Summary of EEG data analysis pipeline.

<p>Cross-spectral density between channel pairs was estimated using dwPLI. Symmetric connectivity matrices generated were thresholded before the estimation of graph-theoretic metrics. In the connectivity matrix shown (bottom left), the threshold has been set to depict only top 30% of strongest connections. In the network topograph (bottom middle), intra-modular links in modules identified by the Louvain algorithm are indicated by colour.</p

Baseline alpha band networks predict loss of responsiveness during moderate sedation.

<p>Participants in the drowsy group had relatively lower small-worldness (A) already at baseline. Median split of participants based on baseline small-worldness predicted eventual loss of responsiveness (B) despite similar blood levels of drug concentration during moderate sedation (C).</p

Phase-amplitude coupling (PAC) between slow and alpha oscillations.

<p>Coupling between ongoing slow phase and alpha power over occipital channels delineated in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004669#pcbi.1004669.g005" target="_blank">Fig 5A</a> (top left) shifted from a trough-max to a peak-max (C) distribution in the drowsy group during moderate sedation, resulting in a significant interaction between group and sedation in PAC values (A). Crucially, these subject-wise PAC values significantly correlated with drug concentrations measured in blood across both groups during moderate sedation (B).</p

Alpha band power changes as a function of sedation.

<p>(A) Alpha power topography in the drowsy group progressively switched from an occipital to a frontal pattern during moderate sedation, while the responsive group remained stable throughout. (B) The resulting interaction between group and level of sedation on their alpha power contributions from frontal vs. occipital channels was statistically significant (F(3) = 10.1, p = 0.0008). (C) Even amongst the responsive group, reduction in relative occipital alpha power during moderate sedation was correlated with relatively slower reaction time, relative to baseline.</p

Summary of alpha connectivity changes.

<p>There were significant differences in the levels of local clustering (A) and global path lengths (C) between responsive and drowsy groups during mild and moderate sedation. Alpha networks in the drowsy group were hence significantly less locally and globally efficient. Crucially, these differences between the groups were apparent even at baseline, when the groups were behaviourally indistinguishable. Within the responsive group, decreasing levels of local (B) and global (D) efficiency were associated with slowing of reaction times during moderate sedation, relative to baseline. There were also significant differences in meso-scale modularity (E) and the presence of hub-like nodes with high participation coefficients (F) between responsive and drowsy groups during moderate sedation. Alpha networks in the drowsy group were more modular, with weaker hubs, even at baseline. Error bars depict standard error of the mean.</p

Experimental manipulation and measurement of behaviour and propofol concentration in blood plasma.

<p>(A) Resting state EEG data were collected for four ~7 minute periods from each participant: at baseline before administration of propofol, at mild sedation, moderate sedation, and finally at recovery. Each resting state data collection was followed by a two-choice speeded response task to assess behavioural responsiveness. Blood samples were collected and analysed offline to measure and correlate actual levels of propofol in plasma with EEG measures. (B) Two sub-groups of participants, <i>responsive</i> and <i>drowsy</i>, were identified based on binomial modelling of the change in their behavioural responsiveness due to sedation. (C) Reaction times in the responsive group were slower during moderate sedation. (D) Measured drug concentrations in blood plasma overlapped between the two groups.</p

Relating Cue Responses to Aberrant PE During Blocking.

<p>The degree to which subjects inappropriately engage DLPFC during blocking trials correlated positively with their tendency to stronger GSR responses to ketamine-reactivated cues. This result is internally consistent with the Stage 3 finding – excessive responses during blocking and attenuated responses during its violation portend further memory strengthening in the context of ketamine. Plot features the difference in GSR response to the cue reactivated under ketamine from the cue reactivated under placebo on x-axis, rDLPFC responses during blocking trials (compared with control trials) on the y-axis.</p

GSR Responses to Fear Cues Across Study Days.

<p><i>A. Skin Conductance Responses to Cues after Initial Conditioning (Day 1).</i> Subjects means skin conductance responses to the final 3 trials at the end of initial conditioning on Day 1. Y-axis represents subjects Galvanic Skin Responses to the cues (ketamine in red, placebo in blue; solid lines represent the to be reactivated cues (CS₁) and dashed lines represent CS₂ (non-predictive and non-reactivated). Error bars represent SEM. <i>B. Skin Conductance Responses to Cues in Extinction (Day 3).</i> Subjects showed an elevated skin conductance response to the ketamine-reactivated cue compared with the cue reactivated under placebo. Error bars represent SEM. Line graph: Y-axis represents subjects GSR responses to blocks of four extinction trials to cues reactivated under ketamine and placebo. Ketamine data are shown in red, placebo in blue; solid lines represent the reactivated cues (CS₁) and dashed lines represent CS₂ (non-predictive and non-reactivated). Error bars represent SEM. <i>C. Skin Conductance Responses to Cues Following US reminder (Day 3, post extinction).</i> When subjects were re-exposed to the loud noise outcome and then presented with the cues 5 more times in extinction, responses to the ketamine reactivated cue returned most strongly. Y-axis represents galvanic skin conductance response. Ketamine data are shown in red, placebo in blue; solid lines represent the reactivated cues (CS₁) and dashed lines represent CS₂ (non-predictive and non-reactivated). Error bars represent SEM.</p

Blocking Behavior and its Relation to Brain Responses.

<p><i>A. Behavioral Predictions For Blocked and Control Cues.</i> Subjects predicted with low confidence about the blocked cue, when exposed to it at Stage 3; confirming that blocking had taken place. Error bars represent SEM. Y-axis represents subjects' predictive strength; their degree of confidence (duration of predictive button push response) multiplied by correctness of their prediction. Hence lower scores reflect uncertain and unstable predictions, which we observed to blocked cues when compared with blocking control cues (whose causal association with the allergy is more robust). <i>B. Relating Predictions about the Blocked Cue (Stage 3) to Blocking Responses.</i> Subjects who showed the lowest confidence when predicting what would happen following the blocked cue had the most attenuated right DLPFC response during blocking trials. X-axis represents the right DLPFC parameter estimates extracted from a contrast image comparing blocking trials with blocking control trials. Y-axis represents subjects' behavioral predictions about the blocked cues prior to seeing their predictive outcomes at the first trials of Stage 3. <i>C. Relating Brain Responses During Blocking to those during Violation.</i> Subjects with the most attenuated DLPFC response during blocking showed the greatest right DLPFC response when that blocking contingency was subsequently violated. X-axis represents the right DLPFC response to observing the blocked cue causing the allergic response during Violation (Stage 3), compared with control event. Y-axis represents right DLPFC response to blocking trials compared with blocking-control trials.</p

Responses to Fear Cues and their Relationship to PE Brain Responses.

<p><i>A</i>. <i>Ratings of the Cues after Extinction and their relationship to Violation Responses</i>. Subjects rated the cue reactivated under ketamine as significantly more arousing than the cue reactivated under placebo. Those same subjects showed an aberrant striatal response during the violation of blocking indicative of inappropriate learning. Error bars represent SEM. Bar Graph: Y-axis represents subjects Final Arousal Ratings after the extinction trials, corrected by their initial ratings of the cues at baseline, such that residual ratings reflect conditioning. Scatterplot: X-axis represents those same Arousal ratings. Y-Axis represents parameter estimates extracted from right striatum from the contrast of blocking violation trials with their matched control events. <i>B. Skin Conductance Responses to Fear Cues and their relationship to violation Responses.</i> Subjects showed an elevated skin conductance response to the ketamine-reactivated cue compared with the cue reactivated under placebo. Subjects who showed the strongest skin conductance responses to cues reactivated under ketamine also showed the most inappropriate DLPFC response to the violation of blocking, indicating that they had learned inappropriately about the blocked cue. Error bars represent SEM. Line graph: Y-axis represents subjects GSR responses to blocks of four extinction trials to cues reactivated under ketamine and placebo. Scatterplot: X-axis represents the GSR to the first extinction trial (Ketamine minus placebo). Y-Axis represents parameter estimates extracted from right DLPFC from the contrast of blocking violation trials with their matched control events.</p