Electrophysiological receptor mapping of GABA-A receptors

The non-invasive study of cortical oscillations provides a window onto neuronal processing. Temporal correlation of these oscillations between distinct anatomical regions is considered a marker of functional connectedness. As the most abundant inhibitory neurotransmitter in the mammalian brain, {gamma}-aminobutyric acid (GABA) is thought to play a crucial role in shaping the frequency and amplitude of oscillations, which thereby suggests a further role for GABA in shaping the topography of functional connectivity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations and availability) through oral administration of the GAT1-blocker tiagabine (15 mg). We show that the spatial distribution of connectivity effects corresponds to template maps of flumazenil PET maps of GABAA receptor distribution. In a placebo-controlled crossover design, we collected resting MEG recordings from 15 healthy male individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo pill. Using amplitude envelope correlations (AECs) we quantified the functional connectivity in discrete frequency bands across the whole brain, using the 90-region Automatic Anatomical Labelling atlas (AAL90), as well as quantifying the average oscillatory activity at each region. Analysis of variance in connectivity using a drug-by-time (2x4) design revealed interaction effects, accompanied by main effects of drug and time. Post-hoc permutation testing of each post-drug recording against the respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, and across 1- 3- and 5- hour recordings following tiagabine, but not placebo. The same analysis applied to the activity of each region also revealed a significant interaction, with post-hoc permutation testing signalling significant reductions in activity in middle occipital regions across delta, theta, alpha and beta frequency bands. Crucially, we show that the spatial distribution of both connectivity and activity changes with tiagabine overlaps significantly with template quantitative GABAA maps derived from flumazenil volume-of-distribution (FMZ-VT) PET, clearly demonstrating a mechanistic link between GABA availability, GABAA receptor distribution and low-frequency network oscillations. We therefore propose a utility for functional connectivity and activity measures as receptor-mapping tools in pharmacological imaging.