Mean number of draws to decision. Error bars are 95% confidence intervals.

<p>Mean number of draws to decision. Error bars are 95% confidence intervals.</p

a,b. Mean confidence estimates for the two sequences in which participants were asked to rate the confidence of their decision.

<p>The red line represents the methamphetamine condition; blue represents the placebo condition, and green represents the combined amisulpride and methamphetamine condition.</p

Mean number of draws to decision.

<p>Mean number of draws to decision.</p

a,b. Draws to decisions of the individual participants in two experimental conditions during their 3 visits.

<p>a,b. Draws to decisions of the individual participants in two experimental conditions during their 3 visits.</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

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

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

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

Memory Strengthening or Extinction Failure?

<p><i>A. Skin Conductance Responses.</i> Skin conductance responses to the CS+ at the end of Day 1 (pre-reactivation, mean of final three trials) and the beginning of Day 3 (post reactivation, trial 1) for both the ketamine and placebo visits. Error bars represent SEM. <i>B. Sucking Pressure.</i> Anticipatory sucking to the cue predicting pleasant juice at the end of Day 1 (pre-reactivation) and the beginning of Day 3 (post-reactivation). Error bars represent SEM. <i>C. Expectancy Ratings.</i> Anticipatory liking ratings in response to the cue predicting pleasant juice at the end of Day 1 (pre-reactivation) and the beginning of Day 3 (post-reactivation). Error bars represent SEM.</p

Appetitive Memory Reactivation.

<p><i>A. Liking ratings of the liquid predicting cues</i>. Behavioral ratings of the cues on the first extinction trial (Day 3), following reactivation under ketamine or placebo (Day 2). Subjects liked the cue that had been reactivated under ketamine more than they liked the other cues and the cues from the placebo session. Error bars represent SEM. <i>B. Anticipatory sucking responses to the liquid predicting cues.</i> Anticipatory sucking in response to the first presentation of each cue type in extinction (Day 3) following reactivation under ketamine or placebo (Day 2). Subjects engaged in more anticipatory sucking prior to the cue that was reactivated under ketamine, the day after the ketamine session than the non-reactivated cues and the cues reactivated under placebo. Error bars represent SEM.</p