Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences
May 23, 2022
Pedro A. M. Mediano, Fernando E. Rosas, Andrea I. Luppi et al.
73 citations
Emergence—how galaxies form or consciousness arises from neurons—lacks formal tools for rigorous study. This article summarizes, elaborates, and extends a recent formal theory of causal emergence based on information decomposition, which is quantifiable and empirically testable. The theory links emergence to information about a system's temporal evolution that cannot be obtained from its parts separately. The article provides an accessible but rigorous introduction to this framework, discussing its merits in various scenarios, interpretation issues, and potential misunderstandings, highlighting the distinctive benefits of this formalism.
Human Brain Mapping
March 19, 2021
Andrea I. Luppi, Daniel Golkowski, Andreas Ranft et al.
72 citations
The human brain alternates between states of high integration and segregation, which are thought to support consciousness. Using dynamic functional connectivity and graph theory on resting-state fMRI data from healthy volunteers, the authors show that the integrated state is especially vulnerable to the anaesthetic sevoflurane. At higher doses (3% vol and burst-suppression), anaesthesia reduces the complexity and small-world character of integrated brain states and disrupts the temporal balance between integration and segregation. These effects reverse upon recovery, linking them to consciousness. Reduced anticorrelations between the default mode and executive control networks also reconfigure dynamically depending on the brain's integration state. The breakdown of the integrated sub-state may serve as a generalisable biomarker of loss and recovery of consciousness.
Science Advances
June 14, 2023
Leor Roseman, Christopher Timmermann, Daniel Golkowski et al.
65 citations
The effects of mind-altering drugs on brain function arise from complex interactions with multiple neurotransmitter systems, not just one. By linking the distribution of 19 neurotransmitter receptors and transporters (measured with PET) to changes in functional connectivity (measured with fMRI) caused by 10 drugs—anesthetics (propofol, sevoflurane, ketamine), psychedelics (LSD, psilocybin, DMT, ayahuasca), and others (MDMA, modafinil, methylphenidate)—the work shows a many-to-many mapping between drug effects and neurotransmitter systems. The drugs' impacts follow hierarchical gradients of brain structure and function, and regional susceptibility to drug-induced changes mirrors susceptibility to structural alterations from brain disorders.
bioRxiv
November 26, 2020
Andrea I. Luppi, Pedro A.M. Mediano, Fernando E. Rosas et al.
49 citations
preprint
The brain coordinates information from many sources to create a unified conscious experience. Combining network science and information theory, the authors identify a “synergistic global workspace” where gateway regions gather synergistic information from specialized brain modules, integrate it, and then broadcast it widely via broadcaster regions. Functional MRI shows that gateway regions correspond to the default mode network and broadcasters to the executive control network. Loss of consciousness from general anesthesia or disorders of consciousness reduces the workspace’s ability to integrate information, which is restored upon recovery. This work reconciles aspects of the Global Neuronal Workspace and Integrated Information Theory.
Neuroscience of Consciousness
November 1, 2021
Andrea I. Luppi, Pedro A. M. Mediano, Fernando E. Rosas et al.
42 citations
Consciousness can be better understood by decomposing it into distinct information-theoretic elements rather than measuring it as a single quantity of integrated information. The authors propose Integrated Information Decomposition (ΦID), which provides a formal argument that whether consciousness is an emergent phenomenon depends on its information-theoretic composition. Two organisms may have the same amount of integrated information yet differ in composition. A new measure, ΦR, and the ΦR-ing ratio quantify how efficiently information is used for conscious processing. This approach enables identification of qualitatively different 'modes of consciousness' and mapping them to phenomenology, starting with selfhood. ΦID offers new ways to explore the relationship between information, consciousness, and neural dynamics.
NeuroImage
July 1, 2022
Fran Hancock, Joana Cabral, Andrea I. Luppi et al.
40 citations
Dynamic functional connectivity (dFC) in resting-state fMRI is promising for clinical biomarkers, but its reliability and interpretability are debated. This study combined phase-based dFC metrics from dynamical systems, stochastic processes, and information dynamics to assess their interrelationships and reliability. Novel relationships between metrics allowed building a predictive model for integrated information. Global metastability, reflecting simultaneous coupling and decoupling tendencies, was the most representative and stable metric in brain parcellations including cerebellar regions. Spatiotemporal patterns of phase-locking changed slowly and continuously over time. The findings suggest that most resting-state fMRI dynamics reflect an interrelated complexity profile unique to each acquisition, challenging cross-sectional designs for neuromarker discovery and indicating individual life-trajectories may be more informative.
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.
Trends in Neurosciences
May 31, 2024
Andrea I. Luppi, Fernando E. Rosas, Pedro A. M. Mediano et al.
23 citations
Unconsciousness increases the coupling between brain structure and function across scales, while psychedelics may decouple brain function from structure. Anaesthetics, psychedelics, and disorders of consciousness can produce similar reconfigurations along the brain's unimodal-transmodal functional axis. Decomposing brain function into fundamental constituents of time, space, and information has driven recent advances in understanding consciousness and the brain's functional organisation. Computational modelling offers a path toward mechanistic integration, and decomposition approaches may help translate discoveries across species.
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)
May 12, 2023
Christopher Timmermann, Emma Eckernäs, Leor Roseman et al.
17 citations
preprint
The serotonergic psychedelic DMT rapidly induces a profoundly immersive altered state lasting less than 20 minutes, allowing the entire drug experience to be captured during a single fMRI scan. Using network control theory, which quantifies the input needed to drive transitions between brain states, brain structure and function were integrated to map energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. Global control energy was reduced following DMT compared to placebo. Longitudinal trajectories of global control energy correlated with EEG signal diversity and subjective drug intensity ratings. Regional effects correlated with serotonin 2a receptor density. Receptor distribution and pharmacokinetic information successfully recapitulated DMT's effects on global control energy trajectories.
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.
Pedro A.M. Mediano, Fernando E. Rosas, Andrea I. Luppi et al.
10 citations
A new method called Complexity via State-space Entropy Rate (CSER) estimates neural signal complexity with better temporal resolution and spectral decomposition than the standard Lempel-Ziv complexity (LZ) approach. CSER matches LZ in distinguishing conscious states but offers two key advantages: it can break complexity down by frequency bands, and it provides temporal resolution about 100 times finer. Using MEG, EEG, and ECoG data from humans and monkeys, CSER revealed that gamma-band activity primarily drives complexity changes across states of consciousness. In an auditory mismatch negativity experiment, CSER detected early entropy increases roughly 20 milliseconds before the standard event-related potential. This method enables finer-grained study of how signal complexity relates to cognitive processes and conscious states.
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)
July 13, 2022
Andrea I. Luppi, Justine Y. Hansen, R. Adapa et al.
5 citations
preprint
Psychoactive drugs reshape brain function by engaging multiple neurotransmitter systems simultaneously. By mapping the distribution of 19 neurotransmitter receptors and transporters (via PET) and the connectivity changes caused by 10 drugs (anesthetics, psychedelics, and stimulants), the study shows that drug effects are organized along hierarchical gradients of brain structure and function. Additionally, brain regions susceptible to drug-induced changes are also vulnerable to structural alterations from brain disorders. These findings reveal systematic links between molecular neurochemistry and large-scale functional reorganization.
Andrea I. Luppi, Pedro Mediano, Fernando Rosas et al.
5 citations
preprint
Consciousness can be understood not as a single unified thing but as composed of distinct information-theoretic elements. A new approach called Integrated Information Decomposition (ΦID) shifts from measuring how much integrated information a system has to analyzing its composition. This provides a formal way to determine whether consciousness is an emergent phenomenon based on that composition. Two organisms can have the same amount of integrated information yet differ in its composition. A new measure, ΦR, and the ΦR-ing rate quantify how efficiently an entity uses information for conscious processing. This decomposition identifies qualitatively different 'modes of consciousness,' enabling mapping between phenomenology and information-theoretic structure, starting with selfhood.
Neuropsychopharmacology
September 12, 2025
Jakub Vohryzek, Andrea I. Luppi, Selen Atasoy et al.
2 citations
The brain's function depends on its structural wiring, and psychedelics alter this relationship. Using connectome harmonic decomposition, a method linking brain activity to the network of white matter pathways, the authors show that under N,N-dimethyltryptamine (DMT), the brain's harmonic repertoire shifts similarly to that seen with psilocybin, LSD, and ketamine. Repertoire entropy—a measure of the diversity of brain states—increases under DMT. For the first time, the energy spectrum difference and repertoire entropy of connectome harmonics track the intensity of subjective experience in real time, indicating a close coupling between brain network dynamics and conscious experience.
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)
January 13, 2026
Iván Mindlin, Carlos Coronel-Oliveros, Jacobo Sitt et al.
A biologically grounded inhibitory homeostatic plasticity rule embedded into the Dynamic Mean Field (DMF) model creates a Homeostatic Dynamic Mean Field (HDMF) model that dynamically tunes local excitation-inhibition balance. The HDMF reproduces statistical observables of brain activity as well as the original DMF, can sustain neuromodulatory perturbations without overhead computations, and generates unprecedented sleep-like slow-wave activity that can coexist with wake-like asynchronous dynamics, permitting modeling of dissociated states of consciousness such as parasomnias. A single homeostatic rule broadens the stability and expressiveness of the DMF, providing a unified platform for studying how local adaptive processes shape the diverse global dynamics of the human brain.
bioRxiv Preprint Server
April 12, 2021
Peter Coppola, Lennart R.b. Spindler, Andrea I. Luppi et al.
preprint
The diversity of brain dynamics within small-world network topology, measured as sample entropy (dSW-E), consistently predicts levels of awareness across sedation and disorders of consciousness, even after accounting for underlying functional connectivity dynamics. Both subcortical and cortical areas show predictive value, but subcortical regions exhibit higher and more robust effect sizes. The dynamic reorganization of the functional information architecture, especially in the subcortex, emerges with awareness and offers explanatory power beyond the complexity of dynamic functional connectivity alone.
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.
NeuroImage
February 11, 2023
Andrea I. Luppi, Pedro A.M. Mediano, Fernando E. Rosas et al.
High-level brain functions are thought to arise from coordinated activity across neural systems, but this has been hard to test empirically. Using a framework called Integrated Information Decomposition, which quantifies emergence in dynamical systems, the authors analyzed functional MRI data and found that emergent and hierarchical neural dynamics are significantly reduced in chronically unresponsive patients with severe brain injury. Emergence capacity was positively correlated with hierarchical organization in brain activity. Combining network control theory and whole-brain modeling, the authors show that reduced emergent and hierarchical dynamics in these patients can be explained by disruptions in the structural connectome. The results suggest that chronic unresponsiveness after severe brain injury may stem from structural damage to neural infrastructure needed for emergent brain dynamics.