This randomised, double-blind, placebo-controlled study (n=30) investigated the effects of psilocybin (12mg/70kg) on emotional face processing as measured with EEG and found a reduced neural response to both neutral and emotional faces induced by psilocybin due to a psilocybin-induced increase in top-down control.
Introduction
Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood.
Methods
Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration.
Results
Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168-189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211-242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168-189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211-242 ms interval.
Discussion
Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control.
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Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)
Carhart-Harris, R. L., Leech, R., Williams, T. M. et al. · British Journal of Psychiatry (2018)
Carter, O., Burr, D. C., Pettigrew, J. D. et al. · Journal of Cognitive Neuroscience (2006)
Kometer, M., Cahn, B. R., Andel, D. et al. · Biological Psychiatry (2011)
Facial expressions are central to social behaviour, and accurate emotional face processing is disrupted in mood disorders. Previous work has implicated the brain's serotonergic system in these processes: selective serotonin reuptake inhibitors (SSRIs) and receptor-directed manipulations alter behavioural recognition of emotional faces and neural responses in regions such as the amygdala, parahippocampal gyrus and prefrontal cortex. Acute administration of psilocybin, a serotonin 5-HT1A/2A receptor agonist, has been reported to impair aspects of emotional face processing, particularly affecting the fine-grained, structural encoding of facial features occurring around 170 ms after stimulus onset, but the detailed spatiotemporal brain mechanisms underlying these effects remain unclear. Bernasconi and colleagues set out to characterise those mechanisms by applying electrical neuroimaging to visual evoked potentials (VEPs) elicited by neutral, fearful and happy faces under placebo and psilocybin. The study aimed to disentangle whether psilocybin-induced changes reflect alterations in overall response strength versus changes in topography (generator configuration) and to localise those effects with a distributed source model (LAURA). This approach allows separation of amplitude (Global Field Power), topographic (global dissimilarity) and latency effects across time, providing a temporally precise picture of psilocybin's impact on emotional face processing.
Thirty healthy volunteers (16 males; mean age 25 ± 0.6 years; 27 right-handed) without personal or first-degree family histories of major psychiatric disorder participated after screening with clinical interview instruments. Exclusion included drug dependence and positive urine drug tests; a small number of participants reported minimal prior recreational drug use. The study received ethics approval and national authorisation for psilocybin use. A randomised, double-blind, placebo-controlled crossover design was used: each participant completed two sessions at least two weeks apart, receiving 170 μg/kg psilocybin or lactose placebo in identical gelatin capsules. Subjective acute effects were assessed with the Altered State of Consciousness (ASC) questionnaire at 360 minutes post-treatment. The experimental task was an EEG passive-viewing emotional face paradigm with backward masking. Target faces (neutral, fearful, happy) were sourced from the Ekman–Friesen set, with task-irrelevant features removed so that only eyes, eyebrows, nose and mouth remained visible. Targets were followed by a neutral-face mask of the same identity. Targets were presented for either 10 ms (unconscious condition) or 200 ms (conscious condition); the present paper focuses on conscious processing (the unconscious data are to be reported elsewhere). Each session comprised 240 target–mask trials (40 trials per valence per duration), presented in a sound-attenuated, electrically shielded booth. EEG was recorded with a 64-channel Biosemi ActiveTwo system at 512 Hz. Epochs ranged from 100 ms prestimulus to 500 ms poststimulus. Preprocessing included semiautomated artifact rejection (±60 μV), interpolation of contaminated electrodes with 3D splines, average referencing and band-pass filtering (0.18–40 Hz). The baseline was defined as the 100 ms prestimulus period, but no prestimulus baseline correction was applied because preparatory processes might differ across drug conditions and baseline correction can alter topography. Average accepted trial counts per condition were approximately 30–33 trials and did not differ significantly across drug or valence conditions, reducing concern about signal-to-noise confounds. Analyses followed an electrical neuroimaging workflow. First, traditional electrode-wise voltage waveform analyses were run via timewise 2-way ANOVAs (treatment × face valence) to visualise effects. The primary, reference-independent analyses comprised Global Field Power (GFP) to index instantaneous scalp electric field strength, and global dissimilarity (DISS) to test topographic changes; both were assessed time point by time point with a temporal persistence criterion of ∼15 ms to limit false positives. Significant GFP interaction windows were then submitted to distributed source estimation using the LAURA inverse solution with the SMAC lead-field and a 3005-node gray-matter grid. Source-level statistics used 2-way ANOVAs (treatment × face valence) at each node, with significance constrained to P < 0.05 and clusters of at least 21 contiguous nodes (AlphaSim used to determine the spatial threshold).
Subjective effects: Psilocybin robustly increased ASC scores. A treatment × scale interaction (F1,319 = 11.263; P < 0.001) was followed by post hoc tests showing increases on most ASC subscales (all P < 0.001, Bonferroni-corrected), with the exceptions of anxiety and spiritual experience, which did not differ from placebo. Voltage waveform observations: Visual inspection at an occipital electrode suggested psilocybin reduced the N170 component and produced a latency shift at about 200 ms, largely independent of valence. Timewise electrode-level 2-way ANOVAs revealed a significant treatment × face interaction in several windows including 152–183 ms and 193–265 ms. Main effects of treatment and face valence were also observed across multiple poststimulus intervals; these electrode-based analyses were presented mainly for contextualisation, since the authors relied primarily on reference-independent measures for interpretation. Global Field Power (GFP): The key GFP analysis identified two time windows showing a significant treatment × face valence interaction: 168–189 ms (F2,51 = 8.673; P = 0.00051) and 211–242 ms (F2,51 = 7.365; P = 0.0014). Post hoc tests on GFP reported in the extracted text indicated a significant decrease in GFP for neutral and happy faces during 168–189 ms (P < 0.01, Bonferroni-corrected), and a significant decrease only for happy faces during 211–242 ms (P < 0.01, Bonferroni-corrected). The nonparametric DISS statistics did not reveal a significant treatment × face valence interaction across the 0–500 ms epoch; main effects of treatment and of face valence were observed in separate windows. Source estimations (LAURA): Distributed inverse solutions were computed over the two GFP interaction windows. Over 168–189 ms, a significant treatment × face valence interaction emerged in right fusiform gyrus, bilateral parahippocampal gyrus, middle–posterior cingulate cortex, amygdala, right insula, left middle–superior temporal gyrus and right inferior frontal cortex (cluster criterion kE = 21). Over 211–242 ms, significant interactions were located in right lingual and fusiform gyri, middle–inferior occipital gyrus, bilateral hippocampus and right parahippocampal gyrus, middle–inferior temporal gyrus and right precentral gyrus. Cluster-level follow-up: The authors subdivided significant regions into clusters and examined mean source scalar values per cluster. For the first interval (168–189 ms) four clusters (left superior temporal gyrus; bilateral cingulate cortex; left parahippocampal gyrus; right insula/parahippocampal region) showed significant reductions in activity for neutral and fearful faces (P < 0.01, Bonferroni-corrected) but not for happy faces. For the second interval (211–242 ms) clusters in right prefrontal cortex, right occipito-temporal cortex and left superior temporal gyrus showed significant reductions exclusively for happy faces (P < 0.01, Bonferroni-corrected). Note on an apparent inconsistency in the extracted text: the GFP post hoc results for the first interval are reported as decreased GFP for neutral and happy faces, whereas the source-cluster analyses report reductions for neutral and fearful faces. The extraction does not clearly resolve this discrepancy.
Bernasconi and colleagues interpret their findings as evidence that psilocybin produces selective, temporally dissociable modulations of the neuronal correlates of emotional face processing. Two distinct poststimulus windows were emphasised: an early/moderate-latency modulation around 168–189 ms, aligning with the structural encoding or fine-grained categorisation of faces, and a later modulation around 211–242 ms, consistent with subsequent stages of expression decoding. The authors argue these latencies fit an established sequence in which an initial coarse categorisation occurs at about 100 ms and is followed by finer structural encoding roughly 50 ms later. Source localisations implicated both core visual face-processing areas (fusiform, occipito-temporal cortex, lingual gyrus) and limbic regions (amygdala, parahippocampal gyrus, hippocampus), with effects tending to lateralise to the right hemisphere. From these patterns the investigators propose that psilocybin reduces neural responses within this network, and they frame this as compatible with an increase in top-down prefrontal control over limbic regions mediated by 5-HT2A receptor stimulation on cortical pyramidal cells. This mechanistic interpretation is presented cautiously: the authors note it is speculative because the present study did not assess functional connectivity directly. The Discussion positions the results relative to prior serotonergic manipulations. Differences between psilocybin and SSRIs are highlighted: SSRIs have produced mixed effects on happy-face processing and, in some studies, modulations at later latencies (∼250 ms), whereas the current data suggest a receptor-subtype-specific action of psilocybin on earlier structural encoding. The authors also note that faster processing of negative stimuli observed in some event-related potential (ERP) literature is broadly consistent with their temporal pattern, though some ERP studies report the opposite and the literature is heterogeneous. Limitations acknowledged in the extracted text include the absence of direct connectivity measures to test the top-down control hypothesis, and that unconscious-face processing data were not included in this report. The authors also concede pharmacological differences between psilocybin and SSRIs complicate direct comparisons. They conclude by emphasising that this study is the first to map the spatiotemporal brain dynamics of psilocybin-induced modulations of emotional face processing in healthy volunteers and that the pattern of reduced neural responses is consistent with enhanced prefrontal top-down modulation affecting fine-grained facial categorisation.
Facial expressions provide information on our emotional state. Therefore, accurate face processing is essential for appropriate social interaction and behavior. Furthermore, impaired emotional face processing has been closely related to mood disorders (e.g., major depression and anxiety). For instance, mood disorders patients, compared with healthy, are characterized by an increased attentional bias to negative stimuli) and enhanced neural response to threat stimuli within the extensive neural network of emotional face processing. Several studies demonstrated that serotonergic antidepressants shift the attentional bias from negative to positive, and reduce the neurophysiolgical response to threat stimulifor discussion), providing evidence for a critical role of the serotonergic system in emotional face processing. Selective serotonin reuptake inhibitors (SSRIs) administration causes an overall increase of extracellular serotonin (5-HT) level in the brain, by reducing presynaptic serotonin reuptake. Behaviorally, acute SSRIs administration in healthy subjects improve the recognition of both fearful) and happy faces, whereas prolonged administration reduces the recognition of fearful faces. Furthermore, neuroimaging studies revealed a face valence selective effect of SSRIs on neural processing. For instance, causing a reduced neural response to fearful faces within the amygdala, parahippocampal, and medial prefrontal cortex. Results for happy faces processing are less consistent, showing either an increased (e.g.,)o rn o n s i g n i ficantly decreased (e.g.,) amygdala activity after SSRIs administration. Growing evidence suggests that specific serotonin receptor subtypes are critically involved in mood disorders. For instance, it has been shown that the selective 5-HT1A/2A receptor agonist psilocybin modulates the neural activity within circuits related to emotion regulation. Accordingly, acute psilocybin administration modulates emotional face processing. For instance,demonstrated that psilocybin reduces the electrophysiological response to both neutral and fearful faces. Specifically, they showed a temporal selective effect of psilocybin on emotional face processing; psilocybin did not modulate the first rapidcourse emotion categorization, occurring at ∼100 ms poststimulus onset, but rather the fine-grained analysis of the facial features (i.e., "structural encoding"), occurring at ∼170 ms. Taken together, these results provide a first evidence that the selective 5-HT1A/2A receptor agonist psilocybin modulates emotional face processing. However, the spatiotemporal dynamics of the neurophysiological alterations underlying these psilocybin-induced effects remains poorly understood. To further elucidate this issue, in the present study we conducted electrical neuroimaging analyses on visual evoked potentials (VEPs) in response to facial expressions (fearful, happy, and neutral) under placebo and psilocybin. Electrical neuroimaging analyses allow to differentiate modulations in response strength and topography, and localize effects using a distributed source model (LAURA). Thus, the present study provides a differentiated description of the neurophysiological mechanisms underpinning psilocybin's effects on emotional face processing.
Thirty healthy (27 right-handed) participants 16 males (mean ± SEM age: 25 ± 0.6 years), with normal or corrected-to-normal vision participated in the study. Participants were healthy according to medical history, clinical examination, electrocardiography, and blood analysis. They were screened by the DIA-X diagnostic expert system, a semistructured psychiatric interview to exclude individuals with personal or family (first-degree relatives) histories of major psychiatric disorders, and by the Symptom Checklist (SCL-90-R). Furthermore, they underwent to the Mini-International Neuropsychiatric Interview (M.I.N.I.), a structured psychiatric interview. Participants were excluded, if they had history of drug dependence, as assessed by a selfmade consumption questionnaire, or if they were currently using drugs as assessed by a urine drug test. Nevertheless, seven participants were occasional smokers (<6 cigarettes/day), 7 participants reported a sporadic or rare cannabis use in the past (<2 joints/month), one participant reported previous experience with MDMA (one pill lifetime), and one reported previous experience with psilocybin (one administration lifetime). The study was approved by the Ethics Committee of the Canton of Zurich, Switzerland. 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.
Using a randomized, double-blind, placebo-controlled design, all participants received either psilocybin or placebo in 2 separate sessions, separated by at least 2 weeks. Psilocybin was obtained through the Swiss Federal Office for Public Health. Psilocybin (170 μg/kg) and lactose placebo were administered in gelatin capsules of identical number and appearance, as previously described. Participants remained monitored until all acute drug effects had worn off, and were subsequently released into the custody of a partner.
The Altered State of Consciousness (ASC) questionnaire, a visual analog and self-rating scale, was used to assess the subjective psychological effects induced by psilocybin. A recent evaluation of the ASC questionnaire has constructed eleven new lower order scales, which were used in this study. The ASC questionnaire was applied 360-min post-treatment to retrospectively rate subjective experiences since drug intake.
The experiment consisted in an EEG passive-viewing emotional face task. All target emotional faces were backward masked with a neutral face. Participants were instructed to determine the emotional valence of each face (neutral, fearful, and happy) no response was required. They performed the experiment twice (distinct sessions/days), one for each treatment (i.e., placebo and psilocybin). Stimuli were black and white images taken from the Ekman-Friesen series. The target images were neutral and basic emotional expressions (i.e., fearful and happy faces). The masking photograph was always a neutral face of the same identity. For each face valence, 6 different identities were used. To limit confounds by low-level face processing qualities, faces were modified using Photoshop 2.0 (Adobe Systems Incorporated, San Jose, CA, USA) such that task-irrelevant features were removed and that the only visible features of the faces were the eyes, eyebrows, nose, and mouth. Stimuli were displayed in the center of the monitor and subtended a visual angle of 3°horizontally and 4.4°vertically. Each trial began with a fixation cross-lasting for 2000 ms. The target faces (i.e., neutral, fearful, and happy) were presented for either 10 ms (unconscious condition) or 200 ms (conscious condition). Each target face was immediately followed by a mask (i.e., neutral face) lasting for 150 ms. For each experimental session, a total of 40 trials (target-mask pairs) were presented for each face valence and for the 2 target durations, resulting in a total of 240 images. Target faces were randomly presented with equal probability. The experiment was conducted in a sound attenuated and electrically shielded booth. Stimulus delivery and participants' responses were controlled by Eprime 2.0 (Psychology Software Tools, PA, USA). Timing issues were controlled using an oscilloscope. Because recent evidence revealed that psilocybin attenuates the explicit recognition of negative expressions) and that its effect on VEPs to emotional face expressions were more pronounced during conscious than nonconscious processing, in the present study, we specifically aimed to further explore the effect of psilocybin on the conscious processing of emotional faces by disentangling the spatiotemporal brain dynamics of this effect. The EEG data recorded during unconscious face processing will be included in a further study.
Continuous EEG was acquired at 512 Hz through a 64-channel Biosemi ActiveTwo AD-box referenced to the common mode sense (CMS; active electrode) and grounded to the driven right leg (DRL; passive electrode), which functions as a feedback loop driving the average potential across the electrode montage to the amplifier zero. Data preprocessing and analyses were performed using Cartool Software;). The EEG epochs were defined from 100 ms prestimulus (i.e., emotional face) to 500 ms poststimulus onset. All analyses were always conducted over the full ERP epoch. EEG epochs from 100 ms pre-to 500 ms poststimulus onset were averaged from each participant to calculate ERPs for each treatment (i.e., placebo or psilocybin) and face valence (i.e., neutral, fearful, and happy), generating separate 2 × 3 within-subject designs. In addition to visual inspection, a semiautomated ±60 μV artifact rejection criterion was applied in order to reject epochs with eye blinks and/or other sources of transient noise. Prior to groupaveraging for each experimental condition, data at artifactcontaminated electrodes from each participant were interpolated using 3D splines. Data were then recalculated against the average reference and band-pass-filtered (0.18-40 Hz). The baseline was defined as the 100 ms prestimulus period. No prestimulus baseline correction was applied for the following reasons: 1) we could not assume that the preparatory processes were similar across conditions (i.e., with and without treatment) 2) baseline correction can affect the topography of the data and potentially shift statistical effects in time. The average number of accepted EEG epochs per each drug condition were: Condition 1 ( placebo) neutral face: (mean ± SEM; 32.8 ± 1.13), fearful face: (mean ± SEM; 32.5 ± 1.35), happy face (mean ± SEM; 31.86 ± 1.23); condition 2 ( psilocybin) neutral face: (mean ± SEM; 31.5 ± 1.26), fearful face: (mean ± SEM; 31.13 ± 1.26), happy face (mean ± SEM; 30.09 ± 1.19). Conditions were not significantly different (2-way ANOVA: interaction treatment × face: F 2,58 = 0.177; P-values >0.8; main effect face: F 2;58 = 1.41; P-values >0.3; main effect treatment: F 1,29 = 0.64, P-values >0.5). Because the number of accepted epochs did not differ significantly across conditions we can exclude that our effects followed from differences in signal-to-noise ratios.
Effects of psilocybin on emotional face processing were identified with a stepwise analysis procedure referred as electrical neuroimaging, implemented in Cartool;site/fbmlab/cartool). By analyzing the ERPs using Electrical Neuroimaging, we were allowed to assess and differentiate effects following from: 1) strength modulations of statistically indistinguishable generator configurations (i.e., Global Field Power modulations in absence of topographic modulations), 2) topographic modulations across conditions, resulting from changes in the intracranial sources configuration, 3) latency shifts across conditions. Because each analyses is independent one from the other, any combination of these neurophysiologic phenomena can be assessed. Finally, we used the local autoregressive average distributed linear inverse solution (LAURA; Grave de Peraltato visualize and statistically assess the likely underlying sources of effects identified in the previous analysis steps (GFP and/or topographic modulations).
A first level of analysis was performed by submitting the VEPs data to a 2-way ANOVA using the within-subject factors treatment ( placebo; psilocybin) and face valence (neutral; fear; happy) at each scalp electrode as a function of peristimulus time. Note that only effects meeting or exceeding the P-values 0.05 criterion for at ∼15 consecutive milliseconds were considered reliable. This analysis was included to give a visual impression of specific effects within the dataset, and to facilitate the contextualization of our results with other VEP studies (e.g.,). However, due to the electrode reference-dependent nature of statistical analyses of AEP waveforms (a change of the reference electrode will result in a change in statistical outcomesfor discussion), our primary analyses and basis for interpretation were the electrode reference-independent analyses detailed below.
Changes in the strength of the electric field at the scalp were calculated using the global field power (GFP), a reference electrode-independent analyses, for each participant and experimental condition. GFP measures the strength of the electric field at the scalp, independently of its spatial distribution across the electrode montage. The GFP is calculated as the square root of the mean of the squared value recorded at each electrode and represents the spatial standard deviation of the electric field at the scalp at each instant in time. Modulations in GFP were statistically analyzed at each time-point using a 2-way ANOVA using within-subject factors of treatment and face valence. We would like to point out that to reduce the risk of false-positive results arising from multiple tests only effects at least of a P-values 0.05 criterion lasting at least ∼15 consecutive milliseconds were considered reliable (Guthrie and Buchwald 1991, similar criterions were used previously, e.g., De.
Topographic modulations were identified using global dissimilarity (DISS), which is calculated as the root mean square of the difference between 2 strength-normalized vectors (i.e., the instantaneous voltage potentials across the electrode montage). The DISS value between the face valences as a function of treatment were compared time-point by time-point with an empirical distribution derived from a bootstrapping procedure (5000 permutations per data point), based on randomly reassigning data across conditions for each participants (detailed in. DISS is an electrode reference-independent analysis. Moreover, GFP and DISS are 2 orthogonal analyses because DISS is insensitive to pure amplitude modulations across conditions. A topographic modulation is neurophysiological interpreted as a changes following from a significant differences in the configuration of the intracranial generators. As for GFP analyses, temporal autocorrelation was corrected through the application of a ∼15 continuous milliseconds as temporal criterion for the persistence of differential significant effects.
We estimated the electrical activity in the brain using a distributed linear inverse solution applying the local autoregressive average regularization approach (LAURA), comprising biophysical laws as constraints (Grave de Peralta). For the lead field matrix calculation, we applied the spherical model with anatomical constraints (SMAC) method, which transforms the MRI to the best-fitting sphere using homogeneous transformation operators. It then determines a regular grid of 3005 solution points in the gray matter of this spherical MRI and computes the lead field matrix using the known analytical solution for a spherical head model with 3 shells of different conductivities as defined by. The periods of significant treatment × face valence interaction determined in the GFP analysis were used as period of interest, on which carry out the source estimations for each experimental condition. To increases the signal-to-noise ratio, VEPs for each participant and each experimental condition were separately averaged across the abovementioned time periods when significant treatment × face valence interactions were identified in the GFP analysis. The inverse solution was then estimated for each of the 3005 nodes. These data were then submitted to a 2-way ANOVA using within-subject factors of treatment and face valence. To correct for multiple testing and temporal autocorrelation, only nodes with P-values <0.05 2-tailed and clusters of at least 21 contiguous nodes were considered significant (these criteria were published elsewhere, e.g.,). The spatial criterion was determined using the AlphaSim program (. gov/afni/doc/manual/AlphaSim). The results of source estimations were rendered on the Montreal Neurological Institute's average brain with thecoordinates.
Psilocybin produced alterations on the global ASC scores (Fig.). A 2-way treatment × scale interaction indicated significant difference on specific scales (F 1,319 = 11.263; P < 0.001). Furthermore, post hoc testing on this interaction showed that psilocybin versus placebo significantly increased all scores (all P-values <0.001; Bonferroni corrected), with the exception of anxiety (P-value >0.9; Bonferroni corrected) and spiritual experience scores (P-values >0.4; Bon ferroni corrected).
A first level of analysis of the VEPs to emotional faces was performed using individual voltage waveforms, visual inspection of an occipital electrode (P8) indicate several effects: first a main effect of treatment, such that psilocybin appears to reduce the N170 response and a shift in latency, to the right, at ∼200 ms poststimulus, independently of the face valence. Second, as expected, the N170 component is modulated by the emotional faces (fear and happy) vs. neutral face. These observations were statistically evaluated via a timewise 2-way ANOVA (treatment × face valence). A significant (P-value <0.05; >15 continuous milliseconds) treatment × face interaction was observed over the period 152-183 and 193-265 ms (Fig.). Furthermore, there was a main effect of treatment (P-value <0.05; >15 continuous milliseconds) over the 152-183 and 193-265 ms poststimulus interval; a main effect of face (P-value <0.05; >15 continuous milliseconds) was observed over 66-92, 105-220, and 230-367 ms poststimulus interval (results not shown). A second level of analysis of the VEPs was performed using group-averaged VEPs evoked by emotional face (i.e., neutral, happy and fear), which were compared as a function of treatment ( placebo vs. psilocybin). Time-wise 2-way ANOVA (treatment × face valence) analyses was performed as a function of peristimulus time at each of the scalp electrodes. Statistically significant interaction between treatment and face valence (P-value <0.05, >15 consecutive milliseconds) were observed at ∼100-300 ms poststimulus stimulus (Fig.). Furthermore, a main effect of treatment was observed over the period: ∼120-140, ∼170-220 and ∼230-400 ms poststimulus and a main effect of face valence over the period: ∼160-200 and ∼240-360 ms (Figs.and). The reader should have in mind that our conclusions over the possible causes of the psilocybin-induced modulation of emotional face processing are based on analyses of electrode reference-independent features of the global electric field at the scalp (see below).
Of main interest to the aims of the present study, the time-point by time-point 2-way ANOVA on GFP evidenced a significant interaction between treatment and face valence over the period 168-189 ms (F 2,51 = 8.673; P = 0.00051) and 211-242 ms (F 2,51 = 7.365; P = 0.0014) after the stimulus onset (Fig.), in accordance with a psilocybin-induced response modulation (vs. placebo). Post hoc t-test on GFP over the 168-189 ms pointed out a significant decrease in GFP for both neutral and happy (P-values <0.01; Bonferroni corrected), while over the period 211-242 ms a significant decrease in GFP only for happy faces (P-value <0.01; Bonferroni corrected) (results not shown). A main effect of treatment (t-values >3.565; P-values <0.05; >15 consecutive milliseconds) was observed over the 94-143 and 180-219 ms poststimulus periods, and a main effect of face valence (t-values >2.536; P-values <0.05; >15 consecutive milliseconds) over the 37-59, 105-139, 176-246 and 303-354 ms poststimulus periods (Figs.and). By contrast, the nonparametric DISS statistics (used to assess topographic modulations across conditions) did not reveal significant interaction between treatment and face valence over the 500 ms poststimulus (P-values <0.05; >15 consecutive milliseconds; Figure). A main effect of treatment was observed over the -26-103; 99-219; 110-220 and 230-304 ms poststimulus periods (Fig.) and a main effect of face valence over the 156-214 and 250-364 ms poststimulus periods (Fig.). Since the aim of the study was to identify neurophysiological modulation induced by psilocybin to emotional face processing, the 2 periods of significant GFP interaction (treatment × face valence) were selected as time period submitted to source estimations.
LAURA distributed source estimations were calculated over the 168-189 and 211-242 ms poststimulus time periods, which indicated a significant GFP interaction between treatment and face valence. Over the 168-189 ms period a significant interaction treatment × face valence (F 2,58 > 5.26; P-values <0.03; kE=21 contiguous solution points) was observed within the visual areas (right fusiform gyrus), limbic areas (bilateral parahippocampal gyrus, middle-posterior cingulate cortex and amygdala), temporoparietal areas (right insula; left middle-superior temporal gyrus) and the prefrontal areas (right inferior frontal cortex) (Fig.). Over the 211-242 ms period a significant interaction (F (2,58) >10.13; P-values <0.01; kE = 21 contiguous solution points) was observed within the visual area (right lingual gyrus, fusiform gyrus and middle-inferior occipital gyrus), the limbic areas (bilateral hippocampus and right parahippocampal gyrus), temporoparietal areas (middle-inferior temporal gyrus) and the prefrontal areas (right precentral gyrus) (Fig.). To assess the basis of the significant treatment × face valence, brain regions indicating significant treatment × face interaction (see above) were subdivided in distinct clusters according to literature (e.g.,, and the group-average scalar values across the nodes within each clusters were calculated (shown as bar graphs in Fig.and). Over the first time period of interest (168-189 ms) in all 4 clusters (i.e., left STG; bilateral cingulate cortex; left parahippocamal gyrus and right insual/parahippocampal gyrus) significant (P-values <0.01; Bonferoni corrected) reductions of the activity were observed for both neutral and fearful faces, but not for happy faces (P-values >0.5). Over the second period of interest (211-242 ms) for all clusters (i.e., right prefrontal cortex; right occipito-temporal cortex; left STG) significant (P-values <0.01; Bonferoni corrected) reductions in the neurophysiological response were observed exclusively for the happy faces.
We identified the spatiotemporal brain dynamics underlying emotional face processing modulations induced by psilocybin, a serotonin 5-HT1A/2A receptor agonist. Brain mechanisms associated with such modulations were identified by applying electrical neuroimaging analyses to the VEPs in response to emotional faces as a function of treatment (i.e., placebo vs. psilocybin). We identified 2 distinct time periods of strength (GFP) modulation induced by psilocybin administration. Distributed source estimations over these 2 time periods further indicated a face valence specific effect of psilocybin. The collective findings support a model in which serotonin 5-HT1A/2A receptor stimulation has selective and temporal dissociable effects on the neuronal correlates of emotional face processing. The latencies of our effects are consistent with a modulation of the fine-tuning categorization of facial expressions. According to both animal intracranial recording and human electrophysiological studies, which investigated emotional face processing, an initial course categorization of the face occurs already at ∼100 ms poststimulus, as suggested by an increased electrophysiological response to both face vs. object and emotional faces vs. neutral faces. The initial categorization is succeeded by a fine-grained encoding (i.e., "structural encoding") of facial features, as suggested by an increased electrophysiological response to emotional faces observed ∼50 ms after the course categorization. Furthermore, the latency of our effects are also consistent with previous studies, which investigated effects of serotonergic manipulation on faces processing. For instance, Schmidt et al. () demonstrated a psilocybin-induced modulation of the structural encoding of emotional faces occurring at ∼170 ms after the stimulus onset. However, further studies, which investigated the effects of acute selective serotonin reuptake inhibitors (SSRIs), observed a modulation of the emotional "expression decoding" (occurring at ∼250 ms) but not of the "structural encoding"). The incongruence with our results might be due to a more specific effect of psilocybin vs. SSRIs on the 5-HT system (see. Source estimations over the 168-189 ms time period revealed a reduced neurophysiological response to both neutral and fearful faces within right fusiform gyrus, temporoparietal cortices, prefrontal areas and bilateral limbic areas, as well as a reduced response to happy faces within the right lingual gyrus, fusiform gyrus, middle-inferior occipital gyrus, bilateral limbic areas, temporoparietal cortices and the prefrontal areas over the 211-242 ms poststimulus period. The temporal selective effects of psilocybin on emotional face processing (i.e., initial effect on both fearful and neutral faces, followed by effect on happy faces) are consistent with previous ERPs studies, which suggested a faster processing of negative compared with positive stimuli, due to the ecological importance of detecting signals of danger). However, few ERPs studies demonstrated that happy faces are processed faster than fearful faces (e.g.,. According to the authors, this counterintuitive result might be explained by the fact that negative stimuli are processed within a subcortical-slower pathway via the superior colliculus and pulvinar to the amygdala, consistent with anatomical studies in monkey. Furthermore, over both periods of interest a stronger activity was localized predominantly within the right hemisphere, in line with previous studies that demonstrated a right lateralization of the emotional processing within the first 200 ms poststimulus (e.g.,for discussion). Furthermore, our source localizations are consistent with previous fMRI studies, which investigated neurophysiological modulations induced by citalopram, a SSRI. For instance, neurophysiological modulations were observed within the "core system" of the emotional face processing network, comprising occipital face-sensitive areas, the lateral fusiform gyrus (identity recognition), the superior temporal cortex (expression recognition), and within the "extended system" including the amygdala, the orbitofrontal cortex and the posterior cingulate cortex (emotion recognition). During emotional face processing, these regions are functionally connected (e.g.,, where the key structure of this network is the amygdala (e.g.,. Thus, the observed impaired emotional face processing after psilocybin administration might be associated with an impaired functional connectivity between the amygdala and other key structures for emotional face processing (Vollenweider and Kometer 2010 for discussion). However, this is clearly speculative. In fact, in the present study used source localization exclusively to identify changes in neural activity induced by psilocybin and did not taken into account changes in functional connectivity among regions critically involved during emotional faces processing. This issue will be addressed in further connectivity studies. Furthermore, the difference between the effects induced by SSRIs (increased or no effect) and psilocybin on happy face processing might be due to different pharmacological effect of the 2 compounds. Whereas SSRIs increase serotonin level in the whole brain, psilocybin has a more specificaffinity for serotonin 2A receptors, essentially located on the pyramidal cells within the PFC). Accordingly, reduced serotonin level by acute tryptophan depletion (ATD) did not modulate the structural encoding of emotional facesproviding additional evidence for a more specific pharmacological action of psilocybin. Mechanistically, we interpret the reduced neurophysiological response across all face valences as modulation of selective attention induced by psilocybin, consistent with previous studies, which demonstrated an attenuation of the visual attentional performance in a dose-dependent manner. Over both 168-189 and 211-242 ms poststimulus intervals we observed a pure change in response strength induced by psilocybin, consistent with a quantitative modulation of the attention level. Accordingly,ERPs study demonstrated that when facial expressions were attended an increased N170 was measured for facial expressions vs. neutral faces. This was not the case when attention was directed to the face gender, suggesting a top-down attentional control on emotional face processing. In line with these results,demonstrated a reduced attentional performance in visual tasks due to an increased top-down control. Furthermore,suggested that attention modulates the structural encoding of faces, which occurs at ∼170 ms after the stimulus onset. The top-down control during emotional face processing was shown to modulate the activity within the amygdala, occipito-temporal visual cortex, orbitofrontal and posterior cingulate cortex, independent of the emotional valence. Evidence from animal and human PET imaging studies support the putative modulation of the top-down control induced by psilocybin. In fact, they suggest that activity within the PFC is modulated by the 5-HT2A receptors on pyramidal cells). Thus, stimulation of the 5-HT2A receptors with psilocybin results in an enhanced top-down control of the PFC over limbic areas. Additional evidence of a serotonin-induced modulation of the PFC top-down control over the limbic areas is provided by studies on patients with depression and anxiety, which are characterized by an impaired serotonergic systemfor a review). Depressed patients were associated with a reduced PFC activity as well as hyperactivity within the amygdala, parahippocampal gyrus, and fusiform gyrus in response to negative stimuli. Likely, the hyperactivity is due to a reduced top-down control of the PFC. Collectively, these results support the hypothesis of a modulation of the top-down control of the PFC over the limbic areas induced by the serotonergic system. In conclusion, the present results are the first reporting the spatiotemporal brain dynamics of psilocybin-induced modulations of emotional face processing in healthy volunteers, providing new insights on the role of the serotonergic system on emotional face processing. We demonstrated a reduced neural response to both neutral and emotional faces induced by psilocybin, due to a psilocybin-induced increase in top-down control. The timing of our effects suggests that psilocybin modulates the fine-grained emotional face categorization.
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