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  • Journal article
    Buchborn T, Lyons T, Song C, Feilding A, Knöpfel Tet al., 2023,

    Cortical correlates of psychedelic-induced shaking behavior revealed by voltage imaging

    , International Journal of Molecular Sciences, Vol: 24, ISSN: 1422-0067

    (1) From mouse to man, shaking behavior (head twitches and/or wet dog shakes) is a reliable readout of psychedelic drug action. Shaking behavior like psychedelia is thought to be mediated by serotonin 2A receptors on cortical pyramidal cells. The involvement of pyramidal cells in psychedelic-induced shaking behavior remains hypothetical, though, as experimental in vivo evidence is limited. (2) Here, we use cell type-specific voltage imaging in awake mice to address this issue. We intersectionally express the genetically encoded voltage indicator VSFP Butterfly 1.2 in layer 2/3 pyramidal neurons. We simultaneously capture cortical hemodynamics and cell type-specific voltage activity while mice display psychedelic shaking behavior. (3) Shaking behavior is preceded by high-frequency oscillations and overlaps with low-frequency oscillations in the motor cortex. Oscillations spectrally mirror the rhythmics of shaking behavior and reflect layer 2/3 pyramidal cell activity complemented by hemodynamics. (4) Our results reveal a clear cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior and open a promising methodological avenue relating a cross-mammalian psychedelic effect to cell-type specific brain dynamics.

  • Journal article
    Singleton SP, Timmermann C, Luppi AI, Eckernäs E, Roseman L, Carhart-Harris RL, Kuceyeski Aet al., 2023,

    Time-resolved network control analysis links reduced control energy under DMT with the serotonin 2a receptor, signal diversity, and subjective experience.

    , bioRxiv

    Psychedelics offer a profound window into the functioning of the human brain and mind through their robust acute effects on perception, subjective experience, and brain activity patterns. In recent work using a receptor-informed network control theory framework, we demonstrated that the serotonergic psychedelics lysergic acid diethylamide (LSD) and psilocybin flatten the brain's control energy landscape in a manner that covaries with more dynamic and entropic brain activity. Contrary to LSD and psilocybin, whose effects last for hours, the serotonergic psychedelic N,N-dimethyltryptamine (DMT) rapidly induces a profoundly immersive altered state of consciousness lasting less than 20 minutes, allowing for the entirety of the drug experience to be captured during a single resting-state fMRI scan. Using network control theory, which quantifies the amount of input necessary to drive transitions between functional brain states, we integrate brain structure and function to map the energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. Consistent with previous work, we find that global control energy is reduced following injection with DMT compared to placebo. We additionally show longitudinal trajectories of global control energy correlate with longitudinal trajectories of EEG signal diversity (a measure of entropy) and subjective ratings of drug intensity. We interrogate these same relationships on a regional level and find that the spatial patterns of DMT's effects on these metrics are correlated with serotonin 2a receptor density (obtained from separately acquired PET data). Using receptor distribution and pharmacokinetic information, we were able to successfully recapitulate the effects of DMT on global control energy trajectories, demonstrating a proof-of-concept for the use of control models in predicting pharmacological intervention effects on brain dynamics.

  • Journal article
    Spriggs M, Bornemann J, Murphy-Beiner A, Murphy R, Thurgur H, Schlag AKet al., 2023,

    ARC: a framework for access, reciprocity and conduct in psychedelic therapies

    , Frontiers in Psychology, Vol: 14, Pages: 1-8, ISSN: 1664-1078

    The field of psychedelic assisted therapy (PAT) is growing at an unprecedented pace. The immense pressures this places on those working in this burgeoning field have already begun to raise important questions about risk and responsibility. It is imperative that the development of an ethical and equitable infrastructure for psychedelic care is prioritized to support this rapid expansion of PAT in research and clinical settings. Here we present Access, Reciprocity and Conduct (ARC); a framework for a culturally informed ethical infrastructure for ARC in psychedelic therapies. These three parallel yet interdependent pillars of ARC provide the bedrock for a sustainable psychedelic infrastructure which prioritized equal access to PAT for those in need of mental health treatment (Access), promotes the safety of those delivering and receiving PAT in clinical contexts (Conduct), and respects the traditional and spiritual uses of psychedelic medicines which often precede their clinical use (Reciprocity). In the development of ARC, we are taking a novel dual-phase co-design approach. The first phase involves co-development of an ethics statement for each arm with stakeholders from research, industry, therapy, community, and indigenous settings. A second phase will further disseminate the statements for collaborative review to a wider audience from these different stakeholder communities within the psychedelic therapy field to invite feedback and further refinement. By presenting ARC at this early stage, we hope to draw upon the collective wisdom of the wider psychedelic community and inspire the open dialogue and collaboration upon which the process of co-design depends. We aim to offer a framework through which psychedelic researchers, therapists and other stakeholders, may begin tackling the complex ethical questions arising within their own organizations and individual practice of PAT.

  • Journal article
    Girn M, Rosas FE, Daws RE, Gallen CL, Gazzaley A, Carhart-Harris RLet al., 2023,

    A complex systems perspective on psychedelic brain action

    , TRENDS IN COGNITIVE SCIENCES, Vol: 27, Pages: 433-445, ISSN: 1364-6613
  • Journal article
    Good M, Joel Z, Benway T, Routledge C, Timmermann C, Erritzoe D, Weaver R, Allen G, Hughes C, Topping H, Bowman A, James Eet al., 2023,

    Pharmacokinetics of <i>N</i>,<i>N</i>-dimethyltryptamine in Humans

    , EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, ISSN: 0378-7966
  • Journal article
    Martinez Mediano P, Rosas FE, Luppi AI, Noreika V, Seth AK, Carhart-Harris RL, Barnett L, Bor Det al., 2023,

    Spectrally and temporally resolved estimation of neural signal diversity

    , eLife, ISSN: 2050-084X

    Quantifying the complexity of neural activity has provided fundamental insights into cognition,consciousness, and clinical conditions. However, the most widely used approach to estimate thecomplexity of neural dynamics, Lempel-Ziv complexity (LZ), has fundamental limitations thatsubstantially restrict its domain of applicability. In this article we leverage the information-theoreticfoundations of LZ to overcome these limitations by introducing a complexity estimator based onstate-space models — which we dub Complexity via State-space Entropy Rate (CSER). While having aperformance equivalent to LZ in discriminating states of consciousness, CSER boasts two crucialadvantages: 1) CSER offers a principled decomposition into spectral components, which allows usto rigorously investigate the relationship between complexity and spectral power; and 2) CSERprovides a temporal resolution two orders of magnitude better than LZ, which allows complexityanalyses of e.g. event-locked neural signals. As a proof of principle, we use MEG, EEG and ECoGdatasets of humans and monkeys to show that CSER identifies the gamma band as the main driverof complexity changes across states of consciousness; and reveals early entropy increases thatprecede the standard ERP in an auditory mismatch negativity paradigm by approximately 20ms.Overall, by overcoming the main limitations of LZ and substantially extending its range ofapplicability, CSER opens the door to novel investigations on the fine-grained spectral and temporalstructure of the signal complexity associated with cognitive processes and conscious states.

  • Journal article
    Herzog R, Mediano PAM, Rosas FE, Lodder P, Carhart-Harris R, Perl YS, Tagliazucchi E, Cofre Ret al., 2023,

    A whole-brain model of the neural entropy increase elicited by psychedelic drugs

    , SCIENTIFIC REPORTS, Vol: 13, ISSN: 2045-2322
  • Journal article
    Mosurinjohn S, Roseman L, Girn M, 2023,

    Psychedelic-induced mystical experiences: an interdisciplinary discussion and critique

    , Frontiers in Psychiatry, Vol: 14, Pages: 1-12, ISSN: 1664-0640

    Contemporary research on serotonergic psychedelic compounds has been rife with references to so-called ‘mystical’ subjective effects. Several psychometric assessments have been used to assess such effects, and clinical studies have found quantitative associations between ‘mystical experiences’ and positive mental health outcomes. The nascent study of psychedelic-induced mystical experiences, however, has only minimally intersected with relevant contemporary scholarship from disciplines within the social sciences and humanities, such as religious studies and anthropology. Viewed from the perspective of these disciplines—which feature rich historical and cultural literatures on mysticism, religion, and related topics—‘mysticism’ as used in psychedelic research is fraught with limitations and intrinsic biases that are seldom acknowledged. Most notably, existing operationalizations of mystical experiences in psychedelic science fail to historicize the concept and therefore fail to acknowledge its perennialist and specifically Christian bias. Here, we trace the historical genesis of the mystical in psychedelic research in order to illuminate such biases, and also offer suggestions toward more nuanced and culturally-sensitive operationalizations of this phenomenon. In addition, we argue for the value of, and outline, complementary ‘non-mystical’ approaches to understanding putative mystical-type phenomena that may help facilitate empirical investigation and create linkages to existing neuro-psychological constructs. It is our hope that the present paper helps build interdisciplinary bridges that motivate fruitful paths toward stronger theoretical and empirical approaches in the study of psychedelic-induced mystical experiences.

  • Journal article
    Luppi AI, Mediano PAM, Rosas FE, Allanson J, Pickard JD, Williams GB, Craig MM, Finoia P, Peattie ARD, Coppola P, Menon DK, Bor D, Stamatakis EAet al., 2023,

    Reduced emergent character of neural dynamics in patients with a disrupted connectome

    , NeuroImage, Vol: 269, Pages: 1-17, ISSN: 1053-8119

    High-level brain functions are widely believed to emerge from the orchestrated activity of multiple neural systems. However, lacking a formal definition and practical quantification of emergence for experimental data, neuroscientists have been unable to empirically test this long-standing conjecture. Here we investigate this fundamental question by leveraging a recently proposed framework known as “Integrated Information Decomposition,” which establishes a principled information-theoretic approach to operationalise and quantify emergence in dynamical systems — including the human brain. By analysing functional MRI data, our results show that the emergent and hierarchical character of neural dynamics is significantly diminished in chronically unresponsive patients suffering from severe brain injury. At a functional level, we demonstrate that emergence capacity is positively correlated with the extent of hierarchical organisation in brain activity. Furthermore, by combining computational approaches from network control theory and whole-brain biophysical modelling, we show that the reduced capacity for emergent and hierarchical dynamics in severely brain-injured patients can be mechanistically explained by disruptions in the patients’ structural connectome. Overall, our results suggest that chronic unresponsiveness resulting from severe brain injury may be related to structural impairment of the fundamental neural infrastructures required for brain dynamics to support emergence.

  • Journal article
    Morales PA, Korbel J, Rosas FE, 2023,

    Geometric Structures Induced by Deformations of the Legendre Transform

    , ENTROPY, Vol: 25

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