Spatio-temporal dynamics of multimodal EEG-fNIRS signals in the loss and recovery of consciousness under sedation using midazolam and propofol

Abstract

On sedation motivated by the clinical needs for safety and reliability, recent studies have attempted to identify brain-specific signatures for tracking patient transition into and out of consciousness, but the differences in neurophysiological effects between 1) the sedative types and 2) the presence/absence of surgical stimulations still remain unclear. Here we used multimodal electroencephalography-functional near-infrared spectroscopy (EEG-fNIRS) measurements to observe electrical and hemodynamic responses during sedation simultaneously. Forty healthy volunteers were instructed to push the button to administer sedatives in response to auditory stimuli every 9-11 s. To generally illustrate brain activity at repetitive transition points at the loss of consciousness (LOC) and the recovery of consciousness (ROC), patient-controlled sedation was performed using two different sedatives (midazolam (MDZ) and propofol (PPF)) under two surgical conditions. Once consciousness was lost via sedatives, we observed gradually increasing EEG power at lower frequencies (<15 Hz) and decreasing power at higher frequencies (>15 Hz), as well as spatially increased EEG powers in the delta and lower alpha bands, and particularly also in the upper alpha rhythm, at the frontal and parieto-occipital areas over time. During ROC from unconsciousness, these spatio-temporal changes were reversed. Interestingly, the level of consciousness was switched on/off at significantly higher effect-site concentrations of sedatives in the brain according to the use of surgical stimuli, but the spatio-temporal EEG patterns were similar, regardless of the sedative used. We also observed sudden phase shifts in fronto-parietal connectivity at the LOC and the ROC as critical points. fNIRS measurement also revealed mild hemodynamic fluctuations. Compared with general anesthesia, our results provide insights into critical hallmarks of sedative-induced (un)consciousness, which have similar spatio-temporal EEG-fNIRS patterns regardless of the stage and the sedative used.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Experimental designs.

Protocols for both anesthetics for patient-controlled sedation (top), experimental timeline with the calculated plasma concentration, stimulus onset, and button-response sites during electroencephalography and functional near-infrared spectroscopy measurement recordings (bottom).

Fig 2. The selected EEG-fNIRS channel locations of the International 10–20 system.

The selected electroencephalogram (EEG) and functional near infrared spectroscopy (fNIRS) channel locations of the International 10–20 system (62 EEG recording electrodes (black circle), 4 fNIRS sources (blue circle), 10 fNIRS detectors (red circle), and 14 fNIRS channels (green line).

Fig 3. Dynamics of baseline-normalized time-series event-related spectral perturbations (ERSPs) from the five frontal channels (top layer), the corresponding effect-site concentrations (CEs) in the brain (middle layer), and the time-course of reaction curves for auditory stimuli (bottom layer) aligned with respect to the loss of consciousness (LOC) (1st and 3rd), recovery of consciousness (ROC) (2nd and 4th), and recovery (5th column) phases according to the stage using (A) midazolam and (B) propofol.

Magenta vertical lines denote the transition time-points of the LOC, ROC, and recovery.

Fig 4. Time-series event-related spectral perturbation (ERSP) dynamics aligned with the loss of consciousness (LOC), recovery of consciousness (ROC), and recovery phases averaged in five frequency ranges (delta, theta, lower/upper alpha, and beta) within two stages.

Magenta vertical lines denote the transition time-points of the LOC, ROC, and recovery.

Fig 5. Spatial distribution of the event-related spectral perturbation (ERSP) in the upper alpha band at different points during the loss of consciousness (LOC), recovery of consciousness (ROC), and recovery phases according to the stage using (A) midazolam and (B) propofol.

The pre-LOC/ROC was the first 10 s of time intervals for the LOC/ROC, the LOC/ROC was -5 to +5 seconds aligned with transition points, the post-LOC/ROC was the last 10 s of time intervals for the LOC/ROC, and the recovery was the last 10 s before full recovery.

Fig 6. Differences between conscious and unconscious sedation in the spatial EEG distribution of power for the frequency bands.

We selected time-points for unconscious sedation = loss of consciousness (LOC) + 3 min and recovery of consciousness (ROC)—3 min.

Fig 7. Statistical comparison of effect-site concentrations (CEs) in the brain between the different types of conditions for midazolam (left) and propofol (right) during the loss and recovery of consciousness.

Fig 8. Grand-averaged time-courses of reaction curves for auditory stimuli (top layer) and group-level phase difference in the time domain with 5 × 5 fronto-parietal paired channels and two frequency ranges (theta and upper alpha) (bottom layer) for (A) midazolam and (B) propofol.

For group-level phase difference, the x-axis indicates the time intervals of the loss and recovery of consciousness during the two stages, and the y-axis was calculated with a time-series of instantaneous phase differences between all pair-wise combinations of fronto-parietal channels to show the phase relationship between channels [51, 52].

Fig 9. Time course oxygenated (HbO) and deoxygenated (HbR) hemoglobin measurements during the loss of consciousness (LOC) and recovery of consciousness (ROC) for (A) midazolam and (B) propofol administration during the non-scaling stage.

Each shaded area indicates the selected time intervals with the statistical significance (Blue: HbO, Green: HbR). Vertical lines denote the transition points of the LOC and ROC.