Interictal EEG source connectivity to localize the epileptogenic zone in patients with drug-resistant epilepsy: A machine learning approach.

OBJECTIVE: To deconstruct the epileptogenic networks of patients with drug-resistant epilepsy (DRE) using source functional connectivity (FC) analysis; unveil the FC biomarkers of the epileptogenic zone (EZ); and develop machine learning (ML) models to estimate the EZ using brief interictal electroencephalography (EEG) data. METHODS: We analyzed scalp EEG from 50 patients with DRE who had surgery. We reconstructed the activity (electrical source imaging [ESI]) of virtual sensors (VSs) across the whole cortex and computed FC separately for epileptiform and non-epileptiform EEG epochs (with or without spikes). In patients with good outcome (Engel 1a), four cortical regions were defined: EZ (resection) and three non-epileptogenic zones (NEZs) in the same and opposite hemispheres. Region-specific FC features in six frequency bands and three spatial ranges (long, short, inner) were compared between regions (Wilcoxon sign-rank). We developed ML classifiers to identify the VSs in the EZ using VS-specific FC features. Cross-validation was performed using good outcome data. Performance was compared with poor outcomes and interictal spike localization. RESULTS: FC differed between EZ and NEZs (p < .05) during non-epileptiform and epileptiform epochs, showing higher FC in the EZ than its homotopic contralateral NEZ. During epileptiform epochs, the NEZ in the epileptogenic hemisphere showed higher FC than its contralateral NEZ. In good outcome patients, the ML classifiers reached 75% accuracy to the resection (91% sensitivity; 74% specificity; distance from EZ: 38 mm) using epileptiform epochs (gamma and beta frequency bands) and 62% accuracy using broadband non-epileptiform epochs, both outperforming spike localization (accuracy = 47%; p < .05; distance from EZ: 57 mm). Lower performance was seen in poor outcomes. SIGNIFICANCE: We present an FC approach to extract EZ biomarkers from brief EEG data. Increased FC in various frequencies characterized the EZ during epileptiform and non-epileptiform epochs. FC-based ML models identified the resection better in good than poor outcome patients, demonstrating their potential for presurgical use in pediatric DRE.

Non-invasive mapping of epileptogenic networks predicts surgical outcome.

Epilepsy is increasingly considered a disorder of brain networks. Studying these networks with functional connectivity can help identify hubs that facilitate the spread of epileptiform activity. Surgical resection of these hubs may lead patients who suffer from drug-resistant epilepsy to seizure freedom. Here, we aim to map non-invasively epileptogenic networks, through the virtual implantation of sensors estimated with electric and magnetic source imaging, in patients with drug-resistant epilepsy. We hypothesize that highly connected hubs identified non-invasively with source imaging can predict the epileptogenic zone and the surgical outcome better than spikes localized with conventional source localization methods (dipoles). We retrospectively analysed simultaneous high-density electroencephalography (EEG) and magnetoencephalography data recorded from 37 children and young adults with drug-resistant epilepsy who underwent neurosurgery. Using source imaging, we estimated virtual sensors at locations where intracranial EEG contacts were placed. On data with and without spikes, we computed undirected functional connectivity between sensors/contacts using amplitude envelope correlation and phase locking value for physiologically relevant frequency bands. From each functional connectivity matrix, we generated an undirected network containing the strongest connections within sensors/contacts using the minimum spanning tree. For each sensor/contact, we computed graph centrality measures. We compared functional connectivity and their derived graph centrality of sensors/contacts inside resection for good (n = 22, ILAE I) and poor (n = 15, ILAE II-VI) outcome patients, tested their ability to predict the epileptogenic zone in good-outcome patients, examined the association between highly connected hubs removal and surgical outcome and performed leave-one-out cross-validation to support their prognostic value. We also compared the predictive values of functional connectivity with those of dipoles. Finally, we tested the reliability of virtual sensor measures via Spearman's correlation with intracranial EEG at population- and patient-level. We observed higher functional connectivity inside than outside resection (P < 0.05, Wilcoxon signed-rank test) for good-outcome patients, on data with and without spikes across different bands for intracranial EEG and electric/magnetic source imaging and few differences for poor-outcome patients. These functional connectivity measures were predictive of both the epileptogenic zone and outcome (positive and negative predictive values ≥55%, validated using leave-one-out cross-validation) outperforming dipoles on spikes. Significant correlations were found between source imaging and intracranial EEG measures (0.4 ≤ rho ≤ 0.9, P < 0.05). Our findings suggest that virtual implantation of sensors through source imaging can non-invasively identify highly connected hubs in patients with drug-resistant epilepsy, even in the absence of frank epileptiform activity. Surgical resection of these hubs predicts outcome better than dipoles.

Spike propagation mapping reveals effective connectivity and predicts surgical outcome in epilepsy.

Neurosurgical intervention is the best available treatment for selected patients with drug resistant epilepsy. For these patients, surgical planning requires biomarkers that delineate the epileptogenic zone, the brain area that is indispensable for the generation of seizures. Interictal spikes recorded with electrophysiological techniques are considered key biomarkers of epilepsy. Yet, they lack specificity, mostly because they propagate across brain areas forming networks. Understanding the relationship between interictal spike propagation and functional connections among the involved brain areas may help develop novel biomarkers that can delineate the epileptogenic zone with high precision. Here, we reveal the relationship between spike propagation and effective connectivity among onset and areas of spread and assess the prognostic value of resecting these areas. We analysed intracranial EEG data from 43 children with drug resistant epilepsy who underwent invasive monitoring for neurosurgical planning. Using electric source imaging, we mapped spike propagation in the source domain and identified three zones: onset, early-spread and late-spread. For each zone, we calculated the overlap and distance from surgical resection. We then estimated a virtual sensor for each zone and the direction of information flow among them via Granger causality. Finally, we compared the prognostic value of resecting these zones, the clinically-defined seizure onset zone and the spike onset on intracranial EEG channels by estimating their overlap with resection. We observed a spike propagation in source space for 37 patients with a median duration of 95 ms (interquartile range: 34-206), a spatial displacement of 14 cm (7.5-22 cm) and a velocity of 0.5 m/s (0.3-0.8 m/s). In patients with good surgical outcome (25 patients, Engel I), the onset had higher overlap with resection [96% (40-100%)] than early-spread [86% (34-100%), P = 0.01] and late-spread [59% (12-100%), P = 0.002], and it was also closer to resection than late-spread [5 mm versus 9 mm, P = 0.007]. We found an information flow from onset to early-spread in 66% of patients with good outcomes, and from early-spread to onset in 50% of patients with poor outcome. Finally, resection of spike onset, but not area of spike spread or the seizure onset zone, predicted outcome with positive predictive value of 79% and negative predictive value of 56% (P = 0.04). Spatiotemporal mapping of spike propagation reveals information flow from onset to areas of spread in epilepsy brain. Surgical resection of the spike onset disrupts the epileptogenic network and may render patients with drug resistant epilepsy seizure-free without having to wait for a seizure to occur during intracranial monitoring.

Sleep Spindle Generation Before and After Epilepsy Surgery: A Source Imaging Study in Children with Drug-Resistant Epilepsy.

INTRODUCTION: Literature lacks studies investigating the cortical generation of sleep spindles in drug-resistant epilepsy (DRE) and how they evolve after resection of the epileptogenic zone (EZ). Here, we examined sleep EEGs of children with focal DRE who became seizure-free after focal epilepsy surgery, and aimed to investigate the changes in the spindle generation before and after the surgery using low-density scalp EEG and electrical source imaging (ESI). METHODS: We analyzed N2-sleep EEGs from 19 children with DRE before and after surgery. We identified slow (8-12 Hz) and fast spindles (13-16 Hz), computed their spectral features and cortical generators through ESI and computed their distance from the EZ and irritative zone (IZ). We performed two-way ANOVA testing the effect of spindle type (slow vs. fast) and surgical phase (pre-surgery vs. post-surgery) on each feature. RESULTS: Power, frequency and cortical activation of slow spindles increased after surgery (p < 0.005), while this was not seen for fast spindles. Before surgery, the cortical generators of slow spindles were closer to the EZ (57.3 vs. 66.2 mm, p = 0.007) and IZ (41.3 vs. 55.5 mm, p = 0.02) than fast spindle generators. CONCLUSIONS: Our data indicate alterations in the EEG slow spindles after resective epilepsy surgery. Fast spindle generation on the contrary did not change after surgery. Although the study is limited by its retrospective nature, lack of healthy controls, and reduced cortical spatial sampling, our findings suggest a spatial relationship between the slow spindles and the epileptogenic generators.

Noninvasive Mapping of Ripple Onset Predicts Outcome in Epilepsy Surgery.

OBJECTIVE: Intracranial electroencephalographic (icEEG) studies show that interictal ripples propagate across the brain of children with medically refractory epilepsy (MRE), and the onset of this propagation (ripple onset zone [ROZ]) estimates the epileptogenic zone. It is still unknown whether we can map this propagation noninvasively. The goal of this study is to map ripples (ripple zone [RZ]) and their propagation onset (ROZ) using high-density EEG (HD-EEG) and magnetoencephalography (MEG), and to estimate their prognostic value in pediatric epilepsy surgery. METHODS: We retrospectively analyzed simultaneous HD-EEG and MEG data from 28 children with MRE who underwent icEEG and epilepsy surgery. Using electric and magnetic source imaging, we estimated virtual sensors (VSs) at brain locations that matched the icEEG implantation. We detected ripples on VSs, defined the virtual RZ and virtual ROZ, and estimated their distance from icEEG. We assessed the predictive value of resecting virtual RZ and virtual ROZ for postsurgical outcome. Interictal spike localization on HD-EEG and MEG was also performed and compared with ripples. RESULTS: We mapped ripple propagation in all patients with HD-EEG and in 27 (96%) patients with MEG. The distance from icEEG did not differ between HD-EEG and MEG when mapping the RZ (26-27mm, p = 0.6) or ROZ (22-24mm, p = 0.4). Resecting the virtual ROZ, but not virtual RZ or the sources of spikes, was associated with good outcome for HD-EEG (p = 0.016) and MEG (p = 0.047). INTERPRETATION: HD-EEG and MEG can map interictal ripples and their propagation onset (virtual ROZ). Noninvasively mapping the ripple onset may augment epilepsy surgery planning and improve surgical outcome of children with MRE. ANN NEUROL 2021;89:911-925.

Association between semiologic, autonomic, and electrographic seizure characteristics in children with generalized tonic-clonic seizures.

INTRODUCTION: Generalized tonic-clonic seizures (GTCS) are associated with elevated electrodermal activity (EDA) and postictal generalized electroencephalographic suppression (PGES), markers that may indicate sudden unexpected death in epilepsy (SUDEP) risk. This study investigated the association of GTCS semiology, EDA, and PGES in children with epilepsy. METHODS: Patients admitted to the Boston Children's Hospital long-term video-EEG monitoring unit wore a sensor that records EDA. We selected patients with at least one GTCS and reviewed video-EEGs for semiology, tonic and clonic phase duration, total clinical seizure duration, electrographic onset, offset, and PGES. We grouped patients into three semiology classes: GTCS 1: bilateral symmetric tonic arm extension, GTCS 2: no specific tonic arm extension or flexion, GTCS 3: unilateral or asymmetrical arm extension, tonic arm flexion or posturing that does not fit into GTCS 1 or 2. We analyzed the correlation between semiology, EDA, and PGES, and measured the area under the curve (AUC) of the ictal EDA (seizure onset to one hour after), subtracting baseline EDA (one-hour seizure-free before seizure onset). Using generalized estimating equation (GEE) and linear regression, we analyzed all seizures and single episodes per patient. RESULTS: We included 30 patients (median age 13.8 ±â€¯3.6 years, 46.7% females) and 53 seizures. With GEE, GTCS 1 was associated with longer PGES duration compared to GTCS 2 (Estimate (ß) = -26.32 s, 95% Confidence Interval (CI): -36.46 to -16.18, p < 0.001), and the presence of PGES was associated with greater EDA change (ß = 429604 µS, 95% CI: 3550.96 to 855657.04, p = 0.048). With single-episode analysis, GTCS 1 had greater EDA change than GTCS 2 ((ß = -601339 µS, 95% CI: -1167016.56 to -35661.44, p = 0.047). EDA increased with PGES presence (ß = 637500 µS, 95% CI: 183571.84 to 1091428.16, p = 0.01) and duration (ß = 16794 µS, 95% CI: 5729.8 to 27858.2, p = 0.006). Patients with GTCS 1 had longer PGES duration compared to GTCS 2 (ß = -30.53 s, 95% CI: -44.6 to -16.46, p < 0.001) and GTCS 3 (ß = -22.07 s, 95% CI: -38.95 to -5.19, p = 0.016). CONCLUSION: In children with epilepsy, PGES correlates with greater ictal EDA. GTCS 1 correlated with longer PGES duration and may indirectly correlate with greater ictal EDA. Our study suggests potential applications in monitoring and preventing SUDEP in these patients.

Photoplethysmographic evaluation of generalized tonic-clonic seizures.

OBJECTIVE: Photoplethysmography (PPG) is an optical technique measuring variations of blood perfusion in peripheral tissues. We evaluated alterations in PPG signals in relationship to the occurrence of generalized tonic-clonic seizures (GTCSs) in patients with epilepsy to evaluate the feasibility of seizure detection. METHODS: During electroencephalographic (EEG) long-term monitoring, patients wore portable wristband sensor(s) on their wrists or ankles recording PPG signals. We analyzed PPG signals during three time periods, which were defined with respect to seizures detected on EEG: (1) baseline (>30 minutes prior to seizure), (2) preseizure period, and (3) postseizure period. Furthermore, we selected five random control segments during seizure-free periods. PPG features, including frequency, amplitude, duration, slope, smoothness, and area under the curve, were automatically calculated. We used a linear mixed-effect model to evaluate changes in PPG features between different time periods in an attempt to identify signal changes that detect seizures. RESULTS: We prospectively enrolled 174 patients from the epilepsy monitoring unit at Boston Children's Hospital. Twenty-five GTCSs were recorded from 13 patients. Data from the first recorded GTCS of each patient were included in the analysis. We observed an increase in PPG frequency during pre- and postseizure periods that was higher than the changes during seizure-free periods (frequency increase: preseizure = 0.22 Hz, postseizure = 0.58 Hz vs changes during seizure-free period = 0.05 Hz). The PPG slope decreased significantly by 56.71 nW/s during preseizure periods compared to seizure-free periods. Additionally, the smoothness increased significantly by 0.22 nW/s during the postseizure period compared to seizure-free periods. SIGNIFICANCE: Monitoring of PPG signals may assist in the detection of GTCSs in patients with epilepsy. PPG may serve as a promising biomarker for future seizure detection systems and may contribute to future seizure prediction systems.

Photoplethysmography: A measure for the function of the autonomic nervous system in focal impaired awareness seizures.

OBJECTIVES: Photoplethysmography (PPG) reflects variations of blood perfusion in tissues, which may signify seizure-related autonomic changes. The aim of this study is to assess the variability of PPG signals and their value in detecting peri-ictal changes in patients with focal impaired awareness seizures (FIASs). METHODS: PPG data were recorded using a wearable sensor placed on the wrist or ankle of children with epilepsy admitted for long-term video-electroencephalographic monitoring. We analyzed PPG data in four different periods: seizure-free, preictal, ictal, and postictal. Multiple features were automatically extracted from the PPG signal-frequency, duration, amplitude, increasing and decreasing slopes, smoothness, and area under the curve (AUC)-and were used to identify preictal, ictal, or postictal changes by comparing them with seizure-free periods and with each other using a linear mixed-effects model. RESULTS: We studied PPG in 11 patients (18 FIASs), including seizure-free, preictal, and postictal periods, and a subset of eight patients (12 FIASs) including the ictal period. Compared to the seizure-free period, we found significant changes in PPG (1) during the ictal period across all features; (2) during the preictal period in amplitude, duration, increasing slope, and AUC; and (3) during the postictal period in decreasing slope. SIGNIFICANCE: Specific PPG changes can be seen before, during, and after FIASs. The peri-ictal changes in the PPG features of patients with FIASs suggest potential applications of PPG monitoring for seizure detection.

Surgical resection of ripple onset predicts outcome in pediatric epilepsy.

OBJECTIVE: In patients with medically refractory epilepsy (MRE), interictal ripples (80-250Hz) are observed in large brain areas whose resection may be unnecessary for seizure freedom. This limits their utility as epilepsy biomarkers for surgery. We assessed the spatiotemporal propagation of interictal ripples on intracranial electroencephalography (iEEG) in children with MRE, compared it with the propagation of spikes, identified ripples that initiated propagation (onset-ripples), and evaluated their clinical value as epilepsy biomarkers. METHODS: Twenty-seven children who underwent epilepsy surgery were studied. We identified propagation sequences of ripples and spikes across multiple iEEG contacts and calculated each ripple or spike latency from the propagation onset. We classified ripples and spikes into categories (ie, onset, spread, and isolated) based on their spatiotemporal characteristics and correlated their mean rate inside and outside resection with outcome (good outcome, Engel 1 versus poor outcome, Engel≥2). We determined, as onset-zone, spread-zone, and isolated-zone, the areas generating the corresponding ripple or spike category and evaluated the predictive value of their resection. RESULTS: We observed ripple propagation in all patients and spike propagation in 25 patients. Mean rate of onset-ripples inside resection predicted the outcome (odds ratio = 5.37; p = 0.02) and correlated with Engel class (rho = -0.55; p = 0.003). Resection of the onset-ripple-zone was associated with good outcome (p = 0.047). No association was found for the spread-ripple-zone, isolated-ripple-zone, or any spike-zone. INTERPRETATION: Interictal ripples propagate across iEEG contacts in children with MRE. The association between the onset-ripple-zone resection and good outcome indicates that onset-ripples are promising epilepsy biomarkers, which estimate the epileptogenic tissue better than spread-ripples or onset-spikes. Ann Neurol 2018;84:331-346.

Quantifying Neonatal Sucking Performance: Promise of New Methods.

Neonatal feeding has been traditionally understudied so guidelines and evidence-based support for common feeding practices are limited. A major contributing factor to the paucity of evidence-based practice in this area has been the lack of simple-to-use, low-cost tools for monitoring sucking performance. We describe new methods for quantifying neonatal sucking performance that hold significant clinical and research promise. We present early results from an ongoing study investigating neonatal sucking as a marker of risk for adverse neurodevelopmental outcomes. We include quantitative measures of sucking performance to better understand how movement variability evolves during skill acquisition. Results showed the coefficient of variation of suck duration was significantly different between preterm neonates at high risk for developmental concerns (HRPT) and preterm neonates at low risk for developmental concerns (LRPT). For HRPT, results indicated the coefficient of variation of suck smoothness increased from initial feeding to discharge and remained significantly greater than healthy full-term newborns (FT) at discharge. There was no significant difference in our measures between FT and LRPT at discharge. Our findings highlight the need to include neonatal sucking assessment as part of routine clinical care in order to capture the relative risk of adverse neurodevelopmental outcomes at discharge.

Development of goal-directed action selection guided by intrinsic motivations: an experiment with children.

Action selection is extremely important, particularly when the accomplishment of competitive tasks may require access to limited motor resources. The spontaneous exploration of the world plays a fundamental role in the development of this capacity, providing subjects with an increasingly diverse set of opportunities to acquire, practice and refine the understanding of action-outcome connection. The computational modeling literature proposed a number of specific mechanisms for autonomous agents to discover and target interesting outcomes: intrinsic motivations hold a central importance among those mechanisms. Unfortunately, the study of the acquisition of action-outcome relation was mostly carried out with experiments involving extrinsic tasks, either based on rewards or on predefined task goals. This work presents a new experimental paradigm to study the effect of intrinsic motivation on action-outcome relation learning and action selection during free exploration of the world. Three- and four-year-old children were observed during the free exploration of a new toy: half of them were allowed to develop the knowledge concerning its functioning; the other half were not allowed to learn anything. The knowledge acquired during the free exploration of the toy was subsequently assessed and compared.

A new calibration methodology for thorax and upper limbs motion capture in children using magneto and inertial sensors.

Recent advances in wearable sensor technologies for motion capture have produced devices, mainly based on magneto and inertial measurement units (M-IMU), that are now suitable for out-of-the-lab use with children. In fact, the reduced size, weight and the wireless connectivity meet the requirement of minimum obtrusivity and give scientists the possibility to analyze children's motion in daily life contexts. Typical use of magneto and inertial measurement units (M-IMU) motion capture systems is based on attaching a sensing unit to each body segment of interest. The correct use of this setup requires a specific calibration methodology that allows mapping measurements from the sensors' frames of reference into useful kinematic information in the human limbs' frames of reference. The present work addresses this specific issue, presenting a calibration protocol to capture the kinematics of the upper limbs and thorax in typically developing (TD) children. The proposed method allows the construction, on each body segment, of a meaningful system of coordinates that are representative of real physiological motions and that are referred to as functional frames (FFs). We will also present a novel cost function for the Levenberg-Marquardt algorithm, to retrieve the rotation matrices between each sensor frame (SF) and the corresponding FF. Reported results on a group of 40 children suggest that the method is repeatable and reliable, opening the way to the extensive use of this technology for out-of-the-lab motion capture in children.

Technological solutions and main indices for the assessment of newborns' nutritive sucking: a review.

Nutritive Sucking (NS) is a highly organized process that is essential for infants' feeding during the first six months of their life. It requires the complex coordination of sucking, swallowing and breathing. The infant's inability to perform a safe and successful oral feeding can be an early detector of immaturity of the Central Nervous System (CNS). Even though the importance of early sucking measures has been confirmed over the years, the need for standardized instrumental assessment tools still exists. Clinicians would benefit from specifically designed devices to assess oral feeding ability in their routine clinical monitoring and decision-making process. This work is a review of the main instrumental solutions developed to assess an infant's NS behavior, with a detailed survey of the main quantities and indices measured and/or estimated to characterize sucking behavior skills and their development. The adopted sensing measuring systems will be described, and their main advantages and weaknesses will be discussed, taking into account their application to clinical practice, or to at-home monitoring as post-discharge assessment tools. Finally, the study will highlight the most suitable sensing solutions and give some prompts for further research.

Magnetoencephalography for the pediatric population, indications, acquisition and interpretation for the clinician.

Magnetoencephalography (MEG) is an imaging technique that enables the assessment of cortical activity via direct measures of neurophysiology. It is a non-invasive and passive technique that is completely painless. MEG has gained increasing prominence in the field of pediatric neuroimaging. This dedicated review article for the pediatric population summarizes the fundamental technical and clinical aspects of MEG for the clinician. We discuss methods tailored for children to improve data quality, including child-friendly MEG facility environments and strategies to mitigate motion artifacts. We provide an in-depth overview on accurate localization of neural sources and different analysis methods, as well as data interpretation. The contemporary platforms and approaches of two quaternary pediatric referral centers are illustrated, shedding light on practical implementations in clinical settings. Finally, we describe the expanding clinical applications of MEG, including its pivotal role in presurgical evaluation of epilepsy patients, presurgical mapping of eloquent cortices (somatosensory and motor cortices, visual and auditory cortices, lateralization of language), its emerging relevance in autism spectrum disorder research and potential future clinical applications, and its utility in assessing mild traumatic brain injury. In conclusion, this review serves as a comprehensive resource of clinicians as well as researchers, offering insights into the evolving landscape of pediatric MEG. It discusses the importance of technical advancements, data acquisition strategies, and expanding clinical applications in harnessing the full potential of MEG to study neurological conditions in the pediatric population.

Electromagnetic source imaging predicts surgical outcome in children with focal cortical dysplasia.

OBJECTIVE: To evaluate the diagnostic accuracy of electromagnetic source imaging (EMSI) in localizing spikes and predict surgical outcome in children with drug resistant epilepsy (DRE) due to focal cortical dysplasia (FCD). METHODS: We retrospectively analyzed magnetoencephalography (MEG) and high-density (HD-EEG) data from 23 children with FCD-associated DRE who underwent intracranial EEG and surgery. We localized spikes using equivalent current dipole (ECD) fitting, dipole clustering, and dynamical statistical parametric mapping (dSPM) on EMSI, electric source imaging (ESI), and magnetic source imaging (MSI). We calculated the distance from the seizure onset zone (DSOZ) and resection (DRES). We estimated receiver operating characteristic (ROC) curves with Youden's index (J) to predict outcome. RESULTS: EMSI presented shorter DSOZ (15.18 ± 9.06 mm) and DRES (8.56 ± 6.24 mm) compared to ESI (DSOZ: 25.04 ± 16.20 mm, p < 0.009; DRES: 18.88 ± 17.30 mm, p < 0.03) and MSI (DSOZ: 23.37 ± 8.98 mm, p < 0.03; DRES: 15.51 ± 10.11 mm, p < 0.02) for clustering in patients with good outcome. Clustering showed shorter DSOZ and DRES compared to ECD fitting and dSPM (p < 0.05). EMSI had higher performance as outcome predictor (J = 70.63%) compared to ESI (J = 41.27%) and MSI (J = 33.33%) for clustering. CONCLUSIONS: EMSI provides superior localization and improved predictive performance than individual modalities. SIGNIFICANCE: EMSI can help the surgical planning and facilitate the localization of epileptogenic foci.

Functional connectivity discriminates epileptogenic states and predicts surgical outcome in children with drug resistant epilepsy.

Normal brain functioning emerges from a complex interplay among regions forming networks. In epilepsy, these networks are disrupted causing seizures. Highly connected nodes in these networks are epilepsy surgery targets. Here, we assess whether functional connectivity (FC) using intracranial electroencephalography can quantify brain regions epileptogenicity and predict surgical outcome in children with drug resistant epilepsy (DRE). We computed FC between electrodes on different states (i.e. interictal without spikes, interictal with spikes, pre-ictal, ictal, and post-ictal) and frequency bands. We then estimated the electrodes' nodal strength. We compared nodal strength between states, inside and outside resection for good- (n = 22, Engel I) and poor-outcome (n = 9, Engel II-IV) patients, respectively, and tested their utility to predict the epileptogenic zone and outcome. We observed a hierarchical epileptogenic organization among states for nodal strength: lower FC during interictal and pre-ictal states followed by higher FC during ictal and post-ictal states (p < 0.05). We further observed higher FC inside resection (p < 0.05) for good-outcome patients on different states and bands, and no differences for poor-outcome patients. Resection of nodes with high FC was predictive of outcome (positive and negative predictive values: 47-100%). Our findings suggest that FC can discriminate epileptogenic states and predict outcome in patients with DRE.

Phase-amplitude coupling between low- and high-frequency activities as preoperative biomarker of focal cortical dysplasia subtypes.

OBJECTIVE: To evaluate whether ictal phase-amplitude coupling (PAC) between high-frequency activity and low-frequency activity could be used as a preoperative biomarker of Focal Cortical Dysplasia (FCD) subtypes. We hypothesize that FCD seizures present unique PAC characteristics that may be linked to their specific histopathological features. METHODS: We retrospectively examined 12 children with FCD and refractory epilepsy who underwent successful epilepsy surgery. We identified ictal onsets recorded with stereo-EEG. We estimated the strength of PAC between low-frequencies and high-frequencies for each seizure by means of modulation index. Generalized mixed effect models and receiver operating characteristic (ROC) curve analysis were used to test the association between ictal PAC and FCD subtypes. RESULTS: Ictal PAC was significantly higher in patients with FCD type II compared to type I, only on SOZ-electrodes (p < 0.005). No differences in ictal PAC were found on non-SOZ electrodes. Pre-ictal PAC registered on SOZ electrodes predicted FCD histopathology with a classification accuracy > 0.9 (p < 0.05). CONCLUSIONS: The correlations between histopathology and neurophysiology provide evidence for the contribution of ictal PAC as a preoperative biomarker of FCD subtypes. SIGNIFICANCE: Developed into a proper clinical application, such a technique may help improve clinical management and facilitate the prediction of surgical outcome in patients with FCD undergoing stereo-EEG monitoring.

Virtual implantation using conventional scalp EEG delineates seizure onset and predicts surgical outcome in children with epilepsy.

OBJECTIVE: Delineation of the seizure onset zone (SOZ) is required in children with drug resistant epilepsy (DRE) undergoing neurosurgery. Intracranial EEG (icEEG) serves as gold standard but has limitations. Here, we examine the utility of virtual implantation with electrical source imaging (ESI) on ictal scalp EEG for mapping the SOZ and predict surgical outcome. METHODS: We retrospectively analyzed EEG data from 35 children with DRE who underwent surgery and dichotomized into seizure-free (SF) and non-seizure-free (NSF). We estimated virtual sensors (VSs) at brain locations that matched icEEG implantation and compared ictal patterns at VSs vs icEEG. We calculated the agreement between VSs SOZ and clinically defined SOZ and built receiver operating characteristic (ROC) curves to test whether it predicted outcome. RESULTS: Twenty-one patients were SF after surgery. Moderate agreement between virtual and icEEG patterns was observed (kappa = 0.45, p < 0.001). Virtual SOZ agreement with clinically defined SOZ was higher in SF vs NSF patients (66.6% vs 41.6%, p = 0.01). Anatomical concordance of virtual SOZ with clinically defined SOZ predicted outcome (AUC = 0.73; 95% CI: 0.57-0.89; sensitivity = 66.7%; specificity = 78.6%; accuracy = 71.4%). CONCLUSIONS: Virtual implantation on ictal scalp EEG can approximate the SOZ and predict outcome. SIGNIFICANCE: SOZ mapping with VSs may contribute to tailoring icEEG implantation and predict outcome.

Novel User-Friendly Application for MRI Segmentation of Brain Resection following Epilepsy Surgery.

Delineation of resected brain cavities on magnetic resonance images (MRIs) of epilepsy surgery patients is essential for neuroimaging/neurophysiology studies investigating biomarkers of the epileptogenic zone. The gold standard to delineate the resection on MRI remains manual slice-by-slice tracing by experts. Here, we proposed and validated a semiautomated MRI segmentation pipeline, generating an accurate model of the resection and its anatomical labeling, and developed a graphical user interface (GUI) for user-friendly usage. We retrieved pre- and postoperative MRIs from 35 patients who had focal epilepsy surgery, implemented a region-growing algorithm to delineate the resection on postoperative MRIs and tested its performance while varying different tuning parameters. Similarity between our output and hand-drawn gold standards was evaluated via dice similarity coefficient (DSC; range: 0-1). Additionally, the best segmentation pipeline was trained to provide an automated anatomical report of the resection (based on presurgical brain atlas). We found that the best-performing set of parameters presented DSC of 0.83 (0.72-0.85), high robustness to seed-selection variability and anatomical accuracy of 90% to the clinical postoperative MRI report. We presented a novel user-friendly open-source GUI that implements a semiautomated segmentation pipeline specifically optimized to generate resection models and their anatomical reports from epilepsy surgery patients, while minimizing user interaction.

A Role for Data Science in Precision Nutrition and Early Brain Development.

Multimodal brain magnetic resonance imaging (MRI) can provide biomarkers of early influences on neurodevelopment such as nutrition, environmental and genetic factors. As the exposure to early influences can be separated from neurodevelopmental outcomes by many months or years, MRI markers can serve as an important intermediate outcome in multivariate analyses of neurodevelopmental determinants. Key to the success of such work are recent advances in data science as well as the growth of relevant data resources. Multimodal MRI assessment of neurodevelopment can be supplemented with other biomarkers of neurodevelopment such as electroencephalograms, magnetoencephalogram, and non-imaging biomarkers. This review focuses on how maternal nutrition impacts infant brain development, with three purposes: (1) to summarize the current knowledge about how nutrition in stages of pregnancy and breastfeeding impact infant brain development; (2) to discuss multimodal MRI and other measures of early neurodevelopment; and (3) to discuss potential opportunities for data science and artificial intelligence to advance precision nutrition. We hope this review can facilitate the collaborative march toward precision nutrition during pregnancy and the first year of life.