Brain connectivity under light sedation with midazolam and ketamine during task performance and the periodic experience of pain: Examining concordance between different approaches for seed-based connectivity analysis.

Abstract

This work focused on functional connectivity changes under midazolam and ketamine sedation during performance of a memory task, with the periodic experience of pain. To maximize ability to compare to previous and future work, we performed secondary region of interest (ROI)-to-ROI functional connectivity analyses on these data, using two granularities of scale for ROIs. These findings are compared to the results of a previous seed-to-voxel analysis methodology, employed in the primary analysis. Healthy adult volunteers participated in this randomized crossover 3T functional MRI study under no drug, followed by subanesthetic doses of midazolam or ketamine achieving minimal sedation. Periodic painful stimulation was delivered while subjects repeatedly performed a memory-encoding task. Atlas-based and network-level ROIs were used from within Conn Toolbox (ver 18). Timing of experimental task events was regressed from the data to assess drug-induced changes in background connectivity, using ROI-to-ROI methodology. Compared to saline, ROI-to-ROI connectivity changes under ketamine did not survive correction for multiple comparisons, thus data presented is from 16 subjects in a paired analysis between saline and midazolam. In both ROI-to-ROI analyses, the predominant direction of change was towards increased connectivity under midazolam, compared to saline. These connectivity increases occurred between functionally-distinct brain areas, with a posterior-predominant spatial distribution that included many long-range connectivity changes. During performance of an experimental task that involved periodic painful stimulation, compared to saline, low-dose midazolam was associated with robust increases in functional connectivity. This finding was concordant across different seed-based analyses for midazolam, but not ketamine. The neuroimaging drug trial from which this data was drawn was pre-registered (NCT-02515890) prior to enrollment of the first subject.