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Increased variance/amplitude fluctuations in the hippocampus post-psilocybin. The charts on the left show the complete time series from the hippocampus (left in blue, right in green) in 3 different individual subjects during the 12 min scan in which they received psilocybin. The transparent red vertical line indicates the beginning and duration of the 60 s infusion of psilocybin. The images on the right show the right hippocampal region where the increases in variance were especially marked.

Increased variance/amplitude fluctuations in the hippocampus post-psilocybin. The charts on the left show the complete time series from the hippocampus (left in blue, right in green) in 3 different individual subjects during the 12 min scan in which they received psilocybin. The transparent red vertical line indicates the beginning and duration of the 60 s infusion of psilocybin. The images on the right show the right hippocampal region where the increases in variance were especially marked.

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... Early psychedelic therapists took advantage of these properties of music to facilitate emotional release and peak experiences (Bonny, 1972). Psychedelic therapy is a method by which a patient is administered a classic serotonergic psychedelic -for example, psilocybin -with psychological support and is encouraged to direct their attention inward while listening to a playlist of music, often resulting in profound emotionality and spontaneous psychological insight (Carhart-Harris et al., 2014). Psilocybin, like all classic psychedelics, elicits its principal effects through agonism at the serotonin (5-HT) 2a receptor (Nichols, 2004), widely expressed in the cortex (Varnas et al., 2004), to markedly alter consciousness, including changes in perception and emotionality (Carhart-harris et al., 2016;Hasler et al., 2004). ...
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Background: Music listening is a staple and valued component of psychedelic therapy, and previous work has shown that psychedelics can acutely enhance music-evoked emotion. Aims: The present study sought to examine subjective responses to music before and after psilocybin therapy for treatment-resistant depression, while functional magnetic resonance imaging (fMRI) data was acquired. Methods: Nineteen patients with treatment-resistant depression received a low oral dose (10 mg) of psilocybin, and a high dose (25 mg) 1 week later. fMRI was performed 1 week prior to the first dosing session and 1 day after the second. Two scans were conducted on each day: one with music and one without. Visual analogue scale ratings of music-evoked 'pleasure' plus ratings of other evoked emotions (21-item Geneva Emotional Music Scale) were completed after each scan. Given its role in musical reward, the nucleus accumbens (NAc) was chosen as region of interest for functional connectivity (FC) analyses. Effects of drug (vs placebo) and music (vs no music) on subjective and FC outcomes were assessed. Anhedonia symptoms were assessed pre- and post-treatment (Snaith-Hamilton Pleasure Scale). Results: Results revealed a significant increase in music-evoked emotion following treatment with psilocybin that correlated with post-treatment reductions in anhedonia. A post-treatment reduction in NAc FC with areas resembling the default mode network was observed during music listening (vs no music). Conclusion: These results are consistent with current thinking on the role of psychedelics in enhancing music-evoked pleasure and provide some new insight into correlative brain mechanisms.
... Alternatively, one may also view the decrease in fetal cortical entropy with maturation through the lens of the entropic brain hypothesis (EBH) (50,51). EBH emphasizes the entropy of spontaneous, rather than perturbed, brain activity as an index of the informational and phenomenological richness of conscious states. ...
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... Alongside a reduction in activity within the DMN, STEs also appear to be linked to an increase in spontaneous and dynamic brain activity, especially among high-level association networks (Schartner et al., 2017;Tagliazucchi, 2020;Blatchford et al., 2021). In a phenomenon sometimes called the 'entropic brain' in psychedelic research (Carhart-Harris et al., 2014;Herzog et al., 2020), brain activity becomes disorganized allowing for an increased connectivity between usually distinct brain networks. For example, Carhart-Harris et al. (2013) showed that the DMN and the Task-Positive Network (which serves to support focused attention), whose activities are usually negatively correlated, displayed greater functional connectivity under the effect of psychedelics. ...
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... Functional imaging studies in contemporary psychedelic research have highlighted the potential role of changes in resting state functional connectivity (rsFC) in the default mode network (DMN), which is involved in a variety of functions including self-referential thought and sense of self. In healthy participants, both psilocybin and ayahuasca (containing N,N-DMT) acutely decrease rsFC in the DMN [59][60][61]. Patients with AN have increased rsFC between the DMN and angular gyrus, which was correlated with selfreported problems in interoceptive awareness [62]. Increased rsFC between the DMN and frontoparietal network has also been observed in AN and is associated with self-reported measures of persistence [63]. ...
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... The result, phenomenologically, is a reduction in the generation of familiar narratives along with a rush of unusual, unexpected content, all of which can lead to freer associations and enhanced imagination and creativity in a type of thinking Freud dubbed primary process (Frecska et al., 2012;Harman et al., 1966;K.C.R. Fox et al., 2018). The circuits activated in REM sleep, psychosis, depersonalization, and dreamlike experiences are also prominent in psychedelic experience (Carhart-Harris et al., 2014;Nour & Carhart-Harris, 2017). ...
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As interest in psychedelics as treatments for psychological problems grows, it is important for psychoanalysts to learn about them. Our patients will come to us to discuss their psychedelic experiences; additionally, psychedelics deserve reconsideration as meaningful collaborators with our field, at both the theoretical and clinical levels. After a brief history of these agents, the paper engages three specific areas: 1) psychedelics’ capacity to evoke egolysis, or ego dissolution, and mystical states; 2) their capacity to support hyperassociative states, free association, and emergence of unconscious material, and 3) the role of set and setting in psychedelic therapy. Drawing from the fields of neuropsychoanalysis, phenomenological research and neuroanthropology, the paper offers a discourse that connects mind and brain and psychedelics in ways meaningful for psychoanalysts.
... Carhart- Harris et al. (2014) propose that psychedelic states (along with REM sleep and onset-phase psychosis) are dominated by "primary states," a regressive style of cognition more present in infancy and early childhood (p. 6). Returning to this state of primary consciousness might allow one to finally experience the traumatic breakdown one experienced in infancy, but which could never be symbolized and brought into consciousness. ...
... 54). Much has been written about the neurological processes that mediate these states (Carhart-Harris et al., 2014;Fischman, 2019), but I want to focus on the descriptive rather than technical aspects of the research. 1 Winnicott's work on regression has been debated in the analytic literature (Quagelli, 2020) and Bollas cautions against a regression to dependence in his work with patients emphasizing the importance of keeping the patient's own assets and ego strength as a presence in the room and the work. ...
... There is much overlap in the three categories I examined in this paper and there are many other concepts which psychoanalytic theory could offer in an effort to conceptualize the psychic processes underlying psychedelic experience. Carhart- Harris et al. (2014) suggest that psychedelic research offers a path to integrate cognitive neuroscience with psychoanalytic theory, allowing psychoanalysis to establish itself as the science of the mind Freud hoped that it would become. 2 There is room in the research for a shift away from a model where psychotherapy is an adjunct to the psychedelic experience, offering preparation and integration, to one in which psychotherapy remains primary and psychedelics are used as a catalyst for deepening the therapeutic process. I hope others will continue to think about what psychoanalytic theory can offer the burgeoning field of psychedelic-assisted psychotherapy and what psychedelic research in turn can offer to our understanding of the mind. ...
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... Similarly, psilocybin, LSD and other psychedelics exert neurotrophic effects [201,202,215], and thus may act similarly in the context of addiction-reward circuitry. It was also proposed, based on evidence from functional magnetic resonance imaging (fMRI) studies in humans, that psychedelics induce a state of increased brain entropy and relax rigidly held pre-existing beliefs and associated neural connectivity, allowing the brain to revise and reform thoughts, beliefs and behavioral patterns [183,216]. Notably, patients attribute alcohol use cessation to the subjective psychedelic experience, describing life-changing realizations and highly meaningful cognitive experiences during psychedelic treatment [206], suggesting that increased neuroplasticity in acute psychedelic treatment may promote adaptive rewiring of the brain pathological circuitry through active cognitive processes [183,184]. ...
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There is much excitement surrounding recent research of promising, mechanistically novel psychotherapeutics – psychedelic, anesthetic, and dissociative agents – as they have demonstrated surprising efficacy in treating central nervous system (CNS) disorders, such as mood disorders and addiction. However, the mechanisms by which these drugs provide such profound psychological benefits are still to be fully elucidated. Microglia, the CNS’s resident innate immune cells, are emerging as a cellular target for psychiatric disorders because of their critical role in regulating neuroplasticity and the inflammatory environment of the brain. The following paper is a review of recent literature surrounding these neuropharmacological therapies and their demonstrated or hypothesized interactions with microglia. Through investigating the mechanism of action of psychedelics, such as psilocybin and lysergic acid diethylamide, ketamine, and propofol, we demonstrate a largely under-investigated role for microglia in much of the emerging research surrounding these pharmacological agents. Among others, we detail sigma-1 receptors, serotonergic and γ-aminobutyric acid signalling, and tryptophan metabolism as pathways through which these agents modulate microglial phagocytic activity and inflammatory mediator release, inducing their therapeutic effects. The current review includes a discussion on future directions in the field of microglial pharmacology and covers bidirectional implications of microglia and these novel pharmacological agents in aging and age-related disease, glial cell heterogeneity, and state-of-the-art methodologies in microglial research. Graphical Abstract
... Contemporary neuroscientific theories have tackled consciousness by proposing that functional relationships among neurophysiological events are fundamental to the emergence of consciousness [1][2][3][4] . This may underpin the seemingly unitary nature of experience via the integration of different information (e.g., visual and auditory) and may mediate the dynamic meta-stable re-organisation which is essential to normal brain function and characterises a typical stream of consciousness [5][6][7][8][9][10][11] . ...
... We hypothesise that individuals in a normal conscious resting state will display specific dynamic characteristics in network transitions (e.g., have higher unpredictability) and will show a more complex landscape or repertoire of states 1,2,4,45 . We analyse four conditions, presented here in order of presumed level of awareness: Healthy Controls: Awake and Moderate propofol sedation; (18 participants 49 ; Collected in Cambridge, UK); 11 patients in a minimally conscious state (MCS, collected in Cambridge, UK); and 12 participants with Unresponsive Wakefulness Syndrome (UWS, collected in Cambridge, UK). ...
... To ensure results are reproducible, we also use an additional propofol anaesthesia dataset 28 , comprised of 16 participants in a control awake, mild sedation and deep sedation conditions. We predict that the measures of intrinsic dynamics will reliably scale with decreasing levels of consciousness 1,2,4,50 . We make use of several brain region definitions (Supplementary Note 1), various preprocessing techniques (Supplementary Note 2) and data to assess convergence of results. ...
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Typical consciousness can be defined as an individual-specific stream of experiences. Modern consciousness research on dynamic functional connectivity uses clustering techniques to create common bases on which to compare different individuals. We propose an alternative approach by combining modern theories of consciousness and insights arising from phenomenology and dynamical systems theory. This approach enables a representation of an individual’s connectivity dynamics in an intrinsically-defined, individual-specific landscape. Given the wealth of evidence relating functional connectivity to experiential states, we assume this landscape is a proxy measure of an individual’s stream of consciousness. By investigating the properties of this landscape in individuals in different states of consciousness, we show that consciousness is associated with short term transitions that are less predictable, quicker, but, on average, more constant. We also show that temporally-specific connectivity states are less easily describable by network patterns that are distant in time, suggesting a richer space of possible states. We show that the cortex, cerebellum and subcortex all display consciousness-relevant dynamics and discuss the implication of our results in forming a point of contact between dynamical systems interpretations and phenomenology.
... Brain entropy accounts of psychedelics propose that altered states of consciousness observed following administration of psychedelics result from increased entropy in the brain (Carhart-Harris et al., 2014;Carhart-Harris and Friston, 2019). Even though testing these accounts was not the goal of this study, we note that overall our results are in agreement with this proposal. ...
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Psychedelics have emerged as promising candidate treatments for various psychiatric conditions, and given their clinical potential, there is a need to identify biomarkers that underlie their effects. Here, we investigate the neural mechanisms of lysergic acid diethylamide (LSD) using regression dynamic causal modelling (rDCM), a novel technique that assesses whole-brain effective connectivity (EC) during resting-state functional magnetic resonance imaging (fMRI). We modelled data from two randomized, placebo-controlled, double-blind, cross-over trials, in which 45 participants were administered 100 μg LSD and placebo in two resting-state fMRI sessions. We compared EC against whole-brain functional connectivity (FC) using classical statistics and machine learning methods. Multivariate analyses of EC parameters revealed widespread increases in interregional connectivity and reduced self-inhibition under LSD compared to placebo, with the notable exception of primarily decreased interregional connectivity and increased self-inhibition in occipital brain regions. This finding suggests that LSD perturbs the Excitation/Inhibition balance of the brain. Moreover, random forests classified LSD vs. placebo states based on FC and EC with comparably high accuracy (FC: 85.56%, EC: 91.11%) suggesting that both EC and FC are promising candidates for clinically-relevant biomarkers of LSD effects.
... Additionally, both cognitively and neurobiologically, the state of flow shares overlap with other altered states of consciousness, including meditative and psychedelic states, states of traumatic stress, and socalled peak or optimal experiences (Carhart- Harris et al., 2012Harris et al., , 2014Brandmeyer et al., 2019;Wheeler and Dyer, 2020). While scientists have explored some of the neurobiological changes beneath the aforementioned altered states (Brewer et al., 2011;Nash et al., 2018;Yanes and Loprinzi, 2018), the precise neural mechanisms underpinning the onset of flow and the state itself remain unclear, both empirically and theoretically. ...
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Flow is a cognitive state that manifests when there is complete attentional absorption while performing a task. Flow occurs when certain internal as well as external conditions are present, including intense concentration, a sense of control, feedback, and a balance between the challenge of the task and the relevant skillset. Phenomenologically, flow is accompanied by a loss of self-consciousness, seamless integration of action and awareness, and acute changes in time perception. Research has begun to uncover some of the neurophysiological correlates of flow, as well as some of the state’s neuromodulatory processes. We comprehensively review this work and consider the neurodynamics of the onset of the state, considering large-scale brain networks, as well as dopaminergic, noradrenergic, and endocannabinoid systems. To accomplish this, we outline an evidence-based hypothetical situation, and consider the flow state in a broader context including other profound alterations in consciousness, such as the psychedelic state and the state of traumatic stress that can induce PTSD. We present a broad theoretical framework which may motivate future testable hypotheses.