Healthy VolunteersNeuroimaging & Brain MeasuresLSD

Effective connectivity changes in LSD-induced altered states of consciousness in humans

In a double-blind, placebo-controlled cross-over study using spectral dynamic causal modelling of resting-state fMRI, the authors show that LSD alters effective connectivity within cortico–striato–thalamo–cortical circuits by increasing thalamus→posterior cingulate connectivity via serotonin 2A (5‑HT2A) receptor activation and decreasing ventral striatum→thalamus connectivity independently of 5‑HT2A. These results support the thalamic filter model of psychedelic action and advance mechanistic understanding relevant to therapeutic development.

Authors

  • Franz Vollenweider
  • Katrin Preller
  • Philipp Stämpfli

Published

PNAS
individual Study

Abstract

Psychedelics exert unique effects on human consciousness. The thalamic filter model suggests that core effects of psychedelics may result from gating deficits, based on a disintegration of information processing within cortico–striato–thalamo-cortical (CSTC) feedback loops. To test this hypothesis, we characterized changes in directed (effective) connectivity between selected CTSC regions after acute administration of lysergic acid diethylamide (LSD), and after pretreatment with Ketanserin (a selective serotonin 2A receptor antagonist) plus LSD in a double-blind, randomized, placebo-controlled, cross-over study in 25 healthy participants. We used spectral dynamic causal modeling (DCM) for resting-state fMRI data. Fully connected DCM models were specified for each treatment condition to investigate the connectivity between the following areas: thalamus, ventral striatum, posterior cingulate cortex, and temporal cortex. Our results confirm major predictions proposed in the CSTC model and provide evidence that LSD alters effective connectivity within CSTC pathways that have been implicated in the gating of sensory and sensorimotor information to the cortex. In particular, LSD increased effective connectivity from the thalamus to the posterior cingulate cortex in a way that depended on serotonin 2A receptor activation, and decreased effective connectivity from the ventral striatum to the thalamus independently of serotonin 2A receptor activation. Together, these results advance our mechanistic understanding of the action of psychedelics in health and disease. This is important for the development of new pharmacological therapeutics and also increases our understanding of the mechanisms underlying the potential clinical efficacy of psychedelics.

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Research Summary of 'Effective connectivity changes in LSD-induced altered states of consciousness in humans'

Introduction

Classic psychedelics produce profound alterations in mood, perception, cognition, and the sense of self, yet the neural mechanisms that give rise to these altered states remain incompletely understood. One influential account, the cortico‑striato‑thalamo‑cortical (CSTC) or thalamic‑filter model, proposes that psychedelics disrupt the thalamus’s capacity to gate sensory and sensorimotor information to the cortex, producing ‘‘sensory flooding’’ and cognitive disintegration. Neurotransmitter systems implicated in this model include serotonergic (notably 5‑HT2A), dopaminergic and glutamatergic pathways, but direct tests of the model’s predictions in humans have been lacking. Preller and colleagues set out to test the CSTC gating hypothesis by characterising directed (effective) connectivity among key CSTC nodes after acute administration of lysergic acid diethylamide (LSD), and after pretreatment with the selective 5‑HT2A antagonist ketanserin (Ket). Using spectral dynamic causal modelling (DCM) applied to resting‑state fMRI in a double‑blind, randomised, placebo‑controlled, crossover sample of healthy participants, the study tested two primary predictions: LSD would increase thalamus→cortex effective connectivity and reduce striatal (ventral striatum, VS) influence on the thalamus, and many of these LSD effects would depend on 5‑HT2A receptor stimulation.

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Study Details

References (24)

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