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Neuroimaging & Brain MeasuresHealthy VolunteersPsilocybin

Broadband Cortical Desynchronization Underlies the Human Psychedelic State

Using MEG in healthy volunteers after intravenous psilocybin, the study shows broadband reductions in spontaneous cortical oscillatory power—especially in posterior association cortices and default‑mode network regions—while visually and motor‑induced gamma oscillations were preserved. Dynamic causal modelling indicates this desynchronisation is likely driven by 5‑HT2A‑mediated excitation of deep‑layer pyramidal neurons (notably in posterior cingulate cortex), linking cortical desynchronisation to the psychedelic state.

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Authors

Suresh Muthukumaraswamy
Robin Carhart-Harris
David Nutt

Published

September 18, 2013

Journal of Neuroscience

individual Study

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Abstract

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin—prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2Areceptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2Areceptor-mediated excitation of deep pyramidal cells.

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Research Summary of 'Broadband Cortical Desynchronization Underlies the Human Psychedelic State'

Introduction

Psychedelic drugs produce profound alterations of consciousness and have shown promise in a range of clinical and experimental settings, but the neural mechanisms that underlie these effects remain poorly understood. Previous human EEG studies and animal local field potential recordings have reported reduced cortical synchrony or high-frequency activity after psychedelic administration, and recent fMRI work has shown decreased blood flow in association cortices and subcortical structures after psilocybin. However, fMRI provides an indirect, slow measure of neural activity and EEG has limited spatial resolution and sensitivity to high-frequency components, leaving a gap in knowledge about broadband (1–100 Hz) electrophysiological changes during the acute psychedelic state. To address this gap, Muthukumaraswamy and colleagues used magnetoencephalography (MEG) to record spontaneous and stimulus-induced oscillatory activity in healthy volunteers during placebo and psilocybin infusion. The aims were to characterise broadband changes in oscillatory power and network-level activity, test whether low-level induced gamma responses were preserved, and use dynamic causal modelling (DCM) of source-level spectra to infer which cortical cell populations might mediate drug-induced desynchronization via 5-HT2A receptor mechanisms.

References (13)

Papers cited by this study that are also in Blossom

The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability

Carhart-Harris, R. L., Williams, T. M., Sessa, B. et al. · Journal of Psychopharmacology (2010)

Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

Carhart-Harris, R. L., Erritzoe, D., Williams, T. et al. · PNAS (2012)

Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis

Carhart-Harris, R. L., Leech, R., Erritzoe, D. et al. · Schizophrenia Bulletin (2012)

241 cited

Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance

Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)

Methods

Design and participants: The study used a within-subject, single-blind, fixed-order design in which 15 healthy male volunteers with prior psychedelic experience underwent two MEG sessions: placebo (saline) first and psilocybin (2 mg in 10 ml saline) second. Exclusion criteria included age under 21, personal or family history of psychiatric disorder, substance dependence, cardiovascular disease, pregnancy, phobia relevant to scanning, and recent hallucinogen use (<6 weeks). One participant was excluded from MEG analyses because of excessive artefacts. Drug administration and behavioural measures: In each session participants completed a resting-state recording consisting of 5 min preinfusion baseline, a 60 s infusion, and 5 min postinfusion resting data. Approximately 6 min after infusion they performed a 10 min visuomotor task designed to elicit stimulus-induced gamma-band oscillations in visual and motor cortices. Subjective effects were rated in the scanner using a visual-analog "high" scale and, after scanning, a 23-item questionnaire probing characteristic psychedelic phenomena. MEG acquisition and preprocessing: Whole-head MEG data were acquired with a 275-channel CTF system sampled at 600 Hz, with additional reference channels and concurrent recordings of ECG, EOG, EMG and finger displacement. Anatomical MRI scans were acquired for source localisation and coregistration. Resting data were high-pass filtered at 1 Hz, segmented into 2 s epochs, and infusion-period data were discarded. After artefact rejection there were 150 epochs pre- and postinfusion for analysis (one participant removed entirely for artefacts). Source localisation and spectral analysis: Beamformer source reconstruction was performed using synthetic aperture magnetometry (SAM) at 4 mm resolution for six frequency bands: delta (1–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz), low gamma (30–50 Hz) and high gamma (50–100 Hz). Group-level paired interaction tests (post versus pre for psilocybin relative to placebo) were conducted after spatial normalisation to MNI space, with nonparametric permutation testing (5,000 permutations) and multiple-comparison correction; a cluster-based approach was used for the 50–100 Hz band. Resting-state network analysis: Beamformer time courses were computed on an 8 mm grid, envelopes obtained via the Hilbert transform, downsampled to 1 Hz and concatenated across subjects. Temporal independent component analysis (ICA) was applied per frequency band after dimensionality reduction to 20 principal components, producing 15 components per band. Components were classified and 11 network components of interest were analysed for condition effects using repeated-measures ANOVAs with permutation testing. Dynamic causal modelling: To infer synaptic mechanisms, the investigators applied DCM for steady-state responses to source-reconstructed spectra from the posterior cingulate cortex (PCC)/precuneus. The canonical microcircuit neural-mass model comprised spiny stellate cells, inhibitory interneurons, superficial pyramidal and deep pyramidal populations. Drug effects were modelled as changes in the gain of each population (four β parameters mapping to stellate, superficial pyramidal, inhibitory interneuron and deep pyramidal gain). Models were inverted using variational Bayesian (variational Laplace) estimation and paired t tests compared β parameter changes between placebo and psilocybin, with Bonferroni correction for multiple comparisons. Visuomotor induced responses: For visual and motor tasks, epochs were defined around stimulus onset and EMG markers; SAM localisation in gamma ranges identified peak voxels and virtual sensors. Time–frequency analyses were produced by narrow-band filtering in 0.5 Hz steps and Hilbert envelopes; both baseline-corrected and unbaselined maps were examined. Statistical comparisons used permutation-based paired t tests with cluster correction.

Results

Subjective effects and behaviour: Participants reported robust subjective effects after psilocybin. Mean self-rated intensity was 78.2% (SE 5.5%) at 5 min postinfusion and 65.4% (SE 4.7%) at 15 min; placebo produced negligible ratings (~0.7%). On the visuomotor task, reaction times were marginally slower after psilocybin (295 ms, SE 15) than placebo (260 ms, SE 22; t = 2.56, p = 0.023). Spontaneous oscillatory activity and source localisation: Beamformer contrasts of post- versus preinfusion (psilocybin relative to placebo) revealed widespread decreases in oscillatory power across a broad frequency range, localised predominantly to association cortices and areas of the default-mode network (DMN) such as the posterior cingulate cortex (PCC) and precuneus. In posterior association regions decreases spanned delta through low gamma (1–50 Hz), while bilateral prefrontal cortices showed decreases from alpha up to high gamma (8–100 Hz). No regions showed increases in oscillatory power. Head-position comparisons indicated no significant differential movement between drug and placebo sessions. Resting-state networks: Temporal ICA recovered 11 functional networks; seven of these showed significant post-psilocybin decreases in oscillatory power in their respective frequency bands (p < 0.01, uncorrected). Four additional networks exhibited consistent decreases that did not reach the study's significance threshold. Dynamic causal modelling: DCM applied to PCC spectral data focused on four gain parameters (β1–β4) corresponding to the four neural subpopulations. Paired tests with Bonferroni correction (p = 0.0125) identified a psilocybin-dependent increase in the excitability (gain) of deep-layer pyramidal cells (β4: t = 3.23, p = 0.0065). The other β parameters did not survive correction (β1 t = −1.86, p = 0.085; β2 t = −2.31, p = 0.03; β3 t = −1.11, p = 0.028). Visually and motor-induced oscillations: Analyses of task-evoked responses showed the expected transient gamma bursts and beta dynamics for motor responses and gamma plus alpha desynchronization for visual stimulation. No significant differences between psilocybin and placebo were observed in induced motor gamma (60–90 Hz) or beta (15–30 Hz), nor in visual gamma (35–80 Hz). Baseline visual-cortex alpha power was reduced after psilocybin (t = 4.02, p = 0.0015), consistent with resting-state findings; baseline gamma did not differ. These results indicate that some low-level, stimulus-induced oscillatory responses were relatively preserved despite broad spontaneous desynchronization. Psychometric correlations: Exploratory correlations restricted to PCC alpha-power decreases revealed significant associations (Bonferroni-adjusted p = 0.0022): reductions in PCC alpha correlated with ratings of "ego disintegration" (R^2 = 0.66, p = 0.00016) and with the experience having a "supernatural quality" (R^2 = 0.53, p = 0.00018). Deep-layer pyramidal excitation (β4) correlated with the magnitude of PCC alpha decreases (R^2 = 0.42, p = 0.0056) and with ego-disintegration ratings (R^2 = 0.42, p = 0.005). The authors note these correlations are exploratory and require replication.

Discussion

Muthukumaraswamy and colleagues interpret their findings as evidence that acute psilocybin produces a broadband desynchronization of cortical oscillatory rhythms, particularly in association cortices and regions of the default-mode network. They argue this represents a general collapse or disorganisation of the normal rhythmic structure of cortical activity rather than selective band-limited effects. The spatial pattern of desynchronization overlapped with regions previously identified by fMRI and with the known cortical distribution of 5-HT2A receptors, notably high binding in the PCC. By applying DCM to PCC spectra, the investigators present a mechanistic account in which increased excitability of deep-layer (layer 5) pyramidal neurons best explains the observed spectral changes; this is consistent with animal data showing 5-HT2A-mediated increases in excitatory postsynaptic potentials in layer 5 pyramidal cells. The authors link marked decreases in alpha power—especially in the PCC—to interference with intrinsic alpha rhythms of deep pyramidal neurons, noting that layer 5 cells are implicated in top-down signalling and that alpha rhythms relate to perceptual processing of space and time. Despite pronounced spontaneous desynchronization, low-level stimulus-induced gamma responses in visual and motor cortices were largely preserved, suggesting some basic evoked oscillatory mechanisms remain intact during the psychedelic state. The authors relate their results to prior observations of decreased BOLD and hemodynamic measures under psilocybin and discuss the possibility that 5-HT2A receptor activation induces a decoupling between hemodynamics and oscillatory activity. Limitations acknowledged by the study team include the use of psychedelic-experienced participants, which limits generalisability to naive individuals; the fixed-order, single-blind design (placebo always administered first), which was chosen to avoid contaminating the placebo condition but could allow subtle order effects; and the necessary removal of artefact-contaminated MEG segments, which might have excluded phenomena correlated with certain aspects of the psychedelic state. The authors also caution about the spatial precision of MEG relative to fMRI and PET. Finally, the investigators suggest a speculative link to predictive-coding frameworks: hyperexcitability of deep-layer pyramidal cells could bias top-down inference, allowing internally generated models to intrude on perception and thereby account for subjective phenomena such as ego dissolution. They also note potential clinical relevance, proposing that disruption of frontoparietal connectivity via 5-HT2A stimulation could underlie therapeutic actions of psychedelics in disorders characterised by pathological network activity, while emphasising that such implications require further research.

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CONCLUSION

The present study examined the neural effects of a classic psychedelic drug using MEG. We observed a broadband desynchronization of cortical oscillatory rhythms after psilocybin infusion ). Four parameters (␤ 1, 2, 3, 4 ) encoding gain were allowed to vary between presessions and postsessions. These four parameters allow the gain of the four cell types to differ between Pre and Post. Data fitted were the source-modeled spectral response of the PCC. c, The parameter estimates for the four cell types for both psilocybin and placebo. The only parameter that was significantly altered (placebo versus psilocybin) was the ␤ 4 parameter (t ϭ 3.23, p ϭ 0.0065), using a paired t test over subjects. Note: the Bonferonni-adjusted significance level of p ϭ 0.0125 (0.05/4) for these tests. The direction of effect indicated that the obtained spectral responses were best modeled by increased excitability of the deep pyramidal cell population. All individual data and model fits can be found in Figure. The results for all ␤ parameters were as follows: ␤ 1 (t ϭ Ϫ1.86, p ϭ 0.085); ␤ 2 (t ϭ Ϫ2.31, p ϭ 0.03); ␤ 3 (t ϭ Ϫ1.11, p ϭ 0.028); and ␤ 4 (t ϭ Ϫ3.23, p ϭ 0.0065). Hence, only ␤ 4 survived multiple-comparison correction. and decreased brain network integrity. The results are consistent with those of previous EEGand fMRI studiesin humans and electrophysiological recordings in animals, and they significantly extend our understanding of the mechanisms by which psychedelics alter oscillatory brain activity. By exploring the neuronal source of the decreases in oscillatory power with dynamic causal modeling, we present a model of the mechanism of action of psychedelics in the PCC. This begins at the cellular level with excitation of layer 5 pyramidal neurons, and extends to the macroscopic level with cortical desynchronization and decreased brain network integrity. We postulate that this excitation occurs via stimulation of 5-HT 2A receptors, which are densely expressed there. Previous pharmacological EEG and MEG studies have found increases and decreases in oscillatory power in different frequency bands post-drug infusion. That the decreases here occurred in all of the frequency bands implies a general collapse of the normal rhythmic structure of cortical activity. This supports the claim that psychedelics decrease, or, more accurately, disorganize, spontaneous brain activity. Moreover, the selective localization of the decreases to association cortices is consistent with previous fMRI workand suggests that the reduced blood flow reported therein may relate to desynchronized neural activity. Indeed, the MEG source localization results we find here are highly consistent with previous fMRI results using the same pharmacological intervention. Some of the key areas of overlap include the PCC, precuneus, superior and middle frontal gyri, anterior cingulate gyri, and supramarginal and precentral gyri. These mostly represent hub areas of association cortex rather than primary sensory cortex. The PCC showed especially marked effects in both studies, and these correlated with the drug's subjective effects (e.g., note the highly significant correlation between PCC alpha decreases and ratings of ego disturbance observed here). It is significant also that the spatial location of the effects observed with fMRI and MEG are consistent with the known distribution of 5-HT 2A receptors. Explicitly, in a PET study of 5-HT 2A receptor binding using 18 F-altanserin in 136 participants, association cortices had the highest binding potentials, and the PCC was highest of all. The posterior association cortices showed desynchonization in a lower frequency range (1-50 Hz), whereas frontal association cortices showed higher frequency changes (8 -100 Hz). These frequency differences may reflect the different resting rhythms that these areas spontaneously generate. It is important not to overinterpret the specificity of MEG source localization data, as these data have inferior spatial resolution compared with both fMRI and PET. We did note, in some single-participant data, strong highfrequency desynchronizations in posterior association areas. However, these were quite inconsistent across both individuals and cortical locations, and did not survive at the group-level analysis. Further investigations will be needed to explain these individual differences in observed neural responses to psychedelic drugs. A number of previous studies have investigated the relationship between blood flow metrics and oscillatory activity. These have generally found an inverse relationship between BOLD activity and alpha/beta rhythms, while a positive relationship is found between gamma-band activity and BOLD activity. With psilocybin, however, we observe a decrease in BOLD activity and a general decrease in oscillatory activity during resting-state conditions. The hypercapnic challenge delivered bysuggests that the BOLD decreases seen in that study were not a confound of psilocybin working directly on the cerebral vasculature. Consistent with our human data, administration of the relatively selective 5-HT 2A receptor agonist DOI in rats resulted in dose-dependent decreases in broadband (including high-frequencies) oscillatory power and multiunit activity in the orbitofrontal and anterior cingulate cortices. This suggests a generalized reduction in neural activity (at least in terms of oscillations and hemodynamics) with 5-HT 2A receptor activation and a decoupling of the usual relationship between BOLD and neural oscillations. In the present study, some of the largest decreases in oscillatory power were found in areas of the DMN (Fig.) consistent with recent fMRI studies revealing decreased blood flow in these regions after psilocybin infusion. The DMN consumes more energy, receives more perfusion, and is more widely connectedthan other cortical regions. It undergoes significant ontogenetic developmentand underwent significant evolutionary expansion, and its connectivity has been found to relate to personality. Several recent intracranial studieshave demonstrated that broadband, high-frequency, task-related suppression of DMN areas correlates with improved task performance. In these studies, during task performance, activity in task-positive networks emerges, whereas in the psychedelic state studied here a pharmacologically For each, the grand-averaged peak source location for each was located in pericalcarine cortex. b, Grand-averaged time-frequency spectrograms showing source-level oscillatory amplitude changes following visual stimulation with a grating patch (stimulus onset at time ϭ 0) following administration of either placebo or psilocybin. Spectrograms are displayed as the percentage change from the prestimulus baseline and were computed for frequencies up to 150 Hz, but are truncated here to 100 Hz for visualization purposes. c, Envelopes of oscillatory amplitude for the gamma (35-80 Hz) and alpha (8 -13 Hz) bands, respectively. Although there was a tendency for slightly reduced alpha desynchronization with psilocybin, this was not statistically significant. driven suppression of all observed networks was seen, suggesting a general disorganization of network-level brain activity during resting conditions. Psilocin is a mixed serotonin receptor agonist. However, the potency of psychedelics correlates positively with their affinity for the 5-HT 2A receptor, and pretreatment with the 5-HT 2A receptor antagonist ketanserin blocks the hallucinogenic effects of psilocybin in humans. 5-HT 2A receptors are densely expressed in cortical regions, particularly in cortical layer 5. The present modeling results, indicating increased excitation of deeplayer pyramidal cells, are entirely consistent with previous research. Stimulation of the 5-HT 2A receptor has been shown to enhance spontaneous EPSPs/EPSCs in neocortical layer 5 pyramidal cells by reducing outward potassium currentsand to cause increased glutamatergic recurrent activity in layer 5 of the cortex. It is noteworthy that, while the decreases in spectral power seen here were broad, decreases in the alpha frequency were especially marked-particularly in the PCC where 5-HT 2A receptors are densely expressed. Layer 5 pyramidal cells fire with an intrinsic alpha rhythmand spontaneous alpha oscillations are closely linked to perceptual processing, including processing of space and time. Thus, the marked decreases in alpha power observed here with psilocybin were likely due to interference with the intrinsic alpha oscillations of deep-layer pyramidal neurons via stimulation of 5-HT 2A receptors, although we observed marked changes in spontaneous brain activity after psilocybin, but no effects on low-level induced gamma-band responses. There are some limitations to the present work. Participants all had previous experience with psychedelic drugs. This was to minimize the risk of adverse responses by excluding volunteers who had a history of reacting negatively to psychedelics. However, that we used experienced participants limits the generalizability of the present results to psychedelic-naive individuals. Also, we used a fixed-order scanning protocol to avoid contaminating the placebo condition with subacute drug effects. A balanced-order design with a prolonged period between scans may be an alternative experimental design, although it would be difficult to perform in practice. However, we suggest that any potential order effects would likely be subtle relative to the marked neuronal and subjective effects of psilocybin. Reinforcing this view, in our previous fMRI work with psilocybin, similar results were observed with balanced (BOLD) and fixed (ASL) order scanning. This was also a single-blind design. However, in experiments such as this, comparing the acute effects of potent psychoactive drugs with those of a (necessarily) inert placebo, participants quickly become "unblinded" to the experimental manipulation, thus diminishing the value of blinding. Finally, it was necessary to remove periods of MEG data that were contaminated by large-muscle artifacts/head movements in the preprocessing stage. If these artifacts were correlated with particular aspects of the psychedelic state, then this (necessary) preprocessing step precluded their detection. Previous theoretical accounts of positive psychotic symptoms suggest that delusional thinking represents a failure of neural mechanisms to accurately encode predictions and prediction error or "surprise". In one prediction-coding model of global brain function based on the free-energy principle, activity in deep-layer projection neurons en-codes top-down inferences about the world. Speculatively, if deep-layer pyramidal cells were to become hyperexcitable during the psychedelic state, information processing would be biased in the direction of inference-such that implicit models of the world become spontaneously manifest-intruding into consciousness without prior invitation from sensory data. This could explain many of the subjective effects of psychedelics. Finally, the therapeutic potential of psychedelics is currently attracting much interest. Frontoparietal connectivity has been found to correlate with rumination in depression, and deficient 5-HT 2A receptor stimulation have been found to be associated with trait neuroticismand pessimism. Here we found decreased frontoparietal connectivity after psilocybin infusion, consistent with previous fMRI findings. Thus, the ability of serotonergic psychedelics to disrupt pathological patterns of brain activity via stimulation of 5-HT 2A receptors may underlie their therapeutic potential in psychiatric settings, and breakdown of brain networks may be a fundamental feature of the psychedelic state.

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