Stimulus-related modulation in the 1/f spectral slope suggests an impaired inhibition during a working memory task in people with multiple sclerosis.

BACKGROUND: An imbalance of excitatory and inhibitory synaptic transmission in multiple sclerosis (MS) may lead to cognitive impairment, such as impaired working memory. The 1/f slope of electroencephalography/magnetoencephalography (EEG/MEG) power spectra is shown to be a non-invasive proxy of excitation/inhibition balance. A flatter slope is associated with higher excitation/lower inhibition. OBJECTIVES: To assess the 1/f slope modulation induced by stimulus and its association with behavioral and cognitive measures. METHODS: We analyzed MEG recordings of 38 healthy controls (HCs) and 79 people with multiple sclerosis (pwMS) while performing an n-back task including target and distractor stimuli. Target trials require an answer, while distractor trials do not. We computed the 1/f spectral slope through the fitting oscillations and one over f (FOOOF) algorithm within the time windows 1 second before and after each stimulus presentation. RESULTS: We observed a flatter 1/f slope after distractor stimuli in pwMS compared to HCs. The 1/f slope was significantly steeper after stimulus for both HCs and pwMS and was significantly correlated with reaction times. This modulation in 1/f slope was significantly correlated with visuospatial memory assessed by the BVMT-R test. CONCLUSION: Our results suggest possible inhibitory mechanism deficits in pwMS during a working memory task.

The Finger Dexterity Test: Validation study of a smartphone-based manual dexterity assessment.

BACKGROUND: The Nine-Hole Peg Test (9HPT) is the golden standard to measure manual dexterity in people with multiple sclerosis (MS). However, administration requires trained personnel and dedicated time during a clinical visit. OBJECTIVES: The objective of this study is to validate a smartphone-based test for remote manual dexterity assessment, the icompanion Finger Dexterity Test (FDT), to be included into the icompanion application. METHODS: A total of 65 MS and 81 healthy subjects were tested, and 20 healthy subjects were retested 2 weeks later. RESULTS: The FDT significantly correlated with the 9HPT (dominant: ρ = 0.62, p < 0.001; non-dominant: ρ = 0.52, p < 0.001). MS subjects had significantly higher FDT scores than healthy subjects (dominant: p = 0.015; non-dominant: p = 0.013), which was not the case for the 9HPT. A significant correlation with age (dominant: ρ = 0.46, p < 0.001; non-dominant: ρ = 0.40, p = 0.002), Expanded Disability Status Scale (EDSS, dominant: ρ = 0.36, p = 0.005; non-dominant: ρ = 0.31, p = 0.024), and disease duration for the non-dominant hand (ρ = 0.31, p = 0.016) was observed. There was a good test-retest reliability in healthy subjects (dominant: r = 0.69, p = 0.001; non-dominant: r = 0.87, p < 0.001). CONCLUSIONS: The icompanion FDT shows a moderate-to-good concurrent validity and test-retest reliability, differentiates between the MS subjects and healthy controls, and correlates with clinical parameters. This test can be implemented into routine MS care for remote follow-up of manual dexterity.

Clinical effectiveness of coronavirus disease 2019 vaccination in patients with multiple sclerosis stratified by disease-modifying treatment.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were concurrently on disease-modifying treatment (DMT) with B-cell depleting agents or sphingosine-1-phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID-19 vaccination. METHODS: Since March 2020, demographics and clinical data of patients with MS who developed COVID-19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be 'protected by vaccination' if they were (i) fully vaccinated and (ii) tested positive for COVID-19 in the period ranging from 14 days to 6 months after the last administered vaccine. RESULTS: On 19 December 2022, 418 COVID-19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being 'unprotected by vaccination' was significantly associated with a worse COVID-19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio [OR] 3.96), in patients on ongoing DMT other than anti-CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti-CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis. CONCLUSIONS: Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B-cell depleting agents.

The spectral slope as a marker of excitation/inhibition ratio and cognitive functioning in multiple sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission and potentially cognitive impairment. Current methods for measuring the excitation/inhibition (E/I) ratio are mostly invasive, but recent research combining neurocomputational modeling with measurements of local field potentials has indicated that the slope with which the power spectrum of neuronal activity captured by electro- and/or magnetoencephalography rolls off, is a non-invasive biomarker of the E/I ratio. A steeper roll-off is associated with a stronger inhibition. This novel method can be applied to assess the E/I ratio in people with multiple sclerosis (pwMS), detect the effect of medication such as benzodiazepines, and explore its utility as a biomarker for cognition. We recruited 44 healthy control subjects and 95 pwMS who underwent resting-state magnetoencephalographic recordings. The 1/f spectral slope of the neural power spectra was calculated for each subject and for each brain region. As expected, the spectral slope was significantly steeper in pwMS treated with benzodiazepines (BZDs) compared to pwMS not receiving BZDs (p = .01). In the sub-cohort of pwMS not treated with BZDs, we observed a steeper slope in cognitively impaired pwMS compared to cognitively preserved pwMS (p = .01) and healthy subjects (p = .02). Furthermore, we observed a significant correlation between 1/f spectral slope and verbal and spatial working memory functioning in the brain regions located in the prefrontal and parietal cortex. In this study, we highlighted the value of the spectral slope in MS by quantifying the effect of benzodiazepines and by putting it forward as a potential biomarker of cognitive deficits in pwMS.

Reduced alpha2 power is associated with slowed information processing speed in multiple sclerosis.

OBJECTIVE: Cognitive impairment is common in multiple sclerosis (MS), significantly impacts daily functioning, is time-consuming to assess, and is prone to practice effects. We examined whether the alpha band power measured with magnetoencephalography (MEG) is associated with the different cognitive domains affected by MS. METHODS: Sixty-eight MS patients and 47 healthy controls underwent MEG, T1- and FLAIR-weighted magnetic resonance imaging (MRI), and neuropsychological testing. Alpha power in the occipital cortex was quantified in the alpha1 (8-10 Hz) and alpha2 (10-12 Hz) bands. Next, we performed best subset regression to assess the added value of neurophysiological measures to commonly available MRI measures. RESULTS: Alpha2 power significantly correlated with information processing speed (p < 0.001) and was always retained in all multilinear models, whereas thalamic volume was retained in 80% of all models. Alpha1 power was correlated with visual memory (p < 0.001) but only retained in 38% of all models. CONCLUSIONS: Alpha2 (10-12 Hz) power in rest is associated with IPS, independent of standard MRI parameters. This study stresses that a multimodal assessment, including structural and functional biomarkers, is likely required to characterize cognitive impairment in MS. Resting-state neurophysiology is thus a promising tool to understand and follow up changes in IPS.

Associating Alzheimer's disease pathology with its cerebrospinal fluid biomarkers.

Alzheimer's disease CSF biomarkers 42 amino acid long amyloid-ß peptide (Aß1-42), total tau protein (T-tau), and tau protein phosphorylated at threonine 181 (P-tau181) are considered surrogate biomarkers of Alzheimer's disease pathology, and significantly improve diagnostic accuracy. Their ability to reflect neuropathological changes later in the disease course is not well characterized. This study aimed to assess the potential of CSF biomarkers measured in mid to late stage Alzheimer's disease to reflect post-mortem neuropathological changes. Individuals were selected from two autopsy cohorts of Alzheimer's disease patients in Antwerp and Amsterdam. Neuropathological diagnosis was performed according to the updated consensus National Institute on Aging-Alzheimer's Association guidelines, which includes quantification of amyloid-ß plaque, neurofibrillary tangle, and neuritic plaque load. CSF samples were analysed for Aß1-42, T-tau, and P-tau181 by ELISA. One hundred and fourteen cases of pure definite Alzheimer's disease were included in the study (mean age 74 years, disease duration 6 years at CSF sampling, 50% females). Median interval between CSF sampling and death was 1 year. We found no association between Aß1-42 and Alzheimer's disease neuropathological change profile. In contrast, an association of P-tau181 and T-tau with Alzheimer's disease neuropathological change profile was observed. P-tau181 was associated with all three individual Montine scores, and the associations became stronger and more significant as the interval between lumbar puncture and death increased. T-tau was also associated with all three Montine scores, but in individuals with longer intervals from lumbar puncture to death only. Stratification of the cohort according to APOE ε4 carrier status revealed that the associations applied mostly to APOE ε4 non-carriers. Our data suggest that similar to what has been reported for Aß1-42, plateau levels of P-tau181 and T-tau are reached during the disease course, albeit at later disease stages, reducing the potential of tau biomarkers to monitor Alzheimer's disease pathology as the disease progresses. As a consequence, CSF biomarkers, which are performant for clinical diagnosis of early Alzheimer's disease, may not be well suited for staging or monitoring Alzheimer's disease pathology as it progresses through later stages.

Plasma glial fibrillary acidic protein and neurofilament light chain in relation to disability worsening in multiple sclerosis.

BACKGROUND: Predicting disability worsening in multiple sclerosis (MS) remains an important challenge. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) seem promising biomarkers. Studies investigating blood GFAP in relation to longitudinal outcome measures in MS are scarce. OBJECTIVE: To compare plasma-GFAP (p-GFAP) and plasma-NfL (p-NfL) levels in relation to sustained disability worsening. METHODS: We measured baseline p-GFAP and p-NfL in a prospective cohort of 115 individuals with MS and 30 matched controls, using Single Molecule Array (Simoa). Disability worsening was defined as an increase in at least one of three measures (Expanded Disability Status Scale, Timed 25-foot walk, 9-Hole Peg test), confirmed after 6 months and persistent upon data closure. RESULTS: In a multivariable Cox proportional-hazards model, p-GFAP was not significantly associated with sustained disability worsening after 4.40 ± 0.82 years, while p-NfL (HR = 1.046, p = 0.001), EDSS (HR = 1.24, p = 0.039), and disease duration (HR = 1.048, p = 0.017) were. Area under the curve of ROC curves in relation to worsening was 0.61 for p-GFAP (p = 0.031) and 0.63 for p-NfL (p = 0.015). Kaplan-Meier curves showed similar patterns for both proteins. CONCLUSION: p-NfL emerged as a significant explanatory variable for worsening in Cox regression analysis, and p-GFAP did not. Both p-GFAP and p-NfL were related to worsening based on ROC curves.

Higher susceptibility to 6 Hz corneal kindling and lower responsiveness to antiseizure drugs in mouse models of Alzheimer's disease.

OBJECTIVE: Epileptic spikes and seizures seem present early in the disease process of Alzheimer's disease (AD). However, it is unclear how soluble and insoluble amyloid beta (Aß) and tau proteins affect seizure development in vivo. We aim to contribute to this field by assessing the vulnerability to 6 Hz corneal kindling of young female mice from two well-characterized transgenic AD models and by testing their responsiveness to selected antiseizure drugs (ASDs). METHODS: We used 7-week-old triple transgenic (3xTg) mice that have both amyloid and tau mutations, and amyloid precursor protein Swedish/presenillin 1 dE9 (APP/PS1) mice, bearing only amyloid-related mutations. We assessed the absence of plaques via immunohistochemistry and analyzed the concentrations of both soluble and insoluble forms of Aß1-42 and total tau (t-tau) in brain hippocampal and prefrontal cortical tissue. Seven-week-old mice of the different genotypes were subjected to the 6 Hz corneal kindling model. After kindling acquisition, we tested the anticonvulsant effects of three marketed ASDs (levetiracetam, brivaracetam, and lamotrigine) in fully kindled mice. RESULTS: No Aß plaques were present in either genotype. Soluble Aß1-42 levels were increased in both AD genotypes, whereas insoluble Aß1-42 concentrations were only elevated in APP/PS1 mice compared with their respective controls. Soluble and insoluble forms of t-tau were increased in 3xTg mice only. 3xTg and APP/PS1 mice displayed more severe seizures induced by 6 Hz corneal kindling from the first stimulation onward and were more rapidly kindled compared with control mice. In fully kindled AD mice, ASDs had less-pronounced anticonvulsive effects compared with controls. SIGNIFICANCE: Mutations increasing Aß only or both Aß and tau in the brain enhance susceptibility for seizures and kindling in mice. The effect of ASDs on seizures measured by the Racine scale is less pronounced in both investigated AD models and suggests that seizures of young AD mice are more difficult to treat.

Brain age as a surrogate marker for cognitive performance in multiple sclerosis.

BACKGROUND AND PURPOSE: Data from neuro-imaging techniques allow us to estimate a brain's age. Brain age is easily interpretable as 'how old the brain looks' and could therefore be an attractive communication tool for brain health in clinical practice. This study aimed to investigate its clinical utility by investigating the relationship between brain age and cognitive performance in multiple sclerosis (MS). METHODS: A linear regression model was trained to predict age from brain magnetic resonance imaging volumetric features and sex in a healthy control dataset (HC_train, n = 1673). This model was used to predict brain age in two test sets: HC_test (n = 50) and MS_test (n = 201). Brain-predicted age difference (BPAD) was calculated as BPAD = brain age minus chronological age. Cognitive performance was assessed by the Symbol Digit Modalities Test (SDMT). RESULTS: Brain age was significantly related to SDMT scores in the MS_test dataset (r = -0.46, p < 0.001) and contributed uniquely to variance in SDMT beyond chronological age, reflected by a significant correlation between BPAD and SDMT (r = -0.24, p < 0.001) and a significant weight (-0.25, p = 0.002) in a multivariate regression equation with age. CONCLUSIONS: Brain age is a candidate biomarker for cognitive dysfunction in MS and an easy to grasp metric for brain health.

Identifying neural signatures mediating behavioral symptoms and psychosis onset: High-dimensional whole brain functional mediation analysis.

Along the pathway from behavioral symptoms to the development of psychotic disorders sits the multivariate mediating brain. The functional organization and structural topography of large-scale multivariate neural mediators among patients with brain disorders, however, are not well understood. Here, we design a high-dimensional brain-wide functional mediation framework to investigate brain regions that intermediate between baseline behavioral symptoms and future conversion to full psychosis among individuals at clinical high risk (CHR). Using resting-state functional magnetic resonance imaging (fMRI) data from 263 CHR subjects, we extract an α brain atlas and a ß brain atlas: the former underlines brain areas associated with prodromal symptoms and the latter highlights brain areas associated with disease onset. In parallel, we identify and separate mediators that potentially positively and negatively mediate symptoms and psychosis, respectively, and quantify the effect of each neural mediator on disease development. Taken together, these results paint a brain-wide picture of neural markers that are potentially mediating behavioral symptoms and the development of psychotic disorders; additionally, they underscore a statistical framework that is useful to uncover large-scale intermediating variables in a regulatory biological system.

The role of hippocampal theta oscillations in working memory impairment in multiple sclerosis.

Working memory (WM) problems are frequently present in people with multiple sclerosis (MS). Even though hippocampal damage has been repeatedly shown to play an important role, the underlying neurophysiological mechanisms remain unclear. This study aimed to investigate the neurophysiological underpinnings of WM impairment in MS using magnetoencephalography (MEG) data from a visual-verbal 2-back task. We analysed MEG recordings of 79 MS patients and 38 healthy subjects through event-related fields and theta (4-8 Hz) and alpha (8-13 Hz) oscillatory processes. Data was source reconstructed and parcellated based on previous findings in the healthy subject sample. MS patients showed a smaller maximum theta power increase in the right hippocampus between 0 and 400 ms than healthy subjects (p = .014). This theta power increase value correlated negatively with reaction time on the task in MS (r = -.32, p = .029). Evidence was provided that this relationship could not be explained by a 'common cause' confounding relationship with MS-related neuronal damage. This study provides the first neurophysiological evidence of the influence of hippocampal dysfunction on WM performance in MS.

Brain dysconnectivity relates to disability and cognitive impairment in multiple sclerosis.

The pathophysiology of cognitive dysfunction in multiple sclerosis (MS) is still unclear. This magnetoencephalography (MEG) study investigates the impact of MS on brain resting-state functional connectivity (rsFC) and its relationship to disability and cognitive impairment. We investigated rsFC based on power envelope correlation within and between different frequency bands, in a large cohort of participants consisting of 99 MS patients and 47 healthy subjects. Correlations were investigated between rsFC and outcomes on disability, disease duration and 7 neuropsychological scores within each group, while stringently correcting for multiple comparisons and possible confounding factors. Specific dysconnections correlating with MS-induced physical disability and disease duration were found within the sensorimotor and language networks, respectively. Global network-level reductions in within- and cross-network rsFC were observed in the default-mode network. Healthy subjects and patients significantly differed in their scores on cognitive fatigue and verbal fluency. Healthy subjects and patients showed different correlation patterns between rsFC and cognitive fatigue or verbal fluency, both of which involved a shift in patients from the posterior default-mode network to the language network. Introducing electrophysiological rsFC in a regression model of verbal fluency and cognitive fatigue in MS patients significantly increased the explained variance compared to a regression limited to structural MRI markers (relative thalamic volume and lesion load). This MEG study demonstrates that MS induces distinct changes in the resting-state functional brain architecture that relate to disability, disease duration and specific cognitive functioning alterations. It highlights the potential value of electrophysiological intrinsic rsFC for monitoring the cognitive impairment in patients with MS.

Sativex® (nabiximols) cannabinoid oromucosal spray in patients with resistant multiple sclerosis spasticity: the Belgian experience.

BACKGROUND: This retrospective study evaluates patient-reported outcomes in patients with multiple sclerosis (MS) spasticity who were treated with a cannabinoid oromucosal spray (Sativex®, USAN name: nabiximols) after not sufficiently responding to previous anti-spasticity medications. METHODS: Of 276 patients from eight centers in Belgium who began treatment prior to 31 December 2017, effectiveness assessment data were available for 238 patients during the test period of 4 to 8/12 weeks, and for smaller patient cohorts with continued treatment for 6/12 months. RESULTS: Mean 0-10 spasticity Numerical Rating Scale (NRS) scores improved from 8.1 at baseline to 5.2 (week 4), 4.6 (week 8) and 4.1 (week 12). Mean EuroQoL Visual Analogue Scale (EQ VAS) scores increased from 39 at baseline to 52 (week 4), 57 (week 8) and 59 (week 12). Mean NRS and EQ VAS scores remained in the same 12 weeks' range in patients with longer-term data. The average dose of cannabinoid oromucosal spray was 6 sprays/day. Most of the 93 out of 276 patients, with initial prescription (33.7%), who discontinued treatment by week 12 did so within the first 8 weeks, mainly due to lack of effectiveness. By week 12, 171 (74%) of the 230 effectiveness evaluable patients reported a clinically meaningful response, corresponding to ≥30% NRS improvement. The tolerability of cannabinoid oromucosal spray was consistent with its known safety profile. CONCLUSIONS: More than 60% of the patients with MS who started add-on treatment with cannabinoid oromucosal spray reported a clinically relevant symptomatic effect and continued treatment after 12 weeks.

Spatiotemporal and spectral dynamics of multi-item working memory as revealed by the n-back task using MEG.

Multi-item working memory (WM) is a complex cognitive function thought to arise from specific frequency band oscillations and their interactions. While some theories and consistent findings have been established, there is still a lot of unclarity about the sources, temporal dynamics, and roles of event-related fields (ERFs) and theta, alpha, and beta oscillations during WM activity. In this study, we performed an extensive whole-brain ERF and time-frequency analysis on n-back magnetoencephalography data from 38 healthy controls. We identified the previously unknown sources of the n-back M300, the right inferior temporal and parahippocampal gyrus and left inferior temporal gyrus, and frontal theta power increase, the orbitofrontal cortex. We shed new light on the role of the precuneus during n-back activity, based on an early ERF and theta power increase, and suggest it to be a crucial link between lower-level and higher-level information processing. In addition, we provide strong evidence for the central role of the hippocampus in multi-item WM behavior through the dynamics of theta and alpha oscillatory changes. Almost simultaneous alpha power decreases observed in the hippocampus and occipital fusiform gyri, regions known to be involved in letter processing, suggest that these regions together enable letter recognition, encoding and storage in WM. In summary, this study offers an extensive investigation into the spatial, temporal, and spectral characteristics of n-back multi-item WM activity.

Feasibility of Real Time Internet-Based Teleconsultation in Patients With Multiple Sclerosis: Interventional Pilot Study.

BACKGROUND: Telemedicine (TM) is currently flourishing in rural and emergency settings, but its implementation in the routine management of chronic neurological disorders has developed with more hesitation. Limited access to specialized care facilities and expanding patient populations, combined with unprecedented mobility restrictions imposed by the coronavirus disease pandemic, are currently stressing the need for remote solutions in this field. Studies in patients with multiple sclerosis (MS) have been heterogeneous in objectives and methodology but generally support the concept that TM interventions produce clinical benefits, cost-effectiveness, and user satisfaction. Nonetheless, data on live interaction between patients and health care providers for MS teleconsultation purposes remain scarce. OBJECTIVE: The aim of this study is to demonstrate the feasibility of planned real time audiovisual teleconsultation over the internet for patients with MS. METHODS: A total of 20 patients with MS presenting at a specialized MS center in Belgium were recruited for this study. One teleconsultation was scheduled for each participant. Patients were provided a unique hyperlink by mail in advance, leading them automatically and directly to the virtual waiting room, where they could accept or decline our incoming call. All teleconsultations were performed by a trained medical student with the intention to keep the conversation similar to what is usually discussed during a classic face-to-face MS consultation; no remote physical exams were performed. The approach was considered feasible if at least 80% of the planned TM visits could be successfully completed at the foreseen moment. Patient satisfaction (technical quality, convenience, and overall quality of care) was evaluated at the end of each teleconsultation by means of 5-point Likert scales containing the categories very unsatisfied, unsatisfied, neutral, satisfied, and highly satisfied. RESULTS: Out of 20 consultations, 17 were successfully completed (85%). Failures were due to patients not responding (n=2) and technical issues (n=1). Out of the 17 consultations, 17 patients declared themselves satisfied or highly satisfied for technical quality, 15 patients for convenience, and 16 patients for overall quality of care. CONCLUSIONS: Planned real time audiovisual teleconsultation over the internet is feasible and highly appreciated in patients with MS. Incorporation of such services in routine clinical MS practice is expected to improve access to specialized care facilities for affected patients.

Cortical Mapping in Conventional and High Dose Spinal Cord Stimulation: An Exploratory Power Spectrum and Functional Connectivity Analysis With Electroencephalography.

OBJECTIVES: Spinal cord stimulation (SCS) is considered an effective pain-relieving treatment for patients with Failed Back Surgery Syndrome (FBSS). Despite the clinical effectiveness, it is unknown whether the altered functional connectivity in such patients, as compared to healthy persons, can be influenced by SCS. Therefore, the goal of this study is to evaluate whether brain connectivity assessed by EEG differs between baseline and SCS in patients with FBSS. MATERIALS AND METHODS: Eight patients with FBSS underwent a resting-state EEG protocol before SCS, 1.5 months and 2.5 months after receiving SCS. At each frequency band, power spectrums were compared for no SCS, conventional (CON) SCS and High Dose (HD) SCS. Functional connectivity, with the aid of eConnectome was also calculated. RESULTS: Significant differences in the average power density spectrum over the whole scalp were observed between no SCS, CON SCS and HD SCS in delta, theta and beta frequency bands (p < 0.01). The average power spectrum for CON SCS was significantly lower than the average power spectrum for HD SCS. Marked increases in strength of the information flow between electrode pair FC3-TP9 in the beta frequency band (p = 0.006) were found in favor of HD SCS. CONCLUSIONS: The differences in power spectrum and connectivity between the three conditions lead to the hypothesis that HD SCS differs from CON SCS on average power spectrum, suggesting that HD SCS may have a higher contribution on the excitatory bottom-up pathway.

Do the posterior midline cortices belong to the electrophysiological default-mode network?

The default-mode network (DMN) and its principal core hubs in the posterior midline cortices (PMC), i.e., the precuneus and the posterior cingulate cortex, play a critical role in the human brain structural and functional architecture. Because of their centrality, they are affected by a wide spectrum of brain disorders, e.g., Alzheimer's disease. Non-invasive electrophysiological techniques such as magnetoencephalography (MEG) are crucial to the investigation of the neurophysiology of the DMN and its alteration by brain disorders. However, MEG studies relying on band-limited power envelope correlation diverge in their ability to identify the PMC as a part of the DMN in healthy subjects at rest. Since these works were based on different MEG recording systems and different source reconstruction pipelines, we compared DMN functional connectivity estimated with two distinct MEG systems (Elekta, now MEGIN, and CTF) and two widely used reconstruction algorithms (Minimum Norm Estimation and linearly constrained minimum variance Beamformer). Our results identified the reconstruction method as the critical factor influencing PMC functional connectivity, which was significantly dampened by the Beamformer. On this basis, we recommend that future electrophysiological studies on the DMN should rely on Minimum Norm Estimation (or close variants) rather than on the classical Beamformer. Crucially, based on analytic knowledge about these two reconstruction algorithms, we demonstrated with simulations that this empirical observation could be explained by the existence of a spontaneous linear, approximately zero-lag synchronization structure between areas of the DMN or among multiple sources within the PMC. This finding highlights a novel property of the neural dynamics and functional architecture of a core human brain network at rest.

Altered transient brain dynamics in multiple sclerosis: Treatment or pathology?

Multiple sclerosis (MS) is a demyelinating, neuroinflammatory, and -degenerative disease that affects the brain's neurophysiological functioning through brain atrophy, a reduced conduction velocity and decreased connectivity. Currently, little is known on how MS affects the fast temporal dynamics of activation and deactivation of the different large-scale, ongoing brain networks. In this study, we investigated whether these temporal dynamics are affected in MS patients and whether these changes are induced by the pathology or by the use of benzodiazepines (BZDs), an important symptomatic treatment that aims at reducing insomnia, spasticity and anxiety and reinforces the inhibitory effect of GABA. To this aim, we employed a novel method capable of detecting these fast dynamics in 90 MS patients and 46 healthy controls. We demonstrated a less dynamic frontal default mode network in male MS patients and a reduced activation of the same network in female MS patients, regardless of BZD usage. Additionally, BZDs strongly altered the brain's dynamics by increasing the time spent in the deactivating sensorimotor network and the activating occipital network. Furthermore, BZDs induced a decreased power in the theta band and an increased power in the beta band. The latter was strongly expressed in those states without activation of the sensorimotor network. In summary, we demonstrate gender-dependent changes to the brain dynamics in the frontal DMN and strong effects from BZDs. This study is the first to characterise the effect of multiple sclerosis and BZDs in vivo in a spatially, temporally and spectrally defined way.

Single MRI-Based Volumetric Assessment in Clinical Practice Is Associated With MS-Related Disability.

BACKGROUND: The added value of brain volume measurements in the clinical practice of multiple sclerosis (MS) has been questioned. PURPOSE: To investigate the contribution of volume measures obtained with magnetic resonance scans performed as part of regular care to predict measures of cognitive and physical MS disability in a real-world setting. STUDY TYPE: Retrospective. SUBJECTS: In all, 470 adults with diagnosed MS. FIELD STRENGTH/SEQUENCE: 3D fluid attenuation inversion recovery (FLAIR) and 3D T1 -weighted MR images at 3.0T MR. ASSESSMENT: Lesion and brain volume were measured by an automated method, MSmetrix, developed by icometrix. STATISTICAL TESTS: We used stepwise linear regression models to assess the added value of a single volumetric assessment in predicting Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Brain volumes categorized into quartiles were used as predictive variables in a time-to-event analysis and Cox proportional hazard regression with time to worsening from baseline as outcome measures. RESULTS: Brain and lesion volume in relapsing onset MS strongly contributed to the best models, with a substantial role for age in the EDSS model and a modest role for education in the SDMT model. Adding MR volumetric information increased the explained variance from 17% to 28% in the best model for EDSS and from 9% to 25% in the best model for SDMT. A significantly reduced hazard (P < 0.05) of SDMT worsening was found in the highest normalized brain volume quartiles (1375-1608 ml), compared with the lowest quartile (1201-1374 ml) in the total study population. DATA CONCLUSION: Our findings indicate that a single brain volumetric assessment contributes to the prediction of MS-related disability, with distinct patterns for EDSS as a measure of physical disability, and SDMT as a measure of cognitive disability. A threshold effect for the lowest brain volumes with regard to SDMT worsening over time was found. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1312-1321.

Fluoxetine in progressive multiple sclerosis: The FLUOX-PMS trial.

BACKGROUND: Preclinical studies suggest that fluoxetine has neuroprotective properties that might reduce axonal degeneration in multiple sclerosis (MS). OBJECTIVE: To determine whether fluoxetine slows accumulation of disability in progressive MS. METHODS: In a double-blind multicenter phase 2 trial, patients with primary or secondary progressive MS were randomized to fluoxetine 40 mg/day or placebo for a period of 108 weeks. Clinical assessments were performed every 12 weeks by trained study nurses who visited the patients at their home. The primary outcome was the time to a 12-week confirmed 20% increase in the Timed 25 Foot Walk or 9-Hole Peg test. Secondary outcomes included the Hauser ambulation index, cognitive tests, fatigue, and brain magnetic resonance imaging (MRI). RESULTS: In the efficacy analysis, 69 patients received fluoxetine and 68 patients received placebo. Using the log-rank test (p = 0.258) and Cox regression analysis (p = 0.253), we found no significant difference in the primary outcome between the two groups. Due to an unexpected slow rate of progression in the placebo group, there was insufficient statistical power to detect a potential benefit of fluoxetine. We found no differences between the two groups for secondary outcomes. CONCLUSION: The trial failed to demonstrate a neuroprotective effect of fluoxetine in patients with progressive MS.