Frontiers in Neurology

Introduction: High-intensity locomotor training (HIT) is recommended for improving walking capacity, but treatment responses are variable. Understanding the brain changes underlying responsiveness to training could provide insight into this variability. Emerging evidence suggests upregulation of the contralesional cortico-reticulospinal tract (CRST) may contribute to walking function after stroke. However, it is unclear whether CRST upregulation is supportive or maladaptive, and no studies have examined CRST changes after HIT. This study investigated how CRST and corticospinal tract (CST) strength and laterality reorganize, and their relationship with walking capacity after locomotor HIT. Methods: Ten participants with chronic stroke completed a 4-week no-intervention control phase then 4-weeks of HIT. Diffusion MRI and 6-minute walk distance were obtained at weeks 0, 4, and 8. Analysis tested changes in ipsilesional and contralesional CRST and CST strength and laterality. Associations between changes in tract laterality and walking capacity were examined. Results: During the treatment phase (vs. the control phase), there were significantly greater increases in contralesional CRST strength (1.02 SD [95% CI: 0.25, 1.79]), contralesional CRST laterality (4.44 [2.15, 6.72]), and 6-minute walk distance (33 meters [17, 50]). Walking capacity improvements were associated with changes in CRST laterality (r = 0.77, p = 0.01), but not CST laterality (r = -0.01, p = 0.98). Discussion: Following HIT, increases in contralesional CRST strength and laterality were observed. CRST laterality changes were strongly associated with walking improvements, suggesting a possible supportive role of contralesional CRST in mediating training-related improvements in walking function after stroke.

Background:Stroke continues to be one of the major causes of death and long-term disability worldwide, with a greater impact in low-and middle-income countries. In India, there is limited evidence examining stroke burden and its changes over time and across regions. Therefore, we aimed to assess the burden of stroke in India from 1990 to 2023 using the latest data from the Global Burden of Disease (GBD) Study, along with projections up to 2035. Methods:We used estimates from the GBD 2023 study to examine stroke incidence, prevalence, mortality, and disability-adjusted life years (DALYs) in India from 1990 to 2023. Age-standardized rates were analyzed to understand how these measures have changed over time. We also conducted state-level analyses to explore regional differences in stroke burden. The contributions of all major modifiable risk factors were assessed using population-attributable fractions. In addition, we projected future trends in stroke burden up to 2035. Results:From 1990-2023, the percentage change in overall stroke burden in India showed minimal variation across key indicators. Incidence remained largely stable (0.00%[-0.04 to 0.05]), while prevalence showed a slight increase(0.06%[0.03 to 0.10]). Mortality (-0.11%[-0.36 to 0.20]) and DALYs (-0.17%[-0.38 to 0.12]) demonstrated modest declines over the study period. Notable regional disparities were evident, with states such as Chhattisgarh, Assam, and Jharkhand bearing the highest burden. High systolic blood pressure remained the leading risk factor in 2023, contributing the largest share of stroke-related deaths, followed by dietary risks, air pollution, tobacco use, and high body mass index. Future projections indicate that by 2035, stroke prevalence is likely to increase, while incidence, mortality, and DALYs are expected to show only modest changes. Conclusions: Stroke remains a major and growing public health challenge in India with a continuing increase in burden despite slight improvements in age-standardized rates over time. Addressing this challenge will require stronger prevention efforts, better control of key risk factors, and focused strategies to reduce regional disparities in stroke burden nationwide.

Background. Up to 70% of stroke survivors develop cognitive impairment, yet clinicians lack non-invasive vascular biomarkers that could meaningfully inform risk stratification. Carotid-femoral pulse wave velocity (cfPWV), the gold-standard measurement of central arterial stiffness, is a novel biomarker of vascular aging linked to cognitive impairment. This study evaluated the association between cfPWV and post-stroke cognitive impairment, as measured by the Montreal Cognitive Assessment (MoCA), in individuals [≥]6 months post-stroke. Methods. This is a secondary cross-sectional analysis of baseline data from a randomized control trial. Logistic regression analyses examined the association between cfPWV (m/s) and MoCA score at the primary cut point of [≤]26/30, with secondary cut points of [≤]24/30 and [≤]22/30. Models were adjusted for age, sex, systolic blood pressure, type-2 diabetes, National Institutes of Health Stroke Scale (NIHSS) score, and smoking status. Results. Of 82 participants enrolled in the main trial, 68 participants (n = 45 males, age 64.6 {+/-} 9.6 years, 1.8 {+/-} 1.2 years post-stroke) with mild-to-moderate stroke severity (NIHSS median [IQR] = 1 [2]) were included. In the fully adjusted model using the MoCA [≤]26/30 cut point, each 1 m/s increase in cfPWV was associated with a 35% increase in the odds of post-stroke cognitive impairment (adjusted OR [aOR] = 1.35; 95% CI 1.06, 1.81; p = 0.027; Area Under the Curve [AUC] = 0.77). Consistent associations were observed at the MoCA [≤]24/30 (aOR = 1.41; 95% CI 1.04, 2.01; p = 0.037; AUC = 0.88) and MoCA [≤]22/30 (aOR = 1.33; 95% CI 1.03, 1.79; p = 0.039; AUC = 0.82) cut points. Conclusions. Higher cfPWV was independently associated with post-stroke cognitive impairment across clinically referenced MoCA cut points. cfPWV may be a complementary vascular biomarker to support cognitive risk stratification and identify stroke survivors who could benefit from closer monitoring or vascular-targeted intervention.

Background: Stroke is a time-sensitive neurological emergency in which early EMS activation and presentation to definitive care are cornerstones of effective therapy. Large language models (LLMs) are increasingly consulted by the public for medical advice, but the veracity of the guidance provided by commercially available models responding to potential stroke symptoms is not well understood. Methods: We performed a cross-model benchmarking study comparing the triage choices of three frontier LLMs (Claude Sonnet 4.6, GPT-4o, and Llama 3.3-70b-versatile) on first-person vignettes describing a unilateral arm symptom on waking, across 10 symptom descriptors, and two clinical phases (before and after a partially reassuring self-examination), with or without a clinical distractor (n=50 per condition). Results: Claude sought emergency care most often, Llama least, and GPT-4o in between, diverging most sharply in the post-examination phase where Claude called 911 in 100% of runs, Llama called for non-emergency help in 100%, and GPT-4o was symptom-dependent. A distractor shifted behavior away from emergency care in almost all conditions: calling 911 fell from 37.9% to 14.6% and waiting rose from 0% to 45.9% in the post-examination vignette. Responses were also sensitive to symptom word: weak, limp, heavy, and clumsy generated higher alarm, whereas numb, tingly, odd, strange, and weird generated less urgent responses. Conclusions: The increasing use of LLMs for medical advice has significant public health implications. Commercially available LLMs show significant model-to-model variability and framing sensitivity when confronted with potential stroke symptoms, including under-recognition of canonical CDC warning descriptors, underscoring the need for systematic benchmarking as these tools become de facto first points of contact for patients experiencing neurological emergencies.

Background: Huntington ' s disease (HD) causes progressive postural control deficits, but how sensory reweighting mechanisms degrade across disease stages remains poorly understood. Objective: To determine whether objective markers of postural sway track disease severity and altered sensory reweighting across the HD spectrum. Methods: Ninety-seven adults (46 {+/-} 14 yrs) were categorized into four groups: 29 with HD, 27 pre-manifest (PM), 28 not at risk (AR-), and 13 age-matched healthy controls (HC). Participants performed three trials of quiet standing with eyes open and eyes closed on a force plate. Results: Manifest HD individuals exhibited greater AP, ML, and total COP sway displacement compared with the PM, AR-, and HC groups. HD and PM groups demonstrated greater instability with eyes closed. COP wavelet power was concentrated below 1 Hz across all groups. The eyes-open to eyes-closed change in 0-1 Hz power predicted total COP sway in HC (68%), AR- (45%), and PM (46%), but this relation was substantially weaker in HD. Conclusions: Progressive weakening of oscillatory-sway coupling distinguishes manifest HD from premanifest stages. PM individuals demonstrate early sensory reweighting deficits that manifest only when vision is removed, while HD individuals show decoupled oscillatory activity that fails to support stable postural regulation. This progressive decoupling may serve as a candidate marker of disease conversion prior to overt motor diagnosis.

Background: Growing evidence suggests that urinary {beta}-amyloid precursor protein (A{beta}PP) fragments can serve as an early screening biomarker for mild cognitive impairment and dementia. However, in reality, older adults, regardless of the presence of cognitive decline, often suffer from multiple age-related conditions and are on multiple medications. How these comorbidities and treatments affect the performance of early diagnostic biomarkers remains unclear. Methods : This study further validated the sensitivity, specificity, and clinical value of the Qankorey (R) urinary {beta}-amyloid protein detection kit in early dementia screening through a randomized community screening (n=51187) conducted in Changsha, and a multicenter case-control study conducted at Yuquan Hospital (Tsinghua University), Tiantan Hospital (Capital Medical University), Beijing Friendship Hospital, Zibo 148 Hospital (Shandong), and the Third People's Hospital of Yunnan Province. The multicenter case-control study included 898 participants, comprising 266 healthy, age-matched controls without any comorbidities, 167 patients with mild cognitive impairment/Alzheimer's disease (MCI/AD), and 465 non-AD patients with various comorbidities and age-related diseases. Results: The kit showed a significant age-dependent positive rate in both men and women in Changsha, increasing from 6.29% to 15.40%. The number of weakly positive/positive/negative individuals in the healthy group, non-AD group, and MCI/AD group were 8/12/246 (positive rate 7.52%), 41/16/409 (12.23%), and 77/44/46 (72.46%), respectively, with a Kappa value of 0.669, indicating that the method performed well in the clinical diagnosis of MCI/AD, consistent with previously published results. Among the 8 weakly positive healthy subjects, 6 were found to have brain abnormalities by MRI/CT examination. Comorbidity analysis showed that memory decline was the most significant risk factor (P=9.6 x 10^-23, Fisher's exact test), followed by dizziness (P=1.3 x 10^-14;) , hyperlipidemia (P=3.2 x 10^-12) , history of stroke (P=0.0011), and hypertension (P=0.0058). Treatment analysis showed that cardiovascular drugs and antithrombotic drugs significantly reduced the risk of dementia (P values were 0.0061 and 0.0081, respectively), followed by hypoglycemic drugs (P=0.0358). For AD patients, those receiving only memantine showed a slightly lower positive test rate (P=0.0532). Conclusion: Our findings confirm the diagnostic value of urinary {beta}-amyloid protein detection in MCI and AD-related dementia. Furthermore, this kit can be used in practical clinical applications to assess the risk of cognitive decline and treatment efficacy across various diseases.

Background: Frontotemporal dementia (FTD) lacks widely accessible disease-specific biomarkers. Optical coherence tomography (OCT) and OCT angiography (OCTA) may provide non-invasive measures of retinal changes associated with neurodegeneration. We conducted a systematic review and meta-analysis evaluating retinal biomarkers in FTD compared with Alzheimer disease (AD) and controls. Methods: A systematic search of PubMed and Embase was conducted through April 25, 2026 according to PRISMA guidelines. Studies evaluating OCT/OCTA biomarkers in FTD with comparator groups were included. Inverse weighted random-effects models, publication bias assessments, and meta-regressions were performed. Results: Ten studies involving 139 individuals with FTD, 87 with AD, 29 with mild cognitive impairment, 14 with TDP-43 proteinopathy, 5 with tauopathy, and 255 controls were included in the systematic review; five studies were eligible for meta-analysis. Compared with AD, individuals with FTD demonstrated significantly thinner retinal nerve fiber layer (RNFL) thickness (SMD = -0.61, 95% CI -0.98, -0.24). Compared with controls, individuals with FTD exhibited significantly thinner ganglion cell layer-inner plexiform layer (GCL-IPL) thickness (SMD = -0.55, 95% CI -1.02, -0.08), whereas pooled analyses across multiple retinal biomarkers were non-significant (SMD = -0.19, 95% CI -0.52, 0.14). RNFL thickness correlated negatively with female % in FTD and positively with age in both AD and controls. Conclusions: Individuals with FTD exhibit lower RNFL thickness than AD and lower GCL-IPL thickness than controls, suggesting retinal alterations may reflect neurodegeneration. However, larger longitudinal studies with standardized OCT/OCTA protocols are needed to determine the diagnostic and prognostic utility of retinal biomarkers in FTD

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: Spinal pain, including neck pain and low back pain (LBP), is a common musculoskeletal condition and major contributor to disability worldwide. Evidence comparing disability, fatigue and mental health across acute and chronic stages remains limited, particularly in conflict-affected and low-resource settings. This study assessed these outcomes among patients with acute and chronic neck pain and LBP in the Gaza Strip. Methods: A comparative cross-sectional study was conducted among 410 adults attending outpatient physical therapy at Nasser Medical Complex, Khan Younis, Gaza Strip. Participants included 204 with neck pain and 206 with LBP, classified as acute neck pain (n=101), chronic neck pain (n=103), acute LBP (n=102) and chronic LBP (n=104). Disability, fatigue, psychological distress and sleep disturbance were assessed using the Neck Disability Index (NDI)/Oswestry Disability Index (ODI), Fatigue Severity Scale (FSS), Patient Health Questionnaire-4 (PHQ-4) and PROMIS Sleep Disturbance Short Form 8a. Independent t-tests, adjusted linear regression, correlation analyses, clinical-threshold analyses and binary logistic regression were performed. Results: Chronic neck pain and chronic LBP were associated with significantly higher disability, fatigue and psychological distress than acute pain. Chronic neck pain patients had higher NDI, FSS and PHQ-4 scores than acute neck pain patients; chronic LBP patients had higher ODI, FSS and PHQ-4 scores than acute LBP patients (all p<0.001). Sleep disturbance did not differ significantly between groups. Female participants reported higher psychological distress in both pain groups, with higher fatigue in neck pain and higher disability in LBP. Adjusted analyses confirmed that chronic pain status remained associated with higher disability, fatigue and psychological distress. Fatigue was the most consistent factor independently associated with chronic pain status. Conclusions: Chronic spinal pain was associated with greater disability, fatigue and psychological distress than acute spinal pain, while sleep disturbance was common across groups. These findings support early multidimensional assessment, including screening for fatigue and psychological distress. Longitudinal studies are needed to clarify whether these factors contribute to transition from acute to chronic spinal pain.

Introduction: Blood neurofilament light chain (NfL) is an accessible biomarker of neuroaxonal injury across a broad range of neurological disorders, but its clinical implementation requires robust cross-platform analytical and clinical comparability. The objective of this study was to evaluate the analytical and clinical comparability of plasma NfL measurements using Simoa and Lumipulse across different neurological conditions, by assessing cross-platform agreement and the ability of both assays to distinguish neurological diseases from healthy controls. Paired CSF analyses were performed in a subset of participants to biologically anchor plasma findings to the central compartment. Methods: 383 individuals were included, comprising healthy controls and patients with neurodegenerative conditions, multiple sclerosis and stroke. Plasma NfL was measured in all participants using both Simoa and Lumipulse, with paired CSF analyses in a subset of 92 individuals The Lumipulse testing intermediate precision and between-day repeatability was assessed as by the CLSI EP15. Cross-platform agreement for plasma NfL was evaluated using correlation analyses, Passing-Bablok regression and Bland-Altman analysis. Associations between plasma/CSF NfL concentrations were assessed using Spearman's rank correlation analysis for each platform, separately. Age-adjusted cross-diagnostic differences were evaluated using permutation ANCOVA and multiple linear regression models for each platform, separately. Results: Plasma NfL measured by Simoa and Lumipulse showed strong cross-platform concordance in the whole cohort ({rho}=0.90), with similarly strong concordance observed for CSF NfL in the subset with paired samples ({rho}=0.90). Method-comparison analyses in plasma demonstrated consistent agreement between platforms, with identifiable constant and proportional bias, alongside systematically higher absolute plasma NfL values measured by Lumipulse. Within-platform analyses showed significant correlations between plasma and CSF NfL concentrations ({rho}=0.72 for Simoa; {rho}=0.78 for Lumipulse). Noteworthy, Lumipulse NfL CSF and Blood kits exhibited high precision and analytical accuracy. Across both assays, plasma NfL increased with age and was significantly elevated in patients with neurological disorders compared with healthy controls. Discussion: Simoa and Lumipulse capture a consistent biological signal in plasma across patients with neurological disorders, although their absolute NfL values differ, supporting the use of platform-specific reference ranges in clinical practice.

Brain-derived tau (BD-tau) is an emerging blood-based biomarker for neurodegeneration, yet there are currently limited well validated BD-tau assays available for research and clinical use. To enhance access to this vital biomarker for neurological disorders including traumatic brain injury (TBI), we developed a novel blood-based immunoassay for BD-tau on the ultra-sensitive Quanterix HD-X platform using Single Molecule Array technology. Analytical validation assessed dilution linearity, specificity, precision, detection limits, and spike recovery, each recording robust metrics in agreement with international expert recommendations. The assay demonstrated robust validation metrics, achieving between-run stability of 95% when analyzing aliquots from six independent plasma and serum samples across five analytical runs. It also showed strong dilution linearity when diluted four-fold and achieved over 90% recovery when spiked with cerebrospinal fluid. Next, we evaluated the clinical utility of the assay in cohorts of individuals with traumatic brain injury (TBI), where strong performances were recorded whether using the 2-step or 3-step assay formats ({rho}= 0.94; p < 0.0001). Furthermore, plasma BD-tau distinguished samples from TBI patients based on time from injury and severity (AUC=0.93). Plasma BD-tau differentiated between favorable and unfavorable functional outcomes in the acute-severe group. Our findings underscore the significant potential of the BD-tau assay as a biomarker for TBI in the severe phase.

Objectives: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder with predominant striatal pathology in affected males, who frequently show hyperechogenicity of the lentiform nucleus on transcranial sonography. We aim to investigate female mutation carriers and female healthy controls using transcranial sonography to identify potential abnormalities in the striatum, substantia nigra, and ventricular system. Methods: We examined 81 participants (35 female mutation carriers and 46 female controls) using transcranial sonography to assess the presence of hyperechogenicity of the lentiform nucleus, the area of substantia nigra hyperechogenicity, and the widths of the lateral and third ventricles. Clinical evaluation focused on dystonic and parkinsonian symptoms, and we determined genotypes relevant for four X-linked dystonia-parkinsonism genetic modifiers. Results: Female mutation carriers showed more subtle parkinsonian signs compared with controls. The prevalence of hyperechogenicity of the lentiform nucleus was higher in female mutation carriers and was associated with a more unfavorable genetic modifier profile. No relevant abnormalities were observed in the substantia nigra or the ventricular system. Imbalanced X-chromosome inactivation in favor of the wildtype allele expression was not significantly associated with clinical severity or hyperechogenicity of the lentiform nucleus frequency, although female mutation carriers with such an imbalance showed no parkinsonian signs and only rarely hyperechogenicity of the lentiform nucleus (1/8, 13%). Conclusions: Women carrying the X-linked dystonia-parkinsonism-causing variant display subtle parkinsonian signs and frequently exhibit hyperechogenicity of the lentiform nucleus, supporting hyperechogenicity of the lentiform nucleus as a sensitive imaging marker of early neurodegenerative change, especially in those with higher genetic risk.

Importance: Accurate prediction of chronic traumatic encephalopathy (CTE) remains challenging in life. Objective: To assess the reliability and validity of the NINDS traumatic encephalopathy syndrome (TES) criteria to predict CTE pathology in life. Design: Clinicopathological Diagnostic/Prognostic Study Setting: Six brain banks with varied recruitment criteria Participants: Brain donors were selected across 6 brain banks (15+ donors each), 5 age groups spanning ages 20 to 80+ (25+ donors each) and 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): (1) college or professional American football; (2) less than college football; (3) college or professional contact sports, non-football; (4) less than college contact sports, non-football; (5) military combat, no contact sports; (6) military combat and contact sports; (7) concussion with loss of consciousness, no RHI; (8) moderate to severe TBI, no RHI; (9) no RHI/TBI. Exposures: Blinded to neuropathological information, clinicians reviewed prospective study and medical records and conducted informant interviews, and an expert panel adjudicated TES diagnoses, including provisional levels of certainty for CTE pathology (suggestive/possible/probable). TES diagnoses were a priori dichotomized: TES with possible/probable CTE (CTEpos/prob) vs. no TES/TES with suggestive CTE (CTEsug). Main Outcomes and Measures: Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). CTE diagnoses were a priori dichotomized: stages II-IV vs. no CTE/stage I. Results: Among 193 brain donors [men:153 (79.3%), mean age:66.4 (SD:22.0)], 57 (29.5%) donors met clinical criteria for CTEpos/prob and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. There was high agreement between panelists for CTEpos/prob vs. no TES/CTEsug (ICC:0.95, 95%CI:0.88-0.97). CTEpos/prob sensitivity, specificity, positive likelihood ratio (LR) and negative LR for CTE stages II-IV were: 0.77 (95%CI:0.64-0.89), 0.84 (95%CI:0.78-0.90), 4.8 (95%CI:3.02-7.61), 0.28 (95%CI:0.15-0.50); age[&ge;]50:0.90 (95%CI:0.80-1), 0.90 (95%CI:0.85-0.96), 9.2 (95%CI:4.9-17.27), 0.11 (95%CI:0.04-0.33). All younger false positives (age<50; n=13) had a mental health, substance use and/or pain disorder. All older false positives (age[&ge;]50; n=11) had non-CTE neurodegenerative and vascular pathologies. Among 10 false negatives, 8 had stage II CTE. Conclusions and Relevance: The NINDS TES criteria demonstrated good reliability, sensitivity and specificity, and provided moderate to large evidence to both rule out and rule in CTE pathology, particularly above age 50.

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.

Background: Post-stroke apathy (PSA) is a common, disabling syndrome with few evidence-based treatment options. We evaluated the safety, feasibility, acceptability, and evidence of effects of a three-day accelerated intermittent theta burst stimulation-repetitive transcranial magnetic stimulation (iTBS-rTMS) protocol targeting the left dorsomedial prefrontal cortex (dmPFC) in chronic stroke survivors with apathy. Methods: Stroke survivors with symptomatic apathy received open-label iTBS-rTMS at the left dmPFC (21,600 pulses across 36 sessions; 3 treatment days; 12 sessions/day within one week). Safety endpoints included adverse events, neuroradiological findings, and objective cognitive performance. Secondary outcomes included measures of apathy and other neuropsychiatric symptoms as well as psychosocial functioning, including quality of life and caregiver burden. Participants were followed up for one month. Results: Fourteen participants (mean age = 61.8 {+/-} 14.0 years; mean time since stroke = 55.6 {+/-} 31.6 months) completed the iTBS-rTMS treatment course. No serious adverse events occurred. Participants rated the treatment as highly acceptable, and cognitive performance was stable from pre- to post-rTMS with no treatment-related changes on structural MRI. Regarding apathy, participants had significant improvements with moderate to large effect sizes on the Lille Apathy Rating Scale (LARS), on both self (d = 0.78) and caregiver-rated versions (d = 1.28), p<0.05 pretreatment-to-one-month follow-up. In addition, secondary measures of psychosocial function also showed improvement with moderate to large effect sizes (Stroke Specific Quality of Life Scale: d = 0.62; Zarit Burden Interview: d = 0.72), and the Brief Inventory of Psychosocial Function: d = 0.89). Conclusions: In chronic stroke survivors with PSA, accelerated iTBS-rTMS targeting the left dmPFC appears to be safe, feasible, tolerable, and highly acceptable, with preliminary evidence suggesting a potential role in reducing apathy and secondarily promoting improvements in quality of life, caregiver burden, and broader psychosocial function.

BackgroundEndovascular thrombectomy (EVT) is the standard of care for acute ischemic stroke caused by large-vessel occlusion. However, the additional benefit of intravenous thrombolysis (IVT) before EVT remains controversial. This systematic review and meta-analysis evaluated the efficacy and safety of bridging therapy (EVT plus IVT) compared with EVT alone. MethodsThis systematic review and meta-analysis was conducted according to PRISMA 2020 and Cochrane Handbook recommendations and prospectively registered in PROSPERO. PubMed, EMbase, Scopus, and the Cochrane Library were searched for randomized controlled trials published between 1st January 2015 and 30th April 2026 comparing EVT plus IVT versus EVT alone in acute ischemic stroke. Random-effects meta-analysis was performed to estimate pooled odds ratios (ORs) with 95% confidence intervals (CIs). Primary outcomes included functional independence at 90 days and successful recanalization. Secondary outcomes included symptomatic intracranial hemorrhage (sICH) and all-cause mortality. ResultsEleven randomized controlled trials involving 4,419 patients were included in the meta-analysis. Compared with EVT alone, bridging therapy was associated with significantly better functional independence at 90 days (OR=1.25; 95% CI: 1.02-1.53). Patients receiving EVT plus IVT also demonstrated a trend toward higher rates of successful recanalization (OR=1.25; 95% CI: 0.95-1.64) and lower 90-day mortality (OR=0.84; 95% CI: 0.67-1.04). The risk of sICH was comparable between the two treatment strategies (OR=1.07; 95% CI: 0.81-1.40). Overall, the certainty of evidence was rated as moderate. ConclusionsBridging therapy before EVT may improve functional outcomes and recanalization without increasing sICH, supporting its use as a reasonable treatment strategy in eligible patients with acute ischemic stroke.

Introduction: Aphasia is an acquired language disorder with a significant negative functional impact. Much of the research on aphasia has focused on word-level language comprehension and production. Further evaluation of discourse-level tasks, both at behavioral and neural levels, will allow for an ecologically valid understanding of the functional implications of language impairment in this population. Method: This study evaluated bilateral frontal, temporal, and parietal cortical activity during computer-based narrative production in 14 young neurotypical individuals, 17 individuals with post-stroke aphasia, and 15 age-matched neurotypical participants using functional near-infrared spectroscopy (fNIRS). Oxygenated hemoglobin (HbO) was measured during narrative production following short video clips and compared to HbO during counting aloud. In addition, behavioral measures quantifying in-task performance were correlated with averaged HbO values. Results: Young neurotypical individuals showed greater cortical activity in bilateral language regions for narrative production compared to counting aloud. In contrast, people with aphasia showed positive condition-related effects in the right frontal ROI and the age-matched group showed positive condition-related effects in the left frontal and right precentral ROIs. Each group showed different patterns in relationships between cortical activity and discourse performance measures. Conclusion: Overall, young participants showing more consistent condition-related effects for narrative discourse production than individuals with aphasia and age-matched controls. This study shows the potential for fNIRS to evaluate cortical activity for ecologically valid language tasks in individuals with post-stroke aphasia.

Spastic dysarthria diagnosis through subjective neurologist auditory-perceptual assessment remains standard practice despite known inaccuracy. To address this gap, we developed an objective framework grounded in phonetic evidence that spastic dysarthria preferentially impairs initial consonant articulation, using automatic speech recognition (ASR) to quantify dysarthria and localize corticobulbar lesions. We created four reading sentences targeting groups of initial consonants: labial (facial), lingual-alveolar (tongue), and velopharyngeal (pharyngeal/soft-palate) sentence, along with a mixed-consonant sentence for comparative evaluation. Thirty-seven patients with neuroimaging-confirmed corticobulbar lesions and 37 controls read each sentence. ASR transcribed dysarthric speech into text, and we computed a "syllable-error score" by counting incorrectly transcribed syllables. This yields a clinically meaningful feature that makes syllable-level phonetic errors explicit. Logistic regression models were trained for each sentence, and performance was summarized by the area under the receiver operating characteristic curve (AUC) across 10,000 resampled train-test splits. Consonant-specific sentences significantly outperformed the mixed sentence: the lingual-alveolar sentence performed best with (median AUC 0.88), followed by the labial (0.80), then the velopharyngeal sentence (0.72), while the mixed-consonant sentence was lowest (0.67). These results suggest that the interpretable ASR-derived syllable error feature, combined with a relevant machine learning classifier could inform clinical insight into consonant-specific vulnerability in spastic dysarthria, with lingual-alveolar consonants appearing particularly informative. Overall, this novel ASR-based framework, together with phonetics-informed feature design provides objective, accurate, and clinically meaningful digital quantification for spastic dysarthria detection and corticobulbar lesion localization.

Background: Comorbidities are common in multiple sclerosis (MS) and may influence disability outcomes, but their dynamic impact on bidirectional disability transitions and long-term disability remains incompletely understood. Better understanding of this longitudinal relationship could inform personalized disability management strategies for people with MS. Methods: We leveraged two large electronic health record (EHR)-linked MS registries and applied multi-state Markov models (MSMs) to examine the extent to which individual comorbidities and overall comorbidity burden were associated with short-term disability transitions, long-term disability transition probabilities, and expected time spent in each disability state. We additionally compared MSM-based predictions of confirmed disability worsening (CDW) with Cox proportional hazards (CoxPH) model-based predictions using the integrated Brier score with bootstrap validation. Results: Among 3,723 patients with MS (74.6% female; 86.2% non-Hispanic White; mean age=41.9 years; mean disease duration=5.4 years) contributing 41,860 disability assessments over a mean follow-up of 7.3 years, higher cardiometabolic and psychiatric comorbidity burden was associated with increased transition intensity toward worse disability states and decreased transition intensity toward improvement, with a stepwise gradient across burden levels. Compared with patients without comorbidities, those with [&ge;]4 comorbidities had a 28% higher risk of worsening (HR=1.28 [1.06, 1.55]) and a 20% lower risk of improvement (HR=0.80 [0.67, 0.95]). Each individual comorbidity was significantly associated with worse disability transitions. Long-term estimates indicated a higher 5-year probability of severe disability and fewer years spent in the no-disability state among patients with greater comorbidity burden. CoxPH models showed directionally consistent associations but lower predictive accuracy for CDW compared with MSMs. Conclusion: Cardiometabolic and psychiatric comorbidities are associated with worse disability trajectories in MS, reducing improvement and accelerating progression. By providing a nuanced framework to quantify short-term disability transitions and long-term disability patterns, MSMs may have real-world clinical utility in disability prediction.

Background and Purpose Prognostication after acute ischemic stroke often relies on limited variables and simple risk scores, despite richer information being available at admission. We developed a multimodal AI model using admission data to predict modified Rankin Scale (mRS) outcomes and compared it to established tools. Methods In a retrospective study of ischemic stroke/TIA patients, we trained three modality-specific models on admission non-contrast head CT, history and physical notes, and structured clinical variables, and combined them in a weighted-average ensemble. We predicted binary (mRS 0-2 versus 3-6) and ordinal mRS (0-6) outcomes at discharge and 90 days. Performance on an external test cohort was compared with THRIVE and SPAN-100 scores using AUROC, AUPRC, Brier score, mean absolute error (MAE), and quadratic weighted kappa (QWK). Results A total of 6,915 patients were split into training, validation and testing cohorts in a 3:1:1 ratio. For discharge binary mRS (n=1596), the multimodal ensemble achieved significantly better discrimination (AUROC 0.859, AUPRC 0.858) with 25-61% lower Brier scores than THRIVE or SPAN?100 (all p<0.001). For 90?day binary mRS (n=207), the model also outperformed both THRIVE and SPAN-100 (AUROC 0.838, AUPRC 0.805, with 3-38% lower Brier scores). Ordinal mRS prediction showed similarly strong performance with significantly better QWK at discharge and numerically lower MAE. The multimodal ensemble model reassigned about one?third of patients to different risk categories versus THRIVE and was closer to the true discharge outcome in ~74% of discordant cases. Conclusions We developed a well-calibrated multimodal AI model for prediction of discharge and 90-day post-stroke functional outcomes using only data present at the time of admission. This model outperforms existing prognostic tools and can support early clinical decision-making.