RECOVER-NEURO: study protocol for a multi-center, multi-arm, phase 2, randomized, active comparator trial evaluating three interventions for cognitive dysfunction in post-acute sequelae of SARS-CoV-2 infection (PASC).

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: 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: ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.

A new look at cognitive functioning in pediatric MS.

OBJECTIVE: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. METHODS: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. RESULTS: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores (ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite (p = 0.03), Symbol Digit Modalities Test (p = 0.02), Rey Auditory Verbal Learning Test (p = 0.01), and Cogstate choice reaction time (p < 0.001). CONCLUSION: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Potential of Transcranial Direct Current Stimulation in Alzheimer's Disease: Optimizing Trials Toward Clinical Use.

Transcranial direct current stimulation (tDCS) is a safe and well-tolerated noninvasive method for stimulating the brain that is rapidly developing into a treatment method for various neurological and psychiatric conditions. In particular, there is growing evidence of a therapeutic role for tDCS in ameliorating or delaying the cognitive decline in Alzheimer's disease (AD). We provide a brief overview of the current development and application status of tDCS as a nonpharmacological therapeutic method for AD and mild cognitive impairment (MCI), summarize the levels of evidence, and identify the improvements needed for clinical applications. We also suggest future directions for large-scale controlled clinical trials of tDCS in AD and MCI, and emphasize the necessity of identifying the mechanistic targets to facilitate clinical applications.

A novel disease specific scale to characterize the symptoms and impacts of fatigue in US adults with relapsing multiple sclerosis: A real-world study.

BACKGROUND: Fatigue is among the most frequent and disabling symptoms in patients with relapsing multiple sclerosis (RMS). OBJECTIVE: To measure MS fatigue and its impact on daily life in a real-world US population using an MS-specific patient-reported outcome (PRO) instrument, the Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS). METHODS: This ongoing prospective study recruited RMS patients from an online patient community (Carenity) across US. Baseline assessment data are reported. Participants completed questionnaires, including the 20-item FSIQ-RMS questionnaire, with the first seven symptom-related items collected daily for seven days, and the other 13 items on the seventh day assessing impacts of fatigue. The FSIQ-RMS scores range from 0 to 100 (higher score=greater severity). The impact of fatigue on several aspects of patients' lives was rated from 0 (no impact) to 10 (very high impact). Data on disease history, disease status, sleep, social and emotional functioning were also captured. Baseline assessment data of 300 RMS patients are reported while follow-up assessments up to 18 months are planned. RESULTS: 300 RMS participants completed the 7-day assessment (mean age 43.0 years, 88% women). Fatigue was rated as severe, with a mean score of 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Participants who were not in relapse (78%) reported less severe fatigue than those in relapse (22%): mean±SD symptom score of 54.6 ± 17.8 vs. 67.0 ± 19.7, p< 0.001. Fatigue had a higher intensity among those with depression than without (49% vs. 51%, with mean ± SD symptom score of 62.8 ± 16.9 vs. 52.1 ± 19.3, p< 0.001), and among those with sleep disorder than without (27% vs. 73%, 61.2 ± 19.2 vs. 55.9 ± 18.6; p< 0.05). The most common factor associated with increased fatigue was heat exposure (82%). Most participants (52%) reported experiencing fatigue before their MS diagnosis. CONCLUSION: Fatigue influences daily functioning for most patients with RMS. The FSIQ-RMS is a novel and MS-specific PRO measure that can advance the understanding and management of fatigue.

No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: Real-world evidence from MS PATHS.

BACKGROUND: Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy. METHODS: Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EID + SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons. RESULTS: The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; p = 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; p = 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; p = 0.566) and -0.11% (-0.25%, -0.10%; p = 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p<0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p<0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; p = 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p<0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison. CONCLUSIONS: The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics.

Enhancing Mood, Cognition, and Quality of Life in Pediatric Multiple Sclerosis.

Pediatric-onset multiple sclerosis (POMS), representing approximately 5% of all MS cases, affects the central nervous system during its ongoing development. POMS is most commonly diagnosed during adolescence but can occur in younger children as well. For pediatric patients with MS, it is critical to manage the full impact of the disease and monitor for any effects on school and social functioning. Disease management includes not only disease-modifying therapies but also strategies to optimize wellbeing. We review the interventions with the highest evidence of ability to improve the disease course and quality of life in POMS. High levels of vitamin D and a diet low in saturated fat are associated with lower relapse rates. Exercise ameliorates fatigue and sleep. Behavioral strategies for sleep hygiene and mood regulation can also improve fatigue and perceived health. POMS management should be addressed holistically, including assessing overall symptom burden as well as the psychological and functional impact of the disease.

Virtual reality is a feasible intervention platform in multiple sclerosis: A pilot protocol and acute improvements in affect.

BACKGROUND: People living with multiple sclerosis (MS) experience a high symptom burden that interferes with daily functioning. Virtual reality (VR) is an emerging technology with a range of potential therapeutic applications that may include ameliorating the experience of some common MS symptoms. OBJECTIVE: We tested the feasibility and tolerability of a VR intervention and its preliminary effects on affect. METHODS: Participants with MS were recruited to complete a pilot study of eight sessions of VR over four weeks. RESULTS: A total of n = 16 participants with MS completed the study (age range: 28-63). Feasibility goals were met with 100% of the sample completing at least n = 4/8 of their intervention sessions, with a total of 119/128 (93%) completed sessions. Two of the n = 16 participants experienced brief adverse events (balance, vertigo) but these resolved with headset removal and were not otherwise treatment limiting. There was a preliminary indication of overall improved affect from baseline to intervention end, with significantly improved positive affect (t(15) = -3.19, p = 0.006) and decreased negative affect (t(15) = 2.25, p = 0.040). CONCLUSION: VR interventions are feasible, safe, and tolerable for individuals living with MS and may improve affect.

Cognitive Telerehabilitation with Transcranial Direct Current Stimulation Improves Cognitive and Emotional Functioning Following a Traumatic Brain Injury: A Case Study.

OBJECTIVE: Cognitive deficits following a traumatic brain injury (TBI) are a leading cause of disability in young adults and there is a critical need for novel approaches to improve cognitive outcomes in TBI survivors. Transcranial direct current stimulation (tDCS) paired with cognitive remediation has emerged as a viable, cost-effective, noninvasive approach for treating cognitive impairments in a wide variety of neurological conditions. Here, we report the first case study utilizing remotely supervised tDCS (RS-tDCS) protocol paired with cognitive remediation in a 29-year-old man with persisting cognitive and emotional sequelae following TBI. METHOD: Neuropsychological measures were administered before and after the patient completed 20 daily sessions of RS-tDCS (2.0 mA × 20 minutes, left anodal dorsolateral prefrontal cortex montage). During the daily stimulation period, he completed adaptive cognitive training. All treatment procedures were delivered at home and monitored in real time via videoconference with a study technician. RESULTS: Following 20 RS-tDCS and cognitive training sessions, he had significant improvements (>1 SD) on tests of attention and working memory, semantic fluency, and information processing speed. Mood was also improved. CONCLUSIONS: This is the first demonstration of at-home telerehabilitation with RS-tDCS and cognitive training to improve cognitive outcomes following TBI.

An Interview-Based Assessment of the Experience of Cognitive Impairment in Multiple Sclerosis: The Cognitive Assessment Interview (CAI).

Background: Cognitive impairment is a common feature of multiple sclerosis (MS). A semi-structured interview, including informant input, can characterize the experience of individuals living with MS and cognitive involvement. Objective: We administered the Cognitive Assessment Interview (CAI), a patient- and informant-based semi-structured interview, to characterize the experience of cognitive impairments in those living with MS. Methods: Trained raters administered the CAI to a sample of MS participants and their informants enrolled for a trial of cognitive remediation. Cognitive impairments on the CAI were characterized and compared to those captured by neuropsychological and self-report measures. Results: A total of n = 109 MS participants (mean age = 50.3 ± 12.2) and their available informants (n = 71) were interviewed. Participants reported experiencing processing speed (90/106, 85%), working memory (87/109, 80%), and learning and memory (79/109, 72%) problems most commonly. CAI-based ratings were moderately correlated with a self-report measure (Multiple Sclerosis Neuropsychological Screening Questionnaire, r s = 0.52, p < 0.001) and only mildly correlated with objective neuropsychological measures specific to executive functions (r s = 0.21, p = 0.029). For those with informant interviews, ratings were overall consistent, suggesting that the CAI is valid even in cases in which an informant is unavailable and the interview is conducted with the patient alone (as is often the case in clinical and research settings). Conclusions: The CAI provides a semi-structured interview to characterize the experience of cognitive impairment in MS, with findings representing real-world functioning, adding valuable information to both self-report measures and neuropsychological assessment.

Remote administration of the symbol digit modalities test to individuals with multiple sclerosis is reliable: A short report.

BACKGROUND: The Symbol Digit Modalities Test (SDMT) is the gold standard for cognitive screening in multiple sclerosis (MS). OBJECTIVE: Due to the recent COVID-19 pandemic and the increased need for virtual clinical visits, we examined the reliability of remote administration of the SDMT vs. standard in-person administration to individuals with MS. METHODS: Pearson's correlation analysis was performed between SDMT scores on the in-person and remote administrations. RESULTS: For n = 132 participants, remote and in-person SDMT scores were strongly correlated (r = .80, p = .000). CONCLUSION: Remote administration of the SDMT is a reliable cognitive screening approach in MS.

Early neuropsychological markers of cognitive involvement in multiple sclerosis.

BACKGROUND: Cognitive impairment due to multiple sclerosis (MS) is common and often limits occupational functioning, contributes to disability, and reduces quality of life. Early detection of cognitive involvement in MS is critical for treatment planning and intervention, and frequent, regular cognitive monitoring may provide insight into subtle changes in disease progression. OBJECTIVE: To compare the sensitivity and specificity of clinical, computer-based and experimental measures to early cognitive involvement in MS. METHODS: Cognitive functioning was compared in MS participants early in the disease course to matched healthy controls using conventional, computer-based and functional assessments: the Brief International Cognitive Assessment in MS (BICAMS); the computer-based Cogstate Brief Battery (CBB); the Attention Network Test-Interaction (ANT-I), including intra-individual variability; and the Test of Everyday Cognitive Ability (TECA), a functional measure of instrumental activities of daily living. RESULTS: MS participants (n = 25, mean disease duration= 5.82 ± 3.65 years) and demographically matched healthy controls (n = 29) completed the cognitive assessments. The Cogstate measure of choice reaction time (AUC = 0.73, p = .004), intra-individual variability on the ANT-I (AUC = 0.79, p = .001), and TECA (AUC = 0.78, p = .001) scores were the most sensitive and specific markers of cognitive involvement in MS. CONCLUSIONS: Brief, repeatable, computer-based measures of reaction time and variability detect early MS associated cognitive involvement.

Telerehabilitation benefits patients with multiple sclerosis in an urban setting.

INTRODUCTION: People living with multiple sclerosis (MS) often require rehabilitation to manage their symptoms. Telerehabilitation offers improved access to treatment options by reducing travel time and cost. Our telerehabilitation program pairs training exercises simultaneously with transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique. In the current study, we characterized the benefits of our remotely supervised tDCS (RS-tDCS) at-home telerehabilitation protocol in an urban sample of MS participants. METHODS: Participants with MS were recruited to complete a telerehabilitation trial using tDCS paired with cognitive rehabilitation at-home using remote supervision (RS-tDCS). Participant time and travel costs for study visits to our clinic in midtown New York City were calculated. RESULTS: Forty-four patients with MS (aged 18 to 71) with mild to severe neurologic disability (Expanded Disability Status Scale score median = 3.5, range: 0.0 to 8.0) completed the survey. Round-trip clinic attendance required 2.3 ± 2.3 h and US $27.04 ± 38.13 for out-of-pocket expenses. Participants rated difficulty of clinic attendance as moderately to significantly difficult (2.5 ± 1.3). Severity of neurologic disability accounted for the greatest variance in difficulty attending clinic (30%, p < 0.001). RS-tDCS had 95% treatment compliance and 93% of participants reported satisfaction with the at-home treatment. DISCUSSION: Attending clinic is associated with significant costs for patients with neurologic disorders, even in urban settings. Rehabilitation can be delivered at home and supervised in real-time via videoconference.

Update on the Use of Transcranial Electrical Brain Stimulation to Manage Acute and Chronic COVID-19 Symptoms.

The coronavirus disease 19 (COVID-19) pandemic has resulted in the urgent need to develop and deploy treatment approaches that can minimize mortality and morbidity. As infection, resulting illness, and the often prolonged recovery period continue to be characterized, therapeutic roles for transcranial electrical stimulation (tES) have emerged as promising non-pharmacological interventions. tES techniques have established therapeutic potential for managing a range of conditions relevant to COVID-19 illness and recovery, and may further be relevant for the general management of increased mental health problems during this time. Furthermore, these tES techniques can be inexpensive, portable, and allow for trained self-administration. Here, we summarize the rationale for using tES techniques, specifically transcranial Direct Current Stimulation (tDCS), across the COVID-19 clinical course, and index ongoing efforts to evaluate the inclusion of tES optimal clinical care.

Gait and Functional Mobility in Multiple Sclerosis: Immediate Effects of Transcranial Direct Current Stimulation (tDCS) Paired With Aerobic Exercise.

Walking impairments are a debilitating feature of multiple sclerosis (MS) because of the direct interference with daily activity. The management of motor symptoms in those with MS remains a therapeutic challenge. Transcranial direct current stimulation (tDCS) is a type of non-invasive brain stimulation that is emerging as a promising rehabilitative tool but requires further characterization to determine its optimal therapeutic use. In this randomized, sham-controlled proof-of-concept study, we tested the immediate effects of a single tDCS session on walking and functional mobility in those with MS. Seventeen participants with MS completed one 20-min session of aerobic exercise, randomly assigned to be paired with either active (2.5 mA, n = 9) or sham (n = 8) tDCS over the primary motor cortex (M1). The groups (active vs. sham) were matched according to gender (50% vs. 60% F), age (52.1 ± 12.85 vs. 54.2 ± 8.5 years), and level of neurological disability (median Expanded Disability Status Scale score 5.5 vs. 5). Gait speed on the 10-m walk test and the Timed Up and Go (TUG) time were measured by a wearable inertial sensor immediately before and following the 20-min session, with changes compared between conditions and time. There were no significant differences in gait speed or TUG time changes following the session in the full sample or between the active vs. sham groups. These findings suggest that a single session of anodal tDCS over M1 is not sufficient to affect walking and functional mobility in those with MS. Instead, behavioral motor response of tDCS is likely to be cumulative, and the effects of multiple tDCS sessions require further study. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03658668.

Functional Connectivity and Structural Disruption in the Default-Mode Network Predicts Cognitive Rehabilitation Outcomes in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Efficacy of restorative cognitive rehabilitation can be predicted from baseline patient factors. In addition, patient profiles of functional connectivity are associated with cognitive reserve and moderate the structure-cognition relationship in people with multiple sclerosis (PwMS). Such interactions may help predict which PwMS will benefit most from cognitive rehabilitation. Our objective was to determine whether patient response to restorative cognitive rehabilitation is predictable from baseline structural network disruption and whether this relationship is moderated by functional connectivity. METHODS: For this single-arm repeated measures study, we recruited 25 PwMS for a 12-week program. Following magnetic resonance imaging, participants were tested using the Symbol Digit Modalities Test (SDMT) pre- and postrehabilitation. Baseline patterns of structural and functional connectivity were characterized relative to healthy controls. RESULTS: Lower white matter tract disruption in a network of region-pairs centered on the precuneus and posterior cingulate (default-mode network regions) predicted greater postrehabilitation SDMT improvement (P = .048). This relationship was moderated by profiles of functional connectivity within the network (R2 = .385, P = .017, Interaction ß = -.415). CONCLUSION: Patient response to restorative cognitive rehabilitation is predictable from the interaction between structural network disruption and functional connectivity in the default-mode network. This effect may be related to cognitive reserve.

Supervised transcranial direct current stimulation (tDCS) at home: A guide for clinical research and practice.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a method of noninvasive neuromodulation and potential therapeutic tool to improve functioning and relieve symptoms across a range of central and peripheral nervous system conditions. Evidence suggests that the effects of tDCS are cumulative with consecutive daily applications needed to achieve clinically meaningful effects. Therefore, there is growing interest in delivering tDCS away from the clinic or research facility, usually at home. OBJECTIVE: To provide a comprehensive guide to operationalize safe and responsible use of tDCS in home settings for both investigative and clinical use. METHODS: Providing treatment at home can improve access and compliance by decreasing the burden of time and travel for patients and their caregivers, as well as to reach those in remote locations and/or living with more advanced disabilities. RESULTS: To date, methodological approaches for at-home tDCS delivery have varied. After implementing the first basic guidelines for at-home tDCS in clinical trials, this work describes a comprehensive guide for facilitating safe and responsible use of tDCS in home settings enabling access for repeated administration over time. CONCLUSION: These guidelines provide a reference and standard for practice when employing the use of tDCS outside of the clinic setting.

Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline.

BACKGROUND: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS. OBJECTIVE: To screen for cognitive impairment early in the course of POMS and analyze predictive factors. METHODS: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free. RESULTS: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing (n = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT. CONCLUSION: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.