GABAergic cortical network physiology in frontotemporal lobar degeneration

Abstract

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy (PSP). Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABA-ergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 people with bvFTD, 15 people with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural magnetic resonance imaging, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: Once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from Parametric Empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABA-ergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following Tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explain the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalised selection of drugs and stratification of patients for future clinical trials.

Cortical and subcortical changes in resting-state neuronal activity and connectivity in early symptomatic ALS and advanced frontotemporal dementia

“…In patients with bvFTD, reduced GABA levels in the right inferior frontal gyrus were found, and reduced GABA and glutamate concentrations in this region were both associated with disinhibition, a key symptom of bvFTD ( Murley et al, 2020 ). Interestingly, a relation between GABA levels and beta generation, as well as the back-propagation of information, has been postulated recently ( Adams et al, 2021 ). In addition, it has been proposed that disruption of behavioural control arises from reduced gamma-band (and cross-frequency theta to alpha) connectivity of the inferior frontal gyrus, cortex, together with increased gamma-band connectivity among pre-supplementary motor area and motor regions ( Hughes et al, 2018 ).…”

Synaptic loss in behavioural variant frontotemporal dementia revealed by [11C]UCB-J PET

“…Early synaptic dysfunction in these regions may explain the subtle pre-symptomatic behavioural change and executive dysfunction. In addition, synaptic loss may determine the neurophysiological signatures of bvFTD as assayed by magnetoencephalography (Hughes et al ., 2018; Sami et al ., 2018; Adams et al ., 2021; Shaw et al ., 2021; Copet et al ., 2022) as in Alzheimer’s disease (Coomans et al ., 2021).…”

Evidence and implications of abnormal predictive coding in dementia

“… 157 GABAergic modulation of feedback predictions and feedforward prediction errors may also contribute to the impairment of predictive coding from frontotemporal lobar degeneration. 23 , 24 …”

“… 44 Patients with behavioural variant frontotemporal dementia show reduced mismatch negativity response, as a product of impaired inhibitory connections and reduced GABA concentrations in the frontal cortex. 23 , 24 These patients show reduced precision in higher levels of the auditory hierarchy, leading to errors in encoding of conditional expectations at lower levels. 22 …”