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.

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.

Computational modeling of seizure spread on a cortical surface.

In the field of computational epilepsy, neural field models helped to understand some large-scale features of seizure dynamics. These insights however remain on general levels, without translation to the clinical settings via personalization of the model with the patient-specific structure. In particular, a link was suggested between epileptic seizures spreading across the cortical surface and the so-called theta-alpha activity (TAA) pattern seen on intracranial electrographic signals, yet this link was not demonstrated on a patient-specific level. Here we present a single patient computational study linking the seizure spreading across the patient-specific cortical surface with a specific instance of the TAA pattern recorded in the patient. Using the realistic geometry of the cortical surface we perform the simulations of seizure dynamics in The Virtual Brain platform, and we show that the simulated electrographic signals qualitatively agree with the recorded signals. Furthermore, the comparison with the simulations performed on surrogate surfaces reveals that the best quantitative fit is obtained for the real surface. The work illustrates how the patient-specific cortical geometry can be utilized in The Virtual Brain for personalized model building, and the importance of such approach.

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.

Evidence for spreading seizure as a cause of theta-alpha activity electrographic pattern in stereo-EEG seizure recordings.

Intracranial electroencephalography is a standard tool in clinical evaluation of patients with focal epilepsy. Various early electrographic seizure patterns differing in frequency, amplitude, and waveform of the oscillations are observed. The pattern most common in the areas of seizure propagation is the so-called theta-alpha activity (TAA), whose defining features are oscillations in the θ - α range and gradually increasing amplitude. A deeper understanding of the mechanism underlying the generation of the TAA pattern is however lacking. In this work we evaluate the hypothesis that the TAA patterns are caused by seizures spreading across the cortex. To do so, we perform simulations of seizure dynamics on detailed patient-derived cortical surfaces using the spreading seizure model as well as reference models with one or two homogeneous sources. We then detect the occurrences of the TAA patterns both in the simulated stereo-electroencephalographic signals and in the signals of recorded epileptic seizures from a cohort of fifty patients, and we compare the features of the groups of detected TAA patterns to assess the plausibility of the different models. Our results show that spreading seizure hypothesis is qualitatively consistent with the evidence available in the seizure recordings, and it can explain the features of the detected TAA groups best among the examined models.

VEP atlas: An anatomic and functional human brain atlas dedicated to epilepsy patients.

BACKGROUND: Several automated parcellation atlases of the human brain have been developed over the past decades, based on various criteria, and have been applied in basic and clinical research. NEW METHOD: Here we present the Virtual Epileptic Patient (VEP) atlas that offers a new automated brain region parcellation and labeling, which has been developed for the specific use in the domains of epileptology and functional neurosurgery and is able to apply at individual patient's level. RESULTS: It comprises 162 brain regions, including 73 cortical and 8 subcortical regions per hemisphere. We demonstrate the successful application of the VEP atlas in a cohort of 50 retrospective patients. The structural organization is complemented by the functional variation of stereotactic intracerebral EEG (SEEG) signal data features establishing brain region-specific 3d-maps. COMPARISON WITH EXISTING METHODS: The VEP atlas integrates both anatomical and functional definitions in the same atlas, adapted to applications for epilepsy patients and individualizable. CONCLUSION: The covariation of structural and functional organization is the basis for current efforts of patient-specific large-scale brain network modeling exploiting virtual brain technologies for the identification of the epileptogenic regions in an ongoing prospective clinical trial EPINOV.