Increased thalamic resting state connectivity as a core driver of LSD-induced hallucinations

This randomized, placebo-controlled, double-blind crossover study (n=20) administered LSD (100 μg) to investigate whether the resting-state connectivity of the thalamic brain network is a driver of hallucinations using fMRI. It found that the subjective ratings on ‘visionary restructuralization’ and ‘auditory alterations’ correlated significantly with elevated functional connectivity between the thalamus and other cortical brain regions.

Abstract

“Introduction: It has been proposed that the thalamocortical system is an important site of action of hallucinogenic drugs and an essential component of the neural correlates of consciousness. Hallucinogenic drugs such as LSD can be used to induce profoundly altered states of consciousness, and it is thus of interest to test the effects of these drugs on this system.

Method: 100 μg LSD was administrated orally to 20 healthy participants prior to fMRI assessment. Whole brain thalamic functional connectivity was measured using ROI‐to‐ROI and ROI‐to‐voxel approaches. Correlation analyses were used to explore relationships between thalamic connectivity to regions involved in auditory and visual hallucinations and subjective ratings on auditory and visual drug effects.

Results: LSD caused significant alterations in all dimensions of the 5D‐ASC scale and significantly increased thalamic functional connectivity to various cortical regions. Furthermore, LSD‐induced functional connectivity measures between the thalamus and the right fusiform gyrus and insula correlated significantly with subjective auditory and visual drug effects.

Conclusion: Hallucinogenic drug effects might be provoked by facilitations of cortical excitability via thalamocortical interactions. Our findings have implications for the understanding of the mechanism of action of hallucinogenic drugs and provide further insight into the role of the 5‐HT2A‐receptor in altered states of consciousness.”

Authors: Felix Müller, Claudia Lenz, Patrick Dolder, Undine Lang, Matthias E. Liechti, André Schmidt & Stefan Borgwardt

Summary

Introduction

Substances known as hallucinogenic drugs alter the human psyche in a profound way, including alterations in cognition, emotions and perception. The thalamus may be an important site of action for hallucinogenic drugs, as evidenced by increased thalamocortical resting-state functional connectivity.

The thalamocortical system has been closely associated with consciousness. It has been shown that the thalamus is the common site of action of at least eight different anaesthetics, and that thalamocortical connectivity is the only measure that is restored after recovery from unconsciousness.

Aims of the study

This study used resting-state fMRI to investigate the acute brain effects of LSD in healthy participants. It found that LSD increased thalamocortical connectivity, which was associated with subjective visual and auditory changes.

Material and methods

We used a double-blind, placebo-controlled, cross-over design and a washout period of at least 7 days between study sessions to examine the effects of LSD on the brain.

Image acquisition and preprocessing

Scanning was conducted on a three Tesla MRI system using a 20-channel phased array radio frequency head coil. A total of 300 volumes were acquired, including five dummy scan volumes to ensure signal stabilisation.

All images were slice time corrected, realigned, co-registered, normalised into a standard stereotactic space, smoothed with a 5 mm full width at half maximum Gaussian kernel, and noise corrected using ART.

Thalamic resting-state functional connectivity analysis

Three functional connectivity analyses were performed: ROI-to-ROI, ROI-to-voxel, and global correlation. Global correlation is a data-driven, whole brain measure for network centrality.

All analysis used structural ROIs defined according to the Harvard – Oxford atlas for cortical and subcortical structures and the automated anatomical labelling atlas for the cerebellum. Time courses were compared using bivariate correlations, and effects of the drug and the placebo condition were estimated using two-tailed one-sample t tests.

The 5-ASC major dimensions ‘visionary restructuralization’ and ‘auditory alterations’ were correlated with rFC measures between the bilateral thalamus and regions known to be involved in auditory and visual hallucinations respectively.

Functional connectivity analysis

LSD increased connectivity between the thalamus and 104 out of 130 investigated regions, and decreased connectivity between the left thalamus and vermis 10.

We used a ROI-to-voxel approach to analyze connectivity patterns in the occipital lobe and found that LSD increased connectivity relative to placebo.

Global correlation analysis showed increased network centrality in a cluster comprising the left and right thalamus, the left and right caudate, and the right putamen.

Relation of thalamocortical connectivity to drug plasma levels and subjective effect ratings

Plasma levels of LSD did not correlate with thalamocortical rFC measures, and the 5D-ASC item ‘I felt sleepy’ did not significantly correlate with any of the investigated rFC measures.

Discussion

In this study, healthy subjects were given LSD and shown to have globally increased thalamocortical resting-state functional connectivity compared with placebo. This connectivity was correlated with subjective drug effect ratings on visual and auditory hallucinations.

The notion that hallucinogens affect the thalamus has been under debate for years. Recent studies have reported diverging effects of psilocybin, mescaline and DMT on the thalamus, including decreased glucose metabolism and blood flow, unchanged or increased functional connectivity, and increased global functional connectivity.

Functional significance of increased thalamocortical connectivity

The thalamus is thought to be a complex system of connections between the cortex and thalamus, which generate oscillatory rhythms. The thalamocortical system is also reflected in rsfMRI, with a good agreement between the measured rsfMRI connectivity and the known anatomy. Thalamocortical interactions via cross-frequency coupling have been implicated in memory formation and memory retrieval.

Potential mechanisms of increased thalamocortical rFC under LSD exposure and relationship to subjective drug effects

The data suggest that the thalamocortical resting-state FC best corresponds to fluctuations in low frequencies, and that large-scale interactions via slow frequencies changes might facilitate local cortical excitability, possibly via CFC. This mechanism could explain correlations between thalamocortical connectivity and auditory and visual alterations observed in our study.

LSD affects thalamocortical connectivity by activating serotonin 5-HT2A-receptors, which are expressed in the reticular nucleus. The reticular nucleus is also involved in thalamic oscillations and manipulation of this system might alter synchronised thalamic activity. The thalamus is also part of the cortico-basal-ganglia-thalamo-cortical circuitry, which is involved in motor function, emotions and cognition. The striatum is the main input structure of the basal ganglia, which receives afferents from various cortical regions.

The thalamus and the thalamocortical system have been proposed as an important neural correlate of consciousness. This system is believed to integrate different sensations within one unified experience, which is one of the phenomenological core features of consciousness. According to the models referred to, consciousness experience is based on coherent oscillations in the thalamocortical system, and is fusion of sensory information with non-specific loops that allows for a single consciousness experience.

Our study has several limitations, such as the small sample size, unblinded treatment assignment, and the fact that the MRI environment might have influenced the subjective drug effects. However, the documentation of plasma LSD concentrations, the absence of significant differences in head movement between conditions, and the larger sample size are strengths.