Spatio-temporal EEG dynamics

For quantitative observation of the spectral EEG dynamics around the LOC and ROC during sedation, we used event-related spectral perturbations (ERSPs) in the spatio-temporal EEG domain during two stages (non-scaling vs. dental scaling) and with two sedatives (MDZ vs. PPF) [50]. We performed subject-level baseline-subtraction for the LOC, ROC, and recovery by subtracting the mean of the baseline spectrum for each subject. To reduce spatial blur distortion of the EEG signal, we then averaged the EEG channels from five frontal areas (AF3–4, F1–2, and Fz) that are strongly associated with the depth of anesthesia according to previous studies [10] (Fig 3 and S1 Fig for an individual subject). In addition, CEs in the brain were calculated to allow comparison of time-series EEG patterns during sedation according to the different types of sedatives, as well as the different stages. Moreover, behavioral response curves were calculated as the speed of response, indicated by time-lapse between the the button press and the auditory stimulus for behavioral evaluation of the level of consciousness throughout the experiment. We then generated moving-average EEG spectrograms of group-level time courses for five predefined frequency bands to compare frequency-wise EEG oscillations in the spatio-temporal domain (Fig 4).

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larger image TIFF original image Download: 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. https://doi.org/10.1371/journal.pone.0187743.g003

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larger image TIFF original image Download: 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. https://doi.org/10.1371/journal.pone.0187743.g004

For both stages, during MDZ-induced sedation, we observed increased EEG spectral dynamics in the delta, theta, lower alpha, and upper alpha frequency bands, whereas beta/gamma power was decreased during the LOC interval. There was a marked increase in the upper alpha power. During the non-scaling stage, we observed rising and falling curves with steeper slopes at the LOC point (i.e., time = 0) compared with those observed during the scaling stage (Figs 3A and 4A). During the ROC interval, these EEG spectral dynamics in ERSP occurred in reverse. ERSP patterns clearly decreased in the aforementioned four frequency bands, whereas spectral power in the beta/gamma band increased. Dynamic changes in ERSP around the ROC point for each frequency band were rapidly shifted during both stages. During the final recovery, spectral EEG dynamics in all frequency bands slowly reverted to the spectral powers observed at baseline (Fig 4). Time-series ERSP powers in the beta/gamma band were, on average, maintained at relatively higher levels during the scaling stage in both the LOC and ROC intervals. On the other hand, CEs of MDZ gradually increased for both intervals, even until 3 min after the LOC, and were slightly reduced until the ROC following delivery of the next bolus injection when patients pressed the button.

For both stages, EEG spectral patterns obtained with PPF-induced sedation were broadly in line with those observed under MDZ-induced sedation for the delta, theta, lower alpha, highlighted upper alpha, and beta/gamma frequency bands during the LOC interval, although the EEG spectral power was relatively higher than that observed with MDZ. For both stages, the rising and falling curves also had steep slopes from the LOC point until 1 or 2 min after the LOC for each subject (Figs 3B and 4B). During the ROC interval, in contrast to the pattern observed for the LOC, we noted gradually increasing and decreasing EEG spectral patterns in the selected frequency bands. In addition, the EEG spectral powers in all frequency bands slowly converged to the spectral powers observed at baseline during the recovery. During both stages, CEs of PPF increased until immediately after the LOC and then gradually diminished until the subjects recovered consciousness. Due to the fast recovery from PPF-induced sedation, the LOC and ROC intervals overlapped in some subjects. During the scaling stage, PPF also had higher CEs in the brain. After the ROC, the CE of PPF increased again due to the next bolus injection of PPF. A comparison of the ERSP spectral powers between PPF and MDZ revealed a greater enhancement of power in every frequency range for PPF-induced sedation than for MDZ-induced sedation. For both sedatives, when transitioning through consciousness evels, the changes in the upper alpha power were the most significant.

To represent the spatial distribution of EEG changes over time, we included topographical maps of the highlighted upper alpha frequency in predefined time intervals in Fig 5 and S2 Fig for for an individual subject. We selected specific time intervals based on the LOC, ROC, and recovery points as follows: 1) pre-LOC/ROC, first 10 s during the LOC/ROC; 2) LOC/ROC, -5–5 s relative to the LOC/ROC; 3) post-LOC/ROC, last 10 s during the LOC/ROC; and 4) recovery, last 10 s of the experiment. We found that, with a change in the level of consciousness, most but not all spatial EEG patterns in the frontal and parieto-occipital EEG channels changed markedly. During both MDZ and PPF-induced sedation stages, most frontal areas were clearly activated during unconsciousness (post-LOC and pre-ROC) and were deactivated after the ROC. During the scaling stage, spatial EEG patterns were similar to those observed during the non-scaling stage, whereas ERSP at the pre-LOC was higher. For both sedatives, significant differences in spectral power were observed at time-points corresponding to the induction and emergence of consciousness. When comparing the two stages in the pre-LOC, the spectral power in the frontal area was relatively enhanced during the scaling stage. Table 1 summarizes statistical tests between frontal EEG spectral powers within time intervals of consciousness and unconsciousness (i.e. Pre-LOC vs. Post-LOC and Pre-ROC vs. Post-ROC) in every frequency range according to the stages and sedatives used. When we compared level of consciousness around the LOC and ROC for each sedative and stage, a paired t-test revealed that EEG spectral powers were significantly changed in almost every time interval. Additionally, EEG spectral dynamics in the upper alpha band were highly significant, regardless of the type of sedative and the stage.

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larger image TIFF original image Download: 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. https://doi.org/10.1371/journal.pone.0187743.g005

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larger image TIFF original image Download: Table 1. Statistical comparison of frequency-wise event-related spectral changes around the transition of consciousness with respect to anesthetics and stages. *, **, and *** indicate the level of significant improvement with p < 0.05, p < 0.01, and p < 0.001, respectively. p-values are based on paired t-tests. https://doi.org/10.1371/journal.pone.0187743.t001

When performing frequency-wise spatio-spectral comparisons between the baseline and unconscious states (during the post-LOC and pre-ROC), the spatial distributions in the pre-frontal and parieto-occipital areas differed for delta, in the parieto-occipital area for lower alpha, and in the temporal and frontal area for upper alpha rhythms, for both sedatives (Fig 6). EEG spectral powers were higher during PPF sedation than during MDZ sedation, particularly in the frontal area for lower alpha, and in the occipital area for upper alpha rhythms. We used a subject-level paired t-test to compare CEs at the LOC and ROC (Fig 7). For both sedatives, the difference in CEs between stages was statistically significant. This result illustrates that on average, the CEs for MDZ were approximately 2-fold higher during the non-scaling stage than those during the scaling stage, whereas the CEs for PPF were smaller but significantly different between the two stages at both the LOC and ROC (MDZ, p < 0.001 at the LOC and p < 0.001 at the ROC; PPF, p < 0.01 at the LOC and p < 0.001 at the ROC). With MDZ, most subjects lost and recovered consciousness with similar CEs, whereas with PPF, most subjects recovered consciousness (during the ROC) with CEs lower than those observed during the LOC for both stages.

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larger image TIFF original image Download: 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. https://doi.org/10.1371/journal.pone.0187743.g006