Scientific Reports
October 20, 2020
Rubén Herzog, Pedro A. M. Mediano, Fernando E. Rosas et al.
60 citations
Psychedelic drugs such as lysergic acid diethylamide, which activate the serotonin 2A receptor, produce profound changes in consciousness and increase entropy in spontaneous neural activity. This study provides the first model-based explanation for that entropy increase by extending a whole-brain model of serotonergic neuromodulation. The model reproduced the overall entropy rise seen in previous experiments. Entropy changes were not uniform: some brain regions showed increased entropy while others showed decreases, indicating a topographical reconfiguration driven by receptor activation. At the whole-brain level, this reconfiguration was not well explained by receptor density but was closely related to the brain's anatomical connectivity topology.
Scientific reports
April 17, 2023
Rubén Herzog, Pedro A M Mediano, Fernando E Rosas et al.
51 citations
Psychedelic drugs such as LSD, which activate the serotonin 2A receptor, produce profound changes in consciousness and are linked to increased entropy in spontaneous brain activity. This study provides the first model-based explanation for that entropy increase by extending a whole-brain model of serotonin neuromodulation. The model reproduced the overall rise in neural entropy seen in prior experiments. Entropy increased across all brain regions, with the largest effects in visuo-occipital areas. At the whole-brain level, this reconfiguration was not well explained by the density of serotonin 2A receptors but was closely related to the topological properties of the brain's anatomical connectivity.
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.
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.
Frontiers in Psychiatry
November 5, 2021
Enzo Tagliazucchi, Federico Zamberlán, Federico Cavanna et al.
23 citations
Inhaled DMT, a classic psychedelic, produces short but profound shifts in consciousness. In 35 healthy volunteers, electroencephalography recorded before and during the drug's acute effects in a natural setting showed marked reductions in alpha and beta brain oscillations and increases in delta, theta, and gamma power, particularly in posterior regions. The power of fronto-temporal theta oscillations inversely correlated with feelings of unity and transcendence—core features of mystical-type experiences. These findings suggest that baseline brain activity prior to psychedelic use may help predict the likelihood of such experiences, which are linked to lasting well-being and improved therapeutic outcomes.
bioRxiv (Cold Spring Harbor Laboratory)
August 20, 2020
Carla Pallavicini, Federico Cavanna, Federico Zamberlán et al.
17 citations
preprint
Inhaled DMT, a short-acting psychedelic found in plants and animals, was studied in 35 experienced participants in natural settings using wireless EEG and questionnaires. DMT reduced alpha brain waves (8-12 Hz) across the scalp while increasing delta (1-4 Hz) and gamma (30-40 Hz) waves. Increases in gamma power correlated with reports of mystical-type experiences. DMT also altered global synchrony and metastability in gamma and alpha bands and increased signal complexity. These findings align with prior psychedelic research and suggest EEG markers for mystical experiences in natural contexts, underscoring the value of studying these compounds in real-world settings.
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.
Annals of the New York Academy of Sciences
July 21, 2025
Marcel Socoró-garrigosa, Yonatan Sanz Perl, Morten L Kringelbach et al.
3 citations
The scale at which the brain represents information remains a key question in neuroscience. Evidence shows that information is encoded not just in localized areas but across distributed, hierarchical networks. The hierarchy of causal influences shaping brain activity patterns is a signature of different brain states, relevant to neuropsychiatric disorders. Using whole-brain models guided by the thermodynamics of mind framework, researchers estimated brain hierarchy and studied in-silico transitions in static functional connectivity. Applying this to major depressive disorder, they built resting-state whole-brain models of depressed patients before and after treatment with psilocybin or escitalopram.
bioRxiv (Cold Spring Harbor Laboratory)
August 19, 2024
Naji Alnagger, Paolo Cardone, Charlotte Martial et al.
3 citations
preprint
Disorders of consciousness, such as unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), have few treatments. Using whole-brain computational models built from individual patients' fMRI and diffusion-weighted imaging data, this virtual clinical trial simulated the effects of LSD and psilocybin. The psychedelics shifted the brains of patients with disorders of consciousness closer to a critical dynamical state, with a larger effect in MCS patients. In UWS patients, the treatment response depended on structural connectivity, whereas in MCS patients it aligned with baseline functional connectivity. These results provide a computational foundation for considering psychedelics in treating disorders of consciousness and highlight the role of computational modeling in drug discovery and personalized medicine.
bioRxiv Preprint Server
March 11, 2021
Enzo Tagliazucchi, Federico Zamberlan, Federico Cavanna et al.
3 citations
preprint
Inhaled DMT, a classic psychedelic, produces brief but profound changes in consciousness that vary with context. Using wireless EEG and source imaging, researchers mapped changes in neural oscillations. Frontal and temporal theta power inversely correlated with feelings of unity and transcendence—hallmarks of mystical-type experiences. A machine learning model confirmed the robustness of these results. The findings align with the idea that pre-drug mindset influences subjective experience. Priming individuals to lower theta power before taking a serotonergic psychedelic might increase the likelihood of mystical-type experiences, potentially enhancing well-being and therapeutic outcomes.
Advanced Science
November 20, 2025
Paolo Cardone, Charlotte Martial, Yonatan Sanz Perl et al.
2 citations
Simulated administration of LSD and psilocybin in computational models of patients with disorders of consciousness (DoC), including unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), shifted brain activity closer to criticality—the phase transition between order and chaos. The effect was greater in MCS patients. In UWS patients, the treatment response correlated with structural connectivity, while in MCS patients it aligned with baseline functional connectivity. These results provide a computational foundation for using psychedelics in DoC treatment and highlight the potential role of computational modeling in drug discovery and personalized medicine.
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.
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.
bioRxiv Preprint Server
June 7, 2026
Andrea I. Luppi, Dragana Manasova, Justine Y. Hansen et al.
preprint
Functional connectivity in the awake human brain is shaped primarily by cognitive co-activation—the tendency of brain regions to work together during mental tasks—more than by structural or molecular constraints. This predominance is systematically lost across five datasets involving pharmacological and pathological perturbations of consciousness (chronic disorders of consciousness; anesthesia with sevoflurane, propofol, or ketamine), when cognition is disconnected from the environment or abolished. During such states, the predictors of functional architecture shift away from cognitive co-activation and toward anatomical and molecular constraints.
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.
bioRxiv Preprint Server
September 28, 2022
Yonatan Sanz Perl, Carla Pallavicini, Juan Piccinini et al.
preprint
Brain states are often described on a single scale from full consciousness to unconsciousness, but this ignores the complex, high-dimensional nature of brain activity. By combining whole-brain modeling, data augmentation, and deep learning, researchers mapped states of consciousness into a low-dimensional space where distances reflect similarities between states. They found an orderly trajectory from wakefulness to brain-injured patients, with coordinates related to functional modularity and structure-function coupling, both increasing as consciousness is lost. Model perturbations provided a geometric interpretation of state stability and reversibility. The work suggests conscious awareness depends on functional patterns encoded as a low-dimensional trajectory within the vast space of brain configurations.
arXiv Preprint Archive
December 19, 2020
Yonatan Sanz Perl, Hernan Bocaccio, Ignacio Perez-Ipina et al.
Consciousness depends on brain activity that is far from thermodynamic equilibrium. Analyzing electrocorticography data from non-human primates during sleep and various anesthetics, and fMRI data from humans during deep sleep and propofol anesthesia, all states of reduced consciousness showed dynamics closer to equilibrium than conscious wakefulness. This was measured by entropy production and the curl of probability flux in phase space. Non-equilibrium macroscopic brain dynamics therefore serve as a robust signature of consciousness, offering a statistical mechanics approach to studying cognition and awareness.
arXiv Preprint Archive
August 6, 2020
Rodrigo Cofré, Rubén Herzog, Pedro A. M. Mediano et al.
Altered states of consciousness, such as those experienced during dreaming or meditation, offer a way to study how large-scale brain activity relates to different subjective experiences. This paper advocates a research program that combines bottom-up generative models of whole-brain activity, based on known properties of neural tissue, with top-down signatures proposed by theories of consciousness. The authors define altered states, discuss relevant brain-activity signatures, and introduce whole-brain models to explore the mechanisms behind these states. They argue that systematically investigating altered states through bottom-up modeling can clarify the biophysical, informational, and dynamical foundations of consciousness.
bioRxiv Preprint Server
July 2, 2020
Yonatan Sanz Perl, Carla Pallavicini, Ignacio Pérez Ipiña et al.
preprint
The level of consciousness—how conscious someone is—is often measured by how similar their brain activity is to normal wakefulness. However, this approach misses important information about how stable that state is. Using computer models of the whole brain, the authors show that the stability of a conscious state—how easily it can be disrupted—provides additional, complementary information. They propose a new framework that sorts brain states by both their similarity to wakefulness and their stability, which helps distinguish between different types of unconsciousness: natural sleep, anesthesia, and brain injury. This framework offers a more complete way to characterize and differentiate states of consciousness.