Advertisement

Effective Connectivity of Functionally Anticorrelated Networks Under Lysergic Acid Diethylamide

Open AccessPublished:August 06, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.07.013

      Abstract

      Background

      Classic psychedelic-induced ego dissolution involves a shift in the sense of self and a blurring of the boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated with the balance of anticorrelated activity between the default mode network, which directs attention inward, and the salience network, which recruits the dorsal attention network to direct attention outward.

      Methods

      To test whether changes in anticorrelated networks underlie the peak effects of lysergic acid diethylamide (LSD), we applied dynamic causal modeling to infer effective connectivity of resting-state functional magnetic resonance imaging scans from a study of 25 healthy adults who were administered 100 μg of LSD or placebo.

      Results

      We found that inhibitory effective connectivity from the salience network to the default mode network became excitatory, and inhibitory effective connectivity from the default mode network to the dorsal attention network decreased under the peak effect of LSD.

      Conclusions

      The effective connectivity changes we identified may reflect diminution of the functional anticorrelation between resting-state networks that may be a key neural mechanism of LSD and underlie ego dissolution. Our findings suggest that changes to the sense of self and subject-object boundaries across different states of consciousness may depend upon the organized balance of effective connectivity of resting-state networks.

      Keywords

      Classic psychedelics are powerful substances with low toxicity that can temporarily alter brain activity and produce profound changes to consciousness (
      • Vollenweider F.X.
      • Leenders K.L.
      • Scharfetter C.
      • Maguire P.
      • Stadelmann O.
      • Angst J.
      Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis.
      ,
      • Vollenweider F.X.
      Advances and pathophysiological models of hallucinogenic drug actions in humans: A preamble to schizophrenia research.
      ,
      • Preller K.H.
      • Vollenweider F.X.
      Phenomenology, structure, and dynamic of psychedelic states [published correction appears in Curr Top Behav Neurosci 2018; 36:1].
      ,
      • Johnson M.
      • Richards W.
      • Griffiths R.
      Human hallucinogen research: Guidelines for safety.
      ,
      • Carhart-Harris R.L.
      How do psychedelics work?.
      ). Their mind-altering effects, which are undergoing translation into modern clinical therapies, may constitute a crucial component of their therapeutic efficacy (
      • Roseman L.
      • Nutt D.J.
      • Carhart-Harris R.L.
      Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression.
      ,
      • Yaden D.B.
      • Griffiths R.R.
      The subjective effects of psychedelics are necessary for their enduring therapeutic effects.
      ). The subjective effects of classic psychedelics are characterized by ego dissolution (
      • Preller K.H.
      • Vollenweider F.X.
      Phenomenology, structure, and dynamic of psychedelic states [published correction appears in Curr Top Behav Neurosci 2018; 36:1].
      ,
      • Stoliker D.
      • Egan G.F.
      • Friston K.J.
      • Razi A.
      Neural mechanisms and psychology of psychedelic ego dissolution.
      ), described as a shift in the sense of self and a loss of boundary between the subjective and the objective worlds (
      • Dittrich A.
      The standardized psychometric assessment of altered states of consciousness (ASCs) in humans.
      ,
      • Studerus E.
      • Gamma A.
      • Vollenweider F.X.
      Psychometric evaluation of the altered states of consciousness rating scale (OAV).
      ,
      • Vollenweider F.X.
      • Smallridge J.W.
      Classic psychedelic drugs: Update of biological mechanisms.
      ,
      • Lebedev A.V.
      • Lövdén M.
      • Rosenthal G.
      • Feilding A.
      • Nutt D.J.
      • Carhart-Harris R.L.
      Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin.
      ,
      • Grof S.
      LSD Psychotherapy.
      ). Ego dissolution is suggested as a valid construct (
      • Dittrich A.
      The standardized psychometric assessment of altered states of consciousness (ASCs) in humans.
      ,
      • Studerus E.
      • Gamma A.
      • Vollenweider F.X.
      Psychometric evaluation of the altered states of consciousness rating scale (OAV).
      ,
      • Nour M.M.
      • Evans L.
      • Nutt D.
      • Carhart-Harris R.L.
      Ego-dissolution and psychedelics: Validation of the ego-dissolution inventory (EDI).
      ) and is thought to involve changes to resting-state network (RSN) activity (
      • Stoliker D.
      • Egan G.F.
      • Friston K.J.
      • Razi A.
      Neural mechanisms and psychology of psychedelic ego dissolution.
      ,
      • Müller F.
      • Dolder P.C.
      • Schmidt A.
      • Liechti M.E.
      • Borgwardt S.
      Altered network hub connectivity after acute LSD administration.
      ,
      • Preller K.H.
      • Burt J.B.
      • Ji J.L.
      • Schleifer C.H.
      • Adkinson B.D.
      • Stämpfli P.
      • et al.
      Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor.
      ).
      Functional magnetic resonance imaging (fMRI) investigations indicate that activity across the brain is functionally integrated and forms multiple RSNs (
      • Raichle M.E.
      The brain’s default mode network.
      ). RSNs are associated with mental activity, and the balance of connectivity between them is associated with the direction of conscious attention (
      • Friston K.J.
      Functional and effective connectivity: A review.
      ,
      • Greicius M.D.
      • Menon V.
      Default-mode activity during a passive sensory task: Uncoupled from deactivation but impacting activation.
      ,
      • Fox M.D.
      • Snyder A.Z.
      • Vincent J.L.
      • Corbetta M.
      • Van Essen D.C.
      • Raichle M.E.
      The human brain is intrinsically organized into dynamic, anticorrelated functional networks.
      ). The default mode network (DMN), which is composed of the medial prefrontal cortex, posterior cingulate cortex, and (bilateral) angular gyrus, is an RSN that activates primarily in the absence of immediate, external, goal-directed attention (
      • Raichle M.E.
      • MacLeod A.M.
      • Snyder A.Z.
      • Powers W.J.
      • Gusnard D.A.
      • Shulman G.L.
      A default mode of brain function.
      ). Its function in self-focused thinking and attention suggests its close relationship to the ego (
      • Andrews-Hanna J.R.
      • Smallwood J.
      • Spreng R.N.
      The default network and self-generated thought: Component processes, dynamic control, and clinical relevance.
      ). In contrast, the dorsal attention network (DAN) is an RSN that is activated during external-focused task-driven attention (
      • Corbetta M.
      • Shulman G.L.
      Control of goal-directed and stimulus-driven attention in the brain.
      ,
      • Fox M.D.
      • Raichle M.E.
      Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging.
      ) and is usually considered to be composed of the frontal eye field and the intraparietal sulcus bilaterally. The activity of the DMN and the DAN are identified as anticorrelated and predictably alternate with the inward or outward switching of attention (
      • Fox M.D.
      • Snyder A.Z.
      • Vincent J.L.
      • Corbetta M.
      • Van Essen D.C.
      • Raichle M.E.
      The human brain is intrinsically organized into dynamic, anticorrelated functional networks.
      ). The DMN-DAN anticorrelation can be hypothesized to be a mechanism maintaining the boundary between the subject (observer) and object (observation) that is altered during experiences of psychedelic ego dissolution.
      A third RSN, the salience network (SN), acts as the switching mechanism coordinating the direction of attention between internal and external stimuli (
      • Liang X.
      • He Y.
      • Salmeron B.J.
      • Gu H.
      • Stein E.A.
      • Yang Y.
      Interactions between the salience and default-mode networks are disrupted in cocaine addiction.
      ,
      • Seeley W.W.
      • Menon V.
      • Schatzberg A.F.
      • Keller J.
      • Glover G.H.
      • Kenna H.
      • et al.
      Dissociable intrinsic connectivity networks for salience processing and executive control.
      ) and recruits neural activity in response to stimuli. The SN’s cardinal regions are the dorsal anterior cingulate cortex (dACC) and the anterior insula (AI). The dACC and the AI are consistently coactivated across cognitive tasks (
      • Swick D.
      • Ashley V.
      • Turken U.
      Are the neural correlates of stopping and not going identical? Quantitative meta-analysis of two response inhibition tasks.
      ). However, the dACC is more involved in response selection and conflict monitoring (
      • Ide J.S.
      • Shenoy P.
      • Yu A.J.
      • Li C.S.
      Bayesian prediction and evaluation in the anterior cingulate cortex.
      ,
      • Menon V.
      Large-scale brain networks and psychopathology: A unifying triple network model.
      ), while the AI receives greater multimodal sensory input (
      • Averbeck B.B.
      • Seo M.
      The statistical neuroanatomy of frontal networks in the macaque.
      ,
      • Vogt B.A.
      • Pandya D.N.
      Cingulate cortex of the rhesus monkey: II. Cortical afferents.
      ), detects behaviorally relevant stimuli (
      • Menon V.
      Salience Network.
      ), coordinates responses to stimuli [for example, anxiety (
      • Ju A.
      • Fernandez-Arroyo B.
      • Wu Y.
      • Jacky D.
      • Beyeler A.
      Expression of serotonin 1A and 2A receptors in molecular- and projection-defined neurons of the mouse insular cortex.
      )], and coordinates the dynamic interactions of anticorrelated networks (
      • Menon V.
      • Uddin L.Q.
      Saliency, switching, attention and control: A network model of insula function.
      ,
      • Sridharan D.
      • Levitin D.J.
      • Menon V.
      A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks.
      ).
      Coordinated interactions between these networks produce important biopsychological functions. The SN coactivation with the DAN coincides with the detection of bottom-up features in the visual environment that are infrequent or biologically significant (
      • Fecteau J.H.
      • Munoz D.P.
      Salience, relevance, and firing: A priority map for target selection.
      ,
      • Egner T.
      • Monti J.M.P.
      • Trittschuh E.H.
      • Wieneke C.A.
      • Hirsch J.
      • Mesulam M.M.
      Neural integration of top-down spatial and feature-based information in visual search.
      ,
      • Szczepanski S.M.
      • Pinsk M.A.
      • Douglas M.M.
      • Kastner S.
      • Saalmann Y.B.
      Functional and structural architecture of the human dorsal frontoparietal attention network.
      ) and also enables the detection of resources relevant to higher-order goals (
      • Menon V.
      Salience Network.
      ). Furthermore, anticorrelated function between the SN and DMN is a biomarker of efficient cognition (
      • Putcha D.
      • Ross R.S.
      • Cronin-Golomb A.
      • Janes A.C.
      • Stern C.E.
      Salience and default mode network coupling predicts cognition in aging and Parkinson’s disease.
      ,
      • Chand G.B.
      • Wu J.
      • Hajjar I.
      • Qiu D.
      Interactions of the salience network and its subsystems with the default-mode and the central-executive networks in normal aging and mild cognitive impairment.
      ). Trauma to the white matter tracts within the SN that connect the right AI (rAI) and the dACC predicts dysregulated DMN function (
      • Bonnelle V.
      • Ham T.E.
      • Leech R.
      • Kinnunen K.M.
      • Mehta M.A.
      • Greenwood R.J.
      • et al.
      Salience network integrity predicts default mode network function after traumatic brain injury.
      ). Importantly, abnormality of the SN connectivity and its anticorrelated interactions is indicative of schizophrenia (
      • Manoliu A.
      • Riedl V.
      • Zherdin A.
      • Mühlau M.
      • Schwerthöffer D.
      • Scherr M.
      • et al.
      Aberrant dependence of default mode/central executive network interactions on anterior insular salience network activity in schizophrenia.
      ), psychosis (
      • Wotruba D.
      • Michels L.
      • Buechler R.
      • Metzler S.
      • Theodoridou A.
      • Gerstenberg M.
      • et al.
      Aberrant coupling within and across the default mode, task-positive, and salience network in subjects at risk for psychosis.
      ,
      • Palaniyappan L.
      • Liddle P.F.
      Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction.
      ), and internalizing disorders (
      • Peterson A.
      • Thome J.
      • Frewen P.
      • Lanius R.A.
      Resting-state neuroimaging studies: A new way of identifying differences and similarities among the anxiety disorders?.
      ) [see Menon (
      • Menon V.
      Large-scale brain networks and psychopathology: A unifying triple network model.
      ,
      • Menon V.
      Salience Network.
      ) for a review of associations of SN with psychopathology].
      The DMN and SN have previously been investigated in relation to unique senses of self. The SN has been suggested to be involved in an aspect of self, defined as the basic sense of being rooted within a body, termed the minimal or embodied self (
      • Lebedev A.V.
      • Lövdén M.
      • Rosenthal G.
      • Feilding A.
      • Nutt D.J.
      • Carhart-Harris R.L.
      Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin.
      ,
      • Blanke O.
      • Metzinger T.
      Full-body illusions and minimal phenomenal selfhood.
      ,
      • Legrand D.
      • Ruby P.
      What is self-specific? Theoretical investigation and critical review of neuroimaging results.
      ). This association is supported by changes to the SN documented in psychopathology (
      • Liu C.H.
      • Guo J.
      • Lu S.L.
      • Tang L.R.
      • Fan J.
      • Wang C.Y.
      • et al.
      Increased salience network activity in patients with insomnia complaints in major depressive disorder.
      ), meditation (
      • Doll A.
      • Hölzel B.K.
      • Boucard C.C.
      • Wohlschläger A.M.
      • Sorg C.
      Mindfulness is associated with intrinsic functional connectivity between default mode and salience networks.
      ,
      • Ramírez-Barrantes R.
      • Arancibia M.
      • Stojanova J.
      • Aspé-Sánchez M.
      • Córdova C.
      • Henríquez-Ch R.A.
      Default mode network, meditation, and age-associated brain changes: What can we learn from the impact of mental training on well-being as a psychotherapeutic approach?.
      ), and psychedelic-induced ego dissolution (
      • Lebedev A.V.
      • Lövdén M.
      • Rosenthal G.
      • Feilding A.
      • Nutt D.J.
      • Carhart-Harris R.L.
      Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin.
      ) (see Table S1 for a subset of psychedelic findings related to networks and regions of interest). The prereflective qualities that define the minimal self have also been suggested as antecedents of the narrative aspect of self (
      • Nour M.M.
      • Carhart-Harris R.L.
      Psychedelics and the science of self-experience.
      ,
      • Ho J.T.
      • Preller K.H.
      • Lenggenhager B.
      Neuropharmacological modulation of the aberrant bodily self through psychedelics.
      ). The narrative aspect of self is believed to be under the control of the DMN and describes self-related mental activity and personal identity (
      • Metzinger T.
      Being No One: The Self-Model Theory of Subjectivity.
      ,
      • Millière R.
      Looking for the self: Phenomenology, neurophysiology and philosophical significance of drug-induced ego dissolution.
      ). For example, the DMN encodes the detail of ongoing experience and performs mental simulation (
      • Sormaz M.
      • Murphy C.
      • Wang H.T.
      • Hymers M.
      • Karapanagiotidis T.
      • Poerio G.
      • et al.
      Default mode network can support the level of detail in experience during active task states [published correction appears in Proc Natl Acad Sci U S A 2018; 115:E11198].
      ,
      • Dohmatob E.
      • Dumas G.
      • Bzdok D.
      Dark control: The default mode network as a reinforcement learning agent.
      ). These parallels have led to exploratory investigations of the DMN under psychedelic-induced ego dissolution that indicate a general pattern of reduced connectivity (
      • Vollenweider F.X.
      • Preller K.H.
      Psychedelic drugs: Neurobiology and potential for treatment of psychiatric disorders.
      ,
      • Carhart-Harris R.L.
      • Friston K.J.
      The default-mode, ego-functions and free-energy: A neurobiological account of Freudian ideas.
      ,
      • Cieri F.
      • Esposito R.
      Psychoanalysis and neuroscience: The bridge between mind and brain.
      ,
      • Ruban A.
      • Kołodziej A.
      Changes in default-mode network activity and functional connectivity as an indicator of psychedelic-assisted psychotherapy effectiveness.
      ).
      Reduced connectivity in the DMN is a feature of improved mental health and has also been identified in meditation (
      • Hasenkamp W.
      • Wilson-Mendenhall C.D.
      • Duncan E.
      • Barsalou L.W.
      Mind wandering and attention during focused meditation: A fine-grained temporal analysis of fluctuating cognitive states.
      ,
      • Brewer J.A.
      • Worhunsky P.D.
      • Gray J.R.
      • Tang Y.Y.
      • Weber J.
      • Kober H.
      Meditation experience is associated with differences in default mode network activity and connectivity.
      ,
      • Batchelor S.
      Buddhism Without Beliefs: A Contemporary Guide to Awakening.
      ,
      • Millière R.
      • Carhart-Harris R.L.
      • Roseman L.
      • Trautwein F.M.
      • Berkovich-Ohana A.
      Psychedelics, meditation, and self-consciousness.
      ). Seeking cessation of the self in the practice of meditation resembles psychedelic ego dissolution and aligns with an early interpretation of psychedelics noted in filtration theory, which suggests that psychedelics disinhibit cognitive defenses (
      • Batchelor S.
      Buddhism Without Beliefs: A Contemporary Guide to Awakening.
      ,
      • Millière R.
      • Carhart-Harris R.L.
      • Roseman L.
      • Trautwein F.M.
      • Berkovich-Ohana A.
      Psychedelics, meditation, and self-consciousness.
      ,
      • Osmond H.
      A review of the clinical effects of psychotomimetic agents.
      ,
      • Swanson L.R.
      Unifying theories of psychedelic drug effects.
      ). Meditation has also demonstrated clinical utility that reflects reports of reduced symptoms of patients experiencing internalizing mental health disorders following psychedelic therapy (
      • Ruban A.
      • Kołodziej A.
      Changes in default-mode network activity and functional connectivity as an indicator of psychedelic-assisted psychotherapy effectiveness.
      ,
      • Nutt D.
      • Carhart-Harris R.
      The current status of psychedelics in psychiatry.
      ,
      • Carhart-Harris R.L.
      • Bolstridge M.
      • Day C.M.J.
      • Rucker J.
      • Watts R.
      • Erritzoe D.E.
      • et al.
      Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up.
      ,
      • Goyal M.
      • Singh S.
      • Sibinga E.M.
      • Gould N.F.
      • Rowland-Seymour A.
      • Sharma R.
      • et al.
      Meditation programs for psychological stress and well-being: A systematic review and meta-analysis.
      ). Altered self-boundaries may be important to these therapeutic outcomes (
      • Roseman L.
      • Nutt D.J.
      • Carhart-Harris R.L.
      Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression.
      ,
      • Ross S.
      • Bossis A.
      • Guss J.
      • Agin-Liebes G.
      • Malone T.
      • Cohen B.
      • et al.
      Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial.
      ,
      • Griffiths R.R.
      • Johnson M.W.
      • Carducci M.A.
      • Umbricht A.
      • Richards W.A.
      • Richards B.D.
      • et al.
      Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.
      ). For example, an altered relationship between self and other induced by meditation practice that encourages selflessness suggests a neuropsychological mechanism of altered self-boundaries that can enhance well-being (
      • Dambrun M.
      Self-centeredness and selflessness: Happiness correlates and mediating psychological processes.
      ). Pertinently, a form of meditation termed nondual awareness meditation reduces the anticorrelation of extrinsic and intrinsic activated brain regions and produces a subjective experience of dissolving subject-object boundaries (
      • Josipovic Z.
      • Dinstein I.
      • Weber J.
      • Heeger D.J.
      Influence of meditation on anti-correlated networks in the brain.
      ). Altered subject-object boundaries suggest anticorrelated networks under the control of the SN as a neural mechanism of ego dissolution.
      Anticorrelation between the DMN and task-positive networks under the serotonergic psychedelic psilocybin has previously been investigated, with the findings demonstrating reduced anticorrelation when participants experienced ego dissolution under psilocybin (intravenous infusion, 2 mg dissolved in 10 mL saline) (
      • Carhart-Harris R.L.
      • Leech R.
      • Erritzoe D.
      • Williams T.M.
      • Stone J.M.
      • Evans J.
      • et al.
      Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis.
      ). However, a similar investigation under the serotonergic psychedelic ayahuasca (oral brew, 2.2. mL/kg body weight, containing 0.8 mg/mL DMT and 0.21 mg/mL harmine) failed to identify anticorrelation changes (
      • Palhano-Fontes F.
      • Andrade K.C.
      • Tofoli L.F.
      • Santos A.C.
      • Crippa J.A.
      • Hallak J.E.
      • et al.
      The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network.
      ). The inability of functional connectivity analyses to determine the direction of connectivity between networks in these studies suggests the value of adopting mechanistic approaches to determine changes in effective connectivity of networks under psychedelics. Dynamic causal modeling (DCM) is a Bayesian method of inference based on task-based or resting-state fMRI time-series activity of brain regions (
      • Friston K.J.
      • Harrison L.
      • Penny W.
      Dynamic causal modelling.
      ,
      • Friston K.J.
      • Kahan J.
      • Biswal B.
      • Razi A.
      A DCM for resting state fMRI.
      ). DCM can disentangle hierarchical RSN and regional interactions by determination of the directionality of connectivity. DCM has previously been applied to investigate thalamic connectivity to the cortex under lysergic acid diethylamide (LSD) (
      • Preller K.H.
      • Razi A.
      • Zeidman P.
      • Stämpfli P.
      • Friston K.J.
      • Vollenweider F.X.
      Effective connectivity changes in LSD-induced altered states of consciousness in humans.
      ), and DCM has also indicated that the SN is at the apex of the DMN and DAN triple network hierarchy (
      • Zhou Y.
      • Friston K.J.
      • Zeidman P.
      • Chen J.
      • Li S.
      • Razi A.
      The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
      ). The SN’s position in this hierarchy and its mediating role in controlling the switching of DAN and DMN activity suggests that change to the SN by psychedelics may influence their patterns of anticorrelated activity. The SN and DMN share associations with aspects of self, and the importance of their connectivity in psychopathology suggests that change in their connectivity may be a mechanism of ego dissolution that underlies a shift in the sense of self (
      • Northoff G.
      • Heinzel A.
      • de Greck M.
      • Bermpohl F.
      • Dobrowolny H.
      • Panksepp J.
      Self-referential processing in our brain—A meta-analysis of imaging studies on the self.
      ,
      • Scalabrini A.
      • Vai B.
      • Poletti S.
      • Damiani S.
      • Mucci C.
      • Colombo C.
      • et al.
      All roads lead to the default-mode network-global source of DMN abnormalities in major depressive disorder.
      ).
      Therefore, to understand the neural mechanisms of psychedelics that may underlie ego dissolution and inform the biological basis of the subject-object relationship, the directed changes to these networks under 100 μg of the classic psychedelic LSD were investigated. LSD effects were examined across placebo (2 weeks apart from LSD administration), peak effects at 75 minutes, and later effects at 300 minutes post-LSD administration using DCM analysis to reveal regional and network connectivity changes. Ego dissolution (quantified as oceanic boundlessness) was measured using the 5-Dimensional Altered States of Consciousness Scale (5D-ASC) (see the Supplement) (
      • Studerus E.
      • Gamma A.
      • Vollenweider F.X.
      Psychometric evaluation of the altered states of consciousness rating scale (OAV).
      ). Based on previous research that associated the networks under investigation to self and subject-object boundaries, we hypothesized that the association between effective connectivity would change during the peak effects of LSD and ego dissolution. DMN-DAN change may relate to subject-object boundaries, and SN-DMN change may relate to the self. However, the direction of excitatory-inhibitory connectivity change remained exploratory. Moreover, the moderate dose of LSD provided to study participants, whose experience of ego dissolution undoubtably varied, limits our ability to measure ego dissolution. Therefore, we quantified the results as a measure of LSD-induced connectivity changes that may effectuate ego dissolution. In addition, we measured connectivity of regions composing the networks of interest and the efferent-afferent (hierarchical) connectivity strength between networks.

      Methods and Materials

      Design

      A double-blind, randomized, placebo-controlled crossover study was performed. Testing days occurred 2 weeks apart, and participants were orally administered either LSD after pretreatment with 179-mg mannitol and 1-mg Aerosil (LSD condition), or 179-mg mannitol and 1-mg Aerosil after pretreatment with 179-mg mannitol and 1-mg Aerosil (placebo condition). Resting-state scans (10 minutes each) were taken 75 minutes and 300 minutes following administration. See the Supplement for participant, MRI, and preprocessing details.

      Extraction of Region Coordinates Across Subjects

      Group independent component analysis of fMRI Toolbox (http://mialab.mrn.org/ software/gift) (
      • Calhoun V.D.
      • Adali T.
      • Pearlson G.D.
      • Pekar J.J.
      A method for making group inferences from functional MRI data using independent component analysis [published correction appears in Hum Brain Mapp 2002; 16:131].
      ) was used to identify the 3 resting-state networks of interest from placebo scans. Preprocessed resting-state fMRI data were spatially sorted into 20 components (
      • Biswal B.B.
      • Mennes M.
      • Zuo X.N.
      • Gohel S.
      • Kelly C.
      • Smith S.M.
      • et al.
      Toward discovery science of human brain function.
      ,
      • Shirer W.R.
      • Ryali S.
      • Rykhlevskaia E.
      • Menon V.
      • Greicius M.D.
      Decoding subject-driven cognitive states with whole-brain connectivity patterns.
      ,
      • Tsvetanov K.A.
      • Henson R.N.
      • Tyler L.K.
      • Razi A.
      • Geerligs L.
      • Ham T.E.
      • et al.
      Extrinsic and intrinsic brain network connectivity maintains cognition across the lifespan despite accelerated decay of regional brain activation.
      ) and spatially matched with preexisting network templates (
      • Shirer W.R.
      • Ryali S.
      • Rykhlevskaia E.
      • Menon V.
      • Greicius M.D.
      Decoding subject-driven cognitive states with whole-brain connectivity patterns.
      ).
      Networks were composed of cardinal regions constituting a core part of the DMN (
      • Andrews-Hanna J.R.
      • Reidler J.S.
      • Sepulcre J.
      • Poulin R.
      • Buckner R.L.
      Functional-anatomic fractionation of the brain’s default network.
      ,
      • Dixon M.L.
      • Andrews-Hanna J.R.
      • Spreng R.N.
      • Irving Z.C.
      • Mills C.
      • Girn M.
      • Christoff K.
      Interactions between the default network and dorsal attention network vary across default subsystems, time, and cognitive states.
      ), which reliably show anticorrelation with the DAN and SN (
      • Dixon M.L.
      • Andrews-Hanna J.R.
      • Spreng R.N.
      • Irving Z.C.
      • Mills C.
      • Girn M.
      • Christoff K.
      Interactions between the default network and dorsal attention network vary across default subsystems, time, and cognitive states.
      ,
      • Fransson P.
      Spontaneous low-frequency BOLD signal fluctuations: An fMRI investigation of the resting-state default mode of brain function hypothesis.
      ,
      • Fox M.D.
      • Zhang D.
      • Snyder A.Z.
      • Raichle M.E.
      The global signal and observed anticorrelated resting state brain networks.
      ,
      • Uddin L.Q.
      • Kelly A.M.
      • Biswal B.B.
      • Castellanos F.X.
      • Milham M.P.
      Functional connectivity of default mode network components: Correlation, anticorrelation, and causality.
      ,
      • Chen J.E.
      • Glover G.H.
      • Greicius M.D.
      • Chang C.
      Dissociated patterns of anti-correlations with dorsal and ventral default-mode networks at rest.
      ) and followed the selection of regions in a related investigation by Zhou et al. (
      • Zhou Y.
      • Friston K.J.
      • Zeidman P.
      • Chen J.
      • Li S.
      • Razi A.
      The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
      ). Identification of cardinal nodes within each intrinsic network, averaged across our subjects, was located using peak RSN activity of clusters within networks (p = .05) visualized using xjView toolbox (https://www.alivelearn.net/xjview). Associations between peak coordinates and cardinal nodes of network regions of interest (ROIs) were determined by expert visual inspection. The Montreal Neurological Institute coordinates of the selected ROIs are listed in Table 1.
      Table 1Coordinates of Regions of Interest
      RegionMNI CoordinatesNetwork
      xyz
      PCC0−7338DMN
      mPFC05332DMN
      lAG−54−6129DMN
      rAG57−5820DMN
      dACC01741SN
      lAI−4814−7SN
      rAI4814−7SN
      lFEF−30−1068DAN
      rFEF30−768DAN
      lIPS/SPL−42−4362DAN
      rIPS/SPL39−4065DAN
      The default mode network (DMN) comprises the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), and left and right angular gyrus (lAG and rAG); the salience network (SN) comprises the dorsal anterior cingulate cortex (dACC) and left and right anterior insula (lAI and rAI); and the dorsal attention network (DAN) comprises the left and right frontal eye field (lFEF and rFEF), and left and right inferior parietal sulcus/superior parietal lobule (lIPS/SPL and rIPS/SPL).
      MNI, Montreal Neurological Institute.
      A general linear model was used to regress 6 head motion parameters (3 translation and 3 rotational), white matter signals, and cerebrospinal fluid signals from preprocessed data. One subject was excluded from the analysis because no activation was found in one or more ROIs. We also used global signal regression in our preprocessing pipeline. Global signal regression allowed us to observe anticorrelation in most study participants and was therefore considered appropriate for this study. The time series for each ROI was computed as the first principal component of the voxel activity within a 6-mm sphere centered on the ROI coordinates (as listed in Table 1). See Figure S1 for anticorrelation functional connectivity validation.

      Specification and Inversion of DCM

      A fully connected DCM was specified using the 11 ROIs defined in Table 1, without any exogenous inputs. The DCM for each subject was then inverted using spectral DCM (
      • Friston K.J.
      • Kahan J.
      • Biswal B.
      • Razi A.
      A DCM for resting state fMRI.
      ,
      • Razi A.
      • Kahan J.
      • Rees G.
      • Friston K.J.
      Construct validation of a DCM for resting state fMRI.
      ) to infer the effective connectivity that best explained the observed cross-spectral density for each subject. This procedure was repeated for each of the 3 testing conditions. The DCM fitted the data very well, and the amount of explained variance was more than 85% across all subjects and averaged 91%.

      Second-Level Analysis Using the Parametric Empirical Bayes Method

      The effective connectivity inferred by spectral DCM for each subject was taken to the second (group) level to test hypotheses about between-subjects effects. A general linear model was used to decompose individual differences in effective connectivity into hypothesized group-average connection strengths plus unexplained noise. Hypotheses on the group-level parameters were tested within the parametric empirical Bayes framework (
      • Friston K.J.
      • Litvak V.
      • Oswal A.
      • Razi A.
      • Stephan K.E.
      • van Wijk B.C.M.
      • et al.
      Bayesian model reduction and empirical Bayes for group (DCM) studies.
      ), where both the expected values and the covariance of the parameters are taken into account. That is, precise parameter estimates influence the group-level result more strongly than uncertain estimates, which are downweighted. Bayesian model reduction was used as an efficient form of Bayesian model selection (
      • Friston K.J.
      • Litvak V.
      • Oswal A.
      • Razi A.
      • Stephan K.E.
      • van Wijk B.C.M.
      • et al.
      Bayesian model reduction and empirical Bayes for group (DCM) studies.
      ).

      Network-Level Effective Connectivity and Hierarchical Organization

      The expected network-level connectivity was computed as the sum of the expected effective connectivity values between the corresponding ROIs. Then, following Zhou et al. (
      • Zhou Y.
      • Friston K.J.
      • Zeidman P.
      • Chen J.
      • Li S.
      • Razi A.
      The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
      ), the hierarchical connectivity strength of each network was obtained by computing the difference between its averaged efferent and afferent connections (i.e., absolute values) (see the Supplement). A similar approach was used for analyzing hierarchical projections in the monkey brain (
      • Goulas A.
      • Uylings H.B.
      • Stiers P.
      Mapping the hierarchical layout of the structural network of the macaque prefrontal cortex.
      ) and prefrontal cortex hierarchical organization in humans (
      • Zhou Y.
      • Friston K.J.
      • Zeidman P.
      • Chen J.
      • Li S.
      • Razi A.
      The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
      ,
      • Nee D.E.
      • D’Esposito M.
      The hierarchical organization of the lateral prefrontal cortex.
      ). For clarity, we refer to hierarchical change as afferent and efferent connectivity differences.

      Results

      Acute Effects

      Between-Network Changes in Effective Connectivity

      The first resting-state fMRI scan was acquired 75 minutes after administration of LSD, which is during the peak effects of LSD. The connectivity strength between networks was computed as the difference between averaged and unsigned efferent and afferent connection parameters between networks (see Methods and Materials for further details) (
      • Zhou Y.
      • Friston K.J.
      • Zeidman P.
      • Chen J.
      • Li S.
      • Razi A.
      The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
      ). As shown in Figure 1, at this time, group-level, between-network effective connectivity increased from the SN to the DMN, causing the directed connection to become excitatory. A similar change was observed in the excitatory connectivity from the DMN to the DAN, which resulted in reduced inhibitory connectivity. SN to DMN and DMN to DAN changes from placebo were greatest during the peak effects at 75 minutes and were reduced in the later effects at 300 minutes (Figure 1). These changes show increased afferent connections of the SN and increased efferent connections of the DMN and the DAN from placebo (SN = −1.16 Hz, DMN = +0.32 Hz, DAN = +0.41 Hz) (see the Supplement for explanation and quantitative analysis). See the Supplement for functional connectivity. See the Supplement and Figure 2 for between-region changes in effective connectivity for acute (peak) effects.
      Figure thumbnail gr1
      Figure 1Network effective connectivity change under peak effects of LSD. (A) Highlighted connections show changes in effective connectivity compared with placebo signifying peak effect. (B) Network effective connectivity change graphed across placebo, peak effects, and later effects. Same data as panels (A) and (B) but plotted as a line graph for better visualization. Values display effect sizes (posterior expectations) of connections in hertz. All displayed connections are for posterior probability > .99. DAN, dorsal attention network; DMN, default mode network; SN, salience network.
      Figure thumbnail gr2
      Figure 2Region effective connectivity signifying peak and lasting effects of lysergic acid diethylamide (LSD). Red lines and lettering indicate excitatory change; blue lines and lettering indicate inhibitory change. Only connections with change from placebo to 75 minutes post-LSD > 0.1 Hz are included. Panel (A) illustrates effective connectivity with change > 0.1 Hz from peak effects at 75 minutes to the later effects at 300 minutes, signifying connectivity unique to the peak effects of LSD. See for posterior expectations (effect sizes) and credible intervals. Panel (B) illustrates effective connectivity with change < 0.1 Hz from peak effects at 75 minutes to the later effects at 300 minutes, signifying connectivity changes that last over the effects of LSD. See for posterior expectations (effect size) and credible intervals. All results are for posterior probability > .99. See the for further results and discussion of between-region changes in effective connectivity. dACC, dorsal anterior cingulate cortex; lAG, left angular gyrus; lAI, left anterior insula; lFEF, left frontal eye field; lIPS, left inferior parietal sulcus; mPFC, medial prefrontal cortex; PCC, posterior cingulate cortex; rAG, right angular gyrus; rAI, right anterior insula; rFEF right frontal eye field; rIPS, right inferior parietal sulcus.

      Lasting Effects

      Between-Network Changes in Effective Connectivity

      LSD effects are also distinguished by changes from placebo that last across time under LSD. Increased DAN to DMN and decreased DMN to SN effective connectivity at 75 minutes remained evident 300 minutes after LSD administration (Figure 1; see Figure S3 for effect size and posterior probabilities). See the Supplement and Figure 2 for between-region changes in effective connectivity for lasting effects.

      Behavioral Associations to Ego Dissolution

      The oceanic boundlessness (ego dissolution) dimension of the 5D-ASC was assessed 720 minutes after the administration of LSD. Effective connectivity changes 75 minutes after LSD administration that were associated with ego dissolution are outlined in the Supplement and presented in Figure S4. We also computed effective connectivity behavioral associations with the global mean scores on the 5D-ASC 720 minutes after the administration of LSD. Effective connections with positive association to ego dissolution overlapped all effective connections with positive association to the global score of subjective effects and accounted for 13 of 15 connections identified (see Figure S4). We used the statistical threshold of posterior probability > .99 for these analyses, which amounts to very strong evidence.
      The results demonstrated increased effective connectivity of the DMN to the DAN and of the SN to the DMN during the peak effects of LSD. These changes corresponded with reduced SN increased afferent connections and coincided with a fading of the functional anticorrelation (see Figure S1 for functional connectivity results). Moreover, behavioral associations with effective connectivity suggest that measuring ego dissolution associated with the RSNs captured the overall subjective effects of LSD (see Figure S4).

      Discussion

      This investigation seeks to understand how effective connectivity between anticorrelated large-scale brain networks is related to serotonergic psychedelics and ego dissolution. Our analysis revealed between-network effective connectivity changes that occurred with a diminution of the pattern of anticorrelation under the peak effects of LSD. Bidirectional changes in effective connectivity between the DMN and the DAN were investigated for their hypothesized relationship to subject-object boundaries. We identified reduced inhibition of the DMN to the DAN under the peak effects of LSD. The reduced inhibition is largely lost in the later effects, when ego dissolution dissipates. This indicates reduced inhibition of the DMN to the DAN as a feature of peak LSD effects that may relate to the fading of the functional anticorrelation between these networks. Reduced DMN to DAN inhibition may also represent increased transmission and connection of the narrative self to the sense of object. For instance, the sense of identity may be more readily ascribed to task focus and may, for example, add a quality of identity to the meaning of precepts. Coupling between the DAN and the DMN has also been related to distractibility (
      • Poole V.N.
      • Robinson M.E.
      • Singleton O.
      • DeGutis J.
      • Milberg W.P.
      • McGlinchey R.E.
      • et al.
      Intrinsic functional connectivity predicts individual differences in distractibility.
      ,
      • Amer T.
      • Anderson J.A.E.
      • Campbell K.L.
      • Hasher L.
      • Grady C.L.
      Age differences in the neural correlates of distraction regulation: A network interaction approach.
      ). Under psychedelics, distractibility may relate to context sensitivity and confound environmental stimulus from internal stimulus. For example, inhibition of alpha band oscillations under psychedelics may reduce the excitation elicited by external visual stimuli (
      • Kometer M.
      • Vollenweider F.X.
      Serotonergic hallucinogen-induced visual perceptual alterations.
      ). Reduced alpha oscillations have been identified in the DMN (
      • Carhart-Harris R.L.
      • Muthukumaraswamy S.
      • Roseman L.
      • Kaelen M.
      • Droog W.
      • Murphy K.
      • et al.
      Neural correlates of the LSD experience revealed by multimodal neuroimaging.
      ,
      • Muthukumaraswamy S.D.
      • Carhart-Harris R.L.
      • Moran R.J.
      • Brookes M.J.
      • Williams T.M.
      • Errtizoe D.
      • et al.
      Broadband cortical desynchronization underlies the human psychedelic state.
      ) and may blur the DMN’s capacity for mental simulation with DAN resources ordinarily engaged in external attention. This interpretation may suggest a common mechanism underlying distractibility (i.e., reduced vigilance) and the blending of subject and object under psychedelics. See the Supplement for region-level changes in DMN-DAN effective connectivity.
      Moreover, hierarchical organization and strength of networks were calculated using efferent versus afferent connections (
      • Zhou Y.
      • Friston K.J.
      • Zeidman P.
      • Chen J.
      • Li S.
      • Razi A.
      The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
      ). The DMN and the DAN showed increased efferent connectivity strength during the peak effects of LSD and segregate from the SN under the peak effects of LSD (see the Supplement). The increase in efferent connectivity strength of the DMN and the DAN reinforces evidence of their fading anticorrelation, which underlies psychedelic subjective effects (see Figure S4) and may contribute to the dissolution of the boundary between the subject and the object. The opposite effective connectivity from the DAN to the DMN also displays reduced inhibition under LSD. However, this change remains over the course of time, suggesting that it is not a primary mechanism of the reduced functional anticorrelation between them or the peak effects of LSD.
      Inclusion of the SN in this analysis enabled measurement of its effective connectivity to the DMN and the DAN under LSD. The change to the coordinated balance of networks under the control of the SN by LSD may be an important but overlooked neural mechanism of ego dissolution suggested by the superiority of the SN in this hierarchy of triple networks (
      • Zhou Y.
      • Friston K.J.
      • Zeidman P.
      • Chen J.
      • Li S.
      • Razi A.
      The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
      ). Previous reports of reduced anticorrelation (
      • Carhart-Harris R.L.
      • Leech R.
      • Erritzoe D.
      • Williams T.M.
      • Stone J.M.
      • Evans J.
      • et al.
      Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis.
      ) and reduced SN integrity (
      • Lebedev A.V.
      • Lövdén M.
      • Rosenthal G.
      • Feilding A.
      • Nutt D.J.
      • Carhart-Harris R.L.
      Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin.
      ) in occurrences of ego dissolution and its hypothesized function in basic conscious awareness also indicate the value of measuring SN connectivity in the anticorrelation between the DMN and the DAN. Moreover, ego dissolution has previously been suggested to involve the breakdown of subpersonal processes underlying the minimal self, a suggestion that is consistent with Bayesian models of phenomenal selfhood in which the subjective structure of conscious experience is determined from the optimization of prediction in perception and action (
      • Millière R.
      Looking for the self: Phenomenology, neurophysiology and philosophical significance of drug-induced ego dissolution.
      ,
      • Clark A.
      Whatever next? Predictive brains, situated agents, and the future of cognitive science.
      ,
      • Friston K.
      The free-energy principle: A unified brain theory?.
      ). The change in the SN effective connectivity under the peak effects of LSD is our most pronounced finding. SN connectivity to the DMN changes from inhibitory to excitatory before returning to inhibitory in the later effects. This flip of valence suggests that SN connectivity change to the DMN is mechanistic in the peak effects of LSD and may indirectly influence the DMN-DAN interactions. The opposite connection, the DMN to the SN, shows an inverse pattern of change from placebo, suggesting reduced DMN influence over the SN, which lasts over time. The SN to DMN connectivity change may therefore be a more likely mechanism of ego dissolution representing a quietening of narrative self in the peak effects of LSD that reduces in the later effects. SN to DMN change is accompanied by increased SN afferent connections and increased DMN efferent connections. We demonstrated that the divergence of SN and DMN efferent-afferent strength under the peak effects of LSD shifts the hierarchical order of the SN beneath the DMN. See the Supplement for region-level changes in SN-DMN effective connectivity.
      Taken together, under the peak effects of LSD, a strong increase in change of effective connectivity, and a widening of the gap between the efferent-afferent connectivity strength of the SN compared with the DMN and the DAN shifts in a direction antithetical to normal hierarchical organization (
      • Zhou Y.
      • Friston K.J.
      • Zeidman P.
      • Chen J.
      • Li S.
      • Razi A.
      The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
      ). This may be said to resemble a collapse—or flattening—of the hierarchy during peak effects of LSD when ego dissolution occurs (Figure 1; Supplement). Similar results that express hierarchical flattening have been identified as the reduced differentiation between global functional integration between cortical regions and decreased modularity between various brain networks (
      • Petri G.
      • Expert P.
      • Turkheimer F.
      • Carhart-Harris R.
      • Nutt D.
      • Hellyer P.J.
      • Vaccarino F.
      Homological scaffolds of brain functional networks.
      ,
      • Tagliazucchi E.
      • Roseman L.
      • Kaelen M.
      • Orban C.
      • Muthukumaraswamy S.D.
      • Murphy K.
      • et al.
      Increased global functional connectivity correlates with LSD-induced ego dissolution.
      ,
      • Girn M.
      • Roseman L.
      • Bernhardt B.
      • Smallwood J.
      • Carhart-Harris R.
      • Nathan Spreng R.
      Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex.
      ). Effective connectivity explains this effect as increased excitatory connectivity from the SN to the DMN and increased inhibition from the DMN to the SN. These directed connection changes and the efferent-afferent changes underlie the effects of 100 μg of LSD across our group of participants and may function to alter the relationship between the minimal and narrative senses of self. Although more precise measurement of ego dissolution is required to confirm this hypothesis, the direction of this change suggests that the influence of the minimal self traverses over the narrative self and may relate to the shift in sense of self described under ego dissolution.
      Modeling the connectivity of ego dissolution can provide a means to determine the neural mechanisms that underlie the perception of inner and outer reality. This research establishes important steps to identify the change in network interactions associated with the dichotomy of the subject-object relationship under LSD. Understanding network changes that induce psychedelic subjective effects informs the neural mechanisms of psychedelic ego dissolution and advances our understanding of connectivity associated with the sense of self and the sense of separation between the self and the world. The networks involved in this interaction are important in cognitive function and mental well-being, suggesting that understanding the change in networks occurring due to psychedelics may help elucidate mechanisms of psychedelic clinical therapy. Consideration of practical and theoretical challenges may aid future research directed to study ego dissolution and the anticorrelation between brain networks.
      Our relatively small sample size (n = 20) is clearly a limitation. Sample size and processing pipeline strongly affect the reliability of results. Small sample size may also account for unexpected placebo effective connectivity in our study participants. A second practical limitation is the large variance of participant subjective responses to a standard dose of LSD (100 μg). Averaging the connectivity of participants experiencing highly variable subjective shifts in consciousness may dilute the effective connectivity representing subjective effects of LSD. An alternative to increased sample size may be predetermining participant dose response and including only participants with high subjective responses in the analysis, although score variance can benefit the analysis of behavioral associations. Moreover, in this analysis, we did not ascertain to what degree ego dissolution was felt during the acquired scans. Future analyses should pay closer attention to the level of ego dissolution at the time of imaging. See the Supplement for further discussion and limitations.
      Future work to extend the current scope of analysis to include connectivity dynamics of additional task-positive networks anticorrelated to the DMN and under control of the SN is required. For example, nonpsychedelic research involving the central executive network, also known as the frontoparietal central executive network, has been conducted to investigate schizophrenia (
      • Menon V.
      Large-scale brain networks and psychopathology: A unifying triple network model.
      ,
      • Leptourgos P.
      • Fortier-Davy M.
      • Carhart-Harris R.
      • Corlett P.R.
      • Dupuis D.
      • Halberstadt A.L.
      • et al.
      Hallucinations under psychedelics and in the schizophrenia spectrum: An interdisciplinary and multiscale comparison.
      ), meditation (
      • Doll A.
      • Hölzel B.K.
      • Boucard C.C.
      • Wohlschläger A.M.
      • Sorg C.
      Mindfulness is associated with intrinsic functional connectivity between default mode and salience networks.
      ), and control of attention (
      • Corbetta M.
      • Shulman G.L.
      Control of goal-directed and stimulus-driven attention in the brain.
      ). Its importance is further signified by investigations of large-scale network interactions and anticorrelations with the DMN (
      • Andrews-Hanna J.R.
      • Smallwood J.
      • Spreng R.N.
      The default network and self-generated thought: Component processes, dynamic control, and clinical relevance.
      ,
      • Bolton T.A.W.
      • Wotruba D.
      • Buechler R.
      • Theodoridou A.
      • Michels L.
      • Kollias S.
      • et al.
      Triple network model dynamically revisited: Lower salience network state switching in pre-psychosis.
      ,
      • Menon V.
      The triple network model, insight, and large-scale brain organization in autism.
      ). Inclusion of the central executive network in anticorrelation investigations may provide a more complete account of anticorrelated network changes associated with ego dissolution.
      The between-network balance of anticorrelated activity of specific RSNs depends on subtle adjustments to network activation. Mental well-being and efficient cognition rely on the balance of these interactions. LSD appears to shift the balance of network activation and diminish the anticorrelation between brain networks responsible for internal and external modes of perception. These findings suggest the effective connectivity of anticorrelated network interactions as a network-level neural mechanism of ego dissolution. Observed increases in effective connectivity from the DMN to the DAN and altered network efferent-afferent differences under peak effects may account for the blurring of the boundary between subject and object experienced in ego dissolution. Ego dissolution also involves a shift in the sense of self that may be explained by changes to the interactions between the SN and the DMN. These networks are related to distinct aspects of self. Increased effective connectivity from the SN to the DMN was our most notable finding that emphasized increased salience functions reaching the DMN under the peak effects of LSD. Future research is recommended to relate micro- and meso-level dynamics to identified network effective connectivity changes and to investigate therapeutic associations between subject-object and self-other relationships affected by ego dissolution. This association may help identify network connectivity changes that support psychedelic therapeutic outcomes and help explain the psychological association between ego dissolution and well-being. The neuroscientific study of psychedelic-induced ego dissolution reminds us that constructs and representations of self and internal and external reality exist in connectivity dynamics. This intriguing understanding may inspire future investigations of sentience and consciousness to learn how normal brain function mechanisms contribute to the subject-object relationship and frame our perspective of reality.

      Acknowledgments and Disclosures

      This work was supported by the Swiss Neuromatrix Foundation (Grant No. 2015-0103 [to FXV]), Usona Institute (Grant No. 2015-2056 [to FXV]), Australian Research Council Discovery Early Career Research Award Fellowship (Grant No. DE170100128 [to AR]), Australian Research Council Discovery Project (Grant No. DP200100757 [to AR]), and Australian National Health and Medical Research Council (Investigator Grant No. 1194910 [to AR]). Wellcome Centre for Human Neuroimaging was supported by core funding ( Wellcome Grant No. 203147/Z/16/Z [to AR]).
      DS and AR were responsible for conceptualization of the study; DS, LN, and AR were responsible for methodology, conducting the investigation, and visualization; AR was responsible for supervision; DS wrote the original draft of this article; DS, LN, AR, GE, KP, and FXV reviewed and edited the manuscript.
      A previous version of this article was published as a preprint on medRxiv: https://doi.org/10.1101/2021.12.28.21268391.
      All data are available in the main text, Supplement, or by request to the corresponding author.
      The authors report no biomedical financial interests or potential conflicts of interest.

      References

        • Vollenweider F.X.
        • Leenders K.L.
        • Scharfetter C.
        • Maguire P.
        • Stadelmann O.
        • Angst J.
        Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis.
        Neuropsychopharmacology. 1997; 16: 357-372
        • Vollenweider F.X.
        Advances and pathophysiological models of hallucinogenic drug actions in humans: A preamble to schizophrenia research.
        Pharmacopsychiatry. 1998; 31: 92-103
        • Preller K.H.
        • Vollenweider F.X.
        Phenomenology, structure, and dynamic of psychedelic states [published correction appears in Curr Top Behav Neurosci 2018; 36:1].
        Curr Top Behav Neurosci. 2018; 36: 221-256
        • Johnson M.
        • Richards W.
        • Griffiths R.
        Human hallucinogen research: Guidelines for safety.
        J Psychopharmacol. 2008; 22: 603-620
        • Carhart-Harris R.L.
        How do psychedelics work?.
        Curr Opin Psychiatry. 2019; 32: 16-21
        • Roseman L.
        • Nutt D.J.
        • Carhart-Harris R.L.
        Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression.
        Front Pharmacol. 2018; 8: 974
        • Yaden D.B.
        • Griffiths R.R.
        The subjective effects of psychedelics are necessary for their enduring therapeutic effects.
        ACS Pharmacol Transl Sci. 2020; 4: 568-572
        • Stoliker D.
        • Egan G.F.
        • Friston K.J.
        • Razi A.
        Neural mechanisms and psychology of psychedelic ego dissolution.
        Pharmacol Rev. 2022; 74: 874-917
        • Dittrich A.
        The standardized psychometric assessment of altered states of consciousness (ASCs) in humans.
        Pharmacopsychiatry. 1998; 31: 80-84
        • Studerus E.
        • Gamma A.
        • Vollenweider F.X.
        Psychometric evaluation of the altered states of consciousness rating scale (OAV).
        PLoS One. 2010; 5e12412
        • Vollenweider F.X.
        • Smallridge J.W.
        Classic psychedelic drugs: Update of biological mechanisms.
        Pharmacopsychiatry. 2022; 55: 121-138
        • Lebedev A.V.
        • Lövdén M.
        • Rosenthal G.
        • Feilding A.
        • Nutt D.J.
        • Carhart-Harris R.L.
        Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin.
        Hum Brain Mapp. 2015; 36: 3137-3153
        • Grof S.
        LSD Psychotherapy.
        Hunter House Publishers, California1980
        • Nour M.M.
        • Evans L.
        • Nutt D.
        • Carhart-Harris R.L.
        Ego-dissolution and psychedelics: Validation of the ego-dissolution inventory (EDI).
        Front Hum Neurosci. 2016; 10: 269
        • Müller F.
        • Dolder P.C.
        • Schmidt A.
        • Liechti M.E.
        • Borgwardt S.
        Altered network hub connectivity after acute LSD administration.
        NeuroImage Clin. 2018; 18: 694-701
        • Preller K.H.
        • Burt J.B.
        • Ji J.L.
        • Schleifer C.H.
        • Adkinson B.D.
        • Stämpfli P.
        • et al.
        Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor.
        Elife. 2018; 7e35082
        • Raichle M.E.
        The brain’s default mode network.
        Annu Rev Neurosci. 2015; 38: 433-447
        • Friston K.J.
        Functional and effective connectivity: A review.
        Brain Connect. 2011; 1: 13-36
        • Greicius M.D.
        • Menon V.
        Default-mode activity during a passive sensory task: Uncoupled from deactivation but impacting activation.
        J Cogn Neurosci. 2004; 16: 1484-1492
        • Fox M.D.
        • Snyder A.Z.
        • Vincent J.L.
        • Corbetta M.
        • Van Essen D.C.
        • Raichle M.E.
        The human brain is intrinsically organized into dynamic, anticorrelated functional networks.
        Proc Natl Acad Sci U S A. 2005; 102: 9673-9678
        • Raichle M.E.
        • MacLeod A.M.
        • Snyder A.Z.
        • Powers W.J.
        • Gusnard D.A.
        • Shulman G.L.
        A default mode of brain function.
        Proc Natl Acad Sci U S A. 2001; 98: 676-682
        • Andrews-Hanna J.R.
        • Smallwood J.
        • Spreng R.N.
        The default network and self-generated thought: Component processes, dynamic control, and clinical relevance.
        Ann N Y Acad Sci. 2014; 1316: 29-52
        • Corbetta M.
        • Shulman G.L.
        Control of goal-directed and stimulus-driven attention in the brain.
        Nat Rev Neurosci. 2002; 3: 201-215
        • Fox M.D.
        • Raichle M.E.
        Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging.
        Nat Rev Neurosci. 2007; 8: 700-711
        • Liang X.
        • He Y.
        • Salmeron B.J.
        • Gu H.
        • Stein E.A.
        • Yang Y.
        Interactions between the salience and default-mode networks are disrupted in cocaine addiction.
        J Neurosci. 2015; 35: 8081-8090
        • Seeley W.W.
        • Menon V.
        • Schatzberg A.F.
        • Keller J.
        • Glover G.H.
        • Kenna H.
        • et al.
        Dissociable intrinsic connectivity networks for salience processing and executive control.
        J Neurosci. 2007; 27: 2349-2356
        • Swick D.
        • Ashley V.
        • Turken U.
        Are the neural correlates of stopping and not going identical? Quantitative meta-analysis of two response inhibition tasks.
        Neuroimage. 2011; 56: 1655-1665
        • Ide J.S.
        • Shenoy P.
        • Yu A.J.
        • Li C.S.
        Bayesian prediction and evaluation in the anterior cingulate cortex.
        J Neurosci. 2013; 33: 2039-2047
        • Menon V.
        Large-scale brain networks and psychopathology: A unifying triple network model.
        Trends Cogn Sci. 2011; 15: 483-506
        • Averbeck B.B.
        • Seo M.
        The statistical neuroanatomy of frontal networks in the macaque.
        PLoS Comput Biol. 2008; 4e1000050
        • Vogt B.A.
        • Pandya D.N.
        Cingulate cortex of the rhesus monkey: II. Cortical afferents.
        J Comp Neurol. 1987; 262: 271-289
        • Menon V.
        Salience Network.
        in: Toga A.W. Brain Mapping: An Encyclopedic Reference. vol. 2. Elsevier, Amsterdam2015: 597-611
        • Ju A.
        • Fernandez-Arroyo B.
        • Wu Y.
        • Jacky D.
        • Beyeler A.
        Expression of serotonin 1A and 2A receptors in molecular- and projection-defined neurons of the mouse insular cortex.
        Mol Brain. 2020; 13: 99
        • Menon V.
        • Uddin L.Q.
        Saliency, switching, attention and control: A network model of insula function.
        Brain Struct Funct. 2010; 214: 655-667
        • Sridharan D.
        • Levitin D.J.
        • Menon V.
        A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks.
        Proc Natl Acad Sci U S A. 2008; 105: 12569-12574
        • Fecteau J.H.
        • Munoz D.P.
        Salience, relevance, and firing: A priority map for target selection.
        Trends Cogn Sci. 2006; 10: 382-390
        • Egner T.
        • Monti J.M.P.
        • Trittschuh E.H.
        • Wieneke C.A.
        • Hirsch J.
        • Mesulam M.M.
        Neural integration of top-down spatial and feature-based information in visual search.
        J Neurosci. 2008; 28: 6141-6151
        • Szczepanski S.M.
        • Pinsk M.A.
        • Douglas M.M.
        • Kastner S.
        • Saalmann Y.B.
        Functional and structural architecture of the human dorsal frontoparietal attention network.
        Proc Natl Acad Sci U S A. 2013; 110: 15806-15811
        • Putcha D.
        • Ross R.S.
        • Cronin-Golomb A.
        • Janes A.C.
        • Stern C.E.
        Salience and default mode network coupling predicts cognition in aging and Parkinson’s disease.
        J Int Neuropsychol Soc. 2016; 22: 205-215
        • Chand G.B.
        • Wu J.
        • Hajjar I.
        • Qiu D.
        Interactions of the salience network and its subsystems with the default-mode and the central-executive networks in normal aging and mild cognitive impairment.
        Brain Connect. 2017; 7: 401-412
        • Bonnelle V.
        • Ham T.E.
        • Leech R.
        • Kinnunen K.M.
        • Mehta M.A.
        • Greenwood R.J.
        • et al.
        Salience network integrity predicts default mode network function after traumatic brain injury.
        Proc Natl Acad Sci U S A. 2012; 109: 4690-4695
        • Manoliu A.
        • Riedl V.
        • Zherdin A.
        • Mühlau M.
        • Schwerthöffer D.
        • Scherr M.
        • et al.
        Aberrant dependence of default mode/central executive network interactions on anterior insular salience network activity in schizophrenia.
        Schizophr Bull. 2014; 40: 428-437
        • Wotruba D.
        • Michels L.
        • Buechler R.
        • Metzler S.
        • Theodoridou A.
        • Gerstenberg M.
        • et al.
        Aberrant coupling within and across the default mode, task-positive, and salience network in subjects at risk for psychosis.
        Schizophr Bull. 2014; 40: 1095-1104
        • Palaniyappan L.
        • Liddle P.F.
        Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction.
        J Psychiatry Neurosci. 2012; 37: 17-27
        • Peterson A.
        • Thome J.
        • Frewen P.
        • Lanius R.A.
        Resting-state neuroimaging studies: A new way of identifying differences and similarities among the anxiety disorders?.
        Can J Psychiatry. 2014; 59: 294-300
        • Blanke O.
        • Metzinger T.
        Full-body illusions and minimal phenomenal selfhood.
        Trends Cogn Sci. 2009; 13: 7-13
        • Legrand D.
        • Ruby P.
        What is self-specific? Theoretical investigation and critical review of neuroimaging results.
        Psychol Rev. 2009; 116: 252-282
        • Liu C.H.
        • Guo J.
        • Lu S.L.
        • Tang L.R.
        • Fan J.
        • Wang C.Y.
        • et al.
        Increased salience network activity in patients with insomnia complaints in major depressive disorder.
        Front Psychiatry. 2018; 9: 93
        • Doll A.
        • Hölzel B.K.
        • Boucard C.C.
        • Wohlschläger A.M.
        • Sorg C.
        Mindfulness is associated with intrinsic functional connectivity between default mode and salience networks.
        Front Hum Neurosci. 2015; 9: 461
        • Ramírez-Barrantes R.
        • Arancibia M.
        • Stojanova J.
        • Aspé-Sánchez M.
        • Córdova C.
        • Henríquez-Ch R.A.
        Default mode network, meditation, and age-associated brain changes: What can we learn from the impact of mental training on well-being as a psychotherapeutic approach?.
        Neural Plast. 2019; 20197067592
        • Nour M.M.
        • Carhart-Harris R.L.
        Psychedelics and the science of self-experience.
        Br J Psychiatry. 2017; 210: 177-179
        • Ho J.T.
        • Preller K.H.
        • Lenggenhager B.
        Neuropharmacological modulation of the aberrant bodily self through psychedelics.
        Neurosci Biobehav Rev. 2020; 108: 526-541
        • Metzinger T.
        Being No One: The Self-Model Theory of Subjectivity.
        MIT Press, Cambridge, MA2003
        • Millière R.
        Looking for the self: Phenomenology, neurophysiology and philosophical significance of drug-induced ego dissolution.
        Front Hum Neurosci. 2017; 11: 245
        • Sormaz M.
        • Murphy C.
        • Wang H.T.
        • Hymers M.
        • Karapanagiotidis T.
        • Poerio G.
        • et al.
        Default mode network can support the level of detail in experience during active task states [published correction appears in Proc Natl Acad Sci U S A 2018; 115:E11198].
        Proc Natl Acad Sci U S A. 2018; 115: 9318-9323
        • Dohmatob E.
        • Dumas G.
        • Bzdok D.
        Dark control: The default mode network as a reinforcement learning agent.
        Hum Brain Mapp. 2020; 41: 3318-3341
        • Vollenweider F.X.
        • Preller K.H.
        Psychedelic drugs: Neurobiology and potential for treatment of psychiatric disorders.
        Nat Rev Neurosci. 2020; 21: 611-624
        • Carhart-Harris R.L.
        • Friston K.J.
        The default-mode, ego-functions and free-energy: A neurobiological account of Freudian ideas.
        Brain. 2010; 133: 1265-1283
        • Cieri F.
        • Esposito R.
        Psychoanalysis and neuroscience: The bridge between mind and brain.
        Front Psychol. 2019; 10: 1790
        • Ruban A.
        • Kołodziej A.
        Changes in default-mode network activity and functional connectivity as an indicator of psychedelic-assisted psychotherapy effectiveness.
        Neuropsychiatria i Neuropsychol. 2018; 13: 91-97
        • Hasenkamp W.
        • Wilson-Mendenhall C.D.
        • Duncan E.
        • Barsalou L.W.
        Mind wandering and attention during focused meditation: A fine-grained temporal analysis of fluctuating cognitive states.
        Neuroimage. 2012; 59: 750-760
        • Brewer J.A.
        • Worhunsky P.D.
        • Gray J.R.
        • Tang Y.Y.
        • Weber J.
        • Kober H.
        Meditation experience is associated with differences in default mode network activity and connectivity.
        Proc Natl Acad Sci U S A. 2011; 108: 20254-20259
        • Batchelor S.
        Buddhism Without Beliefs: A Contemporary Guide to Awakening.
        Bloomsbury Publishing, London2008
        • Millière R.
        • Carhart-Harris R.L.
        • Roseman L.
        • Trautwein F.M.
        • Berkovich-Ohana A.
        Psychedelics, meditation, and self-consciousness.
        Front Psychol. 2018; 9: 1475
        • Osmond H.
        A review of the clinical effects of psychotomimetic agents.
        Ann N Y Acad Sci. 1957; 66: 418-434
        • Swanson L.R.
        Unifying theories of psychedelic drug effects.
        Front Pharmacol. 2018; 9: 172
        • Nutt D.
        • Carhart-Harris R.
        The current status of psychedelics in psychiatry.
        JAMA Psychiatry. 2021; 78: 121-122
        • Carhart-Harris R.L.
        • Bolstridge M.
        • Day C.M.J.
        • Rucker J.
        • Watts R.
        • Erritzoe D.E.
        • et al.
        Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up.
        Psychopharmacology. 2018; 235: 399-408
        • Goyal M.
        • Singh S.
        • Sibinga E.M.
        • Gould N.F.
        • Rowland-Seymour A.
        • Sharma R.
        • et al.
        Meditation programs for psychological stress and well-being: A systematic review and meta-analysis.
        JAMA Intern Med. 2014; 174: 357-368
        • Ross S.
        • Bossis A.
        • Guss J.
        • Agin-Liebes G.
        • Malone T.
        • Cohen B.
        • et al.
        Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial.
        J Psychopharmacol. 2016; 30: 1165-1180
        • Griffiths R.R.
        • Johnson M.W.
        • Carducci M.A.
        • Umbricht A.
        • Richards W.A.
        • Richards B.D.
        • et al.
        Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.
        J Psychopharmacol. 2016; 30: 1181-1197
        • Dambrun M.
        Self-centeredness and selflessness: Happiness correlates and mediating psychological processes.
        PeerJ. 2017; 5e3306
        • Josipovic Z.
        • Dinstein I.
        • Weber J.
        • Heeger D.J.
        Influence of meditation on anti-correlated networks in the brain.
        Front Hum Neurosci. 2012; 5: 183
        • Carhart-Harris R.L.
        • Leech R.
        • Erritzoe D.
        • Williams T.M.
        • Stone J.M.
        • Evans J.
        • et al.
        Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis.
        Schizophr Bull. 2013; 39: 1343-1351
        • Palhano-Fontes F.
        • Andrade K.C.
        • Tofoli L.F.
        • Santos A.C.
        • Crippa J.A.
        • Hallak J.E.
        • et al.
        The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network.
        PLoS One. 2015; 10e0118143
        • Friston K.J.
        • Harrison L.
        • Penny W.
        Dynamic causal modelling.
        Neuroimage. 2003; 19: 1273-1302
        • Friston K.J.
        • Kahan J.
        • Biswal B.
        • Razi A.
        A DCM for resting state fMRI.
        NeuroImage. 2014; 94: 396-407
        • Preller K.H.
        • Razi A.
        • Zeidman P.
        • Stämpfli P.
        • Friston K.J.
        • Vollenweider F.X.
        Effective connectivity changes in LSD-induced altered states of consciousness in humans.
        Proc Natl Acad Sci U S A. 2019; 116: 2743-2748
        • Zhou Y.
        • Friston K.J.
        • Zeidman P.
        • Chen J.
        • Li S.
        • Razi A.
        The hierarchical organization of the default, dorsal attention and salience networks in adolescents and young adults.
        Cereb Cortex. 2018; 28: 726-737
        • Northoff G.
        • Heinzel A.
        • de Greck M.
        • Bermpohl F.
        • Dobrowolny H.
        • Panksepp J.
        Self-referential processing in our brain—A meta-analysis of imaging studies on the self.
        Neuroimage. 2006; 31: 440-457
        • Scalabrini A.
        • Vai B.
        • Poletti S.
        • Damiani S.
        • Mucci C.
        • Colombo C.
        • et al.
        All roads lead to the default-mode network-global source of DMN abnormalities in major depressive disorder.
        Neuropsychopharmacology. 2020; 45: 2058-2069
        • Calhoun V.D.
        • Adali T.
        • Pearlson G.D.
        • Pekar J.J.
        A method for making group inferences from functional MRI data using independent component analysis [published correction appears in Hum Brain Mapp 2002; 16:131].
        Hum Brain Mapp. 2001; 14: 140-151
        • Biswal B.B.
        • Mennes M.
        • Zuo X.N.
        • Gohel S.
        • Kelly C.
        • Smith S.M.
        • et al.
        Toward discovery science of human brain function.
        Proc Natl Acad Sci U S A. 2010; 107: 4734-4739
        • Shirer W.R.
        • Ryali S.
        • Rykhlevskaia E.
        • Menon V.
        • Greicius M.D.
        Decoding subject-driven cognitive states with whole-brain connectivity patterns.
        Cereb Cortex. 2012; 22: 158-165
        • Tsvetanov K.A.
        • Henson R.N.
        • Tyler L.K.
        • Razi A.
        • Geerligs L.
        • Ham T.E.
        • et al.
        Extrinsic and intrinsic brain network connectivity maintains cognition across the lifespan despite accelerated decay of regional brain activation.
        J Neurosci. 2016; 36: 3115-3126
        • Andrews-Hanna J.R.
        • Reidler J.S.
        • Sepulcre J.
        • Poulin R.
        • Buckner R.L.
        Functional-anatomic fractionation of the brain’s default network.
        Neuron. 2010; 65: 550-562
        • Dixon M.L.
        • Andrews-Hanna J.R.
        • Spreng R.N.
        • Irving Z.C.
        • Mills C.
        • Girn M.
        • Christoff K.
        Interactions between the default network and dorsal attention network vary across default subsystems, time, and cognitive states.
        Neuroimage. 2017; 147: 632-649
        • Fransson P.
        Spontaneous low-frequency BOLD signal fluctuations: An fMRI investigation of the resting-state default mode of brain function hypothesis.
        Hum Brain Mapp. 2005; 26: 15-29
        • Fox M.D.
        • Zhang D.
        • Snyder A.Z.
        • Raichle M.E.
        The global signal and observed anticorrelated resting state brain networks.
        J Neurophysiol. 2009; 101: 3270-3283
        • Uddin L.Q.
        • Kelly A.M.
        • Biswal B.B.
        • Castellanos F.X.
        • Milham M.P.
        Functional connectivity of default mode network components: Correlation, anticorrelation, and causality.
        Hum Brain Mapp. 2009; 30: 625-637
        • Chen J.E.
        • Glover G.H.
        • Greicius M.D.
        • Chang C.
        Dissociated patterns of anti-correlations with dorsal and ventral default-mode networks at rest.
        Hum Brain Mapp. 2017; 38: 2454-2465
        • Razi A.
        • Kahan J.
        • Rees G.
        • Friston K.J.
        Construct validation of a DCM for resting state fMRI.
        NeuroImage. 2015; 106: 1-14
        • Friston K.J.
        • Litvak V.
        • Oswal A.
        • Razi A.
        • Stephan K.E.
        • van Wijk B.C.M.
        • et al.
        Bayesian model reduction and empirical Bayes for group (DCM) studies.
        Neuroimage. 2016; 128: 413-431
        • Goulas A.
        • Uylings H.B.
        • Stiers P.
        Mapping the hierarchical layout of the structural network of the macaque prefrontal cortex.
        Cereb Cortex. 2014; 24: 1178-1194
        • Nee D.E.
        • D’Esposito M.
        The hierarchical organization of the lateral prefrontal cortex.
        Elife. 2016; 5e12112
        • Poole V.N.
        • Robinson M.E.
        • Singleton O.
        • DeGutis J.
        • Milberg W.P.
        • McGlinchey R.E.
        • et al.
        Intrinsic functional connectivity predicts individual differences in distractibility.
        Neuropsychologia. 2016; 86: 176-182
        • Amer T.
        • Anderson J.A.E.
        • Campbell K.L.
        • Hasher L.
        • Grady C.L.
        Age differences in the neural correlates of distraction regulation: A network interaction approach.
        Neuroimage. 2016; 139: 231-239
        • Kometer M.
        • Vollenweider F.X.
        Serotonergic hallucinogen-induced visual perceptual alterations.
        Curr Top Behav Neurosci. 2018; 36: 257-282
        • Carhart-Harris R.L.
        • Muthukumaraswamy S.
        • Roseman L.
        • Kaelen M.
        • Droog W.
        • Murphy K.
        • et al.
        Neural correlates of the LSD experience revealed by multimodal neuroimaging.
        Proc Natl Acad Sci U S A. 2016; 113: 4853-4858
        • Muthukumaraswamy S.D.
        • Carhart-Harris R.L.
        • Moran R.J.
        • Brookes M.J.
        • Williams T.M.
        • Errtizoe D.
        • et al.
        Broadband cortical desynchronization underlies the human psychedelic state.
        J Neurosci. 2013; 33: 15171-15183
        • Clark A.
        Whatever next? Predictive brains, situated agents, and the future of cognitive science.
        Behav Brain Sci. 2013; 36: 181-204
        • Friston K.
        The free-energy principle: A unified brain theory?.
        Nat Rev Neurosci. 2010; 11: 127-138
        • Petri G.
        • Expert P.
        • Turkheimer F.
        • Carhart-Harris R.
        • Nutt D.
        • Hellyer P.J.
        • Vaccarino F.
        Homological scaffolds of brain functional networks.
        J R Soc Interface. 2014; 1120140873
        • Tagliazucchi E.
        • Roseman L.
        • Kaelen M.
        • Orban C.
        • Muthukumaraswamy S.D.
        • Murphy K.
        • et al.
        Increased global functional connectivity correlates with LSD-induced ego dissolution.
        Curr Biol. 2016; 26: 1043-1050
        • Girn M.
        • Roseman L.
        • Bernhardt B.
        • Smallwood J.
        • Carhart-Harris R.
        • Nathan Spreng R.
        Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex.
        Neuroimage. 2022; 256119220
        • Leptourgos P.
        • Fortier-Davy M.
        • Carhart-Harris R.
        • Corlett P.R.
        • Dupuis D.
        • Halberstadt A.L.
        • et al.
        Hallucinations under psychedelics and in the schizophrenia spectrum: An interdisciplinary and multiscale comparison.
        Schizophr Bull. 2020; 46: 1396-1408
        • Bolton T.A.W.
        • Wotruba D.
        • Buechler R.
        • Theodoridou A.
        • Michels L.
        • Kollias S.
        • et al.
        Triple network model dynamically revisited: Lower salience network state switching in pre-psychosis.
        Front Physiol. 2020; 11: 66
        • Menon V.
        The triple network model, insight, and large-scale brain organization in autism.
        Biol Psychiatry. 2018; 84: 236-238