Temporal Irreversibility of Large-Scale Brain Dynamics in Alzheimer's Disease.

Healthy brain dynamics can be understood as the emergence of a complex system far from thermodynamic equilibrium. Brain dynamics are temporally irreversible and thus establish a preferred direction in time (i.e., arrow of time). However, little is known about how the time-reversal symmetry of spontaneous brain activity is affected by Alzheimer's disease (AD). We hypothesized that the level of irreversibility would be compromised in AD, signaling a fundamental shift in the collective properties of brain activity toward equilibrium dynamics. We investigated the irreversibility from resting-state fMRI and EEG data in male and female human patients with AD and elderly healthy control subjects (HCs). We quantified the level of irreversibility and, thus, proximity to nonequilibrium dynamics by comparing forward and backward time series through time-shifted correlations. AD was associated with a breakdown of temporal irreversibility at the global, local, and network levels, and at multiple oscillatory frequency bands. At the local level, temporoparietal and frontal regions were affected by AD. The limbic, frontoparietal, default mode, and salience networks were the most compromised at the network level. The temporal reversibility was associated with cognitive decline in AD and gray matter volume in HCs. The irreversibility of brain dynamics provided higher accuracy and more distinctive information than classical neurocognitive measures when differentiating AD from control subjects. Findings were validated using an out-of-sample cohort. Present results offer new evidence regarding pathophysiological links between the entropy generation rate of brain dynamics and the clinical presentation of AD, opening new avenues for dementia characterization at different levels.SIGNIFICANCE STATEMENT By assessing the irreversibility of large-scale dynamics across multiple brain signals, we provide a precise signature capable of distinguishing Alzheimer's disease (AD) at the global, local, and network levels and different oscillatory regimes. Irreversibility of limbic, frontoparietal, default-mode, and salience networks was the most compromised by AD compared with more sensory-motor networks. Moreover, the time-irreversibility properties associated with cognitive decline and atrophy outperformed and complemented classical neurocognitive markers of AD in predictive classification performance. Findings were generalized and replicated with an out-of-sample validation procedure. We provide novel multilevel evidence of reduced irreversibility in AD brain dynamics that has the potential to open new avenues for understating neurodegeneration in terms of the temporal asymmetry of brain dynamics.

Brain health in diverse settings: How age, demographics and cognition shape brain function.

Diversity in brain health is influenced by individual differences in demographics and cognition. However, most studies on brain health and diseases have typically controlled for these factors rather than explored their potential to predict brain signals. Here, we assessed the role of individual differences in demographics (age, sex, and education; n = 1298) and cognition (n = 725) as predictors of different metrics usually used in case-control studies. These included power spectrum and aperiodic (1/f slope, knee, offset) metrics, as well as complexity (fractal dimension estimation, permutation entropy, Wiener entropy, spectral structure variability) and connectivity (graph-theoretic mutual information, conditional mutual information, organizational information) from the source space resting-state EEG activity in a diverse sample from the global south and north populations. Brain-phenotype models were computed using EEG metrics reflecting local activity (power spectrum and aperiodic components) and brain dynamics and interactions (complexity and graph-theoretic measures). Electrophysiological brain dynamics were modulated by individual differences despite the varied methods of data acquisition and assessments across multiple centers, indicating that results were unlikely to be accounted for by methodological discrepancies. Variations in brain signals were mainly influenced by age and cognition, while education and sex exhibited less importance. Power spectrum activity and graph-theoretic measures were the most sensitive in capturing individual differences. Older age, poorer cognition, and being male were associated with reduced alpha power, whereas older age and less education were associated with reduced network integration and segregation. Findings suggest that basic individual differences impact core metrics of brain function that are used in standard case-control studies. Considering individual variability and diversity in global settings would contribute to a more tailored understanding of brain function.

Viscous dynamics associated with hypoexcitation and structural disintegration in neurodegeneration via generative whole-brain modeling.

INTRODUCTION: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) lack mechanistic biophysical modeling in diverse, underrepresented populations. Electroencephalography (EEG) is a high temporal resolution, cost-effective technique for studying dementia globally, but lacks mechanistic models and produces non-replicable results. METHODS: We developed a generative whole-brain model that combines EEG source-level metaconnectivity, anatomical priors, and a perturbational approach. This model was applied to Global South participants (AD, bvFTD, and healthy controls). RESULTS: Metaconnectivity outperformed pairwise connectivity and revealed more viscous dynamics in patients, with altered metaconnectivity patterns associated with multimodal disease presentation. The biophysical model showed that connectome disintegration and hypoexcitability triggered altered metaconnectivity dynamics and identified critical regions for brain stimulation. We replicated the main results in a second subset of participants for validation with unharmonized, heterogeneous recording settings. DISCUSSION: The results provide a novel agenda for developing mechanistic model-inspired characterization and therapies in clinical, translational, and computational neuroscience settings.

Source space connectomics of neurodegeneration: One-metric approach does not fit all.

Brain functional connectivity in dementia has been assessed with dissimilar EEG connectivity metrics and estimation procedures, thereby increasing results' heterogeneity. In this scenario, joint analyses integrating information from different metrics may allow for a more comprehensive characterization of brain functional interactions in different dementia subtypes. To test this hypothesis, resting-state electroencephalogram (rsEEG) was recorded in individuals with Alzheimer's Disease (AD), behavioral variant frontotemporal dementia (bvFTD), and healthy controls (HCs). Whole-brain functional connectivity was estimated in the EEG source space using 101 different types of functional connectivity, capturing linear and nonlinear interactions in both time and frequency-domains. Multivariate machine learning and progressive feature elimination was run to discriminate AD from HCs, and bvFTD from HCs, based on joint analyses of i) EEG frequency bands, ii) complementary frequency-domain metrics (e.g., instantaneous, lagged, and total connectivity), and iii) time-domain metrics with different linearity assumption (e.g., Pearson correlation coefficient and mutual information). <10% of all possible connections were responsible for the differences between patients and controls, and atypical connectivity was never captured by >1/4 of all possible connectivity measures. Joint analyses revealed patterns of hypoconnectivity (patientsHCs) in both groups was mainly identified in frontotemporal regions. These atypicalities were differently captured by frequency- and time-domain connectivity metrics, in a bandwidth-specific fashion. The multi-metric representation of source space whole-brain functional connectivity evidenced the inadequacy of single-metric approaches, and resulted in a valid alternative for the selection problem in EEG connectivity. These joint analyses reveal patterns of brain functional interdependence that are overlooked with single metrics approaches, contributing to a more reliable and interpretable description of atypical functional connectivity in neurodegeneration.

Genuine high-order interactions in brain networks and neurodegeneration.

Brain functional networks have been traditionally studied considering only interactions between pairs of regions, neglecting the richer information encoded in higher orders of interactions. In consequence, most of the connectivity studies in neurodegeneration and dementia use standard pairwise metrics. Here, we developed a genuine high-order functional connectivity (HOFC) approach that captures interactions between 3 or more regions across spatiotemporal scales, delivering a more biologically plausible characterization of the pathophysiology of neurodegeneration. We applied HOFC to multimodal (electroencephalography [EEG], and functional magnetic resonance imaging [fMRI]) data from patients diagnosed with behavioral variant of frontotemporal dementia (bvFTD), Alzheimer's disease (AD), and healthy controls. HOFC revealed large effect sizes, which, in comparison to standard pairwise metrics, provided a more accurate and parsimonious characterization of neurodegeneration. The multimodal characterization of neurodegeneration revealed hypo and hyperconnectivity on medium to large-scale brain networks, with a larger contribution of the former. Regions as the amygdala, the insula, and frontal gyrus were associated with both effects, suggesting potential compensatory processes in hub regions. fMRI revealed hypoconnectivity in AD between regions of the default mode, salience, visual, and auditory networks, while in bvFTD between regions of the default mode, salience, and somatomotor networks. EEG revealed hypoconnectivity in the γ band between frontal, limbic, and sensory regions in AD, and in the δ band between frontal, temporal, parietal and posterior areas in bvFTD, suggesting additional pathophysiological processes that fMRI alone can not capture. Classification accuracy was comparable with standard biomarkers and robust against confounders such as sample size, age, education, and motor artifacts (from fMRI and EEG). We conclude that high-order interactions provide a detailed, EEG- and fMRI compatible, biologically plausible, and psychopathological-specific characterization of different neurodegenerative conditions.

Chaos versus noise as drivers of multistability in neural networks.

The multistable behavior of neural networks is actively being studied as a landmark of ongoing cerebral activity, reported in both functional Magnetic Resonance Imaging (fMRI) and electro- or magnetoencephalography recordings. This consists of a continuous jumping between different partially synchronized states in the absence of external stimuli. It is thought to be an important mechanism for dealing with sensory novelty and to allow for efficient coding of information in an ever-changing surrounding environment. Many advances have been made to understand how network topology, connection delays, and noise can contribute to building this dynamic. Little or no attention, however, has been paid to the difference between local chaotic and stochastic influences on the switching between different network states. Using a conductance-based neural model that can have chaotic dynamics, we showed that a network can show multistable dynamics in a certain range of global connectivity strength and under deterministic conditions. In the present work, we characterize the multistable dynamics when the networks are, in addition to chaotic, subject to ion channel stochasticity in the form of multiplicative (channel) or additive (current) noise. We calculate the Functional Connectivity Dynamics matrix by comparing the Functional Connectivity (FC) matrices that describe the pair-wise phase synchronization in a moving window fashion and performing clustering of FCs. Moderate noise can enhance the multistable behavior that is evoked by chaos, resulting in more heterogeneous synchronization patterns, while more intense noise abolishes multistability. In networks composed of nonchaotic nodes, some noise can induce multistability in an otherwise synchronized, nonchaotic network. Finally, we found the same results regardless of the multiplicative or additive nature of noise.

Biophysical models applied to dementia patients reveal links between geographical origin, gender, disease duration, and loss of neural inhibition.

BACKGROUND: The hypothesis of decreased neural inhibition in dementia has been sparsely studied in functional magnetic resonance imaging (fMRI) data across patients with different dementia subtypes, and the role of social and demographic heterogeneities on this hypothesis remains to be addressed. METHODS: We inferred regional inhibition by fitting a biophysical whole-brain model (dynamic mean field model with realistic inter-areal connectivity) to fMRI data from 414 participants, including patients with Alzheimer's disease, behavioral variant frontotemporal dementia, and controls. We then investigated the effect of disease condition, and demographic and clinical variables on the local inhibitory feedback, a variable related to the maintenance of balanced neural excitation/inhibition. RESULTS: Decreased local inhibitory feedback was inferred from the biophysical modeling results in dementia patients, specific to brain areas presenting neurodegeneration. This loss of local inhibition correlated positively with years with disease, and showed differences regarding the gender and geographical origin of the patients. The model correctly reproduced known disease-related changes in functional connectivity. CONCLUSIONS: Results suggest a critical link between abnormal neural and circuit-level excitability levels, the loss of grey matter observed in dementia, and the reorganization of functional connectivity, while highlighting the sensitivity of the underlying biophysical mechanism to demographic and clinical heterogeneities in the patient population.

High-order brain interactions in ketamine during rest and task: A double-blinded cross-over design using portable EEG.

In a double-blinded cross-over design, 30 adults (mean age = 25.57, SD = 3.74; all male) were administered racemic ketamine and compared against saline infusion as a control. Both task-driven (auditory oddball paradigm) and resting-state EEG were recorded. HOI were computed using advanced multivariate information theory tools, allowing us to quantify nonlinear statistical dependencies between all possible electrode combinations. Results: Ketamine increased redundancy in brain dynamics, most significantly in the alpha frequency band. Redundancy was more evident during the resting state, associated with a shift in conscious states towards more dissociative tendencies. Furthermore, in the task-driven context (auditory oddball), the impact of ketamine on redundancy was more significant for predictable (standard stimuli) compared to deviant ones. Finally, associations were observed between ketamine's HOI and experiences of derealization. Conclusions: Ketamine appears to increase redundancy and genuine HOI across metrics, suggesting these effects correlate with consciousness alterations towards dissociation. HOI represents an innovative method to combine all signal spatial interactions obtained from low-density dry EEG in drug interventions, as it is the only approach that exploits all possible combinations from different electrodes. This research emphasizes the potential of complexity measures coupled with portable EEG devices in monitoring shifts in consciousness, especially when paired with low-density configurations, paving the way for better understanding and monitoring of pharmacological-induced changes.

High-order brain interactions in ketamine during rest and task: a double-blinded cross-over design using portable EEG on male participants.

Ketamine is a dissociative anesthetic that induces a shift in global consciousness states and related brain dynamics. Portable low-density EEG systems could be used to monitor these effects. However, previous evidence is almost null and lacks adequate methods to address global dynamics with a small number of electrodes. This study delves into brain high-order interactions (HOI) to explore the effects of ketamine using portable EEG. In a double-blinded cross-over design, 30 male adults (mean age = 25.57, SD = 3.74) were administered racemic ketamine and compared against saline infusion as a control. Both task-driven (auditory oddball paradigm) and resting-state EEG were recorded. HOI were computed using advanced multivariate information theory tools, allowing us to quantify nonlinear statistical dependencies between all possible electrode combinations. Ketamine induced an increase in redundancy in brain dynamics (copies of the same information that can be retrieved from 3 or more electrodes), most significantly in the alpha frequency band. Redundancy was more evident during resting state, associated with a shift in conscious states towards more dissociative tendencies. Furthermore, in the task-driven context (auditory oddball), the impact of ketamine on redundancy was more significant for predictable (standard stimuli) compared to deviant ones. Finally, associations were observed between ketamine's HOI and experiences of derealization. Ketamine appears to increase redundancy and HOI across psychometric measures, suggesting these effects are correlated with alterations in consciousness towards dissociation. In comparisons with event-related potential (ERP) or standard functional connectivity metrics, HOI represent an innovative method to combine all signal spatial interactions obtained from low-density dry EEG in drug interventions, as it is the only approach that exploits all possible combinations between electrodes. This research emphasizes the potential of complexity measures coupled with portable EEG devices in monitoring shifts in consciousness, especially when paired with low-density configurations, paving the way for better understanding and monitoring of pharmacological-induced changes.

Brain clocks capture diversity and disparities in aging and dementia across geographically diverse populations.

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of diversity (including geographical, socioeconomic, sociodemographic, sex and neurodegeneration) on the brain-age gap is unknown. We analyzed datasets from 5,306 participants across 15 countries (7 Latin American and Caribbean countries (LAC) and 8 non-LAC countries). Based on higher-order interactions, we developed a brain-age gap deep learning architecture for functional magnetic resonance imaging (2,953) and electroencephalography (2,353). The datasets comprised healthy controls and individuals with mild cognitive impairment, Alzheimer disease and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (functional magnetic resonance imaging: mean directional error = 5.60, root mean square error (r.m.s.e.) = 11.91; electroencephalography: mean directional error = 5.34, r.m.s.e. = 9.82) associated with frontoposterior networks compared with non-LAC models. Structural socioeconomic inequality, pollution and health disparities were influential predictors of increased brain-age gaps, especially in LAC (R² = 0.37, F² = 0.59, r.m.s.e. = 6.9). An ascending brain-age gap from healthy controls to mild cognitive impairment to Alzheimer disease was found. In LAC, we observed larger brain-age gaps in females in control and Alzheimer disease groups compared with the respective males. The results were not explained by variations in signal quality, demographics or acquisition methods. These findings provide a quantitative framework capturing the diversity of accelerated brain aging.

Brain clocks capture diversity and disparity in aging and dementia.

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of multimodal diversity (geographical, socioeconomic, sociodemographic, sex, neurodegeneration) on the brain age gap (BAG) is unknown. Here, we analyzed datasets from 5,306 participants across 15 countries (7 Latin American countries -LAC, 8 non-LAC). Based on higher-order interactions in brain signals, we developed a BAG deep learning architecture for functional magnetic resonance imaging (fMRI=2,953) and electroencephalography (EEG=2,353). The datasets comprised healthy controls, and individuals with mild cognitive impairment, Alzheimer's disease, and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (fMRI: MDE=5.60, RMSE=11.91; EEG: MDE=5.34, RMSE=9.82) compared to non-LAC, associated with frontoposterior networks. Structural socioeconomic inequality and other disparity-related factors (pollution, health disparities) were influential predictors of increased brain age gaps, especially in LAC (R2=0.37, F2=0.59, RMSE=6.9). A gradient of increasing BAG from controls to mild cognitive impairment to Alzheimer's disease was found. In LAC, we observed larger BAGs in females in control and Alzheimer's disease groups compared to respective males. Results were not explained by variations in signal quality, demographics, or acquisition methods. Findings provide a quantitative framework capturing the multimodal diversity of accelerated brain aging.

A whole-brain model of the neural entropy increase elicited by psychedelic drugs.

Psychedelic drugs, including lysergic acid diethylamide (LSD) and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, mediating both acute alterations in consciousness and long-term effects. However, no clear mechanistic explanation for this entropy increase has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in all regions, but the larger effect were localised in visuo-occipital regions. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain's anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.

Model-based whole-brain perturbational landscape of neurodegenerative diseases.

The treatment of neurodegenerative diseases is hindered by lack of interventions capable of steering multimodal whole-brain dynamics towards patterns indicative of preserved brain health. To address this problem, we combined deep learning with a model capable of reproducing whole-brain functional connectivity in patients diagnosed with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). These models included disease-specific atrophy maps as priors to modulate local parameters, revealing increased stability of hippocampal and insular dynamics as signatures of brain atrophy in AD and bvFTD, respectively. Using variational autoencoders, we visualized different pathologies and their severity as the evolution of trajectories in a low-dimensional latent space. Finally, we perturbed the model to reveal key AD- and bvFTD-specific regions to induce transitions from pathological to healthy brain states. Overall, we obtained novel insights on disease progression and control by means of external stimulation, while identifying dynamical mechanisms that underlie functional alterations in neurodegeneration.

Harmonized multi-metric and multi-centric assessment of EEG source space connectivity for dementia characterization.

Introduction: Harmonization protocols that address batch effects and cross-site methodological differences in multi-center studies are critical for strengthening electroencephalography (EEG) signatures of functional connectivity (FC) as potential dementia biomarkers. Methods: We implemented an automatic processing pipeline incorporating electrode layout integrations, patient-control normalizations, and multi-metric EEG source space connectomics analyses. Results: Spline interpolations of EEG signals onto a head mesh model with 6067 virtual electrodes resulted in an effective method for integrating electrode layouts. Z-score transformations of EEG time series resulted in source space connectivity matrices with high bilateral symmetry, reinforced long-range connections, and diminished short-range functional interactions. A composite FC metric allowed for accurate multicentric classifications of Alzheimer's disease and behavioral variant frontotemporal dementia. Discussion: Harmonized multi-metric analysis of EEG source space connectivity can address data heterogeneities in multi-centric studies, representing a powerful tool for accurately characterizing dementia.

Scalable and accurate method for neuronal ensemble detection in spiking neural networks.

We propose a novel, scalable, and accurate method for detecting neuronal ensembles from a population of spiking neurons. Our approach offers a simple yet powerful tool to study ensemble activity. It relies on clustering synchronous population activity (population vectors), allows the participation of neurons in different ensembles, has few parameters to tune and is computationally efficient. To validate the performance and generality of our method, we generated synthetic data, where we found that our method accurately detects neuronal ensembles for a wide range of simulation parameters. We found that our method outperforms current alternative methodologies. We used spike trains of retinal ganglion cells obtained from multi-electrode array recordings under a simple ON-OFF light stimulus to test our method. We found a consistent stimuli-evoked ensemble activity intermingled with spontaneously active ensembles and irregular activity. Our results suggest that the early visual system activity could be organized in distinguishable functional ensembles. We provide a Graphic User Interface, which facilitates the use of our method by the scientific community.

A mechanistic model of the neural entropy increase elicited by psychedelic drugs.

Psychedelic drugs, including lysergic acid diethylamide and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, mediating both acute alterations in consciousness and long-term effects. However, no clear mechanistic explanation for this entropy increase has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in some regions and decreased in others, suggesting a topographical reconfiguration mediated by 5HT2A-R activation. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain's anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.

Whole-Brain Models to Explore Altered States of Consciousness from the Bottom Up.

The scope of human consciousness includes states departing from what most of us experience as ordinary wakefulness. These altered states of consciousness constitute a prime opportunity to study how global changes in brain activity relate to different varieties of subjective experience. We consider the problem of explaining how global signatures of altered consciousness arise from the interplay between large-scale connectivity and local dynamical rules that can be traced to known properties of neural tissue. For this purpose, we advocate a research program aimed at bridging the gap between bottom-up generative models of whole-brain activity and the top-down signatures proposed by theories of consciousness. Throughout this paper, we define altered states of consciousness, discuss relevant signatures of consciousness observed in brain activity, and introduce whole-brain models to explore the biophysics of altered consciousness from the bottom-up. We discuss the potential of our proposal in view of the current state of the art, give specific examples of how this research agenda might play out, and emphasize how a systematic investigation of altered states of consciousness via bottom-up modeling may help us better understand the biophysical, informational, and dynamical underpinnings of consciousness.

Characterization of Retinal Functionality at Different Eccentricities in a Diurnal Rodent.

Although the properties of the neurons of the visual system that process central and peripheral regions of the visual field have been widely researched in the visual cortex and the LGN, they have scarcely been documented for the retina. The retina is the first step in integrating optical signals, and despite considerable efforts to functionally characterize the different types of retinal ganglion cells (RGCs), a clear account of the particular functionality of cells with central vs. peripheral fields is still wanting. Here, we use electrophysiological recordings, gathered from retinas of the diurnal rodent Octodon degus, to show that RGCs with peripheral receptive fields (RF) are larger, faster, and have shorter transient responses. This translates into higher sensitivity at high temporal frequencies and a full frequency bandwidth when compared to RGCs with more central RF. We also observed that imbalances between ON and OFF cell populations are preserved with eccentricity. Finally, the high diversity of functional types of RGCs highlights the complexity of the computational strategies implemented in the early stages of visual processing, which could inspire the development of bio-inspired artificial systems.