Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex
OpenAlex – May 03, 2020
Source: OpenAlex
Summary
Psilocybin and LSD, potent serotonergic hallucinogens, dramatically alter brain organization. Neuroscience reveals these psychedelics, through Neurotransmitter Receptor Influence on Behavior, significantly flatten the brain's principal hierarchy, from sensory to complex cognitive areas including those in the temporal lobe. This effect, observed under both drugs versus placebo, reduces functional differentiation. Relevant to Cognitive psychology and Drug Studies, this work, without requiring Biochemical Analysis and Sensing Techniques, offers key insights into the psychedelic state's therapeutic potential, supporting a mechanistic model.
Abstract
Abstract 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 pharmacological resting-state fMRI data to assess cortical organization in the LSD and psilocybin state. 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 confirmed that this was underpinned by increased unimodal-transmodal crosstalk. In addition, LSD-dependent principal gradient changes tracked changes in self-reported ego-dissolution. 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 a pharmacological manipulation, specifically highlighting an important relationship between cortical organization and serotonergic modulation.