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Enhanced Repertoire of Brain Dynamical States During the Psychedelic Experience

Enhanced Repertoire of Brain Dynamical States During the Psychedelic Experience

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Published by Dimitrije
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 00:000–000, 2014. VC 2014 Wiley Periodicals, Inc.
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 00:000–000, 2014. VC 2014 Wiley Periodicals, Inc.

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Enhanced Repertoire of Brain Dynamical StatesDuring the Psychedelic Experience
Enzo Tagliazucchi,
1
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 Robin Carhart-Harris,
2
Robert Leech,
3
David Nutt,
2
and Dante R. Chialvo
4
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 BrainSciences, Imperial College London, United Kingdom
4
Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Buenos Aires, Argentina
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Abstract:
 The study of rapid changes in brain dynamics and functional connectivity (FC) is of increasinginterest in neuroimaging. Brain states departing from normal waking consciousness are expected to beaccompanied by alterations in the aforementioned dynamics. In particular, the psychedelic experienceproduced by psilocybin (a substance found in “magic mushrooms”) is characterized by unconstrainedcognition and profound alterations in the perception of time, space and selfhood. Considering the spon-taneous and subjective manifestation of these effects, we hypothesize that neural correlates of the psyche-delic experience can be found in the dynamics and variability of spontaneous brain activity fluctuationsand connectivity, measurable with functional Magnetic Resonance Imaging (fMRI). Fifteen healthy sub- jects 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 andtotal spectral power, resulting in increased signal variability bilaterally in the hippocampi and anteriorcingulate 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 atten-tion networks. A novel framework enabled us to track different connectivity states explored by the brainduring rest. This approach revealed a wider repertoire of connectivity states post-psilocybin than duringcontrol conditions. Together, the present results provide a comprehensive account of the effects of psilo-cybin on dynamical behavior in the human brain at a macroscopic level and may have implications forour understanding of the unconstrained, hyper-associative quality of consciousness in the psychedelicstate.
 Hum Brain Mapp 00:000–000, 2014
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Key words:
 Psilocybin; fMRI; functional connectivity; resting state; psychedelic state
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Contract grant sponsors: CONICET (Argentina) and LOEWENeuronale Koordination Forschungsschwerpunkt Frankfurt—NeFF (Germany).*Correspondence to: Enzo Tagliazucchi, Neurology Departmentand Brain Imaging Center, Goethe University, Frankfurt amMain, Germany. E-mail: tagliazucchi.enzo@googlemail.comReceived for publication 11 January 2014; Revised 21 May 2014;Accepted 23 May 2014.DOI: 10.1002/hbm.22562Published online 00 Month 2014 in Wiley Online Library(wileyonlinelibrary.com).
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INTRODUCTION
Psilocybin (phophoryl-4-hydroxy-dimethyltryptamine) isthe phosphorylated ester of the main psychoactive com-pound found in magic mushrooms. Pharmacologicallyrelated to the prototypical psychedelic LSD, psilocybin hasa long history of ceremonial use via mushroom ingestionand, in modern times, psychedelics have been assessed astools to enhance the psychotherapeutic process [Grobet al., 2011; Krebs et al., 2012; Moreno et al., 2006]. Thesubjective effects of psychedelics include (but are not lim-ited to) unconstrained, hyperassociative cognition, dis-torted sensory perception (including synesthesia andvisions of dynamic geometric patterns) and alterations inone’s sense of self, time and space. There is recent prelimi-nary evidence that psychedelics may be effective in thetreatment of anxiety related to dying [Grob et al., 2011]and obsessive compulsive disorder [Moreno et al., 2006]and there are neurobiological reasons to consider theirpotential as antidepressants [Carhart-Harris et al., 2012,2013]. Similar to ketamine (another novel candidate antide-pressant) psychedelics may also mimic certain psychoticstates such as the altered quality of consciousness that issometimes seen in the onset-phase of a first psychotic epi-sode [Carhart-Harris et al., 2014]. There is also evidence toconsider similarities between the psychology and neurobi-ology of the psychedelic state and Rapid Eye Movement(REM) sleep [Carhart-Harris, 2007; Carhart-Harris andNutt, 2014], the sleep stage associated with vivid dreaming[Aserinsky and Kleitman, 1953].The potential therapeutic use of psychedelics, as well astheir capacity to modulate the quality of conscious experi-ence in a relatively unique and profound manner, empha-sizes the importance of studying these drugs and howthey act on the brain to produce their novel effects. Onepotentially powerful way to approach this problem is toexploit human neuroimaging to measure changes in brainactivity during the induction of the psychedelic state. Theneural correlates of the psychedelic experience induced bypsilocybin have been recently assessed using Arterial SpinLabeling (ASL) and BOLD fMRI [Carhart-Harris et al.,2012]. This work found that psilocybin results in a reduc-tion of both CBF and BOLD signal in major subcorticaland cortical hub structures such as the thalamus, posteriorcingulate (PCC) and medial prefrontal cortex (mPFC) andin decreased resting state functional connectivity (RSFC) between the normally highly coupled mPFC and PCC.Furthermore, our most recent study used magnetoence-phalography (MEG) to more directly measure altered neu-ral activity post-psilocybin and here we found decreasedoscillatory power in the same cortical hub structures[Muthukumaraswamy et al., 2013, see also Carhart-Harriset al., 2014 for a review on this work).These results establish that psilocybin markedly affectsBOLD, CBF, RSFC, and oscillatory electrophysiologicalmeasures in strategically important brain structures, pre-sumably involved in information integration and routing[Carhart-Harris et al., 2014; de Pasquale et al., 2012; Hag-mann et al., 2008; Leech et al., 2012]. However, the effectsof psilocybin on the variance of brain activity parametersacross time has been relatively understudied and this lineof enquiry may be particularly informative in terms of shedding new light on the mechanisms by which psyche-delics elicit their characteristic psychological effects. Thus,the main objective of this article is to examine how psilo-cybin modulates the dynamics and temporal variability of resting state BOLD activity. Once regarded as physiologi-cal noise, a large body of research has now establishedthat resting state fluctuations in brain activity have enor-mous neurophysiological and functional relevance [Foxand Raichle, 2007]. Spontaneous fluctuations self-organizeinto internally coherent spatiotemporal patterns of activitythat reflect neural systems engaged during distinct cogni-tive states (termed “intrinsic” or “resting statenetworks”—RSNs) [Fox and Raichle, 2005; Raichle, 2011;Smith et al., 2009]. It has been suggested that the varietyof spontaneous activity patterns that the brain enters dur-ing task-free conditions reflects the naturally itinerant andvariegated quality of normal consciousness [Raichle, 2011].However, spatio-temporal patterns of resting state activityare globally well preserved in states such as sleep [Bolyet al., 2009, 2012; Brodbeck et al., 2012; Larson-Prior et al.,2009; Tagliazucchi et al., 2013a,b,c] in which there is areduced level of awareness—although very specificchanges in connectivity occur across NREM sleep, allow-ing the decoding of the sleep stage from fMRI data[Tagliazucchi et al., 2012c; Tagliazucchi and Laufs, 2014].Thus, if the subjective quality of consciousness is markedlydifferent in deep sleep relative to the normal wakeful state(for example) yet FC measures remain largely preserved,this would suggest that these measures provide limitedinformation about the biological mechanisms underlyingdifferent conscious states. Similarly, intra-RSN FC isdecreased under psilocybin [Carhart-Harris et al., 2013]yet subjective reports of unconstrained or even“expanded” consciousness are common among users (seeCarhart-Harris et al. [2014] for a discussion). Thus, thepresent analyses are motivated by the view that more sen-sitive and specific indices are required to develop ourunderstanding of the neurobiology of conscious states, andthat measures which factor in variance over time may beparticularly informative.A key feature of spontaneous brain activity is itsdynamical nature. In analogy to other self-organized sys-tems in nature, the brain has been described as a systemresiding in (or at least near to) a critical point or transitionzone between states of order and disorder [Chialvo, 2010;Haimovici et al., 2013; Tagliazucchi and Chialvo, 2011;Tagliazucchi et al., 2012a]. In this critical zone, it ishypothesized that the brain can explore a maximal reper-toire of its possible dynamical states, a feature whichcould confer obvious evolutionary advantages in terms of cognitive and behavioral flexibility. It has even been pro-posed that this cognitive flexibility and range may be a
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key property of adult human consciousness itself [Tononi,2012]. An interesting research question therefore iswhether changes in spontaneous brain activity produced by psilocybin are consistent with a displacement from thiscritical point—perhaps towards a more entropic or super-critical state (i.e. one closer to the extreme of disorder thannormal waking consciousness) [Carhart-Harris et al., 2014].Further motivating this hypothesis are subjective reportsof hyper-associative cognition under psychedelics, indica-tive of unconstrained brain dynamics. Thus, in order totest this hypothesis, it makes conceptual sense to focus onvariability in activity and FC parameters over time, insteadof the default procedure of averaging these over a pro-longed period. In what follows, we present empirical datathat tests the hypothesis that brain activity becomes lessordered in the psychedelic state and that the repertoire of possible states is enhanced. After the relevant findingshave been presented, we engage in a discussion to suggestpossible strategies that may further characterize quantita-tively where the “psychedelic brain” resides in state spacerelative to the dynamical position occupied by normalwaking consciousness.
MATERIALS AND METHODSStudy Overview and Design
This was a within-subjects placebo-controlled study. Thestudy was approved by a local NHS Research Ethics Com-mittee and University of Bristol Research and Develop-ment department, and conducted in accordance withGood Clinical Practice guidelines. A Home Office Licensewas obtained for storage and handling of a Schedule 1drug and the University of Bristol sponsored the research.
Participants
This is a new analysis on previously published data[Carhart-Harris et al., 2012, 2013]. Fifteen healthy subjectstook part: 13 males and 2 females (mean age
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32,SD
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8.9). Recruitment was via word of mouth. All sub- jects were required to give informed consent and undergohealth screens prior to enrollment. Study inclusion criteriawere: at least 21 years of age, no personal or immediatefamily history of a major psychiatric disorder, substancedependence, cardiovascular disease, and no history of asignificant adverse response to a hallucinogenic drug. Allof the subjects had used psilocybin at least once before(mean number of uses per subject
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16.4, SD
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27.2) butnot within 6 weeks of the study.
Anatomical Scans
Image acquisition was performed on a 3T GE HDx sys-tem. Anatomical scans were performed before eachfunctional scan and thus during sobriety. These werethree-dimensional fast spoiled gradient echo scans in anaxial orientation, with field of view
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192 andmatrix
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 192 to yield 1 mm isotropic voxelresolution (repetition time/echo time [TR/TE]
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7.9/3.0ms; inversion time
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450 ms; flip angle
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20
).
Drug Infusion
All subjects underwent two 12 min eyes closed restingstate BOLD fMRI scans on two separate occasions at least7 days apart: placebo (10 ml saline, 60 s intravenous injec-tion) was given on one occasion and psilocybin (2 mg dis-solved in 10 ml saline, 60 s infusion) on the other. Sevenof the subjects received psilocybin in scan 1, and 8received it in scan 2. Injections were given manually by adoctor within the scanning suite. The 60 s infusions beganexactly 6 min after the start of the 12 min scans. The sub- jective effects of psilocybin were felt almost immediatelyafter injection and were sustained for the remainder of theRS scan. For more details on the subjective effects of intra-venous psilocybin see [Carhart-Harris et al., 2012, 2013].
fMRI Data Acquisition and Preprocessing
BOLD-weighted fMRI data were acquired using a gradi-ent echo planar imaging sequence, TR/TE 3,000/35 ms,field-of-view
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192 mm, 64
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 64 acquisition matrix, paral-lel acceleration factor
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2, 90
flip angle. Fifty-three obliqueaxial slices were acquired in an interleaved fashion, each3 mm thick with zero slice gap (3
 3
 3
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 3 mm voxels). Atotal of 240 volumes were acquired, with infusion takingplace in the middle of the session. Data were motion cor-rected using FSL MCFLIRT and a high-pass filter of 100 swas applied. Data were smoothed using a Gaussian kernelof 5 mm FWHM. Motion time courses were regressedfrom the data during the preprocessing step, together withaverage CSF and white matter time courses. As an addi-tional control to exclude epochs of large movement ampli-tude, all volumes associated with a mean headdisplacement larger than 1 SD were erased from theanalysis.
Analysis of Spatiotemporal Dynamics
The methods here employed are based on a statisticalphysics framework useful for characterizing fluctuations insystems composed of large number of coupled degrees of freedom. From this perspective, fluctuating activity in aparticular region and correlations between differentregions are interdependent or related [Ross, 1966]. There-fore, any change in the cortical dynamics due to a givenintervention is expected to be reflected both at the level of the variance of the activity at one region and in thestrength of the interactions between different regions. Inwhat follows, the methodology accounting for these twoaspects (i.e. the temporal variability and the dynamical
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