This double-blind, placebo-controlled, within-subject study (n=15) looked specifically at the claustrum and found many changes in the connectiveness to other parts of the brain.

Abstract

“Psychedelic drugs, including the serotonin 2a (5-HT_2A) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT_2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 min after blinded oral administration of placebo and 10 mg/70 kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT_2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.”

Authors: Frederick S. Barrett, Samuel R. Krimmel, Roland R. Griffiths, David A. Seminowicz & Brian N. Mathur

Summary

Psychedelic drugs, including psilocybin, induce widespread dysregulation of cortical activity, but the circuit-level mechanisms underlying this effect are unclear. This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT2A receptor signaling in claustrum functioning.

Introduction

Psilocybin, a classic psychedelic drug, acutely alters sensory perception and executive function and may have long-term therapeutic value in treating a variety of neuropsychiatric disorders. However, the exact mechanisms through which these effects occur are unclear.

Psilocybin acts as a partial agonist of the serotonin 2a (5-HT2A) receptor, which modulates glutamatergic signaling across a range of cortical and subcortical afferents. The claustrum is a subcortical telencephalic nucleus that is significantly functionally connected both with task-positive control networks and the default mode network.

Using functional magnetic resonance imaging, we show that psilocybin alters claustrum activity and functional brain connectivity, and that these effects are associated with subjective effects of psilocybin.

20 healthy volunteers participated in a blinded, placebo-controlled study of the effects of psilocybin on meditation. They provided written informed consent, were medically and psychologically healthy, and had completed two to three 90-min fMRI scanning sessions in a previous study.

All participants were Caucasian and non-Hispanic, had completed a baccalaureate, masters, or doctoral or professional degree, and were confirmed negative for pregnancy and recent illicit drug use before enrollment and on the morning of drug administration and scanning procedures.

2.2. Procedures

In this study, participants received psychological support before, during and after psilocybin administration and scanning procedures. This support included preparation, close supportive care during sessions, and de-briefing.

Participants completed two scanning procedures, one after placebo administration and the other after administration of 10 mg/70 kg psilocybin. The timing of the scanning procedures coincided with peak subjective effects of this dose of psilocybin.

This study was conducted as part of a clinical trial at Johns Hopkins Medicine. No serious adverse events were encountered.

2.3. Subjective effects ratings

After each resting-state scan, participants rated a series of subjective effects on a verbal 11 point scale from 0 (none; not at all) to 10 (extreme; strongest imaginable). They also rated two dimensions of more general emotional experience: positive emotional valence and negative emotional valence.

2.4. MRI acquisition

Data were collected using 3T Philips Achieva MRI scanners at the Kennedy Krieger Institute in Baltimore, MD, using echo planar imaging and MPRAGE. One high-resolution T1-weighted anatomical scan was also collected for each participant.

2.5. Preprocessing

Preprocessing steps consisted of slice timing correction, realignment, coregistration, segmentation, and normalization of the structural and realigned functional images to a standard MNI template. Resting-state data were further preprocessed by simultaneous regression, which included nuisance variables, detrending, despiking, and band pass filtering using the CONN toolbox. Global signal was not removed, as doing so can introduce structured statistical artifacts into resting-state functional connectivity data.

We preprocessed whole-brain BOLD data and extracted 264 ROI time courses using a sphere with 10 mm diameter around each ROI coordinate.

We used our previously reported method of small region confound correction (SRCC) to isolate ROI time courses for the left and right claustrum from the surrounding insula and putamen, and then used these corrected timeseries as the claustrum seeds in all subsequent analyses.

2.6. Analysis

We calculated the amplitude of low-frequency fluctuations and the variance of each claustrum ROI timecourse, and then compared the results between placebo and psilocybin conditions using a paired Student’s T-test. We then fitted a general linear model.

Psilocybin had an effect on connectivity in each network, assessed separately for each network defined in the Power atlas.

z ¼ 1 þ βpsilocybin þð1jsubjectÞþð1jROI Þ

We measured the association of claustrum connectivity with measures of network modularity and network integrity during psilocybin use. Increases in participation coefficient across nodes of a network represent increased network modularity, whereas decreases in participation coefficient across nodes represent decreased network modularity.

DV ¼ 1 þ βclaustrum connectivity þð1jsubjectÞþð1jROI Þ

Separate models were fit with DV, network integrity, network modularity, and ßclaustrum_connectivity as parameters. Mixed-effects models were fitted in MATLAB, and likelihood ratio tests demonstrated that models including both subject and ROI as random effects produced better fits.

We used paired T-tests to analyze psilocybin effects on claustrum activity and connectivity. We also used mixed effects ANOVAs and planned comparisons to compare claustrum connectivity to insula and putamen connectivity.

We used general linear models to estimate the associations between psilocybin subjective effect outcome measures and blood-oxygenation level-dependent signal and amplitude of low-frequency fluctuations in BOLD signal in the left and right claustrum.

3.2. Integrity of blinding procedures

More than half of the participants rated their subjective drug effects as greater than 0 for the placebo scan. However, the average rating of strength was significantly greater during psilocybin than placebo.

3.3. Psilocybin decreases the amplitude of low frequency fluctuations and variance in Bilateral claustrum

Psilocybin reduced variance in BOLD signal and amplitude of low-frequency fluctuations in the left claustrum, right claustrum, and left putamen compared to placebo. It did not affect the left insula, right insula, or right putamen.

3.4. Psilocybin alters claustrum connectivity with brain networks that support perception and cognition

A main effect of network predicting connectivity between the claustrum and cortical ROIs was observed for both left claustrum and right claustrum models.

Psilocybin administration decreased connectivity of the left claustrum with the fronto-parietal task control network, increased connectivity of the right claustrum with the auditory network, and increased connectivity of the right claustrum with the default mode network.

3.6. Associations between subjective and neural effects

The relationship between subjective effects and changes in the activity of the claustrum compared to flanking regions was specific, with a negative relationship between ratings of the overall strength of drug effects and both ALFF and variance of the right claustrum.

Discussion

A method was developed to assess claustrum activity and connectivity, and psilocybin reduced both left and right claustrum activity and connectivity with brain networks that support sensory and cognitive processes.

4.1. Psilocybin decreased claustrum connectivity with the auditory cortex

A high psychedelic dose results in a marked alteration of sensory experience, including a sense of being in a dream-like or imaginal state. The claustrum may contribute to psilocybin-induced disruptions in sensory experience.

4.2. Psilocybin alters claustrum connectivity with networks that support cognition

Subjective effects of psychedelic drugs include shifts in attention and executive function, which may reflect difficulties with attention. These effects may manifest in difficulties putting the experience into words, as well as in dissociation, depersonalization, confusion, and paranoid delusions.

Psilocybin decreases connectivity of the right claustrum with the default mode network (DMN) and auditory networks, and increases connectivity with the frontal prefrontal cortex (FPTC). This may explain why psilocybin causes subjectively sensed alterations in executive function.

4.3. Psilocybin alters default mode network integrity and fronto-partial task control network modularity by reducing claustrum functional connectivity with these networks

Psilocybin acutely reduces connectivity of the default mode network (DMN) and increases connectivity of task-positive networks, and this connectivity disruption correlates with ratings of subjective effects and peak (mystical, or ego-dissolutive) experiences.

4.4. Association with subjective effects

We assessed subjective effects measures after each resting-state scan, and found modest associations between right and left corrected claustrum variance and amplitude and subjective measures of mystical experience, ineffability, and overall strength of drug effect.

4.5. Limitations

The present findings have a number of limitations, including that the order of drug administration was fixed across participants, that expectancy due to drug condition order effects was not a major confound, and that diurnal variations in stress hormones may have contributed to these findings. This study used a single dose of psilocybin and involved a high-selected sample of individuals who had previously been administered a high dose of psilocybin in an experimental setting.

The dose of psilocybin administered in the current study was moderate (10 mg/70 kg), and was lower than the doses evaluated for clinical efficacy in the context of mood disorders and substance use disorders.

4.6. Future directions

We observed clear effects of an interaction between drug condition and network on claustrum connectivity, but also observed a large distribution of claustrum connectivity values. Future studies should explore the effects of psychedelic drugs on claustrum connectivity in individuals with and without previous exposure to psychedelics.

Conclusion

The widespread connectivity of the claustrum suggests that this structure may be implicated in neuropsychiatric disorders, including mood and substance use disorders. Psilocybin may also have an effect on claustrum activity and connectivity.

Acknowledgements

The authors gratefully acknowledge Terri Brawner, Ivana Kusevic, Kathleen Kahl, Mary Cosimano, Taylor Marcus, Annie Umbricht, M.D., Darrick May, M.D., Theresa Carbonaro, Ph.D., Laura Doyle, and Kishore Bharadwaj.