Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network

Introduction

Mueller and colleagues contextualise their work within two parallel lines of investigation: first, subanesthetic doses of the NMDAR antagonist S-ketamine produce transient behavioural effects in healthy people that resemble positive and negative symptoms of acute psychosis, making ketamine a widely used pharmacological model of glutamatergic dysfunction in schizophrenia; second, resting-state functional MRI (RS-fMRI) permits non-hypothesis-driven characterisation of intrinsic brain networks and their connectivity, which may reveal neural mechanisms underlying those behavioural effects. Previous RS-fMRI studies of ketamine have reported heterogeneous findings, including increases or decreases of global or region-specific connectivity, variable effects across networks such as the default mode network (DMN), salience network (SN) and executive control network (ECN), and inconsistencies that may relate to dose, infusion protocol, seed choice and timing of acquisition. The authors note an unmet need to identify imaging markers that reliably index ketamine-induced psychotomimetic effects and that could serve as surrogate outcome measures in dose–response or translational studies. This study sets out to test whether subanesthetic S-ketamine alters functional connectivity within four large resting-state networks implicated in schizophrenia—the DMN, dorsal attention network (DAN), ECN and SN—and whether connectivity changes relate to concurrent clinical symptom changes. Using a double-blind, randomised, placebo-controlled cross-over design in healthy male volunteers, the investigators performed seed-to-voxel RS-fMRI analyses and assessed whether ketamine-induced connectivity changes could accurately discriminate drug versus placebo (via receiver operating characteristic analysis) and correlate with changes on the Positive and Negative Syndrome Scale (PANSS) and the 5D-ASC altered-states questionnaire. The aim was to evaluate whether such connectivity changes might qualify as candidate functional biomarkers for ketamine-induced side effects, particularly negative symptoms.