Abstract:
The success rate of clinical trials for central nervous system (CNS) drugs would be aided by improved identification of pharmacological biomarkers. Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are non-invasive methods with the potential to provide these objective measures of CNS drug action. Their simultaneous recording allows the combination of their opposing strengths and mitigation of their opposing weaknesses, including the utilisation of a direct electrophysiological measure of neural activity to help disentangle the neural and physiological contributions to the blood-oxygen-level-dependent (BOLD) signal. This thesis aimed to establish the feasibility and effectiveness of simultaneous EEG/fMRI when developing biomarkers for subanaesthetic ketamine and midazolam.
Overall, analyses of drug-induced spectral power changes, functional connectivity, and working memory processes reflected prior literature where EEG and fMRI were recorded independently. This allowed confidence that simultaneous imaging was not degrading the data and combined with pre-processing data quality analyses provided evidence for the feasibility of simultaneous EEG/fMRI in a drug study.
A recurrent theme throughout the analyses was that of each modality providing unique information. The spectral profiles and representations of working memory processes lacked a clear spatial correspondence between modalities, and formal comparisons of changes to functional connectomes yielded little conclusive evidence of simple relationships between the two signal types. The distinctive information imparted by both modalities instils impetus to develop drug biomarkers in both modalities. Combining information from the EEG and fMRI signals provided biomarker information over that gained from assessing the modalities independently. Temporal correlations between EEG power modulations and the BOLD signal were modified by drug administration. Additionally, comparison of the relative strengths of task-induced changes allowed for more in-depth analysis of the EEG/fMRI relationship. Furthermore, electrophysiological results combined with an assessment of multiple methods to remove BOLD signal artefacts endorsed an argument for tailoring pharmacological fMRI pre-processing to the unique noise structure of each drug under investigation. Combined with other advantages of concurrent recording, such as removing session-to-session variance, these results demonstrated that simultaneous EEG/fMRI is effective at providing information for the development of biomarkers of drug action.