326. Ketamine-induced changes of cerebral glucose metabolism in healthy humans: evidence from [18F]FDG functional PET

Abstract

Abstract Background Ketamine is a N-methyl-D-aspartate receptor antagonist with rapid-acting antidepressant properties and characteristic dissociative side effects, yet its neuronal mechanisms remain only partially understood. Previous studies have primarily used pharmacological magnetic resonance imaging (phMRI) to characterize ketamine-induced neuronal alterations (Höflich et al., 2017; Maltbie, Kaundinya, & Howell, 2017). Allthough phMRI offer high temporal and spatial resolution, neuronal activity is assessed indirectly via oxygen metabolism, and neurovascular factors (Doyle et al., 2013; J.L. Reed et al., 2019). In contrast, functional PET (fPET) with [18F]Fluorodeoxyglucose ([18F]FDG) offer a complementary and direct measure (Leybaert, 2005), to quantify cerebral glucose metabolism. Previous studies using [18F]FDG PET to investigate ketamine’s neurophysiological effect, have been restricted to static metabolic rates (Vollenweider et al., 1997), thereby being unable to assess its dynamic effects. Aims & Objectives We aimed to capture acute ketamine-induced changes in cerebral glucose metabolism within a functional PET (fPET) framework. Method In this double-blind, randomized, cross-over study twenty-three healthy volunteers (mean age ± SD = 25.48 ± 4.08 years, 14 male) underwent two 75-minute [18F]FDG simultaneous PET/MR scans, during which they received either 0.25mg*kg-1 (S)-ketamine or a 0.9% saline placebo intravenously. 20 minutes after tracer application and fPET acquisition start, the study drug was administred following a block design comprising three 5-minutes infusion blocks separated by 10-minute drug-free intervals. fPET data were reconstructed into 30 seconds frames and preprocessed as described previously (M.B. Reed et al., 2024). Baseline-corrected [18F]FDG time activity curves were obtained across grey-matter voxels, capturing drug-induced changes in cerebral glucose metabolism, and used for a voxel-wise intersubject correlation analysis, and subsequent comparison between conditions in a repeated measures ANOVA (p < 0.05, FWE-corrected). Results Ketamine induced widespread and significantly increased cortical intersubject correlations, most predominantly in frontal cortical regions and the right hippocampus. The nine most significant regions and highest T-values are displayed in the Table below. Discussion & Conclusions (S)-Ketamine administration elicited metabolic responses primarily within hubs of the default mode and frontoparietal control network, with additional but fewer clusters in regions associated with the visual, sensorimotor and salience networks. These synchronous, temporally dynamic metabolic changes may contribute to ketamine’s rapid-onset and transient neuropsychological effects. In summary, our findings provide metabolic sensitive insight into ketamine’s impact on neuronal function.