Faculty Bibliography

Transcranial direct current stimulation (tDCS) is a promising therapy with a growing number of applications. However, clinical studies to date have been limited by small sample sizes and few sessions studied. To increase enrollment and extend treatment, we developed a protocol for remotelysupervised or RS-tDCS to enable participants to receive treatment from home while monitored in real-time.1, 2 Here we present the findings of two studies in multiple sclerosis (MS), the first being an open label feasibility study with 1.5mA x 20 minutes and the second being a randomized, controlled clinical trial of active 2.0mA or sham x 20 minutes. In addition, we have extended the protocol for use in Parkinson's disease (PD), completing 10 open-label 2.0 mA sessions x 20 minutes. All sessions were performed using a dorsolateral prefrontal cortex montage (DLPFC) and were paired with cognitive training tasks. This study adds to previous safety evidence.3 Methods Eligibility criteria were purposefully broad in both studies to assess the feasibility of a remote-supervision protocol . The criteria required that patients had a definite diagnosis of MS (all subtypes), were between the ages of 18-70, had no history of serious brain trauma, and were physically, visually, and cognitively competent enough to perform study procedures. Additonally, participants were required to enroll in the study with a healthcare proxy if their disability was greater than an Expanded Disability Status Scale (EDSS) Score of 6.5. Eligibility criteria for the Parkinson's Disease (PD) cohort was similar to the MS criteria, albeit with a larger age range for participation (30-89) and without the EDSS score requirement. The RS-tDCS protocol included a baseline screening and tolerabilty test, followed by training in device operation. Participants were then sent home with a study kit that included a laptop computer and tDCS equipment. Each remote session was selfadministered with guidance from a study technician, while constant supervision was maintained via videoconferencing. Extensive safety and stop criteria were followed to prevent any adverse events or misuse. The studies used the Soterix Mini-CT device that delivered a 20 minute session of a specific current "dose" or sham, based on a preprogrammed one-time use code that was provided by the study technician at each session. Safety and tolerability were measured by assessing both experiences of minor adverse events and pain ratings. Following each session, participants were asked if they had experienced any adverse events, which were read aloud froma list of those most commonly reported. Pain ratings (using a visual analogue scale, 1-10) were measured before, during, and after each session. Any participants experiencing pain or adverse events above an intensity of seven were discontinued from the study as per study protocols. Study 1 MS participants (n=26) were recruited between the dates of March 2015 and February 2016 at the Lourie Center for Pediatric MS at Stony Brook University. This trial was an open-label study and all participants knowingly received the active tDCS therapy. 1.5mA of tDCS therapy was administered for 20 minutes each day for 10 days. Study 2 Participants with MS (n=15) were recruited between January 2016 and September 2016 at the MS Care Center at New York University Langone Medical Center. This study is an ongoing, actively recruiting, randomized, double-blinded, controlled clinical trial using RS-tDCS. All MS patients were randomized to either the active condition (20 minutes of 2.0mA tDCS) or the sham condition. The sham condition served as the control in this study and aimed to deceive participants into believing they were receiving the 20 minutes of tDCS by ramping up at the first minute of the session and ramping down at the last minute of the session. All participants who received the sham condition were offered 10 sessions of 2.0mA open-label tDCS following completion of 20 sessions of sham. Study 3 Participants with PD (n=4) were recruited between the dates of June 2016 and October 2016 at the Fresco Institute for Parkinson's and Movement Disorders at the New York University Langone Medical Center. Using the aforementioned remotelysupervised protocol established for MS, participants in the PD cohort received openlabel 2.0 mA tDCS for 10 sessions to assess the feasibility and generalizability of the remotely-supervised protocol for this new cohort. Results Study 1 Patients with MS (n=26) were recruited and completed study procedures. Two patients were discontinued during the course of the study. The first of the two was discontinued due to personal obligations, and the second was discontinued due to extreme sensations of skin burning (8.5/10 on the analogue scale) without any physical burns. The burning sensation did not continue after termination of the session. Overall, 248 sessions were successfully completed with this cohort. Study 2 Patients with MS (n=17) were recruited and completed study procedures. Only one participant was discontinued from the blinded active condition due to serious headaches at an intensity above 7. One participant who was originally assigned to the sham condition and who opted for the extended, open label sessions voluntarily withdrew due to resurgence of headaches (the headaches did not meet our criteria of discontinuing the patient). 147 sessions of the active 2.0 blinded condition were succesfully completed. 135 shammed sessions were successfully completed. 54 sessions of the open-label, extended sessions following sham were completed. Study 3 Participants with PD (n=4) were recruited and completed study procedures. No participants voluntarily withdrew from this cohort nor were any discontinued. 40 sessions were successfully completed. In total, 624 sessions have been completed using the RS-tDCS protocol. Three participants have been discontinued and one has voluntarily withdrew from the study. Participants who were discontinued due to adverse events found that they reverted to their baseline state when terminating the intervention. The percent of adverse events experienced is presented below in Fig. 1. This Figure does not include information regarding the intensity or duration of the adverse events experienced. Instead, it reports the frequency of advese events experienced, which accounts for the high incidence rate of adverse events in the sham condition. Table 1 accounts for the intensity of the most commonly reported adverse events. The table also includes the number of adverse events reported relative to the number of total sessions. On average, an intensity above 3 was not reported for any of the most common adverse events in any stimulation condition. Discussion The RS-tDCS protocol is safe and tolerable in both MS and PD participants, and continues to lead to high rates of compliance with treatment sessions. No serious adverse events have been reported. The most common side effects reported are skin tingling and itching. Of note, across conditions, the 1.5mA open label condition reported the highest rates of side effects. This may be accounted for by open-label treatment, where participants may have been more focused on potential effects of the stimulation. The 2.0mA open label condition may not be as comparable to the 1.5mA open label condition due to a smaller sample size in the 2.0mA condition. Over all, none of the adverse events were severe, with intensity below 3 on a visual analogue scale of 1-10. Both 1.5 and 2.0mA tDCS are safe and tolerable forms of treatment in both MS and PD, and may be generalizable for clinical study in a wide range of neurologic and psychiatric disorders. (Figure Presented)

Objective: To explore the feasibility and safety of remotely supervised transcranial direct current stimulation RS-tDCS) paired with computerized cognitive training exercises in participants with Parkinson's disease (PD). Background: tDCS is a recent therapeutic development with potential to ameliorate symptoms of PD including motor, sensory, mood, and cognition.. However, multiple treatment sessions are necessary for a cumulative benefit. The requirement to travel to the clinic for daily clinic treatment sessions has limited the design of clinical trials in PD to date. Here, we used a RS-tDCS protocol validated for use in patients with multiple sclerosis (MS), a condition that shares with PD significant impairment in mobility, cognition, and high prevalence of fatigue. Design/Methods: Each participant completed 10 tDCS sessions (20-minute each, 1.5-2.0-mA, dorsolateral prefrontal cortex montage) using the remotely-supervised protocol. Feasibility of the approach was assessed based on a series of checkpoints, addressing attendance and tolerability and safety of the 40 sessions paired with simultaneous CT. Results: A total of 40 sessions were completed with 100% compliance. All participants were able to quickly learn self-administration and the set up time decreased through the 10 sessions for those who struggled with set up in the beginning. No serious adverse events were reported. Most commonly reported side effects were skin tingling and burning sensation. The most intense side effect was burning sensation at intensity of 4, which qualifies as "mild" on scale from 1 [minimal] to 10 [severe]. Time that these side effects were noticed by participants throughout the duration of the study also tended to decrease. RS-tDCS range of 1.5-2.0mA was tolerable for all participants Conclusions: RS-tDCS was feasible and safe in PD participants and can be paired with tele-rehabilitation. This study encourages using this innovative protocol for larger studies and clinical trials in PD patients

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: 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: 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: 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 examine whether a history of childhood adversity (i.e. abuse, dysfunction) influence clinical features of multiple sclerosis (MS) in adult patients. maltreatment, and household Background: Multiple epidemiological studies have linked adverse childhood experiences to changes in brain structure and stress-responsive physiologic mechanisms. Such changes have been found to profoundly increase risk for chronic disease, poorer emotional and social functioning, and cognitive impairment in adulthood. However, the specific role of these experiences in MS remains unclear. Design/Methods: Participants with MS were recruited from a cohort that previously completed a larger cognitive remediation trial. Measures included the Adverse Childhood Experience (ACE) and Resilience Questionnaire (RQ) self-report inventories. ACE and RQ scores were compiled into a composite score to provide a more comprehensive measure of endured childhood adversity, and these measures were compared to individual disease features. Results: A total of 76 participants completed the study (mean age 49.8+/-12.5 and 80% female). ACE scores were significantly and inversely correlated with RQ scores (r = -0.46, p<0.001), suggesting that greater childhood adversity corresponds with poorer psychological resilience. ACE, but not RQ, significantly predicted age of onset (r= -0.31, p=0.03 and r= -1.91, p=0.18 respectively). Both ACE and RQ were linked to estimated premorbid cognitive functioning (r= -0.30, p=0.009 and r= -0.27, p=0.02). However, the composite score of both measures offered the strongest predictive value for the impact of childhood adversity on age of onset (r= -0.31, p=0.02) and premorbid cognitive functioning (r = -0.32, p=0.005). Neither ACE nor RQ were related to age, current disability, or current level of cognitive impairment measured by the Symbol Digit Modalities Test (SDMT). Conclusions: Cumulative stress due to adverse childhood experiences and decreased psychological resilience may increase the likelihood of earlier MS onset and predict poorer premorbid cognitive functioning in adulthood

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

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.