Multiple high dose tDCS sessions produces perceived improvement and stabilisation in a person with a MAPT gene, presenting clinically as semantic variant primary progressive aphasia with severe cognitive impairment

Howard Chertkow is Senior Scientist and Chair in Cognitive Neurology and Innovation, Rotman Research Institute, Baycrest Health Sciences; Dr. Chertkow is supported by a Foundation Grant from the CIHR (Canadian Institutes for Health Research), along with the Weston Foundation and the Baycrest Health Sciences Foundation. The data was collected at the Lady Davis Institute and Jewish General Hospital Memory Clinic at McGill University in Montreal, and at the Rotman Research Institute at Baycrest Health Sciences in Toronto Dr. Chertkow has participated as a site PI in pharmaceutical trial activities in the past five years sponsored by: Hoffmann-La Roche Limited, TauRx, and Immunocal (site investigator for trials). This study was supported by a grant from the Canadian Institutes of Health Research (CIHR) to Howard Chertkow and Alexander Thiel. The internal research board of the Jewish General Hospital approved the use of humans for this study. Dear sir, A 60-year-old woman (LaA) was referred to the Department of Neurology at the Jewish General Hospital, Montreal, in 2014 with the diagnosis of primary progressive aphasia of a semantic variant (svPPA). A previously submitted genetic test performed by Athena Diagnostics® in mid-2013 also confirmed a pathogenic heterozygous missense autosomal dominant mutation at the MAPT gene. The positive result is consistent with the predisposition of developing non-fluent or semantic variant Frontotemporal Dementia (FTD), both associated with this gene mutation. By 2019, she had progressed to a severe global aphasic state, showing a floor effect on cognitive screening tests like the MoCA and MMSE. Nevertheless, she maintained the ability to follow general instructions, complete simple tasks, and could voice her willingness or reluctance to do an activity. Because previous studies suggested tDCS could produce a beneficial effect for people with dementia [[1]Elder G.J. Taylor J. Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias?.Alzheimer’s Res Ther. 2014; 6https://doi.org/10.1186/s13195-014-0074-1Crossref PubMed Scopus (88) Google Scholar], consent was obtained from the participant and her family to conduct tDCS stimulation sessions. To our knowledge, no previous study has assessed the benefits of tDCS in a person with a MAPT gene. Furthermore, tDCS has rarely been attempted in individuals with severe dementia in whom conventional objective tools of measurement show floor effects. We were interested in assessing whether a benefit could be derived in an individual with a severe neurodegenerative aphasic impairment. In three separate rounds, tDCS was administered for 20 minutes at 20 sessions (five times a week for four weeks), as approved by the ethics board of the Jewish General Hospital. We administered 5 mA of tDCS from a Soterix© machine that was subsequently split to two anode electrodes (5 × 7cm), over the left and right supraorbital frontal areas, such that each anode electrode received 2.5 mA of stimulation. Overlying the left and right occipital lobes, two cathode electrodes (5 × 7cm) were placed. tDCS was real in the first and third rounds, but SHAM in the second round, to produce an A-B-A pattern of stimulation (i.e., real-sham-real). To ensure tDCS still occurred while LaA was engaged, she was asked to play a game with a research assistant. LaA was asked to roll back a tennis ball in the opposite direction rolled to her, while also avoiding a central pillar (see supplementary video). Also, to increase energy levels and alleviate boredom, music familiar to LaA was played while she rolled the ball, and she was encouraged to interact and sing along with the music. Each round was separated by four months to ensure stimulation effects washed out before commencing the subsequent round. As an outcome measure of efficacy, we collected subjective ratings from a blinded caregiver (her nurse), examining how the perceived benefit from tDCS changed over time. A questionnaire consisting of Likert scales for various categories was sent two-weeks and one-month post-stimulation to be filled out by her nurse, who on average spent 25 hours per week with LaA. This caregiver was blind to whether a given condition was real or sham. Each questionnaire presented a 7-point Likert scale for multiple categories (memory, orientation and attention, everyday skills, hygiene, mood, sleep, false beliefs, energy levels, cooperativeness, inhibition levels, daily habits, physical abilities, motivation, and insight) that asked to what extent change had been observed since the cessation of tDCS stimulation. These categories were derived from the Cambridge Behaviour Inventory (CBI), an informant-based questionnaire that assesses behavioural changes across a range of neurodegenerative disorders [[2]Wear H.J. Wedderburn C.J. Mioshi E. Williams-Gray C.H. Mason S.L. Barker R.A. Hodges J.R. The Cambridge behavioural inventory revised.Dementia & Neuropsychologia. 2008; 2: 102-107Crossref PubMed Google Scholar]. The mid-point was used to indicate “no change”, with a little bit worse, somewhat worse, much worse to the left of the mid-point, and a little bit better, somewhat better, and much better to the right of the mid-point. For each questionnaire, the caregiver was asked to circle the most appropriate response for each category. Each questionnaire was identical and always asked the caregiver to report what perceived changed there was for the presented categories since stimulation had been ceased. Each completed Likert-Scale was converted into a numerical response by assigning a value score from −3 to +3 for the circled responses. For example, ‘much worse’ would receive a score of −3, ‘no change’ would receive a score of 0, and ‘much better’ would receive a score of 3, with all the other values between these poles. Once the results for all categories were transformed into numerical values, we summed the scores given for the different categories to produce a ‘general improvement score.’ Because there were 14 categories, the maximum possible score that could be obtained was 42. The two-week post-stimulation scores were largest in the first round (14), smaller in the second round (12), and further reduced in the third round (11). Some categories were reported as ‘no change’ or ‘a bit worse’, whereas key categories that were reported as improved included everyday skills, disinhibition, eating habits, awareness of illness, and energy levels. In the one-month post-stimulation questionnaires, these scores were found to increase slightly when real tDCS was given, but decreased when sham stimulation was given, as can be observed in the figure below (Fig. 1). In each round of stimulation, a positive general impression score was reported by the caregiver, which suggests that sessions alone produced some improvement. At the same time, the general impression score recorded at two-weeks post-stimulation was lower in each subsequent round (14 vs. 12 vs. 11), which suggests that as the LaA’s disease continued to progress, the improvement noted from each round also decreased. Crucially, however, these scores increased one-month post-stimulation when real tDCS stimulation was given, but decreased when sham stimulation was given. Because the real tDCS rounds had a similar pattern of increase, whereas the score in the sham round decreased, the results suggest that the administration of tDCS produced improvement that lasted longer, and produced a genuine improvement in the participant that was perceived by the caregiver. Therefore, the results suggest that tDCS can be beneficial for people with a MAPT gene for helping to maintain improvement gains, even when cognition is severely impaired. Carlos Roncero – Reports no disclosures. Aleksandar Popov – Reports no disclosures. Howard Chertkow – Reports no disclosures. There are no known conflicts of interest. This study was supported by a grant from the Canadian Institutes of Health Research (CIHR) to Howard Chertkow and Alexander Thiel. The following is the Supplementary data to this article:https://www.brainstimjrnl.com/cms/asset/6f91dc38-8c65-4cf3-a9fa-dbf41b2a5220/mmc1.mp4Loading ... Download .mp4 (6.46 MB) Help with .mp4 files Multimedia component 1

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