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

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 3 T 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.