Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex.
Manesh Girn, Leor Roseman, Boris C. Bernhardt, Jonathan Smallwood, Robin Carhart-Harris, R. Nathan Spreng
Neuroimage April 25, 2022 DOI: 10.1016/j.neuroimage.2022.119220 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Re-analysis of two pharmacological resting-state fMRI datasets Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Healthy volunteers from two previously published studies |
| Interventions | Lysergic acid diethylamide (LSD) psilocybin |
| Topics | LSD Psilocybin Serotonin |
| Keywords | Psychedelics Powerful compounds Brain reorganization Brain's internal hierarchy Brain regions Less specialized Consciousness & perception Conventional mental frameworks |
| Citations | 112 |
| Key points | LSD and psilocybin flatten the principal gradient of cortical connectivity, reducing hierarchical organization between unimodal and transmodal cortex. |
Abstract
Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelic compounds with potential in the treatment of mental health disorders. Past neuroimaging investigations have revealed that both compounds can elicit significant changes to whole-brain functional organization and dynamics. A recent proposal linked past findings into a unified model and hypothesized reduced whole-brain hierarchical organization as a key mechanism underlying the psychedelic state, but this has yet to be directly tested. We applied a non-linear dimensionality reduction technique previously used to map hierarchical connectivity gradients to assess cortical organization in the LSD and psilocybin state from two previously published pharmacological resting-state fMRI datasets (N = 15 and 9, respectively). Results supported our primary hypothesis: The principal gradient of cortical connectivity, describing a hierarchy from unimodal to transmodal cortex, was significantly flattened under both drugs relative to their respective placebo conditions. Between-condition contrasts revealed that this was driven by a reduction of functional differentiation at both hierarchical extremes - default and frontoparietal networks at the upper end, and somatomotor at the lower. Gradient-based connectivity mapping indicated that this was underpinned by a disruption of modular unimodal connectivity and increased unimodal-transmodal crosstalk. Results involving the second and third gradient, which, respectively represent axes of sensory and executive differentiation, also showed significant alterations across both drugs. These findings provide support for a recent mechanistic model of the psychedelic state relevant to therapeutic applications of psychedelics. More fundamentally, we provide the first evidence that macroscale connectivity gradients are sensitive to an acute pharmacological manipulation, supporting a role for psychedelics as scientific tools to perturb cortical functional organization.
Comparable studies
Other experimental studies on LSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Neural correlates of the LSD experience revealed by multimodal neuroimaging. Human participants | 2016 | Experimental study | |
| Crystal structure of an LSD-bound human serotonin receptor | 2017 | Experimental study with structural biology and molecular dynamics simulations | |
| Lysergic Acid Diethylamide: Sensitive Neuronal Units in the Midbrain Raphe Midbrain neurons containing serotonin | 1968 | Experimental study | |
| Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD. Human brain | 2017 | Experimental study | |
| LSD-Assisted Psychotherapy in Patients with Terminal Cancer Cancer patients | 1973 | Experimental study | n = 60 |
Citations in the library
Cited by 83
- Human brain effects of DMT assessed via EEG-fMRI. Proceedings of the National Academy of Sciences March 28, 2023
- Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain's control energy landscape. Nature Communications October 3, 2022
- Canalization and plasticity in psychopathology Neuropharmacology December 27, 2022
- A complex systems perspective on psychedelic brain action. Trends in Cognitive Sciences February 3, 2023
- In vivo mapping of pharmacologically induced functional reorganization onto the human brain’s neurotransmitter landscape Science Advances June 14, 2023
and 78 more in the library
Cites 44
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
and 39 more in the library