Faculty Bibliography

Introduction: Fatigue is one of the most prevalent and largely under-assessed non-motor symptoms in PD. Current potential therapies have limited effectiveness. Presently, tDCS has shown potential to improve certain symptoms of PD. We designed an RS-tDCS protocol to allow study participation from a patient's home while maintaining clinical trial standards. We utilized a live video-conferencing platform and specially designed equipment that 'unlocks' one session at a time.Study objective: to assess feasibility and explore the therapeutic potential of remotely supervised tDCS (RS-tDCS) paired with cognitive training (CT) for Parkinson's disease (PD) related fatigue: preliminary results. Method(s): Preliminary analysis of eighteen PD patients, age 35-89 that participated in a double-blind, randomized, sham controlled study with RS-tDCS paired with CT. Each participant completed 10 tDCS sessions (20-minute, 2.0-mA, bi-frontal DLPFC montage, left anodal), over a span of two weeks. After completion, 10 additional open label sessions were offered. Tolerability, safety and compliance were evaluated. Preliminary clinical effects were measured with the fatigue severity scale (FSS). Result(s): A total of 18 participants completed 330 RS-tDCS sessions (Table1); one subject did not complete 10 optional sessions and one withdrew consent. Tolerability of 2.0 mA stimulation with <=6 on visual analog scale for pain (VAS-Pain) was 100%. Systematically recorded side effects were: tingling 22.4%, itching 8.2%, burning sensation 11.5%, dizziness 0.3%, headache 3.3%, sleepiness 0.3%, and nausea 0.9% (Figure1). No serious AEs were reported. Compliance was 100% as subjects completed all required visits with no attrition or interruptions. Preliminary fatigue clinical effects of 10 sessions showed a significant decrease of FSS (p < 0.05) only in the real RS-tDCS group (Figure2). Further analysis of 20 real RS-tDCS sessions (10 Rand_real +10 Open_label) showed a greater significant decrease in FSS (p < 0.05) (Figure2). Responders (>30% FSS improvement) were 44% after 10 RS-tDCS sessions and 62% after 20 sessions. Conclusion(s): At-home RS-tDCS therapy paired with CT is safe and well-tolerated by PD patients, with the advantages of ease of recruitment and subject compliance. Acceptability was achieved by easy setup and intuitive design of the device. At-home RS-tDCS therapy paired with CT shows potential to remediate fatigue symptoms in PD but the small sample size limits efficacy conclusions. Our paradigm may be influential in designing future studies that will facilitate clinical trials with a larger subject population and extended trial duration. Supported by Grant No. PDF-TRG-1722 from the Parkinson's Foundation.

Introduction: Virtual reality (VR) can be used to manage symptomatic burden in people with neurological disorders. VR treatment can be both distracting and immersive and can effectively reorient subjective attention. People with multiple sclerosis (MS) can experience a high symptomatic burden and present with comorbidities that can be managed by VR treatment. This study investigates whether VR rehabilitation can be feasible and efficacious for people with MS. Method(s): People with MS were recruited to complete 8 weekly VR sessions using the HTC Vive Pro VR System. Participants completed one of two treatment schedules: Schedule A which consisted of interactive VR exercises and Schedule B which consisted of passively viewed 360degree videos. Participant completed self-report measures before and after each treatment session. Result(s): Four participants have been enrolled in the study to date with two participants assigned to each treatment schedule. A single participant experience motion sickness during Schedule B's 360degree videos and was stopped during that treatment session but remains in the study and interested in future treatments. All other participants tolerated the stimulation well with no adverse events. All participants experienced improved affect following the VR treatment. Conclusion(s): VR treatment is feasible for MS patients and leads to enhanced affect and mood. 2 Introduction: Virtual reality (VR) is an emerging technology that presents tremendous opportunities for the modulation of a person's perceptive input. For decades, VR has been presented as the future of technological interface but had remained largely impractical. Recent advances in computer processing and engineering have yielded commercially available VR headsets that are relatively inexpensive, highly immersive, and capable of running on medium to high end personal computers. VR has been shown to be efficacious in distracting post-surgical and burn patients from pain they may experience through the use of interactive virtual environments. One of the initial studies that investigated the analgesic effect of VR utilized VR software titled "SnowWorld", where users interact with penguins in a snowy environment, and led to a reduction of perceived pain in a cohort of pediatric burn patients. The theory of limited conscious attention helps to explain why such a distraction is beneficial to perceived pain; humans have a limited amount of attention that can be attributed to any given stimulus and by consuming as much of the attention as possible with VR, the self-appraisal of pain is thereby limited. In sum, VR is a potentially powerful tool for distraction from physical and emotional trauma. Beyond distraction, VR can be used to reorient one's sense of subjective presence or the feeling of actually residing in an environment. The ability to look in 360degree establishes a convincing illusion of reality and one's presence in the illusion can be further magnified when one can interact with the virtual environment with the use of their hands or body. A fully immersive experience can fundamentally alter one's perception and mindset and can even affect one's physiological state. People with multiple sclerosis (MS) experience significant symptomatic burden, often including chronic pain, fatigue, and depressed mood. Those with MS stand to gain from such a treatment, as reduction of perceived symptoms can lead to enhancements of quality of life. To determine whether patients with multiple sclerosis can tolerate and benefit from immersive VR, we have initiated a study at NYU Langone Health's Department of Neurology. Here, we present the study design and initial results. 3 Methods: This study is currently ongoing and all procedures have been approved by NYULH's institutional review board. All participants have provided informed consent. Eligibility criteria included a diagnosed neurological disorder and no current or uncontrolled epilepsy, vertigo, mood disorders, psychosis, or schizophrenia. Patients diagnosed with MS were recruited to complete eight sessions of guided VR over eight weeks (one session per week). Participants were assigned to either complete interactive VR exercises in which they used handheld controllers and the headset to interact with a virtual setting (schedule A) or to passively watch 360degree videos (schedule B). Both schedules were experienced through use of the HTC Vive Pro VR system. Schedule A utilized Virtual Embodiment TrainingTM software by Karuna Labs, Inc. which emphasizes reduction of physical symptoms through instructed rehabilitation exercises. For example, one such exercise instructs participants to operate a ballista and fire it at targets that appear nearby the participant. As participants perform the task, they must rotate toward their left or right while the program assesses the range of motion exhibited by the participant to determine how far the target will be placed. The exercises were conducted in VR for 30 minutes with a final five minutes of passive, guided meditation at the close of each session. [Figure presented] Schedule B consisted of passively viewed 360degree videos for 30 minutes each session. No video was repeated to any participant over the course of the study. Similar to schedule A, each session of schedule B also closed out with an additional five minutes of passive, guided meditation. It should be noted that both Schedule A and B may benefit patients with neurological disorders equally as the literature suggests that either schedule will lead to symptomatic benefit. However, we expect that schedule A will lead to a higher subjective presence in the virtual environment due to the interactive nature of the schedule, and therefore greater symptom reduction. Participants completed a battery of self-report questionnaires and cognitive measures at baseline and treatment end visits and a small set of measures pre- and post- session over the course of the study. Of relevance, participants completed a measure of positive and negative affect (Positive and Negative Affect Schedule or PANAS) before and after each treatment session. 4 Results: To date, n=4 participants have been recruited to the study and n=2 participants have been assigned to schedule A while n=2 participants have been assigned to schedule B. The VR treatment has been well-tolerated in n=3 participants while a single participant experienced motion sickness and was subsequently discontinued from that treatment session (but remains interested in returning for additional treatments). While no participant has completed the entirety of their eight week schedule yet, changes in pre- and post-session PANAS data is available and can provide signals of the acute effects of the VR treatment. Effect size analysis shows that participants immediately felt an increase in their positive affect (PA, Cohen's d = 0.27) and a large decrease in their negative affect (NA, Cohen's d =1.95) following VR. Participants in Schedule A (which consisted of the interactive virtual exercises) particularly experienced a larger improvement in positive affect than those in schedule B (which consisted of the passive 360degree videos). [Figure presented] 5 Discussion and Conclusion(s): A small cohort of participants with MS completed VR treatments with only a single instance of an adverse event that quickly resolved following removal of the VR headset. Additionally, affect improvements were observed in all 4 participants after VR treatment, with the strongest improvements in those that completed the VR exercises that involved interaction with the virtual environment. All participants indicated satisfaction with the treatment and a desire to continue. Importantly, all participants were highly immersed in their treatment and often remarked so following the treatment. As previously described, immersion is essential to an effective VR treatment session. In the future, we hope to incorporate objective measures of immersion such as eye tracking that may provide insight into processing and engagement of the participant. A scalable and quantifiable objective measure of immersion may reveal which VR techniques and software promote the greatest level of symptomatic benefit. While our findings are limited by a small cohort of participants that have completed a single VR treatment session, the initial signals of efficacy and tolerability are promising. This study remains active and will continue to recruit participants in hopes of collecting pilot data that could be used for power calculations in future clinical trials. References: [1] Hoffman, H.G., et al. Effectiveness of virtual reality-based pain control with multiple treatments. Clin J Pain; 2001; 17(3): p. 229-35. [2] Schmitt, YS., et al. A randomized, controlled trial of immersive virtual reality analgesia, during physical therapy for pediatric burns. Burns: journal of the International Society for Burn Injuries; 2011; 37:61-8.

Introduction: VR immersion therapy is a practical, noninvasive and riskless technique with promising applications for rehabilitation. Preliminary studies have demonstrated its feasibility and effectiveness for various therapies targeting depression, anxiety disorders, and PTSD using exposure, relaxation, and mindfulness techniques. VR has also been shown to be an effective pain management tool for acute and chronic pain relief. These techniques tend to focus on distraction and redirecting cognitive resources from pain attention towards the VR stimuli. Patients with neurological disorders have high comorbidity rates for emotional disorders and disease-related pain. As the theorized mechanisms for VR therapy benefit are not disease-specific, we expect neurological patients to have generalized benefit. We propose VR for use in therapeutic paradigms to manage symptom burden in those with neurological disorders. Method(s): We recruited patients previously diagnosed with a neurological disorder. Participants completed a baseline assessment, multiple 1-hour virtual reality immersion sessions, and one follow-up assessment. Each participant completed self-report measures including the Patient Reported Outcomes Measurement Information System (PROMIS) along with side effect visual analog scales (i.e. fatigue and nausea), and the Positive and Negative Affect Schedule (PANAS) before and after each session to assess any symptom severity changes. VR sessions include structured schedules of virtual pain management, cyber painting, walking through vivid and calming settings, solving puzzles, among other therapeutic and immersive activities. Each session is constructed beforehand with different immersion activities by study personnel in order to provide interactive diversity to maintain participant engagement and immersion necessary for efficacious treatment. Result(s): The trial is currently underway. Results regarding compliance, feasibility, and efficacy will be presented. Conclusion(s): Virtual Reality therapy is a feasible treatment modality that can benefit participants diagnosed with neurological disorders by reducing symptom burden and other reported neurological complaints.

Chronic neurological disease often presents with comorbidities such as mood disorders, fatigue, and cognitive impairment. Noninvasive brain stimulation is a potential non- pharmacologic treatment option. Transcranial direct current stimulation (tDCS) delivers a low amplitude (1 - 4 mA) direct current through scalp electrodes and has been shown to be safe and well tolerated. Though various non-invasive neuromodulation technologies are available (e.g., transcranial magnetic stimulation), tDCS has many advantages compared to other stimulation methods including ease of use, lower cost, and better tolerability. tDCS has been shown to enhance mood, decrease fatigue, and improved rehabilitative outcomes in patients with neurological disorders. Currently, tDCS has not been approved for clinical implementation, often preventing those who can most benefit from this treatment with no access or left to attempt consumer self-treatment. As its benefit is cumulative, extended treatment schedules are needed in order to enhance the outcome and efficacy of cognitive or physical training reducing the feasibility of daily visits to the clinic. To overcome both the feasibility obstacle of consecutive, daily, in-clinic tDCS sessions and to serve populations that would most benefit from this treatment, we have studied long term treatment schedules (up to 60 sessions) in people with neurological disorders. Here we present four cases of extended tDCS treatments paired with cognitive training. 2 Methods: Adult patients with any neurological disorder referred for cognitive rehabilitation with tDCS were eligible for this study. Participants with an estimated premorbid level of cognitive functioning in the below average range (estimated by reading recognition on the Wide Range Achievement Test-4th Edition and a Symbol Digit Modalities Test >=3.0 SD published age- referenced normative means) were excluded to ensure basic cognitive capacity to participate. Eligible participants were enrolled in an open-label trial administering up to 60 RS-tDCS (up to 2.5 mA depending on the participant's tolerability of the stimulation for 20 minutes). Following our remotely supervised or RS-tDCS protocol [3], all tDCS was paired with cognitive training targeting cognitive processing speed and working memory (online research portals from Lumos Labs or Posit Science). Montage was dependent on the specific area of deficit. Sessions were administered daily for 5 days per week. At the baseline visit, participants were administered measures of cognitive and motor functioning and self-report symptom inventories. Participants were instructed on how to self- administer tDCS from home with live remote supervision via HIPAA compliant videoconferencing. If a participant did not meet the criteria for at-home treatment, they had the option to have sessions in clinic. Treatment was then delivered at home using the RS-tDCS telerehabilitation protocol [3]. Participants returned to clinic after treatment for follow up assessments. 3 Results: Case 1: A 19-year old woman with a seven year history of MS presented with moderate recurrent episodes of major depression. She received 40 sessions of cognitive training plus RS-tDCS sessions with dorsolateral prefrontal cortex (DLPFC) montage, left anodal (1.5mA x 20 minutes). After the initial 20 session treatment period, her depression resolved (BDI score decreased from 12 to 0) with improved cognitive processing speed (SDMT score improved from58 to 69). Her depression gradually returned and she completed a second set of 20 treatments, again responding with resolution of depressive symptoms. Case 2: A 35-year-old man with idiopathic hypersomnia received 40 sessions with DLPFC montage, left anodal (2.0 x 20 minutes). He had participated in multiple medication trials and had experienced minimal benefit with stimulants. Symptoms at baseline included mental fogginess, reduced attention, overall cognitive difficulties, constant daytime sleepiness, and low quality of life. Despite published reports of tDCS benefitting hypersomnia [2], no change was found on any self-report or cognitive measures. PROMIS scales (fatigue, positive affect, sleep related impairment, and pain) changed following completion of sessions from 37 to 38, 27 to 28, 56 to 55, and 3 to 3, respectively. Case 3: A 65-year-old woman with frontotemporal dementia received 60 sessions with DLPFC montage, left anodal (2.5 mA x 20 minutes). Cognitive testing, mood, and symptom inventories (Wechsler Adult Intelligence Scale, selected subtests, Delis-Kaplan Executive Function System, selected subtests, Symbol Digit Modalities Test, Brief Visual Memory Test-Revised, Beck Depression Inventory, PROMIS scales: fatigue, positive affect, sleep impairment, and depression, and the Fatigue Severity Scale) were administered at baseline and follow-up. Following completion of all sessions, there was a significant improvements in processing speed (SDMT score of 34 to 50), working memory (WAIS digit span scaled score of 11 to 12), verbal fluency (D-KEFS scaled scores of 11 to 17), delayed visual memory (BVMT-R z score of -1.08 to -0.17), Hamilton Depression Rating Scale score dropped from 15 to 11 and mood improved across sessions as shown by linear increases in positive affect. Case 4: A 71-year-old woman with progressive cerebellar ataxia received 60 sessions with a cerebellar montage (2.5 mA x 20 minutes). Symptoms at baseline included unsteady gait, difficulty ambulating in a straight line, and fine motor impairment. Shehad underwent numerous medication trials with no lasting benefit. The Lafayette grooved pegboard scores were significantly different for both hands from the baseline assessment. The patient performed 18% faster with the dominant hand, and 19% with the non-dominant hand, with a reduction amount to 2.07 and 1.92 in the z-score for the dominant and non-dominant hand respectively. Before the intervention, the Time Up and Go Test (TUG) score was 11.90s using a cane. At follow up, TUG score was 9.88s without any walking-aid. Following treatment, a mild improvement was observed in the 25 foot walking test (25-FWT), the patient completed the test 7% faster and without walking-aid compared to the baseline assessment. 4 Discussion and Conclusion(s): RS-tDCS is a safe, well-tolerated non-pharmacological option for the management of common neurologic disorder comorbidities. Continued research is needed in order to determine who best will respond to the treatment and optimal dosing parameters including potential taper schedules in order to achieve and maintain clinical benefit. References: 1. Brunoni, A.R., et al., Cognitive effects of transcranial direct current stimulation in depression: Results from the SELECT-TDCS trial and insights for further clinical trials. J Affect Disord, 2016. 202: p. 46-52. 2. Galbiati, A., et al. (2016). "The effects of Transcranial Direct Current Stimulation (tDCS) on Idiopathic Hypersomnia: a pilot study." Arch Ital Biol 154(1): 1-5 3. Charvet L, Shaw M, Dobbs B, Frontario A, Sherman K, Bikson M, et al. Remotely Supervised Transcranial Direct Current Stimulation Increases the Benefit of At-Home Cognitive Training in Multiple Sclerosis. Neuromodulation. 2017.

BACKGROUND AND PURPOSE/OBJECTIVE:Pediatric-onset multiple sclerosis (POMS) is a demyelinating disorder with unique clinical challenges. A brief computer-administered cognitive screening battery measuring processing speed (Cogstate) and the Brief International Cognitive Assessment in MS (BICAMS) detect cognitive impairment in POMS. The neuroanatomic correlates of these deficits are incompletely understood. The purpose of this study is to define the neuroanatomic underpinnings of deficits identified with cognitive screening batteries in POMS. METHODS:Participants with POMS and age-matched healthy controls (HCs) were screened with Cogstate and BICAMS. Diffusion tensor imaging assessed region-wise and tractography-based fractional anisotropy (FA). RESULTS:The POMS (n = 15) and HC (n = 21) groups were matched on age (mean ages 17.9 ± 3.2 vs. 17.8 ± 3.3 years, respectively) and on an estimate of general intellectual functioning. The Cogstate composite revealed significant slowing in POMS relative to HCs (P = .004), but the BICAMS composite did not significantly distinguish the groups (P = .10). The Cogstate composite showed moderate-to-strong correlations with regional FA (r = -.67 to -.82) and significantly associated with uncinate fasciculus FA following multiple comparisons correction (P = .002) in POMS. However, the BICAMS composite measure showed only weak-to-moderate correlations with FA in POMS (r = -.19 to -.57), with none surviving multiple comparisons correction. CONCLUSIONS:Computer-administered measures of cognitive processing are particularly sensitive in POMS and are closely linked to white matter FA.