Parameter estimation in a whole-brain network model of epilepsy: Comparison of parallel global optimization solvers.

The Virtual Epileptic Patient (VEP) refers to a computer-based representation of a patient with epilepsy that combines personalized anatomical data with dynamical models of abnormal brain activities. It is capable of generating spatio-temporal seizure patterns that resemble those recorded with invasive methods such as stereoelectro EEG data, allowing for the evaluation of clinical hypotheses before planning surgery. This study highlights the effectiveness of calibrating VEP models using a global optimization approach. The approach utilizes SaCeSS, a cooperative metaheuristic capable of parallel computation, to yield high-quality solutions without requiring excessive computational time. Through extensive benchmarking on synthetic data, our proposal successfully solved a set of different configurations of VEP models, demonstrating better scalability and superior performance against other parallel solvers. These results were further enhanced using a Bayesian optimization framework for hyperparameter tuning, with significant gains in terms of both accuracy and computational cost. Additionally, we added a scalable uncertainty quantification phase after model calibration, and used it to assess the variability in estimated parameters across different problems. Overall, this study has the potential to improve the estimation of pathological brain areas in drug-resistant epilepsy, thereby to inform the clinical decision-making process.

Virtual brain twins: from basic neuroscience to clinical use.

Virtual brain twins are personalized, generative and adaptive brain models based on data from an individual's brain for scientific and clinical use. After a description of the key elements of virtual brain twins, we present the standard model for personalized whole-brain network models. The personalization is accomplished using a subject's brain imaging data by three means: (1) assemble cortical and subcortical areas in the subject-specific brain space; (2) directly map connectivity into the brain models, which can be generalized to other parameters; and (3) estimate relevant parameters through model inversion, typically using probabilistic machine learning. We present the use of personalized whole-brain network models in healthy ageing and five clinical diseases: epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and psychiatric disorders. Specifically, we introduce spatial masks for relevant parameters and demonstrate their use based on the physiological and pathophysiological hypotheses. Finally, we pinpoint the key challenges and future directions.

The virtual aging brain: Causal inference supports interhemispheric dedifferentiation in healthy aging.

The mechanisms of cognitive decline and its variability during healthy aging are not fully understood, but have been associated with reorganization of white matter tracts and functional brain networks. Here, we built a brain network modeling framework to infer the causal link between structural connectivity and functional architecture and the consequent cognitive decline in aging. By applying in-silico interhemispheric degradation of structural connectivity, we reproduced the process of functional dedifferentiation during aging. Thereby, we found the global modulation of brain dynamics by structural connectivity to increase with age, which was steeper in older adults with poor cognitive performance. We validated our causal hypothesis via a deep-learning Bayesian approach. Our results might be the first mechanistic demonstration of dedifferentiation during aging leading to cognitive decline.

Amortized Bayesian inference on generative dynamical network models of epilepsy using deep neural density estimators.

Whole-brain modeling of epilepsy combines personalized anatomical data with dynamical models of abnormal activities to generate spatio-temporal seizure patterns as observed in brain imaging data. Such a parametric simulator is equipped with a stochastic generative process, which itself provides the basis for inference and prediction of the local and global brain dynamics affected by disorders. However, the calculation of likelihood function at whole-brain scale is often intractable. Thus, likelihood-free algorithms are required to efficiently estimate the parameters pertaining to the hypothetical areas, ideally including the uncertainty. In this study, we introduce the simulation-based inference for the virtual epileptic patient model (SBI-VEP), enabling us to amortize the approximate posterior of the generative process from a low-dimensional representation of whole-brain epileptic patterns. The state-of-the-art deep learning algorithms for conditional density estimation are used to readily retrieve the statistical relationships between parameters and observations through a sequence of invertible transformations. We show that the SBI-VEP is able to efficiently estimate the posterior distribution of parameters linked to the extent of the epileptogenic and propagation zones from sparse intracranial electroencephalography recordings. The presented Bayesian methodology can deal with non-linear latent dynamics and parameter degeneracy, paving the way for fast and reliable inference on brain disorders from neuroimaging modalities.

Characterization of regional differences in resting-state fMRI with a data-driven network model of brain dynamics.

Model-based data analysis of whole-brain dynamics links the observed data to model parameters in a network of neural masses. Recently, studies focused on the role of regional variance of model parameters. Such analyses however necessarily depend on the properties of preselected neural mass model. We introduce a method to infer from the functional data both the neural mass model representing the regional dynamics and the region- and subject-specific parameters while respecting the known network structure. We apply the method to human resting-state fMRI. We find that the underlying dynamics can be described as noisy fluctuations around a single fixed point. The method reliably discovers three regional parameters with clear and distinct role in the dynamics, one of which is strongly correlated with the first principal component of the gene expression spatial map. The present approach opens a novel way to the analysis of resting-state fMRI with possible applications for understanding the brain dynamics during aging or neurodegeneration.

Personalised virtual brain models in epilepsy.

Individuals with drug-resistant focal epilepsy are candidates for surgical treatment as a curative option. Before surgery can take place, the patient must have a presurgical evaluation to establish whether and how surgical treatment might stop their seizures without causing neurological deficits. Virtual brains are a new digital modelling technology that map the brain network of a person with epilepsy, using data derived from MRI. This technique produces a computer simulation of seizures and brain imaging signals, such as those that would be recorded with intracranial EEG. When combined with machine learning, virtual brains can be used to estimate the extent and organisation of the epileptogenic zone (ie, the brain regions related to seizure generation and the spatiotemporal dynamics during seizure onset). Virtual brains could, in the future, be used for clinical decision making, to improve precision in localisation of seizure activity, and for surgical planning, but at the moment these models have some limitations, such as low spatial resolution. As evidence accumulates in support of the predictive power of personalised virtual brain models, and as methods are tested in clinical trials, virtual brains might inform clinical practice in the near future.

Delineating epileptogenic networks using brain imaging data and personalized modeling in drug-resistant epilepsy.

Precise estimates of epileptogenic zone networks (EZNs) are crucial for planning intervention strategies to treat drug-resistant focal epilepsy. Here, we present the virtual epileptic patient (VEP), a workflow that uses personalized brain models and machine learning methods to estimate EZNs and to aid surgical strategies. The structural scaffold of the patient-specific whole-brain network model is constructed from anatomical T1 and diffusion-weighted magnetic resonance imaging. Each network node is equipped with a mathematical dynamical model to simulate seizure activity. Bayesian inference methods sample and optimize key parameters of the personalized model using functional stereoelectroencephalography recordings of patients' seizures. These key parameters together with their personalized model determine a given patient's EZN. Personalized models were further used to predict the outcome of surgical intervention using virtual surgeries. We evaluated the VEP workflow retrospectively using 53 patients with drug-resistant focal epilepsy. VEPs reproduced the clinically defined EZNs with a precision of 0.6, where the physical distance between epileptogenic regions identified by VEP and the clinically defined EZNs was small. Compared with the resected brain regions of 25 patients who underwent surgery, VEP showed lower false discovery rates in seizure-free patients (mean, 0.028) than in non-seizure-free patients (mean, 0.407). VEP is now being evaluated in an ongoing clinical trial (EPINOV) with an expected 356 prospective patients with epilepsy.

Brain simulation as a cloud service: The Virtual Brain on EBRAINS.

The Virtual Brain (TVB) is now available as open-source services on the cloud research platform EBRAINS (ebrains.eu). It offers software for constructing, simulating and analysing brain network models including the TVB simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional brain networks; combined simulation of large-scale brain networks with small-scale spiking networks; automatic conversion of user-specified model equations into fast simulation code; simulation-ready brain models of patients and healthy volunteers; Bayesian parameter optimization in epilepsy patient models; data and software for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability, and clinical translation.

Identifying spatio-temporal seizure propagation patterns in epilepsy using Bayesian inference.

Focal drug resistant epilepsy is a neurological disorder characterized by seizures caused by abnormal activity originating in one or more regions together called as epileptogenic zone. Treatment for such patients involves surgical resection of affected regions. Epileptogenic zone is typically identified using stereotactic EEG recordings from the electrodes implanted into the patient's brain. Identifying the epileptogenic zone is a challenging problem due to the spatial sparsity of electrode implantation. We propose a probabilistic hierarchical model of seizure propagation patterns, based on a phenomenological model of seizure dynamics called Epileptor. Using Bayesian inference, the Epileptor model is optimized to build patient specific virtual models that best fit to the log power of intracranial recordings. First, accuracy of the model predictions and identifiability of the model are investigated using synthetic data. Then, model predictions are evaluated against a retrospective patient cohort of 25 patients with varying surgical outcomes. In the patients who are seizure free after surgery, model predictions showed good match with the clinical hypothesis. In patients where surgery failed to achieve seizure freedom model predictions showed a strong mismatch. Our results demonstrate that proposed probabilistic model could be a valuable tool to aid the clinicians in identifying the seizure focus.

On the influence of prior information evaluated by fully Bayesian criteria in a personalized whole-brain model of epilepsy spread.

Individualized anatomical information has been used as prior knowledge in Bayesian inference paradigms of whole-brain network models. However, the actual sensitivity to such personalized information in priors is still unknown. In this study, we introduce the use of fully Bayesian information criteria and leave-one-out cross-validation technique on the subject-specific information to assess different epileptogenicity hypotheses regarding the location of pathological brain areas based on a priori knowledge from dynamical system properties. The Bayesian Virtual Epileptic Patient (BVEP) model, which relies on the fusion of structural data of individuals, a generative model of epileptiform discharges, and a self-tuning Monte Carlo sampling algorithm, is used to infer the spatial map of epileptogenicity across different brain areas. Our results indicate that measuring the out-of-sample prediction accuracy of the BVEP model with informative priors enables reliable and efficient evaluation of potential hypotheses regarding the degree of epileptogenicity across different brain regions. In contrast, while using uninformative priors, the information criteria are unable to provide strong evidence about the epileptogenicity of brain areas. We also show that the fully Bayesian criteria correctly assess different hypotheses about both structural and functional components of whole-brain models that differ across individuals. The fully Bayesian information-theory based approach used in this study suggests a patient-specific strategy for epileptogenicity hypothesis testing in generative brain network models of epilepsy to improve surgical outcomes.

Data-driven method to infer the seizure propagation patterns in an epileptic brain from intracranial electroencephalography.

Surgical interventions in epileptic patients aimed at the removal of the epileptogenic zone have success rates at only 60-70%. This failure can be partly attributed to the insufficient spatial sampling by the implanted intracranial electrodes during the clinical evaluation, leading to an incomplete picture of spatio-temporal seizure organization in the regions that are not directly observed. Utilizing the partial observations of the seizure spreading through the brain network, complemented by the assumption that the epileptic seizures spread along the structural connections, we infer if and when are the unobserved regions recruited in the seizure. To this end we introduce a data-driven model of seizure recruitment and propagation across a weighted network, which we invert using the Bayesian inference framework. Using a leave-one-out cross-validation scheme on a cohort of 45 patients we demonstrate that the method can improve the predictions of the states of the unobserved regions compared to an empirical estimate that does not use the structural information, yet it is on the same level as the estimate that takes the structure into account. Furthermore, a comparison with the performed surgical resection and the surgery outcome indicates a link between the inferred excitable regions and the actual epileptogenic zone. The results emphasize the importance of the structural connectome in the large-scale spatio-temporal organization of epileptic seizures and introduce a novel way to integrate the patient-specific connectome and intracranial seizure recordings in a whole-brain computational model of seizure spread.

Optimal Model Parameter Estimation from EEG Power Spectrum Features Observed during General Anesthesia.

Mathematical modeling is a powerful tool that enables researchers to describe the experimentally observed dynamics of complex systems. Starting with a robust model including model parameters, it is necessary to choose an appropriate set of model parameters to reproduce experimental data. However, estimating an optimal solution of the inverse problem, i.e., finding a set of model parameters that yields the best possible fit to the experimental data, is a very challenging problem. In the present work, we use different optimization algorithms based on a frequentist approach, as well as Monte Carlo Markov Chain methods based on Bayesian inference techniques to solve the considered inverse problems. We first probe two case studies with synthetic data and study models described by a stochastic non-delayed linear second-order differential equation and a stochastic linear delay differential equation. In a third case study, a thalamo-cortical neural mass model is fitted to the EEG spectral power measured during general anesthesia induced by anesthetics propofol and desflurane. We show that the proposed neural mass model fits very well to the observed EEG power spectra, particularly to the power spectral peaks within δ - (0 - 4 Hz) and α - (8 - 13 Hz) frequency ranges. Furthermore, for each case study, we perform a practical identifiability analysis by estimating the confidence regions of the parameter estimates and interpret the corresponding correlation and sensitivity matrices. Our results indicate that estimating the model parameters from analytically computed spectral power, we are able to accurately estimate the unknown parameters while avoiding the computational costs due to numerical integration of the model equations.

Anesthetic action on the transmission delay between cortex and thalamus explains the beta-buzz observed under propofol anesthesia.

In recent years, more and more surgeries under general anesthesia have been performed with the assistance of electroencephalogram (EEG) monitors. An increase in anesthetic concentration leads to characteristic changes in the power spectra of the EEG. Although tracking the anesthetic-induced changes in EEG rhythms can be employed to estimate the depth of anesthesia, their precise underlying mechanisms are still unknown. A prominent feature in the EEG of some patients is the emergence of a strong power peak in the ß-frequency band, which moves to the α-frequency band while increasing the anesthetic concentration. This feature is called the beta-buzz. In the present study, we use a thalamo-cortical neural population feedback model to reproduce observed characteristic features in frontal EEG power obtained experimentally during propofol general anesthesia, such as this beta-buzz. First, we find that the spectral power peak in the α- and δ-frequency ranges depend on the decay rate constant of excitatory and inhibitory synapses, but the anesthetic action on synapses does not explain the beta-buzz. Moreover, considering the action of propofol on the transmission delay between cortex and thalamus, the model reveals that the beta-buzz may result from a prolongation of the transmission delay by increasing propofol concentration. A corresponding relationship between transmission delay and anesthetic blood concentration is derived. Finally, an analytical stability study demonstrates that increasing propofol concentration moves the systems resting state towards its stability threshold.

How the cortico-thalamic feedback affects the EEG power spectrum over frontal and occipital regions during propofol-induced sedation.

Increasing concentrations of the anaesthetic agent propofol initially induces sedation before achieving full general anaesthesia. During this state of anaesthesia, the observed specific changes in electroencephalographic (EEG) rhythms comprise increased activity in the δ- (0.5-4 Hz) and α- (8-13 Hz) frequency bands over the frontal region, but increased δ- and decreased α-activity over the occipital region. It is known that the cortex, the thalamus, and the thalamo-cortical feedback loop contribute to some degree to the propofol-induced changes in the EEG power spectrum. However the precise role of each structure to the dynamics of the EEG is unknown. In this paper we apply a thalamo-cortical neuronal population model to reproduce the power spectrum changes in EEG during propofol-induced anaesthesia sedation. The model reproduces the power spectrum features observed experimentally both in frontal and occipital electrodes. Moreover, a detailed analysis of the model indicates the importance of multiple resting states in brain activity. The work suggests that the α-activity originates from the cortico-thalamic relay interaction, whereas the emergence of δ-activity results from the full cortico-reticular-relay-cortical feedback loop with a prominent enforced thalamic reticular-relay interaction. This model suggests an important role for synaptic GABAergic receptors at relay neurons and, more generally, for the thalamus in the generation of both the δ- and the α- EEG patterns that are seen during propofol anaesthesia sedation.

Anesthetic action on extra-synaptic receptors: effects in neural population models of EEG activity.

The role of extra-synaptic receptors in the regulation of excitation and inhibition in the brain has attracted increasing attention. Because activity in the extra-synaptic receptors plays a role in regulating the level of excitation and inhibition in the brain, they may be important in determining the level of consciousness. This paper reviews briefly the literature on extra-synaptic GABA and NMDA receptors and their affinity to anesthetic drugs. We propose a neural population model that illustrates how the effect of the anesthetic drug propofol on GABAergic extra-synaptic receptors results in changes in neural population activity and the electroencephalogram (EEG). Our results show that increased tonic inhibition in inhibitory cortical neurons cause a dramatic increase in the power of both δ- and α- bands. Conversely, the effects of increased tonic inhibition in cortical excitatory neurons and thalamic relay neurons have the opposite effect and decrease the power in these bands. The increased δ-activity is in accord with observed data for deepening propofol anesthesia; but is absolutely dependent on the inclusion of extrasynaptic (tonic) GABA action in the model.