GABAergic Modulation of Beta Power Enhances Motor Adaptation in Frontotemporal Lobar Degeneration

Abstract The impairment of behavioural control is a characteristic feature of disorders associated with frontotemporal lobar degeneration (FTLD). Behavioural disinhibition and impulsivity in these disorders are linked to abnormal neurophysiology of the frontal lobe, such as the loss beta-band power and changes in prefrontal GABAergic neurotransmission. Here we test the hypothesis that a pharmacological increase of GABA would concurrently improve cortical beta-band power and adaptive behavioural control in people with behavioural-variant frontotemporal dementia (bvFTD), and progressive supranuclear palsy (PSP, Richardson's syndrome). We recorded magnetoencephalography during a visuomotor task that measures participants' ability to adapt motor responses to visual feedback. Tiagabine, a GABA re-uptake inhibitor, was used as a pharmacological probe in a double-blind placebo controlled crossover design. The study included 11 people with bvFTD, 11 people with PSP and 20 healthy age-matched controls. Behavioural performance and beta power were examined with linear mixed models examined changes in, to estimate motor learning over time and the response to tiagabine. Significant beta power differences were source-localised using linear-constraint minimum variance beamformer. As predicted, participants with bvFTD and PSP were impaired behaviourally, and the beta power associated with movement, learning and accuracy, was diminished compared to controls. Tiagabine facilitated partial recovery of the impairments in behaviour and beta power over trials, moderated by executive function, such that the greatest improvements were seen in those with higher cognitive scores. The beamformer localised the physiological effects of disease and tiagabine treatment to frontal cortices, and confirmed the right prefrontal cortex as a key site of drug by group interaction. We interpret the differential response to tiagabine between bvFTD and PSP as a function of baseline differences in atrophy and physiology. In summary, behavioural and neurophysiological deficits can be mitigated by enhancement of GABAergic neurotransmission. Clinical trials are warranted to test for enduring clinical benefits from this restorative-psychopharmacology strategy. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN10616794 ### Clinical Protocols ### Funding Statement This work was primarily funded by the Wellcome Trust (220258), with additional support from the Medical Research Council (MC\_UU\_00030/14; MR/T033371/1) and the NIHR Cambridge Biomedical Research Centre (NIHR203312), and carried out at/ the NIHR Cambridge Clinical Research Facility. This work was co-funded by the Holt Fellowship, Association of British Neurologists and Patrick Berthoud Trust. We thank the PSP Association & FTD Support Group for raising awareness of the study. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: REC reference: 10/H0310/59 IRAS project ID: 55856 NHS Health Research Authority East of England - Cambridgeshire and Hertfordshire Research Ethics Committee The Old Chapel Royal Standard Place Nottingham NG1 6FS I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the results of this study will be available from the corresponding author, upon reasonable request for academic (non-commercial) purposes, subject to restrictions required to preserve participant confidentiality. A data transfer agreement may be required.