The acute effects of subanaesthetic ketamine in health and depression: Evidence from resting-state electroencephalography and functional magnetic resonance imaging

Abstract

A single subanaesthetic dose of ketamine rapidly alleviates the symptoms of major depressive disorder (MDD). Establishing a more comprehensive understanding of ketamine’s acute neural effects is essential to our understanding of the neurobiology of the antidepressant response. Using simultaneous electroencephalography (EEG) / functional magnetic resonance imaging (fMRI) in healthy volunteers and patients with MDD, the aims of this thesis were to investigate ketamine’s acute neural effects and the impact of ketamine’s cardiovascular and respiratory effects on fMRI analyses. Assessment of ketamine-induced EEG spectral power changes and the pharmacological MRI (phMRI) response showed consistent effects across healthy volunteers and patients with MDD. Physiological noise correction resulted in changes in the ketamine phMRI response. In particular, there is evidence for the decreases in blood oxygenation level-dependent (BOLD) signal in the subgenual anterior cingulate cortex (sgACC), previously suggested to underlie ketamine’s antidepressant effect, being artefactual. Modelling the ketamine phMRI response with EEG spectral power times series revealed multiple time courses of BOLD signal changes, better capturing ketamine’s temporal dynamics. While increases in BOLD signal explained by high gamma power were significantly associated with non-response to ketamine, significant correlations with antidepressant response were not found for other neurophysiological markers when noise correction was applied. EEG and fMRI functional connectivity were assessed in patients with MDD. fMRI connectivity results, particularly those from a node-based analysis, were sensitive to physiological noise correction. Ketamine significantly reduced EEG connectivity in the theta and alpha bands, an effect associated with non-response to ketamine. fMRI connectivity was also reduced but was associated with response to ketamine. Baseline functional connectivity was a significant predictor of antidepressant response to ketamine, with responders showing low baseline delta and theta EEG connectivity and high fMRI node-based connectivity. This thesis demonstrates that ketamine’s acute physiological effects impact the results of fMRI analyses, demonstrating the importance of preprocessing decisions. Using both EEG and fMRI measures, this thesis provides evidence that ketamine’s antidepressant effects are associated with the acute modification of long-range information transfer rather than local activity alone. This modification may allow for the reconfiguration of the aberrant neural network connectivity associated with MDD.