Mapping progressive damage epicenters in epilepsy with generalized tonic-clonic seizures by causal structural covariance network density (CaSCNd).

AIMS: Mapping progressive patterns of structural damage in epilepsies with idiopathic and secondarily generalized tonic-clonic seizures with causal structural covariance networks and multiple analysis strategies. METHODS: Patients with idiopathic generalized tonic-clonic seizures (IGTCS) (n = 114) and secondarily generalized tonic-clonic seizures (SGTCS) (n = 125) were recruited. Morphometric parameter of gray matter volume was analyzed on structural MRI. Structural covariance network based on granger causality analysis (CaSCN) was performed on the cross-sectional morphometric data sorted by disease durations of patients. Seed-based CaSCN analysis was firstly carried out to map the progressive and influential patterns of damage to thalamus-related structures. A novel technique for voxel-based CaSCN density (CaSCNd) analysis was further proposed, enabling for identifying the epicenter of structural brain damage during the disease process. RESULTS: The thalamus-associated CaSCNs demonstrated different patterns of progressive damage in two types of generalized tonic-clonic seizures. In IGTCS, the structural damage was predominantly driven from the thalamus, and expanded to the cortex, while in SGTCS, the damage was predominantly driven from the cortex, and expanded to the thalamus through the basal ganglia. CaSCNd analysis revealed that the IGTCS had an out-effect epicenter in the thalamus, whereas the SGTCS had equipotent in- and out-effects in the thalamus, cortex, and basal ganglia. CONCLUSION: CaSCN revealed distinct damage patterns in the two types of GTCS, featuring with measurement of structural brain damage from the accumulating effect over a relatively long time period. Our work provided evidence for understanding network impairment mechanism underlying different GTCSs.

The role of the primary sensorimotor system in generalized epilepsy: Evidence from the cerebello-cerebral functional integration.

The interaction between cerebellum and cerebrum participates widely in function from motor processing to high-level cognitive and affective processing. Because of the motor symptom, idiopathic generalized epilepsy (IGE) patients with generalized tonic-clonic seizure have been recognized to associate with motor abnormalities, but the functional interaction in the cerebello-cerebral circuit is still poorly understood. Resting-state functional magnetic resonance imaging data were collected for 101 IGE patients and 106 healthy controls. The voxel-based functional connectivity (FC) between cerebral cortex and the cerebellum was contacted. The functional gradient and independent components analysis were applied to evaluate cerebello-cerebral functional integration on the voxel-based FC. Cerebellar motor components were further linked to cerebellar gradient. Results revealed cerebellar motor functional modules were closely related to cerebral motor components. The altered mapping of cerebral motor components to cerebellum was observed in motor module in patients with IGE. In addition, patients also showed compression in cerebello-cerebral functional gradient between motor and cognition modules. Interestingly, the contribution of the motor components to the gradient was unbalanced between bilateral primary sensorimotor components in patients: the increase was observed in cerebellar cognitive module for the dominant hemisphere primary sensorimotor, but the decrease was found in the cerebellar cognitive module for the nondominant hemisphere primary sensorimotor. The present findings suggest that the cerebral primary motor system affects the hierarchical architecture of cerebellum, and substantially contributes to the functional integration evidence to understand the motor functional abnormality in IGE patients.

Default mode function in patients with generalised epilepsy syndromes: from generalised to focal findings.

INTRODUCTION: Many recent studies have suggested that generalised epilepsy is associated with cortical epileptogenic focus, and therefore distinguishing between focal and generalised often becomes difficult. AIM OF STUDY: We aimed to detect differences between default mode function in patients with idiopathic generalised epilepsy who have discharges on EEG, and healthy persons. MATERIAL AND METHODS: This was a case-control study; we performed EEG analysis with LORETA in 17 patients with a type of generalised epilepsy and a control group represented by 17 healthy age-matched persons. We performed statistical non- -parametric tests for current density electrical distribution for our two groups ('t-statistic on Log transformed data') and we defined regions of interest (ROIs) from the default mode network. In the second part, we compared the average activation for each ROI for each timeframe in the epoch for the group with epilepsy, and for controls (we performed a Wilcoxon rank-sum test for two means). RESULTS: In the first part, we obtained that in the medial frontal gyrus (BA 9) delta oscillations significantly differed in patients with epilepsy who had electrical discharges on EEG in resting state conditions compared to healthy controls (medial frontal gyrus in this group had a greater number of synchronously oscillating neurons than did the controls). In the second part, we ran statistics on our localised activity from the default mode network (defined ROIs) and we obtained statistically significant differences in the left medial frontal gyrus (the values were higher for the group with epilepsy, p-value = 0.0066). CONCLUSIONS AND CLINICAL IMPLICATIONS: It may be possible to move from a 'generalised theory' about epilepsy to a 'focused theory' by understanding how various areas of interest are activated within default mode networks. Insights into the pathophysiology of generalised epilepsy may lead to new treatment options.

Multi-spectral diffusion MRI mega-analysis in genetic generalized epilepsy: Relation to outcomes.

BACKGROUND AND OBJECTIVES: Genetic generalized epilepsy (GGE) is the most common form of generalized epilepsy. Although individual patients with GGE typically present without structural alterations, group differences have been demonstrated in GGE and some GGE subtypes like juvenile myoclonic epilepsy (GGE-JME). Previous studies usually involved only small cohorts from single centers and therefore could not assess imaging markers of multiple GGE subtypes. METHODS: We performed a diffusion MRI mega-analysis in 192 participants consisting of 126 controls and 66 patients with GGE from four different cohorts and two different epilepsy centers. We applied whole-brain multi-site harmonization and analyzed fractional anisotropy (FA), as well as mean, radial and axial diffusivity (MD/RD/AD) to assess differences between controls, patients with GGE and the common GGE subtypes, i.e. GGE with generalized tonic-clonic seizures only (GGE-GTCS), GGE-JME and absence epilepsy (GGE-AE). We also analyzed relationships with patients' response to anti-seizure-medication (ASM). RESULTS: Relative to controls, we identified decreased anisotropy and increased RD in patients with GGE. We found no significant effects of disease duration, age of onset or seizure frequency on diffusion metrics. Patients with JME had increased MD and RD when compared to controls, while patients with GGE-GTCS showed decreased MD/AD when compared to controls. Compared to patients with GGE-AE, patients with GGE-GTCS had lower AD/MD. Compared to patients with GGE-GTCS, patients with GGE-JME had higher MD/RD and AD. Moreover, we found lower FA in patients with refractory when compared to patients with non-refractory GGE in the right cortico-spinal tract, but no significant differences in patients with active versus controlled epilepsy. DISCUSSION: We provide evidence that clinically defined GGE as a whole and GGE-subtypes harbor marked microstructural differences detectable with diffusion MRI. Moreover, we found an association between microstructural changes and treatment resistance. Our findings have important implications for future full-resolution multi-site studies when assessing GGE, its subtypes and ASM refractoriness.

Comparison of Resting-State EEG Network Analyses With and Without Parallel MRI in Genetic Generalized Epilepsy.

Genetic generalized epilepsy (GGE) is conceptualized as a brain disorder involving distributed bilateral networks. To study these networks, simultaneous EEG-fMRI measurements can be used. However, inside-MRI EEG suffers from strong MR-related artifacts; it is not established whether EEG-based metrics in EEG-fMRI resting-state measurements are suitable for the analysis of group differences at source-level. We evaluated the impact of the inside-MR measurement condition on statistical group comparisons of EEG on source-level power and functional connectivity in patients with GGE versus healthy controls. We studied the cross-modal spatial relation of statistical group differences in seed-based FC derived from EEG and parallel fMRI. We found a significant increase in power and a frequency-specific change in functional connectivity for the inside MR-scanner compared to the outside MR-scanner condition. For power, we found reduced group difference between GGE and controls both in terms of statistical significance as well as effect size. Group differences for ImCoh remained similar both in terms of statistical significance as well as effect size. We found increased seed-based FC for GGE patients from the thalamus to the precuneus cortex region in fMRI, and in the theta band of simultaneous EEG. Our findings suggest that the analysis of EEG functional connectivity based on ImCoh is suitable for MR-EEG, and that relative group difference in a comparison of patients with GGE against controls are preserved. Spatial correspondence of seed-based FC group differences between the two modalities was found for the thalamus.

Unbalance between working memory task-activation and task-deactivation networks in epilepsy: Simultaneous EEG-fMRI study.

Working memory (WM) is a cognitive function involving emergent properties of theta oscillations and large-scale network interactions. The synchronization of WM task-related networks in the brain enhanced WM performance. However, how these networks regulate WM processing is not well known, and the alteration of the interaction among these networks may play an important role in patients with cognitive dysfunction. In this study, we used simultaneous EEG-fMRI to examine the features of theta oscillations and the functional interactions among activation/deactivation networks during the n-back WM task in patients with idiopathic generalized epilepsy (IGE). The results showed that there was more enhancement of frontal theta power along with WM load increase in IGE, and the theta power was positively correlated with the accuracy of the WM tasks. Moreover, fMRI activations/deactivations correlated with n-back tasks were estimated, and we found that the IGE group had increased and widespread activations in high-load WM tasks, including the frontoparietal activation network and task-related deactivation areas, such as the default mode network and primary visual and auditory networks. In addition, the network connectivity results demonstrated decreased counteraction between the activation network and deactivation network, and the counteraction was correlated with the higher theta power in IGE. These results indicated the important role of the interactions between activation and deactivation networks during the WM process, and the unbalance among them may indicate the pathophysiological mechanism of cognitive dysfunction in generalized epilepsy.

Distinct genetic basis of common epilepsies and structural magnetic resonance imaging measures.

Focal and generalized epilepsies are associated with robust differences in magnetic resonance imaging (MRI) measures of subcortical structures, gray matter, and white matter. However, it is unknown whether such structural brain differences reflect the cause or consequence of epilepsy or its treatment. Analyses of common genetic variants underlying both common epilepsy risk and variability in structural brain measures can give further insights, as such inherited variants are not influenced by disease or treatment. Here, we performed genetic correlation analyses using data from the largest genome-wide association study (GWAS) on common epilepsy (n = 27 559 cases and 42 436 controls) and GWASs on MRI measures of white (n = 33 292) or gray matter (n = 51 665). We did not detect any significant genetic correlation between any type of common epilepsy and any of 280 measures of gray matter, white matter, or subcortical structures. These results suggest that there are distinct genetic bases underlying risk of common epilepsy and for structural brain measures. This would imply that the genetic basis of normal structural brain variation is unrelated to that of common epilepsy. Structural changes in epilepsy could rather be the consequence of epilepsy, its comorbidities, or its treatment, offering a cumulative record of disease.

Midbrain structure volume, estimated myelin and functional connectivity in idiopathic generalised epilepsy.

BACKGROUND: Structural and functional neuroimaging studies often overlook lower basal ganglia structures located in and adjacent to the midbrain due to poor contrast on clinically acquired T1-weighted scans. Here, we acquired T1-weighted, T2-weighted, and resting-state fMRI scans to investigate differences in volume, estimated myelin content and functional connectivity of the substantia nigra (SN), subthalamic nuclei (SubTN) and red nuclei (RN) of the midbrain in IGE. METHODS: Thirty-three patients with IGE (23 refractory, 10 non-refractory) and 39 age and sex-matched healthy controls underwent MR imaging. Midbrain structures were automatically segmented from T2-weighted images and structural volumes were calculated. The estimated myelin content for each structure was determined using a T1-weighted/T2-weighted ratio method. Resting-state functional connectivity analysis of midbrain structures (seed-based) was performed using the CONN toolbox. RESULTS: An increased volume of the right RN was found in IGE and structural volumes of the right SubTN differed between patients with non-refractory and refractory IGE. However, no volume findings survived corrections for multiple comparisons. No myelin alterations of midbrain structures were found for any subject groups. We found functional connectivity alterations including significantly decreased connectivity between the left SN and the thalamus and significantly increased connectivity between the right SubTN and the superior frontal gyrus in IGE. CONCLUSIONS: We report volumetric and functional connectivity alterations of the midbrain in patients with IGE. We postulate that potential increases in structural volumes are due to increased iron deposition that impacts T2-weighted contrast. These findings are consistent with previous studies demonstrating pathophysiological abnormalities of the lower basal ganglia in animal models of generalised epilepsy.

Altered neurovascular coupling in children with idiopathic generalized epilepsy.

AIMS: Alterations in neuronal activity and cerebral hemodynamics have been reported in idiopathic generalized epilepsy (IGE) patients, possibly resulting in neurovascular decoupling; however, no neuroimaging evidence confirmed this disruption. This study aimed to investigate the possible presence of neurovascular decoupling and its clinical implications in childhood IGE using resting-state fMRI and arterial spin labeling imaging. METHODS: IGE patients and healthy participants underwent resting-state fMRI and arterial spin labeling imaging to calculate degree centrality (DC) and cerebral blood flow (CBF), respectively. Across-voxel CBF-DC correlations were analyzed to evaluate the neurovascular coupling within the whole gray matter, and the regional coupling of brain region was assessed with the CBF/DC ratio. RESULTS: The study included 26 children with IGE and 35 sex- and age-matched healthy controls (HCs). Compared with the HCs, the IGE group presented lower across-voxel CBF-DC correlations, higher CBF/DC ratio in the right posterior cingulate cortex/precuneus, middle frontal gyrus, and medial frontal gyrus (MFG), and lower ratio in the left inferior frontal gyrus. The increased CBF/DC ratio in the right MFG was correlated with lower performance intelligence quotient scores in the IGE group. CONCLUSION: Children with IGE present altered neurovascular coupling, associated with lower performance intelligence quotient scores. The study shed a new insight into the pathophysiology of epilepsy and provided potential imaging biomarkers of cognitive performances in children with IGE.

Distributed source localization of epileptiform discharges in juvenile myoclonic epilepsy: Standardized low-resolution brain electromagnetic tomography (sLORETA) Study.

Juvenile myoclonic epilepsy (JME) is a common generalized epilepsy syndrome considered the prototype of idiopathic generalized epilepsy. To date, generalized and focal seizures have been the fundamental concepts for classifying seizure types. In several studies, focal features of JME have been reported predominantly in the frontal lobe. However, results in previous studies are inconsistent. Therefore, we investigated the origin of epileptiform discharges in JME. We performed electroencephalography source localization using a distributed model with standardized low-resolution brain electromagnetic tomography. In 20 patients with JME, standardized low-resolution brain electromagnetic tomography images corresponding to the midpoint of the ascending phase and the negative peak of epileptiform discharges were obtained from a total of 362 electroencephalography epochs (181 epochs at each timepoint). At the ascending phase, the maximal current source density was located in the frontal lobe (58.6%), followed by the parietal (26.5%) and occipital lobes (8.8%). At the negative peak, the maximal current source density was located in the frontal lobe (69.1%), followed by the parietal (11.6%) and occipital lobes (9.4%). In the ascending phase, 41.4% of discharges were located outside the frontal lobe, and 30.9% were in the negative peak. Frontal predominance of epileptiform discharges was observed; however, source localization extending to various cortical regions also was identified. This widespread pattern was more prominent in the ascending phase (P = .038). The study results showed that JME includes widespread cortical regions over the frontal lobe. The current concept of generalized epilepsy and pathophysiology in JME needs further validation.

Network connectivity in primary generalized tonic-clonic seizures.

OBJECTIVE: To determine EEG spatiospectral activation and connectivity in the generalized tonic-clonic seizure (GTCS) semiological subtypes. METHODS: 39 patients with genetic generalized epilepsy (GGE) who had GTCS (n = 58) during video-EEG monitoring were identified in the Vanderbilt Epilepsy database. GTCSs were classified as absence tonic-clonic, myoclonic tonic-clonic, or tonic-clonic. Patient characteristics and semiological features were compared. Spectral power and node degree, a network measure of connectivity, were calculated at two seizure epochs, electrographic and tonic-start. RESULTS: Different GTCS subtypes occurred within individual patients. At electrographic-onset, all subtypes activated midline frontal cortex at delta/theta and beta frequencies but differed in network connectivity. In all subtypes, GTCS evolution from electrographic to tonic-start associated with preserved beta frequency spectral power, but reduced connectivity and delta/theta power. CONCLUSIONS: Our findings suggest that at GTCS onset, the subtypes activate similar cortical regions and their different initial semiologies relate to their distinct onset long-range connectivity. Upon transition to the tonic-start epoch, the ictal activity is predominantly conveyed by ß frequency activity and connectivity. SIGNIFICANCE: Future neurostimulation therapies for medically intractable GTCSs may target the same brain regions for all GTCS subtypes and may be most effective prior to the tonic-start epoch.

Combined electrophysiological and morphological phenotypes in patients with genetic generalized epilepsy and their healthy siblings.

OBJECTIVE: Genetic generalized epilepsy (GGE) is characterized by aberrant neuronal dynamics and subtle structural alterations. We evaluated whether a combination of magnetic and electrical neuronal signals and cortical thickness would provide complementary information about network pathology in GGE. We also investigated whether these imaging phenotypes were present in healthy siblings of the patients to test for genetic influence. METHODS: In this cross-sectional study, we analyzed 5 min of resting state data acquired using electroencephalography (EEG) and magnetoencephalography (MEG) in patients, their siblings, and controls, matched for age and sex. We computed source-reconstructed power and connectivity in six frequency bands (1-40 Hz) and cortical thickness (derived from magnetic resonance imaging). Group differences were assessed using permutation analysis of linear models for each modality separately and jointly for all modalities using a nonparametric combination. RESULTS: Patients with GGE (n = 23) had higher power than controls (n = 35) in all frequencies, with a more posterior focus in MEG than EEG. Connectivity was also increased, particularly in frontotemporal and central regions in theta (strongest in EEG) and low beta frequencies (strongest in MEG), which was eminent in the joint EEG/MEG analysis. EEG showed weaker connectivity differences in higher frequencies, possibly related to drug effects. The inclusion of cortical thickness reinforced group differences in connectivity and power. Siblings (n = 18) had functional and structural patterns intermediate between those of patients and controls. SIGNIFICANCE: EEG detected increased connectivity and power in GGE similar to MEG, but with different spectral sensitivity, highlighting the importance of theta and beta oscillations. Cortical thickness reductions in GGE corresponded to functional imaging patterns. Our multimodal approach extends the understanding of the resting state in GGE and points to genetic underpinnings of the imaging markers studied, providing new insights into the causes and consequences of epilepsy.

Altered Structural Brain Networks in Refractory and Nonrefractory Idiopathic Generalized Epilepsy.

Introduction: Idiopathic generalized epilepsy (IGE) is a collection of generalized nonlesional epileptic network disorders. Around 20-40% of patients with IGE are refractory to antiseizure medication, and mechanisms underlying refractoriness are poorly understood. Here, we characterize structural brain network alterations and determine whether network alterations differ between patients with refractory and nonrefractory IGE. Methods: Thirty-three patients with IGE (10 nonrefractory and 23 refractory) and 39 age- and sex-matched healthy controls were studied. Network nodes were segmented from T1-weighted images, while connections between these nodes (edges) were reconstructed from diffusion magnetic resonance imaging (MRI). Diffusion networks of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and streamline count (Count) were studied. Differences between all patients, refractory, nonrefractory, and control groups were computed using network-based statistics. Nodal volume differences between groups were computed using Cohen's d effect size calculation. Results: Patients had significantly decreased bihemispheric FA and Count networks and increased MD and RD networks compared with controls. Alterations in network architecture, with respect to controls, differed depending on treatment outcome, including predominant FA network alterations in refractory IGE and increased nodal volume in nonrefractory IGE. Diffusion MRI networks were not influenced by nodal volume. Discussion: Although a nonlesional disorder, patients with IGE have bihemispheric structural network alterations that may differ between patients with refractory and nonrefractory IGE. Given that distinct nodal volume and FA network alterations were observed between treatment outcome groups, a multifaceted network analysis may be useful for identifying imaging biomarkers of refractory IGE.

Probabilistic mapping of thalamic nuclei and thalamocortical functional connectivity in idiopathic generalised epilepsy.

It is well established that abnormal thalamocortical systems play an important role in the generation and maintenance of primary generalised seizures. However, it is currently unknown which thalamic nuclei and how nuclear-specific thalamocortical functional connectivity are differentially impacted in patients with medically refractory and non-refractory idiopathic generalised epilepsy (IGE). In the present study, we performed structural and resting-state functional magnetic resonance imaging (MRI) in patients with refractory and non-refractory IGE, segmented the thalamus into constituent nuclear regions using a probabilistic MRI segmentation method and determined thalamocortical functional connectivity using seed-to-voxel connectivity analyses. We report significant volume reduction of the left and right anterior thalamic nuclei only in patients with refractory IGE. Compared to healthy controls, patients with refractory and non-refractory IGE had significant alterations of functional connectivity between the centromedian nucleus and cortex, but only patients with refractory IGE had altered cortical connectivity with the ventral lateral nuclear group. Patients with refractory IGE had significantly increased functional connectivity between the left and right ventral lateral posterior nuclei and cortical regions compared to patients with non-refractory IGE. Cortical effects were predominantly located in the frontal lobe. Atrophy of the anterior thalamic nuclei and resting-state functional hyperconnectivity between ventral lateral nuclei and cerebral cortex may be imaging markers of pharmacoresistance in patients with IGE. These structural and functional abnormalities fit well with the known importance of thalamocortical systems in the generation and maintenance of primary generalised seizures, and the increasing recognition of the importance of limbic pathways in IGE.

Distinct effects of the basal ganglia and cerebellum on the thalamocortical pathway in idiopathic generalized epilepsy.

The aberrant thalamocortical pathways of epilepsy have been detected recently, while its underlying effects on epilepsy are still not well understood. Exploring pathoglytic changes in two important thalamocortical pathways, that is, the basal ganglia (BG)-thalamocortical and the cerebellum-thalamocortical pathways, in people with idiopathic generalized epilepsy (IGE), could deepen our understanding on the pathological mechanism of this disease. These two pathways were reconstructed and investigated in this study by combining diffusion and functional MRI. Both pathways showed connectivity changes with the perception and cognition systems in patients. Consistent functional connectivity (FC) changes were observed mainly in perception regions, revealing the aberrant integration of sensorimotor and visual information in IGE. The pathway-specific FC alterations in high-order regions give neuroimaging evidence of the neural mechanisms of cognitive impairment and epileptic activities in IGE. Abnormal functional and structural integration of cerebellum, basal ganglia and thalamus could result in an imbalance of inhibition and excitability in brain systems of IGE. This study located the regulated cortical regions of BG and cerebellum which been affected in IGE, established possible links between the neuroimaging findings and epileptic symptoms, and enriched the understanding of the regulatory effects of BG and cerebellum on epilepsy.

Connective profiles and antagonism between dynamic and static connectivity underlying generalized epilepsy.

This study aims to characterize the connective profiles and the coupling relationship between dynamic and static functional connectivity (dFC and sFC) in large-scale brain networks in patients with generalized epilepsy (GE). Functional, structural and diffuse MRI data were collected from 83 patients with GE and 106 matched healthy controls (HC). Resting-state BOLD time course was deconvolved to neural time course using a blind hemodynamic deconvolution method. Then, five connective profiles, including the structural connectivity (SC) and BOLD/neural time course-derived sFC/dFC networks, were constructed based on the proposed whole brain atlas. Network-level weighted correlation probability (NWCP) were proposed to evaluate the association between dFC and sFC. Both the BOLD signal and neural time course showed highly concordant findings and the present study emphasized the consistent findings between two functional approaches. The patients with GE showed hypervariability and enhancement of FC, and notably decreased SC in the subcortical network. Besides, increased dFC, weaker anatomic links, and complex alterations of sFC were observed in the default mode network of GE. Moreover, significantly increased SC and predominantly increased sFC were found in the frontoparietal network. Remarkably, antagonism between dFC and sFC was observed in large-scale networks in HC, while patients with GE showed significantly decreased antagonism in core epileptic networks. In sum, our study revealed distinct connective profiles in different epileptic networks and provided new clues to the brain network mechanism of epilepsy from the perspective of antagonism between dynamic and static functional connectivity.

Systematically disrupted functional gradient of the cortical connectome in generalized epilepsy: Initial discovery and independent sample replication.

Genetic generalized epilepsy is a network disorder typically involving distributed areas identified by classical neuroanatomy. However, the finer topological relationships in terms of continuous spatial arrangement between these systems are still ambiguous. Connectome gradients provide the topological representations of human macroscale hierarchy in an abstract low-dimensional space by embedding the functional connectome into a set of axes. Leveraging connectome gradients, we systematically scrutinized abnormalities of functional connectome gradient in patients with genetic generalized epilepsy with tonic-clonic seizure (GGE-GTCS, n = 78) compared to healthy controls (HC, n = 85), and further examined the reproducibility across multiple processing configurations and in an independent validation sample (patients with GGE-GTCS, n = 28; HC, n = 31). Our findings demonstrated an extended principal gradient at different spatial scales, network-level and vertex-level, in patients with GGE-GTCS. We found consistent results across processing parameters and in validation sample. The extended principal gradient revealed the excessive functional segregation between unimodal and transmodal systems associated with duration of epilepsy and age at seizure onset in patients. Furthermore, the connectivity profile of regions with abnormal principal gradients verified the disrupted functional hierarchy revealed by gradients. Together, our findings provided a novel view of functional system hierarchy alterations, which facilitated a continuous spatial arrangement of macroscale networks, to increase our understanding of the functional connectome hierarchy in generalized epilepsy.

Co-existence of idiopathic generalized and focal epilepsy suggested by simultaneous EEG-fMRI: a case report.

We present a rare patient clinically suspected to have mixed idiopathic generalized and focal epilepsy, which was supported by BOLD pattern based on EEG-fMRI. A 37-year-old female with three types of refractory seizures starting at age six - tonic with breathing difficulties and confusion, generalized tonic-clonic, and focal with brief impairment of awareness and versive head movement, initially thought to represent atypical absences - was evaluated by EEG-fMRI. She was also shown to have three types of interictal epileptic discharges: generalized spike or polyspikes and slow waves, and left fronto-temporal and right fronto-temporal discharges. We assessed BOLD activation and deactivation for each type. For generalized patterns, the BOLD activation and deactivation were typical of that seen in primary generalized epilepsy. Whereas maximum activation for left fronto-temporal EEG patterns was observed in the left superior frontal gyrus and posterior superior temporal gyrus, maximum activation for right fronto-temporal patterns was bilateral in the right posterior middle temporal gyrus and left posterior middle temporal gyrus. The EEG-fMRI results suggested that the patient had both refractory idiopathic generalized and focal epilepsy, and not a generalized epilepsy originating from a focus.

Dynamic Temporospatial Patterns of Functional Connectivity and Alterations in Idiopathic Generalized Epilepsy.

The dynamic profile of brain function has received much attention in recent years and is also a focus in the study of epilepsy. The present study aims to integrate the dynamics of temporal and spatial characteristics to provide comprehensive and novel understanding of epileptic dynamics. Resting state fMRI data were collected from eighty-three patients with idiopathic generalized epilepsy (IGE) and 87 healthy controls (HC). Specifically, we explored the temporal and spatial variation of functional connectivity density (tvFCD and svFCD) in the whole brain. Using a sliding-window approach, for a given region, the standard variation of the FCD series was calculated as the tvFCD and the variation of voxel-wise spatial distribution was calculated as the svFCD. We found primary, high-level, and sub-cortical networks demonstrated distinct tvFCD and svFCD patterns in HC. In general, the high-level networks showed the highest variation, the subcortical and primary networks showed moderate variation, and the limbic system showed the lowest variation. Relative to HC, the patients with IGE showed weaken temporal and enhanced spatial variation in the default mode network and weaken temporospatial variation in the subcortical network. Besides, enhanced temporospatial variation in sensorimotor and high-level networks was also observed in patients. The hyper-synchronization of specific brain networks was inferred to be associated with the phenomenon responsible for the intrinsic propensity of generation and propagation of epileptic activities. The disrupted dynamic characteristics of sensorimotor and high-level networks might potentially contribute to the driven motion and cognition phenotypes in patients. In all, presently provided evidence from the temporospatial variation of functional interaction shed light on the dynamics underlying neuropathological profiles of epilepsy.

Seizure outcome during bilateral, continuous, thalamic centromedian nuclei deep brain stimulation in patients with generalized epilepsy: a prospective, open-label study.

OBJECTIVE: We report on the seizure frequency and attention outcome during thalamic centromedian stimulation (CM-DBS) in patients with refractory generalized epilepsy (GE). METHODS: Twenty consecutive patients with GE who were submitted to CM-DBS and had at least one year of follow-up were prospectively studied. The CM was targeted bilaterally. Stimulation intensity was ramped up (bipolar, continuous, 130 Hz; 300µsec) until 4.5 V or until side effects developed. Contacts` position was determined on postoperative volumetric MRI scans. Attention was qualitatively evaluated using the SNAP-IV (Swanson, Nolan, and Pelham) questionnaire. Patients were considered responders during CM-DBS if an at least 50% seizure frequency reduction was obtained compared to baseline. RESULTS: Median age was 15.5 years (13 males). Median follow-up time was 2.55 years. EEG disclosed generalized spike-and wave discharges in all patients. MRI was normal in 10 patients, showed diffuse atrophy in 6 patients, and showed abnormalities in 4 patients (3 patients had bilateral cortical development abnormalities and one had unilateral hemispheric atrophy). Patients presented with daily multiple seizure types (8 to 66 per day; median: 37), including tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic seizures. Mean DBS intensity was 4.3 V. An insertional effect was noted in 14 patients. CM-DBS was able to significantly reduce the frequency of tonic (p < 0.001), atypical absence seizures (p < 0.001), atonic seizures (p = 0.001) and bilateral generalized tonic-clonic seizures (p = 0.004). One patient became seizure-free. Ninety percent of the patients were considered responders (>50% seizure frequency reduction). All patients showed some improvement in attention. The mean number of items in which improvement was noted in the SNAP-IV questionnaire was 4.8. There was a significant relationship between overall seizure frequency reduction and improvement of attention (p = 0.033). DISCUSSION: This prospective, open label study included a large, homogeneous cohort and provided evidence on the efficacy of CM-DBS in reducing the seizure burden and increasing attention in patients with refractory generalized epilepsy.