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

Katrin H Preller, Adeel Razi, Peter Zeidman, Philipp Stämpfli, Karl J Friston, Franz X Vollenweider

Journal: Proceedings of the National Academy of Sciences of the United States of America 2019;116(7):2743-2748

PMID: 30692255

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.

Address: Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, 8006 Zurich, Switzerland; [email protected].; The Wellcome Centre for Human Neuroimaging, University College London, WC1N 3AR London, United Kingdom.; The Wellcome Centre for Human Neuroimaging, University College London, WC1N 3AR London, United Kingdom.; Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, 3168 VIC, Australia.; Monash Biomedical Imaging, Monash University, Clayton, 3168 VIC, Australia.; Department of Electronic Engineering, NED University of Engineering and Technology, 75270 Karachi, Pakistan.; The Wellcome Centre for Human Neuroimaging, University College London, WC1N 3AR London, United Kingdom.; Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, 8006 Zurich, Switzerland.; Medical Research Center of the Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital of the University of Zurich, 8006 Zurich, Switzerland.; Department of Child and Adolescent Psychiatry, Psychiatric Hospital of the University of Zurich, 8006 Zurich, Switzerland.; Neuropsychopharmacology and Brain Imaging, Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry Zurich, 8006 Zurich, Switzerland.

DOI: 10.1073/pnas.1815129116

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MeSH Terms: Brain, Consciousness, Cross-Over Studies, Double-Blind Method, Hallucinogens, Humans, Lysergic Acid Diethylamide, Placebos, Receptor, Serotonin, 5-HT2A, Serotonin Antagonists