Faculty Bibliography

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.

The neuropsychological aspects of multiple sclerosis (MS) have evolved over the past three decades. What was once thought to be a rare occurrence, cognitive dysfunction is now viewed as one of the most disabling symptoms of the disease, with devastating effects on patients' quality of life. This selective review will highlight major innovations and scientific discoveries in the areas of neuropathology, neuroimaging, diagnosis, and treatment that pertain to our understanding of the neuropsychological aspects of MS. Specifically, we focus on the recent discovery that MS produces pathogical lesions of gray matter (GM) that have consequences for cognitive functions. Methods for imaging these GM lesions in MS are discussed along with multimodal imaging studies that integrate structural and functional imaging methods to provide a better understanding of the relationship between cognitive test performance and functional reserve. Innovations in the screening and comprehensive assessment of cognitive disorders are presented along with recent research that examines cognitive dysfunction in pediatric MS. Results of innovative outcome studies in cognitive rehabilitation are discussed. Finally, we highlight trends for potential future innovations over the next decade. (JINS, 2017, 23, 832-842).

Background: Fatigue is known for being one of the most debilitating and common symptoms of multiple sclerosis (MS). Despite its prevalence, though, reliable treatment options are lacking. Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation treatment that uses low amperage (2.0 mA) electric current to stimulate cortical regions. tDCS has been shown to improve fatigue in MS following consecutive daily treatment sessions. We have recently developed and shown the feasibility of a remotely supervised tDCS (RS-tDCS) protocol to ease the burden of daily sessions and allow patients to complete the treatment at home. We aim to evaluate the efficacy of RS-tDCS in fatigue management for patients with MS. Methods: We enrolled n = 31 patients with MS (all subtypes) into a randomly controlled, double-blind trial; n = 27 patients provided data for analysis with n = 15 randomized to the active group and n = 12 in the placebo or "sham" group. Participants came to the clinic for baseline and follow-up measures including self-report forms on fatigue. At baseline they were also trained in operating the tDCS headset. Participants then took the device home where they complete 20 sessions of tDCS (20 minutes, 2.0 mA, dorsolateral prefrontal cortex montage, left anodal) paired with cognitive training. Results: Our primary outcome measure was the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue scale. When comparing change in PROMIS Fatigue between the active and sham tDCS groups we found that active tDCS participants had significantly greater reductions in fatigue (mean change in Active =-5.6 +/- 8.9 vs. Sham = 0.9 +/- 1.9, p = 0.02 conditions). We analyzed the within-subject effect tDCS had and found a significant, beneficial effect in the active group (pre-treatment mean = 26.6 +/- 9.2, post-treatment mean = 21.0 +/- 6.4, p = 0.04) and no such effect in the sham group (pre-treatment mean = 22.9 +/- 7.9, post-treatment mean = 23.8 +/- 8.4, p = 0.15). Finally, we calculated Cohen's d effect size (Active d =-0.71, Sham d = 0.11). Conclusions: These data suggest that RS-tDCS provides significant reduction in MS-related fatigue

BACKGROUND: Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade. OBJECTIVE: To examine potential environmental factors in pediatric MS using geographic information systems (GIS). METHODS: Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects' geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence <20 or >/=20 miles from the recruiting center), using logistic regression. RESULTS: Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p = 0.90 < 20 miles from center; p = 0.43 >/= 20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR = 2.83; 95%CI 1.5, 5.4) and those who reside >/= 20 miles from a referral center (OR = 1.61; 95%CI 1.2, 2.3). CONCLUSION: Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures.

Objective: To test the relation between intra-individual variability (IIV) and cognition across the lifespan in multiple sclerosis (MS). Background: The Symbol Digit Modalities Test (SDMT) is a widely-used screen of cognitive functioning in MS across the lifespan. IIV in reaction time is a novel index of consistency across sustained performance. IIV been shown to be highly sensitive to general CNS integrity and global morbidity, and may serve as a cognitive biomarker in MS. Design/Methods: Patients with clinically-definite MS were recruited through the Lourie Center for Pediatric Multiple Sclerosis and the NYU Langone MS Comprehensive Care Center. Healthy controls were recruited for comparison purposes and utilized for the creation of the linear model that is necessary to calculate IIV scores. The SDMT and Cogstate Brief Battery were administered to all participants. The Cogstate Brief Battery consists of simple and choice reaction time tasks from which reaction time IIV was calculated. Results: A total of 187 MS participants completed the assessments ranging in age from 8 to 68 years (mean 32.9+/-17.6 years). Mean detection and identification IIV was calculated across the Cogstate reaction time measures, and predicted performance on the SDMT (r= -0.394, p<0.001). When compared to healthy controls, the effect sizes were nearly equivalent (Cohen's d = 0.53 and SDMT = 0.55, respectively). Conclusions: IIV in reaction time tasks may be used as a sensitive measure of performance variability in patients with MS and is related to cognitive performance as well. IIV is impaired in MS across the lifespan, including pediatric patients. IIV is a novel and sensitive marker of cognitive involvement in patients with MS, and may predict future cognitive decline as in other diseases

Objective: Speeded Saccadic Eye Movement Predicts Symbol Digit Modalities Test Performance in Multiple Sclerosis Background: Multiple sclerosis is an autoimmune demyelinating disease with estimates of cognitive impairment above 30% in pediatric and 50% in adult patients. The SDMT, a widely-used screening tool that measures speeded information processing, has been used to track cognitive decline in MS. The K-D test is a brief measure of saccadic eye movement speed using a timed number naming test, commonly used for the detection of mild traumatic brain injury. Here, we tested the sensitivity of the K-D test in MS and its association with performance on the SDMT. Design/Methods: Adult and pediatric patients with clinically-definite MS were consecutively recruited through the NYU Langone MS Comprehensive Care Center. All participants completed the SDMT and K-D at a single visit. Results: A total of 30 participants completed the assessments ranging in age from 13 to 72 years (mean 38 +/- 19 years), were 74% female, and with an EDSS range 0.0 to 6.5. Relative to age normative data, the K-D indicated greater impairment than the SDMT (74% vs. 48%, respectively). Controlling for age, both tests were significantly correlated (r=0.44, p =0.02), demonstrating a close contribution of oculomotor function to SDMT performance. Conclusions: The K-D test is sensitive to detecting impairment in MS across the lifespan. Performance on the SDMT is closely associated with oculomotor function in MS

Objective: To test whether the Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS) predicts real-world functioning as measured by timed instrumental activities of daily living (ADLs). Background: The BICAMS is a cognitive screen that is widely-used in clinical practice and research to assess cognitive impairment in persons with multiple sclerosis (MS). It is important for cognitive measures to predict daily functioning. We compared performance on the BICAMS to a test consisting of ten timed instrumental activities of daily living, called the Test of Everyday Cognitive Ability or TECA. Design/Methods: All participants were administered the TECA along with three BICAMS measures: Symbol Digit Modalities Test (SDMT), the Brief Visuospatial Memory Test-Revised (BVMT-R), and either the Rey Auditory Verbal Learning Test (RAVLT) or substituted with the Selective Reminding Test (SRT). The TECA items were scored according to time and errors and averaged for one representative score, with higher scores indicating greater impairment. BICAMS measures were transformed to age-normative z scores for comparison, with scores of <-1.5 considered impaired, and one or more impaired scores indicating overall BICAMS impairment. Results: A total of n=177 MS patients (mean age 45+/- 14 years, 73% female) with a median EDSS=3.0 (range of 0.0 to 8.0) completed the study. Overall, 37% met BICAMS impairment criteria. Each of the individual BICAMS measures significantly predicted performance on the TECA: SDMT, r=-.53, p<.001, BVMT-R r= -0.32, p <0.001, and Verbal Learning r= -.34, p <0.001. Worse TECA scores were associated with poorer performance on the BICAMS. Conclusions: The TECA is a measure of timed instrumental activities of daily living that is valid for use in a diverse MS population. BICAMS significantly predicts performance on the TECA, indicating that it is a useful indicator of real-world functioning

Objective: To test whether home delivery of tDCS paired with cognitive training can improve cognitive outcomes in participants with multiple sclerosis (MS). Background: Cognitive impairment is a common debilitating MS symptom. Transcranial direct current stimulation (tDCS) paired with cognitive training presents itself as a possible option for those with cognitive impairment, but requires daily sessions, placing strain on patients. Here we explore the feasibility and efficacy of a remotely- supervised tDCS protocol (RS-tDCS) paired with cognitive training for patients with MS. Design/Methods: MS participants completed 10 sessions of tDCS paired with cognitive training (1.5 mA x 20 minutes, dorsolateral prefrontal cortex montage). RS-tDCS participants were compared to a control group of adults with MS who underwent ten 20-minute cognitive training sessions through the same remotely-supervised procedures. Cognitive outcomes were tested by composite scores measuring change in performance on standard measures (Brief International Cognitive Assessment in MS or BICAMS), basic attention (Attention Network Test-Interaction (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). Results: After ten sessions, the RS-tDCS group (n=25) compared to the control group (n=20) had significant improvements in complex attention (p = 0.01) and response variability (p = 0.01) composites. The groups did not differ in change of measures of basic attention (p = 0.95) or standard BICAMS cognitive measures (p = 0.99). Conclusions: RS-tDCS paired with cognitive training is effective for enhancing complex attention and reducing response variability. The benefit of telerehabilitation using RS-tDCS combined with cognitive training may be generalizable to other conditions

Objective: Report initial results from the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) project. Background: The Learning Health System (LHS) concept involves collecting standardized clinical and imaging data during the course of patient care. The data would then serve two purposes simultaneously: data-driven clinical care decisions and systematic learning. Design/Methods: MS PATHS was designed around the LHS concept, through collaborative meetings in 2015-2016. MS PATHS participants self-administer the Multiple Sclerosis Performance Test (MSPT) at routine clinical visits. MSPT is an iPad-based medical device designed and validated for MS. MSPT includes components of the MSFC-4, NeuroQoL, and a standardized MS history. For imaging data, brain MRIs are acquired on 3T Siemens scanners using identical image acquisition parameters, to allow generation of highly standardized MRI-metrics. Participants may also elect to contribute to a biorepository. Results: As of Oct 19, 2016, seven US centers were participating in MS PATHS in collaboration with Biogen, under guidance of a steering committee of 3 neurologists and 1 neuroradiologist from participating centers and a Biogen representative. From May 17, 2016 through October 19, 2016, 1507 patients with MS were enrolled in MS PATHS, 317 with two or more visits. Data from 1127 MSPT assessments are currently available in the LHS database, 342 with brain MRIs. Opt-in rate for data sharing has exceeded 90%, suggesting the study will yield a representative population from participating centers. Across patients currently enrolled (mean+- SD): age=52+/-12 years, Walking Speed Test = 8.46 +/- 5.54 sec, and Dominant Hand Manual Dexterity Test = 28.3 +/- 7.7 sec. Updated results and lessons learned will be presented. Conclusions: MS PATHS is the first LHS established in MS. Enrollment has been rapid, and patient acceptance high. Standardized, comprehensive clinical and imaging data collection will accelerate collaborative research efforts and support data-driven patient management