People with multiple sclerosis (MS) often present with cognitive deficits that cannot fully be attributed to focal brain alterations. Whole-brain network changes show stronger relations, but MS network insights have mostly focused on either structural or functional (single-layer) networks, while recent work has shown the importance of multilayer frontoparietal network integration for cognition. Here, we explored the cognitive relevance of multilayer integration of the frontoparietal network in relapsing-remitting MS (n = 780) using diffusion and resting-state fMRI. Cognitive relations were first assessed for nodal multilayer eigenvector centrality, averaged over frontoparietal network nodes as a measure of integration, and post hoc for mean eccentricity for both single layer and multilayers. Higher multilayer frontoparietal network centrality was associated with worse Symbol Digit Modalities Test (SDMT) performance (β = -.117, p = .005). Mean eccentricity of single-layer diffusion (β = -.123, p < .001) and multilayer networks (β = .085, p = .018) were associated with SDMT performance. However, results could not be replicated using a different anatomical parcellation. This study showed that cognition in MS is related to multilayer network parameters. Nevertheless, correlations were weak and atlas specific, suggesting that a binary structure-function multilayer network approach is not particularly relevant as a correlate of cognition in MS.

Post-stroke epilepsy (PSE) is a clinically relevant complication after ischemic stroke. While lesion location and established clinical risk factors contribute to PSE risk, the role of lesion-induced disruption of neurotransmitter-specific brain networks remains unclear. We retrospectively analyzed 251 patients with acute large-vessel occlusion ischemic stroke treated with mechanical thrombectomy. Binary lesion masks were embedded into normative neurotransmitter-informed structural connectomes derived from PET-based receptor and transporter density maps, yielding damage scores for 19 neurotransmitter systems and a global measure of structural disconnection. Partial least squares (PLS) regression was used for feature selection, followed by multivariable logistic regression adjusted for age, sex, and SeLECT. As a secondary internal resampling analysis, elastic-net logistic regression with repeated stratified cross-validation was used to assess whether the identified pattern remained informative under regularization. Twenty-six patients (10.4%) developed PSE. PLS identified a neurochemical signature dominated by serotonergic and µ-opioid–informed systems. In adjusted models, damage to 5-HT1a, 5-HT2a, and µ-opioid networks showed the strongest and most robust associations with PSE, independent of clinical predictors and global structural disconnection. Cholinergic network measures showed weaker and less consistent effects. In repeated internal cross-validation, the same networks were selected more consistently and were associated with higher discrimination than the clinical base model. Lesion-induced disruption of specific neurotransmitter-informed structural networks, most robustly serotonergic and µ-opioid systems, is associated with PSE and showed incremental signal in internal cross-validation beyond established clinical risk factors. These findings provide a mechanistically interpretable extension to existing PSE risk models.

Clinical progression is strongly linked to grey matter atrophy in multiple sclerosis (MS), detectable early on MRI and progressing non-randomly across the brain. However, the mechanisms driving its spatio-temporal progression and individual variability remain unclear. Using MRIs from 2,187 participants, alongside normative data, we systematically investigated network-based mechanisms underlying MS-related atrophy. Regional atrophy colocalised with functional cortical hubs, supporting the nodal stress hypothesis, and propagated along anatomical and functional connections, consistent with transneuronal degeneration. Lesional disconnection and transcriptomic vulnerability played marginal roles. Patient- and subgroup-level analyses revealed that network-based mechanisms are specifically linked to MS-related neurodegeneration and may operate differently in distinct subtypes or disease phases. Atrophy patterns were anchored to the connectivity profiles of disease epicentres involving the visual, sensorimotor, and temporal cortices, and the hippocampi and thalami. Network-based measures enhanced the prediction of future atrophy progression in individual with MS, providing a mechanistic framework to understand neurodegeneration in MS.

BACKGROUND:Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically defined by three cardinal motor symptoms: bradykinesia, rigidity, and tremor. Although the natural history of bradykinesia and rigidity is well described, the evolution of tremor as the disease progresses remains controversial. OBJECTIVES:The goal was to clinically characterize long-term trajectories of rest, postural, and action tremor in PD and examine their neural network correlates using longitudinal resting-state functional magnetic resonance imaging (rs-fMRI). METHODS:In this retrospective longitudinal cohort study, we analyzed 93 tremor-positive PD patients (mean disease duration: 3.6 years), each with up to six clinical assessments over 4.2 years. Linear mixed-effects models assessed temporal change in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Fahn-Tolosa-Marín Tremor Rating Scale (FTM-TRS) scores. Rs-fMRI data from 30 tremor-affected patients (mean interval, 3.35 years) were analyzed for seed-to-whole-brain connectivity and connectivity between predefined brain regions. RESULTS:Bradykinesia (β = +0.09, P < 0.001) and rigidity (β = +0.06, P < 0.001) worsened, whereas total FTM-TRS scores declined by 0.49 points/year (P = 0.037), driven by reductions in postural (P < 0.001) and action tremor (P = 0.033); resting tremor remained stable. Rs-fMRI revealed longitudinal changes in cerebellar- and thalamic-seed-to-whole-brain connectivity. CONCLUSIONS:Tremor in PD evolves along distinct clinical courses, often stabilizing or improving as other motor features worsen. These findings are consistent with partially adaptive reorganization within tremor-related networks and underscore the importance of identifying patient subtypes with divergent trajectories to inform prognosis and optimize therapy. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Disruptions to brain networks, measured using structural (sMRI), diffusion (dMRI), or functional (fMRI) MRI, have been shown in people with multiple sclerosis (PwMS), highlighting the relevance of regions in the core of the connectome but yielding mixed results depending on the studied connectivity domain. Using a multilayer network approach, we integrated these three modalities to portray an enriched representation of the brain's core-periphery organization and explore its alterations in PwMS. In this retrospective cross-sectional study, we selected PwMS and healthy controls with complete multimodal brain MRI acquisitions from 13 European centers within the MAGNIMS network. Physical disability and cognition were assessed with the Expanded Disability Status Scale (EDSS) and the symbol digit modalities test (SDMT), respectively. SMRI, dMRI, and resting-state fMRI data were parcellated into 100 cortical and 14 subcortical regions to obtain networks of morphological covariance, structural connectivity, and functional connectivity. Connectivity matrices were merged in a multiplex, from which regional coreness-the probability of a node being part of the multiplex core-and coreness disruption index (κ)-the global weakening of the core-periphery structure-were computed. The associations of κ with disease status (PwMS vs. healthy controls), clinical phenotype, level of physical disability (EDSS ≥ 4 vs. EDSS < 4), and cognitive impairment (SDMT z-score < -1.5) were tested within a linear model framework. Using random forest permutation feature importance, we assessed the relative contribution of κ in the multiplex and single-layer domains, in addition to conventional MRI measures (brain and lesion volumes), in predicting disease status, physical disability, and cognitive impairment. We studied 1048 PwMS (695F, mean ± SD age: 43.3 ± 11.4 years) and 436 healthy controls (250F, mean ± SD age: 38.3 ± 11.8 years). PwMS showed significant disruption of the multiplex core-periphery organization (κ = -0.14, Hedges' g = 0.49, p < 0.001), correlating with clinical phenotype (F = 3.90, p = 0.009), EDSS (Hedges' g = 0.18, p = 0.01), and SDMT (Hedges' g = 0.30, p < 0.001). Multiplex κ was the only connectomic measure adding to conventional MRI in predicting disease status and cognitive impairment, while physical disability also depended on single-layer contributions. In conclusion, we show that multilayer networks represent a biologically and clinically meaningful framework to model multimodal MRI data, with disruption of the core-periphery structure emerging as a potential connectomic biomarker for disease severity and cognitive impairment in PwMS.

Long-Covid is associated with cognitive deficits in memory, attention, or executive function. However, the associated cerebral structural and functional changes are insufficiently studied to date. We investigated 39 long-Covid patients with (n = 16) and without (n = 23) cognitive impairment. Impairment was defined by a pronounced deficit (-1.5 SD) in at least one cognitive domain including memory, attention, executive function, and verbal fluency. All participants underwent structural and functional resting-state magnetic resonance imaging (MRI). We assessed differences in resting-state networks (within and between networks) between both groups as well as structural differences in total gray matter and subcortical volumes. Both groups did not differ in demographic or disease-related characteristics. Patients with cognitive deficits showed higher functional connectivity (FC) between the default mode network (DMN) and parts of the posterior supramarginal gyrus, angular gyrus and posterior-occipital part of the middle temporal gyrus, compared to those cognitively unimpaired. In addition, inter-network analyses indicated a stronger connectivity between the visual and ventral stream network in those with cognitive impairment. We found no volumetric differences between the two groups. Our results indicate that altered FC with the DMN as well as a stronger connectivity between the visual and ventral stream network in cognitively impaired long-Covid patients are associated with worse cognitive performance and therefore suggests a maladaptive functional change.

BACKGROUND:Walking impairment is one of the most debilitating symptoms of multiple sclerosis (MS). A better understanding of brain mechanisms underlying successful gait training could help to improve development of targeted therapy. We therefore investigated changes in brain activation associated with improvements in walking function after rhythmic-cued gait training. METHODS:Thirty-one people with MS (pwMS; median EDSS = 2.5, range:2.0-5.0) and 17 age- and sex-matched healthy controls (HC) completed behavioural and MRI assessments at baseline and post-intervention (four weeks after baseline). All included pwMS received a four-week actual and/or imagined gait training with rhythmic-auditory cueing, while HC received no intervention. All participants performed a bipedal ankle plantar- and dorsiflexion and a corresponding motor-imagery task during fMRI. PwMS displaying a > 5 % walking distance increase in the 2-Minute Walk Test (2MWT) from baseline to post-intervention were defined as responders. RESULTS:Responders did not differ from non-responders in terms of demographics, clinical variables, and walking function at baseline. Responders, non-responders, and HC showed similar movement-related brain activation at baseline. At post-intervention, responders showed decreased brain activation within the premotor cortex, precuneus, and middle frontal gyrus during the movement task. Stronger decreases within these areas were associated with higher walking function improvements in all pwMS after controlling for potential confounders. No association was observed between walking function and motor imagery-related brain activation changes. CONCLUSION:Improved walking function after rhythmic-cued gait training was associated with reduced brain activation in motor planning and attention areas. This suggests a more efficient recruitment of areas subserving motor function after successful training.

The long-term non-motor outcome of young adults with ischemic stroke (IS) or transient ischemic attack (TIA) is poorly understood. Therefore, in this observational cohort study, we explored the prevalence of impairment and factors influencing clinical and neuropsychological outcomes and return-to-work a decade post-stroke. After a median follow-up duration of 10.4 years, 163 patients (median age at index event: 46.0 years, 44.8% female, 121 IS and 42 TIA) of the "Stroke in Young Fabry Patients study" attended an in-person follow-up in three European centers. We assessed clinical, neuropsychological, and return-to-work data. A decade post-stroke, most patients (74.8%) showed excellent outcome, scoring 0-1 on the modified Rankin Scale (mRS) and 68.0% had returned to work. However, at follow-up, 27.2% of patients showed cognitive impairment and 27.6% suffered from fatigue. Anxiety and depression were reported by 38.0% and 18.5%, respectively. Even among patients with excellent functional outcome (mRS 0-1), 24.6% showed cognitive problems, 37.7% suffered from anxiety, 22.1% from fatigue, and 12.4% from depression. Female patients had higher rates of anxiety (52.1% vs. 26.7%), fatigue (37.0% vs. 20.0%), and depression (27.4% vs. 11.2%), compared to male patients.In linear regression, female sex was associated with a higher likelihood for anxiety (odds ratio (OR = 2.89, 95% confidence interval (CI) = 0.62-5.16), fatigue (OR = 3.23, CI = 1.52-4.93), and depression (OR = 2.86, CI = 1.12-4.59). Hypertension at follow-up (52.1%) was associated with worse functional outcome (OR = 3.03, CI = 1.32-6.95), while patients smoking at follow-up (20.2%) had higher rates of anxiety (OR = 4.09, CI = 1.21-6.97) and depression (OR = 3.40, CI = 0.87-5.21). Despite excellent functional outcome, many young stroke patients experience neuropsychological impairment, highlighting the need for targeted screening and treatment. Particularly young women are at higher risk for post-stroke depression, anxiety, and fatigue. Hypertension and smoking were modifiable risk factors contributing to worse outcomes in this young stroke cohort.

BACKGROUND:The long-term non-motor outcome of young adults with ischemic stroke (IS) or transient ischemic attack (TIA) is poorly understood. AIMS:Therefore, in this observational cohort study, we explored the prevalence of impairment and factors influencing clinical and neuropsychological outcomes and return-to-work a decade post-stroke. METHODS:After a median follow-up duration of 10.4 years, 163 patients (median age at index event: 46.0 years, 44.8% female, 121 IS and 42 TIA) of the "Stroke in Young Fabry Patients study" attended an in-person follow-up in three European centers. We assessed clinical, neuropsychological, and return-to-work data. RESULTS:A decade post-stroke, most patients (74.8%) showed excellent outcome, scoring 0-1 on the modified Rankin Scale (mRS) and 68.0% had returned to work. However, at follow-up, 27.2% of patients showed cognitive impairment and 27.6% suffered from fatigue. Anxiety and depression were reported by 38.0% and 18.5%, respectively. Even among patients with excellent functional outcome (mRS 0-1), 24.6% showed cognitive problems, 37.7% suffered from anxiety, 22.1% from fatigue, and 12.4% from depression. Female patients had higher rates of anxiety (52.1% vs. 26.7%), fatigue (37.0% vs. 20.0%), and depression (27.4% vs. 11.2%), compared to male patients.In linear regression, female sex was associated with a higher likelihood for anxiety (odds ratio (OR = 2.89, 95% confidence interval (CI) = 0.62-5.16), fatigue (OR = 3.23, CI = 1.52-4.93), and depression (OR = 2.86, CI = 1.12-4.59). Hypertension at follow-up (52.1%) was associated with worse functional outcome (OR = 3.03, CI = 1.32-6.95), while patients smoking at follow-up (20.2%) had higher rates of anxiety (OR = 4.09, CI = 1.21-6.97) and depression (OR = 3.40, CI = 0.87-5.21). CONCLUSIONS:Despite excellent functional outcome, many young stroke patients experience neuropsychological impairment, highlighting the need for targeted screening and treatment. Particularly young women are at higher risk for post-stroke depression, anxiety, and fatigue. Hypertension and smoking were modifiable risk factors contributing to worse outcomes in this young stroke cohort.