Neural mechanisms of imagery under psilocybin

Visual alterations under classic psychedelics can include rich phenomenological accounts of eyes-closed imagery. Preclinical evidence suggests agonism of the 5-HT2A receptor may reduce synaptic gain to produce psychedelic-induced imagery. However, this has not been investigated in humans. To infer the directed connectivity changes to visual sensory connectivity underlying psychedelic visual imagery in healthy adults, we applied dynamic causal modelling to the resting state eyes-closed functional MRI scans of 24 subjects after administration of 0.2mg/kg of the serotonergic psychedelic drug, psilocybin (magic mushrooms), or placebo. The effective connectivity model included the early visual area, fusiform gyrus, intraparietal sulcus, and inferior frontal gyrus was modelled. We observed a pattern of increased self-inhibition of both early visual and higher visual-association regions under psilocybin that was consistent with preclinical findings. We also observed a pattern of reduced excitation and inhibition from visual-association regions to earlier visual areas that indicated top-down connectivity is enhanced during visual imagery. The results were associated with behavioural measures of complex and elementary imagery taken after the scans, suggesting psilocybin-induced deprivation of sensory activity amplifies endogenous neural activity associated with the perception of eyes-closed visual imagery. The findings inform our basic and clinical understanding of visual perception and identify neural mechanisms that contribute to psychedelic-induced eyes-closed visual imagery. Significance statement Our study is the first measurement of the effects of a 5-HT2A receptor agonist on synaptic gain of the visual system in humans and advances the understanding of the psychopharmacology of visual perception. Our findings are consistent with preclinical evidence and elucidate the effects of psychedelics on neural mechanisms of the visual system. Specifically, we identify manifestations of visual imagery in the absence of stimuli result from decreased self-connectivity of the visual system and increased reliance on top-down connectivity. The findings have relevance to understanding clinical hallucinations and offers avenues for exploring the neurology and utility of visual imagery in psychedelic-assisted-psychotherapy. Moreover, our study advances the broader field of neuroimaging by identifying the hierarchical organisation of brain connectivity underlying perception. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03736980 ### Funding Statement Heffter Research Institute (Grant No. 1- 190420) Swiss Neuromatrix Foundation (Grant No. 2016-0111), Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908), Slovenian Research Agency (ARRS) (Grant Nos. J7-8275, J7-6829,Council Discovery Early Career Research Award Fellowship DE170100128 (to AR), Australian Research Council Discovery Project grant DP200100757 (AR), Australian National Health and Medical Research Council Investigator grant 1194910 (AR), Wellcome Centre for Human Neuroimaging supported by core funding from Wellcome grant 203147/Z/16/Z (AR) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The data analysed in this paper were collected as part of a previous study (registered at ClinicalTrials.gov ([NCT03736980][1])), which is reported in ([Preller et al., 2020][2], doi: 10.1016/j.biopsych.2019.12.027) and was approved by the Cantonal Ethics Committee of Zurich. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03736980&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F06%2F2022.09.07.22279700.atom [2]: #ref-45