Psychedelics Align Brain Activity with Context

Stoliker and colleagues frame the study around how psychedelics reorganise brain connectivity in ways that depend on psychological and sensory context. Earlier research has shown that agents such as psilocybin act at 5-HT2A receptors to induce structural and functional plasticity, relax constraints on associative networks such as the default mode network (DMN), and can produce profound subjective effects including intensified immersion and self-boundary dissolution. However, prior human studies have often used small samples, single imaging modalities, or limited contexts, leaving open how context shapes large-scale functional integration and the neural mechanisms that relate reorganisation to subjective and therapeutic outcomes. This study set out to address those gaps by acquiring a large, multimodal dataset (fMRI and high-density EEG) in a predominantly psychedelic-naïve cohort and systematically varying contextual conditions (eyes-closed rest, guided meditation, music listening, and eyes-open movie watching). Using a fixed 19 mg oral psilocybin dose and repeated baseline (no-psilocybin) and post-dose imaging, the investigators aimed to map how psilocybin changes global and local connectivity, signal variability, directed interactions (via dynamic causal modelling), and low-dimensional neural embeddings, and how those neural changes covary with subjective experience and short-term psychological changes. The work emphasises context-sensitive mechanisms and introduces machine-learning embedding approaches to link neural dynamics with phenomenology and potential adaptive outcomes.

The study used an open-label, within-subject design with two imaging sessions per participant: a baseline (no-psilocybin) session and a session after a standardised 19 mg oral dose of psilocybin. Each session included both multi‑echo, multi‑band BOLD fMRI and 64-channel wet EEG recordings across four repeated conditions: eyes-closed resting state, guided meditation (eyes closed), music listening (eyes closed), and an eyes-open naturalistic movie (moving clouds, no audio). Scans durations were reported for each condition and the fMRI and EEG acquisitions were organised according to BIDS. Participants were healthy, psychedelic‑naïve adults recruited with screening to exclude psychiatric, neurological, substance‑use and MRI‑contraindicated conditions; the initial recruitment was 65 adults aged 18–55. After exclusions and incomplete sessions, volumetric fMRI data were available for 64 participants at baseline and 61 after psilocybin; preprocessed EEG data were available for 63 baseline and 58 psilocybin sessions. Half the cohort were randomly assigned to an 8‑week mindfulness-based cognitive therapy programme prior to dosing to assess preconditioning effects; engagement metrics were recorded. Neuroimaging preprocessing combined fMRIprep for anatomical and functional preprocessing with multi‑echo ICA denoising (tedana) and a single regression cleaning step to remove white matter, CSF, motion and non‑BOLD components, then projection to the fsLR32k cortical surface. Quality control used MRIQC metrics and principled exclusion of scans with excessive framewise displacement. Functional analyses included vertex-wise Global Functional Connectivity (GFC) computed as mean Fisher‑z correlations across vertices within each hemisphere, standard deviation (SD) maps of BOLD time series, parcel-wise FC using a 332‑parcel scheme (Schaefer cortical parcellation plus a 32‑parcel subcortical atlas), and network modularity computed with the Brain Connectivity Toolbox. The authors explicitly advised against performing global signal regression (GSR) or z‑scoring when computing GFC, providing a mathematical rationale and showing these transforms can alter interpretation. Directed (effective) connectivity was estimated with spectral Dynamic Causal Modelling (DCM) focused on six regions within the DMN and anterior hippocampus (bilateral aHip, bilateral inferior parietal cortex, mPFC, PCC), with Parametric Empirical Bayes used for group‑level inference. Two machine‑learning embedding approaches characterised low‑dimensional neural dynamics: CEBRA‑Time (contrastive embeddings tailored to temporal analyses) produced subject‑specific three‑dimensional neural trajectories across concatenated conditions, while a Temporal Attention‑enhanced Variational Graph Recurrent Neural Network (TAVRNN) modelled evolving FC matrices across 332 parcels to produce two‑dimensional ROI embeddings capturing temporal evolution. EEG preprocessing used automated RELAX with multistep artifact reduction and re-referencing; spectral power (theta, alpha, beta, gamma) and signal diversity (Lempel‑Ziv complexity) were computed per condition. Behavioural measures included the 11‑Dimensional Altered States of Consciousness (11D‑ASC) scale, MEQ30, AES‑M for music aesthetics, a novel mindset questionnaire the day after dosing, and follow‑up scales (Nature Relatedness NR‑6, LAP‑R) at one month.

Global functional connectivity and BOLD variability. Under psilocybin, eyes‑closed conditions showed a marked reorganisation in GFC: associative cortex exhibited increased GFC (percentage changes up to +72%, Cohen's d ≈ 0.53) while sensory regions, particularly occipital cortex, showed decreased GFC (percentage decreases up to 39%, Cohen's d = 0.55). These effects formed significant spatial clusters identified with TFCE. GFC during eyes‑open movie watching increased in both sensory and associative areas; however, applying GSR or z‑scoring altered the movie results, underscoring preprocessing sensitivity. Standard deviation (SD) maps revealed a spatially dependent redistribution of BOLD variability: SD increased in orbitofrontal, occipitotemporal and inferior temporal regions and right somatosensory cortex during eyes‑open states, while SD decreased in early visual areas during eyes‑closed conditions. The spatial pattern of SD changes broadly mirrored GFC changes, and group‑level effects were robust though individual variability in GFC responses was substantial. State separation, modularity and network‑level FC. Histograms of GFC showed reduced separation between eyes‑open and eyes‑closed distributions under psilocybin, a convergence that was statistically significant across multiple resting‑state networks and particularly pronounced in visual networks. Functional modularity decreased under psilocybin, indicating reduced segregation; within‑network connectivity decreased more than between‑network connectivity, consistent with reorganisation of canonical network architecture. Machine‑learning embeddings and subjective experience. CEBRA‑Time embeddings produced low‑dimensional neural trajectories whose condition‑specific clustering tightened with stronger subjective effects. Participants with higher MEQ30 and 11D‑ASC scores exhibited embeddings that were more separable by condition, and classification accuracy of condition labels from embeddings correlated positively with subscales indexed as positively felt associative effects (self‑ and boundary‑dissolving dimensions) while correlations with sensory subscales were weaker and negative/dysphoric subscales showed minimal association. Participants who reported late‑onset effects had embeddings resembling baseline scans, linking acute subjective timing to neural reorganisation within the imaging window. TAVRNN produced complementary findings: under psilocybin, ROIs showed tighter within‑network clustering alongside increased global cohesion across networks; both local and global patterns scaled with subjective intensity. Subjective and longitudinal psychological outcomes. Behavioural data showed robust subjective effects from the standardised 19 mg dose: roughly half the participants retrospectively ranked the session among their top five most meaningful experiences, and many rated high intensity. MEQ30 and 11D‑ASC distributions showed substantial group‑level responses with wide individual variability. One‑month follow‑up revealed group‑level increases in death acceptance (LAP‑R; p = 0.0006, d = 0.49) and personal meaning (LAP‑R; p = 0.0004, d = 0.51). Nature relatedness (NR‑6) also increased (t(55) = -3.37, p = 0.0014, d = 0.26). Correlations between day‑after mindset change scores and subjective subscales indicated insightfulness had the strongest association (r = 0.65, p ≈ 10^-7), with mystical/positive/blissful subdimensions showing r = 0.4–0.6 (p < 0.00003); sensory effects correlated more weakly (r = 0.18–0.4, p < 0.05) and negative experiences had minimal, non‑significant associations (r < 0.1). Directed connectivity. Spectral DCM of an anterior hippocampus–DMN circuit revealed context‑dependent modulation of effective connectivity between baseline and psilocybin sessions. Specific patterns included consistent inhibition from left inferior parietal cortex to right anterior hippocampus across tasks (but not at rest), PCC→aHip R excitation and mPFC→aHip R inhibition during rest, bilateral IPC inhibition of hippocampi during meditation, asymmetric hippocampal inhibition during music, and the strongest changes during eyes‑open movie stimuli with predominating cortical inhibition onto hippocampi and intra‑cortical excitation. These directed changes were interpreted as context‑sensitive reorganisation of cortico‑subcortical interactions. EEG findings and convergence across modalities. EEG corroborated fMRI results: under eyes‑closed psilocybin, theta/alpha/beta power decreased while gamma power increased, with movie viewing attenuating many of these shifts except for gamma increases in early visual areas. The alpha power difference between eyes‑open and eyes‑closed was reduced by 48% under psilocybin (robust Cohen's d = 0.79, Mann‑Whitney U p < 10^-19), consistent with a unification of internally and externally directed processing. Lempel‑Ziv complexity increased, particularly in eyes‑closed conditions, indicating higher signal diversity. Music was rated as more meaningful under psilocybin (15–25% increase; Cohen's d > 0.67; Mann‑Whitney p < 0.001). Interventions and adverse events. The pre‑dosing mindfulness training (8 weeks) produced no statistically significant differences in acute subjective effects, next‑day mindset scores, or connectivity metrics. Adverse events were infrequent: transient headaches (n = 3) and three participants required brief follow‑up psychological support; a small number of participants did not complete imaging due to adverse responses or incidental findings, which determined the final sample counts reported above.

The authors interpret their findings as evidence that psilocybin reorganises large‑scale brain dynamics in a context‑sensitive manner, shifting eyes‑closed activity toward patterns that engage associative networks and thereby aligning neural dynamics with environmental and psychological context. They introduce the construct of 'embeddedness' to describe a brain state in which internal (associative) and external (sensory) processing become more coherently integrated; embeddedness is linked to positively felt associative subjective effects such as unity and bliss and to short‑term adaptive changes in mindset and meaning. Machine‑learning embeddings (CEBRA and TAVRNN) are presented as tools that reveal hidden coherence in low‑dimensional neural trajectories and that covary with the quality and timing of subjective experience, suggesting potential utility for predicting or monitoring state‑dependent psychological outcomes. Relative to previous work, the investigators highlight that their large, multimodal dataset clarifies prior inconsistencies around whether sensory or associative connectivity increases under psychedelics and demonstrates that preprocessing choices such as GSR and z‑scoring can materially affect interpretations. They also note concordance across fMRI and high‑density EEG, strengthening the case that observed effects are not solely vascular. Context manipulations—eyes‑open visual stimulation, music and meditation—produced distinct patterns of directed connectivity in the anterior hippocampus–DMN circuit, suggesting that curated sensory and cognitive environments can shape acute circuit dynamics and potentially guide behavioural outcomes. The authors acknowledge several sources of uncertainty. Individual responses varied substantially despite group‑level effects, and some analyses (for example, movie results) were sensitive to preprocessing transforms; they therefore caution against indiscriminate use of GSR and z‑scoring in GFC analyses. They also note that while embeddings correlated with adaptive short‑term changes, further work is required to test generalisability across clinical populations and more diverse samples. Finally, although the standardised 19 mg dose produced robust subjective and neural effects in this healthy cohort, the open‑label design and single fixed dose limit causal inference about dose‑dependent effects and therapeutic mechanisms. In terms of implications, the authors propose that recognising the dominant role of associative processes under psychedelics reframes how context is used in research and clinical settings: structured environments and targeted stimuli may be leveraged to shape neural reorganisation and psychological outcomes. Machine‑learning embeddings are advanced as promising biomarkers for state‑dependent neural organisation that might inform precision psychiatry and consciousness research, but the authors stress the need for replication, translational work in clinical samples, and careful methodological choices when computing connectivity metrics.