Faculty Bibliography

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.

Introduction: Pediatric onset multiple sclerosis (POMS) is a demyelinating disorder occurring in the context of neurodevelopment with unique clinical challenges due to the potential for disease-related cognitive impairment. A brief cognitive screening battery of computer administered measures of processing speed (Cogstate) and the Brief International Cognitive Assessment in MS (BICAMS) detects cognitive impairment in POMS. However, the neuroanatomic correlates of these deficits are incompletely understood. We have sought to define the neuroimaging correlates of deficits identified with a cognitive screening battery in POMS.
Objective(s): To test the links between white matter integrity and cognitive functioning in pediatric MS patients and matched healthy controls.
Aim(s): Participants cognitive performance as measured by the BICAMS and Cogstate assessments was compared to magnetic resonance imaging (MRI) outcomes.
Method(s): Participants with POMS and age-matched healthy controls (HC) completed cognitive screening with Cogstate and the BICAMS along with 64-direction MRI based diffusion tensor imaging (DTI).
Result(s): The POMS group (n= 15, mean age 17.9+/-3.2 years) compared to the HC group (n= 21, mean age 17.8+/-3.3 years) were significantly slower on a composite Cogstate score (p=0.004), but the groups did not significantly differ using a composite BICAMS score (p = 0.10). The POMS group also presented with increased fractional anisotropy (FA) in the thalamus (p=0.01) and reduced FA in the corpus callosum (p=0.05) and temporal lobe white matter (p=0.03) relative to HCs. Controlling for age and sex within groups, the measured slowed processing speed (Cogstate composite) significantly negatively correlated with regional fractional anisotropy (FA) in the corpus callosum, temporal and occipital lobe white matter, and in the tractography-based uncinate fasciculus in the POMS sample (p=0.002 to 0.025), whereas the reduced verbal learning (RAVLT) was significantly negatively correlated with thalamic FA (p = 0.046). Of these effects, only the relationship between the Cogstate composite and temporal lobe FA was significant in the HCs (p=0.013).
Conclusion(s): Computer administered measures of cognitive processing speed are particularly sensitive to slowing in POMS and are closely linked to MRI diffusion measures

Introduction: Cognitive impairment represents a frequent and troubling symptom of multiple sclerosis (MS) in need of treatment options. Transcranial direct current stimulation (tDCS) uses scalpbased electrodes to pass mild electrical current (< 4mA) through target cortical brain regions and is a safe and well-tolerated treatment. We have developed a protocol to deliver remotely supervised cognitive remediation paired with tDCS to individuals with MS at home.
Objective(s): To test whether at-home cognitive remediation augmented with tDCS will lead to improved training outcomes in MS.
Aim(s): Cognitive processing speed was assessed at baseline and study end by the Cogstate Brief Battery. Age normative z scores were computed for the Cogstate Brief Battery scores, with outcome measured by change in the average z score of information processing assessments.
Method(s): MS participants with cognitive impairment were recruited and randomized to complete 40 sessions of either active or sham tDCS paired with either adaptive or non-adaptive cognitive training (aCT or nCT). Training was completed at home using study-provided equipment and remotely supervised via videoconference using our established probed (RS-tDCS). Training was 20 minutes in duration and was completed five times a week (M-F) for approximately eight weeks. Participants were blinded and received active (2.5mA) or sham stimulation and cognitive training simultaneously during each session.
Result(s): To date, n=19 MS participants have successfully complete the 40 session training program at home: n=6 in active/aCT, n=8 in Sham/aCT, and n=5 in active/nCT. Mean age was 49+/-15 years of age and mean years of education was 16.5+/-2.1. The majority of participants had the RRMS subtype (63%, with 11% PPMS, and 26% SPMS). The participants were matched on cognitive status as measured by the symbol digit modality test (ANOVA p=0.09). tDCS and the cognitive training were uniformly well tolerated with no safety concerns. At the group level, all three groups showed improvement from baseline (0.75, 0.56, 0.59 z-score improvement for each condition respectively), indicating that both tDCS and aCT can be of benefit. Further, as predicted, the active tDCS paired with aCT experienced the greatest benefit (Cohen's d = 0.51).
Conclusion(s): Our telerehabiltiation protocol allows for participants to receive extended cognitive training paired with tDCS at home, resulting in improved outcomes from cognitive remediation

Introduction: Cognitive impairment is common and often disabling in multiple sclerosis (MS), but the risk factors and mechanisms underlying cognitive decline remain poorly understood. Pediatric MS (MS onset < 18 years of age) is unique due to the demyelinating process occurring in the context of development.
Objective(s): To compare cognitive functions in newly diagnosed patients with either adult- or pediatric-onset MS (AOMS vs. POMS).
Aim(s): To test performance in newly diagnosed MS patients using the Symbol Digit Modalities Test (SDMT) and a computer-based measure sensitive to processing speed deficits (Cogstate).
Method(s): As part of an ongoing multi-center longitudinal cognition trial, AOMS and POMS participants were recruited from outpatient visits and matched by years of disease. At the baseline evaluation, all participants were administered the Wide Range Achievement Test-4 (WRAT-4), the SDMT and the Cogstate Brief Battery, which includes three measures of information processing speed tasks:simple (DET) and choice (IDN) reaction time and working memory (ONB). Cogstate scores were converted to z-scores and then averaged for one composite z-score.
Result(s): A total of n=64 participants completed baseline assessments with n= 32 in the AOMS group (mean age 33.36 ?+/- 5.82) and n= 32 in the POMS group (mean age 11.31 ?+/- 3.64). All participants had relapsing remitting disease and the groups were matched for disease duration (4.91 ?+/- 3.05 years for AOMS vs. 6.38 ?+/- 3.54 for POMS). The POMS group had higher estimated premorbid IQ (WRAT-4 reading 112.7 ?+/- 18.5 vs. 105.4 ?+/- 13.4), though the result did not reach significance (p=0.07). Neither group's cognitive performances fell into the impaired range relative to age-normative means. However, the AOMS compared to the POMS group consistently performed significantly worse on the SDMT (mean z-score -0.26 ?+/- 1.15 for AOMS vs. 0.68 ?+/- 1.53 for POMS, p=0.01) and slower on the Cogstate composite (mean z-score of -1.04 ?+/- 1.09 for AOMS vs. 0.35 ?+/- 1.15 for POMS, p=0.04). Estimated premorbid IQ was correlated with SDMT, but not Cogstate performance (r=0.56 p=0.001 and r=0.13 p=0.35, respectively). Age of disease onset was significantly negatively correlated with cognitive processing (SDMT: r= -0.32, p= 0.01 and Cogstate DET: r= -0.33, p=0.02), further indicating that older age of onset is associated with greater cognitive impairment.
Conclusion(s): Adult MS is associated with larger cognitive involvement than pediatric MS

Background: Adaptable cognitive training interventions are accessible online from home for people with multiple sclerosis (PwMS), including for those with limited mobility, and have been shown to significantly improve cognition relative to control treatments. However, individual responsiveness to treatment is highly variable. Baseline clinical and MRI factors may contribute to this variability.
Objective(s): To determine whether specific baseline clinical and neuropathological MRI factors predict the success of online cognitive training in PwMS.
Method(s): 46 PwMS (30 RRMS, 16 PMS) were recruited for a 12-week home-based cognitive rehabilitation program. Subjects were recruited from a cohort of individuals with MRI previously collected (~2.3 years prior) for a larger study (Zivadinov, et al., 2017). Baseline and follow-up neuropsychological assessment included standard tests of cognition (SDMT, BVMTR, CVLT-II) and executive function (DKEFS), as well as clinical questionnaires. Participants were asked to complete 5 training sessions per week for approximately 50 minutes per session. Forward stepwise selection was applied using baseline clinical measures, including age, sex, EDSS, fatigue, depression, personality, disease course, and education, to predict longitudinal change in SDMT performance following rehabilitation from brain MRI measures. A separate, analogous regression analysis was applied to investigate MRI predictors of SDMT performance improvement, and included lateral ventricular volume (LVV), gray matter volume (GMV), and T2 lesion volume (T2LV).
Result(s): Disease course (RRMS vs PMS) was a statistically significant clinical predictor of improvement on SDMT performance following rehabilitation (beta=-0.336, p=0.026). The RRMS subgroup showed a 4.34 +/-5.74 point improvement (p< 0.0001), while there was no significant change in the PMS group (0.25 +/-4.73 points, p=0.835). Among MRI measures, baseline GMV was significantly related to improvement on SDMT performance (beta=0.367, p=0.014).
Conclusion(s): Remote cognitive rehabilitation therapy is more effective for individuals with RRMS, rather than those with PMS. Furthermore, increased baseline GMV is also predictive of greater cognitive improvement following rehabilitation

Background: Clinical observations and emerging studies suggest that African American (AA) people with multiple sclerosis (MS) tend to fare worse than their Caucasian American (CA) counterparts. Existing studies are limited by few AA participants and could often not evaluate other potential contributing factors.
Objective(s): To compare socio-economic and clinical characteristics of a large population of AA and CA people with MS.
Method(s): MS PATHS is a network of 10 large MS centers located in the United States (7) and Europe (3); standardized collection of socio-demographic characteristics, including self-reported racial identity, as well as clinical and disease information are acquired at least annually during routine clinic visits. We included US-based MS PATHS participants with self-reported AA and CA racial identities who provided socio-economic and MS characteristics. We compared AA vs. CA with respect to socio-economic and MS metrics including disability (via Patient Determined Disease Steps [PDDS]) and objective neurological outcomes (via walking speed, manual dexterity and processing speed) using generalized linear models, as appropriate. Models for PDDS and neurologic outcomes were adjusted for age, sex, disease subtype and duration, employment, insurance status.
Result(s): Of US-based eligible participants in MS PATHS, 909 (14%) identify as AAs while 5842 (86%) identify as CAs and were included in the analyses. Relative to CAs, AAs tended to be younger (Mean 49.7y [standard deviation; SD: 12.3y] vs. 45.6y [12.5]; p< 0.0001), have fewer years of education (14.8y [2.6] vs. 14.1y [2.8]; p< 0.0001), have Medicaid insurance (48% vs. 30%; P< 0.0001) and be currently on disability or not working (29% vs. 39%; p< 0.0001). AAs had a 58% multivariable-adjusted higher odds of severe vs. mild disability relative to CAs (OR: 1.56; 95% CI: 1.21-2.02). They also had significantly slower walking and manual dexterity speeds (multivariable-adjusted mean %difference [95% CI]: 25-foot walking speed: 10% slower [7%-13%]; manual dexterity: 7% slower [5%-9%]) and significantly lower processing speed scores (multivariable-adjusted mean difference-4.32 [-5.09-3.56]).
Conclusion(s): In this large sample of AA and CA people with MS, self-reported AA identity was associated with indicators of lower socio-economic status and with greater disease severity across a broad array of neurological assessments

BACKGROUND:Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has been shown to improve common symptoms of neurological disorders like depressed mood, fatigue, motor deficits and cognitive dysfunction. tDCS requires daily treatment sessions in order to be effective. We developed a remotely supervised tDCS (RS-tDCS) protocol for participants with multiple sclerosis (MS) to increase accessibility of tDCS, reducing clinician, patient, and caregiver burden. The goal of this protocol is to facilitate home use for larger trials with extended treatment periods. In this study we determine the generalizability of RS-tDCS paired with cognitive training (CT) by testing its feasibility in participants with Parkinson's disease (PD). METHODS:Following the methods in our MS protocol development, we enrolled sixteen participants (n = 12 male, n = 4 female; mean age 66 years) with PD to complete ten open-label sessions of RS-tDCS paired with CT (2.0 mA × 20 min) at home under the remote supervision of a trained study technician. Tolerability data were collected before, during, and after each individual session. Baseline and follow-up measures included symptom inventories (fatigue and sleep) and cognitive assessments. RESULTS:RS-tDCS was feasible and tolerable for patients with PD, with at-home access leading to high protocol compliance. Side effects were mostly limited to mild sensations of transient itching and burning under the electrode sites. Similar to prior finding sin MS, we found preliminary efficacy for improvement of fatigue and cognitive processing speed in PD. CONCLUSIONS:RS-tDCS paired with CT is feasible for participants with PD to receive at home treatment. Signals of benefit for reduced fatigue and improved cognitive processing speed are consistent across the PD and MS samples. RS-tDCS can be generalized to provide tDCS to a range of patients with neurologic disorders for at-home rehabilitation. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT02746705 . Registered April 21st 2016.