GABAergic modulation of beta power enhances motor adaptation in frontotemporal lobar degeneration

Abstract

AbstractThe 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.