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, as generative models of 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 in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminarspecific 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 drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. 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 pharmacomagnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine

“…Only layer 6 thalamic-projection pyramidal cells and thalamic relay populations possess M and H channels (see Fig. 1 ), which enables these populations to exhibit their characteristic bursting behaviour ( Adams et al., 2020 ), while differentiating the intrinsic activation profile of layer 6 pyramidal populations from that of layer 5. This formulation is an extension of the NMDA model of Moran ( Gilbert et al., 2016 ; Moran et al., 2011c ) (CMM_NMDA in the SPM DCM toolbox) and includes the same voltage switch to represent the NMDA magnesium block; …”

“…In the TCM, the cortex-thalamus-cortex loop incorporated a delay of 11 ms, made up of 8 ms cortex to thalamus and 3 ms thalamus to cortex, in accordance with previous models ( Lumer, 1997 ; Traub, 2004 ). However, since there is large variation in modelling estimates of these delays in the literature ( Adams et al., 2020 ; Hashemi et al., 2017 ; Roberts and Robinson, 2008 ) we parameterised these delays, allowing them to vary during data fitting.…”

“…Methods including Dynamic Causal Modelling (DCM) ( Friston et al., 2003 ; Kiebel et al., 2008 ; Moran et al., 2007 , 2011b ) provide a framework for generating typical and atypical empirical features in electrophysiological time series (e.g. ( Adams et al., 2020 ; Cooray et al., 2015 ; Gilbert et al., 2016 ; Shaw et al., 2019 )). In DCM, the subsequent fitting (inverting) of parameterised neuronal models to empirical data features, acquired under different pharmacological or task states, permits an in-silico assay of usually unobservable neuronal states such as synaptic connectivity between cell populations, or the decay times of specific receptor types.…”

The interaction between endogenous GABA, functional connectivity and behavioral flexibility is critically altered with advanced age

“…These drug-induced changes of evoked responses have been hypothesized to indicate at least two distinct mechanisms in neural processing that are vulnerable to increasing inhibition, namely a potential disturbance of refractory mechanisms leading to hyperpolarization [54] and an alteration of the excitatory drive [55]. Previous findings showing that elevated GABA concentration affects pyramidal and inter-neuronal cell populations and exerts effects on both phasic and tonic inhibitory signaling in superficial and deep cortical layers serve as a potential explanation [56–58]. Simply speaking, too much inhibition may turn into overall excitation.…”

Modelling thalamocortical circuitry shows that visually induced LTP changes laminar connectivity in human visual cortex

“…The thalamocortical model presented here extends this architecture to include an additional set of cortical inhibitory interneurons (allowing separate superficial and deep populations). Furthermore, we include an additional population of cortico-thalamic (aka thalamic projection) pyramidal neurons in layer VI [ 45 ]. For the thalamus, we model one population of (excitatory) relay cells and one population of (inhibitory) reticular cells.…”