Brain Research

Robot-assisted hematoma puncture has seen significant development in primary hospitals across the country. Sino Plan software system is the core of the intelligent surgical robot, independently developed by Sinovation.We conducted a comparative study of imaging indicators, such as residual hematoma volume and hematoma clearance rate, as well as prognostic indicators, in patients who underwent hematoma puncture at our hospital over a 9-year period, before and after the introduction of Sino Plan.The results indicated that following the application of Sino Plan, the hematoma clearance rate was significantly enhanced, and the residual hematoma volume was markedly reduced. Regarding patient prognosis, there was no significant difference in GCS scores between the two groups, but the incidence of adverse prognostic events was lower in patients where Sino Plan was utilized.In conclusion, this 9-year retrospective analysis at our hospital reveals that Sino Plan offers distinct advantages. However, its application in certain special cases suggests that further improvements to the software are warranted to better meet the demands of more specific clinical scenarios.

Purpose. The choroid plexus (ChP) is the primary source of cerebrospinal fluid and an emerging marker of cerebral health, with enlargement and hypoperfusion reported in aging and neurodegeneration. However, frequent ChP calcifications can confound volumetric and perfusion measures. Although computed tomography (CT) is the gold standard for detecting calcification, it is rarely available in research MRI. Quantitative susceptibility mapping (QSM) offers an alternative sensitive to diamagnetic mineralization but lacks validated susceptibility thresholds. Method. Participants underwent CT and MRI within four weeks, including 3D T1-weighted and a multi-echo gradient echo QSM MRI. ChP calcifications were identified on CT using standard diagnostic criteria. Using the Bayes decision boundary framework, we identified optimal susceptibility thresholds for detecting diamagnetic signals consistent with calcification and compared these thresholds with multiple density levels measured on gold standard CT images. Results. Across all participants (n=20; age=62.2+-12.0 yrs), the optimal susceptibility threshold separating background ChP signal from calcifications was -0.10 ppm at 60 HU (low-density) and -0.15 ppm at 100 HU (high-density). Susceptibility values within calcified tissue exhibited a linear relationship with CT-derived tissue density. A significant positive association was observed between ChP volume and calcification volume among participants with detectable calcification (beta=2.26, p=0.047). Conclusion. This work should provide a practical framework for quantifying ChP calcifications routinely from MRI. The observed relationship between ChP volume and calcification volume highlights the importance of accounting for calcified tissue, particularly when calcification burden is substantial, when investigating ChP abnormalities in aging and neurodegenerative disease.

INTRODUCTION: Alzheimers disease (AD) is a multifactorial disorder, yet current research largely focuses on downstream biomarkers with limited attention to environmental contributors. Experimental studies suggest that per and polyfluoroalkyl substances (PFAS) may contribute to neuroimmune and neurodegenerative pathways relevant to AD. OBJECTIVE: To examine associations between PFAS exposure and neuroimmune and AD related plasma biomarkers in cognitively unimpaired rural adults. METHODS: In a cross sectional pilot study (n=48), serum concentrations of 33 PFAS were measured, including four legacy compounds (PFOS, PFHxS, PFOA, PFNA). Plasma neuroimmune related (ITGB2, SMOC1, TREM2, GFAP) and AD related biomarkers (Ab42/40, ptau217) were detected using proteomic analysis. RESULTS: PFOS showed moderate associations with ITGB2, SMOC1, and Ab42/40 in unadjusted analyses, which attenuated after adjustment for age. PFOA and PFNA demonstrated consistent inverse associations with TREM2 before and after adjustment. DISCUSSION: Findings suggest possible compound specific PFAS associations with immune and amyloid related biomarkers, supporting further investigation in longitudinal and PFAS mixture based studies.

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a genetic disease characterized by spasticity and ataxia which reflects involvement of the corticospinal tracts (CST) and cerebellum. The primary involvement of the middle cerebellar peduncles (MCP) and transverse pontine fibers (TPF) at the crossing with the CST, and their role in the pathophysiology of the disease, is currently debated. Objectives: Advanced MRI techniques capable of isolating sub-voxel microstructural parameters can test the hypothesis that the MCP and TPF are abnormally large, compressing the CST at their crossing, and potentially impairing CST development. Methods: Tract macro- and micro-structural properties, including axon and tract caliber, axon density and geometry, and myelin content were estimated from diffusion-relaxometry and magnetization transfer imaging. These features were analyzed along segments of the CST, MCP, and TPF of 9 patients and 9 age-matched controls. Results: While the CST showed significant decreases in tract size, axon caliber, and myelination throughout its length compared to controls (p<0.01), the MCP and TPF were relatively unaffected. In our group, neither the MCP nor the pons were enlarged. The proximal MCP showed an increase in axon caliber. Conclusions: The increase in fractional anisotropy and axon density towards the center of the TPF could be driven by geometric confounds related to differences in the relative sizes of the CST and TPF compared to controls. This highlights the importance of investigating tract-specific microstructural profiles, particularly in regions of geometric complexity. The findings confirm the involvement of the CST, with a relatively limited involvement of the MCP and TPF.

Although the associations between cerebrovascular dysfunctions and Alzheimer's disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-{beta} PET, and plasma assay tests for amyloid-{beta} 42, amyloid-{beta} 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-{beta} quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-{beta} at baseline, but the associations were significantly attenuated after further adjusting for amyloid-{beta} and tau, respectively. Plasma amyloid-{beta} 42/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-{beta}, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-{beta} and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects. Keywords: Alzheimer's disease, Cerebral blood flow, White matter hyperintensities, Tau pathology, Amyloid-{beta}.

Objective Astrocyte activation is increasingly recognized as an important component of multiple sclerosis (MS) pathology. Natalizumab (NTZ), a highly effective therapy for relapsing-remitting MS (RRMS), primarily blocks leukocyte trafficking into the central nervous system. However, its effects on astrocytic metabolism remain unclear. We investigated astrocyte-associated metabolic changes after NTZ treatment using quantitative 1-11C-acetate positron emission tomography (PET). Methods Seven patients with RRMS underwent quantitative 1-11C-acetate PET before and after NTZ treatment. PET-derived k2, an index of oxidative acetate metabolism, was analyzed voxel-wise and within GM and white-matter volumes of interest. Clinical status and brain magnetic resonance imaging (MRI) findings were assessed, and cognitive performance was evaluated using Rao's Brief Repeatable Battery of Neuropsychological Tests. Results After NTZ treatment, k2 decreased in all patients compared with pretreatment levels. Both gray and white matter showed significant reductions, and voxel-based analysis demonstrated widespread decreases across cortical and subcortical regions of the cerebrum and cerebellum, with no regions showing significant posttreatment increases. MRI showed no worsening; Expanded Disability Status Scale scores were stable or improved, and cognitive performance was generally stable, with improvements in selected subtests. Interpretation Quantitative 1-11C-acetate PET demonstrated a whole-brain reduction in astrocyte-associated metabolism after NTZ treatment in RRMS, most prominently in gray matter. NTZ may modulate astrocyte activity, in addition to its established effects on peripheral immune cell trafficking.

Background and Objectives In ADHD, a heterogeneous neurodevelopmental condition, behavioral and motor manifestations may reflect multiple inefficient or perturbed inhibitory systems. To evaluate Transcranial Magnetic Stimulation (TMS) evoked cortical silent period (CSP) duration, an indicator of GABA(B) receptor-mediated inhibition in motor cortex, as a potential biomarker of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. Method We retrospectively analyzed TMS data, obtained using both round and figure-of-8 coils, from three cross-sectional studies conducted in 8- to 12-year-old children with ADHD (n=79; 10.7 +/- 1.5 years old) and age-and-sex-matched typically developing controls (n=96; 10.5 +/- 1.4 years old). Results Median CSP was 32% shorter in ADHD (p=0.02). Regression analysis demonstrated a relationship between shorter CSP and both lower active motor thresholds (p < 0.0001) and more severe hyperactivity symptom rating (p = 0.026). Test-retest CSP measures in 83 children showed moderate reliability (intraclass correlation 0.77 [ADHD], 0.75 [controls]). Conclusion TMS-evoked CSP may be a useful biomarker in future investigations of ADHD subtypes, domains of impaired function, or treatment outcomes.

The impact of social parameters on brain health among people with traumatic brain injury (TBI) has been extensively documented. However, translation of this evidence into policy and clinical practice remains limited. This may reflect a lack of coordinated and equity-driven approaches to brain health that integrate diverse stakeholder perspectives, limiting progress toward equity-oriented research and service delivery models. We conducted a convergent parallel mixed-methods study guided by the REporting guideline for PRIority SEtting of health research (REPRISE). We utilized the PROGRESS-Plus framework (Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, and context-specific parameters) to ensure systematic consideration of social parameters in the study. For Objective 1, we synthesized existing evidence on social parameters and brain health outcomes. For Objective 2, we surveyed people with lived experience of TBI, family members/friends, clinicians, researchers, and community leaders across the globe to assess their prioritization of social parameters relevant to brain health. For Objective 3, we integrated evidence synthesis and stakeholder input through a structured Round Robin consensus activity to prioritize actionable areas for feasibility and impact. The activity culminated in the development of a knowledge mobilization agenda designed to inform equity-centred policy, research, and clinical practice. In Objective 1, we identified 59 publications with evidence on the effect of PROGRESS-Plus parameters on brain health outcomes following TBI. Meta-research highlighted that education, age, and country-level indicators are prognostic for brain health after TBI. In Objective 2, the highest-ranked priorities of 113 stakeholders across four continents (North America, Europe, Africa, and Oceania) were education, access to benefits, and income. These priorities were at the centre of discussion in Objective 3, which comprised idea sharing, refinement and thematic clustering, and a final prioritization poll. The resulting final 15 priorities were organized into two tracks: Track A, actions feasible in the short term, and Track B, longer-term implementation priorities. Building on this priority-setting process, co-created with stakeholders around the globe, the findings provide a roadmap for integration of social parameters in TBI research, knowledge exchange, policy, and practice.

Background: Progressive multiple sclerosis (MS) is characterized by ongoing neurodegeneration and limited therapeutic options. Circulating metabolites provide insight into disease biology, yet biomarkers that predict disability progression and reflect treatment response are lacking. We aimed to identify metabolomic signatures associated with longitudinal MRI measures of brain atrophy and to evaluate whether ibudilast treatment was associated with metabolite trajectories over time. Methods: We repeatedly profiled 1,726 plasma metabolites using untargeted UPLC-MS/MS in 244 participants from the 96-week SPRINT-MS randomized trial of oral ibudilast, up to 100 mg daily, versus placebo. Weighted gene co-expression network analysis was used to derive groups of related metabolites. Associations between baseline metabolite groups and longitudinal MRI outcomes were evaluated using linear mixed-effects models adjusted for demographic, clinical, and treatment covariates. The primary outcome was the rate of whole-brain atrophy measured by brain parenchymal fraction (BPF), defined as the proportion of intracranial volume occupied by brain tissue. Secondary outcomes included white matter fraction (WMF), gray matter fraction (GMF), and cortical thickness (CTH). Metabolite groups nominally associated with MRI outcomes, defined as p < 0.05, were followed by individual metabolite analyses to identify potential drivers. Significant metabolites were tested for replication in a comparable real-world observational HEAL-MS cohort with longitudinal MRI data. Lastly, we tested whether ibudilast treatment was associated with metabolite trajectories and performed metabolite set enrichment analysis. Findings: Higher baseline levels of glycerophospholipids were associated with slower decline in both BPF and WMF, and sphingomyelins were similarly associated with slower BPF decline. For example, higher 1-palmityl-2-stearoyl-GPC (O-16:0/18:0) levels were associated with slower BPF decline in SPRINT-MS (beta = 0.016 [95% CI: 0.008, 0.024]; p = 4.35 x 10^-5) and replicated in HEAL-MS (beta = 0.108 [95% CI: 0.006, 0.211]; p = 3.90 x 10^-2). Metabolites associated with GMF preservation were enriched in androgenic steroids and steroid sulfates, with consistent positive associations observed in the replication cohort, whereas metabolites inversely associated with CTH were predominantly xenobiotic-related. Ibudilast treatment was associated with increased sphingomyelin species, such as palmitoyl sphingomyelin (d18:1/16:0; beta = 0.185 [95% CI: 0.085, 0.286]; FDR = 1.79 x 10^-2), and decreased levels of amino acid-related metabolites, such as anthranilate (beta = -0.270 [95% CI: -0.403, -0.137]; FDR = 3.87 x 10^-2). Pathway-based analyses corroborated these findings, highlighting glycerophospholipid and sphingolipid metabolism as key pathways implicated in brain atrophy in MS. Interpretation: Distinct lipid subsets were associated with slower brain atrophy in people with MS, and ibudilast treatment was associated with metabolite alterations in potentially neuroprotective directions. Metabolomics may provide prognostic and pharmacodynamic biomarkers for progressive MS.

ABSTRACT INTRODUCTION: Microscopic fractional anisotropy ({micro}FA), an emerging diffusion MRI metric, may be more sensitive than conventional metrics to gray matter microstructural changes in neurodegeneration. This pilot study compared {micro}FA, mean diffusivity (MD), and volume between genetic frontotemporal dementia (FTD) variant carriers and non-carriers in the insula, frontal pole, and medial orbitofrontal cortex (mOFC). METHODS: Carriers and familial non-carriers of FTD variants in C9orf72, GRN, or MAPT were scanned between October 2024-December 2025. Non-parametric aligned rank transform ANCOVAs were computed to analyze between-group differences in {micro}FA, MD, and volume while controlling for age. RESULTS: Carriers (n=12) exhibited lower insula {micro}FA than non-carriers (n=8): F(1,19)=5.89, 95% CI [-10.7,-0.75], p=0.027, 2p=0.26. No group-differences were observed in other metrics, including MD and volume. DISCUSSION: Reduced {micro}FA in the insula, a region vulnerable to early atrophy in FTD, may be more sensitive to early microstructural changes in genetic FTD than traditional diffusivity measures.

The proliferation of gambling advertising has intensified concerns regarding its influence on vulnerable populations, yet the neural mechanisms underlying cue-reactivity to these stimuli remain underexplored in ecologically valid settings. This study protocol proposes a novel methodological framework to investigate prefrontal cortical responses to gambling advertisements in individuals with varying degrees of gambling experience. Materials and methods: This cross-sectional study will recruit 44 participants, divided into a clinical group (individuals with high-frequency gambling or gambling disorder) and a matched control group. Neural activity will be recorded using fNIRS while participants view gambling-related, neutral, violent, and sexual stimuli. Secondary measures include validated scales for gambling severity (SOGS), impulsivity, sensation seeking, and alexithymia. Data analysis will primarily utilize inter-subject correlation (ISC) to quantify neural synchronization and multiband frequency decomposition to capture dynamic affective processing. Advanced preprocessing, including short-channel regression, will be applied to ensure signal robustness. Discussion: By combining portable neuroimaging with a data-driven ISC approach, this study aims to identify objective neural markers of gambling vulnerability. The findings will provide novel insights into the idiosyncratic processing of commercial stimuli, potentially informing public health policies and the development of more effective evidence-based regulations for gambling marketing.

INTRODUCTION: MethylCog is a 29-CpG blood DNA methylation (DNAm) proxy for general cognitive ability (g). Its incremental association with blood biomarkers of Alzheimer's disease and related dementias (ADRD) and prospective cognitive ability remains unclear. METHODS: In the held-out test set from the original MethylCog study, we tested whether MethylCog explained baseline g beyond four ADRD blood biomarkers, and whether it predicted six-year follow-up g beyond baseline g and biomarkers. RESULTS: MethylCog showed a stronger age-adjusted association with baseline g than individual biomarkers (r=.368 vs absolute r=.083-.162). MethylCog added 10.0% variance beyond all four biomarkers cross-sectionally (p<.001) and predicted six-year follow-up g in the biomarker-adjusted model (beta=.108, p=.002). No individual ADRD biomarker independently predicted follow-up g. DISCUSSION: MethylCog may provide cognition-related DNAm information complementary to blood-based ADRD biomarkers.

INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.

Background Neuropsychiatric fluctuations in Parkinson's disease (PD) often accompany motor fluctuations, but their temporal relationship during the acute levodopa response remains unclear. Objectives To determine whether motor and neuropsychiatric responses occur synchronously during the OFF-to-ON transition. Methods Nineteen fluctuating PD patients underwent a high-resolution levodopa challenge with repeated assessments every 10 minutes for 60 minutes after levodopa administration. Motor symptoms (akinesia, rigidity) and neuropsychiatric fluctuations were quantified. Transition times (t25%-t50%-t75%-t100%) and response profiles were analyzed using correlation and clustering approaches. Results Motor and neuropsychiatric transition times were not correlated at any threshold (all FDR-corrected p>0.05; Bayes factors <1), supporting temporal dissociation. Among 18 patients with complete data, clustering revealed synchronous (6/18), neuropsychiatric-preceding (7/18), and motor-preceding (3/18) profiles. Conclusion Motor and neuropsychiatric responses to levodopa during PD fluctuations are partly independent and follow heterogeneous, patient-specific temporal profiles, supporting the search for distinct biomarkers and future individualized adaptative therapies

Background: The specific 3D morphological substrates distinguishing the newly defined massive and torrential functional tricuspid regurgitation (FTR) phenotypes from standard severe disease remain under-characterized. Objectives: This study investigates the 3D geometric changes of the tricuspid valve (TV) apparatus across the spectrum of FTR, specifically focusing on the structural definition of massive and torrential grades. Methods: Three-dimensional (3D) transesophageal echocardiography (TEE) was performed in 322 patients with FTR secondary to left-sided heart disease. Patients were stratified into mild-moderate (n=166), severe (n=82), and massive-torrential (n=74) groups. TV geometry, including annular dimensions, leaflet tethering, and subvalvular apparatus, was quantified using 3D modeling software. Results: Patients with massive-torrential TR were characterized by advanced age, female predominance, and atrial fibrillation (75%). 3D analysis demonstrated that massive-torrential TR represents a distinct phenotype defined by extreme annular circularization (ellipticity index 1.0) and planar flattening (P < 0.001). Furthermore, these patients exhibited a critical leaflet-annulus uncoupling, where compensatory leaflet growth (relative length < 80%) failed to match the massive annular dilation. Consequently, the regurgitant orifice in massive-torrential grades appeared highly complex, frequently manifesting as multiple irregular orifices. Conclusions: Massive and torrential FTR are characterized by a unique geometric profile involving extreme annular circularization, severe leaflet tethering, and leaflet-annulus uncoupling. These morphological insights suggest that conventional repair strategies may be insufficient for these advanced phenotypes, highlighting the necessity for pre-procedural 3D TEE to guide device selection.

Background: Prostate-specific membrane antigen (PSMA) PET/CT is central to prostate cancer staging and theranostic workflows. To our knowledge, no direct within-patient comparison of [18F]FC303 ([18F]Florastamin) and [68Ga]Ga-PSMA-11 has been reported. We performed a preliminary paired method-comparison study under non-harmonized acquisition protocols. Patients and Methods: Twenty patients with histologically confirmed prostate cancer underwent [68Ga]Ga-PSMA-11 PET/CT (185 +/- 37 MBq, 60 +/- 10 min) followed by [18F]FC303 PET/CT (370 +/- 37 MBq, 105 +/- 15 min) on the same PET/CT system within each patient (median interval, 29.5 days). Index targets were anatomically matched to the biopsied or surgically sampled lesion or target region. The primary malignant set included 18 histologically malignant targets; two histology-negative or indeterminate targets were included only in sensitivity analysis. Fixed [68Ga]Ga-PSMA-11-first scan order and the 45-min uptake-time difference were central interpretive constraints. Results: Across five predefined reference organs, [18F]FC303 showed lower SUVmean than [68Ga]Ga-PSMA-11 (all Benjamini-Hochberg-adjusted p < 0.001; [68Ga]/[18F]FC303 geometric mean ratio [GMR], 1.29-3.89). In the primary malignant set, [18F]FC303 lesion SUVmax was lower than [68Ga]Ga-PSMA-11 (median, 11.3 vs 18.1; paired median difference, -5.50; 95% CI, -6.85 to -2.90; Wilcoxon p = 8.4 x 10-4), with strong rank correlation (Spearman {rho} = 0.90). Passing-Bablok regression yielded {beta} = 1.13 (95% CI, 1.04-1.45), and log-Bland-Altman GMR (FC303/[68Ga]) was 0.75, consistent with proportional non-interchangeability. Tumor-to-liver and tumor-to-mediastinum ratios did not differ significantly (GMR, 1.17 [95% CI, 0.94-1.45] and 0.96 [0.80-1.15], respectively); the study was not powered for equivalence. The n = 20 sensitivity analysis showed consistent directionality. Conclusions: Under non-harmonized acquisition conditions, [18F]FC303 showed lower physiologic reference-organ SUVmean and malignant target-region SUVmax than [68Ga]Ga-PSMA-11, whereas tumor-to-liver and tumor-to-mediastinum ratios were not significantly different. Absolute SUVs were not interchangeable; [68Ga]Ga-PSMA-11-derived SUV thresholds should not be directly transferred to [18F]FC303 without tracer-specific calibration.

We investigated whether people with Parkinson's disease who are dual GBA1+LRRK2 carriers have a milder, LRRK2-like phenotype as previously reported. This was accomplished by comparing clinical features and alpha-synuclein seed amplification assay (SAA) positivity rates between dual GBA1+LRRK2-PD(n=13), GBA1-PD(n=169) and LRRK2-PD(n=175) carriers in a cross-sectional retrospective study of Parkinson's Progression Markers Initiative (PPMI) data. Our results show that GBA1+LRRK2-PD rate(83%) is closer to GBA1-PD rate(87%) rather than LRRK2-PD rate (62%mp-value>0.05). GBA1+LRRK2-PD have both non-motor and motor phenotypic similarity of GBA1-PD(p-value>0.05). This small PPMI cohort indicates that dual GBA1+LRRK2-PD carriers' SAA positivity and phenotype are aligned with GBA1-PD.

Background: Thalamic low-intensity transcranial focused ultrasound (tFUS) has shown promise for increasing behavioral responsiveness in disorders of consciousness (DOC), but no study has examined whether it can causally modulate the well-validated behavioral, electrophysiological, and metabolic biomarkers of DOC impairment. Methods: Sixteen adult patients (44% Female; Age, M=37.81, SD=15.97) with a chronic DOC (Time Since Injury, M=3.39, SD=1.94 years) secondary to severe brain injury (TBI 44%, non-TBI 56%) underwent a 10-day inpatient, longitudinal, single-arm, open-label protocol. tFUS was delivered in a single session targeting the left central thalamus. Well-known behavioral (CRS-R), electrophysiological (EEG {delta}/{beta} ratio), metabolic (18F-FDG PET), and polysomnographic outcomes were assessed at baseline and after sonication. Results: The maximum CRS-R total score increased significantly following tFUS compared to baseline (M=13.27 vs. M=10.33; t(14)=7.407, p<0.001, d=1.913), as did the global EEG {delta}/{beta} ratio (N=14; W=17, p=0.025, r=0.68), with the degree of frontal slowing positively predicting behavioral gains ({tau}b=0.51, p=0.016). Glucose metabolism decreased bilaterally in thalamus and frontal, temporal, and parietal cortices at both post-tFUS timepoints compared to baseline. Finally, N2 sleep increased by 33% following tFUS (N=11; t(10)=2.386, p=0.038, d=0.72), though this did not survive correction. No severe adverse events were observed. Conclusion: Thalamic tFUS can causally modulate well-validated behavioral, electrophysiological, and metabolic biomarkers of DOC. The convergent inhibitory signature across these measures suggests a thalamocortical reset mechanism, complementing existing excitatory neuromodulation approaches and providing the mechanistic foundation for a large, randomized sham-controlled trial.

Introduction: Incomplete recovery from relapses contributes to long-term disability accumulation in relapsing remitting multiple sclerosis (RRMS), yet the relationship between immune regulation and relapse recovery remains poorly defined. Objective: To longitudinally characterize regulatory/effector immune cell dynamics in untreated RRMS patients and assess their association with immune balance and relapse recovery. Methods: Monocytic myeloid-derived suppressor cells (M MDSCs), regulatory T cells (Treg), and effector CD4 T cell subsets were measured in blood from 69 untreated RRMS patients sampled during relapse or remission and reevaluated after 12 months. Associations with clinical recovery after relapse were examined. Results: During relapse, patients exhibited higher M MDSC and Treg frequencies than in remission, while effector T cell subsets remained unchanged. Over one year, M-MDSCs increased consistently regardless of baseline clinical status, whereas Treg frequencies remained stable. Effector to M MDSC ratios were markedly elevated during relapse and declined over time, while effector-to-Treg ratios showed minimal variation. M MDSC levels during relapse were associated with sustained regulatory features at 12 month follow up. Importantly, higher baseline M MDSC levels, but not Treg frequencies, were associated with complete relapse recovery at one year. Conclusion: These findings suggest that circulating M-MDSCs, but not Treg, reflect interindividual differences in immune regulation and clinical recovery after relapse in early RRMS.

Background. Poor sleep quality is common in people with multiple sclerosis (pwMS) and reduces quality of life. Objectives. To examine associations between modifiable factors and sleep quality in pwMS. Methods. In a prospective clinic cohort (2017-2023), we evaluated whether baseline measures of disability, depression, fatigue, and pain were associated with poor sleep quality (Pittsburgh Sleep Quality Index, PSQI) cross-sectionally using covariate-adjusted linear regression, structural equation modeling (SEM), and LASSO logistic regression, and longitudinally using mixed-effects models. Results. In this cohort (n=750; mean age 48.9 years; 80.3% women, 88.7% relapsing type), higher body mass index ({beta} [95% CI]: 0.06 [0.01, 0.12], p=.001) and area deprivation index (6.78 [2.17, 11.39], p<.001) were associated with worse baseline PSQI scores. In adjusted analyses (n=730), disability, depression, fatigue, and pain were each associated with worse sleep. In SEM, pain had a moderate direct effect on sleep ({beta} [95% CI]: 0.56 [0.48, 0.64], p<.001). LASSO models that included pain outperformed the benchmark (AUROC 0.741 vs 0.517). Longitudinally (n=382), time and higher baseline pain predicted worse sleep ({beta} [95% CI]: time in months 0.04 [0.02, 0.06], p<.001; pain 0.36 [0.31, 0.41], p<.001). Conclusion. Pain is a key, potentially modifiable driver of poor sleep quality in pwMS.