Propofol sedation-induced alterations in brain connectivity reflect parvalbumin interneurone distribution in human cerebral cortex

Michael M Craig,Bratislav Misic,Ioannis Pappas,Ram M Adapa,David K Menon,Emmanuel A Stamatakis

doi:10.1016/j.bja.2020.11.035

Abstract

BackgroundPropofol, a commonly used intravenous anaesthetic, binds to type A gamma aminobutyric acid (GABA) receptors in mammalian brain. Previous work on its anaesthetic action has characterised either the biochemistry underlying propofol binding or the associated changes in brain network dynamics during sedation. Despite these advances, no study has focused on understanding how propofol action at the cellular level results in changes in brain network connectivity. MethodsWe used human whole-brain microarray data to generate distribution maps for genes that mark the primary GABAergic cortical interneurone subtypes (somatostatin, parvalbumin [PV], and 5-hydroxytryptamine 3A. Next, 25 healthy participants underwent propofol-induced sedation during resting state functional MRI scanning. We used partial least squares analysis to identify the brain regions in which connectivity patterns were most impacted by propofol sedation. We then correlated these multimodal cortical patterns to determine if a specific interneurone subtype was disproportionately expressed in brain regions in which connectivity patterns were altered during sedation. ResultsBrain networks that were significantly altered by propofol sedation had a high density of PV-expressing GABAergic interneurones. Brain networks that anticorrelated during normal wakefulness, namely the default mode network and attentional and frontoparietal control networks, increased in correlation during sedation. ConclusionsPV-expressing interneurones are highly expressed in brain regions with altered connectivity profiles during propofol-induced sedation. This study also demonstrates the utility of leveraging multiple datasets to address multiscale neurobiological problems.

Highlights

Propofol, a commonly used intravenous anaesthetic, binds to type A gamma aminobutyric acid (GABA) receptors in mammalian brain
To validate the expression maps we examined whether there were interhemispheric differences in expression of each of the GABAergic interneurone subtypes (Fig. 2)
The aim of the present study was to determine whether a specific GABAergic interneurone subtype is important in mediating alterations in cortical brain network connectivity seen in propofol sedation

Summary

Introduction

A commonly used intravenous anaesthetic, binds to type A gamma aminobutyric acid (GABA) receptors in mammalian brain. Previous work on its anaesthetic action has characterised either the biochemistry underlying propofol binding or the associated changes in brain network dynamics during sedation. Despite these advances, no study has focused on understanding how propofol action at the cellular level results in changes in brain network connectivity. We used partial least squares analysis to identify the brain regions in which connectivity patterns were most impacted by propofol sedation. We correlated these multimodal cortical patterns to determine if a specific interneurone subtype was disproportionately expressed in brain regions in which connectivity patterns were altered during sedation.

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