A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA-Epilepsy study.

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analysed from 1069 healthy controls and 1249 patients: temporal lobe epilepsy with hippocampal sclerosis (n = 599), temporal lobe epilepsy with normal MRI (n = 275), genetic generalized epilepsy (n = 182) and non-lesional extratemporal epilepsy (n = 193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fibre tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at P < 0.001). Across 'all epilepsies' lower fractional anisotropy was observed in most fibre tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. There were also less robust increases in mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Individuals with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced reductions in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and increased mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of diffusion abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibres in a large multicentre study of epilepsy. Overall, patients with epilepsy showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding more detailed insights into pathological substrates that may explain cognitive and psychiatric co-morbidities and be used to guide biomarker studies of treatment outcomes and/or genetic research.

The ENIGMA-Epilepsy working group: Mapping disease from large data sets.

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.

Early Stopping in Experimentation With Real-Time Functional Magnetic Resonance Imaging Using a Modified Sequential Probability Ratio Test.

Introduction: Functional magnetic resonance imaging (fMRI) often involves long scanning durations to ensure the associated brain activity can be detected. However, excessive experimentation can lead to many undesirable effects, such as from learning and/or fatigue effects, discomfort for the subject, excessive motion artifacts and loss of sustained attention on task. Overly long experimentation can thus have a detrimental effect on signal quality and accurate voxel activation detection. Here, we propose dynamic experimentation with real-time fMRI using a novel statistically driven approach that invokes early stopping when sufficient statistical evidence for assessing the task-related activation is observed. Methods: Voxel-level sequential probability ratio test (SPRT) statistics based on general linear models (GLMs) were implemented on fMRI scans of a mathematical 1-back task from 12 healthy teenage subjects and 11 teenage subjects born extremely preterm (EPT). This approach is based on likelihood ratios and allows for systematic early stopping based on target statistical error thresholds. We adopt a two-stage estimation approach that allows for accurate estimates of GLM parameters before stopping is considered. Early stopping performance is reported for different first stage lengths, and activation results are compared with full durations. Finally, group comparisons are conducted with both early stopped and full duration scan data. Numerical parallelization was employed to facilitate completion of computations involving a new scan within every repetition time (TR). Results: Use of SPRT demonstrates the feasibility and efficiency gains of automated early stopping, with comparable activation detection as with full protocols. Dynamic stopping of stimulus administration was achieved in around half of subjects, with typical time savings of up to 33% (4 min on a 12 min scan). A group analysis produced similar patterns of activity for control subjects between early stopping and full duration scans. The EPT group, individually, demonstrated more variability in location and extent of the activations compared to the normal term control group. This was apparent in the EPT group results, reflected by fewer and smaller clusters. Conclusion: A systematic statistical approach for early stopping with real-time fMRI experimentation has been implemented. This dynamic approach has promise for reducing subject burden and fatigue effects.

An Integrative Approach to Study Structural and Functional Network Connectivity in Epilepsy Using Imaging and Signal Data.

A key area of research in epilepsy neurological disorder is the characterization of epileptic networks as they form and evolve during seizure events. In this paper, we describe the development and application of an integrative workflow to analyze functional and structural connectivity measures during seizure events using stereotactic electroencephalogram (SEEG) and diffusion weighted imaging data (DWI). We computed structural connectivity measures using electrode locations involved in recording SEEG signal data as reference points to filter fiber tracts. We used a new workflow-based tool to compute functional connectivity measures based on non-linear correlation coefficient, which allows the derivation of directed graph structures to represent coupling between signal data. We applied a hierarchical clustering based network analysis method over the functional connectivity data to characterize the organization of brain network into modules using data from 27 events across 8 seizures in a patient with refractory left insula epilepsy. The visualization of hierarchical clustering values as dendrograms shows the formation of connected clusters first within each insulae followed by merging of clusters across the two insula; however, there are clear differences between the network structures and clusters formed across the 8 seizures of the patient. The analysis of structural connectivity measures showed strong connections between contacts of certain electrodes within the same brain hemisphere with higher prevalence in the perisylvian/opercular areas. The combination of imaging and signal modalities for connectivity analysis provides information about a patient-specific dynamical functional network and examines the underlying structural connections that potentially influences the properties of the epileptic network. We also performed statistical analysis of the absolute changes in correlation values across all 8 seizures during a baseline normative time period and different seizure events, which showed decreased correlation values during seizure onset; however, the changes during ictal phases were varied.

Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study.

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.

Identifying individual differences in adolescent neuropsychological function using the NIH Toolbox: An application of partially ordered classification modeling.

OBJECTIVE: The Cognition Battery of the National Institutes of Heath Toolbox is a commonly utilized set of assessments of neuropsychological abilities, evaluating executive function, attention, working memory, processing speed, and episodic memory. We highlight the utility of an advanced statistical model in providing nuanced characterization of neurocognition in an adolescent population. We propose that partially ordered set (POSET) models are well suited to analyze polyfactorial tasks and identify distinct profiles of cognitive functioning. METHOD: Two models were considered using POSET classification. The first modeled 5 distinct cognitive functions and allowed for multiple functions to contribute to task performance. The second simpler model involved only 2 broader-based functions without polyfactorial task specifications. Existing performance data from 745 adolescents aged 14-17 years were analyzed. Posterior probabilities of classification performance and the discriminatory properties of the estimated response distributions indicated how well the modeling approaches fit the data. RESULTS: The larger first model resulted in 8 profiles or states characterized by combinations of high or low functioning in 5 distinct functions. The simpler second model involved 2 broader-based functions that resulted in 4 states. Comparing model fit criteria, we believe that the finer-grained first model may better reflect the cognitive constructs associated with the tasks. Notably, POSET modeling did not always provide adequate classification of working memory because of the limited design of the Cognition Battery. CONCLUSIONS: We demonstrate that the use of POSET models is a feasible approach for detailed analysis of neurocognitive data that can extract information on cognitive functions, even when provided with limited task batteries. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Associating Cognition With Amyloid Status Using Partially Ordered Set Analysis.

Background: The presence of brain amyloid-beta positivity is associated with cognitive impairment and dementia, but whether there are specific aspects of cognition that are most linked to amyloid-beta is unclear. Analysis of neuropsychological test data presents challenges since a single test often requires drawing upon multiple cognitive functions to perform well. It can thus be imprecise to link performance on a given test to a specific cognitive function. Our objective was to provide insight into how cognitive functions are associated with brain amyloid-beta positivity among samples consisting of cognitively normal and mild cognitively impaired (MCI) subjects, by using partially ordered set models (POSETs). Methods: We used POSET classification models of neuropsychological test data to classify samples to detailed cognitive profiles using ADNI2 and AIBL data. We considered 3 gradations of episodic memory, cognitive flexibility, verbal fluency, attention and perceptual motor speed, and performed group comparisons of cognitive functioning stratified by amyloid positivity (yes/no) and age (<70, 70-80, 81-90 years). We also employed random forest methods stratified by age to assess the effectiveness of cognitive testing in predicting amyloid positivity, in addition to demographic variables, and APOE4 allele count. Results: In ADNI2, differences in episodic memory and attention by amyloid were found for <70, and 70-80 years groups. In AIBL, episodic memory differences were found in the 70-80 years age group. In both studies, no cognitive differences were found in the 81-90 years group. The random forest analysis indicates that variable importance in classification depends on age. Cognitive testing that targets an intermediate level of episodic memory and delayed recall, in addition to APOE4 allele count, are the most important variables in both studies. Conclusions: In the ADNI2 and AIBL samples, the associations between specific cognitive abilities and brain amyloid-beta positivity depended on age, but in general episodic memory was most consistently predictive of brain amyloid-beta positivity. Random forest methods and OOB error rates establish the feasibility of predicting the presence of brain beta-amyloid using cognitive testing, APOE4 genotyping and demographic variables.