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  • Journal article
    Eckernas E, Timmermann C, Carhart-Harris R, Roshammar D, Ashton Met al., 2023,

    N,N-dimethyltryptamine affects electroencephalography response in a concentration-dependent manner-A pharmacokinetic/pharmacodynamic analysis

    , CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, Vol: 12, Pages: 474-486, ISSN: 2163-8306
  • Journal article
    Hancock F, Rosas FE, McCutcheon RAE, Cabral J, Dipasquale O, Turkheimer FEet al., 2023,

    Metastability as a candidate neuromechanistic biomarker of schizophrenia pathology

    , PLoS One, Vol: 18, ISSN: 1932-6203

    The disconnection hypothesis of schizophrenia proposes that symptoms of the disorder arise as a result of aberrant functional integration between segregated areas of the brain. The concept of metastability characterizes the coexistence of competing tendencies for functional integration and functional segregation in the brain, and is therefore well suited for the study of schizophrenia. In this study, we investigate metastability as a candidate neuromechanistic biomarker of schizophrenia pathology, including a demonstration of reliability and face validity. Group-level discrimination, individual-level classification, pathophysiological relevance, and explanatory power were assessed using two independent case-control studies of schizophrenia, the Human Connectome Project Early Psychosis (HCPEP) study (controls n = 53, non-affective psychosis n = 82) and the Cobre study (controls n = 71, cases n = 59). In this work we extend Leading Eigenvector Dynamic Analysis (LEiDA) to capture specific features of dynamic functional connectivity and then implement a novel approach to estimate metastability. We used non-parametric testing to evaluate group-level differences and a naïve Bayes classifier to discriminate cases from controls. Our results show that our new approach is capable of discriminating cases from controls with elevated effect sizes relative to published literature, reflected in an up to 76% area under the curve (AUC) in out-of-sample classification analyses. Additionally, our new metric showed explanatory power of between 81–92% for measures of integration and segregation. Furthermore, our analyses demonstrated that patients with early psychosis exhibit intermittent disconnectivity of subcortical regions with frontal cortex and cerebellar regions, introducing new insights about the mechanistic bases of these conditions. Overall, these findings demonstrate reliability and face validity of metastability as a candidate neuromechanistic biomarker of schizop

  • Journal article
    Gattuso JJ, Perkins D, Ruffell S, Lawrence AJ, Hoyer D, Jacobson LH, Timmermann C, Castle D, Rossell SL, Downey LA, Pagni BA, Galvao-Coelho NL, Nutt D, Sarris Jet al., 2023,

    Default Mode Network Modulation by Psychedelics: A Systematic Review

  • Journal article
    Timmermann Slater CB, Roseman L, Haridas S, Rosas F, Luan L, Kettner H, Martell J, Erritzoe D, Tagliazucchi E, Pallavicini C, Girn M, Alamia A, Leech R, Carhart-Harris Ret al., 2023,

    Human brain effects of DMT assessed via EEG-fMRI

    , Proceedings of the National Academy of Sciences of USA, Vol: 120, Pages: 1-12, ISSN: 0027-8424

    Psychedelics have attracted medical interest, but their effects on human brain function are incompletely understood. In a comprehensive, within-subjects, placebo-controlled design, we acquired multimodal neuroimaging [i.e., EEG-fMRI (electroencephalography-functional MRI)] data to assess the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT) on brain function in 20 healthy volunteers. Simultaneous EEG-fMRI was acquired prior to, during, and after a bolus IV administration of 20 mg DMT, and, separately, placebo. At dosages consistent with the present study, DMT, a serotonin 2A receptor (5-HT2AR) agonist, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. GFC × subjective intensity maps correlated with independent positron emission tomography (PET)-derived 5-HT2AR maps, and both overlapped with meta-analytical data implying human-specific psychological functions. Changes in major EEG-measured neurophysiological properties correlated with specific changes in various fMRI metrics, enriching our understanding of the neural basis of DMT’s effects. The present findings advance on previous work by confirming a predominant action of DMT—and likely other 5-HT2AR agonist psychedelics—on the brain’s transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.

  • Journal article
    Carhart-Harris RL, Chandaria S, Erritzoe DE, Gazzaley A, Girn M, Kettner H, Mediano PAM, Nutt DJ, Rosa FE, Roseman L, Timmermann C, Weiss B, Zeifman RJ, Friston KJet al., 2023,

    Canalization and plasticity in psychopathology

    , NEUROPHARMACOLOGY, Vol: 226, ISSN: 0028-3908
  • Journal article
    Nayak SM, Bari BA, Yaden DB, Spriggs MJ, Rosas FE, Peill JM, Giribaldi B, Erritzoe D, Nutt DJ, Carhart-Harris Ret al., 2023,

    A Bayesian Reanalysis of a Trial of Psilocybin versus Escitalopram for Depression.

    , Psychedelic Med (New Rochelle), Vol: 1, Pages: 18-26

    OBJECTIVES: To perform a Bayesian reanalysis of a recent trial of psilocybin (COMP360) versus escitalopram for Major Depressive Disorder (MDD) in order to provide a more informative interpretation of the indeterminate outcome of a previous frequentist analysis. DESIGN: Reanalysis of a two-arm double-blind placebo controlled trial. PARTICIPANTS: Fifty-nine patients with MDD. INTERVENTIONS: Two doses of psilocybin 25mg and daily oral placebo versus daily escitalopram and 2 doses of psilocybin 1mg, with psychological support for both groups. OUTCOME MEASURES: Quick Inventory of Depressive Symptomatology-Self-Report (QIDS SR-16), and three other depression scales as secondary outcomes: HAMD-17, MADRS, and BDI-1A. RESULTS: Using Bayes factors and 'skeptical priors' which bias estimates towards zero, for the hypothesis that psilocybin is superior by any margin, we found indeterminate evidence for QIDS SR-16, strong evidence for BDI-1A and MADRS, and extremely strong evidence for HAMD-17. For the stronger hypothesis that psilocybin is superior by a 'clinically meaningful amount' (using literature defined values of the minimally clinically important difference), we found moderate evidence against it for QIDS SR-16, indeterminate evidence for BDI-1A and MADRS, and moderate evidence supporting it for HAMD-17. Furthermore, across the board we found extremely strong evidence for psilocybin's non-inferiority versus escitalopram. These findings were robust to prior sensitivity analysis. CONCLUSIONS: This Bayesian reanalysis supports the following inferences: 1) that psilocybin did indeed outperform escitalopram in this trial, but not to an extent that was clinically meaningful--and 2) that psilocybin is almost certainly non-inferior to escitalopram. The present results provide a more precise and nuanced interpretation to previously reported results from this trial, and support the need for further research into the relative efficacy of psilocybin therapy for depression with respe

  • Journal article
    Ruffini G, Damiani G, Lozano-Soldevilla D, Deco N, Rosas FE, Kiani NA, Ponce-Alvarez A, Kringelbach ML, Carhart-Harris R, Deco Get al., 2023,

    LSD-induced increase of Ising temperature and algorithmic complexity of brain dynamics

    , PLoS Computational Biology, Vol: 19, Pages: 1-29, ISSN: 1553-734X

    A topic of growing interest in computational neuroscience is the discovery of fundamental principles underlying global dynamics and the self-organization of the brain. In particular, the notion that the brain operates near criticality has gained considerable support, and recent work has shown that the dynamics of different brain states may be modeled by pairwise maximum entropy Ising models at various distances from a phase transition, i.e., from criticality. Here we aim to characterize two brain states (psychedelics-induced and placebo) as captured by functional magnetic resonance imaging (fMRI), with features derived from the Ising spin model formalism (system temperature, critical point, susceptibility) and from algorithmic complexity. We hypothesized, along the lines of the entropic brain hypothesis, that psychedelics drive brain dynamics into a more disordered state at a higher Ising temperature and increased complexity. We analyze resting state blood-oxygen-level-dependent (BOLD) fMRI data collected in an earlier study from fifteen subjects in a control condition (placebo) and during ingestion of lysergic acid diethylamide (LSD). Working with the automated anatomical labeling (AAL) brain parcellation, we first create "archetype" Ising models representative of the entire dataset (global) and of the data in each condition. Remarkably, we find that such archetypes exhibit a strong correlation with an average structural connectome template obtained from dMRI (r = 0.6). We compare the archetypes from the two conditions and find that the Ising connectivity in the LSD condition is lower than in the placebo one, especially in homotopic links (interhemispheric connectivity), reflecting a significant decrease of homotopic functional connectivity in the LSD condition. The global archetype is then personalized for each individual and condition by adjusting the system temperature. The resulting temperatures are all near but above the critical point of the model i

  • Journal article
    Carhart-Harris RL, 2023,

    Translational Challenges in Psychedelic Medicine

    , NEW ENGLAND JOURNAL OF MEDICINE, Vol: 388, Pages: 476-477, ISSN: 0028-4793
  • Journal article
    Aqil M, Roseman L, 2023,

    More than meets the eye: The role of sensory dimensions in psychedelic brain dynamics, experience, and therapeutics.

    , Neuropharmacology, Vol: 223

    Psychedelics are undergoing a major resurgence of scientific and clinical interest. While multiple theories and frameworks have been proposed, there is yet no universal agreement on the mechanisms underlying the complex effects of psychedelics on subjective experience and brain dynamics, nor their therapeutic benefits. Despite being prominent in psychedelic phenomenology and distinct from those elicited by other classes of hallucinogens, the effects of psychedelics on low-level sensory - particularly visual - dimensions of experience, and corresponding brain dynamics, have often been disregarded by contemporary research as 'epiphenomenal byproducts'. Here, we review available evidence from neuroimaging, pharmacology, questionnaires, and clinical studies; we propose extensions to existing models, provide testable hypotheses for the potential therapeutic roles of psychedelic-induced visual hallucinations, and simulations of visual phenomena relying on low-level cortical dynamics. In sum, we show that psychedelic-induced alterations in low-level sensory dimensions 1) are unlikely to be entirely causally reconducible to high-level alterations, but rather co-occur with them in a dialogical interplay, and 2) are likely to play a causally relevant role in determining high-level alterations and therapeutic outcomes. We conclude that reevaluating the currently underappreciated role of sensory dimensions in psychedelic states will be highly valuable for neuroscience and clinical practice, and that integrating low-level and domain-specific aspects of psychedelic effects into existing nonspecific models is a necessary step to further understand how these substances effect both acute and long-term change in the human brain.

  • Journal article
    Nutt D, Spriggs M, Erritzoe D, 2023,

    Psychedelics therapeutics: What we know, what we think, and what we need to research

    , NEUROPHARMACOLOGY, Vol: 223, ISSN: 0028-3908

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