This double-blind within-subject placebo-controlled study (n=21/drug-condition) investigated the effects of esketamine (38.6mg/70kg) and psilocybin (8.1mg/70kg) concerning brain activity during non-conscious and conscious emotional face processing. Results indicated that both substances impaired the early encoding of fearful face responses, while esketamine also impaired the encoding of happy facial expressions, and these measures were more pronounced during conscious than non-conscious processing.
Rationale
Both glutamate and serotonin (5-HT) play a key role in the pathophysiology of emotional biases. Recent studies indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the 5-HT receptor agonist psilocybin are implicated in emotion processing. However, as yet, no study has systematically compared their contribution to emotional biases.
Objectives
This study used event-related potentials (ERPs) and signal detection theory to compare the effects of the NMDA (via S-ketamine) and 5-HT (via psilocybin) receptor system on non-conscious or conscious emotional face processing biases.
Methods
S-ketamine or psilocybin was administrated to two groups of healthy subjects in a double-blind within-subject placebo-controlled design. We behaviorally assessed objective thresholds for non-conscious discrimination in all drug conditions. Electrophysiological responses to fearful, happy, and neutral faces were subsequently recorded with the face-specific P100 and N170 ERP.
Results
Both S-ketamine and psilocybin impaired the encoding of fearful faces as expressed by a reduced N170 over parieto-occipital brain regions. In contrast, while S-ketamine also impaired the encoding of happy facial expressions, psilocybin had no effect on the N170 in response to happy faces.
Conclusion
This study demonstrates that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170. These findings suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced changes in emotional processing biases and thus provides a framework to study the pathophysiology of dysfunctional emotional biases.
Papers cited by this study that are also in Blossom
Carter, O., Burr, D. C., Pettigrew, J. D. et al. · Journal of Cognitive Neuroscience (2006)
Diazgranados, N., Ibrahim, L., Brutsche, N. E. et al. · JAMA Psychiatry (2010)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Hasler, F., Grimberg, U., Benz, M. A. et al. · Psychopharmacology (2004)
Schmidt and colleagues frame emotional face recognition as a core component of social interaction that can be modulated by neuromodulatory systems, notably serotonin (5-HT) and glutamate. Prior work has shown that serotonergic manipulation (for example, with the SSRI citalopram) can shift processing towards positive emotional information and alter visual evoked responses, while glutamatergic manipulation with the NMDA antagonist ketamine reduces visual responses to fearful faces in functional imaging. Event-related potentials (ERPs) such as the P100 and the face-sensitive N170 provide time-resolved measures of early visual and structural encoding processes and have been used to probe emotional biases in health and affective disorders. This study set out to compare directly how acute manipulation of the NMDA receptor system (via S-ketamine) versus the 5-HT receptor system (via psilocybin) affects conscious and non-conscious processing of emotional faces. Using behavioural discrimination thresholds and ERP measures (P100 and N170), the investigators hypothesised that both drugs would reduce negative face processing and enhance positive face processing, and that drug effects on ERPs might differ between non-conscious and conscious visual presentation. The comparison was designed to probe receptor-specific contributions to early visual signatures of emotional bias and to provide a framework for studying mechanisms relevant to affective disorders.
Healthy student volunteers were recruited and allocated into two independent groups: an S-ketamine group (N = 21; 12 male; mean age 26 ± 5.39 years) and a psilocybin group (N = 21; 13 male; mean age 23 ± 2.22 years). Screening included medical history, clinical examination, ECG, blood tests and structured psychiatric interviews to exclude personal or first-degree family histories of major psychiatric disorders. Substance use histories were recorded and urine drug screens performed; all participants were medication-free for at least 3 weeks. Ethics approval and regulatory authorisation for psilocybin were obtained and written informed consent was provided. A double-blind, within-subject placebo-controlled design was used separately in each group: each subject attended two sessions (placebo and active drug) in counterbalanced order with at least 2 weeks between sessions. S-ketamine was administered intravenously as a bolus (10 mg over 5 min) followed by a continuous infusion (0.006 mg/kg/min for 80 min) with stepwise dose reductions every 10 min as described; placebo infusion matched the procedure with saline/glucose. Psilocybin was given orally at 115 μg/kg in gelatin capsules; a lactose capsule served as placebo. Behavioural and electrophysiological testing occurred during the known plateaus of drug effects (approximately 25 min after ketamine infusion start and 110 min after psilocybin ingestion). Participants completed the Altered State of Consciousness (ASC) questionnaire after acute effects had subsided (≈240 min post-ketamine; ≈360 min post-psilocybin). Stimuli were greyscale faces from the Ekman–Friesen set, standardised for luminance and contrast and presented centrally on a CRT monitor. The study used backward masking to probe non-conscious versus conscious processing. Two discrimination tasks established sensitivity (d') for fearful vs neutral and happy vs neutral faces at target durations of 20, 30, 50, 90 and 170 ms, each followed by a 150 ms neutral mask; five blocks of 40 trials were run per task. For ERP recording, target faces were presented for 10 ms for non-conscious and 200 ms for conscious processing (each followed by the 150 ms neutral mask); no button-press responses were required during ERP trials. EEG was recorded from 64 scalp electrodes (Biosemi ActiveTwo) at 512 Hz with horizontal and vertical EOG channels. Preprocessing included independent component analysis for ocular artifacts, average re-referencing, epoching with a 200 ms prestimulus baseline and 500 ms post-stimulus window, rejection of epochs exceeding ±100 μV, and band-pass filtering (1–30 Hz). P100 and N170 amplitudes were analysed at right (P08/P8/P10/O2) and left (PO7/P7/P9/O1) posterior electrode clusters; the extracted text reports peak windows but the exact latency windows for computation are not fully clear in the extraction. Behavioural sensitivity was analysed using signal detection theory (d') and Student's t tests against chance (d' = 0) to determine thresholds. Repeated-measures ANOVAs assessed effects of treatment, target duration (non-conscious/conscious), valence and laterality, with additional analyses on placebo–drug change scores and linear regressions relating discrimination changes to N170 change scores. The ASC data were analysed by repeated-measures ANOVA across scales with post hoc Fisher's LSD where ANOVA indicated differences.
Facial discrimination thresholds: Under placebo, d' for fearful versus neutral faces was at chance at 20 ms and rose above chance at 30 ms. Under both S-ketamine and psilocybin, performance at 30 ms remained at chance and only reached significance at 50 ms, indicating impaired early discrimination for fearful faces under both drugs. For happy versus neutral discrimination, d' values across durations were generally above chance in all drug conditions. A repeated-measures ANOVA across groups showed increasing d' with longer target durations. Crucially, S-ketamine reduced d' for both fearful (p < 0.001) and happy (p < 0.001) faces relative to placebo, whereas psilocybin reduced d' only for fearful faces (p < 0.001) and not for happy faces (p = 0.87). P100 ERP: Both groups showed larger P100 amplitudes over right than left electrodes. No treatment effects on P100 amplitude were observed for either psilocybin or S-ketamine, and change-score comparisons found no significant differences between the two drugs on the P100, indicating that early fast extraction of emotion-related visual information (as indexed by P100) was not altered by the pharmacological manipulations. N170 ERP: Under placebo, N170 amplitudes were larger over the right than left hemisphere and larger for emotional than neutral faces. Both S-ketamine and psilocybin produced a general reduction of N170 amplitude that was lateralised to right parieto-occipital electrodes and more pronounced during conscious than non-conscious processing. For S-ketamine, the N170 reduction was observed for fearful, neutral and happy faces (overall treatment effect and a treatment × laterality interaction showing the effect only over the right electrodes). Psilocybin also reduced the right-sided N170 overall, but the treatment × valence interaction showed a selective reduction for fearful and neutral faces (p < 0.000001 and p < 0.01, respectively) and no significant effect for happy faces (p = 0.1). Direct comparison of drug change scores found that S-ketamine and psilocybin produced comparable reductions of the N170 for fearful and neutral faces over right electrodes, but differed for happy faces: S-ketamine induced a significantly larger N170 reduction to happy faces than psilocybin (p < 0.05). Linear regression showed no significant relationships between changes in discrimination performance (d' fear or d' happy) and N170 change scores for the corresponding emotions in either group. ASC questionnaire: Both drugs markedly increased global ASC scores relative to placebo. A treatment × scale × group interaction indicated differential subjective profiles: S-ketamine produced higher scores than psilocybin for disembodiment, auditory alterations, and impaired control and cognition, whereas psilocybin produced greater elementary imagery and visual illusions. Both drugs increased most ASC scales relative to placebo, with some scale-specific exceptions noted in the extracted text.
Schmidt and colleagues interpret three principal findings: first, structural encoding of faces as indexed by the N170 is impaired by both S-ketamine and psilocybin, while the earlier P100 component is unaffected; second, the two drugs show dissociable effects on the N170 with both reducing responses to fearful faces but only S-ketamine reducing responses to happy faces; third, drug-induced N170 changes are more pronounced during conscious than non-conscious presentation. On behaviour, the investigators report that both drugs impaired discrimination of fearful faces, whereas only S-ketamine impaired discrimination of happy faces, suggesting a valence-specific behavioural effect of psilocybin. Electrophysiological findings paralleled behaviour: psilocybin reduced N170 amplitudes to fearful and neutral faces but left happy-face N170s unchanged, whereas S-ketamine produced a more general N170 suppression consistent with an overall emotional blunting. The authors link the N170 generators to the fusiform gyrus (FG) and discuss how altered FG–amygdala and FG–prefrontal interactions could underlie the observed ERP changes, citing prior imaging studies that showed ketamine reduces fusiform and amygdala responses to fearful faces. Differences between psilocybin and serotonergic agents such as citalopram are attributed to distinct pharmacological profiles: psilocybin (via its active metabolite psilocin) is a direct 5-HT receptor agonist with affinity for multiple 5-HT receptor subtypes, whereas SSRIs increase extracellular 5-HT via reuptake inhibition. The authors suggest that receptor-subtype-specific actions may explain why psilocybin, but not acute citalopram, modulated the N170 in this study. They also propose that the stronger drug effects during conscious processing may reflect reduced allocation of attentional resources under both drugs, consistent with prior evidence that ketamine and psilocybin impair attention and reduce N170 amplitudes in other object completion tasks. The authors acknowledge unresolved issues and limitations reported in the extracted text. Notably, the lack of a statistically significant relationship between behavioural discrimination changes and N170 changes is highlighted, and they note that the dissociation for happy-face processing between the two drugs cannot be fully explained by the present data. They also discuss concerns about the non-conscious stimulus duration—some evidence suggested conscious perception of happy faces at very short durations—but argue that prior ERP studies support the non-conscious status of presentation times below 20 ms. Finally, the investigators conclude that early visual ERPs, particularly the N170, provide a sensitive window to detect pharmacologically induced changes in emotional processing biases and offer a framework for probing pathophysiological mechanisms underlying dysfunctional emotional biases.
Emotional processing including the recognition of other people's feelings from their facial expression is fundamental to social interaction and behavior. The importance of face recognition in the human social functioning is shown by the fact that emotional faces increase neuronal activity relative to neutral faces in specific brain areas. For example, increased brain responses to emotional faces have been observed in visual face-selective areas of the brain, even when emotional faces were masked to prevent visual awareness. Thus, modulation of facespecific responses in the visual cortex by emotional expressions might correspond to a fundamental regulatory role of basic emotional signals associated with social appraisal and cognition. Emotional face processing can be modulated by serotonin (5-hydroxytryptamine, 5-HT). For example, acute administration of the selective serotonin reuptake inhibitor (SSRI) citalopram facilitated recognition of fear and happy facial expressions in the citalopram treated group relative to the placebo group. In a later study, repeated administration of citalopram in healthy subjects increased the relative processing of positive to negative emotional faces in a manner directly opposite to the negative biases previously described in depression). Both findings suggest important neuropsychological evidence of a possible mechanism of action of antidepressant drugs. The findings are consistent with other studies examining the neurophysiological mechanisms underlying antidepressant effects on emotional processing. In these studies, acute citalopram administration was shown to inhibit visual evoked electrophysiological responses to unpleasant stimuli, while it facilitates visual responses to pleasant stimuli. These studies suggest that this capacity to shift emotional biases-increasing the response to positive and decreasing the response to negative stimuli-seems not only to be characteristic for the action of SSRI on emotional processing but seems also to be highly relevant for the treatment of emotional biases found in depression. In addition, emotional face processing can also be affected by glutamatergic manipulation. Specifically, a functional imaging study in healthy subjects showed that the visual activity in response to fearful faces is abolished under the influence of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Taken together, these findings suggest that acute manipulations of the serotonergic and glutamatergic systems by psilocybin and ketamine may change emotional processing biases as indexed by the assessment of visual evoked responses to emotional expressions. Recent studies used event-related potential (ERP) recording to investigate the time course of non-conscious and conscious emotional face processing. Studies of ERPs generated by faces often focus on key components such as the P100 and the face-sensitive N170. The P100 is an early positive occipital potential, peaking at around 80-120 ms post-stimulus, and reflects rapid extraction of information related to emotion or salience that occurs before more fine-grained perceptual analyses are completed. Modulation of the P100 has been shown with fearful, angry) and positive expressions. The N170 is a negative occipitotemporal potential at approximately 170 ms post-stimulus and is associated with structural encoding of facial configurations. The view that the N170 ERP is not modulated by the emotional content of faces) has been challenged by other findings, even when faces are non-consciously processed). Thus, the N170 reflects not only face sensitivity but also emotion sensitivity during conscious as well as nonconscious face processing. Furthermore, it has been shown that the N170 amplitude correlates with the severity of depressive symptoms, while both the P100 and N170 amplitudes are significantly differed between healthy volunteers and subjects with bipolar disorder. These studies together demonstrate the potential of these ERPs to study pharmacological mechanisms underlying emotional biases and their pathophysiology. In this study, we assessed these ERPs to compare the effects of the glutamate NMDA receptor antagonist ketamine and the 5-HT receptor agonist psilocybin on visual processing stages during emotional face processing. Notably, both ketamine and psilocybin are suggested to modulate neuronal activity in circuits implicated in emotion regulation and to have implications for the treatment of affective disorders. While it has repeatedly been pointed out that acute ketamine administration ameliorates depressive symptoms in treatment-resistant depression within a few hours persisting for several days, a gradual reduction in trait anxiety at 1 and 3 months, as well as in depressive symptoms at 6 months, was observed after a single dose of psilocybin in terminal cancer and anxiety patients. Based on these findings, in this paper we hypothesized that manipulations of both the NMDA and 5-HT receptor system using ketamine and psilocybin may inhibit negative face processing and facilitate the processing of positive faces as expressed by modulations of the P100 and N170 ERP. Given that visual responses are modulated by face visibility, we further predicted that both drug effects on the visual ERPs might vary between non-conscious and conscious face processing. Thus, to test our hypothesis, we examined on the one hand whether psilocybin and ketamine affect visual ERP responses to emotional faces in a valence specific manner and on the other hand whether these drug effects depend on visual awareness.
Healthy subjects were recruited through advertisement from the local universities and were then separated into two groups (S-ketamine group: N021 [male, 12], mean age026±5.39 years; psilocybin group: N021 [male, 13], mean age023±2.22 years, all were students). Subjects were healthy according to medical history, clinical examination, electrocardiography, and blood analysis. Subjects were screened by the DIA-X diagnostic expert system, a semi-structured psychiatric interview to exclude those with personal or family (first-degrees relatives) histories of major psychiatric disorders, and by the Symptom Checklist (SCL-90-R). Furthermore, subjects replied to the Mini-International Neuropsychiatric Interview, a brief, structured psychiatric interview. No subjects had to be excluded using these criteria. We verified the absence of a history of drug dependence by urine drugscreening and a self-made consumption questionnaire. In the S-ketamine group, seven subjects were occasional smokers (<10 cigarettes/day), eight subjects reported a sporadic or rare cannabis use in the past (<3 joints/month), two subjects reported experiences with MDMA (three pills lifetime), two subjects had previous LSD experiences (5 lifetime experiences), and one subject reported having previous experiences with ketamine (one occasions lifetime). In the psilocybin group, eight subjects were occasional smokers (<6 cigarettes/day), eight subjects reported a sporadic or rare cannabis use in the past (<2 joints/month), one subject reported experiences with MDMA (two pills lifetime), two subjects had prior use histories of ingesting psilocybin containing mushrooms (two lifetime experiences), and one subject reported experiences with LSD (two lifetime experiences). All subjects were free of any medication for at least 3 weeks before the experiment. This study was approved by the Ethics Committee of the University Hospital of Psychiatry in Zurich. After receiving a written and oral description of the aim of this study, all participants gave written informed consent statements before inclusion. The use of psilocybin was authorized by the Swiss Federal Office for Public Health, Department of Pharmacology and Narcotics, Berne, Switzerland.
In both groups, subjects underwent two sessions (placebo/ active drug) in a counterbalanced and double-blind fashion at an interval of at least 2 weeks. Subjects were monitored until all drug effects had worn off and were then released into the custody of a partner. For the S-ketamine/placebo infusion, an in-dwelling catheter was placed in the antecubital vein of the nondominant arm. Once the subject was ready, a bolus injection of 10 mg over 5 min was given. Following a 1-min break, a continuous infusion with 0.006 mg/kg/min was administered over 80 min. To keep S-ketamine's plasma level fairly constant, the dose was reduced every 10 min by 10 % as previously described). In the placebo session, the same procedure was followed and an infusion of physiological sodium chloride solution and 5 % glucose was given. Psilocybin (115 μg/kg) and lactose placebo were orally administered in gelatin capsules of identical number and appearance as previously described in studies assessing the acute psychological and physiological effects of psilocybin in healthy humans. Psilocybin was orally given not only to ensure direct comparability with these previous studies and external validity but also to induce stabile psychological effects after 60-90 min post-treatment, lasting for 60-120 min). Furthermore, given the putative therapeutic potential of psilocybin, an oral dosing regimen provides a more personable setup than utilizing an intravenous dosing regime for psilocybin.
The Altered State of Consciousness (ASC) questionnaire, a visual analog and self-rating scale, was used to assess the subjective psychological effects induced by S-ketamine and psilocybin. A recent evaluation study of the ASC questionnaires has constructed 11 new lower-order scales, which were assessed in this study. After the acute effects of S-ketamine (about 240 min post-treatment) and psilocybin (about 360 min after treatment) had subsided, the ASC questionnaire was given to retrospectively rate their introspective experiences since drug intake.
As stimulus material, we took black and white photographs taken from the Ekman-Friesen series. In order to exclude the hair and non-facial contours and further to match for luminance and contrast, each face was modified using Adobe Photoshop as previously done in other studies). The final facial images subtended a visual angle of 3°h orizontally and 4.4°vertically and were displayed in the center of a CRT monitor (refresh rate of 100 Hz). Subjects first underwent a mismatch negativity event-related paradigm for 15 min, which has been published elsewhere). Emotional measures using backward masking paradigms were started 25 min after S-ketamine infusion and 110 min following psilocybin administration during the known plateau. Backward masking paradigms (facial affect discrimination and EEG/ERP recording) were generated by a software dedicated to psychological testing (E-prime;. Backward masking is a key experimental paradigm for investigating sensory unawareness because this method interferes with the activity in the ventral occipitotemporal cortex, an area which is highly relevant for visual awareness. The accuracy of stimulus duration was confirmed using an oscilloscope. Figureshows the backward making procedures for the facial discrimination task (A) and for the subsequent EEG/ERP recording (B). Facial affect discrimination Two discrimination tasks were conducted to establish thresholds for visual awareness in all drug conditions, i.e., to determine the time point, at which subjects can distinguish emotional from neutral expression above chance level. In a first task, subjects had to discriminate fearful from neutral faces, while in a second task they had to discriminate happy from neutral faces. For each discrimination task, target faces consisted of neutral and fearful/happy faces and were presented for 20, 30, 50, 90, or 170 ms). Target faces were immediately followed by a neutral mask of the same person lasting for 150 ms. Participants performed five blocks of 40 trials (target-mask pairs) for each of both tasks, in which target faces were randomly presented with equal probability. Before the presentation of target-mask pairs, a fixation cross was presented for 1,000 ms. Subjects had to make a forcedchoice decision about the valence of the target face (fearful/ happy vs. neutral) via button-press. EEG/ERP recording During subsequent ERP recording, stimuli were identical to those used during the facial affect discrimination. Target faces comprised neutral, fearful, and happy faces and were immediately followed by a neutral mask of the same person for 150 ms. Each trial began with a fixation cross that lasted for 2,000 ms. According to the results of the discrimination tasks, target faces were 10 ms presented during non-conscious processing and 200 ms during conscious processing. No subject response (button-press) was required. However, participants were given instructions that pairs of target-mask faces would be presented and that they would be asked questions about the first faces after testing. Event-related potential recording EEG recordings were made from 64 scalp electrodes using the ActiveTwo system (Biosemi, the Netherlands). The horizontal electroocculogram (EOG) was recorded from electrodes attached on the outer canthus of each eye. Similarly, vertical EOG was recorded from electrodes attached infraorbitally and supraorbitally to the left eye. All electrodes were active silver/ silver chloride electrodes and the offset of all electrodes was below 25 mV. Data were recorded at a sampling rate of 512 Hz. The common mode sense active electrode and the driven right leg passive electrode were used as reference and ground electrodes, respectively (seefaq/cms&drl.htm for more details on this setup). For ERP analysis, independent component analysis was used to remove artifacts due to eye movements and blinks. The EEG data were recalculated offline against average reference. Then, epochs with a 200-ms prestimulus baseline and a 500-ms post-stimulus interval were constructed. Epochs with amplitudes that exceeded ±100 μV at any electrode were excluded from further averaging. After artifact rejection, epochs were averaged for each subject and were digitally filtered with a band-pass filter (1-30 Hz). P100 and N170 ERPs were computed at electrodes P08/P8/P10/O2 (right hemisphere) and PO7/P7/P9/O1 (left hemisphere) as peak positivity/negativity relative to baseline within the 130-200-and 150-250-ms window latency, respectively, as Fig.Schematic of the backward masking paradigms. During the discrimination threshold tasks (a), a fixation cross was first presented for 1,000 ms, followed by the target face, which lasted for 20, 30, 50, 90, or 170 ms, respectively. Finally, a neutral mask of the same person was presented for 150 ms. After each target-mask pair, subjects were asked to answer via key press. During ERP recording (b), the fixation cross was presented for 2,000 ms. The presentation time for the target faces was 10 ms for nonconscious processing and 200 ms for conscious processing previously described.
Discrimination performances were analyzed according to signal detection theory, which provides a measure of sensitivity that is independent of subject's response bias). This procedure avoid potential limitations of subjective self-report performances, in which subjects report no visual awareness but may nonetheless experience some level of awareness. Threshold settings were determined by Student's t tests against chance level (sensitivity indexes of d′00). D's were further subjected to a repeated measurement analysis of variance (ANOVA) with the within-subject factors target duration (20, 30, 50, 90, 170 ms), valence (fearful, happy), and treatment (placebo, drug), as well as with the between-subject factor group (S-ketamine, psilocybin). In a first step, P100 and N170 ERP data were separately analyzed for the S-ketamine and psilocybin group by repeated measurement ANOVAs with the within-subject factors treatment (placebo, S-ketamine, or psilocybin), target duration (non-conscious, conscious), valence (fearful, happy, and neutral), and laterality (right, left). To further compare both drug effects on the specific ERP, in a second step, we computed the change scores between the placebo and both drug conditions (placebo-drug). Change scores were subjected to a repeated-measures ANOVA with the within-subject factors target duration (non-conscious, conscious), valence (fearful, happy, and neutral), and laterality (right, left) and with the between-subject factor group (S-ketamine, psilocybin). Repeated measurement ANOVA on the ASC data with treatment and scale as within-subject factors and group as betweensubject factor was used to examine drug-induced psychological effects. Where the ANOVA null hypotheses of equal means were rejected, we used Fisher's least significant difference tests (LSD) for post hoc testing. For further analysis, we computed the average of the d′ change score (d′ pla-d′ drug) over all target durations as indexed by "d′ fear" and "d′ happy." Given that the activity in face-sensitive areas within the visual cortex increases gradually with subjective rating of recognition success, we used linear regression analysis to examine the relationship between discrimination success (i.e., d′ fear and d′ happy) and N170 changes scores.
Student's t tests against d′00 revealed that for the discrimination of fearful relative to neutral faces (Fig.), d′ at 20 ms under placebo did not significantly differ from chance level (S-ketamine group: mean d′ 00.05, SD 00.31, p 00.5; psilocybin group: mean d′ 00.1, SD 00.35, p 00.19), while d′ at 30 ms became significantly above chance level (S-ketamine group: mean d′00.30, SD00.29) (p< 0.0001; psilocybin group: mean: d′00.36, SD00.63, p< 0.05). In contrast, under the influence of both drugs, d′s at 30 ms were still not above chance level (S-ketamine group: mean d′ 00.12, SD 00.67, p 00.42; psilocybin group: mean d′00.04, SD00.7, p00.81), whereas performances at 50 ms reached significance (S-ketamine group: mean d′00.36, SD00.37, p's<0.001; psilocybin group: mean d′00.20, SD00.33, p<0.05). During the discrimination of happy faces (Fig.), d′ values for each duration time in all drug conditions significantly varied from chance level. Independent of threshold setting, repeated-measures ANOVA over both groups revealed that d′ significantly increased across target durationp 00.09] revealed that Sketamine significantly reduced d′ for both fearful (p < 0.001) and happy faces (p<0.001) relative to placebo, while psilocybin exclusively reduced d′ for fearful (p<0.001) but not for happy faces (p00.87).
Mean of grand averages over both hemisphere of the P100 and N170 ERP during non-conscious and conscious processing are shown in Fig.. P100 event-related potential Repeated-measures ANOVA on the P100 amplitudes revealed generally more pronounced P100 amplitudes over right compared to left electrodes in both the S-ketamine [F (1,20)018.23; p<0.001; η 2 p 00.48] and the psilocybin group [F(1,20)022.22; p<0.001; η 2 p 00.53]. However, no treatment effects were observed for the P100 amplitudes in the psilocybin [F(1,20)00.099; p00.13; η 2 p 03.00] and-ketamine group F(1,20)00.011; p<0.917; η 2 p 00.001]. Comparing the effect of S-ketamine and psilocybin, repeated-measures ANOVA on the change scores for the P100 amplitude showed no main effects and interactions, reflecting an equal influence of S-ketamine and psilocybin on the P100 amplitude.
Repeated-measures ANOVA on the S-ketamine data revealed that N170 amplitudes were generally more pronounced over right compared to left electrodes and more pronounced for emotional relative to neutral faces, as indicated by a significant main effect for laterality (F(1,20)0 25.97; p<0.0001; η 2 p 00.56) and valence (F(2,40)05.47; p< 0.01; η 2 p 00.21). Furthermore, a main effect of treatment was found (F(1, 20) 08.73; p <0.01; η 2 00.30), reflecting the overall N170 reduction under S-ketamine. The treatment× laterality interaction (F(1,20)046.70; p<0.00001; η 2 p 00.71) showed that the treatment effect occurred only over right electrodes (p<0.000001) (Fig., left), but not over left electrodes (p00.14). In general, the S-ketamine effect on the N170 amplitude was more pronounced during conscious (p < 0.00001) (mean difference -1.1 μV) than non-conscious processing (p<0.001) (mean difference -0.6 μV), indicated by Repeated-measures ANOVA on the psilocybin data revealed significant main effects for laterality (F(1,20)0 39.43; p<0.00001; η 2 p 00.66) and treatment (F(1,20)014.21; p<0.01; η 2 p 00.42), reflecting the more pronounced response over right relative to left electrodes (p<0.00001) and the general N170 reduction induced by psilocybin (p<0.01). This treatment effect was found only over right electrodes (F (1,20)06.61; p<0.05; η 2 p 00.25). The main effect of valence indicated the more pronounced N170 amplitude for emotional compared to neutral faces (F(2,40)09.79; p< 0.001; η 2 p 00.33). Furthermore, the laterality×treatment×target duration interaction (F(1,20)04.52; p<0.05; η 2 p 00.18) revealed that the N170 effect over right electrodes was more pronounced during conscious (p<0.000001) (mean difference -1.38 μV) than non-conscious processing (p< 0.01) (mean difference -0.71 μV). Finally, as shown by a significant treatment×valence interaction (F(2,40)05.92; p<0.01; η 2 p 00.23), psilocybin significantly reduced the N170 amplitudes in response to fearful (p<0.000001) and neutral faces (p < 0.01), but not to happy faces (p00.1) (Fig.). Comparing the S-ketamine and psilocybin effects on the N170, repeated-measures ANOVA on the change scores revealed significant main effects for target durationp 00.11). LSD post hoc testing revealed that in general both drug effects were more pronounced over right than left electrodes (p<0.00001) and more pronounced during conscious than non-conscious processing (p<0.05). Most intriguingly in regard to the contribution of glutamate and serotonin to emotional processing, a laterality×valence×group interaction was found (F(2,80)0 4.02; p<0.05; η 2 p 00.09). Particularly, although S-ketamine and psilocybin equally modulated the N170 amplitudes in response to fearful (p00.78) and neutral faces (p00.82) over right electrodes, happy faces were differentially modulated by S-ketamine and psilocybin (p<0.05) (Fig.). Finally, we asked whether the drug-induced changes in the behavioral performances (d′ fear and d′ happy) might be explained through the drug effects on the N170 over right electrodes using linear regression analysis. For both groups, we found no significant relations between d′ fear and N170 change score for fearful faces (psilocybin group: F00.28, p00.757; S-ketamine group: F02.23, p00.136), as well as between d′ happy and N170 change score for happy faces (psilocybin group: F01.25, p00.311; S-ketamine group: F00.974, p00.397).
Both S-ketamine and psilocybin produced similar alterations on the global ASC scores (Fig.). Repeatedmeasures ANOVA on the ASC data showed significant main effects for treatment (F(1,40)080.99; p<0.00001; η 2 p 00.67) and scale (F(11,440)09.73; p<0.000001; η 2 p 00.20). A triple treatment×scale×group interaction indicated significant differences between both drug effects on specific scales05.35; p<0.00001; η 2 p 00.12]. Post hoc testing showed that S-ketamine increased all scales relative to placebo (p's< 0.01), expect for anxiety (p00.09), while psilocybin increased all scales (p's<0.01), expect for auditory alterations (p00.42) and anxiety (p00.36). Moreover, LSD post hoc analysis showed that S-ketamine produced significantly higher scores than psilocybin for disembodiment (p<0.000001), auditory alterations (p<0.05), and for impaired control and cognition (p<0.05). Otherwise, psilocybin produced more pronounced visual illusions and elementary hallucinations than S-ketamine as indexed by the elementary imagery score (p<0.01).
In this paper, we present a suitable approach to compare glutamatergic and serotonergic effects on emotional face processing. Specifically, according to the firstly assessed discrimination thresholds, we used event-related potential recording to investigate the effect of the NMDA receptor antagonist S-ketamine and the 5-HT receptor agonist psilocybin either on conscious or non-conscious emotional face processing. Our study provide three major results: Firstly, the structural encoding of facial configurations as expressed by the N170 ERP is impaired by S-ketamine and psilocybin, while the fast extraction of visual emotion-related information (i.e., P100 ERP) is not affected by both drugs. Secondly, the N170 ERP is differentially modulated by S-ketamine and psilocybin. Although both drugs reduce the N170 ERP responses to fearful faces, the structural encoding of happy faces is only impaired by S-ketamine. Finally, both drug effects on the N170 ERP are more pronounced during conscious than non-conscious processing. In the following, we discuss our results and consider their potential implications. On the behavioral level, regardless of threshold setting, S-ketamine and psilocybin differentially affected facial discrimination performances. Particularly, the subjective ability to discriminate fearful from neutral face identities was impaired following both S-ketamine and psilocybin administration. In contrast, the discrimination performance of happy relative to neutral faces was only affected by S-ketamine but not by psilocybin, suggesting that the effect of psilocybin is valence specific on the behavioral level. On the electrophysiological level, the N170 amplitude was more pronounced for emotional relative to neutral faces in both groups without any drug intake (i.e., under placebo), reflecting an emotional face processing bias as previously reported. Psilocybin impaired the structural encoding of fearful faces as expressed by reduced N170 responses to fearful faces, while no psilocybin-induced N170 alteration in response to happy faces was found in this study. Thus, psilocybin shifted the negative N170 processing bias seen under placebo. These findings differ from previous studies reporting that the SSRI citalopram does not acutely modulate the N170 ERP in response to emotional faces in healthy subjects, whereas later ERPs such as the N250 or the LPP, which have been associated with "expression decoding," are modulated by citalopram. Beyond methodological differences across these studies such as the use of the reference electrodes, the differential effect of psilocybin and citalopram on the N170 ERP may be due to the different pharmacological effects of psilocybin and citalopram on the 5-HT system. While citalopram overall increases 5-HT brain levels, psilocin, the active metabolite of psilocybin, is an agonists at 5-HT receptors which binds with high affinity specifically at 5-HT1, HT2, and 5-HT6 receptors. That the different pharmacological profiles of psilocybin and citalopram on the 5-HT system may be most Fig.Effects of S-ketamine (dashed line) and psilocybin (dotted line) on the ASC scales. Mean scores and ±SE (both n021). Note: *p<0.05, **p< 0.01, and ***p<0.000001 indicate significant differences between drugs. Symptoms scores were expressed as percent of scale maximum Fig.Mean change scores of N170 ERP±SE as a function of face valence over right parietooccipital electrodes. Notably, the N170 ERP reduction for fearful and neutral faces was comparable among both drugs, but the N170 ERP for happy faces was significantly more reduced after S-ketamine (circle) than psilocybin exposure (triangle). *p<0.05 indicates a significant difference between the effect of S-ketamine and psilocybin on happy faces critical in mediating their N170 effects on emotional face processing is further supported by the finding that decreasing brain 5-HT levels by acute tryptophan depletion (ATD) did not affect the N170 during face processing as well. Along this line, the P100 ERP is also differently altered by psilocybin and ATD. Particularly, while ATD enhances the P100 for sad versus joyful faces, in this study no P100 alteration to facial expressions was found under psilocybin. Thus, the sensitivity of the P100 and N170 ERP may differentially depend on 5-HT brain levels and the activation of a set of different 5-HT receptors subtypes. Discussing the effect of S-ketamine on the visual ERPs, the only work with reference to our result is a previous fMRI study, which explored the functional network following ketamine administration during emotional face processing. The key finding of this study was that the amygdala and fusiform gyrus (FG) activity in response to fearful faces under placebo was abolished following ketamine administration. The authors suggested that this ketamine-induced effect on limbic and visual regions is associated with the emotional blunting and depersonalization phenomena that are evident in ketamine states. Such an interpretation is consistent with the present finding that S-ketamine reduced the N170 ERP not only in response to fearful but also to neutral and happy faces, reflecting an overall emotional blunting of visually induced neural responses. According to several source localization studies, the generators of the N170 ERP have been localized to the FG, which encodes the structural configuration of facial features. The significance of structural information encoding in visual perception is shown by a functional relationship between object discrimination performance and FG activity. In particular, a previous study found that FG activity increases gradually with subjective rating of recognition success). An identical relationship was also suggested following citalopram administration in healthy subjects. It has been proposed that the enhanced fear detection in healthy subjects treated with citalopram) may be partly due to an increased activity in the FG. Albeit not statistically underpinned, we observed that both drug effects on the subjective discrimination performances correspond approximately to the electrophysiological changes on the N170 following drug administration (cf. Figs.and). These findings suggest that the relationship between discrimination success and FG activity/N170 amplitude might remain following manipulation of the 5-HT and NMDAR system. However, the lack of a statistical significance warrants further investigations to strengthen this relationship. Neurofunctionally, increased visual evoked responses to relevant emotional expressions are likely mediated via rich interconnections between the FG and the amygdala, the coupling of which is additionally strengthened during attentive viewing of affective faces. Furthermore, emotional face processing also involves prefrontal areas, which are functionally connected with the FG and the amygdala. Critically, both Sketamine and psilocybin were found to deactivate limbic and to increase prefrontal neural activity during resting states in healthy subjects. Thus, it is arguable that the psilocybin-and Sketamine-induced N170 effects in response to fearful faces may be due to functional alterations in the amygdalaprefrontal network. However, why psilocybin and Sketamine had dissociable effects on happy face processing is difficult to derive from the present data. A possible explanation could be that S-ketamine and psilocybin differentially modulate circuitries responsible for the processing of positive expressions because the processing of positive information such as happy faces also involves rewardrelated areas) relative to the processing of negative information and further because the N170 showed priming effects as a function of reward. However, this is highly speculative at the present time. Another key finding of this study was further that the psilocybin-and S-ketamine-induced N170 effect was more pronounced during conscious than non-conscious visual processing independent of the face expression. This finding fits with the assumption that the N170 is associated with perceptual consciousness of the faceand that FG responses are modulated by the level of target visibility. Furthermore, numerous studies have described an increase of the N170 ERP with selective attention, suggesting top-down attentional control. In particular, the visual cortex receives top-down modulation from frontal and parietal areas in relation to visual attentionin the time range of the N170 ERP. In this view, several studies reported that psilocybin attenuates attentional performances. A recent study examining the influence of psilocybin on the spatiotemporal dynamics of object completion and found a dose-dependent reduction of the N170 ERP response. The authors suggested that this reduction might reflect a psilocybin-induced failure to allocate attention. Similarly, previous evidence revealed that ketamine produce cognitive deficits including impairments of attention. Therefore, we suggest that the more pronounced effects of psilocybin and S-ketamine on the N170 during conscious relative to non-conscious processing indicate a drug-induced reduction of attentional resources. One point of contention, however, may be that there is some evidence of conscious perception of happy faces with 20 ms in this study. This means that we cannot infer from the discrimination threshold task that 10 ms is truly non-conscious for the processing of happy faces. However, recent ERP studies confirmed presentation times below 20 ms for non-conscious processing of happy faces. Therefore, it is conceivable to assume that presentation times of 10 ms as used in our ERP experiment are really non-conscious also for the processing of happy faces. Summarized, this study demonstrated that the NMDA and 5-HT receptor systems differentially contribute to the structural encoding of emotional face expressions as expressed by the N170 event-related potential. Our findings confirm the emotion sensitivity of the N170 ERP during conscious and non-conscious face processing as recently reported) and further suggest that the assessment of early visual evoked responses might allow detecting pharmacologically induced change in emotional processing biases and provides thus a suitable framework to study pathophysiological mechanisms underlying dysfunctional emotional biases.
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