GABA-ergic dynamics in human frontotemporal networks confirmed by pharmaco-magnetoencephalography

Abstract

To bridge the gap between preclinical cellular models of disease and in vivo imaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, inverted to magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked ‘mismatch negativity’ response and transiently induced oscillations. Here, we probe GABAergic influences of the networks using double-blind placebo-controlled randomised-crossover administration of the GABA re-uptake inhibitor, tiagabine (oral, 10mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. Moreover, in keeping with the hierarchical coding of beliefs and sensory evidence, we found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco-magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.Significance StatementUnderstanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach correctly identified the effect of a test drug (tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain.

Neural excitation/inhibition imbalance and the treatment of severe depression

“…By regulating the strength of inhibition, the self-connections allowed for sustained activity in the cortex while maintaining a balance between excitation and inhibition throughout the network. A recent magnetoencephalography study using DCM showed that a GABA A reuptake inhibitor altered the strength of inhibitory (self-)connections in humans 26 , indicating that the DCM framework could be used to study the effect of therapeutic interventions on (self-)inhibition.…”

“…The strength of intrinsic self-inhibition can thus be interpreted as a proxy for the regional excitation/inhibition balance 25 . Recently, a study using magnetoencephalography showed that DCM can quantify the increase in tonic inhibition by a GABA reuptake inhibitor 26 . Here, we use spDCM to study the effects of pharmacotherapy and ECT on extrinsic and intrinsic effective connectivity in severely depressed patients.…”

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

“…Tiagabine binds selectively and with high affinity to the GABA reuptake transporter GAT1 elevating the level of GABA in the extracellular fluid and synapse. 34 In health, tiagabine alters beta power widely across the cortex, 35,36 and enhances movement related beta ERD/ERS 37 . However, the behavioural consequences of pharmacologically altering beta are unclear; Muthukumaraswamy et al, 37 reported no drug induced changes in movement performance in their group of young healthy adults although there were observed changes in beta power.…”