Faculty Bibliography

Objective: To evaluate whether tDCS improves fatigue in MS and the role of baseline affect in response, using a remotely-supervised telerehabilitation protocol. Background: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that alters cortical excitability through low amplitude currents. Previous work suggests tDCS as a method for symptomatic management in MS. However, these initial studies have been limited due to small sample sizes and few active treatment sessions. Design/Methods: Participants completed ten 20 minute sessions of tDCS (1.5 mA, dorsolateral prefrontal cortex, left anodal) paired with cognitive training. Sessions were completed from home using our RS-tDCS protocol. All participants completed baseline and follow-up mood and fatigue self-report measures including the Modified Fatigue Impact Scale (MFIS) and the Positive and Negative Affect Schedule (PANAS). Baseline positive affect (PA) and negative affect (NA) were z-transformed and averaged into a representative affect score. Results: Participants (n=25) aged 30 to 69 years with a range of impairment (Expanded Disability Status Scale (EDSS) scores of 1.0 to 8.0) and all subtypes were enrolled. RS-tDCS treatment led to clear improvements in both dimensions of affect (PA, Cohen's d = 0.32 and NA, d = -0.66) and fatigue (MFIS, d = -0.59). Participants' baseline affect score correlated with change in NA (r = 0.61, p < 0.01) and MFIS (r = 0.39, p = 0.06). Among participants who had a baseline affect z-score less than 0 (n=17) indicating affect disturbance, there was a greater magnitude of improvement and significant change from baseline (PA, d = 0.57, p=0.02; NA d = -1.07, p < 0.001; and MFIS d = -0.84, p<0.01). Conclusions: Telerehabilitation using RS-tDCS improves mood and fatigue in MS patients treated at home, with greater effects found in those with baseline features of mood or anxiety

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

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 changes in fine motor speed predict change in cognitive functioning in pediatric onset MS (POMS). Background: Multiple sclerosis is an autoimmune demyelinating disease that has a pediatric (<18 years) onset in 3-5% of all cases. Cognitive impairment is a frequent and disabling symptom for approximately 30% of POMS patients. As in adults, the earliest cognitive involvement can be measured by the Symbol Digit Modalities Test or SDMT, a measure of speeded information processing. Fine motor slowing occurs frequently in both adult and pediatric patients, but its relation to cognitive functioning remains unclear. The Lafayette grooved pegboard serves as a measure of fine motor functioning and has previously been shown to be sensitive in MS samples. Design/Methods: POMS patients were consecutively recruited through the Lourie Center for Pediatric MS and the NYU Langone MS Comprehensive Care Center. All participants completed the SDMT and the Lafayette grooved pegboard (dominant and non-dominant hand conditions) at two separate visits (using an alternate form for the SDMT). Both SDMT and pegboard performances were transformed to age-normative z scores for comparison. Results: A total of n=26 POMS participants completed both assessments. The mean age was 16.5+/-3.08 years and 58% were female. The mean time between study visits was 193+/-148 days. Both measures improved at repeat administration, with mean SDMT and pegboard z scores improving from 0.11+/-1.39 to 0.34+/-1.41 and -1.56+/-1.68 to -1.21+/-2.55, respectively. Change in pegboard performance significantly predicted change in the SDMT (r=0.58, p=0.002)

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: To investigate patient reported outcomes predictive of conversion to SPMS in an aging sample of MS patients. Background: The secondary progressive (SP) phase of multiple sclerosis (MS) is characterized by a progressive accumulation of neurological disability, preceded by a relapsing remitting (RR) disease course. Older age at disease onset, high frequency of relapses and male sex have frequently been found to be predictive of a higher risk of disease conversion. Design/Methods: Subjects are part of the New York State Multiple Sclerosis Consortium (NYSMSC). Patients with an RRMS disease type at study enrollment, age 50 or over, with a disease duration of at least 15 years were selected for this study (n=155). Chi-squared tests and logistic regression modelling were used to investigate the predictive value of patient reported outcomes at study enrollment and conversion to SPMS at year 5. Results: Five years after study enrollment (median disease duration=22 years), 47 (30.3%) RRMS subjects progressed to SPMS. Those who converted were older at study enrollment (54.8 vs 52.1, p=.01), and had a higher Kurtzke Expanded Disability Status Scale (EDSS) at both baseline (3.5 vs 2.6, p<.001), and at year 5 (5.6 vs 3.0, p<.001). Patients who progressed at year 5 were more likely to report lower limb problems at baseline (53.2% vs 21.5%, OR: 3.0, p<.001), and were more likely to report some degree of fatigue (91.5% vs 68.2%, OR: 4.2, p=.004), compared to those who did not progress, even after adjusting for age, disease duration and EDSS. Fatigue and lower limb problems were strongly correlated (p-value=0.001). Conclusions: Fatigue and lower limb problems at baseline were predictive of a higher chance of conversion after 5 years of follow-up. Targeting patients with these symptoms may result in more successfully predicting patients at higher risk of disease conversion and subsequently tailoring therapeutic strategies

Objective: To confirm our preliminary findings of association between EBV, CMV and HSV-1 remote infections, serum 25(OH)vitamin D levels and pediatric-MS in a large national case-control study. Background: Prior studies have suggested possible associations between viral infections acquired during childhood and development of MS. Moreover, vitamin D deficiency and genetic polymorphisms in the vitamin D pathway may alter the immune response and are associated with increased risk of pediatric and adult MS. Design/Methods: Patients with pediatric-onset MS or CIS and frequency-matched controls were recruited at 16 pediatric MS centers across the US. Batched Epstein-Barr virus(EBV)-viral capsid antigen(VCA), Epstein-Barr nuclear antigen-1(EBNA-1), EBV-early antigen(EA), CMV, HSV-1 and -2 serostatus were tested by ELISA.25(OH)vitamin D levels were determined by chemoluminescence. The rates of viral seropositivity and serum levels of vitamin D were compared between cases and controls in analyses adjusted for possible confounders such as age, sex, race and ethnicity. DRB1*1501 status was determined using SNP typing. Results: Serum samples from 360 pediatric cases(mean age: 15.2+/-3.2 years, 64% females, mean disease duration 354+/-321 days)and 496 healthy controls(mean age:14.3+/-3.8 years, 52% females)were tested for EBV, CMV and HSV antibodies and 25(OH)vitamin D. In a model adjusting for age, sex, race and ethnicity, a remote infection with EBV(anti-EBNA1 IgG positive)was strongly associated with higher risk of developing pediatric-onset MS(OR:3.6, 95%CI 2.1-6.3). HSV-1 seropositivity was also associated with pediatric-onset MS(OR:1.4, 95%CI 1.001-2.011). There was no association between serostatus for CMV and HSV-2 and risk of pediatric MS. For vitamin D analyses, we compared controls with 42 cases who were recruited within 45 days of disease onset as serum levels could not yet be substantially altered by vitamin D supplementation. There was a trend towards an association between lower serum levels of vitamin D and the risk of developing pediatric MS. For each 1 ng increase in 25(OH)vitamin D serum levels, there was a 3% reduction in the risk of pediatric MS onset(OR:0.77, 95%CI 0.93-1.01). Analyses stratifying by DRB1*1501 status are ongoing. Conclusions: Our preliminary results support an association between prior EBV and HSV-1 infection, and vitamin D deficiency and development of pediatric-onset MS

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

Cognitive impairment affects more than half of all individuals living with multiple sclerosis (MS). We hypothesized that training at home with an adaptive online cognitive training program would have greater cognitive benefit than ordinary computer games in cognitively-impaired adults with MS. This was a double-blind, randomized, active-placebo-controlled trial. Participants with MS were recruited through Stony Brook Medicine and randomly assigned to either the adaptive cognitive remediation (ACR) program or active control of ordinary computer games for 60 hours over 12 weeks. Training was remotely-supervised and delivered through a study-provided laptop computer. A computer generated, blocked stratification table prepared by statistician provided the randomization schedule and condition was assigned by a study technician. The primary outcome, administered by study psychometrician, was measured by change in a neuropsychological composite measure from baseline to study end. An intent-to-treat analysis was employed and missing primary outcome values were imputed via Markov Chain Monte Carlo method. Participants in the ACR (n = 74) vs. active control (n = 61) training program had significantly greater improvement in the primary outcome of cognitive functioning (mean change in composite z score+/-SD: 0.25+/-0.45 vs. 0.09+/-0.37, p = 0.03, estimated difference = 0.16 with 95% CI: 0.02-0.30), despite greater training time in the active control condition (mean+/-SD:56.9 +/- 34.6 vs. 37.7 +/-23 .8 hours played, p = 0.006). This study provides Class I evidence that adaptive, computer-based cognitive remediation accessed from home can improve cognitive functioning in MS. This telerehabilitation approach allowed for rapid recruitment and high compliance, and can be readily applied to other neurological conditions associated with cognitive dysfunction. TRIAL REGISTRATION: Clinicaltrials.gov NCT02141386.