Proceedings of the National Academy of Sciences
April 13, 2020
Morten L. Kringelbach, Josephine Cruzat, Joana Cabral et al.
326 citations
By combining multimodal neuroimaging data, a framework was developed that demonstrates the fundamental principles of bidirectional coupling between neuronal and neurotransmitter dynamical systems. The work causally explains the functional effects of stimulating specific serotoninergic receptors (5-HT2AR) with psilocybin in healthy humans. This could lead to a better understanding of why psilocybin shows promise as a therapeutic intervention for neuropsychiatric disorders such as depression, anxiety, and addiction.
Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences
May 23, 2022
Jakub Vohryzek, Joana Cabral, Peter Vuust et al.
62 citations
The brain balances order and disorder in its activity patterns to adapt to a complex environment. Depression involves excessively rigid, ordered brain states, while psychedelics induce more disordered, overly flexible states. This review uses dynamical system theory and neuroimaging to characterize how different healthy and altered brain states correspond to distinct spacetime dynamics, potentially guiding new treatments for rebalancing brain states in disease.
Nature Mental Health
August 5, 2024
Gustavo Deco, Yonatan Sanz Perl, Samuel Johnson et al.
39 citations
Two serotonergic interventions—psilocybin therapy and the antidepressant escitalopram—rebalance brain dynamics in major depressive disorder through opposite hierarchical reconfigurations. In a double-blind phase II trial, 22 patients received two 25 mg doses of psilocybin plus daily placebo, while 20 patients received two 1 mg doses of psilocybin plus daily escitalopram. Resting-state fMRI scans before and after treatment, analyzed with generative effective connectivity models, showed that the two treatments produced significantly different and opposite changes in whole-brain hierarchy. Machine learning predicted treatment response with 85% accuracy. The findings suggest that depression may involve disrupted function of brain regions that orchestrate dynamics from the top of the hierarchy.
bioRxiv (Cold Spring Harbor Laboratory)
November 2, 2020
Pedro A. M. Mediano, Fernando E. Rosas, Christopher Timmermann et al.
39 citations
preprint
Psychedelics reliably increase brain entropy (neural signal diversity), an effect linked to psychological changes and opposite to the decrease seen during loss of consciousness. This study investigated how context—specifically stimulus manipulation—modulates that entropy increase. Participants under LSD or placebo experienced eyes-closed versus eyes-open conditions, or no stimulus, music, or video. Brain entropy rose with LSD across all conditions but was largest with eyes closed. Entropy changes consistently matched subjective ratings of the psychedelic experience, except during video viewing, suggesting competition between external stimuli and internal LSD-induced imagery. The findings provide quantitative evidence that context shapes neural dynamics during psychedelic experiences, supporting the practice of eyes-closed psychedelic psychotherapy, and challenge simplistic views of brain entropy as a direct measure of conscious level.
bioRxiv (Cold Spring Harbor Laboratory)
May 17, 2021
S. Parker Singleton, Andrea I. Luppi, Robin L. Carhart-Harris et al.
30 citations
preprint
LSD and psilocybin reduce the amount of energy the brain needs to transition between different activity states, as measured by functional MRI. This flattening of the brain's control energy landscape allows for more frequent state transitions and more diverse (entropic) brain activity. The effects are linked to the spatial distribution of serotonin 2a receptors, the main target of these psychedelics. The findings suggest that these compounds make brain state transitions more facile and temporally diverse, offering a mechanistic explanation for the altered subjective experience induced by psychedelics.
Network Neuroscience
January 1, 2022
Josephine Cruzat, Yonatan Sanz Perl, Anira Escrichs et al.
28 citations
Psychedelic drugs like LSD and psilocybin may treat neuropsychiatric disorders by dose-dependently altering the brain's functional hierarchy—the organization of neural activity across regions. Using a turbulence framework that measures local synchronization (vorticity) in both space and time, researchers found that both drugs produce consistent and distinct effects, particularly compressing the default mode network, a higher-level network. These findings support the hypothesis that psychedelics modulate the functional hierarchy and provide a quantitative comparison of how LSD and psilocybin change brain dynamics, with implications for therapeutic use.
bioRxiv (Cold Spring Harbor Laboratory)
August 10, 2020
Andrea I. Luppi, Jakub Vohryzek, Morten L. Kringelbach et al.
26 citations
preprint
Consciousness arises from how the brain's structural wiring shapes its dynamic activity. By decomposing resting-state fMRI data into harmonic modes of the human structural connectome, a generalizable signature of lost consciousness emerges—whether from anesthesia or brain injury—while a reversed signature characterizes psychedelic states induced by LSD or ketamine, reflecting decoupling of function from structure. This connectome harmonic approach discriminates between behaviorally indistinguishable brain-injured patients and tracks covert consciousness, linking neurobiology to conscious experience.
bioRxiv (Cold Spring Harbor Laboratory)
July 14, 2017
Selen Atasoy, Leor Roseman, Mendel Kaelen et al.
25 citations
preprint
Lysergic acid diethylamide (LSD) alters the energy and power of individual harmonic brain states in a frequency-selective manner, expanding the repertoire of active brain states. This non-random increase in co-activation across frequencies suggests a general re-organization of brain dynamics. The frequency distribution of active brain states under LSD follows power-laws, indicating dynamics at the edge of criticality. These methods offer insights into complex brain dynamics in health and disease.
Annals of the New York Academy of Sciences
November 20, 2023
Katarina Jerotic, Peter Vuust, Morten L. Kringelbach
19 citations
Music and psychedelics have been intertwined throughout human history, from early shamanic rituals to modern psychedelic-assisted therapy. This review examines their interplay, describing how both engage the brain's functional hierarchy for music perception and its psychedelic-induced manipulation. It explores music's role in Western psychedelic therapy and indigenous rituals, focusing on ayahuasca and the Santo Daime Church. The work also considers music's potential to induce altered states of consciousness without psychedelics and the development of psychedelic music. The authors provide an overview of several perspectives on this interaction, a topic of growing interest given increasing excitement about psychedelic interventions' therapeutic efficacy.
bioRxiv (Cold Spring Harbor Laboratory)
November 9, 2023
Fernando E. Rosas, Pedro A. M. Mediano, Christopher Timmermann et al.
14 citations
preprint
Autonomic signals can reveal aspects of subjective and neural states. A Bayesian framework estimated heart rate entropy under psychedelics. Across four drugs—LSD, DMT, psilocybin, and ketamine—mean heart rate, high-frequency heart rate variability, and heart rate entropy consistently increased during the psychedelic experience. These changes predicted various dimensions of the experience. Heart rate entropy increases correlated with brain entropy increases, while other autonomic markers did not. Cost-efficient autonomic measures can reveal detail about subjective and brain states, opening new research avenues in neuroscience.
Research Square
September 20, 2022
Jakub Vohryzek, Joana Cabral, Louis-David Lord et al.
10 citations
Psilocybin therapy for depression shows promise, but how it works is unclear. By comparing responders (those with >50% reduction in symptoms) to non-responders after 10mg and 25mg doses, whole-brain modeling identified specific brain regions whose dynamics shift from a depressive to a healthy state. These regions overlap with maps of serotonin 5-HT2A and 5-HT1A receptors, which psilocin—the active metabolite of psilocybin—activates. The findings provide causal evidence linking serotonergic transmission and recovery from depression via psilocybin.
bioRxiv (Cold Spring Harbor Laboratory)
July 25, 2018
Louis-David Lord, Paul Expert, Selen Atasoy et al.
10 citations
preprint
Brain activity can be viewed as exploring a landscape of different activity patterns over time, shifting between stable states of functional connectivity that support various mental processes. In a study using fMRI data from healthy participants given intravenous psilocybin (the active compound in magic mushrooms), researchers analyzed how this dynamical landscape changes during the psychedelic state. They found that a connectivity state linked to the fronto-parietal control system became strongly destabilized, while transitions toward a globally synchronized state increased. These changes suggest the psychedelic state biases the brain toward global integration at the cost of local network segregation, offering a mechanistic perspective on the subjective psychedelic experience and potential guidance for pharmacological interventions in neuropsychiatric disorders.
bioRxiv (Cold Spring Harbor Laboratory)
May 31, 2024
Jakub Vohryzek, Selen Atasoy, Gustavo Deco et al.
8 citations
preprint
Psychedelic substances like DMT, psilocybin, LSD, and ketamine alter brain function by reshaping the repertoire of connectome harmonics—patterns of neural activity that depend on the brain's structural network of white matter pathways. Under DMT, the entropy of these harmonics increases, indicating a more diverse range of brain states. For the first time, changes in the energy spectrum and entropy of connectome harmonics were shown to track the intensity of subjective experience in real time, suggesting a close link between the brain's harmonic activity and conscious experience.
bioRxiv (Cold Spring Harbor Laboratory)
April 28, 2024
Kenneth Shinozuka, Prejaas Tewarie, Andrea I. Luppi et al.
5 citations
preprint
LSD weakens the brain's directed connectivity hierarchy by increasing the balance between senders and receivers of neural signals. This finding supports the REBUS theory, which proposes that psychedelics flatten the hierarchy of information flow in the brain. Analyzing magnetoencephalography data from 16 healthy participants given 75 micrograms of intravenous LSD, the study found that LSD diminishes the asymmetry of directed connectivity averaged over time. Machine learning classifiers distinguished LSD from placebo more accurately when trained on hierarchy metrics than on traditional functional connectivity measures.
bioRxiv (Cold Spring Harbor Laboratory)
November 7, 2024
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs et al.
4 citations
preprint
Psilocybin induces fast and sustained improvements in mental well-being, yet its long-term mechanisms are not fully understood. Four weeks after a full dose, fronto-striatal-thalamic (FST) circuitry—involved in goal-directed behavior and motivation—shows increased dynamic activity and flexibility in healthy volunteers. Computational modeling indicates that reduced structural constraints on functional dynamics cause this increased flexibility. Long-term changes include increased bottom-up and reduced top-down information flow, mediated by serotonergic (5-HT2A) and dopaminergic (D2) receptor systems. This functional re-organization of FST circuits may represent a common mechanism underlying clinical improvements across neuropsychiatric disorders such as substance abuse, major depression, and anorexia.
bioRxiv (Cold Spring Harbor Laboratory)
June 25, 2024
Milan van Maldegem, Jakub Vohryzek, Selen Atasoy et al.
2 citations
preprint
Ketamine, a dissociative anesthetic, produces different brain dynamics at anesthetic versus sub-anesthetic doses. Using connectome harmonic decomposition (CHD) to analyze resting-state fMRI data from volunteers during ketamine-induced unresponsiveness, the study found increased prevalence of localized harmonics, similar to patterns seen in psychedelic states induced by LSD or psilocybin. This contrasts with traditional GABAergic sedation (e.g., propofol), where global harmonics increase with higher doses. The results indicate that ketamine-induced unresponsiveness does not necessarily suppress conscious experience and influences connectome harmonics oppositely to GABAergic hypnotics. CHD may track alterations in conscious awareness rather than behavioral responsiveness.
bioRxiv (Cold Spring Harbor Laboratory)
October 7, 2023
Kenneth Shinozuka, Katarina Jerotic, Pedro A. M. Mediano et al.
2 citations
preprint
Serotonergic psychedelics such as LSD, psilocybin, and DMT alter consciousness and show therapeutic potential for depression and addiction, but their mechanisms remain unclear. A systematic review and meta-analysis across three levels—phenomenology, neuroimaging, and pharmacology—reveals that medium and high doses of LSD produce significantly stronger visionary restructuring than psilocybin. Neuroimaging shows psychedelics generally strengthen connectivity between brain networks while weakening connectivity within networks. Pharmacologically, LSD triggers more inositol phosphate formation at the 5-HT2A receptor than DMT or psilocin, but no significant differences emerged in receptor selectivity among the drugs. The findings highlight high heterogeneity and risk of bias, underscoring the need for standardized methods.
bioRxiv (Cold Spring Harbor Laboratory)
June 16, 2026
Paulina Clara Dagnino, Irene Acero-Pousa, Gorka Zamora‐lópez et al.
1 citation
Psilocybin and the conventional antidepressant escitalopram produce opposite changes in the brain's hierarchical non-equilibrium dynamics when treating major depressive disorder. Using resting-state fMRI before and after treatment, researchers built whole-brain models and measured how much each patient's brain activity deviated from the fluctuation-dissipation theorem. Baseline measures distinguished treatment responders from non-responders within each group. The deviation from the fluctuation-dissipation theorem may serve as a marker to differentiate the brain effects of psilocybin and escitalopram, contributing to understanding how these treatments work for depression.
bioRxiv (Cold Spring Harbor Laboratory)
December 22, 2024
Jakub Vohryzek, Morten L. Kringelbach, Edmundo Lopez-Sola et al.
1 citation
preprint
Both psychedelic states and reduced states of consciousness flatten the brain's functional hierarchy, yet their behavioral and phenomenological profiles differ. To resolve this paradox, researchers defined hierarchy by the brain's proximity to thermodynamic equilibrium and examined changes induced by three serotonergic psychedelics: psilocybin, LSD, and DMT. All three consistently reduced the functional hierarchy globally. Unlike loss of consciousness, psychedelics moved the brain toward equilibrium while increasing neural activity complexity, indicating a distinct mechanism involving altered configuration and differentiation of resting-state networks. This work demonstrates how statistical mechanics metrics can characterize different global brain states, advancing understanding of consciousness as an emergent collective process.
bioRxiv Preprint Server
January 5, 2021
Beatrice M. Jobst, Selen Atasoy, Adrián Ponce-Alvarez et al.
1 citation
preprint
LSD alters brain dynamics by shifting the brain's global working point further from a stable equilibrium, as shown by consistently higher Perturbational Integration Latency Index (PILI) values after intake. Using a whole-brain computational model perturbed in silico, the largest differences were found in the limbic, visual, and default mode networks. Greater variability of PILI values across brain regions under LSD indicates higher response diversity to external perturbations. These findings provide insights into the brain-wide dynamical changes underlying the psychedelic state and suggest possible clinical applications for psychiatric disorders.
medRxiv
July 8, 2026
Paulina Clara Dagnino, Anne Maj van der Velden, Yonatan Sanz Perl et al.
In people with major depressive disorder, mindfulness-based cognitive therapy (MBCT) plus treatment as usual, compared to treatment as usual alone, alters whole-brain dynamics in ways that may reduce rumination. Using a novel method called complex harmonics decomposition on fMRI data from 80 patients, the study identified low-dimensional spatiotemporal manifolds that capture both local and long-range brain interactions. After MBCT, during rumination, brain regions involved in bodily and interoceptive processing became more consistently integrated across these manifolds. The latent configurations shifted with clinical and behavioral improvements, and the brain showed greater flexibility within the reduced space. These changes may reflect reduced 'stickiness' of ruminative thinking patterns following mindfulness training.
bioRxiv (Cold Spring Harbor Laboratory)
June 26, 2026
Paulina Clara Dagnino, Irene Acero-Pousa, Robin Carhart‐Harris et al.
A central challenge in neuroscience is understanding how the human brain is organised to support optimal functioning and adaptability. One approach to characterise complex brain dynamics is by artificially perturbing whole-brain models. Here, we asked whether whole-brain organisation under perturbation in major depressive disorder (MDD) changes after intervention with psilocybin and escitalopram. First, we built whole-brain models of pre- and post-treatment resting-state functional magnetic resonance imaging (fMRI) and obtained an initial generative effective connectivity (GEC) matrix for each individual.
medRxiv
June 23, 2026
Paulina Clara Dagnino, Anne Maj van der Velden, Henricus G. Ruhé et al.
In people with major depressive disorder, mindfulness-based cognitive therapy (MBCT) plus treatment as usual, compared to treatment as usual alone, increased the hierarchical organization of brain activity during rumination but not at rest. Greater hierarchy—meaning more directional information flow and less recurrent looping—was linked to improvements in clinical and behavioral outcomes. This shift away from self-reinforcing negative mental loops toward more differentiated cognitive and bodily cycles may help explain how MBCT interrupts ruminative thought patterns. Hierarchical brain dynamics could serve as a treatment-sensitive marker and potential mechanism of therapeutic change in MBCT for depression.
bioRxiv (Cold Spring Harbor Laboratory)
January 2, 2025
Marcel Socoró Garrigosa, Yonatan Sanz Perl, Morten L. Kringelbach et al.
preprint
Using whole-brain models guided by the Thermodynamics of Mind framework, the authors estimated the brain hierarchy of specific brain states and simulated transitions between states. Applying this to major depressive disorder, they built models of depressed patients before and after psilocybin and escitalopram treatments. Dynamic sensitivity analysis showed that susceptibility to change was on average reduced by escitalopram and increased by psilocybin, and both treatments promoted healthier transitions. These results align with the post-treatment plasticity window opened by serotonergic psychedelics and with the similar clinical efficacy of both drugs observed in clinical trials.
bioRxiv Preprint Server
December 9, 2025
Tomas Berjaga-Buisan, Juan Manuel Monti, Martina Cortada et al.
preprint
A non-invasive framework using generative whole-brain models of non-equilibrium dynamics reveals that violations of the Fluctuation-Dissipation Theorem (FDT) in spontaneous brain signals are reduced in unresponsive disorders of consciousness and anesthesia compared to conscious states, mirroring patterns seen with the Perturbational Complexity Index (PCI). This links PCI to fundamental physics principles and offers new objective, model-based tools for assessing consciousness loss and recovery.