Faculty Bibliography

Childhood adversity is increasingly recognized as a critical modifier of neurologic disorder development and disease severity, including in the neuroimmune disorder multiple sclerosis (MS). While previous studies have linked early-life adversity to increased MS susceptibility and more severe disease, the underlying biological mechanisms remain poorly understood. This study investigated associations between childhood adversity and MS clinical features, with a focus on two potential pathogenic mechanisms: allostatic load and epigenetic modifications. We evaluated 60 consecutively enrolled young adults with MS; 30 with paediatric-onset MS (POMS) and 30 with adult-onset MS (AOMS). At time of enrolment in this cross-sectional study, participants had MS disease duration of 6 years on average. POMS participants were mean 22.09 (2.66) years and AOMS participants were mean 32.41 (2.19) years old. 62% of participants were female. Childhood adversity was defined using a composite index of individual, family and socioeconomic measures captured by the adverse childhood experiences questionnaire, parental education level and estimated household income during childhood. Clinical outcomes included patient-reported SymptoMScreen questionnaire regarding MS symptom burden and MS neurologist-assessed disability using the Expanded Disability Status Scale (EDSS) of the participant's neurologic exam at the time of enrolment. Circulating biomarkers of allostatic load and genome-wide epigenetic profiles (DNA methylation via RRBS; reduced representation bisulfite sequencing) were also assessed. A history of high childhood adversity was associated with significantly greater patient-reported MS symptom burden (P = 0.001) and higher neurologist-reported EDSS disability scores (P = 0.028), independent of disease duration or timing of treatment initiation. There were no differences between childhood adversity and circulating biomarkers of allostatic load. While childhood adversity was not associated with global epigenetic changes across the entire cohort, stratified analysis revealed divergent methylation patterns by age of MS onset: POMS participants with childhood adversity had increased DNA methylation, whereas AOMS participants with childhood adversity showed decreased methylation compared to individuals without childhood adversity. None of the observed clinical and biologic differences were explained by differences in disease duration or the interval between symptom onset and treatment initiation. Our findings suggest that childhood adversity is associated with increased MS symptom burden and neurologic disability in young adults with MS. Childhood adversity may differentially shape the epigenome, depending on the age of MS onset, with potential implications for disease trajectory and therapeutic vulnerability. These results support the biological embedding of childhood adversity in MS and highlight the need for age- and exposure-sensitive approaches to understanding MS pathogenesis across the lifespan.

IMPORTANCE/UNASSIGNED:Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. OBJECTIVE/UNASSIGNED:To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. INTERVENTIONS/UNASSIGNED:Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. RESULTS/UNASSIGNED:A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT05965739.

OBJECTIVE:To assess real-world effectiveness of switching disease-modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. METHODS:Of 2615 pediatric-onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. RESULTS:A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety-three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52-1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20-0.57; rate ratio: 0.38, 95% CI = 0.21-0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09-0.37; rate ratio: 0.21, 95% CI = 0.10-0.44) (p < 0.001). Adjusted number needed to treat in person-years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03-8.69) and infusion over injectable 1.43 (95% CI = 1.00-3.88). INTERPRETATION/CONCLUSIONS:Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long-term safety data are required. ANN NEUROL 2025.

OBJECTIVE/UNASSIGNED:Chronic non-specific lower back pain (cNSLBP) is a prevalent and disabling condition, imposing a substantial socioeconomic burden due to high healthcare costs and productivity losses, with limited accessible and effective long-term treatment options. Automated Thermo-mechanical Therapy (ATT) is a promising, non-drug intervention that leverages innovative technical advances to provide multimodal pain relief, offering accessibility and low-cost delivery. This study tested ATT for immediate pain relief in individuals with cNSLBP in a single-session, double-blind, randomized controlled trial. METHODS/UNASSIGNED:= 20) in a 40-min session with urn randomization. The active device applied heated cylindrical rollers along the spine, using far-infrared heat and mechanical tissue stimulation tailored to spinal alignment. In the control condition, the device used minimal mechanical therapy intensity without heat, targeting only the cervical area to avoid lower back therapeutic effects. Pre- and post-intervention assessments measured changes in pain intensity (primary outcome) via a 100-mm Visual Analog Scale for Pain (VAS-P100), alongside secondary outcomes assessing pain characteristics, anxiety, and functional mobility. RESULTS/UNASSIGNED:= 0.0031). No adverse events were reported, and all participants tolerated the intervention well. CONCLUSIONS/UNASSIGNED:A single session of ATT provides immediate, significant pain relief in individuals with cNSLBP, supporting its potential as a safe, non-invasive option for managing chronic back pain. Future studies should examine the long-term benefits of repeated ATT sessions and explore mechanistic insights into thermo-mechanical stimulation's effects on pain and function. CLINICAL TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov, identifier: NCT06769321.

This guideline summarizes updated safety data (2017-2025) and provides expert recommendations on the use of low intensity transcranial electrical stimulation (tES) in humans. tES encompasses several techniques including transcranial direct current stimulation (tDCS), oscillatory transcranial direct current stimulation (otDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), transcranial temporal interference stimulation (tTIS), and their combinations or variations. Across over 300,000 sessions involving healthy individuals, patients with neuropsychiatric conditions, and other clinical populations, no tES-related serious adverse events (AEs) have been reported. Moderate AEs are rare and limited to a small range of specific applications. Mild AEs are common and include transient symptoms such as localized sensations (e.g., tingling or burning), headaches, and fatigue. Similar mild AEs are also reported by individuals receiving placebo stimulation. The frequency, magnitude, and type of AEs are comparable across healthy, clinical, and vulnerable groups, including children, elderly, or pregnant women. Combined interventions (e.g., co-application with EEG, TMS, or neuroimaging) have not shown increased safety risks. Safety is well-established for both bipolar and multichannel tES when applied up to 4 mA and up to 60 min per day. Higher intensities and longer stimulation durations may also be safe. Nevertheless, the number of studies using intensities above 4 mA or stimulating longer than 60 min is low. Home-based use of treatments is growing rapidly, leveraging remote supervision to provide patients with greater access and enable repeated, sustained dosing paradigms. We recommend using screening and AE questionnaires in future controlled studies, in particular when planning to extend the stimulation parameters applied. We discuss recent regulatory and ethical issues.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Pediatric multiple sclerosis (MS) affects children and adolescents at an important time for neurologic and cognitive development. Although cognitive impairment has been described, few longitudinal studies of cognitive functioning in pediatric MS with matched controls are available. Here, we report the 2-year follow-up cognitive results of a cohort of participants with MS and healthy controls (HCs) recruited from multiple regions of the United States. METHODS:Three cohorts-participants with pediatric MS, age-matched pediatric HC, and adults with early-onset MS-were recruited across 7 sites through the United States Network of Pediatric MS Centers. Two cognitive batteries, Cogstate Brief Battery (CBB) and Brief International Cognition Assessment for MS (BICAMS), were administered at baseline and follow-up. The primary outcome was the change in CBB composite z-score compared between groups. Change in BICAMS composite z-score was also compared, as were change in z-scores of individual measures. Reliable change indices (RCIs) were calculated to determine meaningful change over time. RESULTS:= 0.022. DISCUSSION/CONCLUSIONS:Most individuals with pediatric MS early in their disease showed stable cognitive function over a 2-year period and had longitudinal changes that were largely similar to pediatric controls. A subset of participants with pediatric MS declined in cognitive processing speed relative to pediatric controls.

BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection (PASC) is characterized by persistent cognitive deficits alongside anxiety and depression symptoms that adversely affect quality of life. Cognitive training (CT) programs and non-invasive neuromodulation, specifically transcranial direct current stimulation (tDCS), have each shown promise for alleviating similar deficits in non-clinical populations. However, their combined efficacy has not yet been evaluated in PASC patients. Therefore, this study aimed to determine whether the combination of CT and tDCS produces benefits for cognitive and mood-related symptoms in individuals with PASC. METHODS:We conducted a double-blind, randomized, sham-controlled clinical trial in adults aged 18-75 with confirmed SARS-CoV-2 infection within the past six months and persisting cognitive complaints. They were randomized to a 4-week in-person intervention of 20 weekday sessions of either active (2 mA anodal-left, cathodal-right prefrontal stimulation) or sham tDCS paired with an app-based CT program. Primary outcomes were six standardized neuropsychological tests assessing verbal memory, working memory, executive functioning, attention, and language, administered at baseline and immediately post-intervention. As secondary outcomes, we assessed changes in depression and anxiety symptoms over the treatment period. RESULTS:Sixty participants (mean age 43.8 ± 13.2 years, 71.7 % women) were randomized to active tDCS + CT or sham tDCS + CT groups, and 52 finished the trial. Compared to sham, tDCS + CT resulted in significantly greater improvement in tests evaluating inhibitory control (effect size [ES] = 0.07, 95 % CI 0 to 0.23, p = 0.046), processing speed (ES = 0.08, 95 % CI 0 to 0.25, p = 0.034), and divided attention (ES = 0.08, 95 % CI 0 to 0.24, p = 0.039), but not in tests evaluating other domains. Both groups improved similarly in depression and anxiety symptoms. Participant's and rater's active guess rates did not differ between groups (ps > 0.20). CONCLUSION/CONCLUSIONS:An intervention with prefrontal targeted tDCS + CT in patients with PASC with cognitive complaints might be effective in improving attention, processing speed and inhibitory control, although further studies are warranted to prospectively confirm these findings. CLINICALTRIALS/RESULTS:GOV: NCT05389592.

BACKGROUND/UNASSIGNED:Cognitive impairment is common in multiple sclerosis (MS). Transcranial direct current stimulation (tDCS) combined with adaptive cognitive training (aCT) may improve clinical outcomes. OBJECTIVE/UNASSIGNED:To evaluate the effect of active vs. sham home-based tDCS + aCT on cognitive function. METHODS/UNASSIGNED:-scores. RESULTS/UNASSIGNED: = .411). CONCLUSIONS/UNASSIGNED:Active vs. sham tDCS + aCT resulted in significantly better cognitive outcomes, with the greatest benefit in those with high neurologic disability.CLINICALTRIALS.GOV; https://clinicaltrials.gov/study/NCT03838770; IDENTIFIER: NCT03838770.

INTRODUCTION/UNASSIGNED:Gait is a critical indicator of neurological health, with changes often signaling underlying decline. We developed a remote gait monitoring protocol using off-the-shelf shoe-based sensors (RunScribe) to assess gait parameters in real-world home settings. This protocol, known as Gait Assessment with Innovative Technologies - Home-based Use and Benefit (GAIT-HUB), was tested in individuals with multiple sclerosis (MS), a population at high risk for gait impairment due to the disease's variable progression. METHODS/UNASSIGNED:Participants with MS completed an in-clinic baseline gait assessment using a validated sensor (G-Sensor®) and three weekly, remotely supervised gait assessments at home using the RunScribe sensors. Gait parameters were compared across devices using intra-class correlation coefficients (ICCs) and Bland-Altman analyses. Longitudinal reliability of remote assessments and system usability score (SUS) were evaluated. RESULTS/UNASSIGNED:Twenty-nine participants (76% women, ages 19-67, PDDS range 0-5) successfully completed the home-based assessments. High agreement between devices was observed for gait speed, stride length, and cadence (ICCs >0.90), though phases like stance and swing showed more variability. Bland-Altman analyses indicated minimal bias in most parameters. Longitudinal assessments demonstrated strong reliability (ICCs >0.87) for key metrics, and SUS indicated good-to-excellent usability of the remote protocol. CONCLUSION/UNASSIGNED:The GAIT-HUB protocol enables reliable and feasible home-based gait monitoring using wearable sensors that patients can easily self-apply. This approach provides valuable insights into daily mobility patterns beyond clinical visits, supporting more precise and timely assessments of functional status between appointments and offering the potential for seamless integration into telemedicine routine care.