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Background: Longitudinal EEG recorded by implanted devices is critical for understanding and managing epilepsy. Recent research reports patient-specific, multi-day cycles in device-detected epileptiform events that coincide with increased likelihood of clinical seizures. Understanding these cycles could elucidate mechanisms generating seizures and advance drug and neurostimulation therapies. Objective/hypothesis: We hypothesize that seizure-correlated cycles are present in background neural activity, independent of interictal epileptiform spikes, and that neurostimulation may temporarily interrupt these cycles. Methods: We analyzed regularly-recorded seizure-free data epochs from 20 patients implanted with a responsive neurostimulation (RNS) device for at least 1.5 years, to explore the relationship between cycles in device-detected interictal epileptiform activity (dIEA), clinician-validated interictal spikes, background EEG features, and neurostimulation. Results: Background EEG features tracked the cycle phase of dIEA in all patients (AUC: 0.63 [0.56–0.67]) with a greater effect size compared to clinically annotated spike rate alone (AUC: 0.55 [0.53–0.61], p

Abstract Objective Epilepsy surgery is an effective treatment for drug‐resistant patients. However, how different surgical approaches affect long‐term brain structure remains poorly characterized. Here, we present a semiautomated method for quantifying structural changes after epilepsy surgery and compare the remote structural effects of two approaches, anterior temporal lobectomy (ATL), and selective amygdalohippocampectomy (SAH). Methods We studied 36 temporal lobe epilepsy patients who underwent resective surgery (ATL = 22, SAH = 14). All patients received same‐scanner MR imaging preoperatively and postoperatively (mean 2 years). To analyze postoperative structural changes, we segmented the resection zone and modified the Advanced Normalization Tools (ANTs) longitudinal cortical pipeline to account for resections. We compared global and regional annualized cortical thinning between surgical treatments. Results Across procedures, there was significant cortical thinning in the ipsilateral insula, fusiform, pericalcarine, and several temporal lobe regions outside the resection zone as well as the contralateral hippocampus. Additionally, increased postoperative cortical thickness was seen in the supramarginal gyrus. Patients treated with ATL exhibited greater annualized cortical thinning compared with SAH cases (ATL: −0.08 ± 0.11 mm per year, SAH: −0.01 ± 0.02 mm per year, t = 2.99, P = 0.006). There were focal postoperative differences between the two treatment groups in the ipsilateral insula (P = 0.039, corrected). Annualized cortical thinning rates correlated with preoperative cortical thickness (r = 0.60, P

Brain maps, or atlases, are essential tools for studying brain function and organization. The abundance of available atlases used across the neuroscience literature, however, creates an implicit challenge that may alter the hypotheses and predictions we make about neurological function and pathophysiology. Here, we demonstrate how parcellation scale, shape, anatomical coverage, and other atlas features may impact our prediction of the brain’s function from its underlying structure. We show how network topology, structure–function correlation (SFC), and the power to test specific hypotheses about epilepsy pathophysiology may change as a result of atlas choice and atlas features. Through the lens of our disease system, we propose a general framework and algorithm for atlas selection. This framework aims to maximize the descriptive, explanatory, and predictive validity of an atlas. Broadly, our framework strives to provide empirical guidance to neuroscience research utilizing the various atlases published over the last century.

Ashourvan et al. apply a pairwise maximum entropy model to intracranial EEG data from epileptic patients to infer structure-function relationships. Their results indicate that the pairwise MEM model provides insight into the structural connectivity of the brain and how it gives rise to activity patterns.

Driscoll, Rosch et al. design transparent graphene-based surface probes to achieve simultaneous electrophysiological recording and calcium imaging of epileptic seizures in mice. This method could be used to investigate circuit dynamics during seizure onset and evolution with high temporal and spatial resolution.

The Unified Huntington's Disease Rating Scale (UHDRS) is the primary clinical assessment tool for rating motor function in patients with Huntington's disease (HD). However, the UHDRS and similar rating scales (e.g., UPDRS) are both subjective and limited to in-office assessments that must be administered by a trained and experienced rater. An objective, automated method of quantifying disease severity would facilitate superior patient care and could be used to better track severity over time. We conducted the present study to evaluate the feasibility of using wearable sensors, coupled with machine learning algorithms, to rate motor function in patients with HD. Fourteen participants with symptomatic HD and 14 healthy controls participated in the study. Each participant wore five adhesive biometric sensors applied to the trunk and each limb while completing brief walking, sitting, and standing tasks during a single office visit. A two-stage machine learning method was employed to classify participants by HD status and to predict UHDRS motor subscores. Linear discriminant analysis correctly classified all participants' HD status except for one control subject with abnormal gait (96.4% accuracy, 92.9% sensitivity, and 100% specificity in leave-one-out cross-validation). Two regression models accurately predicted individual UHDRS subscores for gait, and dystonia within a 10% margin of error. Our regression models also predicted a composite UHDRS score–a sum of left and right arm rigidity, total chorea, total dystonia, bradykinesia, gait, and tandem gait subscores–with an average error below 15%. Machine learning classifiers trained on brief in-office datasets discriminated between controls and participants with HD, and could accurately predict selected motor UHDRS subscores. Our results could enable the future use of biosensors for objective HD assessment in the clinic or remotely and could inform future studies for the use of this technology as a potential endpoint in clinical trials.

Accurate segmentation of surgical resection sites is critical for clinical assessments and neuroimaging research applications, including resection extent determination, predictive modeling of surgery outcome, and masking image processing near resection sites. In this study, an automated resection cavity segmentation algorithm is developed for analyzing postoperative MRI of epilepsy patients and deployed in an easy-to-use graphical user interface (GUI) that estimates remnant brain volumes, including postsurgical hippocampal remnant tissue. This retrospective study included postoperative T1-weighted MRI from 62 temporal lobe epilepsy (TLE) patients who underwent resective surgery. The resection site was manually segmented and reviewed by a neuroradiologist (JMS). A majority vote ensemble algorithm was used to segment surgical resections, using 3 U-Net convolutional neural networks trained on axial, coronal, and sagittal slices, respectively. The algorithm was trained using 5-fold cross validation, with data partitioned into training (N = 27) testing (N = 9), and validation (N = 9) sets, and evaluated on a separate held-out test set (N = 17). Algorithm performance was assessed using Dice-Sørensen coefficient (DSC), Hausdorff distance, and volume estimates. Additionally, we deploy a fully-automated, GUI-based pipeline that compares resection segmentations with preoperative imaging and reports estimates of resected brain structures. The cross-validation and held-out test median DSCs were 0.84 ± 0.08 and 0.74 ± 0.22 (median ± interquartile range) respectively, which approach inter-rater reliability between radiologists (0.84–0.86) as reported in the literature. Median 95 % Hausdorff distances were 3.6 mm and 4.0 mm respectively, indicating high segmentation boundary confidence. Automated and manual resection volume estimates were highly correlated for both cross-validation (r = 0.94, p

A fundamental challenge in neuroscience is to uncover the principles governing how the brain interacts with the external environment. However, assumptions about external stimuli fundamentally constrain current computational models. We show in silico that unknown external stimulation can produce error in the estimated linear time-invariant dynamical system. To address these limitations, we propose an approach to retrieve the external (unknown) input parameters and demonstrate that the estimated system parameters during external input quiescence uncover spatiotemporal profiles of external inputs over external stimulation periods more accurately. Finally, we unveil the expected (and unexpected) sensory and task-related extra-cortical input profiles using functional magnetic resonance imaging data acquired from 96 subjects (Human Connectome Project) during the resting-state and task scans. This dynamical systems model of the brain offers information on the structure and dimensionality of the BOLD signal’s external drivers and shines a light on the likely external sources contributing to the BOLD signal’s non-stationarity. Our findings show the role of exogenous inputs in the BOLD dynamics and highlight the importance of accounting for external inputs to unravel the brain’s time-varying functional dynamics.

BACKGROUND:. Continuous electroencephalogram monitoring is associated with lower mortality in critically ill patients; however, it is underused due to the resource-intensive nature of manually interpreting prolonged streams of continuous electroencephalogram data. Here, we present a novel real-time, machine learning–based alerting and monitoring system for epilepsy and seizures that dramatically reduces the amount of manual electroencephalogram review. METHODS:. We developed a custom data reduction algorithm using a random forest and deployed it within an online cloud-based platform, which streams data and communicates interactively with caregivers via a web interface to display algorithm results. We developed real-time, machine learning–based alerting and monitoring system for epilepsy and seizures on continuous electroencephalogram recordings from 77 patients undergoing routine scalp ICU electroencephalogram monitoring and tested it on an additional 20 patients. RESULTS. We achieved a mean seizure sensitivity of 84% in cross-validation and 85% in testing, as well as a mean specificity of 83% in cross-validation and 86% in testing, corresponding to a high level of data reduction. This study validates a platform for machine learning–assisted continuous electroencephalogram analysis and represents a meaningful step toward improving utility and decreasing cost of continuous electroencephalogram monitoring. We also make our high-quality annotated dataset of 97 ICU continuous electroencephalogram recordings public for others to validate and improve upon our methods.

Abstract The Cleveland Neural Engineering Workshop (NEW) is a biennial meeting started in 2011 as an “unconference” to bring together leaders in the neural engineering and related fields. Since the first iteration of the meeting, NEW has evolved from “just getting together” to a more important purpose of creating, reviewing, and promoting a uniform strategic roadmap for the field. The purpose of this short report, as well as the companion 2015 and 2017 reports, is to provide a historical record of this meeting and the evolution of the roadmap. These reports more importantly establish a baseline for the next meeting to be held in June, 2019. The second Neural Engineering Workshop (NEW) was held in June 2013. The two-day workshop was hosted by the Cleveland Advanced Platform for Technology National Veterans Affairs Center, the Functional Electrical Stimulation National Veterans Affairs Center, and the Case Western Reserve University in Cleveland, Ohio. Participants identified seven areas of future focus in the field of neural engineering: active communications with users, advocacy (regulatory), network building (clinical practice), case studies (clinical and technical), early industrial feedback, value chain resources, engagement, and advocacy (funding). This proceedings document summarizes the meeting outcome.

Brain stimulation has emerged as an effective treatment for a wide range of neurological and psychiatric diseases. Parkinson's disease, epilepsy, and essential tremor have FDA indications for electrical brain stimulation using intracranially implanted electrodes. Interfacing implantable brain devices with local and cloud computing resources have the potential to improve electrical stimulation efficacy, disease tracking, and management. Epilepsy, in particular, is a neurological disease that might benefit from the integration of brain implants with off-the-body computing for tracking disease and therapy. Recent clinical trials have demonstrated seizure forecasting, seizure detection, and therapeutic electrical stimulation in patients with drug-resistant focal epilepsy. In this paper, we describe a next-generation epilepsy management system that integrates local handheld and cloud-computing resources wirelessly coupled to an implanted device with embedded payloads (sensors, intracranial EEG telemetry, electrical stimulation, classifiers, and control policy implementation). The handheld device and cloud computing resources can provide a seamless interface between patients and physicians, and realtime intracranial EEG can be used to classify brain state (wake/sleep, preseizure, and seizure), implement control policies for electrical stimulation, and track patient health. This system creates a flexible platform in which low demand analytics requiring fast response times are embedded in the implanted device and more complex algorithms are implemented in offthebody local and distributed cloud computing environments. The system enables tracking and management of epileptic neural networks operating over time scales ranging from milliseconds to months.

A low and stable impedance at the skin–electrode interface is key to high-fidelity acquisition of biosignals, both acutely and in the long term. However, recording quality is highly variable due to the complex nature of human skin. Here, we present an experimental and modeling framework to investigate the interfacial impedance behavior, and describe how skin interventions affect its stability over time. To illustrate this approach, we report experimental measurements on the skin–electrode impedance using pre-gelled, clinical-grade electrodes in healthy human subjects recorded over 24 h following four skin treatments: (i) mechanical abrasion, (ii) chemical exfoliation, (iii) microporation, and (iv) no treatment. In the immediate post-treatment period, mechanical abrasion yields the lowest initial impedance, whereas the other treatments provide modest improvement compared to untreated skin. After 24 h, however, the impedance becomes more uniform across all groups (

Summary: Optimizing direct electrical stimulation for the treatment of neurological disease remains difficult due to an incomplete understanding of its physical propagation through brain tissue. Here, we use network control theory to predict how stimulation spreads through white matter to influence spatially distributed dynamics. We test the theory’s predictions using a unique dataset comprising diffusion weighted imaging and electrocorticography in epilepsy patients undergoing grid stimulation. We find statistically significant shared variance between the predicted activity state transitions and the observed activity state transitions. We then use an optimal control framework to posit testable hypotheses regarding which brain states and structural properties will efficiently improve memory encoding when stimulated. Our work quantifies the role that white matter architecture plays in guiding the dynamics of direct electrical stimulation and offers empirical support for the utility of network control theory in explaining the brain’s response to stimulation. : Stiso et al. report evidence that network control theory can explain the propagation of electrical stimulation through the human brain and quantify how white matter connectivity is crucial for driving spatially distributed changes in activity. Furthermore, they use network control theory to predict stimulation outcome in specific cognitive contexts. Keywords: brain stimulation, network control theory, brain network

Patients with drug-resistant focal epilepsy are often candidates for invasive surgical therapies. In these patients, it is necessary to accurately localize seizure generators to ensure seizure freedom following intervention. While intracranial electroencephalography (iEEG) is the gold standard for mapping networks for surgery, this approach requires inducing and recording seizures, which may cause patient morbidity. The goal of this study is to evaluate the utility of mapping interictal (non-seizure) iEEG networks to identify targets for surgical treatment. We analyze interictal iEEG recordings and neuroimaging from 27 focal epilepsy patients treated via surgical resection. We generate interictal functional networks by calculating pairwise correlation of iEEG signals across different frequency bands. Using image coregistration and segmentation, we identify electrodes falling within surgically resected tissue (i.e. the resection zone), and compute node-level and edge-level synchrony in relation to the resection zone. We further associate these metrics with post-surgical outcomes. Greater overlap between resected electrodes and highly synchronous electrodes is associated with favorable post-surgical outcomes. Additionally, good-outcome patients have significantly higher connectivity localized within the resection zone compared to those with poorer postoperative seizure control. This finding persists following normalization by a spatially-constrained null model. This study suggests that spatially-informed interictal network synchrony measures can distinguish between good and poor post-surgical outcomes. By capturing clinically-relevant information during interictal periods, our method may ultimately reduce the need for prolonged invasive implants and provide insights into the pathophysiology of an epileptic brain. We discuss next steps for translating these findings into a prospectively useful clinical tool. Keywords: Epilepsy, Intracranial EEG, Functional connectivity

Epilepsy affects 65 million people worldwide, a third of whom have seizures that are resistant to anti-epileptic medications. Some of these patients may be amenable to surgical therapy or treatment with implantable devices, but this usually requires delineation of discrete structural or functional lesion(s), which is challenging in a large percentage of these patients. Advances in neuroimaging and machine learning allow semi-automated detection of malformations of cortical development (MCDs), a common cause of drug resistant epilepsy. A frequently asked question in the field is what techniques currently exist to assist radiologists in identifying these lesions, especially subtle forms of MCDs such as focal cortical dysplasia (FCD) Type I and low grade glial tumors. Below we introduce some of the common lesions encountered in patients with epilepsy and the common imaging findings that radiologists look for in these patients. We then review and discuss the computational techniques introduced over the past 10 years for quantifying and automatically detecting these imaging findings. Due to large variations in the accuracy and implementation of these studies, specific techniques are traditionally used at individual centers, often guided by local expertise, as well as selection bias introduced by the varying prevalence of specific patient populations in different epilepsy centers. We discuss the need for a multi-institutional study that combines features from different imaging modalities as well as computational techniques to definitively assess the utility of specific automated approaches to epilepsy imaging. We conclude that sharing and comparing these different computational techniques through a common data platform provides an opportunity to rigorously test and compare the accuracy of these tools across different patient populations and geographical locations. We propose that these kinds of tools, quantitative imaging analysis methods and open data platforms for aggregating and sharing data and algorithms, can play a vital role in reducing the cost of care, the risks of invasive treatments, and improve overall outcomes for patients with epilepsy.

Intracranial electrodes are a vital component of implantable neurodevices, both for acute diagnostics and chronic treatment with open and closed-loop neuromodulation. Their performance is hampered by acute implantation trauma and chronic inflammation in response to implanted materials and mechanical mismatch between stiff synthetic electrodes and pulsating, natural soft host neural tissue. Flexible electronics based on thin polymer films patterned with microscale conductive features can help alleviate the mechanically induced trauma; however, this strategy alone does not mitigate inflammation at the device-tissue interface. In this study, we propose a biomimetic approach that integrates microscale extracellular matrix (ECM) coatings on microfabricated flexible subdural microelectrodes. Taking advantage of a high-throughput process employing micro-transfer molding and excimer laser micromachining, we fabricate multi-channel subdural microelectrodes primarily composed of ECM protein material and demonstrate that the electrochemical and mechanical properties match those of standard, uncoated controls. In vivo ECoG recordings in rodent brain confirm that the ECM microelectrode coatings and the protein interface do not alter signal fidelity. Astrogliotic, foreign body reaction to ECM coated devices is reduced, compared to uncoated controls, at 7 and 30 days, after subdural implantation in rat somatosensory cortex. We propose microfabricated, flexible, biomimetic electrodes as a new strategy to reduce inflammation at the device-tissue interface and improve the long-term stability of implantable subdural electrodes.

[This corrects the article DOI: 10.1371/journal.pone.0133900.].

The epileptic network is characterized by pathologic, seizure-generating 'foci' embedded in a web of structural and functional connections. Clinically, seizure foci are considered optimal targets for surgery. However, poor surgical outcome suggests a complex relationship between foci and the surrounding network that drives seizure dynamics. We developed a novel technique to objectively track seizure states from dynamic functional networks constructed from intracranial recordings. Each dynamical state captures unique patterns of network connections that indicate synchronized and desynchronized hubs of neural populations. Our approach suggests that seizures are generated when synchronous relationships near foci work in tandem with rapidly changing desynchronous relationships from the surrounding epileptic network. As seizures progress, topographical and geometrical changes in network connectivity strengthen and tighten synchronous connectivity near foci-a mechanism that may aid seizure termination. Collectively, our observations implicate distributed cortical structures in seizure generation, propagation and termination, and may have practical significance in determining which circuits to modulate with implantable devices.

Management of drug resistant focal epilepsy would be greatly assisted by a reliable warning system capable of alerting patients prior to seizures to allow the patient to adjust activities or medication. Such a system requires successful identification of a preictal, or seizure-prone state. Identification of preictal states in continuous long- duration intracranial electroencephalographic (iEEG) recordings of dogs with naturally occurring epilepsy was investigated using a support vector machine (SVM) algorithm. The dogs studied were implanted with a 16-channel ambulatory iEEG recording device with average channel reference for a mean (st. dev.) of 380.4 (+87.5) days producing 220.2 (+104.1) days of intracranial EEG recorded at 400 Hz for analysis. The iEEG records had 51.6 (+52.8) seizures identified, of which 35.8 (+30.4) seizures were preceded by more than 4 hours of seizure-free data. Recorded iEEG data were stratified into 11 contiguous, non-overlapping frequency bands and binned into one-minute synchrony features for analysis. Performance of the SVM classifier was assessed using a 5-fold cross validation approach, where preictal training data were taken from 90 minute windows with a 5 minute pre-seizure offset. Analysis of the optimal preictal training time was performed by repeating the cross validation over a range of preictal windows and comparing results. We show that the optimization of feature selection varies for each subject, i.e. algorithms are subject specific, but achieve prediction performance significantly better than a time-matched Poisson random predictor (p

Seizure forecasting has the potential to create new therapeutic strategies for epilepsy, such as providing patient warnings and delivering preemptive therapy. Progress on seizure forecasting, however, has been hindered by lack of sufficient data to rigorously evaluate the hypothesis that seizures are preceded by physiological changes, and are not simply random events. We investigated seizure forecasting in three dogs with naturally occurring focal epilepsy implanted with a device recording continuous intracranial EEG (iEEG). The iEEG spectral power in six frequency bands: delta (0.1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low-gamma (30-70 Hz), and high-gamma (70-180 Hz), were used as features. Logistic regression classifiers were trained to discriminate labeled pre-ictal and inter-ictal data segments using combinations of the band spectral power features. Performance was assessed on separate test data sets via 10-fold cross-validation. A total of 125 spontaneous seizures were detected in continuous iEEG recordings spanning 6.5 to 15 months from 3 dogs. When considering all seizures, the seizure forecasting algorithm performed significantly better than a Poisson-model chance predictor constrained to have the same time in warning for all 3 dogs over a range of total warning times. Seizure clusters were observed in all 3 dogs, and when the effect of seizure clusters was decreased by considering the subset of seizures separated by at least 4 hours, the forecasting performance remained better than chance for a subset of algorithm parameters. These results demonstrate that seizures in canine epilepsy are not randomly occurring events, and highlight the feasibility of long-term seizure forecasting using iEEG monitoring.