Faculty Bibliography

Introduction: Cognitive impairment represents a frequent and troubling symptom of multiple sclerosis (MS) in need of treatment options. Transcranial direct current stimulation (tDCS) uses scalpbased electrodes to pass mild electrical current (< 4mA) through target cortical brain regions and is a safe and well-tolerated treatment. We have developed a protocol to deliver remotely supervised cognitive remediation paired with tDCS to individuals with MS at home.
Objective(s): To test whether at-home cognitive remediation augmented with tDCS will lead to improved training outcomes in MS.
Aim(s): Cognitive processing speed was assessed at baseline and study end by the Cogstate Brief Battery. Age normative z scores were computed for the Cogstate Brief Battery scores, with outcome measured by change in the average z score of information processing assessments.
Method(s): MS participants with cognitive impairment were recruited and randomized to complete 40 sessions of either active or sham tDCS paired with either adaptive or non-adaptive cognitive training (aCT or nCT). Training was completed at home using study-provided equipment and remotely supervised via videoconference using our established probed (RS-tDCS). Training was 20 minutes in duration and was completed five times a week (M-F) for approximately eight weeks. Participants were blinded and received active (2.5mA) or sham stimulation and cognitive training simultaneously during each session.
Result(s): To date, n=19 MS participants have successfully complete the 40 session training program at home: n=6 in active/aCT, n=8 in Sham/aCT, and n=5 in active/nCT. Mean age was 49+/-15 years of age and mean years of education was 16.5+/-2.1. The majority of participants had the RRMS subtype (63%, with 11% PPMS, and 26% SPMS). The participants were matched on cognitive status as measured by the symbol digit modality test (ANOVA p=0.09). tDCS and the cognitive training were uniformly well tolerated with no safety concerns. At the group level, all three groups showed improvement from baseline (0.75, 0.56, 0.59 z-score improvement for each condition respectively), indicating that both tDCS and aCT can be of benefit. Further, as predicted, the active tDCS paired with aCT experienced the greatest benefit (Cohen's d = 0.51).
Conclusion(s): Our telerehabiltiation protocol allows for participants to receive extended cognitive training paired with tDCS at home, resulting in improved outcomes from cognitive remediation

BACKGROUND:Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS:In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS:-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). CONCLUSIONS:Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIG MS ClinicalTrials.gov number, NCT01892722 .).

OBJECTIVE:Cognitive impairment is a common symptom of multiple sclerosis (MS) that can lead to declines in daily functioning. Timed instrumental activities of daily living (TIADLs) have been useful to bridge between cognitive testing and real-world functioning in disorders such as Alzheimer's disease and other dementias. However, these have not been standardized for general use, and the tasks that are typically employed have not been sensitive to the detection of milder forms of cognitive deficits. We developed a test of ten TIADLs tasks to measure a broader range of functioning, entitled the "Test of Everyday Cognitive Ability" or TECA, and tested its utility in a diverse sample of participants with MS. METHOD/METHODS:TECA performance was characterized in n = 177 participants with MS and compared to healthy controls (n = 49). A subset from each group received repeated administration. In addition, all participants completed a standard battery of neuropsychological measures. RESULTS:TECA performances were significantly different between MS and control participants. Further, MS participants with cognitive impairment performed significantly slower relative to those MS participants without impairment. CONCLUSIONS:The TECA is a TIADLs assessment appropriate for use in those with MS as it includes a broad range of task difficulties, requires minimum motor involvement, and is sensitive to MS-related cognitive impairment. The TECA is a brief and repeatable test of TIADLs and its ease of administration makes it suitable for both clinical practice and research settings.

Background and aims: Approximately 3-5% of Multiple Sclerosis (MS) cases manifest in childhood and adolescence, characteristically with highly active inflammatory disease course. Paediatric-onset MS (POMS) has an impact on brain integrity and may increase Brain Volume Loss (BVL) above age-expected rates. This study assessed the effect of oral Fingolimod up to 0.5mg daily versus intramuscular interferon (IFN) beta-1a 30mug once weekly on MRI outcomes in POMS patients. Methods: In this double-blind, double-dummy, activecontrolled, multicentre study, patients with POMS (aged 10-<18 years) received either Fingolimod (dose adjusted for body weight; N=107) or IFN beta-1a (N=107) for up to 2 years. MRI was performed at baseline and every 6 months until the End Of The Study (EOS) core phase. Key MRI outcomes were the number of new/newly enlarging T2 (n/ neT2) lesions and Gd-enhancing T1 (Gd+T1) lesions, Annual Rate Of Brain Volume Change (ARBVC), annualised rate of number of new T1 hypointense lesions, change in total T2 Hyperintense Lesion Volume (T2LV) and the number of Combined Unique Active Lesions (CUAL). Results: At the EOS, compared with IFN beta-1a, fingolimod significantly reduced the annualised rate of n/ neT2 lesions (52.6%; p<0.001), number of Gd+T1 lesions per scan (66.0%; p<0.001), ARBVC (-0.48% vs. -0.80%, p=0.014), annualised rate of number of new T1 hypointense lesions (62.8%; p<0.001), T2LV (percent change from baseline: 18.4% vs. 32.4%, p<0.001) and CUAL per scan (60.7%; p<0.001). Conclusion: Fingolimod significantly reduced MRI activity and slowed BVL for up to 2 years vs. IFN beta-1a in paediatric-onset MS

OBJECTIVE: To explore the efficacy of remotely-supervised transcranial direct current stimulation (RS-tDCS) paired with cognitive training (CT) exercise in participants with multiple sclerosis (MS). METHODS: In a feasibility study of RS-tDCS in MS, participants completed ten sessions of tDCS paired with CT (1.5 mA x 20 min, dorsolateral prefrontal cortex montage). RS-tDCS participants were compared to a control group of adults with MS who underwent ten 20-min CT sessions through the same remotely supervised procedures. Cognitive outcomes were tested by composite scores measuring change in performance on standard tests (Brief International Cognitive Assessment in MS or BICAMS), basic attention (ANT-I Orienting and Attention Networks, Cogstate Detection), complex attention (ANT-I Executive Network, Cogstate Identification and One-Back), and intra-individual response variability (ANT-I and Cogstate identification; sensitive markers of disease status). RESULTS: After ten sessions, the tDCS group (n = 25) compared to the CT only group (n = 20) had significantly greater improvement in complex attention (p = 0.01) and response variability (p = 0.01) composites. The groups did not differ in measures of basic attention (p = 0.95) or standard cognitive measures (p = 0.99). CONCLUSIONS: These initial findings indicate benefit for RS-tDCS paired with CT in MS. Exploratory analyses indicate that the earliest tDCS cognitive benefit is seen in complex attention and response variability. Telerehabilitation using RS-tDCS combined with CT may lead to improved outcomes in MS.