Faculty Bibliography

BACKGROUND: Cognitive impairment is a common and troubling feature of pediatric-onset multiple sclerosis (POMS). Brief cognitive assessment in the outpatient setting can identify and longitudinally monitor cognitive involvement so that early intervention is possible. OBJECTIVES: The goal of this study was to measure the sensitivity of two cognitive assessment approaches that are brief, repeatable, and suitable for clinical practice and for multicenter investigation. METHODS: Participants with POMS ( n = 69) were consecutively evaluated as part of outpatient neurologic visits and compared to healthy control participants (HC, n = 66) using the Brief International Cognitive Assessment for MS (BICAMS) approach and timed information processing measures from Cogstate, a computer-based assessment. RESULTS: There was strong agreement in the detection rate of impairment between both assessments, with 26% for the BICAMS and 27% for Cogstate. Two of the Cogstate tasks were the most sensitive individual measures. CONCLUSION: Both the BICAMS and Cogstate timed processing measures offer practical, sensitive, and standardized approaches for cognitive screening assessment in POMS.

[This corrects the article DOI: 10.1371/journal.pone.0177177.].

The remotely supervised tDCS (RS-tDCS) protocol enables participation from home through guided and monitored self-administration of tDCS treatment while maintaining clinical standards. The current consensus regarding the efficacy of tDCS is that multiple treatment sessions are needed to observe targeted behavioral reductions in symptom burden. However, the requirement for patients to travel to clinic daily for stimulation sessions presents a major obstacle for potential participants, due to work or family obligations or limited ability to travel. This study presents a protocol that directly overcomes these obstacles by eliminating the need to travel to clinic for daily sessions. This is an updated protocol for remotely supervised self-administration of tDCS for daily treatment sessions paired with a program of computer-based cognitive training for use in clinical trials. Participants only need to attend clinic twice, for a baseline and study-end visit. At baseline, participants are trained and provided with a study stimulation device, and a small laptop computer. Participants then complete the remainder of their stimulation sessions at home while they are monitored via videoconferencing software. Participants complete computerized cognitive remediation during stimulation sessions, which may serve a therapeutic role or as a "placeholder" for other computer-based activity. Computers are enabled for real-time monitoring and remote control by study staff. Outcome measures that assess feasibility and tolerance are administered remotely with the aid of visual analogue scales that are presented onscreen. Following completion of all RS-tDCS sessions, participants return to clinic for a study end visit in which all study equipment is returned. Results support the safety, feasibility, and scalability of the RS-tDCS protocol for use in clinical trials. Across 46 patients, 748 RS-tDCS sessions have been completed. This protocol serves as a model for use in future clinical trials involving tDCS.

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

and Introduction Fatigue is a common and debilitating symptom of multiple sclerosis (MS) with estimates of up to 75% of patients reporting fatigue as their most disabling symptom [1]. Despite its prevalence, fatigue remains a frustrating symptom lacking reliable treatment options. tDCS has been previously shown to improve fatigue in MS patients, but requires daily sessions to be effective [2]. The necessity of daily sessions limits many studies to small sample sizes and few sessions studied, especially for patient populations with disability who may have additional physical barriers to attending daily sessions on top of personal and professional obligations. In response to this issue, we have developed a remotely-supervised tDCS (RS-tDCS) protocol that allows participants to complete tDCS sessions from home. The accessibility of our remote protocol increases both enrollment and compliance; moreover, it allows for an extended number of sessions to be studied [3]. Participants were enrolled in a RS-tDCS feasibility study in which they completed baseline, daily, and study-end measures of fatigue. 2. Methods This study was an open label, exploratory pilot study. Eligibility criteria were relatively broad, enrolling patients with a confirmed diagnosis of MS (all subtypes) between the ages of 18-70 years and a range of neurologic disability as measured by the Expanded Disability Status Scale (EDSS). Those with greater disability (EDSS >= 6.5) participated with the assistance of a caregiver proxy. Participants visited the clinic for baseline and follow-up measures. Here they completed self-report measures of fatigue, the Modified Fatigue Impact Scale (MFIS), and the PROMIS Fatigue measure (with lower scores associated with benefit). The baseline visit also consisted of tDCS training and the first of 10 sessions. Participants completed 9 daily tDCS sessions from home (20 minutes; DLPFC montage; left anodal) paired with brain training games. Before and after each session, participants rated their fatigue on a visual analogue scale. After all sessions were complete participants returned for a follow-up visit where baseline measures were repeated. Paired t-tests were used to analyze change in scores from baseline to follow-up. 3. Results A total of 25 participants were enrolled with all MS subtypes (n = 6 relapseremitting; n = 19 progressive) and a range of disability (EDSS scores ranged from 1.0 to 8.0). Most participants saw positive change in fatigue measures indicating an overall beneficial effect. Individuals' data points are shown in Fig. 1. Paired t-tests were performed to test for significance of the effect, summarized in Table 1. MFIS and daily fatigue measures showed significant improvement while PROMIS Fatigue did not. It is worth noting that n = 16 for the PROMIS Fatigue is due to its late introduction into the study, possibly reducing the power of that specific measure. 4. Discussion and Conclusion These data indicate RS-tDCS as a possible method for improving fatigue in patients with both relapsing-remitting and progressive MS. While benefit is shown to be significant in two of three fatigue measures, the benefit seems to be small. It is possible that higher amperage, more sessions, or longer sessions could bolster the effect we see. Further studies will look at dose-response and involve a sham arm to help validate findings. (Figure Presented)

Introduction One of the most reliably observed effects of transcranial direct current stimulation (tDCS)1 is improvement in working memory performance. However, emotional changes have yet to be thoroughly examined. The left dorsolateral prefrontal cortex (DLPFC) is considered to be a neural substrate of specific aspects of mood 2 and emotion3. For example, studies have shown that it influences emotional stimulus categorization3, emotional evaluation3, and emotional regulation4 and thus, is considered to have a major role in top-down emotional control. Here, we explored whether two emotional orthogonal dimensions, positive and negative affect5, differentially respond to left anodal tDCS using a DLFPC montage. As part of an open-label feasibility trial6, we observed mood changes in a sample of participants with multiple sclerosis (MS). Participants were recruited to develop a remotely-supervised or RS-tDCS protocol where they participated from home using videoconferencing and pairing with cognitively engaging exercises during the stimulation period. A control sample was recruited for comparison where the participants only completed the cognitive training exercise but not the tDCS, otherwise using the same remotely-supervised videoconferencing protocol. Methods Eligibility criteria were purposely broad in order to develop the RS-tDCS protocol, and participants were not recruited to treat any specific symptom (including mood). We enrolled patients with a confirmed diagnosis of MS (all subtypes) between the ages of 18-70 years. Active participants were enrolled in an open label treatment study (RS-tDCS paired with cognitive training), while controls were recruited separately and completed the cognitive training only. Participants visited the clinic for baseline and follow-up measures. After initial training, they completed 9 remotely-supervised sessions from their homes, consisting either of active (1.5 mA stimulation) paired with the cognitive training (CT) or CT alone. Mood outcome was measured with the self-reported Positive and Negative Affect Schedule 7, with scores of Positive Affect (PA) and Negative Affect (NA). Results A total of n=24 participants completed the active condition including the PANAS at both time points and were compared to n=20 in the comparison condition. Groups were generally equivalent (Table 1). Paired t-tests indicated that PA trended towards significant improvement in the active condition only (mean change in PA = -3.2+/-8.3, p=0.07 vs. -1.0+/-5.8, p=0.45) while both groups showed similarly significantly lowered levels of NA (mean change in NA = 5.1+/-7.2, p=0.002 vs. 4.2+/-5.6, p=0.003). As shown in Fig. 1, the proportion of change from baseline to study end across individuals was disproportionately greater for the active condition for PA, while NA remained the same. For both groups, change in NA was significantly predicted by baseline NA, indicating that the higher the NA the more likely for improvement (r's = 0.68 and 0.67 for active and control groups respectively, p's<0.001). However, change in PA was predicted by baseline NA (and not PA) only in the active condition (r=0.48, p=0.02). Discussion: In this study, exploratory analyses indicated that DLPFC (left anodal) tDCS differentially improves PA compared to NA in MS participants. These findings are consistent with the presumed neurobiological substrates of PA but not NA in the dorsolateral and ventromedial frontal regions. This is supported by PA improvements being independent from baseline PA levels, suggesting a broad and beneficial effect of stimulation to the DLPFC region. Of note, both conditions had significant reductions in NA across the 10 sessions. Thus, shared features of the cognitive training and contact with the study technician through videoconferencing at each session may have served to generally reduce features of negative affect. This is supported by higher levels of baseline NA predicting a response, indicating a decrease in features such as irritability and anxiousness as part of general participation in the study. Future studies will utilize neuroimaging to confirm targeted engagement of the DLFPC in order to enhance changes in mood with tDCS in MS participants. We will also characterize changes in mood in participants with clinically significant mood problems at baseline. We hope that tDCS treatment may be generalizable across conditions. (Figure Presented)

and Introduction Cognitive and motor deficits are common debilitating symptoms for individuals living with Parkinson's disease (PD). The severity of cognitive and motor impairment in PD is associated with disease burden and quality of life. (1, 2) Transcranial direct current stimulation (tDCS) is a recent therapeutic development with the potential to ameliorate symptoms of PD. Previous studies have associated tDCS with improvement in motor and cognitive function in patients with PD. (3) However, multiple treatment sessions are necessary for a cumulative benefit. The requirement to travel for daily clinic treatment sessions presents an obstacle for many patients, especially those with higher disability and limited access to transportation. In addition to restricting patient access to repeated treatment sessions, such challenges have also limited the design of clinical trials in PD to date. Recently, we have developed a remotely supervised tDCS (RS-tDCS) protocol that delivers computerized cognitive training (CT) paired with tDCS to individuals with MS. (4) Using the same protocol with extensive safety measures, well-defined guidelines, and specially-designed equipment, we explored the feasibility and adaptability of our RS-tDCS approach for participants with PD. 2. Methods This study was an open-label feasibility study. The eligibility criteria were relatively broad, with the key factors being a definite diagnosis of PD, PD-related changes to cognitive functioning, adequate home facilities, and a score of >= -3 standard deviations on the Symbol Digit Modalities Test (SDMT(5)) to measure disease-related cognitive decline and to ensure that participants had the cognitive ability to understand and participate in study procedures. Each participant completed 10 tDCS sessions (20-minute each, 1.5-2.0-mA, dorsolateral prefrontal cortex or DLPFC montage, which has been verified for effective targeted engagement of fatigue in patients with PD(6), over a span of two weeks using the remotely-supervised protocol. After the initial session at baseline, participants were sent home with a study laptop and tDCS equipment. The tDCS device (Soterix Mini-CT) is dependent on a code to operate, delivering a single 20 minute "dose" per code. All sessions were supervised in real-time using videoconferencing. The tDCS study technician ensured that the headset was correctly placed before providing the single-use activation code for the session. Additionally, study technicians followed a decision-tree series of checkpoints with "STOP" criteria set forth in the protocol that must be cleared in order to proceed at each step. These checkpoints address compliance (attendance and ability to complete the procedures as instructed) and tolerability (if any predefined events are reported at any time or if pain crosses a threshold, participation will be discontinued). For each study session, participants in both conditions were asked to complete a self-report inventory of adverse events and common side effects before and after their sessions (with items derived from a list of the most common tDCS side-effects in previous trials.(7) During the stimulation sessions, participations completed cognitive activating tasks on the computer. Feasibility of the approach was assessed based on the aforementioned series of checkpoints to address attendance, tolerability, and safety of the sessions. 3. Results A total of 50 sessions were completed with 100% compliance. In comparison to the MS sample (n=20) in our RS-tDCS pilot study, the PD participants (n=5) are significantly older (mean = 45.15 in MS vs. mean = 69.80 in PD, p=0.004). The PD cohort exhibited a slightly lesser degree of cognitive impairment in their corresponding age groups as measured by the SDMT (mean z-score = -0.94 in MS vs mean z-score = -0.66 in PD, p=0.90). However, this may be influenced by the higher level of education (mean = 17.4 years) achieved by participants in the PD cohort compared to those in the MS cohort (mean = 15.95 years, p = 0.21), and in addition, inter-individual variability will prominently influence a sample's demographic and disease feature composition in a smaller sample size. All participants were able to quickly learn self-administration. In addition, our RS-tDCS protocol provided the opportunity to coordinate sessions with participants' anti-PD medications, ensuring that CT-paired stimulation could occur within the crucial 1-3 hour time window post-medication for maximum benefit (as recommended by study physicians at the New York University Fresco Institute for Parkinson's and Movement Disorders). No serious adverse events were reported. The most commonly reported side effects were skin tingling and burning sensations. The most intense side effect was a burning sensation at an intensity of 4, which qualifies as "mild" on scale from 1 [minimal] to 10 [severe]. The intensity and duration of time that these side effects were noticed by participants tended to decrease throughout the study. Across the 50 sessions, 96% of the daily self-reported pain ratings related to stimulation that were taken before, mid-way, and after tDCS stimulation were reported as 0, which denotes "no pain" on the visual analog scale ranging from 0-10 that participants used to rate pain from the headset. RS-tDCS range of 1.5-2.0mA was tolerable for all participants in the study. 4. Discussion and Conclusion The RS-tDCS protocol was originally developed and tested in MS participants but designed to be appropriate for more generalizable use. Here, we expand the RS-tDCS protocol for use in PD. The study's high rate of compliance indicates that RS-tDCS is a safe and feasible approach for delivering direct current stimulation for individuals with PD, as with MS, despite the older age of our cohort of participants with PD. Across all 50 sessions, participants with PD found the stimulation to be tolerable. Key concerns for implementing RS-tDCS as an at-home treatment for PD include overall apprehension of technology and the need for technological support among this cohort, given the advanced age range and disabilities. Overall, the data indicate that RS-tDCS is easily implemented to accommodate participants' medication schedules, as well as physical therapy and exercise schedules, to provide maximum benefit and convenience. These findings support the use of the RS-tDCS protocol for clinical study in PD and other movement disorders, as well as the generalizability of the RStDCS approach for participant cohort with varying neurological diseases aside from MS