Ketamine effects on default mode network activity and vigilance: A randomized, placebo‐controlled crossover simultaneous fMRI/EEG study

Summary

Resting-state brain activity is not steady but dynamic, with vigilance fluctuations playing a key role. In a randomized, double-blind, placebo-controlled crossover study of 24 healthy young adults, subanesthetic S-ketamine decreased functional connectivity in the medial prefrontal cortex and increased connectivity in intraparietal cortices, measured with simultaneous EEG-fMRI. Ketamine also shifted EEG power toward slow (delta, theta) and fast (gamma) frequencies. Frontal connectivity negatively related to EEG gamma and theta activity, while parietal connectivity positively related to delta power. These results indicate a direct link between ketamine-induced connectivity changes and reduced vigilance, offering potential surrogate endpoints for understanding ketamine's antidepressant effects.

Study at a glance

Abstract

In resting-state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting-state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine-induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double-blind, placebo-controlled crossover study with subanesthetic S-Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting-state fMRI and EEG data. We conducted seed-based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine-induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009-012399-28).