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      Enhanced repertoire of brain dynamical states during the psychedelic experience

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          Abstract

          The study of rapid changes in brain dynamics and functional connectivity (FC) is of increasing interest in neuroimaging. Brain states departing from normal waking consciousness are expected to be accompanied by alterations in the aforementioned dynamics. In particular, the psychedelic experience produced by psilocybin (a substance found in “magic mushrooms”) is characterized by unconstrained cognition and profound alterations in the perception of time, space and selfhood. Considering the spontaneous and subjective manifestation of these effects, we hypothesize that neural correlates of the psychedelic experience can be found in the dynamics and variability of spontaneous brain activity fluctuations and connectivity, measurable with functional Magnetic Resonance Imaging (fMRI). Fifteen healthy subjects were scanned before, during and after intravenous infusion of psilocybin and an inert placebo. Blood‐Oxygen Level Dependent (BOLD) temporal variability was assessed computing the variance and total spectral power, resulting in increased signal variability bilaterally in the hippocampi and anterior cingulate cortex. Changes in BOLD signal spectral behavior (including spectral scaling exponents) affected exclusively higher brain systems such as the default mode, executive control, and dorsal attention networks. A novel framework enabled us to track different connectivity states explored by the brain during rest. This approach revealed a wider repertoire of connectivity states post‐psilocybin than during control conditions. Together, the present results provide a comprehensive account of the effects of psilocybin on dynamical behavior in the human brain at a macroscopic level and may have implications for our understanding of the unconstrained, hyper‐associative quality of consciousness in the psychedelic state. Hum Brain Mapp 35:5442–5456, 2014. © 2014 Wiley Periodicals, Inc.

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          The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

          Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of “primary states” is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit “criticality,” i.e., the property of being poised at a “critical” point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetized state.
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            Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.

            Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.
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              Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder

              Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD. Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 microg/kg), medium (200 microg/kg), and high (300 microg/kg) doses were assigned in that order, and a very low dose (25 microg/kg) was inserted randomly and in double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Improvement generally lasted past the 24-hour timepoint. In a controlled clinical environment, psilocybin was safely used in subjects with OCD and was associated with acute reductions in core OCD symptoms in several subjects.
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                Author and article information

                Journal
                Hum Brain Mapp
                Hum Brain Mapp
                10.1002/(ISSN)1097-0193
                HBM
                Human Brain Mapping
                John Wiley and Sons Inc. (Hoboken )
                1065-9471
                1097-0193
                03 July 2014
                November 2014
                : 35
                : 11 ( doiID: 10.1002/hbm.v35.11 )
                : 5442-5456
                Affiliations
                [ 1 ] Neurology Department and Brain Imaging Center Goethe University Frankfurt am Main Germany
                [ 2 ] Imperial College London, Centre for Neuropsychopharmacology Division of Experimental Medicine London United Kingdom
                [ 3 ] Computational Cognitive and Clinical Neuroimaging Laboratory (C3NL) Division of Brain Sciences Imperial College London United Kingdom
                [ 4 ] Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET) Buenos Aires Argentina
                Author notes
                [*] [* ]Correspondence to: Enzo Tagliazucchi, Neurology Department and Brain Imaging Center, Goethe University, Frankfurt am Main, Germany. E‐mail: tagliazucchi.enzo@ 123456googlemail.com
                Article
                PMC6869695 PMC6869695 6869695 HBM22562
                10.1002/hbm.22562
                6869695
                24989126
                c1f09262-3538-41c5-868e-0b10bb3d6508
                Copyright © 2014 Wiley Periodicals, Inc.
                History
                : 11 January 2014
                : 21 May 2014
                : 23 May 2014
                Page count
                Pages: 15
                Funding
                Funded by: CONICET (Argentina)
                Funded by: LOEWE Neuronale Koordination Forschungsschwerpunkt Frankfurt—NeFF (Germany)
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                November 2014
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:15.11.2019

                functional connectivity,Psilocybin,fMRI,resting state,psychedelic state

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