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Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions

Shaw, Alexander D. ORCID: https://orcid.org/0000-0001-5741-7526, Chandler, Hannah L., Hamandi, Khalid, Muthukumaraswamy, Suresh D., Hammers, Alexander and Singh, Krish D. ORCID: https://orcid.org/0000-0002-3094-2475 2021. Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions. European Neuropsychopharmacology 50 , pp. 34-45. 10.1016/j.euroneuro.2021.04.005

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Abstract

As the most abundant inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA) plays a crucial role in shaping the frequency and amplitude of oscillations, which suggests a role for GABA in shaping the topography of functional connectivity and activity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) using the GABA transporter 1 (GAT1) blocker, tiagabine (15 mg). In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo. We quantified whole brain activity and functional connectivity in discrete frequency bands. Drug-by-session (2 × 4) analysis of variance in connectivity revealed interaction and main effects. Post-hoc permutation testing of each post-drug recording vs. respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, across 1- 3- and 5- hour recordings following tiagabine only. The same analysis applied to activity revealed significant increases across frontal regions, coupled with reductions in posterior regions, across delta, theta, alpha and beta frequencies. Crucially, the spatial distribution of tiagabine-induced changes overlap with group-averaged maps of the distribution of GABAA receptors, from flumazenil (FMZ-VT) PET, demonstrating a link between GABA availability, GABAA receptor distribution, and low-frequency network oscillations. Our results indicate that the relationship between PET receptor distributions and MEG effects warrants further exploration, since elucidating the nature of this relationship may uncover electrophysiologically-derived maps of oscillatory activity as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Psychology
Cardiff University Brain Research Imaging Centre (CUBRIC)
Publisher: Elsevier
ISSN: 0924-977X
Funders: Wellcome Trust
Date of First Compliant Deposit: 15 April 2021
Date of Acceptance: 4 April 2021
Last Modified: 05 May 2023 23:17
URI: https://orca.cardiff.ac.uk/id/eprint/140501

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