Faculty Bibliography

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.

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.

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.

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.

INTRODUCTION/BACKGROUND:Cannabis use is rising in the United States. Up to 30 % of individuals who use cannabis develop cannabis use disorder (CUD), for which there are no FDA-approved treatments. This randomized controlled trial (RCT) evaluated the feasibility and efficacy of a novel, one-month telehealth intervention of remotely supervised tDCS (RS-tDCS) paired with mindfulness meditation. This home-based telehealth intervention was evaluated in a cohort of women with multiple sclerosis (MS), a vulnerable subpopulation of adults with high rates of CUD. METHODS:The intervention included 20 home-based RS-tDCS sessions targeting the left DLPFC, delivering 2.0mA for 20minutes, paired with guided mindfulness meditation. Sessions were conducted 5 days per week for four weeks. Fifty-two women with MS and CUD (age: 44 ± 10 years) consented to participate; 47 were randomized 2:1 to active or sham tDCS. Feasibility was assessed via retention and adherence, while preliminary efficacy was measured by cannabis use, withdrawal symptoms, and MS-related symptom scales. RESULTS:Of 47 randomized participants (31 active, 16 sham), 39 (83 %) completed the intervention. The active tDCS group showed significant reductions in weekly cannabis use (Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory, DFAQ-CU: 5.3 ± 2.4 vs. 3.9 ± 2.7 days, p = 0.014) and withdrawal symptoms (CWS: p < 0.001). A trend toward reduced MS-related symptoms was observed (SymptoMScreen: p = 0.031). Cognitive performance improvement at the end of the intervention was significant in the active group (p = 0.011 vs. p = 0.172), supporting functional benefits of reduced cannabis use. CONCLUSIONS:This pilot RCT supports the feasibility and preliminary efficacy of telehealth tDCS in a medical subpopulation. Studying women with MS highlights its potential for large-scale RCTs and clinical use.

OBJECTIVE:The application of transcranial direct current stimulation (tDCS) at home for the treatment of depression and other neuropsychiatric disorders presents both significant opportunities and inherent challenges. Ensuring safety and maintaining high-quality stimulation are paramount for the efficacy and safety of at-home tDCS. This study investigates tDCS quality based on its technical parameters as well as safety of at-home and in-clinic tDCS applications comparing the data from two randomized controlled trials in patients with major depressive disorder. METHODS:We analyzed 229 active stimulation sessions from the HomeDC study (at-home tDCS) and 835 sessions from the DepressionDC study (in-clinic tDCS). Notably, five adverse events (skin lesions) were reported exclusively in the at-home cohort, highlighting the critical need for enhanced safety protocols in unsupervised environments. RESULTS:= .097). The at-home tDCS sessions exhibited higher impedance variability (M = 837, SD = 328) compared to in-clinic sessions (M = 579, SD = 309). Furthermore, at-home tDCS sessions resulting in adverse events (AEs) were associated with significantly higher average impedances than sessions without such issues. CONCLUSION/CONCLUSIONS:The study demonstrates that monitoring the technical parameters of at-home tDCS used in this study is essential. However, it may be not sufficient for ensuring safety and promptly detecting or preventing adverse events. Quality control protocols including digital training and monitoring techniques should be systematically developed and tested for a reliable and safe application of at-home tDCS therapies.

More than half of individuals with multiple sclerosis (MS) use cannabis, with up to 20 % at risk of cannabis use disorder (CUD). While some individuals with MS report symptom relief from cannabis use, particularly for pain, sleep, and mood, there is limited support for its evidence-based therapeutic use. In contrast, long-term use has been associated with poorer cognitive and emotional functioning, fatigue, and reduced quality of life. Although reducing or stopping cannabis use has shown benefits, there is a lack of accessible interventions. We recruited nationally for a pilot study of a remotely supervised home-based intervention to reduce cannabis use among women with MS and CUD. The trial response provided critical insights into cannabis use patterns and the significant demand for accessible, effective interventions, highlighting an urgent unmet need within the MS community.

BACKGROUND:Childhood environmental factors back to the prenatal environment can contribute to MS risk. Childhood adversity, which causes biological, behavioral, and epigenetic changes that can be passed down through families, has been understudied in MS. Here, we emphasize the need to understand the role that intergenerational adversity may play among families affected by MS. OBJECTIVE:To evaluate the frequency and types of adverse childhood experiences among parents of children with MS. METHODS:Individuals with pediatric MS (n = 68) were enrolled in a longitudinal study of cognition. At enrollment, the patient and one caregiver or parent completed questionnaires. As the pediatric participants were under age 18 at time of enrollment, one parent completed the Adverse Childhood Experiences (ACEs, a 10-item self-report measure) about the parents' own childhood. Results from the ACE questionnaire among parents of pediatric healthy controls (n = 96) and adults in a national cohort are also reported for comparison. RESULTS:Over half of pediatric MS parents reported at least one ACE exposure. Of parents that did have ACE exposures, the exposures were broad in terms of abuse, neglect, and household dysfunction. Over 10 % of parents reported total ACE scores of 7 or above. CONCLUSION/CONCLUSIONS:Over half of pediatric MS parents experienced some degree of childhood adversity. The impact of intergenerational adversity on the development of pediatric onset MS warrants further study.