Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile
This double-blind, placebo-controlled, cross-over, within-subjects study (n=22) investigated the effects of ketamine (30mg/70kg) on whole-brain functional connectivity in healthy male participants while attenuating pre-synaptic glutamate release directly via pretreatments with the sodium-channel modulator lamotrigine (300 mg), and indirectly via pretreatment with the 5-HT2A receptor antagonist risperidone (2mg). Ketamine induced robust changes in the functional connectivity pattern and produced a shift from a cortically-centered to a sub-cortically-centered brain state. Pre-treatment with risperidone, but not lamotrigine, resulted in a strong modulation of the ketamine-induced hub changes, which suggests that these changes are likely a result of NMDA blockade and possible serotonergic modulation rather than purely modulation of glutamate release.
Abstract
Introduction
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied in relation to the glutamate hypothesis of schizophrenia and increases dissociation, positive and negative symptom ratings. Ketamine effects brain function through changes in brain activity; these activity patterns can be modulated by pre-treatment of compounds known to attenuate the effects of ketamine on glutamate release. Ketamine also has marked effects on brain connectivity; we predicted that these changes would also be modulated by compounds known to attenuate glutamate release.
Methods
Here, we perform task-free pharmacological magnetic resonance imaging (phMRI) to investigate the functional connectivity effects of ketamine in the brain and the potential modulation of these effects by pre-treatment of the compounds lamotrigine and risperidone, compounds hypothesised to differentially modulate glutamate release. Connectivity patterns were assessed by combining windowing, graph theory and multivariate Gaussian process classification.
Results
We demonstrate that ketamine has a robust effect on the functional connectivity of the human brain compared to saline (87.5 % accuracy). Ketamine produced a shift from a cortically centred, to a subcortically centred pattern of connections. This effect is strongly modulated by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based on the differential effect of these compounds on ketamine response, we suggest the observed connectivity effects are primarily due to NMDAR blockade rather than downstream glutamatergic effects.
Discussion
The connectivity changes contrast with amplitude of response for which no differential effect between pre-treatments was detected, highlighting the necessity of these techniques in forming an informed view of the mechanistic effects of pharmacological compounds in the human brain.
Research Summary of 'Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile'
Introduction
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, induces transient glutamatergic dysfunction and acutely produces psychotomimetic effects in healthy volunteers. Earlier neuroimaging work has documented robust ketamine effects on the blood oxygen level-dependent (BOLD) signal, typically analysed in terms of amplitude, and pre-treatment with compounds that reduce glutamate release has been shown to attenuate those amplitude changes. However, ketamine also affects functional connectivity across the brain, and it remains uncertain whether connectivity changes are driven primarily by direct NMDAR blockade or by downstream glutamatergic mechanisms. Joules and colleagues set out to characterise whole-brain task-free functional connectivity changes induced by an acute sub-anaesthetic ketamine infusion and to test whether two pharmacological probes with different mechanisms—lamotrigine (a presynaptic inhibitor of glutamate release via sodium channel modulation) and risperidone (an atypical antipsychotic with 5-HT2A antagonism and reported NMDAR potentiation)—differentially modulate those connectivity effects. Using a multivariate pattern-recognition approach applied to graph-theory centrality metrics, the study aims to identify ketamine-induced connectivity patterns and to determine whether pre-treatment with lamotrigine or risperidone attenuates or alters these patterns, thereby informing mechanistic interpretation.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Create a free account to open full-text PDFs.
Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Author
- APA Citation
Joules, R., Doyle, O. M., Schwarz, A. J., O’Daly, O. G., Brammer, M., Williams, S. C., & Mehta, M. A. (2015). Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile. Psychopharmacology, 232(21-22), 4205-4218. https://doi.org/10.1007/s00213-015-3951-9
References (2)
Papers cited by this study that are also in Blossom
Corlett, P. R., Honey, G. D., Krystal, J. H. et al. · Neuropsychopharmacology (2010)
William Deakin, J. F., Lees, J., McKie, S. et al. · JAMA Psychiatry (2008)
Cited By (7)
Papers in Blossom that reference this study
Moujaes, F., Lisa, J., Rahmati, M. et al. · eLife (2024)
Veraart, J. K. E., Smith-Apeldoorn, S. Y., Bakker, I. M. et al. · International Journal of Neuropsychopharmacology (2021)
Brouwer, A., Carhart-Harris, R. L. · Journal of Psychopharmacology (2020)
Ionescu, D. F., Felicione, J. M., Gosai, A. et al. · Harvard Review of Psychiatry (2018)
Mueller, F., Musso, F., London, M. et al. · NeuroImage (2018)
Carbonaro, T. M., Hurwitz, E., Johnson, M. W. · Psychopharmacology (2017)
Grimm, O., Gass, N., Weber-Fahr, W. et al. · Psychopharmacology (2015)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.