Faculty Bibliography

In our first paper in this series (Epilepsia 2015; 56(5): 674-681), we published recommendations for the indications and expectations for neuropsychological assessment in routine epilepsy care. This partner paper provides a comprehensive overview of the more specialist role of neuropsychological assessment in the pre and postoperative evaluation of epilepsy surgery patients. The paper is in two parts. The first part presents the framework for the mandatory role of neuropsychologists in the presurgical evaluation of epilepsy surgery candidates. A preoperative neuropsychological assessment should be comprised of standardised measures of cognitive function in addition to wider measures of behavioural and psychosocial function. The results from the presurgical assessment are used to: (1) establish a baseline against which change can be measured following surgery; (2) provide a collaborative contribution to seizure characterization, lateralization and localization; (3) provide evidence-based predictions of cognitive risk associated with the proposed surgery; and (4) provide the evidence base for comprehensive preoperative counselling, including exploration of patient expectations of surgical treatment. The second part examines the critical role of the neuropsychologist in the evaluation of postoperative outcomes. Neuropsychological changes following surgery are dynamic and a comprehensive, long-term assessment of these changes following surgery should form an integral part of the postoperative follow-up. The special considerations with respect to pre and postoperative assessment when working with paediatric populations and those with an intellectual disability are also discussed. The paper provides a summary checklist for neuropsychological involvement throughout the epilepsy surgery process, based on the recommendations discussed.

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.

Objective/UNASSIGNED:Assessment of performance validity is a necessary component of any neuropsychological evaluation. Prior research has shown that cutoff scores of ≤6 or ≤7 on Reliable Digit Span (RDS) can detect suboptimal effort across numerous adult clinical populations; however, these scores have not been validated for that purpose in an adult epilepsy population. This investigation aims to determine whether these previously established RDS cutoff scores could detect suboptimal effort in adults with epilepsy. Method/UNASSIGNED:Sixty-three clinically referred adults with a diagnosis of epilepsy or suspected seizures were administered the Digit Span subtest of the Wechsler Adult Intelligence Scale (WAIS-III or WAIS-IV). Most participants (98%) passed Trial 2 of the Test of Memory Malingering (TOMM), achieving a score of ≥45. Results/UNASSIGNED:Previously established cutoff scores of ≤6 and ≤7 on RDS yielded a specificity rate of 85% and 77% respectively. Findings also revealed that RDS scores were positively related to attention and intellectual functioning. Given the less than ideal specificity rate associated with each of these cutoff scores, together with their strong association to cognitive factors, secondary analyses were conducted to identify more optimal cutoff scores. Preliminary results suggest that an RDS cutoff score of ≤4 may be more appropriate in a clinically referred adult epilepsy population with a low average IQ or lower. Conclusions/UNASSIGNED:Preliminary findings indicate that cutoff scores of ≤6 and ≤7 on RDS are not appropriate in adults with epilepsy, especially in individuals with low average IQ or below.

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.

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.

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=.

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.