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.
•Connectivity studies in dementia neglect high-order functional connectivity (HOFC).•HOFC (from 3 to 15 orders of interactions) outperforms standard pairwise approaches.•Rich spatiotemporal hypo- and hyper-HOFC patterns characterize AD and FTD.•HOFC is robust against confounding factors (age, education, missing data, artifacts).•HOFC is a biologically plausible approach for brain networks in neurodegeneration.
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.
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 (patients<HCs) involving convergent temporo-parieto-occipital regions in AD, and fronto-temporo-parietal areas in bvFTD. Hyperconnectivity (patients>HCs) 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.
•Joint connectivity analyses capture complex patters of brain interactions.•A tenth of all possible brain functional interactions are atypical in AD and bvFTD.•Only a reduced set of metrics captures atypical connectivity in AD and bvFTD.•Atypical EEG connectivity in AD and bvFTD is frequency-band specific.•Integration of connectivity metrics strengthens AD and bvFTD classifications.
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.
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.
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.
Despite their differences, biological systems at different spatial scales tend to exhibit common organizational patterns. Unfortunately, these commonalities are often hard to grasp due to the highly ...specialized nature of modern science and the parcelled terminology employed by various scientific sub-disciplines. To explore these common organizational features, this paper provides a comparative study of diverse applications of the maximum entropy principle, which has found many uses at different biological spatial scales ranging from amino acids up to societies. By presenting these studies under a common approach and language, this paper aims to establish a unified view over these seemingly highly heterogeneous scenarios.
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.
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.
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.
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.
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.
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