Species-conserved reconfigurations of brain network topology induced by ketamine.

R Becker,O Grimm,Z Zang,C Clemm Von Hohenberg,N Gass,J I Schweiger,A J Schwarz,E Schenker,A Sartorius,M Spedding,C Risterucci,H Tost,W Weber-Fahr,U Braun,A Meyer-Lindenberg

doi:10.1038/tp.2016.53

Abstract

Species-conserved (intermediate) phenotypes that can be quantified and compared across species offer important advantages for translational research and drug discovery. Here, we investigate the utility of network science methods to assess the pharmacological alterations of the large-scale architecture of brain networks in rats and humans. In a double-blind, placebo-controlled, cross-over study in humans and a placebo-controlled two-group study in rats, we demonstrate that the application of ketamine leads to a topological reconfiguration of large-scale brain networks towards less-integrated and more-segregated information processing in both the species. As these alterations are opposed to those commonly observed in patients suffering from depression, they might indicate systems-level correlates of the antidepressant effect of ketamine.

Highlights

Ketamine, a potent N-methyl-D-aspartate (NMDA)-receptor antagonist, has spurred considerable interest in the preclinical as well as clinical applications
In a double-blind, placebo-controlled, cross-over study in humans and a placebo-controlled two-group study in rats, we demonstrate that the application of ketamine leads to a topological reconfiguration of large-scale brain networks towards less-integrated and more-segregated information processing in both the species
After the application of ketamine, human brain networks showed a decrease in the global and local efficiency compared with placebo (PFDRo0.05), as well as a decrease in the small-world coefficient (PFDRo0.05)

Summary

Introduction

A potent N-methyl-D-aspartate (NMDA)-receptor antagonist, has spurred considerable interest in the preclinical as well as clinical applications. Several studies have probed the underlying neurobiological substrates of these actions in humans[2,9,10,11,12] and animals[6,9,13] using neuroimaging approaches, but have largely focused on specific brain regions[12] and their interactions. The first explicit demonstration of the translational potential of these methods showed altered prefrontal–hippocampal coupling after ketamine application in rats and humans, using a functional magnetic resonance imaging (fMRI) resting-state functional connectivity approach.[9]. Given the ubiquity of NMDA receptors throughout the brain,[14] it is likely that ketamine modulates large-scale neural networks on the system level, beyond alterations in single brain regions or specific circuits

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