Faculty Bibliography

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.

Depression is a common and debilitating disorder affecting millions. First-line treatments fail to achieve remission in about one-third of patients, highlighting a critical treatment need. Transcranial direct current stimulation (tDCS) has emerged as a novel treatment for depression. Therefore, the aim of this review was to provide a comprehensive overview of the last decade of tDCS trials for depression and propose future research directions. To compile studies of the past decade, we conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) of tDCS for depression. A total of 21 RCTs were included, presenting a moderate effect for active tDCS compared to placebo. We also provided a description of study designs, stimulation parameters, and patients' characteristics. Following, we proposed possible strategies to enhance clinical effectiveness and reduce variability in results, including 1) optimization/personalization of tDCS via spatial and temporal target localization; 2) optimized methodological strategies, including home-based, accelerated tDCS protocols and novel trial designs; and 3) investigate patient profile to identify features that can predict treatment response. In conclusion, tDCS holds promise as a treatment for depression, but variability in trial parameters and outcomes underscores the need for its further optimization. Refining and standardizing protocols may enhance its effectiveness.

Fatigue is a common and often debilitating feature of multiple sclerosis (MS) that lacks reliably effective treatment options for most patients. Transcranial direct current stimulation (tDCS), a safe and well-tolerated type of noninvasive brain stimulation, is a low-cost and home-based approach with the potential to reduce fatigue in MS. We conducted a double-blind, sham-controlled, randomized clinical trial to compare active vs. low-dose (sham) tDCS paired with computer-based cognitive training, delivered as a home-based intervention, to reduce MS-related fatigue. Participants with MS-related fatigue, but without depression, were stratified by neurologic disability using the Extended Disability Status Scale (EDSS) and randomized to complete 30 daily sessions over six weeks of either active or sham tDCS paired with online cognitive training (BrainHQ). The primary outcome was the change in PROMIS Fatigue score from baseline to the end of the intervention. A total of 117 participants were randomized, with 92% completing all treatment sessions. Both groups showed significant reductions in fatigue, with no significant difference between them. This suggests that tDCS does not provide any additional benefit over cognitive training alone in reducing fatigue, but confirms the feasibility and tolerance of this home-based intervention.

BACKGROUND/OBJECTIVES/UNASSIGNED:Primary progressive aphasia (PPA) is managed with speech-language therapy (SLT) to slow language decline. Pairing transcranial direct current stimulation (tDCS) with SLT can enhance its effects. However, further research is needed to confirm these findings and guide its clinical use. We evaluated the feasibility of providing an intervention combining tDCS with SLT as a home-based and remotely supervised intervention. METHODS/UNASSIGNED:Participants with confirmed PPA who had word-finding difficulties were recruited for an open-label observational study. The intervention consisted of 20 daily sessions over 1 month, each with 45-min of personalized word retrieval training. During the first 30-min, participants received tDCS over the left inferior frontal gyrus (anode F7, cathode O1) at 2.0 mA. Language measures were remotely administered at baseline and intervention end. RESULTS/UNASSIGNED:= 0.016) from baseline to intervention end. CONCLUSIONS/UNASSIGNED:Our case series demonstrates that home-based tDCS added to SLT is feasible for patients with PPA. However, larger controlled studies are required to confirm its effectiveness in slowing language decline and to fully determine the benefits of this approach. This approach not only facilitates broader access to participation but also enables the extended treatment necessary to evaluate its clinical benefits, moving this treatment closer to clinical availability as a telehealth treatment.

BACKGROUND/UNASSIGNED:Many individuals with progressive multiple sclerosis (PMS) are challenged by reduced manual dexterity and limited rehabilitation options. Transcranial direct current stimulation (tDCS) during motor training can improve rehabilitation outcomes. We developed a protocol for remotely supervising tDCS to deliver sessions of stimulation paired with training at home. OBJECTIVE/UNASSIGNED:This study evaluated the effectiveness of at-home tDCS paired with manual dexterity training for individuals with PMS. METHODS/UNASSIGNED:Sixty-five right-hand dominant participants with PMS and hand impairment were randomized to receive either active or sham M1-SO tDCS paired with manual dexterity training over 4 weeks. Clinical outcomes were measured by the changes in Nine-Hole Peg Test (9-HPT) and Dellon-Modified-Moberg-Pick-Up Test (DMMPUT). RESULTS/UNASSIGNED:= 0.04). CONCLUSION/UNASSIGNED:At-home tDCS paired with manual dexterity training is effective for individuals with PMS, with M1-SO tDCS enhancing training outcomes and offering a promising intervention for improving and preserving hand dexterity.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Psychosocial adversity and stress, known to predispose adults to neurodegenerative and inflammatory immune disorders, are widespread among children who experience socioeconomic disadvantage, and the associated neurotoxicity and proinflammatory profile may predispose these children to multiple sclerosis (MS). We sought to determine associations of socioeconomic disadvantage and psychosocial adversity with odds of pediatric-onset MS (POMS), age at POMS onset, and POMS disease activity. METHODS:This case-control study used data collected across 17 sites in the United States by the Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis Study. Cases (n = 381) were youth aged 3-21 years diagnosed with POMS or a clinically isolated demyelinating syndrome indicating high risk of MS. Frequency-matched controls (n = 611) aged 3-21 years were recruited from the same institutions. Prenatal and postnatal adversity and postnatal socioeconomic factors were assessed using retrospective questionnaires and zip code data. The primary outcome was MS diagnosis. Secondary outcomes were age at onset, relapse rate, and Expanded Disability Status Scale (EDSS). Predictors were maternal education, maternal prenatal stress events, child separation from caregivers during infancy and childhood, parental death during childhood, and childhood neighborhood disadvantage. RESULTS:= 0.025). There were no associations of the socioeconomic variables with age at onset, relapse rate, or EDSS, or of prenatal or postnatal adverse events with risk of POMS, age at onset, relapse rate, or EDSS. DISCUSSION/CONCLUSIONS:Low socioeconomic status at the neighborhood level may increase the risk of POMS while high parental education may be protective against POMS. Although we did not find associations of other evaluated prenatal or postnatal adversities with POMS, future research should explore such associations further by assessing a broader range of stressful childhood experiences.

OBJECTIVES/OBJECTIVE:When administered in repeated daily doses, transcranial direct current stimulation (tDCS) directed to the prefrontal cortex has cumulative efficacy for the treatment of depression. Depression can be marked by altered processing of emotionally salient information. An acute marker of response to tDCS may be measured as an immediate change in emotional information processing. Using an easily administered web-based task, we tested immediate changes in emotional information processing in acute response to tDCS in participants with and without depression. MATERIALS AND METHODS/METHODS:We enrolled n = 21 women with mild-to-moderate depression and n = 20 controls without depression to complete a web-based visual search task before and after 30 minutes of tDCS directed to the prefrontal cortex. The timed task required participants to identify a target face among arrays showing sad, neutral, or mixed (distractor) expressions. RESULTS:At baseline, as predicted, the participants with depression differed from those without in emotional processing speed (mean z score difference -0.66 ± 0.27, p = 0.022) and accuracy in identifying sad stimuli (error rate: 4.4% vs 1.8%, p = 0.039). In response to tDCS, the participants with depression became significantly faster on the distractor condition (pre- vs post-tDCS z scores: -0.45 ± 0.65 vs -0.85 ± 0.65, p = 0.009), suggesting a specific reduction in bias toward negative emotional information. In response to tDCS, the depressed group also had significant improvements in self-reported mood (increased happy, decreased sad and anxious mood). CONCLUSIONS:Participants with depression vs those without were differentiated by their performance of the visual search task at baseline and in response to tDCS. Given that measurable effects on depression scales may require weeks of tDCS treatments, acute change in emotional information processing can serve as an easily obtainable marker of depression and its response to tDCS. CLINICAL TRIAL REGISTRATION/BACKGROUND:The Clinicaltrials.gov registration number for the study is NCT05188248.

BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection (PASC) symptoms have broad impact, and may affect individuals regardless of COVID-19 severity, socioeconomic status, race, ethnicity, or age. A prominent PASC symptom is cognitive dysfunction, colloquially referred to as "brain fog" and characterized by declines in short-term memory, attention, and concentration. Cognitive dysfunction can severely impair quality of life by impairing daily functional skills and preventing timely return to work. METHODS:RECOVER-NEURO is a prospective, multi-center, multi-arm, phase 2, randomized, active-comparator design investigating 3 interventions: (1) BrainHQ is an interactive, online cognitive training program; (2) PASC-Cognitive Recovery is a cognitive rehabilitation program specifically designed to target frequently reported challenges among individuals with brain fog; (3) transcranial direct current stimulation (tDCS) is a noninvasive form of mild electrical brain stimulation. The interventions will be combined to establish 5 arms: (1) BrainHQ; (2) BrainHQ + PASC-Cognitive Recovery; (3) BrainHQ + tDCS-active; (4) BrainHQ + tDCS-sham; and (5) Active Comparator. The interventions will occur for 10 weeks. Assessments will be completed at baseline and at the end of intervention and will include cognitive testing and patient-reported surveys. All study activities can be delivered in Spanish and English. DISCUSSION/CONCLUSIONS:This study is designed to test whether cognitive dysfunction symptoms can be alleviated by the use of pragmatic and established interventions with different mechanisms of action and with prior evidence of improving cognitive function in patients with neurocognitive disorder. If successful, results will provide beneficial treatments for PASC-related cognitive dysfunction. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.