A prospective 5-year longitudinal study detects neurocognitive and imaging correlates of seizure remission in self-limiting Rolandic epilepsy.

OBJECTIVE: Self-limiting Rolandic epilepsy (RE) is the most common epilepsy in school-age children. Seizures are generally infrequent, but cognitive, language, and motor coordination problems can significantly impact the child's life. To better understand brain structure and function changes in RE, we longitudinally assessed neurocognition, cortical thickness, and subcortical volumes. METHODS: At baseline, we recruited 30 participants diagnosed with RE and 24-healthy controls and followed up for 4.94 ± 0.8 years when the participants with RE were in seizure remission. Measures included were as follows: T1-weighted magnetic resonance brain imaging (MRI) with FreeSurfer analysis and detailed neuropsychological assessments. MRI and neuropsychological data were compared between baseline and follow-up in seizure remission. RESULTS: Longitudinal MRI revealed excess cortical thinning in the left-orbitofrontal (p = 0.0001) and pre-central gyrus (p = 0.044). There is a significant association (p = 0.003) between a reduction in cortical thickness in the left-orbitofrontal cluster and improved processing of filtered words. Longitudinal neuropsychology revealed significant improvements in the symptoms of developmental coordination disorder (DCD, p = 0.005) in seizure remission. CONCLUSIONS: There is evidence for altered development of neocortical regions between active seizure state and seizure remission in RE within two clusters maximal in the left-orbitofrontal and pre-central gyrus. There is significant evidence for improvement in motor coordination between active seizures and seizure remission and suggestive evidence for a decline in fluid intelligence and gains in auditory processing.

Decreased thalamocortical connectivity in resolved Rolandic epilepsy.

OBJECTIVE: Median nerve somatosensory evoked fields (SEFs) conduction times reflect the integrity of neural transmission across the thalamocortical circuit. We hypothesized median nerve SEF conduction time would be abnormal in children with Rolandic epilepsy (RE). METHODS: 22 children with RE (10 active; 12 resolved) and 13 age-matched controls underwent structural and diffusion MRI and median nerve and visual stimulation during magnetoencephalography (MEG). N20 SEF responses were identified in contralateral somatosensory cortices. P100 were identified in contralateral occipital cortices as controls. Conduction times were compared between groups in linear models controlling for height. N20 conduction time was also compared to thalamic volume and Rolandic thalamocortical structural connectivity inferred using probabilistic tractography. RESULTS: The RE group had slower N20 conduction compared to controls (p = 0.042, effect size 0.6 ms) and this difference was driven by the resolved RE group (p = 0.046). There was no difference in P100 conduction time between groups (p = 0.83). Ventral thalamic volume positively correlated with N20 conduction time (p = 0.014). CONCLUSIONS: Children with resolved RE have focally decreased Rolandic thalamocortical connectivity. SIGNIFICANCE: These results identify a persistent focal thalamocortical circuit abnormality in resolved RE and suggest that decreased Rolandic thalamocortical connectivity may support symptom resolution in this self-limited epilepsy.

Children with Rolandic epilepsy have micro- and macrostructural abnormalities in white matter constituting networks necessary for language function.

INTRODUCTION: Self-limited epilepsy with centrotemporal spikes is a transient developmental epilepsy with a seizure onset zone localized to the centrotemporal cortex that commonly impacts aspects of language function. To better understand the relationship between these anatomical findings and symptoms, we characterized the language profile and white matter microstructural and macrostructural features in a cohort of children with SeLECTS. METHODS: Children with active SeLECTS (n = 13), resolved SeLECTS (n = 12), and controls (n = 17) underwent high-resolution MRIs including diffusion tensor imaging sequences and multiple standardized neuropsychological measures of language function. We identified the superficial white matter abutting the inferior rolandic cortex and superior temporal gyrus using a cortical parcellation atlas and derived the arcuate fasciculus connecting them using probabilistic tractography. We compared white matter microstructural characteristics (axial, radial and mean diffusivity, and fractional anisotropy) between groups in each region, and tested for linear relationships between diffusivity metrics in these regions and language scores on neuropsychological testing. RESULTS: We found significant differences in several language modalities in children with SeLECTS compared to controls. Children with SeLECTS performed worse on assessments of phonological awareness (p = 0.045) and verbal comprehension (p = 0.050). Reduced performance was more pronounced in children with active SeLECTS compared to controls, namely, phonological awareness (p = 0.028), verbal comprehension (p = 0.028), and verbal category fluency (p = 0.031), with trends toward worse performance also observed in verbal letter fluency (p = 0.052), and the expressive one-word picture vocabulary test (p = 0.068). Children with active SeLECTS perform worse than children with SeLECTS in remission on tests of verbal category fluency (p = 0.009), verbal letter fluency (p = 0.006), and the expressive one-word picture vocabulary test (p = 0.045). We also found abnormal superficial white matter microstructure in centrotemporal ROIs in children with SeLECTS, characterized by increased diffusivity and fractional anisotropy compared to controls (AD p = 0.014, RD p = 0.028, MD p = 0.020, and FA p = 0.024). Structural connectivity of the arcuate fasciculus connecting perisylvian cortical regions was lower in children with SeLECTS (p = 0.045), and in the arcuate fasciculus children with SeLECTS had increased diffusivity (AD p = 0.007, RD p = 0.006, MD p = 0.016), with no difference in fractional anisotropy (p = 0.22). However, linear tests comparing white matter microstructure in areas constituting language networks and language performance did not withstand correction for multiple comparisons in this sample, although a trend was seen between FA in the arcuate fasciculus and verbal category fluency (p = 0.047) and the expressive one-word picture vocabulary test (p = 0.036). CONCLUSION: We found impaired language development in children with SeLECTS, particularly in those with active SeLECTS, as well as abnormalities in the superficial centrotemporal white matter as well as the fibers connecting these regions, the arcuate fasciculus. Although relationships between language performance and white matter abnormalities did not pass correction for multiple comparisons, taken together, these results provide evidence of atypical white matter maturation in fibers involved in language processing, which may contribute to the aspects of language function that are commonly affected by the disorder.

Structural and functional changes in drug-naïve benign childhood epilepsy with centrotemporal spikes and their associated gene expression profiles.

Benign epilepsy with centrotemporal spikes (BECTS) is a common pediatric epilepsy syndrome that has been widely reported to show abnormal brain structure and function. However, the genetic mechanisms underlying structural and functional changes remain largely unknown. Based on the structural and resting-state functional magnetic resonance imaging data of 22 drug-naïve children with BECTS and 33 healthy controls, we conducted voxel-based morphology (VBM) and fractional amplitude of low-frequency fluctuation (fALFF) analyses to compare cortical morphology and spontaneous brain activity between the 2 groups. In combination with the Allen Human Brain Atlas, transcriptome-neuroimaging spatial correlation analyses were applied to explore gene expression profiles associated with gray matter volume (GMV) and fALFF changes in BECTS. VBM analysis demonstrated significantly increased GMV in the right brainstem and right middle cingulate gyrus in BECTS. Moreover, children with BECTS exhibited significantly increased fALFF in left temporal pole, while decreased fALFF in right thalamus and left precuneus. These brain structural and functional alterations were closely related to behavioral and cognitive deficits, and the fALFF-linked gene expression profiles were enriched in voltage-gated ion channel and synaptic activity as well as neuron projection. Our findings suggest that brain morphological and functional abnormalities in children with BECTS involve complex polygenic genetic mechanisms.

Abnormal percent amplitude of fluctuation and functional connectivity within and between networks in benign epilepsy with centrotemporal spikes.

BACKGROUND: Benign epilepsy with centrotemporal spikes (BECTS) is one of the most common childhood epilepsy syndromes. The neural basis of BECTS is still poorly understood. This study aimed to further investigate the possible neural mechanisms of BECTS by comparing percent amplitude of fluctuation (PerAF) of resting-state functional magnetic resonance imaging (RS-fMRI) signal of each brain voxel and connectivity within and between related networks in children with BECTS and healthy controls (HCs). METHODS: Firstly, we used PerAF method to investigate brain functional alteration and defined the regions of interest (ROIs) where children with BECTS exhibited significant PerAF alterations compared to HCs. We then divided these ROIs into different networks based on previous findings and investigated alterations of functional connectivity within and between networks in children with BECTS. Receiver operating characteristic (ROC) curve was employed to assess the reliable biomarker for distinguishing children with BECTS from HCs based on the intergroup PerAF differences. RESULTS: Children with BECTS showed decreased PerAF in the left middle frontal cortex (MFC), right precentral gyrus, left precuneus (PCUN), bilateral posterior cingulate cortex (PCC), left angular gyrus, left inferior parietal lobule (IPL), right supplementary motor area (SMA) and left primary somatosensory cortex (S1) compared to HCs. The IPL and PCC exhibited higher classification power by ROC analysis. Moreover, our findings exhibited increased Intra-network connectivity in the default mode network (DMN), and increased inter-network connectivity of the sensorimotor network (SMN) with Broca's area and DMN. CONCLUSIONS: Our study investigated the abnormal PerAF and functional brain networks in children with BECTS, which might provide new insights into the pathological mechanisms of BECTS.

Transient, developmental functional and structural connectivity abnormalities in the thalamocortical motor network in Rolandic epilepsy.

Rolandic epilepsy (RE) is the most common focal, idiopathic, developmental epilepsy, characterized by a transient period of sleep-potentiated seizures and epileptiform discharges in the inferior Rolandic cortex during childhood. The cause of RE remains unknown but converging evidence has identified abnormalities in the Rolandic thalamocortical circuit. To better localize this transient disease, we evaluated Rolandic thalamocortical functional and structural connectivity in the sensory and motor circuits separately during the symptomatic and asymptomatic phases of this disease. We collected high resolution structural, diffusion, and resting state functional MRI data in a prospective cohort of children with active RE (n = 17), resolved RE (n = 21), and controls (n = 33). We then computed the functional and structural connectivity between the inferior Rolandic cortex and the ventrolateral (VL) nucleus of the thalamus (efferent pathway) and the ventroposterolateral (VPL) nucleus of the thalamus (afferent pathway) across development in children with active, resolved RE and controls. We compared connectivity with age in each group using linear mixed-effects models. We found that children with active RE have increasing thalamocortical functional connectivity between the VL thalamus and inferior motor cortex with age (p = 0.022) that is not observed in controls or resolved RE. In contrast, children with resolved RE have increasing thalamocortical structural connectivity between the VL nucleus and the inferior motor cortex with age (p = 0.025) that is not observed in controls or active RE. No relationships were identified between VPL nuclei and the inferior sensory cortex with age in any group. These findings localize the functional and structural thalamocortical circuit disruption in RE to the efferent thalamocortical motor pathway. Further work is required to determine how these circuit abnormalities contribute to the emergence and resolution of symptoms in this developmental disease.

Functional connectivity differences in speech production networks in Chinese children with Rolandic epilepsy.

Previous studies have demonstrated that language impairments are frequently observed in patients with benign epilepsy with centrotemporal spikes (BECTS). However, how BECTS affects language processing in the Chinese population remains unclear. With the use of functional magnetic resonance imaging (fMRI) in an overt picture-naming task, the present study examined functional connectivity in 27 children with BECTS and 26 healthy controls. The results indicated that children with BECTS showed altered functional connectivity associated with speech production between the left precuneus and the right cerebellum, between the right precuneus and the bilateral thalamus and the left superior temporal gyrus, between the right cuneus and the right postcentral gyrus and the right inferior parietal lobule, and between the right cerebellum and right middle frontal gyrus. Collectively, the findings in this study demonstrate the abnormal functional connectivity basis of speech production in Chinese children with BECTS, providing clues to understanding the brain mechanisms of language-related network in patients with BECTS.

Whole-Brain Dynamic Resting-State Functional Network Analysis in Benign Epilepsy With Centrotemporal Spikes.

Benign epilepsy with centrotemporal spikes (BECTS), the most common type of epilepsy among children, is considered a network disorder. Both fMRI and EEG source imaging (ESI) studies have indicated that BECTS is associated with static resting-state functional network (SFN) alterations (e.g., decreased global efficiency) in source space. However, we find that the abovementioned alterations are not significant when the SFN calculations are performed in the scalp space using only clinical routine low-density (e.g., 19 channels) EEG recordings (shown in our results). In the context of EEG microstates, it is clear that networks in the scalp space with resting-state EEG recordings dynamically reconfigure in a well-organized way based on different functional states. We are therefore inspired to propose a whole-brain dynamic resting-state functional network (DFN) computation method based on resting-state low-density EEG recordings with four classical microstates in scalp space. Notably, on the one hand, this approach is suitable for clinical conditions, and, on the other hand, the dynamic alternations calculated with a DFN may promote our understanding of how the networks change in BECTS. We analysed the changes in a DFN in six frequency bands (δ, θ, αlow, αhigh, ß, and γ) in patients with BECTS compared to those for healthy controls. Superior to traditional SFNs, the proposed DFN can reveal significant differences between individuals with BECTS and healthy controls (e.g., lower global efficiency), thus matching traditional fMRI and ESI methods in the source space. Our method directly performs DFN computations from low-density EEG recordings and avoids complex ESI computations, making it promising for clinical applications, especially in the outpatient diagnosis stage.

Brain magnetic resonance imaging findings and brain volumetric differences in a large series of benign rolandic epilepsy.

BACKGROUND: Several studies with a small sample size have investigated the relationship between structural and functional changes on MRI and the clinical and natural history of BRE. We aim to assess the frequency of incidental epileptogenic lesions on brain MRI in a large cohort of patients diagnosed with BRE and to assess the difference in volumetric brain measurements in BRE patients compared to healthy controls. METHODS: The case-control study includes 214 typical BRE cases and 197 control children with non-epileptic spells. Brain MRIs were evaluated for abnormalities which were classified into normal and abnormal with or without epileptogenic lesions with categorization of epileptogenic lesions. Brain segmentation was also performed for a smaller group of BRE patients and another healthy control group. Pearson's chi-squared test and two-tailed independent samples t-test were used. RESULTS: In patients with BRE, 7% had an epileptogenic lesion on their MRI. The frequency of epileptogenic lesion in the control group was 10.2% and not significantly different from those with BRE (p= 0.2). Significantly higher intracranial and white matter volumes were found in BRE patients compared to the healthy group while lower gray matter volume was found in BRE patients. Cortical and subcortical regions showed either higher or lower volumes with BRE. Interestingly, altered subcallosal cortex development which has a known association with depression was also found in BRE. CONCLUSIONS: Our findings confirm the absence of any association between specific brain MRI abnormalities and BRE. However, the altered cortical and subcortical development in BRE patients suggests a microstructural-functional correlation.

Source EEG reveals that Rolandic epilepsy is a regional epileptic encephalopathy.

Rolandic epilepsy is the most common form of epileptic encephalopathy, characterized by sleep-potentiated inferior Rolandic epileptiform spikes, seizures, and cognitive deficits in school-age children that spontaneously resolve by adolescence. We recently identified a paucity of sleep spindles, physiological thalamocortical rhythms associated with sleep-dependent learning, in the Rolandic cortex during the active phase of this disease. Because spindles are generated in the thalamus and amplified through regional thalamocortical circuits, we hypothesized that: 1) deficits in spindle rate would involve but extend beyond the inferior Rolandic cortex in active epilepsy and 2) regional spindle deficits would better predict cognitive function than inferior Rolandic spindle deficits alone. To test these hypotheses, we obtained high-resolution MRI, high-density EEG recordings, and focused neuropsychological assessments in children with Rolandic epilepsy during active (n = 8, age 9-14.7 years, 3F) and resolved (seizure free for > 1 year, n = 10, age 10.3-16.7 years, 1F) stages of disease and age-matched controls (n = 8, age 8.9-14.5 years, 5F). Using a validated spindle detector applied to estimates of electrical source activity in 31 cortical regions, including the inferior Rolandic cortex, during stages 2 and 3 of non-rapid eye movement sleep, we compared spindle rates in each cortical region across groups. Among detected spindles, we compared spindle features (power, duration, coherence, bilateral synchrony) between groups. We then used regression models to examine the relationship between spindle rate and cognitive function (fine motor dexterity, phonological processing, attention, and intelligence, and a global measure of all functions). We found that spindle rate was reduced in the inferior Rolandic cortices in active but not resolved disease (active P = 0.007; resolved P = 0.2) compared to controls. Spindles in this region were less synchronous between hemispheres in the active group (P = 0.005; resolved P = 0.1) compared to controls; but there were no differences in spindle power, duration, or coherence between groups. Compared to controls, spindle rate in the active group was also reduced in the prefrontal, insular, superior temporal, and posterior parietal regions (i.e., "regional spindle rate", P < 0.039 for all). Independent of group, regional spindle rate positively correlated with fine motor dexterity (P < 1e-3), attention (P = 0.02), intelligence (P = 0.04), and global cognitive performance (P < 1e-4). Compared to the inferior Rolandic spindle rate alone, models including regional spindle rate trended to improve prediction of global cognitive performance (P = 0.052), and markedly improved prediction of fine motor dexterity (P = 0.006). These results identify a spindle disruption in Rolandic epilepsy that extends beyond the epileptic cortex and a potential mechanistic explanation for the broad cognitive deficits that can be observed in this epileptic encephalopathy.

Interictal epileptiform discharges changed epilepsy-related brain network architecture in BECTS.

To investigate directed information flow of epileptiform activity in benign epilepsy with centrotemporal spikes (BECTS) during ictal epileptiform discharges (IEDs) and non-IEDs periods. In this multi-center study, a total of 188 subjects, including 50 BECTS and 138 normal children's controls (NCs) from three different centers (Center 1: females/males, 38/55; mean age, 9.33 ± 2.6 years; Center 2: females/males,7/10; mean age, 8.59 ± 2.32 years; Center 3: females/males, 14/14; mean age, 13 ± 3.42 years) were recruited. The BECTS were classified into IEDs (females/males, 12/15; mean age, 8.15 ± 1.68 years) and non-IEDs (females/males, 10/13; mean age, 9.09 ± 1.98 years) subgroups depending on presence of central-temporal spikes from an EEG-fMRI examination. Three new methods, structural equation parametric modeling, dynamic causal modeling and granger causality density (GCD) were used to determine optimal network architectures for BECTS. Three multicentric NCs determined a reliable and consistent network architecture by structural equation parametric modeling method. Further analyses were used for IEDs and non-IEDs to determine the brain network architecture by structural equation parametric modeling, dynamic causal modeling and GCD, respectively. The brain network architecture of IEDs substate, non-IEDs substate and NCs are different. IEDs promoted the driving effect of the Rolandic areas with more output information flows, and increased the targeted effect of the top of pre-/post-central gyrus with more input information flows. The information flow arises from the Rolandic areas, and subsequently propagates to the top of pre-/post-central gyrus and thalamus. From non-IEDs status to IEDs status, the thalamus load may play an important role in the modulation and regulation of epileptiform activity. These findings shed new light on pathophysiological mechanism of directed localization of epileptiform activity in BECTS.

Influence of epileptogenic region on brain structural changes in Rolandic epilepsy.

To investigate the influence of epileptogenic cortex (Rolandic areas) with executive functions in Rolandic epilepsy using structural covariance analysis of structural magnetic resonance imaging (MRI). Structural MRI data of drug-naive patients with Rolandic epilepsy (n = 70) and typically developing children as healthy controls (n = 83) were analyzed using voxel-based morphometry. Gray matter volumes in the patients were compared with those of healthy controls, and were further correlated with epilepsy duration and cognitive score of executive function, respectively. By applying Granger causal analysis to the sequenced morphometric data according to disease progression information, causal network of structural covariance was constructed to assess the causal influence of structural changes from Rolandic cortices to the regions engaging executive function in the patients. Compared with healthy controls, epilepsy patients showed increased gray matter volume in the Rolandic regions, and also the regions engaging in executive function. Covariance network analyses showed that along with disease progression, the Rolandic regions imposed positive causal influence on the regions engaging in executive function. In the patients with Rolandic epilepsy, epileptogenic regions have causal influence on the structural changes in the regions of executive function, implicating damaging effects of Rolandic epilepsy on human brain.

Alterations in white matter integrity and asymmetry in patients with benign childhood epilepsy with centrotemporal spikes and childhood absence epilepsy: An automated fiber quantification tractography study.

PURPOSE: To investigate whether patients with benign childhood epilepsy with centrotemporal spikes (BECTS) and childhood absence epilepsy (CAE) show distinct patterns of white matter (WM) alterations and structural asymmetry compared with healthy controls and the relationship between WM alterations and epilepsy-related clinical variables. METHODS: We used automated fiber quantification to create tract profiles of fractional anisotropy (FA) and mean diffusivity (MD) in twenty-six patients with BECTS, twenty-nine patients with CAE, and twenty-four healthy controls. Group differences in FA and MD were quantified at 100 equidistant nodes along the fiber tract and these alterations and epilepsy-related clinical variables were correlated. A lateralization index (LI) representing the structural asymmetry of the fiber tract was computed and compared between both patient groups and controls. RESULTS: Compared with healthy controls, the BECTS group showed widespread FA reduction in 43.75% (7/16) and MD elevation in 50% (8/16) of identified fiber tracts, and the CAE group showed regional FA reduction in 31.25% (5/16) and MD elevation in 25% (4/16) of identified fiber tracts. In the BECTS group, FA and MD in the right anterior thalamic radiation positively and negatively correlated with the number of antiepileptic drugs, respectively, and MD in the right arcuate fasciculus (AF) positively correlated with seizure frequency. In the CAE group, the LI values were significantly lower in the inferior fronto-occipital fasciculus and the AF. CONCLUSION: The two childhood epilepsy syndromes display different patterns of WM alterations and structural asymmetry, suggesting that neuroanatomical differences may underlie the different profiles of BECTS and CAE.

Delayed brain development of Rolandic epilepsy profiled by deep learning-based neuroanatomic imaging.

OBJECTIVES: Although Rolandic epilepsy (RE) has been regarded as a brain developmental disorder, neuroimaging studies have not yet ascertained whether RE has brain developmental delay. This study employed deep learning-based neuroanatomic biomarker to measure the changed feature of "brain age" in RE. METHODS: The study constructed a 3D-CNN brain age prediction model through 1155 cases of typically developing children's morphometric brain MRI from open-source datasets and further applied to a local dataset of 167 RE patients and 107 typically developing children. The brain-predicted age difference was measured to quantitatively estimate brain age changes in RE and further investigated the relevancies with cognitive and clinical variables. RESULTS: The brain age estimation network model presented a good performance for brain age prediction in typically developing children. The children with RE showed a 0.45-year delay of brain age by contrast with typically developing children. Delayed brain age was associated with neuroanatomic changes in the Rolandic regions and also associated with cognitive dysfunction of attention. CONCLUSION: This study provided neuroimaging evidence to support the notion that RE has delayed brain development. KEY POINTS: • The children with Rolandic epilepsy showed imaging phenotypes of delayed brain development with increased GM volume and decreased WM volume in the Rolandic regions. • The children with Rolandic epilepsy had a 0.45-year delay of brain-predicted age by comparing with typically developing children, using 3D-CNN-based brain age prediction model. • The delayed brain age was associated with morphometric changes in the Rolandic regions and attentional deficit in Rolandic epilepsy.

Neurodevelopmental origins of self-limiting rolandic epilepsy: Systematic review of MR imaging studies.

OBJECTIVE: Recent neuroimaging studies have revealed differences in cortical and white matter brain structure in children with self-limiting rolandic epilepsy (RE). Despite this, reproducibility of the findings has been difficult, and there is no consensus about where and when structural differences are most apparent. We performed a systematic review of quantitative neuroimaging studies in children with RE to explore these questions. METHODS: Using PRISMA guidelines, we used a multilayered search strategy to identify neuroimaging studies in RE. Publications were included if they were quantitative and derived from controlled group studies and passed a quality assessment. Findings of the studies were presented and stratified by duration of epilepsy and age of participants. RESULTS: We identified six gray matter studies and five white matter studies. Consistent findings were found inside and outside the central sulcus, predominantly within the bilateral frontal and parietal lobes, striatal structures, such as the putamen and white matter, mainly involving the left superior longitudinal fasciculus and connections between the left pre- and postcentral gyrus. Stratification of the T1 studies by age found that cortical thickness differences varied between the under and over 10 year olds. Furthermore, the longer the duration of epilepsy, the less likely differences were detected. In white matter studies, there was a reduction in differences with increased age and duration of epilepsy. SIGNIFICANCE: These findings would suggest that the development of regions of the cortex in children with RE is abnormal. These regions are more widespread than the suspected seizure onset zone. Moreover, the findings would suggest that these differences are evidence of neurodevelopmental delay rather than apparent "damage" from the epilepsy.

Anti-seizure medication correlated changes of cortical morphology in childhood epilepsy with centrotemporal spikes.

To investigate the morphological changes of cerebral cortex correlating with anti-seizure medication in Childhood Epilepsy with Centrotemporal Spikes (CECTS), and their relationships with seizure control. This study included a total of 188 children, including 62 patients with CECTS taking anti-seizure drugs, 56 patients with drug-naive, and 70 healthy controls. A portion of cases were also followed-up for longitudinal analysis. Cortical morphological parameters were quantitatively measured by applying surface-based morphometry analysis to high-resolution three-dimension T1 weighted images. Among the three groups, the morphological indices were compared to quantify any cortical changes affected by seizures and medication. The relationships among anti-seizure medication, seizure controls and cortical morphometry were investigated using causal mediator analysis. The Rolandic cortex of the drug-naive patients showed abnormal cortical thickness by comparing with that of healthy controls, and thinning by comparing with that of patients with medication. The cortical thickness in the Rolandic regions was negatively correlated with duration of medication and duration of seizure-free. Longitudinal analysis further demonstrated that the thickness of Rolandic cortex thinned in post-medication state relative to the pre-medication state. Mediation analysis revealed that morphological alteration of the Rolandic cortex might act as a mediator in the path of anti-seizure medication on seizure control. Our findings highlighted that anti-seizure medication was associated with regression of abnormal increment of cortical thickness in the Rolandic regions in CECTS. The neuroanatomical alteration might be a mediating factor in the process of seizure control by anti-seizure medication.

Reliability and availability of granger causality density in localization of Rolandic focus in BECTS.

A new method, called granger causality density (GCD), could reflect the directed information flow of the epileptiform activity, which is much closely match with excitatory and inhibitory imbalance theory of epilepsy. Here, we investigated if GCD could effectively localize the Rolandic focus in 50 patients with benign childhood epilepsy with central-temporal spikes (BECTS) from 27 normal children. The BECTS were classified into ictal epileptiform discharges (IEDs; 12 females, 15 males;age, 8.15 ± 1.68 years) and non-IEDs (10 females, 13 males; age, 9.09 ± 1.98 years) subgroups depending on the presence of central-temporal spikes. Multiple correlation-modality analyses (Pearson, across-voxel and across-subject correlations) were used to calculate the couplings between the GCD maps and IEDs-related brain activation map. The individual lateralization coefficient of localize IEDs and multiple regression analysis were used to identify the reliability of the GCD method in localizing the Rolandic focus. In this study, multiple correlation-modality analyses showed that the IEDs-related brain activation map and the GCD maps had highly temporal (coefficient ׀r\= 0.56 ~ 0.65) and spatial (\r\=0.53~0.91) (r\=~ couplings. The proposed GCD method and multiple regression analyses showed consistent findings with the clinical EEG recordings in lateralization of Rolandic focus. Furthermore, the GCD method could reflect the epilepsy-related brain activity during non-IEDs substate. Therefore, the proposed GCD method has the potential to be served as an effective and reliable neuroimaging biomarker to localize the Rolandic focus of BECTS. These findings are critical for clinical early diagnosis, and may promote the progression of treatment and management of pediatric epilepsy.

The feasibility and value of extraoperative and adjuvant intraoperative stereoelectroencephalography in rolandic and perirolandic epilepsies.

OBJECTIVE: The objective of this study was to illustrate the feasibility and value of extra- and intraoperative stereoelectroencephalography (SEEG) in patients who underwent resection in rolandic and perirolandic regions. METHODS: The authors retrospectively reviewed all consecutive patients with at least 1 year of postoperative follow-up who underwent extra- and intraoperative SEEG monitoring between January 2015 and January 2017. RESULTS: Four patients with pharmacoresistant rolandic and perirolandic focal epilepsy were identified, who underwent conventional extraoperative invasive SEEG evaluations followed by adjuvant intraoperative SEEG recordings. Conventional extraoperative SEEG evaluations demonstrated ictal and interictal epileptiform activities involving eloquent rolandic and perirolandic cortical areas in all patients. Following extraoperative monitoring, patients underwent preplanned staged resections guided by simultaneous and continuous adjuvant intraoperative SEEG monitoring. Resections, guided by electrode contacts of interest in 3D boundaries, were performed while continuous real-time electrographic data from SEEG recordings were obtained. Staged approaches of resections were performed until there was intraoperative resolution of synchronous rolandic/perirolandic cortex epileptic activities. All patients in the cohort achieved complete seizure freedom (Engel class IA) during the follow-up period ranging from 18 to 50 months. Resection resulted in minimal neurological deficit; 3 patients experienced transient, distal plantar flexion weakness (mild foot drop). CONCLUSIONS: The seizure and functional outcome results of this highly preselected group of patients testifies to the feasibility and demonstrates the value of the combined benefits of both intra- and extraoperative SEEG recordings when resecting the rolandic and perirolandic areas. The novel hybrid method allows a more refined and precise identification of the epileptogenic zone. Consequently, tailored resections can be performed to minimize morbidity as well as to achieve adequate seizure control.

Persistent abnormalities in Rolandic thalamocortical white matter circuits in childhood epilepsy with centrotemporal spikes.

OBJECTIVE: Childhood epilepsy with centrotemporal spikes (CECTS) is a common, focal, transient, developmental epilepsy syndrome characterized by unilateral or bilateral, independent epileptiform spikes in the Rolandic regions of unknown etiology. Given that CECTS presents during a period of dramatic white matter maturation and thatspikes in CECTS are activated during non-rapid eye movement (REM) sleep, we hypothesized that children with CECTS would have aberrant development of white matter connectivity between the thalamus and the Rolandic cortex. We further tested whether Rolandic thalamocortical structural connectivity correlates with spike rate during non-REM sleep. METHODS: Twenty-three children with CECTS (age = 8-15 years) and 19 controls (age = 7-15 years) underwent 3-T structural and diffusion-weighted magnetic resonance imaging and 72-electrode electroencephalographic recordings. Thalamocortical structural connectivity to Rolandic and non-Rolandic cortices was quantified using probabilistic tractography. Developmental changes in connectivity were compared between groups using bootstrap analyses. Longitudinal analysis was performed in four subjects with 1-year follow-up data. Spike rate was quantified during non-REM sleep using manual and automated techniques and compared to Rolandic connectivity using regression analyses. RESULTS: Children with CECTS had aberrant development of thalamocortical connectivity to the Rolandic cortex compared to controls (P = .01), where the expected increase in connectivity with age was not observed in CECTS. There was no difference in the development of thalamocortical connectivity to non-Rolandic regions between CECTS subjects and controls (P = .19). Subjects with CECTS observed longitudinally had reductions in thalamocortical connectivity to the Rolandic cortex over time. No definite relationship was found between Rolandic connectivity and non-REM spike rate (P > .05). SIGNIFICANCE: These data provide evidence that abnormal maturation of thalamocortical white matter circuits to the Rolandic cortex is a feature of CECTS. Our data further suggest that the abnormalities in these tracts do not recover, but are increasingly dysmature over time, implicating a permanent but potentially compensatory process contributing to disease resolution.

Cortical and subcortical volume differences between Benign Epilepsy with Centrotemporal Spikes and Childhood Absence Epilepsy.

OBJECTIVE: Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS) and Childhood Absence Epilepsy (CAE) are the most common childhood epilepsy syndromes and they share a similar age-dependence. However, the two syndromes clearly differ in seizures and EEG patterns. The aim of this study is to investigate whether children of the same age with BECTS, CAE and typically-developing children have significant differences in grey matter volume that may underlie the different profiles of these syndromes. METHODS: Twenty one patients with newly-diagnosed BECTS and 18 newly diagnosed and drug naïve CAE were included and compared to 31 typically-developing children. Voxel-based morphometry was utilized to investigate grey matter volume differences among BECTS, CAE, and controls. We also examined the effect of age on grey matter volume in all three groups. In addition to the whole brain analysis, we chose regions of interest analysis based on previous literature suggesting the involvement of these regions in BECTS or CAE. The group differences of grey matter volume was tested with 2-sample t-test for between two groups' comparisons and ANOVA for three group comparisons. RESULTS: In the whole brain group comparisons, the grey matter volume in CAE was significantly decreased in the areas of right inferior frontal and anterior temporal compared to BECTS and controls (F2,67 = 27.53, p < 0.001). In the control group, grey matter volume in bifrontal lobes showed a negative correlation with age (r=-0.54, p < 0.05), whereas no correlation was found in either CAE or BECTS. With ROI analyses, the grey matter volume of posterior thalami was increased in CAE compared to other 2 groups (p < 0.05). SIGNIFICANCE: This study shows that there are grey matter volume differences between CAE and BECTS. Our findings of grey matter volume differences may suggest that there may be localized, specific differences in brain structure between these two types of epilepsy.