Advancing post-traumatic seizure classification and biomarker identification: Information decomposition based multimodal fusion and explainable machine learning with missing neuroimaging data.

A late post-traumatic seizure (LPTS), a consequence of traumatic brain injury (TBI), can potentially evolve into a lifelong condition known as post-traumatic epilepsy (PTE). Presently, the mechanism that triggers epileptogenesis in TBI patients remains elusive, inspiring the epilepsy community to devise ways to predict which TBI patients will develop PTE and to identify potential biomarkers. In response to this need, our study collected comprehensive, longitudinal multimodal data from 48 TBI patients across multiple participating institutions. A supervised binary classification task was created, contrasting data from LPTS patients with those without LPTS. To accommodate missing modalities in some subjects, we took a two-pronged approach. Firstly, we extended a graphical model-based Bayesian estimator to directly classify subjects with incomplete modality. Secondly, we explored conventional imputation techniques. The imputed multimodal information was then combined, following several fusion and dimensionality reduction techniques found in the literature, and subsequently fitted to a kernel- or a tree-based classifier. For this fusion, we proposed two new algorithms: recursive elimination of correlated components (RECC) that filters information based on the correlation between the already selected features, and information decomposition and selective fusion (IDSF), which effectively recombines information from decomposed multimodal features. Our cross-validation findings showed that the proposed IDSF algorithm delivers superior performance based on the area under the curve (AUC) score. Ultimately, after rigorous statistical comparisons and interpretable machine learning examination using Shapley values of the most frequently selected features, we recommend the two following magnetic resonance imaging (MRI) abnormalities as potential biomarkers: the left anterior limb of internal capsule in diffusion MRI (dMRI), and the right middle temporal gyrus in functional MRI (fMRI).

Functional connectivity alterations in traumatic brain injury patients with late seizures.

PTE is a neurological disorder characterized by recurrent and spontaneous epileptic seizures. PTE is a major public health problem occurring in 2-50% of TBI patients. Identifying PTE biomarkers is crucial for the development of effective treatments. Functional neuroimaging studies in patients with epilepsy and in epileptic rodents have observed that abnormal functional brain activity plays a role in the development of epilepsy. Network representations of complex systems ease quantitative analysis of heterogeneous interactions within a unified mathematical framework. In this work, graph theory was used to study resting state functional magnetic resonance imaging (rs-fMRI) and reveal functional connectivity abnormalities that are associated with seizure development in traumatic brain injury (TBI) patients. We examined rs-fMRI of 75 TBI patients from Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) which aims to identify validated Post-traumatic epilepsy (PTE) biomarkers and antiepileptogenic therapies using multimodal and longitudinal data acquired from 14 international sites. The dataset includes 28 subjects who had at least one late seizure after TBI and 47 subjects who had no seizures within 2 years post-injury. Each subject's neural functional network was investigated by computing the correlation between the low frequency time series of 116 regions of interest (ROIs). Each subject's functional organization was represented as a network consisting of nodes, brain regions, and edges that show the relationship between the nodes. Then, several graph measures concerning the integration and the segregation of the functional brain networks were extracted in order to highlight changes in functional connectivity between the two TBI groups. Results showed that the late seizure-affected group had a compromised balance between integration and segregation and presents functional networks that are hyperconnected, hyperintegrated but at the same time hyposegregated compared with seizure-free patients. Moreover, TBI subjects who developed late seizures had more low betweenness hubs.

Improving the study of brain-behavior relationships by revisiting basic assumptions.

Neuroimaging research has been at the forefront of concerns regarding the failure of experimental findings to replicate. In the study of brain-behavior relationships, past failures to find replicable and robust effects have been attributed to methodological shortcomings. Methodological rigor is important, but there are other overlooked possibilities: most published studies share three foundational assumptions, often implicitly, that may be faulty. In this paper, we consider the empirical evidence from human brain imaging and the study of non-human animals that calls each foundational assumption into question. We then consider the opportunities for a robust science of brain-behavior relationships that await if scientists ground their research efforts in revised assumptions supported by current empirical evidence.

Interaction Between Cerebellum and Cerebral Cortex, Evidence from Dynamic Causal Modeling.

The interaction of the cerebellum with cerebral cortical dynamics is still poorly understood. In this paper, dynamical causal modeling is used to examine the interaction between cerebellum and cerebral cortex as indexed by MRI resting-state functional connectivity in three large-scale networks on healthy young adults (N = 200; Human Connectome Project dataset). These networks correspond roughly to default mode, task positive, and motor as determined by prior cerebellar functional gradient analyses. We find uniform interactions within all considered networks from cerebellum to cerebral cortex, providing support for the notion of a universal cerebellar transform. Our results provide a foundation for future analyses to quantify and further investigate whether this is a property that is unique to the interactions from cerebellum to cerebral cortex.

Automatic Detection of EEG Epileptiform Abnormalities in Traumatic Brain Injury using Deep Learning.

Traumatic brain injury (TBI) is a sudden injury that causes damage to the brain. TBI can have wide-ranging physical, psychological, and cognitive effects. TBI outcomes include acute injuries, such as contusion or hematoma, as well as chronic sequelae that emerge days to years later, including cognitive decline and seizures. Some TBI patients develop posttraumatic epilepsy (PTE), or recurrent and unprovoked seizures following TBI. In recent years, significant efforts have been made to identify biomarkers of epileptogenesis, the process by which a normal brain becomes capable of generating seizures. These biomarkers would allow for a higher standard of care by identifying patients at risk of developing PTE as candidates for antiepileptogenic interventions. In this paper, we use deep neural network architectures to automatically detect potential biomarkers of PTE from electroencephalogram (EEG) data collected between post-injury day 1-7 from patients with moderate-to-severe TBI. Continuous EEG is often part of multimodal monitoring for TBI patients in intensive care units. Clinicians review EEG to identify the presence of epileptiform abnormalities (EAs), such as seizures, periodic discharges, and abnormal rhythmic delta activity, which are potential biomarkers of epileptogenesis. We show that a recurrent neural network trained with continuous EEG data can be used to identify EAs with the highest accuracy of 80.78%, paving the way for robust, automated detection of epileptiform activity in TBI patients.

Comparing Autoregressive and Network Features for Classification of Depression and Anxiety.

Autocorrelation in functional MRI (fMRI) time series has been studied for decades, mostly considered as noise in the time series which is removed via prewhitening with an autoregressive model. Recent results suggest that the coefficients of an autoregressive model t to fMRI data may provide an indicator of underlying brain activity, suggesting that prewhitening could be removing important diagnostic information. This paper explores the explanatory value of these autoregressive features extracted from fMRI by considering the use of these features in a classification task. As a point of comparison, functional network based features are extracted from the same data and used in the same classification task. We find that in most cases, network based features provide better classification accuracy. However, using principal component analysis to combine network based features and autoregressive features for classification based on a support vector machine provides improved classification accuracy compared to single features or network features, suggesting that when properly combined there may be additional information to be gained from autoregressive features.

A Retrospective Outbreak Investigation of a COVID-19 Case Cluster in a Berlin Kindergarten, November 2020.

While SARS-CoV-2 infection activity in German kindergartens during the first year of the pandemic appeared to be overall low, outbreaks did occur. We retrospectively investigated an outbreak in November and December 2020 in a Berlin kindergarten participating in the Berlin Corona School and Kindergarten Study (BECOSS). Interviews were conducted with affected families regarding symptomatology, contact persons and possible sources of infection, as well as relevant information on the conditions on-site and infection prevention measures. A chronology of the outbreak was elaborated, and based on data on contacts and symptoms, we mapped the most likely chains of infection. Overall, 24 individuals, including ten educators, seven children, and seven household members, were infected with SARS-CoV-2 in a four-week time interval. Courses of infection ranged from asymptomatic to severe, with children less affected by symptoms. Viral spread within the facility seemed to occur mainly through kindergarten staff, while children primarily transmitted infections within their families. Interviewees reported that hygiene measures were not always adhered to inside the facility. To prevent outbreaks in kindergartens, especially in the light of current and newly emerging viral variants of concern, strict compliance to hygiene rules, staff vaccinations against SARS-CoV-2, and immediate reaction to suspected cases by quarantining and frequent testing seem reasonable measures.

Lesion Normalization and Supervised Learning in Post-traumatic Seizure Classification with Diffusion MRI.

Traumatic brain injury (TBI) is a serious condition, potentially causing seizures and other lifelong disabilities. Patients who experience at least one seizure one week after TBI (late seizure) are at high risk for lifelong complications of TBI, such as post-traumatic epilepsy (PTE). Identifying which TBI patients are at risk of developing seizures remains a challenge. Although magnetic resonance imaging (MRI) methods that probe structural and functional alterations after TBI are promising for biomarker detection, physical deformations following moderate-severe TBI present problems for standard processing of neuroimaging data, complicating the search for biomarkers. In this work, we consider a prediction task to identify which TBI patients will develop late seizures, using fractional anisotropy (FA) features from white matter tracts in diffusion-weighted MRI (dMRI). To understand how best to account for brain lesions and deformations, four preprocessing strategies are applied to dMRI, including the novel application of a lesion normalization technique to dMRI. The pipeline involving the lesion normalization technique provides the best prediction performance, with a mean accuracy of 0.819 and a mean area under the curve of 0.785. Finally, following statistical analyses of selected features, we recommend the dMRI alterations of a certain white matter tract as a potential biomarker.