studies (2095 participants). The number of people with clinical relapses is probably trivially reduced with interferon beta-1b (RR 0.82, 95% CI 0.73 to 0.93; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 24 months: assessed in 11 studies (5284 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Disability worsening over 36 months: assessed in five studies (2827 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Serious adverse events: assessed in 15 studies (8019 participants). None of the treatments assessed showed moderate or high certainty evidence compared to placebo. Discontinuation due to adverse events: assessed in 21 studies (9981 participants). The number of people who discontinued treatment due to adverse events is trivially increased with interferon beta-1a (odds ratio (OR) 2.93, 95% CI 1.64 to 5.26; high certainty evidence). The number of people who discontinued treatment due to adverse events is probably trivially increased with rituximab (OR 4.00, 95% CI 0.84 to 19.12; moderate certainty evidence); interferon beta-1b (OR 2.98, 95% CI 1.92 to 4.61; moderate certainty evidence); immunoglobulins (OR 1.95, 95% CI 0.99 to 3.84; moderate certainty evidence); glatiramer acetate (OR 3.98, 95% CI 1.48 to 10.72; moderate certainty evidence); natalizumab (OR 1.02, 95% CI 0.55 to 1.90; moderate certainty evidence); siponimod (OR 1.53, 95% CI 0.98 to 2.38; moderate certainty evidence); fingolimod (OR 2.29, 95% CI 1.46 to 3.60; moderate certainty evidence), and ocrelizumab (OR 1.24, 95% CI 0.54 to 2.86; moderate certainty evidence). None of the remaining treatments assessed showed moderate or high certainty evidence compared to placebo. AUTHORS' CONCLUSIONS: The number of people with PMS with relapses is probably slightly reduced with rituximab at two years, and interferon beta-1b at three years, compared to placebo. Both drugs are also probably associated with a slightly higher proportion of withdrawals due to adverse events, as are immunoglobulins, glatiramer acetate, natalizumab, fingolimod, siponimod, and ocrelizumab; we have high confidence that this is the case with interferon beta-1a. We found only low or very low certainty evidence relating to disability progression for the included disease-modifying treatments compared to placebo, largely due to imprecision. We are also uncertain about the effect of interventions on serious adverse events, also because of imprecision. These findings are due in part to the short follow-up of the included RCTs, which lacked detection of less common severe adverse events. Moreover, the funding source of many included studies may have introduced bias into the results. Future research on PMS should include head-to-head rather than placebo-controlled trials, with a longer follow-up of at least three years. Given the relative rarity of PMS, controlled, non-randomised studies on large samples may usefully integrate data from pivotal RCTs. Outcomes valuable and meaningful to people with PMS should be consistently adopted and measured to permit the evaluation of relative effectiveness among treatments.

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis.

BACKGROUND: Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015. OBJECTIVES: To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS. SEARCH METHODS: CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach. MAIN RESULTS: We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.

Combining sodium MRI, proton MR spectroscopic imaging, and intracerebral EEG in epilepsy.

Whole brain ionic and metabolic imaging has potential as a powerful tool for the characterization of brain diseases. We combined sodium MRI (23 Na MRI) and 1 H-MR Spectroscopic Imaging (1 H-MRSI), assessing changes within epileptogenic networks in comparison with electrophysiologically normal networks as defined by stereotactic EEG (SEEG) recordings analysis. We applied a multi-echo density adapted 3D projection reconstruction pulse sequence at 7 T (23 Na-MRI) and a 3D echo-planar spectroscopic imaging sequence at 3 T (1 H-MRSI) in 19 patients suffering from drug-resistant focal epilepsy who underwent presurgical SEEG. We investigated 23 Na MRI parameters including total sodium concentration (TSC) and the sodium signal fraction associated with the short component of T2 * decay (f), alongside the level of metabolites N-acetyl aspartate (NAA), choline compounds (Cho), and total creatine (tCr). All measures were extracted from spherical regions of interest (ROIs) centered between two adjacent SEEG electrode contacts and z-scored against the same ROI in controls. Group comparison showed a significant increase in f only in the epileptogenic zone (EZ) compared to controls and compared to patients' propagation zone (PZ) and non-involved zone (NIZ). TSC was significantly increased in all patients' regions compared to controls. Conversely, NAA levels were significantly lower in patients compared to controls, and lower in the EZ compared to PZ and NIZ. Multiple regression analyzing the relationship between sodium and metabolites levels revealed significant relations in PZ and in NIZ but not in EZ. Our results are in agreement with the energetic failure hypothesis in epileptic regions associated with widespread tissue reorganization.

Validation of Administrative Health Data Algorithms for Identifying Persons with Parkinson's Disease and the 10-Year Prevalence Trend in Bologna, Italy.

INTRODUCTION: Health administrative databases are widely used for the estimation of the prevalence of Parkinson's disease (PD). Few in general, and none used in Italy, have been validated by testing their diagnostic accuracy. The primary objective was to validate two algorithms for the identification of persons with PD using clinical diagnosis as the reference standard on an Italian sample of people with PD. The second objective was to estimate 10-year trends in PD prevalence in the Bologna Local Health Trust from 2010 to 2019. METHODS: Two algorithms (index tests) applied to health administrative databases (hospital discharge, drug prescriptions, exemptions for medical costs) were validated against clinical diagnosis of PD by an expert neurologist (reference standard) in a cohort of consecutive outpatients. Sensitivity and specificity with relative 95% confidence intervals (CIs) were calculated. The prevalence of PD in a specific year was estimated as the ratio between the number of subjects fulfilling any criteria of the algorithm with better diagnostic accuracy and the total population in the same year (×1,000), stratified by age, sex, and district of residence. RESULTS: The two algorithms showed high accuracy for identifying patients with PD: one with greater sensitivity of 94.2% (CI: 88.4-97.6) and the other with greater specificity of 98.1% (CI: 97.7-98.5). For the estimation of prevalence, we chose the most specific algorithm with the fewest total number of misclassified cases. We identified 3,798 people with PD as of December 31, 2019, corresponding to a prevalence of 4.3 per 1,000 inhabitants (CI: 4.2-4.4). Prevalence was higher in males (4.7, CI: 4.5-5.0) than females (3.8, CI: 3.7-4.0) and increased with age. The crude prevalence over time was slightly elevated as it followed a progressive aging of the population. When stratifying the prevalence for age groups, we did not observe a trend except in the 45-64 year category where we observed an increasing trend over time. CONCLUSION: Algorithms based on administrative data are accurate when detecting people with PD in the Italian public health system. In a large northern Italian population, increased prevalence of about 10% was observed in the decade 2010-2019 and is explained by increased life expectancy. These data may be useful in planning the allocation of health care resources for people with PD.

Automatic segmentation of deep grey nuclei using a high-resolution 7T magnetic resonance imaging atlas-Quantification of T1 values in healthy volunteers.

We present a new consensus atlas of deep grey nuclei obtained by shape-based averaging of manual segmentation of two experienced neuroradiologists and optimized from 7T MP2RAGE images acquired at (.6 mm)3 in 60 healthy subjects. A group-wise normalization method was used to build a high-contrast and high-resolution T1 -weighted brain template (.5 mm)3 using data from 30 out of the 60 controls. Delineation of 24 deep grey nuclei per hemisphere, including the claustrum and 12 thalamic nuclei, was then performed by two expert neuroradiologists and reviewed by a third neuroradiologist according to tissue contrast and external references based on the Morel atlas. Corresponding deep grey matter structures were also extracted from the Morel and CIT168 atlases. The data-derived, Morel and CIT168 atlases were all applied at the individual level using non-linear registration to fit the subject reference and to extract absolute mean quantitative T1 values derived from the 3D-MP2RAGE volumes, after correction for residual B1+ biases. Three metrics (the Dice and the volumetric similarity coefficients and a novel Hausdorff distance) were used to estimate the inter-rater agreement of manual MRI segmentation and inter-atlas variability, and these metrics were measured to quantify biases due to image registration, and their impact on the measurements of the quantitative T1 values was highlighted. This represents a fully automated segmentation process permitting the extraction of unbiased normative T1 values in a population of young healthy controls as a reference for characterizing subtle structural alterations of deep grey nuclei relevant to a range of neurological diseases.

Dynamic 23Na MRI - A non-invasive window on neuroglial-vascular mechanisms underlying brain function.

A novel magnetic resonance imaging (MRI) acquisition and reconstruction method for obtaining a series of dynamic sodium 23Na-MRI acquisitions was designed to non-invasively assess the signal variations of brain sodium during a hand motor task in 14 healthy human volunteers on an ultra high field (7T) MR scanner. Regions undergoing activation and deactivation were identified with reference to conventional task-related BOLD functional MRI (fMRI). Activation observed in the left central regions, the supplementary motor areas and the left cerebellum induced an increase in the sodium signal observed at ultra short echo time and a decrease in the 23Na signal observed at long echo time. Based on a simple model of two distinct sodium pools (namely, restricted and mobile sodium), the ultra short echo time measures the totality of sodium whereas the long echo time is mainly sensitive to mobile sodium. This activation pattern is consistent with previously described processes related to an influx of Na+ into the intracellular compartments and a moderate increase in the cerebral blood volume (CBV). In contrast, deactivation observed in the right central regions ipsilateral to the movement, the precuneus and the left cerebellum induced a slight decrease in sodium signal at ultra short echo time and an increase of sodium signal at longer echo times. This inhibitory pattern is compatible with a slight decrease in CBV and an efflux of intracellular Na+ to the extracellular compartments that may reflect neural dendritic spine and astrocytic shrinkage, and an increase of sodium in the extracellular fraction. In conclusion, cerebral dynamic 23Na MRI experiments can provide access to the ionic transients following a functional task occurring within the neuro-glial-vascular ensemble. This has the potential to open up a novel non-invasive window on the mechanisms underlying brain function.

Quantitative Brain Sodium MRI Depicts Corticospinal Impairment in Amyotrophic Lateral Sclerosis.

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that mainly affects the upper and lower motor neurons. Recent sodium (23Na) MRI studies have shown that abnormal sodium concentration is related to neuronal suffering in neurodegenerative conditions. Purpose To use 23Na MRI to investigate abnormal sodium concentrations and map their distribution in the brains of study participants with ALS as compared with healthy control subjects. Materials and Methods Twenty-seven participants with ALS (mean age, 54 years ± 10 [standard deviation], eight women) and 30 healthy control subjects (mean age, 50 years ± 10; 16 women) were prospectively recruited between September 2015 and October 2017 and were examined by using conventional proton MRI and sodium MRI at 3 T. Voxel-based statistical mapping was used to compare quantitative whole-brain total sodium concentration (TSC) maps in participants with ALS with those in control subjects and to localize regions of abnormal elevated TSC. Potential overlap of abnormal elevated TSC with regions of atrophy as detected with 1H MRI also was investigated. Results Voxel-based statistical mapping analyses revealed higher sodium concentration in motor regions (bilateral precentral gyri, corticospinal tracts, and the corpus callosum) of participants with ALS (two-sample t test, P < .005; age and sex as covariates). In these regions, mean TSC was higher in participants with ALS (mean, 45.6 mmol/L wet tissue ± 3.2) than in control subjects (mean, 41.8 mmol/L wet tissue ± 2.7; P < .001; Cohen d = 1.28). Brain regions showing higher TSC represented a volume of 15.4 cm3 that did not overlap with gray matter atrophy occupying a volume of 16.9 cm3. Elevated TSC correlated moderately with corticospinal conduction failure assessed with transcranial magnetic stimulation in the right upper limb (Spearman ρ = -0.57; 95% confidence interval: -0.78, -0.16; P = .005; n = 23). Conclusion Quantitative 23Na MRI is sensitive to alterations of brain sodium homeostasis within disease-relevant regions in patients with amyotrophic lateral sclerosis (ALS). This supports further investigation of abnormal sodium concentration as a potential marker of neurodegenerative processes in patients with ALS that could be used as a secondary endpoint in clinical trials. © RSNA, 2019 Online supplemental material is available for this article.

Metabolic counterparts of sodium accumulation in multiple sclerosis: A whole brain 23Na-MRI and fast 1H-MRSI study.

BACKGROUND: Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. OBJECTIVE: To determine in vivo the metabolic counterpart of brain sodium accumulation. MATERIALS/METHODS: Whole brain 23Na-MR imaging and 3D-1H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T2 lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. RESULTS: MS patients showed significant 23Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; 23Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher 23Na, m-Ins levels with lower NAA in WM T2 lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T2 lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T2 lesions. GM Glx levels were associated with clinical scores. CONCLUSION: Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores.

Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation.

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.

Complementary contributions of concurrent EEG and fMRI connectivity for predicting structural connectivity.

While averaged dynamics of brain function are known to estimate the underlying structure, the exact relationship between large-scale function and structure remains an unsolved issue in network neuroscience. These complex functional dynamics, measured by EEG and fMRI, are thought to arise from a shared underlying structural architecture, which can be measured by diffusion MRI (dMRI). While simulation and data transformation (e.g. graph theory measures) have been proposed to refine the understanding of the underlying function-structure relationship, the potential complementary and/or independent contribution of EEG and fMRI to this relationship is still poorly understood. As such, we explored this relationship by analyzing the function-structure correlation in fourteen healthy subjects with simultaneous resting-state EEG-fMRI and dMRI acquisitions. We show that the combination of EEG and fMRI connectivity better explains dMRI connectivity and that this represents a genuine model improvement over fMRI-only models for both group-averaged connectivity matrices and at the individual level. Furthermore, this model improves the prediction within each resting-state network. The best model fit to underlying structure is mediated by fMRI and EEG-δ connectivity in combination with Euclidean distance and interhemispheric connectivity with more local contributions of EEG-γ at the scale of resting-state networks. This highlights that the factors mediating the relationship between functional and structural metrics of connectivity are context and scale dependent, influenced by topological, geometric and architectural features. It also suggests that fMRI studies employing simultaneous EEG measures may characterize additional and essential parts of the underlying neuronal activity of the resting-state, which might be of special interest for both clinical studies and the investigation of resting-state dynamics.

Brain sodium MRI in human epilepsy: Disturbances of ionic homeostasis reflect the organization of pathological regions.

In light of technical advancements supporting exploration of MR signals other than 1H, sodium (23Na) has received attention as a marker of ionic homeostasis and cell viability. Here, we evaluate for the first time the possibility that 23Na-MRI is sensitive to pathological processes occurring in human epilepsy. A normative sample of 27 controls was used to normalize regions of interest (ROIs) from 1424 unique brain locales on quantitative 23Na-MRI and high-resolution 1H-MPRAGE images. ROIs were based on intracerebral electrodes in ten patients undergoing epileptic network mapping. The stereo-EEG gold standard was used to define regions as belonging to primarily epileptogenic, secondarily irritative and to non-involved regions. Estimates of total sodium concentration (TSC) on 23Na-MRI and cerebrospinal fluid (CSF) on 1H imaging were extracted for each patient ROI, and normalized against the same region in controls. ROIs with disproportionate CSF contributions (ZCSF≥1.96) were excluded. TSC levels were found to be elevated in patients relative to controls except in one patient, who suffered non-convulsive seizures during the scan, in whom we found reduced TSC levels. In the remaining patients, an ANOVA (F1100= 12.37, p<0.0001) revealed a highly significant effect of clinically-defined zones (F1100= 11.13, p<0.0001), with higher normalized TSC in the epileptogenic zone relative to both secondarily irritative (F1100= 11, p=0.0009) and non-involved regions (F1100= 17.8, p<0.0001). We provide the first non-invasive, in vivo evidence of a chronic TSC elevation alongside ZCSF levels within the normative range, associated with the epileptogenic region even during the interictal period in human epilepsy, and the possibility of reduced TSC levels due to seizure. In line with modified homeostatic mechanisms in epilepsy - including altered mechanisms underlying ionic gating, clearance and exchange - we provide the first indication of 23Na-MRI as an assay of altered sodium concentrations occurring in epilepsy associated with the organization of clinically relevant divisions of pathological cortex.

Simultaneous Intracranial EEG-fMRI Shows Inter-Modality Correlation in Time-Resolved Connectivity Within Normal Areas but Not Within Epileptic Regions.

For the first time in research in humans, we used simultaneous icEEG-fMRI to examine the link between connectivity in haemodynamic signals during the resting-state (rs) and connectivity derived from electrophysiological activity in terms of the inter-modal connectivity correlation (IMCC). We quantified IMCC in nine patients with drug-resistant epilepsy (i) within brain networks in 'healthy' non-involved cortical zones (NIZ) and (ii) within brain networks involved in generating seizures and interictal spikes (IZ1) or solely spikes (IZ2). Functional connectivity (h 2 ) estimates for 10 min of resting-state data were obtained between each pair of electrodes within each clinical zone for both icEEG and fMRI. A sliding window approach allowed us to quantify the variability over time of h 2 (vh 2) as an indicator of connectivity dynamics. We observe significant positive IMCC for h 2 and vh 2, for multiple bands in the NIZ only, with the strongest effect in the lower icEEG frequencies. Similarly, intra-modal h 2 and vh 2 were found to be differently modified as a function of different epileptic processes: compared to NIZ, [Formula: see text] was higher in IZ1, but lower in IZ2, while [Formula: see text] showed the inverse pattern. This corroborates previous observations of inter-modal connectivity discrepancies in pathological cortices, while providing the first direct invasive and simultaneous comparison in humans. We also studied time-resolved FC variability multimodally for the first time, finding that IZ1 shows both elevated internal [Formula: see text] and less rich dynamical variability, suggesting that its chronic role in epileptogenesis may be linked to greater homogeneity in self-sustaining pathological oscillatory states.

Nodal approach reveals differential impact of lateralized focal epilepsies on hub reorganization.

The impact of the hemisphere affected by impairment in models of network disease is not fully understood. Among such models, focal epilepsies are characterised by recurrent seizures generated in epileptogenic areas also responsible for wider network dysfunction between seizures. Previous work focusing on functional connectivity within circumscribed networks suggests a divergence of network integrity and compensatory capacity between epilepsies as a function of the laterality of seizure onset. We evaluated the ability of complex network theory to reveal changes in focal epilepsy in global and nodal parameters using graph theoretical analysis of functional connectivity data obtained with resting-state fMRI. Graphs of functional connectivity networks were derived from 19 right and 13 left focal epilepsy patients and 15 controls. Topological metrics (degree, local efficiency, global efficiency and modularity) were computed for a whole-brain, atlas-defined network. We also calculated a hub disruption index for each graph metric, measuring the capacity of the brain network to demonstrate increased connectivity in some nodes for decreased connectivity in others. Our data demonstrate that the patient group as a whole is characterised by network-wide pattern of reorganization, even while global parameters fail to distinguish between groups. Furthermore, multiple metrics indicate that epilepsies with differently lateralized epileptic networks are asymmetric in their burden on functional brain networks; with left epilepsy patients being characterised by reduced efficiency and modularity, while in right epilepsy patients we provide the first evidence that functional brain networks are characterised by enhanced connectivity and efficiency at some nodes whereas reduced in others.

Altered correlation of concurrently recorded EEG-fMRI connectomes in temporal lobe epilepsy.

Whole-brain functional connectivity networks (connectomes) have been characterized at different scales in humans using EEG and fMRI. Multimodal epileptic networks have also been investigated, but the relationship between EEG and fMRI defined networks on a whole-brain scale is unclear. A unified multimodal connectome description, mapping healthy and pathological networks would close this knowledge gap. Here, we characterize the spatial correlation between the EEG and fMRI connectomes in right and left temporal lobe epilepsy (rTLE/lTLE). From two centers, we acquired resting-state concurrent EEG-fMRI of 35 healthy controls and 34 TLE patients. EEG-fMRI data was projected into the Desikan brain atlas, and functional connectomes from both modalities were correlated. EEG and fMRI connectomes were moderately correlated. This correlation was increased in rTLE when compared to controls for EEG-delta/theta/alpha/beta. Conversely, multimodal correlation in lTLE was decreased in respect to controls for EEG-beta. While the alteration was global in rTLE, in lTLE it was locally linked to the default mode network. The increased multimodal correlation in rTLE and decreased correlation in lTLE suggests a modality-specific lateralized differential reorganization in TLE, which needs to be considered when comparing results from different modalities. Each modality provides distinct information, highlighting the benefit of multimodal assessment in epilepsy.

The relationship between resting-state hemodynamic (fMRI) and electrophysiological (EEG) connectivity has been investigated in healthy subjects, but this relationship is unknown in patients with left and right temporal lobe epilepsies (l/rTLE). Does the magnitude of the relationship differ between healthy subjects and patients? What role does the laterality of the epileptic focus play? What are the spatial contributions to this relationship? Here we use concurrent EEG-fMRI recordings of 65 subjects from two centers (35 controls, 34 TLE patients), to assess the correlation between EEG and fMRI connectivity. For all datasets, frequency-specific changes in cross-modal correlation were seen in lTLE and rTLE. EEG and fMRI connectivities do not measure perfectly overlapping brain networks and provide distinct information on brain networks altered in TLE, highlighting the benefit of multimodal assessment to inform about normal and pathological brain function.

Variability by region and method in human brain sodium concentrations estimated by 23Na magnetic resonance imaging: a meta-analysis.

Sodium imaging (23Na-MRI) is of interest in neurological conditions given potential sensitivity to the physiological and metabolic status of tissues. Benchmarks have so far been restricted to parenchyma or grey/white matter (GM/WM). We investigate (1) the availability of evidence, (2) regional pooled estimates and (3) variability attributable to region/methodology. MEDLINE literature search for tissue sodium concentration (TSC) measured in specified 'healthy' brain regions returned 127 reports, plus 278 retrieved from bibliographies. 28 studies met inclusion criteria, including 400 individuals. Reporting variability led to nested data structure, so we used multilevel meta-analysis and a random effects model to pool effect sizes. The pooled mean from 141 TSC estimates was 40.51 mM (95% CI 37.59-43.44; p < 0.001, I2Total=99.4%). Tissue as a moderator was significant (F214 = 65.34, p-val < .01). Six sub-regional pooled means with requisite statistical power were derived. We were unable to consider most methodological and demographic factors sought because of non-reporting, but each factor included beyond tissue improved model fit. Significant residual heterogeneity remained. The current estimates provide an empirical point of departure for better understanding in 23Na-MRI. Improving on current estimates supports: (1) larger, more representative data collection/sharing, including (2) regional data, and (3) agreement on full reporting standards.

Impact of adherence to disease-modifying drugs in multiple sclerosis: A study on Italian real-world data.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system requiring complex diagnostic and therapeutic management. Treatment with Disease Modifying Drugs (DMDs) is aimed at reducing relapse rate and disease disability. Few real-world, population-based data are available on the impact of adherence on relapse rate. The objective of this study was to assess the impact of adherence to DMDs on relapses in a real-world Italian setting. METHODS: Population-based cohort study. People with MS (PwMS) older than 18 years and residing in the Emilia-Romagna region, Northern Italy, were identified through administrative databases using a validated algorithm. A Cox regression model with a time-varying exposure was performed to assess the association between level of adherence to DMDs and relapses over a 5-year period. RESULTS: A total of 2,528 PwMS receiving a first prescription of DMDs between 2015 and 2019 were included (average age of 42, two-thirds female). Highly adherent PwMS had a 25 % lower hazard of experiencing moderate or severe relapses than non-adherent PwMS (Hazard Ratio 0.75, 95 % CI 0.58 to 0.98), after adjusting for age and sex. Several sensitivity analyses supported the main result. CONCLUSION: The results of our study support the hypothesis that a high level of DMD adherence in MS is associated with a lower risk of moderate or severe relapse. Therefore, choosing the DMD with which to start drug treatment and recommending adherence to treatment appear to be crucial aspects involving both physicians and patients.

Identifying unanswered questions and setting the agenda for future systematic research in Multiple Sclerosis. A worldwide, multi-stakeholder Priority Setting project.

BACKGROUND: Eliciting the research priorities of people affected by a condition, carers and health care professionals can increase research value and reduce research waste. The Cochrane Multiple Sclerosis and Rare Disease of CNS Group, in collaboration with the Cochrane Neurological Sciences Field, launched a priority setting exercise with the aim of prioritizing pressing questions to ensure that future systematic reviews are as useful as possible to the people who need them, in all countries, regardless of their economic status. METHOD: Sixteen high priority questions on different aspects of MS were developed by members of a multi-stakeholder priority setting Steering Group (SG). In an anonymous online survey translated into 12 languages researchers, clinicians, people with MS (PwMS) and carers were asked to identify and rank, 5 out of 16 questions as high priority and to provide an explanation for their choice. An additional free-text priority research topic suggestion was allowed. RESULTS: The survey was accessible through MS advocacy associations' social media and Cochrane web pages from October 20, 2020 to February 6, 2021. 1.190 responses (86.73% of all web contacts) were evaluable and included in the analysis. Responses came from 55 countries worldwide, 7 of which provided >75% of respondents and 95% of which were high and upper-middle income countries. 58.8% of respondents live in the EU, 23% in the Americas, 8.9% in the Western Pacific, 2.8% in the Eastern Mediterranean and 0.3% in South Eastern Asia. About 75% of the respondents were PwMS. The five research questions to be answered with the highest priority were: Question (Q)1 "Does MRI help predict disability worsening of PwMS?" (19.9%), Q5 "What are the benefits and harms of treating PwMS with one disease-modifying drug compared to another?" (19.3%), Q3 "Does multidisciplinary care by teams of different social and health professionals improve health outcomes and experiences for PwMS?" (11.9%), Q16 "Does psychological health affect disease progression in PwMS?" (9.2%) and Q10 "What are the benefits and harms of exercise for PwMS?" (7.2%). The multivariable logistic regression analysis indicated a significant influence of geographic area and income level on the ranking of Q1 and a marginal for Q16 as top a priority after accounting for the effect of all other predictors. Approximately 50% of the respondents indicated that they had an important additional suggestion to be considered. CONCLUSION: This international collaborative initiative in the field of MS offers a worldwide perspective on the research questions perceived as pivotal by a geographically representative sample of multiple stakeholders in the field of MS. The results of the survey could guide the prioritization of research on pharmacological and non-pharmacological interventions which could be meaningful and useful for PwMS and carers, avoiding the duplication of efforts and research waste. High quality systematic reviews elicited by priority setting exercises may offer the best available evidence and inform decisions by healthcare providers and policy-makers which can be adapted to the different realities around the world.

Connectivity strength, time lag structure and the epilepsy network in resting-state fMRI.

The relationship between the epilepsy network, intrinsic brain networks and hypersynchrony in epilepsy remains incompletely understood. To converge upon a synthesized understanding of these features, we studied two elements of functional connectivity in epilepsy: correlation and time lag structure using resting state fMRI data from both SEEG-defined epileptic brain regions and whole-brain fMRI analysis. Functional connectivity (FC) was analyzed in 15 patients with epilepsy and 36 controls. Correlation strength and time lag were selected to investigate the magnitude of and temporal interdependency across brain regions. Zone-based analysis was carried out investigating directed correlation strength and time lag between both SEEG-defined nodes of the epilepsy network and between the epileptogenic zone and all other brain regions. Findings were compared between patients and controls and against a functional atlas. FC analysis on the nodal and whole brain levels identifies consistent patterns of altered correlation strength and altered time lag architecture in epilepsy patients compared to controls. These patterns include 1) broadly distributed increased strength of correlation between the seizure onset node and the remainder of the brain, 2) decreased time lag within the seizure onset node, and 3) globally increased time lag throughout all regions of the brain not involved in seizure onset or propagation. Comparing the topographic distribution of findings against a functional atlas, all resting state networks were involved to a variable degree. These local and whole brain findings presented here lead us to propose the network steal hypothesis as a possible mechanistic explanation for the non-seizure clinical manifestations of epilepsy.

Structural Connectivity Alterations in Amyotrophic Lateral Sclerosis: A Graph Theory Based Imaging Study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. Diffusion magnetic resonance imagining (MRI) studies have consistently showed widespread alterations in both motor and non-motor brain regions. However, connectomics and graph theory based approaches have shown inconsistent results. Hub-centered lesion patterns and their impact on local and large-scale brain networks remain to be established. The objective of this work is to characterize topological properties of structural brain connectivity in ALS using an array of local, global and hub-based network metrics. MATERIALS AND METHODS: Magnetic resonance imagining data were acquired from 25 patients with ALS and 26 age-matched healthy controls. Structural network graphs were constructed from diffusion tensor MRI. Network-based statistics (NBS) and graph theory metrics were used to compare structural networks without a priori regions of interest. RESULTS: Patients with ALS exhibited global network alterations with decreased global efficiency (Eglob) (p = 0.03) and a trend of reduced whole brain mean degree (p = 0.05) compared to controls. Six nodes showed significantly decreased mean degree in ALS: left postcentral gyrus, left interparietal and transverse parietal sulcus, left calcarine sulcus, left occipital temporal medial and lingual sulcus, right precentral gyrus and right frontal inferior sulcus (p < 0.01). Hub distribution was comparable between the two groups. There was no selective hub vulnerability or topological reorganization centered on these regions as the hub disruption index (κ) was not significant for the relevant metrics (degree, local efficiency and betweenness centrality). Using NBS, we identified an impaired motor subnetwork of 11 nodes and 10 edges centered on the precentral and the paracentral nodes (p < 0.01). Significant clinical correlations were identified between degree in the frontal area and the disease progression rate of ALS patients (p < 0.01). CONCLUSION: Our study provides evidence that alterations of structural connectivity in ALS are primarily driven by node degree and white matter tract degeneration within an extended network around the precentral and the paracentral areas without hub-centered reorganization.

Distribution of brain sodium long and short relaxation times and concentrations: a multi-echo ultra-high field 23Na MRI study.

Sodium (23Na) MRI proffers the possibility of novel information for neurological research but also particular challenges. Uncertainty can arise in in vivo 23Na estimates from signal losses given the rapidity of T2* decay due to biexponential relaxation with both short (T2*short) and long (T2*long) components. We build on previous work by characterising the decay curve directly via multi-echo imaging at 7 T in 13 controls with the requisite number, distribution and range to assess the distribution of both in vivo T2*short and T2*long and in variation between grey and white matter, and subregions. By modelling the relationship between signal and reference concentration and applying it to in vivo 23Na-MRI signal, 23Na concentrations and apparent transverse relaxation times of different brain regions were measured for the first time. Relaxation components and concentrations differed substantially between regions of differing tissue composition, suggesting sensitivity of multi-echo 23Na-MRI toward features of tissue composition. As such, these results raise the prospect of multi-echo 23Na-MRI as an adjunct source of information on biochemical mechanisms in both physiological and pathophysiological states.