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Effective connectivity of functionally anticorrelated networks under LSD

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 blurring of boundary between the self and the world. A similar phenomenon is identified in psychopathology and is associated to the balance of anticorrelated activity between the default mode network (DMN) – which directs attention inwards – and the salience network (SN) – which recruits the dorsal attention network (DAN) to direct attention outward.

      Methods

      To test whether change in anticorrelated networks underlie the peak effects of LSD, we applied dynamic causal modeling to infer effective connectivity of resting state functional MRI scans from a study of 25 healthy adults who were administered 100μg of LSD, or placebo.

      Results

      We found that inhibitory effective connectivity from the SN to DMN became excitatory, and inhibitory effective connectivity from DMN to DAN decreased under the peak effect of LSD.

      Conclusions

      The effective connectivity changes we identify 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 changes to sense of self and subject-object boundaries across different states of consciousness may depend upon the organised balance of effective connectivity of resting state networks.

      Keywords

      Introduction:

      Classic psychedelics are powerful substances with low toxicity that can temporarily alter brain activity and produce profound changes to consciousness (
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      • Vollenweider F.X.
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      • Preller K.H.
      • Vollenweider F.X.
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      Johnson M, Richards W, Griffiths R (2008): Human hallucinogen research: guidelines for safety. London, England, pp 603-620.

      ,
      • Carhart-Harris R.L.
      How do psychedelics work?.
      ). Their mind altering effects that 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 characterised by ego dissolution (
      • Preller K.H.
      • Vollenweider F.X.
      Phenomenology, Structure, and Dynamic of Psychedelic States.
      ,

      Stoliker D, Egan G, Friston K, Razi A (2021): Neural Mechanisms and Psychology of Psychedelic Ego Dissolution. PsyArXiv.

      ), described as the shift in the sense of self and a loss of boundary between the subjective and the objective world (
      • 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).
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      • Lebedev A.V.
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      • Nutt D.J.
      • Carhart-Harris R.L.
      Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin.
      ,

      Grof S (1980): LSD Psychotherapy. Alameda, CA: Hunter House Publishers.

      ). 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, Friston K, Razi A (2021): Neural Mechanisms and Psychology of Psychedelic Ego Dissolution. PsyArXiv.

      ,
      • Müller F.
      • Dolder P.C.
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      Altered network hub connectivity after acute LSD administration.
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      ).
      Functional magnetic resonance imaging (fMRI) investigations indicate activity across the brain is functionally integrated and forms multiple RSNs (
      • Raichle M.E.
      The brain's default mode network.
      ). RSNs are associated to mental activity and the balance of connectivity between them is associated to the direction of conscious attention (
      • Friston K.J.
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      ,
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      The human brain is intrinsically organized into dynamic, anticorrelated functional networks.
      ). The default mode network (DMN) composed of the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and (bilateral) angular gyrus (AG) is a RSN that activates primarily in the absence of immediate external goal-directed attention (
      • Raichle M.E.
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      ). Its function in self-focused thinking and attention suggests its close relationship to the ego (
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      ). In contrast, the dorsal attention network (DAN) is a RSN activated during external-focused task-driven attention (
      • Corbetta M.
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      ,
      • Fox M.D.
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      ) and is usually considered to be composed of the frontal eye field (FEF) and intraparietal sulcus (IPS) bilaterally. The activity of the DMN and 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 hypothesised 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 resting state network, 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.
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      ) and recruits neural activity in response to stimuli. The SN’s cardinal regions are the dorsal anterior cingulate cortex (dACC) and anterior insula (AI). Both the dACC and AI are consistently coactivated across cognitive tasks (
      • Swick D.
      • Ashley V.
      • Turken U.
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      ). 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.
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      ), while the AI receives greater multimodal sensory input (
      • Averbeck B.B.
      • Seo M.
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      ,
      • Vogt B.A.
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      ), detects behaviourally relevant stimuli (

      Menon V (2015): Salience Network. Elsevier.

      ), coordinates responses to stimuli, for example anxiety (
      • Ju A.
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      • Wu Y.
      • Jacky D.
      • Beyeler A.
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      ) and coordinates the dynamic interactions of anticorrelated networks (
      • Menon V.
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      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. 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.
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      • 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 (2015): Salience Network. Elsevier.

      ). 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.
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      ). Trauma to the white matter tracts within the SN that connect the right AI (rAI) and 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 SN connectivity and its anticorrelated interactions is indicative of schizophrenia (
      • Manoliu A.
      • Riedl V.
      • Zherdin A.
      • Mühlau M.
      • Schwerthöffer D.
      • Scherr M.
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      Aberrant dependence of default mode/central executive network interactions on anterior insular salience network activity in schizophrenia.
      ), psychosis (
      • Wotruba D.
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      • Buechler R.
      • Metzler S.
      • Theodoridou A.
      • Gerstenberg M.
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      Aberrant Coupling Within and Across the Default Mode, Task-Positive, and Salience Network in Subjects at Risk for Psychosis.
      ,
      • Palaniyappan L.
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      Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction.
      ) and internalizing disorders (
      • Peterson A.
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      • Frewen P.
      • Lanius R.A.
      Resting-State Neuroimaging Studies: A New Way of Identifying Differences and Similarities among the Anxiety Disorders?.
      ) (see Menon 2015 for review of SN associations to psychopathology) (
      • Menon V.
      Large-scale brain networks and psychopathology: a unifying triple network model.
      ).
      The DMN and SN have been previously investigated in relation to unique senses of self. The SN has been suggested to be involved in an aspect of the 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.
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      Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin.
      ,
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      ,

      Legrand D, Ruby P (2009): What is self-specific? Theoretical investigation and critical review of neuroimaging results. American Psychological Association, pp 252-282.

      ). This association is supported by changes to the SN documented in psychopathology (
      • Liu C.-H.
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      • 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.
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      • Wohlschläger A.M.
      • Sorg C.
      Mindfulness is associated with intrinsic functional connectivity between default mode and salience networks.
      ,
      • Ramirez Barrantes R.
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      • Córdova C.
      • Henríquez R.A.
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      ) 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 Supplementary Table 1 for a subset of psychedelic findings related to networks and regions of interest). The pre-reflective 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.
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      ). 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 (2003): Being no one: The self-model theory of subjectivity. Cambridge, MA, US: MIT Press.

      ,
      • Millière R.
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      ). 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.
      ,
      • 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.
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      ,
      • Ruban A.
      • Kolodziej A.A.
      Changes in default-mode network activity and functional connectivity as an indicator of psychedelic-assisted psychotherapy effectiveness.
      ).
      Reduced associative 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 (2008): Buddhism without beliefs : a contemporary guide to awakening. London: Bloomsbury.

      ,
      • 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 psychedelics disinhibit cognitive defenses (

      Batchelor S (2008): Buddhism without beliefs : a contemporary guide to awakening. London: Bloomsbury.

      ,
      • 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.
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      ). Meditation also has demonstrated clinical utility that reflects reports of reduced symptoms of patients experiencing internalising mental health disorders following psychedelic therapy (
      • Ruban A.
      • Kolodziej A.A.
      Changes in default-mode network activity and functional connectivity as an indicator of psychedelic-assisted psychotherapy effectiveness.
      ,
      • Nutt D.
      • Carhart-Harris R.
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      ,
      • 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.
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      ). 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.
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      ). For example, altered relationship between self and other by meditation practice that encourage selflessness suggest a neuropsychological mechanism of altered self-boundaries which can enhance wellbeing (
      • 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.
      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, 2mg dissolved in 10ml) (
      • 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 been previously applied to investigate thalamic connectivity to the cortex under 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 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 to control 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 to aspects of self and the importance of their connectivity in psychopathology suggests 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 100μg of the classic psychedelic lysergic acid diethylamide (LSD) were investigated. LSD effects were examined across placebo (two 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 (OBN)) was measured on the five dimensions of altered states of consciousness scale (5D-ASC) (see Supplementary Material)(
      • 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 hypothesised 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 subjects, whose experience of ego dissolution undoubtably varied, limits our ability to measure ego dissolution. Therefore, we quantify the results as a measure of LSD induced connectivity changes that may effectuate ego dissolution. Additionally, we measured connectivity of regions composing the networks of interest and the efferent-afferent (hierarchical) connectivity strength between networks.

      Methods:

      Design

      A double blind, randomized, placebo-controlled, cross-over study was performed. Testing days occurred two 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 pre-treatment with 179 mg Mannitol and 1 mg Aerosil (placebo condition). Resting state scans (10 minutes each) were taken 75- and 300-minutes following administration. See Supplementary Material for participant, MRI and preprocessing detail.

      Extraction of region coordinates across subjects

      Group ICA for fMRI Toolbox (GIFT, http://mialab.mrn.org/ software/gift) (
      • Calhoun V.D.
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      • Pearlson G.D.
      • Pekar J.J.
      A method for making group inferences from functional MRI data using independent component analysis.
      ) was used to identify the three resting state networks of interest from placebo scans. Pre-processed resting state fMRI data were spatially sorted into 20 components (
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      Decoding subject-driven cognitive states with whole-brain connectivity patterns.
      ,
      • Tsvetanov K.A.
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      • Ham T.E.
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      ) and spatially matched with pre-existing 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 DMN (
      • Andrews-Hanna J.R.
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      Functional-anatomic fractionation of the brain's default network.
      ,
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      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.
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      Interactions between the default network and dorsal attention network vary across default subsystems, time, and cognitive states.
      ,
      • Fransson P.
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      ,
      • Fox M.D.
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      The global signal and observed anticorrelated resting state brain networks.
      ,
      • Uddin L.Q.
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      ,
      • Chen J.E.
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      • 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 and colleagues (
      • 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 (ROI) were determined by expert visual inspection. The MNI coordinates of the selected ROIs are listed in Table 1.
      Table 1Coordinates of regions of interest. The DMN comprised of the posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), and left and right angular gyrus (lAG/rAG); the SN comprised of the dorsal anterior cingulate cortex (dACC), left and right anterior insula (lAI/rAI); and the DAN comprised the left and right frontal eye field (lFEF/rFEF) and the left and right inferior parietal sulcus/superior parietal lobule (lIPS(SPL)/rIPS(SPL).
      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
      A generalized linear model (GLM) was used to regress 6 head motion parameters (3 translation and 3 rotational), white matter and cerebrospinal fluid signals from preprocessed data. One subject was excluded as no activation was found in one or more regions of interest. We also used global signal regression in our pre-processing pipeline. Global signal regression allowed us to observe anticorrelation in most subjects 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 centred on the ROI coordinates (as listed in Table 1). See Supplementary Fig. 1 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 explains the observed cross-spectral density for each subject. This procedure was repeated for each of the three testing conditions. The DCM fitted the data very well and explained variance was over 85% across all subjects, and averaged 91%.

      Second level analysis using Parametric Empirical Bayes

      The effective connectivity inferred by spectral DCM for each subject are taken to the second (group) level to test hypotheses about between-subject effects. A General Linear Model (GLM) is employed to decompose individual differences in effective connectivity into hypothesised group-average connection strengths plus unexplained noise. Hypotheses on the group-level parameters are tested within the Parametric Empirical Bayes (PEB) 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 down-weighted. Bayesian model reduction (BMR) is 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., 2018 (
      • 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 Supplementary Material). A similar approach was used for analysing hierarchical projections in the monkey brain (
      • Goulas A.
      • Uylings H.B.M.
      • 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 networks changes in effective connectivity

      The first resting-state fMRI scan was acquired 75 minutes post 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 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 Fig. 1, at this time, group level, between networks, effective connectivity increased from the SN to DMN causing the directed connection to become excitatory. A similar change was observed in the excitatory connectivity from the DMN to the DAN resulting in reduced inhibitory connectivity. SN to DMN and DMN to DAN changes from placebo are greatest during the peak effects at 75 minutes and reduce in the later effects at 300 minutes (see Fig. 1). These changes show increased afferent connections of the SN and increased efferent connections of the DMN and DAN from placebo (SN= -1.16 Hz, DMN = + 0.32 Hz, DAN = +0.41 Hz, see Supplementary Material for explanation and quantitative analysis). See Supplementary Material for functional connectivity and between region changes in effective connectivity for acute effects.
      Figure thumbnail gr1
      Figure 1Network effective connectivity change under peak effects of LSD. (A) Highlighted connections show changes in effective connectivity compared to placebo signifying peak effect. (B) Network effective connectivity change graphed across placebo, peak effects and later effects. Same data as (A) and (B) but plotted as a line graph for better visualization. Values display effect sizes (posterior expectations) of connections in Hz. All displayed connections are for posterior probability > 0.99.
      Figure thumbnail gr2
      Figure 2Region effective connectivity signifying peak and lasting effects of 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 Supplementary Table 2 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 Supplementary Table 3 for posterior expectations (effect size) and credible intervals. All results are for posterior probability > 0.99.

      Lasting Effects

      Between networks 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 remains evident 300 minutes after LSD (see Fig. 1 above, and see Supplementary Fig. 3 for effect size and posterior probabilities). See supplementary Material for between region changes in effective connectivity for lasting effects.

      Behavioural 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 post LSD associated to ego dissolution are outlined in Supplementary Material and demonstrated in Supplementary Fig. 4. We also computed effective connectivity behavioural 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 and accounted for 13 out of 15 connections identified, see Supplementary Fig. 4. We used the statistical threshold of posterior probability > 0.99 for these analyses which amounts to very strong evidence.
      The results demonstrate increased effective connectivity of the DMN to DAN and SN to the DMN during the peak effects of LSD. These changes correspond with reduced SN increased afferent connections and coincide with a fading of the functional anticorrelation (see Supplementary Fig. 1 for functional connectivity results). Moreover, behavioural associations to effective connectivity suggest measuring ego dissolution associated to the RSNs capture the overall subjective effects of LSD, see Supplementary Fig. 4.

      Discussion

      This investigation seeks to understand how effective connectivity between anticorrelated large-scale brain networks is related to serotonergic psychedelic subjective effects and ego dissolution. Our analysis reveals between network effective connectivity changes that occur with a diminution of the pattern of anticorrelation under the peak effects of LSD. Bidirectional changes in effective connectivity between the DMN and DAN were investigated for their 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 DAN as a feature of peak LSD effects that may relate to the fading of the functional anticorrelation between the two networks. Reduced DMN to DAN inhibition may also represent an increased transmission and connection of the narrative self to the sense of object. For instance, 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 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.
      • Campbell K.
      • Hasher L.
      • Grady C.
      Age differences in the neural correlates of distraction regulation: A network interaction approach.
      ). Under psychedelics, distractibility may relate to context sensitivity and confound environment 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 DMN 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-object under psychedelics. See Supplementary Material for regions level changes in DMN-DAN effective connectivity.
      Moreover, hierarchical organisation and strength of networks were calculated using efferent vs 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 DAN showed increased efferent connectivity strength during the peak effects of LSD and segregate from SN, under the peak effects of LSD (see Supplementary Material). The increase in efferent connectivity strength of the DMN and DAN reinforces evidence of their fading anticorrelation that underlie psychedelic subjective effects and may contribute to the dissolution of the boundary between the subject and the object. The opposite effective connectivity from DAN to DMN also displays reduced inhibition under LSD. However, this change remains over the course of time suggesting 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 DAN under LSD. The change to the coordinated balance of networks, under the control of SN, by LSD may be an important but overlooked neural mechanism of ego dissolution suggested by the superiority of 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.
      ), 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 hypothesised function in basic conscious-awareness also indicate the value of measuring SN connectivity in the anticorrelation between DMN and DAN. Moreover, ego dissolution has previously been suggested to involve the breakdown of sub-personal 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 optimisation 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 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 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. The SN has previously been identified to be hierarchically superior to the DMN and DAN (
      • 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.
      ). We demonstrate the divergence of SN and DMN efferent-afferent strength under the peak effects of LSD shift the hierarchical order of the SN beneath the DMN. See Supplementary Material for regions 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 gap between the efferent-afferent connectivity strength of the SN vs the DMN and DAN shifts in a direction antithetical to normal hierarchical organisation. This may be said to resemble a collapse – or flattening – of the hierarchy, during peak effects of LSD, when ego dissolution occurs (see Fig. 1 and Supplementary Material). 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.
      • et al.
      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 100μg 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 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.
      Modelling the connectivity of ego dissolution can provide a means to determine the neural mechanisms that underlie the perception of inner and outer reality. The present 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 inform the neural mechanisms of psychedelic ego dissolution and advance our understanding of connectivity associated to the sense of self and sense of separation between the self and world. The networks involved in this interaction are important in cognitive function and mental wellbeing, suggesting that understanding their change due to psychedelics 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 impact the reliability of results. Small sample size may also account for unexpected placebo effective connectivity in our group of subjects. A second practical limitation is the large variance of participant subjective responses to a standard dose of LSD (100μg). Averaging the connectivity of participants experiencing highly variable subjective shifts in consciousness may dilute the effective connectivity representing LSD’s subjective effects. 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 behavioural 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 Supplementary Material 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, non-psychedelic research involving the CEN (central executive network, also known as the frontoparietal central executive network (FPCEN)) 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.
      • Dupuis D.
      • Halberstadt A.
      • 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.
      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.
      • 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 CEN in anticorrelation investigations may provide a more complete account of anticorrelated network changes associated to ego dissolution.
      The between network balance of anticorrelated activity of specific RSNs depends on subtle adjustments to network activation. Mental wellbeing 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. The 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 DAN and altered network efferent-afferent differences under peak effects may account for the blurring of 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 SN and 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 emphasise 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 investigate subjective and 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 wellbeing. 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

      This article has been posted on medRxiv doi: https://doi.org/10.1101/2021.12.28.21268391
      Funding:
      Swiss Neuromatrix Foundation Grant 2015-0103 (to FXV)
      Usona Institute Grant 2015-2056 (to FXV)
      Australian Research Council Discovery Early Career Research Award Fellowship DE170100128 (to AR)
      Australian Research Council Discovery Project grant DP200100757 (AR)
      Australian National Health and Medical Research Council Investigator grant 1194910 (AR)
      Wellcome Centre for Human Neuroimaging supported by core funding from Wellcome grant 203147/Z/16/Z (AR)
      Author contributions:
      Conceptualization: DS, AR
      Methodology: DS, LN, AR
      Investigation: DS, LN, AR
      Visualization: DS, LN, AR
      Supervision: AR
      Writing—original draft: DS
      Writing—review & editing: DS, LN, AR, GE, KP, FXV
      Competing interests:
      All authors report no biomedical financial interests or potential conflicts of interest.
      Data and materials availability:
      All data are available in the main text, Supplementary Material or by request to the corresponding author.

      Supplementary Material

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