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.

The impact of regional heterogeneity in whole-brain dynamics in the presence of oscillations.

Large variability exists across brain regions in health and disease, considering their cellular and molecular composition, connectivity, and function. Large-scale whole-brain models comprising coupled brain regions provide insights into the underlying dynamics that shape complex patterns of spontaneous brain activity. In particular, biophysically grounded mean-field whole-brain models in the asynchronous regime were used to demonstrate the dynamical consequences of including regional variability. Nevertheless, the role of heterogeneities when brain dynamics are supported by synchronous oscillating state, which is a ubiquitous phenomenon in brain, remains poorly understood. Here, we implemented two models capable of presenting oscillatory behavior with different levels of abstraction: a phenomenological Stuart-Landau model and an exact mean-field model. The fit of these models informed by structural- to functional-weighted MRI signal (T1w/T2w) allowed us to explore the implication of the inclusion of heterogeneities for modeling resting-state fMRI recordings from healthy participants. We found that disease-specific regional functional heterogeneity imposed dynamical consequences within the oscillatory regime in fMRI recordings from neurodegeneration with specific impacts on brain atrophy/structure (Alzheimer's patients). Overall, we found that models with oscillations perform better when structural and functional regional heterogeneities are considered, showing that phenomenological and biophysical models behave similarly at the brink of the Hopf bifurcation.

Low-dimensional organization of global brain states of reduced consciousness.

Brain states are frequently represented using a unidimensional scale measuring the richness of subjective experience (level of consciousness). This description assumes a mapping between the high-dimensional space of whole-brain configurations and the trajectories of brain states associated with changes in consciousness, yet this mapping and its properties remain unclear. We combine whole-brain modeling, data augmentation, and deep learning for dimensionality reduction to determine a mapping representing states of consciousness in a low-dimensional space, where distances parallel similarities between states. An orderly trajectory from wakefulness to patients with brain injury is revealed in a latent space whose coordinates represent metrics related to functional modularity and structure-function coupling, increasing alongside loss of consciousness. Finally, we investigate the effects of model perturbations, providing geometrical interpretation for the stability and reversibility of states. We conclude that conscious awareness depends on functional patterns encoded as a low-dimensional trajectory within the vast space of brain configurations.

The lack of temporal brain dynamics asymmetry as a signature of impaired consciousness states.

Life is a constant battle against equilibrium. From the cellular level to the macroscopic scale, living organisms as dissipative systems require the violation of their detailed balance, i.e. metabolic enzymatic reactions, in order to survive. We present a framework based on temporal asymmetry as a measure of non-equilibrium. By means of statistical physics, it was discovered that temporal asymmetries establish an arrow of time useful for assessing the reversibility in human brain time series. Previous studies in human and non-human primates have shown that decreased consciousness states such as sleep and anaesthesia result in brain dynamics closer to the equilibrium. Furthermore, there is growing interest in the analysis of brain symmetry based on neuroimaging recordings and since it is a non-invasive technique, it can be extended to different brain imaging modalities and applied at different temporo-spatial scales. In the present study, we provide a detailed description of our methodological approach, paying special attention to the theories that motivated this work. We test, for the first time, the reversibility analysis in human functional magnetic resonance imaging data in patients suffering from disorder of consciousness. We verify that the tendency of a decrease in the asymmetry of the brain signal together with the decrease in non-stationarity are key characteristics of impaired consciousness states. We expect that this work will open the way for assessing biomarkers for patients' improvement and classification, as well as motivating further research on the mechanistic understanding underlying states of impaired consciousness.

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.

Toward naturalistic neuroscience: Mechanisms underlying the flattening of brain hierarchy in movie-watching compared to rest and task.

Identifying the functional specialization of the brain has moved from using cognitive tasks and resting state to using ecological relevant, naturalistic movies. We leveraged a large-scale neuroimaging dataset to directly investigate the hierarchical reorganization of functional brain activity when watching naturalistic films compared to performing seven cognitive tasks and resting. A thermodynamics-inspired whole-brain model paradigm revealed the generative underlying mechanisms for changing the balance in causal interactions between brain regions in different conditions. Paradoxically, the hierarchy is flatter for movie-watching, and the level of nonreversibility is significantly smaller in comparison to both rest and tasks, where the latter in turn have the highest levels of hierarchy and nonreversibility. The underlying mechanisms were revealed by the model-based generative effective connectivity (GEC). Naturalistic films could therefore provide a fast and convenient way to measure important changes in GEC (integrating functional and anatomical connectivity) found in, for example, neuropsychiatric disorders. Overall, this study demonstrates the benefits of moving toward a more naturalistic neuroscience.

Temporal irreversibility of neural dynamics as a signature of consciousness.

Dissipative systems evolve in the preferred temporal direction indicated by the thermodynamic arrow of time. The fundamental nature of this temporal asymmetry led us to hypothesize its presence in the neural activity evoked by conscious perception of the physical world, and thus its covariance with the level of conscious awareness. We implemented a data-driven deep learning framework to decode the temporal inversion of electrocorticography signals acquired from non-human primates. Brain activity time series recorded during conscious wakefulness could be distinguished from their inverted counterparts with high accuracy, both using frequency and phase information. However, classification accuracy was reduced for data acquired during deep sleep and under ketamine-induced anesthesia; moreover, the predictions obtained from multiple independent neural networks were less consistent for sleep and anesthesia than for conscious wakefulness. Finally, the analysis of feature importance scores highlighted transitions between slow ($\approx$20 Hz) and fast frequencies (>40 Hz) as the main contributors to the temporal asymmetry observed during conscious wakefulness. Our results show that a preferred temporal direction is manifest in the neural activity evoked by conscious mentation and in the phenomenology of the passage of time, establishing common ground to tackle the relationship between brain and subjective experience.

An integrated resource for functional and structural connectivity of the marmoset brain.

Comprehensive integration of structural and functional connectivity data is required to model brain functions accurately. While resources for studying the structural connectivity of non-human primate brains already exist, their integration with functional connectivity data has remained unavailable. Here we present a comprehensive resource that integrates the most extensive awake marmoset resting-state fMRI data available to date (39 marmoset monkeys, 710 runs, 12117 mins) with previously published cellular-level neuronal tracing data (52 marmoset monkeys, 143 injections) and multi-resolution diffusion MRI datasets. The combination of these data allowed us to (1) map the fine-detailed functional brain networks and cortical parcellations, (2) develop a deep-learning-based parcellation generator that preserves the topographical organization of functional connectivity and reflects individual variabilities, and (3) investigate the structural basis underlying functional connectivity by computational modeling. This resource will enable modeling structure-function relationships and facilitate future comparative and translational studies of primate brains.

Unifying turbulent dynamics framework distinguishes different brain states.

Significant advances have been made by identifying the levels of synchrony of the underlying dynamics of a given brain state. This research has demonstrated that non-conscious dynamics tend to be more synchronous than in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that different brain states are underpinned by dissociable spatiotemporal dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep and disorders of consciousness after coma). The model-free approach was based on Kuramoto's turbulence framework using coupled oscillators. This was extended by a measure of the information cascade across spatial scales. Complementarily, the model-based approach used exhaustive in silico perturbations of whole-brain models fitted to these measures. This allowed studying of the information encoding capabilities in given brain states. Overall, this framework demonstrates that elements from turbulence theory provide excellent tools for describing and differentiating between brain states.

Effects of classic psychedelic drugs on turbulent signatures in brain dynamics.

Psychedelic drugs show promise as safe and effective treatments for neuropsychiatric disorders, yet their mechanisms of action are not fully understood. A fundamental hypothesis is that psychedelics work by dose-dependently changing the functional hierarchy of brain dynamics, but it is unclear whether different psychedelics act similarly. Here, we investigated the changes in the brain's functional hierarchy associated with two different psychedelics (LSD and psilocybin). Using a novel turbulence framework, we were able to determine the vorticity, that is, the local level of synchronization, that allowed us to extend the standard global time-based measure of metastability to become a local-based measure of both space and time. This framework produced detailed signatures of turbulence-based hierarchical change for each psychedelic drug, revealing consistent and discriminate effects on a higher level network, that is, the default mode network. Overall, our findings directly support a prior hypothesis that psychedelics modulate (i.e., "compress") the functional hierarchy and provide a quantification of these changes for two different psychedelics. Implications for therapeutic applications of psychedelics are discussed.

Significant progress has been made in understanding the effects of psychedelics on brain function. One of the main hypotheses is that psychedelics work by changing the functional hierarchy of brain dynamics in a dose-dependent manner, modulating the encoding of the precision of priors, beliefs, or assumptions in the brain. We used a novel turbulence framework to investigate the changes in the brain's functional hierarchy associated with two different psychedelics (LSD and psilocybin). This framework produced detailed signatures of turbulence-based hierarchical change for each psychedelic drug, revealing consistent and discriminate effects on a higher level network, that is, the default mode network.

Dynamic brain fluctuations outperform connectivity measures and mirror pathophysiological profiles across dementia subtypes: A multicenter study.

From molecular mechanisms to global brain networks, atypical fluctuations are the hallmark of neurodegeneration. Yet, traditional fMRI research on resting-state networks (RSNs) has favored static and average connectivity methods, which by overlooking the fluctuation dynamics triggered by neurodegeneration, have yielded inconsistent results. The present multicenter study introduces a data-driven machine learning pipeline based on dynamic connectivity fluctuation analysis (DCFA) on RS-fMRI data from 300 participants belonging to three groups: behavioral variant frontotemporal dementia (bvFTD) patients, Alzheimer's disease (AD) patients, and healthy controls. We considered non-linear oscillatory patterns across combined and individual resting-state networks (RSNs), namely: the salience network (SN), mostly affected in bvFTD; the default mode network (DMN), mostly affected in AD; the executive network (EN), partially compromised in both conditions; the motor network (MN); and the visual network (VN). These RSNs were entered as features for dementia classification using a recent robust machine learning approach (a Bayesian hyperparameter tuned Gradient Boosting Machines (GBM) algorithm), across four independent datasets with different MR scanners and recording parameters. The machine learning classification accuracy analysis revealed a systematic and unique tailored architecture of RSN disruption. The classification accuracy ranking showed that the most affected networks for bvFTD were the SN + EN network pair (mean accuracy = 86.43%, AUC = 0.91, sensitivity = 86.45%, specificity = 87.54%); for AD, the DMN + EN network pair (mean accuracy = 86.63%, AUC = 0.89, sensitivity = 88.37%, specificity = 84.62%); and for the bvFTD vs. AD classification, the DMN + SN network pair (mean accuracy = 82.67%, AUC = 0.86, sensitivity = 81.27%, specificity = 83.01%). Moreover, the DFCA classification systematically outperformed canonical connectivity approaches (including both static and linear dynamic connectivity). Our findings suggest that non-linear dynamical fluctuations surpass two traditional seed-based functional connectivity approaches and provide a pathophysiological characterization of global brain networks in neurodegenerative conditions (AD and bvFTD) across multicenter data.

Generative Embeddings of Brain Collective Dynamics Using Variational Autoencoders.

We consider the problem of encoding pairwise correlations between coupled dynamical systems in a low-dimensional latent space based on few distinct observations. We use variational autoencoders (VAEs) to embed temporal correlations between coupled nonlinear oscillators that model brain states in the wake-sleep cycle into a two-dimensional manifold. Training a VAE with samples generated using two different parameter combinations results in an embedding that encodes the repertoire of collective dynamics, as well as the topology of the underlying connectivity network. We first follow this approach to infer the trajectory of brain states measured from wakefulness to deep sleep from the two end points of this trajectory; then, we show that the same architecture was capable of representing the pairwise correlations of generic Landau-Stuart oscillators coupled by complex network topology.

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.

Modeling regional changes in dynamic stability during sleep and wakefulness.

Global brain states are frequently placed within a unidimensional continuum by correlational studies, ranging from states of deep unconsciousness to ordinary wakefulness. An alternative is their multidimensional and mechanistic characterization in terms of different cognitive capacities, using computational models to reproduce the underlying neural dynamics. We explore this alternative by introducing a semi-empirical model linking regional activation and long-range functional connectivity in the different brain states visited during the natural wake-sleep cycle. Our model combines functional magnetic resonance imaging (fMRI) data, in vivo estimates of structural connectivity, and anatomically-informed priors to constrain the independent variation of regional activation. The best fit to empirical data was achieved using priors based on functionally coherent networks, with the resulting model parameters dividing the cortex into regions presenting opposite dynamical behavior. Frontoparietal regions approached a bifurcation from dynamics at a fixed point governed by noise, while sensorimotor regions approached a bifurcation from oscillatory dynamics. In agreement with human electrophysiological experiments, sleep onset induced subcortical deactivation with low correlation, which was subsequently reversed for deeper stages. Finally, we introduced periodic forcing of variable intensity to simulate external perturbations, and identified the key regions relevant for the recovery of wakefulness from deep sleep. Our model represents sleep as a state with diminished perceptual gating and the latent capacity for global accessibility that is required for rapid arousals. To the extent that the qualitative characterization of local dynamics is exhausted by the dichotomy between unstable and stable behavior, our work highlights how expanding the model parameter space can describe states of consciousness in terms of multiple dimensions with interpretations given by the choice of anatomically-informed priors.

Automatic reconstruction of physiological gestures used in a model of birdsong production.

Highly coordinated learned behaviors are key to understanding neural processes integrating the body and the environment. Birdsong production is a widely studied example of such behavior in which numerous thoracic muscles control respiratory inspiration and expiration: the muscles of the syrinx control syringeal membrane tension, while upper vocal tract morphology controls resonances that modulate the vocal system output. All these muscles have to be coordinated in precise sequences to generate the elaborate vocalizations that characterize an individual's song. Previously we used a low-dimensional description of the biomechanics of birdsong production to investigate the associated neural codes, an approach that complements traditional spectrographic analysis. The prior study used algorithmic yet manual procedures to model singing behavior. In the present work, we present an automatic procedure to extract low-dimensional motor gestures that could predict vocal behavior. We recorded zebra finch songs and generated synthetic copies automatically, using a biomechanical model for the vocal apparatus and vocal tract. This dynamical model described song as a sequence of physiological parameters the birds control during singing. To validate this procedure, we recorded electrophysiological activity of the telencephalic nucleus HVC. HVC neurons were highly selective to the auditory presentation of the bird's own song (BOS) and gave similar selective responses to the automatically generated synthetic model of song (AUTO). Our results demonstrate meaningful dimensionality reduction in terms of physiological parameters that individual birds could actually control. Furthermore, this methodology can be extended to other vocal systems to study fine motor control.

Elemental gesture dynamics are encoded by song premotor cortical neurons.

Quantitative biomechanical models can identify control parameters that are used during movements, and movement parameters that are encoded by premotor neurons. We fit a mathematical dynamical systems model including subsyringeal pressure, syringeal biomechanics and upper-vocal-tract filtering to the songs of zebra finches. This reduces the dimensionality of singing dynamics, described as trajectories (motor 'gestures') in a space of syringeal pressure and tension. Here we assess model performance by characterizing the auditory response 'replay' of song premotor HVC neurons to the presentation of song variants in sleeping birds, and by examining HVC activity in singing birds. HVC projection neurons were excited and interneurons were suppressed within a few milliseconds of the extreme time points of the gesture trajectories. Thus, the HVC precisely encodes vocal motor output through activity at the times of extreme points of movement trajectories. We propose that the sequential activity of HVC neurons is used as a 'forward' model, representing the sequence of gestures in song to make predictions on expected behaviour and evaluate feedback.

Prosthetic avian vocal organ controlled by a freely behaving bird based on a low dimensional model of the biomechanical periphery.

Because of the parallels found with human language production and acquisition, birdsong is an ideal animal model to study general mechanisms underlying complex, learned motor behavior. The rich and diverse vocalizations of songbirds emerge as a result of the interaction between a pattern generator in the brain and a highly nontrivial nonlinear periphery. Much of the complexity of this vocal behavior has been understood by studying the physics of the avian vocal organ, particularly the syrinx. A mathematical model describing the complex periphery as a nonlinear dynamical system leads to the conclusion that nontrivial behavior emerges even when the organ is commanded by simple motor instructions: smooth paths in a low dimensional parameter space. An analysis of the model provides insight into which parameters are responsible for generating a rich variety of diverse vocalizations, and what the physiological meaning of these parameters is. By recording the physiological motor instructions elicited by a spontaneously singing muted bird and computing the model on a Digital Signal Processor in real-time, we produce realistic synthetic vocalizations that replace the bird's own auditory feedback. In this way, we build a bio-prosthetic avian vocal organ driven by a freely behaving bird via its physiologically coded motor commands. Since it is based on a low-dimensional nonlinear mathematical model of the peripheral effector, the emulation of the motor behavior requires light computation, in such a way that our bio-prosthetic device can be implemented on a portable platform.

Reconstruction of physiological instructions from Zebra finch song.

We reconstruct the physiological parameters that control an avian vocal organ during birdsong production using recorded song. The procedure involves fitting the time dependent parameters of an avian vocal organ model. Computationally, the model is implemented as a dynamical system ruling the behavior of the oscillating labia that modulate the air flow during sound production, together with the equations describing the dynamics of pressure fluctuations in the vocal tract. We tested our procedure for Zebra finch song with, simultaneously recorded physiological parameters: air sac pressure and the electromyographic activity of the left and right ventral syringeal muscles. A comparison of the reconstructed instructions with measured physiological parameters during song shows a high degree of correlation. Integrating the model with reconstructed parameters leads to the synthesis of highly realistic songs.

Acoustic signatures of sound source-tract coupling.

Birdsong is a complex behavior, which results from the interaction between a nervous system and a biomechanical peripheral device. While much has been learned about how complex sounds are generated in the vocal organ, little has been learned about the signature on the vocalizations of the nonlinear effects introduced by the acoustic interactions between a sound source and the vocal tract. The variety of morphologies among bird species makes birdsong a most suitable model to study phenomena associated to the production of complex vocalizations. Inspired by the sound production mechanisms of songbirds, in this work we study a mathematical model of a vocal organ, in which a simple sound source interacts with a tract, leading to a delay differential equation. We explore the system numerically, and by taking it to the weakly nonlinear limit, we are able to examine its periodic solutions analytically. By these means we are able to explore the dynamics of oscillatory solutions of a sound source-tract coupled system, which are qualitatively different from those of a sound source-filter model of a vocal organ. Nonlinear features of the solutions are proposed as the underlying mechanisms of observed phenomena in birdsong, such as unilaterally produced "frequency jumps," enhancement of resonances, and the shift of the fundamental frequency observed in heliox experiments.