Physical review. E
July 28, 2021
Yonatan Sanz Perl, Hernan Bocaccio, Carla Pallavicini et al.
82 citations
Conscious wakefulness is characterized by brain dynamics far from thermodynamic equilibrium, while states of reduced consciousness—such as deep sleep and anesthesia induced by propofol, ketamine, or ketamine plus medetomidine—operate closer to equilibrium. This conclusion comes from analyzing electrocorticography data from nonhuman primates and functional magnetic resonance imaging data from humans. Entropy production and the curl of probability flux in phase space reliably distinguished conscious from unconscious states. The findings establish nonequilibrium macroscopic brain dynamics as a robust signature of consciousness and offer a statistical mechanics framework for studying cognition and awareness.
NeuroImage
April 11, 2020
Ignacio Pérez Ipiña, Patricio Donnelly Kehoe, Morten L. Kringelbach et al.
81 citations
A semi-empirical model combining fMRI data, structural connectivity, and anatomically-informed priors shows that brain states during the wake-sleep cycle are better described by multiple dimensions rather than a single continuum. The best fit used priors based on functionally coherent networks, dividing the cortex into regions with opposite dynamics: frontoparietal regions approached a noise-driven bifurcation from fixed-point dynamics, while sensorimotor regions approached a bifurcation from oscillatory dynamics. Sleep onset involved subcortical deactivation with low correlation, reversed in deeper stages. Periodic forcing simulating external perturbations identified key regions for wakefulness recovery. The model characterizes sleep as having diminished perceptual gating but latent capacity for rapid arousal.
Communications Biology
June 29, 2022
Anira Escrichs, Yonatan Sanz Perl, Carme Uribe et al.
67 citations
Different brain states—resting, meditating, deep sleep, and disorders of consciousness after coma—are underpinned by distinct spatiotemporal dynamics that can be characterized using turbulence theory. Non-conscious states tend to be more synchronous, while conscious states are more asynchronous, but the work goes beyond this simple dichotomy. A model-free analysis of human neuroimaging data applied Kuramoto's turbulence framework with coupled oscillators and measured information cascades across spatial scales. A complementary model-based approach used exhaustive computer simulations of whole-brain models fitted to those measures to study information encoding. The framework shows that turbulence theory provides excellent tools for describing and differentiating between brain states.
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.
Network Neuroscience
December 23, 2022
Gustavo Deco, Yonatan Sanz Perl, Laura de la Fuente et al.
43 citations
The default mode network (DMN) may coordinate the recruitment and scheduling of brain networks for solving cognitive tasks, supported by evidence that DMN regions are physically and functionally distant from sensorimotor areas. Using a thermodynamics-inspired, deep learning-based Temporal Evolution NETwork (TENET) framework to measure the 'arrow of time'—a marker of nonreversibility and hierarchy in brain signals—analysis of Human Connectome Project data from nearly a thousand participants suggests the DMN orchestrates hierarchy levels that shift between rest and seven cognitive tasks. This hierarchy differs significantly in health versus neuropsychiatric disorders, offering insights into brain dynamics for cognition.
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.
Interface Focus
April 14, 2023
Elvira G-Guzmán, Yonatan Sanz Perl, Jakub Vohryzek et al.
34 citations
Living systems must constantly work against equilibrium to survive, a property that can be measured through temporal asymmetry in brain signals. Using statistical physics, researchers analyzed reversibility in functional magnetic resonance imaging data from patients with disorders of consciousness. They found that decreased asymmetry and reduced non-stationarity in brain signals characterize impaired consciousness states, consistent with previous findings in sleep and anesthesia. The work aims to identify biomarkers for patient improvement and classification, and to deepen mechanistic understanding of consciousness disorders.
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.
Communications Biology
September 30, 2024
Pablo Castro, Andrea I. Luppi, Enzo Tagliazucchi et al.
21 citations
Brain activity during unconsciousness, whether from general anaesthesia or slow wave sleep, is dominated by a recurrent functional connectivity pattern primarily mediated by structural connectivity and with a reduced capacity to transition to other patterns. Conscious awareness is characterized by richer brain dynamics measured by entropy and a greater repertoire of connectivity states. These findings suggest that the dynamic exploration of functional connectivity states provides robust and generalizable markers for the state of consciousness across different conditions.
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)
July 4, 2021
Gustavo Deco, Yonatan Sanz Perl, Jacobo Sitt et al.
16 citations
preprint
The brain operates far from equilibrium due to forces from the body and environment. Using a deep learning framework called Temporal Evolution NETwork (TENET) applied to large-scale neuroimaging data from over a thousand participants, researchers show that the arrow of time—a thermodynamic measure of non-reversibility—varies with cognitive state. Non-equilibrium levels are higher during tasks than at rest and differ across seven distinct cognitive tasks. In a separate dataset of 265 participants, the framework distinguishes resting-state brain activity in healthy controls from that in schizophrenia, bipolar disorder, and ADHD, with higher non-equilibrium levels in health. This thermodynamics-based approach offers new insights into how brain dynamics orchestrate behavior-environment interactions.
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.
Sci Rep
September 15, 2022
Rubén Herzog, Pedro A. M. Mediano, Fernando E. Rosas et al.
3 citations
A scientific paper was retracted because a typo in the script used to calculate differential entropy made the reported entropy estimations invalid. The corrected calculations no longer show the expected increase in brain signal diversity or complexity that the original analysis had claimed.
bioRxiv Preprint Server
March 11, 2021
Enzo Tagliazucchi, Federico Zamberlán, 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)
October 3, 2025
Marian Martínez-Marín, Jakub Vohryzek, Anira Escrichs et al.
1 citation
preprint
Consciousness levels after coma can be assessed by measuring how far the brain's dynamics are from equilibrium. Using fMRI data and individualized whole-brain models, researchers found that patients with disorders of consciousness—those in a minimally conscious state or unresponsive wakefulness syndrome—show brain activity closer to equilibrium than healthy controls, with the shift increasing as consciousness decreases. Disruptions in hierarchical drive were identified in default-mode network regions and subcortical hubs like the thalamus. Recovery of near-control hierarchy in the visual network distinguished minimally conscious from unresponsive patients, while limbic areas showed similar abnormalities in both groups. Deviation from the fluctuation-dissipation theorem offers a model-based biomarker for clinical stratification.
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.
Hum Brain Mapp
July 1, 2026
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs et al.
A computational model predicts that a single dose of psilocybin can produce lasting changes in the dynamic activity and effective connectivity of fronto-striatal-thalamic brain circuits. The modeling suggests that psilocybin may strengthen connectivity between the prefrontal cortex and striatum while altering thalamic gating, effects that persist beyond the acute drug experience. These changes could underlie the sustained therapeutic benefits observed in clinical settings, such as reduced depressive symptoms and increased psychological flexibility. The findings provide a mechanistic framework for understanding how psilocybin induces long-term neural plasticity and highlight potential circuit targets for treating psychiatric disorders.
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.