Explore the vast range of titles available.

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy. Synapse loss is prominent in the cortex in multiple sclerosis (MS). In a cortical MS model, Jafari et al. show that phagocytes remove synapses by engulfment, which is triggered by local calcium accumulations and prevented by blocking colony-stimulating factor 1 signaling.

BackgroundOptical coherence tomography (OCT) inner retinal metrics reflect neurodegeneration in multiple sclerosis (MS). We explored OCT measures as biomarkers of disease severity in secondary progressive MS (SPMS).MethodsWe investigated people with SPMS from the Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial OCT substudy, analysing brain MRIs, clinical assessments and OCT at baseline and 96 weeks. We measured peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thicknesses. Statistical analysis included correlations, multivariable linear regressions and mixed-effects models.ResultsOf the 212 participants recruited at baseline, 192 attended at 96 weeks follow-up. Baseline pRNFL and GCIPL thickness correlated with Symbol Digit Modalities Test (SDMT) (respectively, r=0.33 (95% CI 0.20 to 0.47); r=0.39 (0.26 to 0.51)) and deep grey matter volume (respectively, r=0.21 (0.07 to 0.35); r=0.28 (0.14 to 0.41)).pRNFL was associated with Expanded Disability Status Scale (EDSS) score change (normalised beta (B)=−0.12 (−0.23 to −0.01)). Baseline pRNFL and GCIPL were associated with Timed 25-Foot Walk change (T25FW) (respectively, B=−0.14 (−0.25 to −0.03); B=−0.20 (−0.31 to −0.10)) and 96-week percentage brain volume change (respectively, B=0.14 (0.03 to 0.25); B=0.23 (0.12 to 0.34)). There were significant annualised thinning rates: pRNFL (−0.83 µm/year) and GCIPL (−0.37 µm/year).ConclusionsIn our cohort of people with SPMS and long disease duration, OCT measures correlated with SDMT and deep grey matter volume at baseline; EDSS, T25FW and whole brain volume change at follow-up.

This study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS). Previous studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment. In this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup. High versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p<0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, -0.32% vs. -0.24%, p=0.044, and teriflunomide, -0.43% vs. -0.29%, p=0.002), thalamic volume (-0.56% vs. -0.31%, p=0.047 and -0.94% vs. -0.49%, p<0.001), and WM volume (-0.30% vs. -0.19%, p=0.083 and -0.38% vs. -0.18%, p=0.003) but not of cGM volume (-0.39% vs. -0.32%, p=0.337 and -0.49% vs. -0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients. This study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients.

Elevated levels of blood-based biomarkers such as neurofilament light chain (NfL) and neuron-specific enolase (NSE) are associated with poor neurological outcome after out-of-hospital cardiac arrest (OHCA). This study investigates the relationship between regional grey matter volume reduction and levels of glial fibrillary acidic protein (GFAP), NfL, NSE, and total-tau (t-tau) protein. This substudy of the Xe-Hypotheca trial included 110 patients randomized to receive either inhaled xenon with target temperature management (TTM) at 33 °C for 24 h ( n  = 55) or TTM alone ( n  = 55). Voxel-based morphometry was used to assess grey matter volume changes in MRI scans acquired 36–52 h and 10 days after OHCA in 45 survivors. Blood biomarkers were measured upon intensive care unit arrival and at 24, 48 and 72 h post-OHCA. NfL levels positively correlated with grey matter volume reduction in the thalamus and cingulate cortex at 24 h post-OHCA. T-tau showed more extensive pattern of significant correlations, increasing in both magnitude and spatial extent from baseline to 48 h post-OHCA. No significant biomarker–volume associations were observed for GFAP or NSE, and no treatment group differences were detected. Elevated NfL and t-tau levels were associated with region-specific grey matter volume reduction within the first 10 days after OHCA. Among the four biomarkers studied, t-tau demonstrated the strongest and most widespread associations, suggesting its potential as a marker for early ischemic grey matter volume reduction after OHCA. ClinicalTrials.gov NCT00879892, 13/04/2009.

Objective To determine whether reliable brain atrophy measures can be obtained from post-contrast 3D T1-weighted images in patients with multiple sclerosis (MS) using FreeSurfer. Methods Twenty-two patients with MS were included, in which 3D T1-weighted MR images were obtained during the same scanner visit, with the same acquisition protocol, before and after administration of gadolinium-based contrast agents (GBCAs). Two FreeSurfer versions (v.6.0.1 and v.7.1.1.) were applied to calculate grey matter (GM) and white matter (WM) volumes and global and regional cortical thickness. The consistency between measures obtained in pre- and post-contrast images was assessed by intra-class correlation coefficient (ICC), the difference was investigated by paired t-tests, and the mean percentage increase or decrease was calculated for total WM and GM matter volume, total deep GM and thalamus volume, and mean cortical thickness. Results Good to excellent reliability was found between all investigated measures, with ICC ranging from 0.926 to 0.996, all p values < 0.001. GM volumes and cortical thickness measurements were significantly higher in post-contrast images by 3.1 to 17.4%, while total WM volume decreased significantly by 1.7% (all p values < 0.001). Conclusion The consistency between values obtained from pre- and post-contrast images was excellent, suggesting it may be possible to extract reliable brain atrophy measurements from T1-weighted images acquired after administration of GBCAs, using FreeSurfer. However, absolute values were systematically different between pre- and post-contrast images, meaning that such images should not be compared directly. Potential systematic effects, possibly dependent on GBCA dose or the delay time after contrast injection, should be investigated. Trial registration Clinical trials.gov. identifier: NCT00360906. Key Points • The influence of gadolinium-based contrast agents (GBCAs) on atrophy measurements is still largely unknown and challenges the use of a considerable source of historical and prospective real-world data. • In 22 patients with multiple sclerosis, the consistency between brain atrophy measurements obtained from pre- and post-contrast images was excellent, suggesting it may be possible to extract reliable atrophy measurements in T1-weighted images acquired after administration of GBCAs, using FreeSurfer. • Absolute values were systematically different between pre- and post-contrast images, meaning that such images should not be compared directly, and measurements extracted from certain regions (e.g., the temporal pole) should be interpreted with caution.

Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI. We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a > 50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques. Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity. Normalization by intracranial volume nullified some between-group differences in volumetric measures. There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.

BackgroundResearch on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings.MethodsParticipants were randomised to: ‘CR plus EX’, ‘CR plus sham EX (EX-S)’, ‘EX plus sham CR (CR-S)’ and ‘CR-S plus EX-S‘ and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task).Results104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25–62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in ‘CR plus EX-S’ (p=0.02). Groups performing CR (ie, ‘CR plus EX’ and ‘CR plus EX-S’) exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. ‘CR plus EX-S’ patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula.ConclusionsIn PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements.Trial registration number NCT03679468.

Background We have earlier reported that inhaled xenon combined with hypothermia attenuates brain white matter injury in comatose survivors of out-of-hospital cardiac arrest (OHCA). A predefined secondary objective was to assess the effect of inhaled xenon on the structural changes in gray matter in comatose survivors after OHCA. Methods Patients were randomly assigned to receive either inhaled xenon combined with target temperature management (33 °C) for 24 h ( n  = 55, xenon group) or target temperature management alone ( n  = 55, control group). A change of brain gray matter volume was assessed with a voxel-based morphometry evaluation of high-resolution structural brain magnetic resonance imaging (MRI) data with Statistical Parametric Mapping. Patients were scheduled to undergo the first MRI between 36 and 52 h and a second MRI 10 days after OHCA. Results Of the 110 randomly assigned patients in the Xe-Hypotheca trial, 66 patients completed both MRI scans. After all imaging-based exclusions, 21 patients in the control group and 24 patients in the xenon group had both scan 1 and scan 2 available for analyses with scans that fulfilled the quality criteria. Compared with the xenon group, the control group had a significant decrease in brain gray matter volume in several clusters in the second scan compared with the first. In a between-group analysis, significant reductions were found in the right amygdala/entorhinal cortex ( p  = 0.025), left amygdala ( p  = 0.043), left middle temporal gyrus ( p  = 0.042), left inferior temporal gyrus ( p  = 0.008), left parahippocampal gyrus ( p  = 0.042), left temporal pole ( p  = 0.042), and left cerebellar cortex ( p  = 0.005). In the remaining gray matter areas, there were no significant changes between the groups. Conclusions In comatose survivors of OHCA, inhaled xenon combined with targeted temperature management preserved gray matter better than hypothermia alone. Clinical trial registration: ClinicalTrials.gov: NCT00879892.

Background Impairment of cardiovascular control is common in multiple sclerosis (MS), possibly due to damage of strategic brain regions such as the insula. Aerobic training (AT) targets cardiopulmonary system and may represent a neuroprotective strategy. Purpose To investigate whether insular damage (T2-hyperintense lesions and volume) is associated with cardiovascular fitness (CF) and influences AT effects in MS. Methods Sixty-one MS patients were randomized to an AT intervention group (MS-AT) and a motor training control group (MS-C). At baseline and after training (24 sessions over 2–3 months), peak of oxygen consumption (VO2max), heart rate reserve (HRR), 6-min walk test (6MWT) and whole brain and insula MRI data were collected. Two healthy control (HC) groups were enrolled for CF and MRI data analysis. Results At baseline, MS patients vs HC showed impaired VO2max, HRR and 6MWT ( p  < 0.001) and widespread gray matter atrophy, including bilateral insula. In MS patients, left insula T2-lesion volume correlated with HRR ( r  = 0.27, p  = 0.042). After training, MS-AT, especially those without insular T2-hyperintense lesions, showed 6MWT improvement ( p  < 0.05) and a stable insular volume, whereas MS-C showed left insular volume loss ( p  < 0.001). Conclusions By increasing 6MWT performance, our results suggest that AT may improve walking capacity and submaximal measure of CF in MS patients. Such beneficial effect may be modulated by insula integrity.

Objectives To better investigate neurobiological heterogeneity in fibromyalgia for its symptom diversity and individual differences. Methods We collected structural MRI data and clinical characteristics of Chinese female fibromyalgia patients and healthy controls matched by age and educational level, then invited qualified patients to undergo either Ba‐Duan‐Jin or pregabalin intervention for 12 weeks randomly. Structural MRI was analyzed by CAT12 software, and the regional volume of gray matter (GMV) was calculated according to the Brainnetome atlas. Fibromyalgia patients were clustered using the HYDRA algorithm to detect disease subtypes. Results Two distinct neuroanatomical subtypes were found among 75 patients. Compared to 93 healthy controls, patients in subtype 1 (n = 38, 50.7%) showed widespread GMV increase, especially in some pain‐related brain regions, while no structural changes were observed in subtype 2 (n = 37, 49.3%). At the baseline before treatment, patients in subtype 1 showed a younger age (p = 0.037), longer illness duration (p = 0.042), and a severer psychological stress state evaluated by the Perceived Stress Scale (p = 0.008). After standardized treatment, subtype 1 patients showed less improvement in pain VAS score (p = 0.027) than subtype 2 patients. In addition, GMV of the bilateral dorsal caudate had negative correlations with stress level (Left r = −0.335, p = 0.040; Right r = −0.341, p = 0.036), and GMV of the left rostral temporal thalamus (r = 0.781, p = 0.038) and lateral amygdala (r = 0.761, p = 0.047) were positively related to the improvement of pain severity after treatment in subtype 1 patients. Conclusions These two neuroanatomical subtypes in fibromyalgia emphasize different underlying neuropathological processes and need future studies to optimize individualized treatment. Trial Registration ClinicalTrials.gov identifier: NCT03890133 This study reveals two distinct neuroanatomical subtypes of fibromyalgia. Differences in clinical symptoms and treatment responses between two subtypes validate the subtype classification and highlight variations in the underlying neuropathological processes of fibromyalgia, offering insights for individualized treatment strategies.