Faculty Bibliography

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.

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:Migraine and epilepsy are comorbid conditions. While it is well known that epilepsy can have an impact on cognitive abilities, there is conflicting evidence in the literature on the relationship between migraine and cognitive function. The aim of this study was to assess whether migraine comorbidity in patients with newly diagnosed focal epilepsy is associated with cognitive dysfunction. METHODS:This is a post hoc analysis of data prospectively collected for the Human Epilepsy Project (HEP). There were 349 participants screened for migraine with the 13 questions used in the American Migraine Prevalence and Prevention (AMPP) study. Participants were also screened for depression using the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E) and the Center for Epidemiologic Studies Depression Scale (CES-D) and for anxiety using the Generalized Anxiety Disorder-7 (GAD-7) scale. Cognitive performance was assessed with the Cogstate Brief Battery and Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS). RESULTS:About a fifth (21.2%) of patients with a new diagnosis of focal epilepsy screened positive for migraine. There were more women and less participants employed full time among the participants with comorbid migraine. They reported slightly more depressive and anxious symptoms than the participants without migraine. Migraine comorbidity was associated with ABNAS memory score (median: 2, range: 0-12, Mann Whitney U p-value: 0.015). However, migraine comorbidity was not associated with Cogstate scores nor ABNAS total scores or other ABNAS domain scores. In linear regressions, depression and anxiety scores were associated with the ABNAS memory score. CONCLUSION/CONCLUSIONS:In this study, there was no association between migraine comorbidity and objective cognitive scores in patients with newly diagnosed focal epilepsy. The relationship between migraine comorbidity and subjective memory deficits seemed to be mediated by the higher prevalence of depression and anxiety symptoms in patients with epilepsy with comorbid migraine.

Magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) may be a distinct syndrome from TLE with mesial temporal sclerosis (TLE-MTS). Imaging and neuropsychological features of TLE-MTS are well-known; yet, these features are only beginning to be described in MRI-negative TLE. This study examined whether a quantitative measure of cortical gray and white matter blurring (GWB) was elevated in the temporal lobes ipsilateral to the seizure onset zone of individuals with MRI-negative TLE relative to TLE-MTS and healthy controls (HCs) and whether GWB elevations were associated with neuropsychological comorbidity. Gray-white matter blurring from 34 cortical regions and hippocampal volumes were quantified and compared across 28 people with MRI-negative TLE, 15 people with TLE-MTS, and 51 HCs. Declarative memory was assessed with standard neuropsychological tests and the intracarotid amobarbital procedure (IAP). In the group with MRI-negative TLE (left and right onsets combined), hippocampal volumes were within normal range but GWB was elevated, relative to HCs, across several mesial and lateral temporal lobe regions ipsilateral to the seizure onset zone. Gray-white matter blurring did not differ between the groups with TLE-MTS and HC or between the groups with TLE-MTS and MRI-negative TLE. The group with MRI-negative TLE could not be distinguished from the group with TLE-MTS on any of the standard neuropsychological tests; however, ipsilateral hippocampal volumes and IAP memory scores were lower in the group with TLE-MTS than in the group with MRI-negative TLE. The group with left MRI-negative TLE had lower general cognitive abilities and verbal fluency relative to the HC group, which adds to the characterization of neuropsychological comorbidities in left MRI-negative TLE. In addition, ipsilateral IAP memory performance was reduced relative to contralateral memory performance in MRI-negative TLE, indicating some degree of ipsilateral memory dysfunction. There was no relationship between hippocampal volume and IAP memory scores in MRI-negative TLE; however, decreased ipsilateral IAP memory scores were correlated with elevated GWB in the ipsilateral superior temporal sulcus of people with left MRI-negative TLE. In sum, GWB elevations in the ipsilateral temporal lobe of people with MRI-negative TLE suggest that GWB may serve as a marker for reduced structural integrity in regions in or near the seizure onset zone. Although mesial temporal abnormalities might be the major driver of memory dysfunction in TLE-MTS, a loss of structural integrity in lateral temporal lobe regions may contribute to IAP memory dysfunction in MRI-negative TLE.

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.

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.