Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile
R. Joules, O. Doyle, A. J. Schwarz, O. O’daly, Michael Brammer, S. Williams, Mitul A Mehta
Psychopharmacology May 19, 2015 DOI: 10.1007/s00213-015-3951-9 via Semantic Scholar
Summary
Ketamine, which blocks N-methyl-D-aspartate receptors (NMDARs), robustly alters functional connectivity in the human brain, shifting patterns from cortex-centered to subcortex-centered connections. This effect was detected with 87.5% accuracy compared to saline. Pre-treatment with risperidone strongly modulated the connectivity changes (81.25% accuracy), whereas lamotrigine did not (43.75% accuracy). The differential modulation suggests the connectivity effects stem primarily from NMDAR blockade rather than downstream glutamate release. No such differential effect was seen in measures of brain response amplitude, underscoring the value of connectivity analysis for understanding how drugs affect the brain.
Study at a glance
| Characteristics | Task-free pharmacological magnetic resonance imaging (phMRI) study Peer reviewed |
|---|---|
| Population | Human participants |
| Keywords | Psychology Medicine |
| Citations | 77 |
| Key finding | Ketamine robustly alters functional connectivity from a cortical to a subcortical pattern, an effect strongly modulated by risperidone but not lamotrigine, indicating the changes are due to NMDAR blockade rather than downstream glutamatergic effects. |
Abstract
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. 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. 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. 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.