Faculty Bibliography

Introduction: Travel to clinic can be difficult due to barriers of time and cost and becomes even more burdensome for MS patients living with disabilities. Telemedicine platforms present a solution by providing supervised treatment and rehabilitation at home. Without barriers to access, patients may be more compliant and adherent to daily rehabilitation exercises. We have a large telerehabilitation research program in MS that pairs rehabilitation with transcranial direct current stimulation (tDCS), an emerging non-invasive brain stimulation technique used to improve outcomes. We provide real-time treatment administration and supervision via HIPAA compliant videoconference, termed remotely supervised tDCS or RS-tDCS.
Objective(s): To characterize the advantages of telemedicine for patients with MS in an urban setting.
Aim(s): To measure barriers to access for participants in our RS-tDCS telerehabilitation program, as well as compliance and adherence to a remotely supervised intervention.
Method(s): Participants with MS were recruited to complete a trial of cognitive remediation paired with RS-tDCS at-home. Participants were surveyed following completion of the intervention and asked to rate their difficulty in attending the clinic (on a 1-5 ordinal scale, 1 = no difficulty and 5 = nearly impossible difficulty) as well as the typical cost of attending clinic. Descriptive statistics and ordinal logistic regression models were used to evaluate the factors driving difficulty of travel.
Result(s): Participants (n=44) reported that round trip travel to the clinic requires an average of 2.3+/-2.3 hours of time and $27.04+/-38.13. Participants rated the difficulty associated with attending clinic as being moderate to significant (2.5+/-1.3). Regression analyses that included disease features produced better models and accounted for greater variance in difficulty attending the clinic, (p< 0.001, McFadden pseudo R2 = .515), as compared with socioeconomic variables alone (p< 0.001, McFadden pseudo R2 = .140). The RS-tDCS protocol was successful in providing treatment (95% compliance to treatment) and 93% of participants reported satisfaction with the treatment and remote protocols.
Conclusion(s): Participants with MS face considerable difficulty reaching the clinic, largely due to increasing neurologic disability. Telemedicine techniques such as RS-tDCS can increase treatment access, reduce physical and financial burden of travel and maintain high rates of treatment adherence

Abstract: Introduction: Fatigue is one of the most prevalent and under-assessed non-motor symptoms in Parkinson's disease (PD). Current therapies have limited effectiveness. Presently, tDCS has shown potential to improve certain symptoms of PD. We designed a tDCS protocol to allow study participation from the 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 PD patients suffering from fatigue.
Method(s): Double-blind, randomized, sham controlled study of RS-tDCS paired with CT. Participants completed 10 daily tDCS sessions (20-minute, 2.0-mA, bi-frontal, F3-F4 montage, left anodal), with the option of 10 additional open label sessions. Evaluation of preliminary clinical effects with the fatigue severity scale (FSS) along with tolerability, safety and compliance were completed.
Result(s): Eighteen participants were screened, 17 enrolled (Table 1), one screen failure. Incidence of the systematically recorded side effects were 22.4% tingling, 11.5% burning sensation, 8.2% itching, 3.3% headache, 0.9% nausea, 0.3% dizziness and 0.3% sleepiness. No serious adverse events reported. Compliance and tolerability were 100%. Preliminary fatigue clinical effects of 10 sessions showed a significant decrease of mean FSS only in the real RS-tDCS group of 8.0 (SD 9.82) points (p < 0.05). Further analysis of 20 RS-tDCS sessions (10 DoubleBlind-real+10 Open-label) showed a further significant decrease in mean FSS of 11.47 (SD 10.7) points (p < 0.05).
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 optimal subject compliance. 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. [Figure presented] Introduction: Parkinson's Disease (PD) is a progressively disabling disease that affects patients and their caregivers' quality of life. PD is a chronic neurodegenerative disease affecting a large number of dopaminergic neurons in the nigrostriatal pathway, responsible for common motor dysfunction such as slowness, tremor and rigidity. The disease also leads to various non-motor symptoms, in particular, fatigue and cognitive disability. The available pharmacotherapy often allows for a relatively good control of symptoms, but complications could arise from the side effects of medications, or the progressive nature of the disease [1]. Certain alternative therapies have emerged such as non-invasive brain stimulation (NIBS) that may potentially improve declining function. Transcranial direct current stimulation (tDCS) is a low-cost, safe and practical treatment compared to other NIBS. tDCS is a portable device that utilizes a weak electrical current to modulate neuronal membrane potentials and cortical excitability [2-3]. Fatigue is a highly prevalent symptom that is largely unrecognized in PD with no current evidence-based treatment [4]. Since tDCS has shown beneficial effects in motor, mood and cognitive symptoms in PD, it may have potential to ameliorate fatigue in PD.
Method(s): The study design is a double blind randomized, sham controlled trial using at-home tDCS paired with CT. Remote supervision of tDCS sessions was performed through a video-conferencing platform. The tele-rehabilitation design has been recently validated and allows participation of patients from the comfort of their homes [5]. Feasibility and preliminary effects of RS-tDCS in PD were tested using a dorsolateral prefrontal cortex (DLPFC) montage (F3-F4 from the EEG 10x20 system). All participants received a baseline physical, neurological, fatigue and cognitive assessments. Participants were asked to complete 10 daily sessions. Once finalized, they were offered 10 additional open label (OpL) sessions. Using a detailed study "stop" criteria [6, 7] flow chart, participants were cleared at each step for their participation to proceed. The primary objectives of the study were to determine the feasibility of RS tDCS paired with CT and explore the potential to ameliorate fatigue in PD. Clinical effects on fatigue were measured with the fatigue severity scale (FSS), a scale largely validated and recommended for this population [4]. FSS was obtained at baseline and after 10 tDCS sessions of 20 minutes with 2 milliamperes (mA) intensity, while participants engaged in computerized based CT. During the visits, acceptability of therapy, tolerability, side effects and other adverse events (AEs) were collected. An optional OpL period allows for a more comprehensive exploratory evaluation of RS-tDCS effects beyond 10 sessions.
Result(s): Eighteen patients were screened and seventeen were enrolled (one screen failure). Only one participant decided to opt out of the OpL portion of the study. Patient demographic characteristics did not differ between groups (Table 1). Pain tolerability of 2.0 mA stimulation with <=6 on visual analog scale for pain (VAS-Pain) was 100%. Incidence of the systematically recorded side effects were 22.4% tingling, 11.5% burning sensation, 8.2% itching, 3.3% headache, 0.9%, nausea, 0.3% dizziness and 0.3% sleepiness. Other adverse events (AEs) are listed in figure 1. No serious AEs were reported. All required visits were completed with no attrition or interruptions (100% compliance). Preliminary fatigue clinical effects of 10 sessions showed a significant decrease of mean FSS only in the real RS-tDCS group of 8.0 (SD 9.82) points (p < 0.05). Further analysis of 20 RS-tDCS sessions (10 DoubleBlind-real+10 Open-label) showed a further significant decrease in mean FSS of 11.47 (SD 10.7) points (p < 0.05) (Figure 2). [Figure presented] Discussion and
Conclusion(s): This novel design of remotely supervised tDCS has allowed conducting tDCS sessions safely and away from the lab setting, in the comfort of participant's homes. This paradigm of NIBS is particularly suited for medical conditions limiting mobility like PD, participants with busy schedules or living far distances from clinics. The initial results of this study showed that this protocol is feasible, acceptable and safe in PD with no major adverse events. [Figure presented] Our study has shown that RS-tDCS holds therapeutic potential for fatigue in people with PD, and showed 20 sessions seemed more favorable than 10 sessions. Trials with a greater sample size and extended treatment duration might be more suitable to establish the real efficacy for this therapy as a treatment of fatigue. Study Supported by Grant No. PDF-TRG-1722 from the Parkinson's Foundation. References [1] Kalia, L. V., & Lang, A. E. Parkinson's disease. Lancet, 386(9996), 896-912. (2015) [2] Priori, A., Berardelli, A., Rona, S., Accornero, N., & Manfredi, M. Polarization of the human motor cortex through the scalp. Neuroreport, 9(10), 2257-2260. (1998) [3] Nitsche, M. A., & Paulus, W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol, 527 Pt 3, 633-639. (2000) [4] Friedman, J. H., Beck, J. C., Chou, K. L., et al. Fatigue in Parkinson's disease: report from a mutidisciplinary symposium. NPJ Parkinsons Dis, 2. (2016) [5] Biagioni, M. C., Sharma, K., Migdadi, H. A., & Cucca, A. Non-Invasive Neuromodulation Therapies for Parkinson's Disease. IntechOpen, DOI: 10.5772/intechopen.75052. (2018) [6] Kasschau, M., Sherman, K., Haider, L., et al. A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation (tDCS) in Multiple Sclerosis (MS). J Vis Exp(106), e53542. (2015) [7] Charvet, L. E., Kasschau, M., Datta, A., et al. Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols. Frontiers in Systems Neuroscience, 9(26). (2015)
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BACKGROUND:Growing evidence supports the efficacy of restorative cognitive training in people with multiple sclerosis (PwMS), but the effects vary across individuals. Differences in treatment efficacy may be related to baseline individual differences. We investigated clinical characteristics and MRI variables to predict response to a previously validated approach to home-based restorative cognitive training. METHODS:In a single-arm repeated measures study, 51 PwMS completed a 12-week at-home restorative cognitive training program called BrainHQ, shown to be effective in a placebo-controlled clinical trial. Baseline demographic, clinical, neuropsychological, and brain MRI factors were captured and the effects of treatment were quantified with Symbol Digit Modalities Test (SDMT). Also measured were indices of treatment compliance. Regression modeling was employed to identify the factors associated with greatest SDMT improvement. RESULTS:As a group, patients improved significantly after training: mean SDMT improving from 49.6 ± 14.7 to 52.6 ± 15.6 (t = 3.91, p<0.001). Greater SDMT improvement correlated positively with treatment exposure (r = 0.38, p = 0.007). Increased post-rehabilitation improvement on SDMT was predicted by baseline relapsing-remitting course (β=-0.34, p = 0.017), higher trait Conscientiousness-Orderliness (β=0.29, p = 0.040), and higher baseline gray matter volume (GMV; β=0.31, p = 0.030). CONCLUSION/CONCLUSIONS:The study was designed to explore the variables that predict favorable outcome in a home-based application of a validated restorative cognitive training program. We find good outcomes are most likely in patients with higher trait Conscientiousness-Orderliness, and relapsing-remitting course. The same was found for individuals with higher GMV. Future work in larger cohorts is needed to support these findings and to investigate the unique needs of individuals according to baseline factors.

BACKGROUND:Fatigue is one of the most commonly experienced symptoms in multiple sclerosis (MS). The neural correlates of fatigue in MS, in general and specifically in early onset, remain poorly understood. This study employed resting-state fMRI (rsfMRI) to investigate the functional connectivity of fatigue in MS patients with early age onset. METHODS:Twenty-seven relapsing-remitting MS patients (20 ± 7yo at the age of diagnosis and 26.0 ± 5.5yo at the time of study) were recruited and 22 patients were studied. Structural and rsfMRI sequences were performed on a 3-Tesla Seimens MRI scanner. Seed-based analysis was performed using CONN Functional Connectivity Toolbox for Statistic Parametric Mapping. The Fatigue Severity Scale (FSS) and the Modified Fatigue Impact scale (MFIS) as well as EDSS, Beck Depression Inventory, and symptomatology were measured. Non-fatigued (N = 12) and fatigued patients (N = 10) were separated based on FSS scores, with a score of 5 or greater being classified as fatigued. Group differences in rsfMRI between non-fatigued and fatigued patients were analyzed. Correlations between these functional connectivity differences and behavioral fatigue scores were also analyzed. RESULTS: = 0.402, p = 0.006). Correlations remained significant after accounting for depression scores. CONCLUSIONS:rsfMRI identified Alterations in two distinct connections (the connectivity between insula and posterior cingulate gyrus and between the right thalamus and right precentral gyrus) that differed between fatigued and non-fatigued patients, as well as correlated with cognitive fatigue severity. These findings suggest that disruption of sensorimotor, high-order motor, and non-motor executive function likely contributes to the neural mechanism of fatigue in MS. Knowledge of the neural mechanisms of underlying MS fatigue could inform more effective treatment strategies.

BACKGROUND:Progressive cerebellar ataxia is a neurodegenerative disorder without effective treatment options that seriously hinders quality of life. Previously, transcranial direct current stimulation (tDCS) has been demonstrated to benefit cerebellar functions (including improved motor control, learning and emotional processing) in healthy individuals and patients with neurological disorders. While tDCS is an emerging therapy, multiple daily sessions are needed for optimal clinical benefit. This case study tests the symptomatic benefit of remotely supervised tDCS (RS-tDCS) for a patient with cerebellar ataxia. METHODS:We report a case of a 71-year-old female patient with progressive cerebellar ataxia, who presented with unsteady gait and balance impairment, treated with tDCS. tDCS was administered using our RS-tDCS protocol and was completed daily in the patient's home (Monday - Friday) with the help of a trained study technician. tDCS was paired with 20 min of simultaneous cognitive training, followed by 20 min of physical exercises directed by a physical therapist. Stimulation consisted of 20 min of 2.5 mA direct current targeting the cerebellum via an anodal electrode and a cathodal electrode placed over the right shoulder. The patient completed baseline and treatment end visits with neurological, cognitive, and motor (Lafayette Grooved Pegboard Test, 25 ft walk test and Timed Up and Go Test) assessments. RESULTS:The patient successfully completed sixty tDCS sessions, 59 of which were administered remotely at the patient's home with the use of real time supervision as enabled by video conferencing. Mild improvement was observed in the patient's gait with a 7% improvement in walking speed, which she completed without a walking-aid at treatment end, which was in stark contrast to her baseline assessment. Improvements were also achieved in manual dexterity, with an increase in pegboard scores bilaterally compared to baseline. CONCLUSIONS:Results from this case report suggest that consecutively administered tDCS treatments paired with cognitive and physical exercise hold promise for improving balance, gait, and manual dexterity in patients with progressive ataxia. Remotely supervised tDCS provides home access to enable the administration over an extended period. Further controlled study in a large group of those with cerebellar ataxia is needed to replicate these findings. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT03049969 . Registered 10 February 2017- Retrospectively registered.

Introduction: Transcranial direct current stimulation (tDCS) is a safe and well-tolerated form of noninvasive brain stimulation that delivers a low amplitude (1 - 4 mA) direct current through scalp electrodes. Cognitive impairment is a common and often disabling symptom of multiple sclerosis (MS) which has been shown to improve with cognitive training paired with tDCS. Here we compared the benefits of tDCS paired with either adaptive cognitive training (aCT) or non-adaptive cognitive training (nCT). To provide the extended treatment sessions needed for cognitive training, we administered tDCS to patients in their homes using our remotely supervised or RS-tDCS protocol. Method(s): MS participants were recruited for a double- blind, randomized, sham-controlled clinical trial with three arms: 1) active 2.5 mA tDCS paired with aCT, 2) sham 2.5 mA tDCS paired with aCT, and 3) active 2.5 mA tDCS paired with non-adaptive computer games (i.e. crossword puzzles, board games). Cognitive functioning and self-report outcomes were assessed during baseline and study visits via the Cogstate Brief Battery tests and Beck Depression Inventory (BDI) and Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires. Result(s): n=19 participants were recruited, of which 6 were randomized to the active condition, 7 to the sham condition, and 6 to the non-adaptive games condition. Comparing change from baseline to treatment end, the active tDCS/aCT group experienced the greatest cognitive improvement (mean z score change = 0.71), followed by sham tDCS/aCT: mean z score change = 0.26 and active tDCS/non-adaptive CT, mean z score change = 0.59). In addition, the active tDCS/aCT group had a greater improvement in the Beck Depression Inventory and PROMIS outcomes on fatigue and sleep. Conclusion(s): Extended treatment with tDCS paired with adaptive cognitive remediation leads to a greater benefit than either therapy alone. 2 Introduction: The symptom burden of multiple sclerosis (MS) often leads to disability and reduced quality of life. Cognitive impairment as well as symptoms such as fatigue and depression are common but remain without reliable treatment options. Cognitive training has shown to be efficacious in enhancing cognitive abilities for patients with neurological disorders. Our group has shown in the past that 60 sessions of adaptive cognitive training (aCT), completed at home via laptop computers and remotely supervised, can improve cognitive functioning in MS. aCT present advantages over traditional one-on-one cognitive rehabilitation such as the ability to complete training remotely in a user's home and reduced clinician burden. Beyond feasibility, aCT maintains the difficulty of its cognitive tasks by adapting in real time (i.e. through reduced stimuli presentation durations or reduced decision making time) to maintain arousal and engagement of the patient. tDCS is a form of noninvasive brain stimulation where a low amperage direct current is passed through scalp electrodes placed to target cortical regions for therapeutic benefit. Previously, we have shown that tDCS improves cognitive outcomes for patients with MS as well as clinical fatigue. This first goal of this study was to demonstrate the feasibility of extending tDCS therapy to 40 sessions in order to optimize therapeutic benefit when pairing with cognitive training. Our second goal was to compare tDCS with an active (adaptive) to placebo (nonadaptive) CT. We hypothesized that the synergistic use of both aCT and tDCS will lead to the greatest benefit to manage the symptoms of MS patients. Using our remotely supervised or RS-tDCS protocol to deliver monitored treatment at home, we compared the combined and relative contribution of each therapy in a long-term study. 3 Methods: Participants with MS were recruited for a double-blind, randomized, sham-controlled clinical trial with three arms. The trial's three arms consisted of: 1) active 2.5 mA tDCS paired with aCT, 2) sham 2.5 mA tDCS paired with aCT, and 3) active 2.5 mA tDCS paired with non-adaptive computer games (i.e. crossword puzzles, board games). Participants completed 40 sessions of their assigned condition from their home following the rigorous standards of RS-tDCS. Each session consisted of twenty minutes of electrical stimulation and cognitive training. All cognitive training, both adaptive and non-adaptive, was delivered through Posit Science's BrainHQ research platform. Participants were administered cognitive and self-report assessments at baseline study visit as well as study end visit to measure any change that occurred over the course of the study. Cognitive outcomes were assessed via the Cogstate Brief Battery and mood and fatigue outcomes were assessed via self-report assessments such as the Beck Depression Inventory (BDI) and Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires. 4 Results: n=19 participants have completed the 40 session study. n=7 were randomized to the aCT/Sham condition, n=6 were randomized to the nCT/Active condition, and n=6 were randomized to the aCT/Active condition. Preliminary efficacy results were calculated based on chance from baseline to treatment end on cognitive measures (Cogstate Brief Battery) and self-reported inventories (BDI and PROMIS). Assessing cognitive composite z-score changes, results indicate that aCT/Active participants demonstrated the greatest cognitive improvement (mean z score change = 0.71), followed by sham tDCS/aCT: mean z score change = 0.26 and active tDCS/non-adaptive CT, mean z score change = 0.59). In addition, the aCT/Active group had a larger improvement in the BDI and PROMIS outcomes on fatigue, mood, and sleep. Preliminary efficacy results for both cognitive assessments and self-report outcomes can be seen below in Figures 1 and 2. [Figure presented] [Figure presented] 3 Discussion and Conclusion(s): In this study we have demonstrated that extended tDCS treatment protocols are well-tolerated and feasible for study. Initial efficacy results suggest a clear advantage for adaptive cognitive training paired with RS-tDCS. As expected, the results from Figure 1 illustrate the greatest composite z-score change, which is indicative of cognitive improvement, were seen in patients under the aCT/Active condition. Figure B demonstrates a clear preliminary mood, fatigue and sleep improvement through the BDI and PROMIS outcomes. For positive affect, the aCT/Active condition shows a strong positive result compared to other conditions, which indicates a strong effect on the mood of MS participants. This same trend is seen in negative affect, fatigue and sleep, where all three variables have a negative change indicating a strong improvement in all three categories. Figure B displays the most favorable outcomes for mood, fatigue, and sleep are seen in participants under the aCT/Active conditions. In sum, extended RS-tDCS paired with adaptive cognitive training leads to greater improvements in cognition and affect, fatigue, and sleep than either therapy alone. While the study is in its preliminary stages, results support the synergistic benefit of tDCS plus an active therapy to lead to earlier and greater therapeutic benefits. References: Bikson, M., et al., Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimul, 2016. Charvet, L., et al., Remotely-delivered cognitive remediation in multiple sclerosis (MS): protocol and results from a pilot study. Multiple Sclerosis Journal - Experimental, Translational and Clinical, 2015. Jensen RE, Moinpour CM, Potosky AL, et al. Responsiveness of 8 Patient-Reported Outcomes Measurement information System (PROMIS) measures in a large, community-based cancer study cohort. Cancer 2016. CogState. CogState 2015. February 10, 2015; Available from: https://urldefense.proofpoint.com/v2/url?u=http- 3A__cogstate.com_&d=DwIBAg&c=j5oPpO0eBH1iio48DtsedeElZfc04rx3ExJHeIIZuCs&r=Vk3H8b3- Ln6FkaEcmPdAL_q5c3LYlceRekv38KQMQsQ&m=Ude_SVbAVWih8UQQ6zoyI8ZGwjva7r8hMLvwlTWqC- I&s=z_LlsVJpt6mPZiI8AD251tPSHVibR3hsMD-JBv8vXK4&e=.

Introduction: MS is a neurodegenerative, autoimmune disease associated with significant symptom burden such as fatigue, cognitive impairment, motor dysfunction, and depression. Thus, there is a need for therapeutic options for accessible symptom management. tDCS is an emerging neuromodulation treatment that delivers low amperage direct current (=2 mA) to targeted brain regions through scalp electrodes. tDCS is thought to lower the neuronal threshold required for action potentials and is often used to augment the benefit achieved through repetitive stimulation. Recent studies have demonstrated that at-home, remotely supervised tDCS (RS-tDCS) sessions can are successful in reducing fatigue in MS, studies have yet to elucidate the longevity of symptom benefit. Method(s): Participants with MS (N = 26) were recruited to complete a 20 sessions of RS-tDCS over a four-week period (5 sessions per week). We utilized a left anodal dorsolateral prefrontal cortex (DLPFC) montage as the target point for the treatment. The tDCS stimulation was at 2.0 mA. Surveys were completed at least one month following completion of the last RS-tDCS session asking whether any treatment benefit was achieved and whether it was sustained. Half the participants (N =13) received a sham/placebo stimulation, while the other half of the participants (N = 13) received the active stimulation. Both lab technicians and participants were blinded to the participant's conditions. Result(s): 65% of all participants reported treatment benefit. 92% (N =12) among the active participants and 38% (N = 5) among sham participants experienced benefit. The active group experienced a greater rate of benefit compared to the sham group (p<0.001). Furthermore, half of the participants assigned to the active condition that reported experiencing benefit also indicated that the benefit persisted (50%) and only a single participant who experienced benefit in the sham condition indicated that benefit persisted (20%). Conclusion(s): RS-tDCS results in symptom improvement in an MS cohort both immediately after the treatment finishes as well as, for many participants, after one month after treatment finishes. More clinical research should be done to elucidate the mechanism of long-lasting neural change due to tDCS that may help to improve MS symptoms. Longer studies should be done to examine whether self-reported benefit increases with number of sessions.