Epileptic Network Research Articles

Research progress in brain connectivity based on functional magnetic resonance approaches to the pathophysiology and comorbidity of epilepsy

<p indent="0mm">Epilepsy results from disruption of the homeostatic network system in the brain and has been recognized as a brain network disorder. Abnormal networks play a key role in the occurrence and development of epilepsy. Functional magnetic resonance-based approaches to brain connectivity are ideal techniques for exploring the complex images of epilepsy networks. The human brain networks primarily include the intrinsic connectivity network, the morphometric structural network, and the diffusion tractography-based anatomical connectivity network. Studies have provided insight into the physiopathogenesis of the epileptic network underlying focal epilepsy, genetic generalized epilepsy, and specific epileptic syndromes. Many recent studies have investigated the role of abnormal brain networks in the pathophysiological mechanisms of various types of epilepsy and their relationship with clinical prognosis to discover targets for clinical intervention and prognosis prediction and have shown promise in localizing epilepsy networks and lesions. Additionally, an increasing number of studies have focused on the deleterious effects of epilepsy on other brain networks to help explain cognitive deficits and psychiatric symptoms. Anti-epileptic treatment studies have yielded information about the side effects and restoration of functional abnormalities after using drugs. Moreover, surgery is the main treatment method for refractory epilepsy. Imaging studies are of great significance for exploring the factors that affect the outcome of surgery and developing reliable and feasible efficacy prediction tools. However, large-scale clinical studies with long-term follow-ups are still needed to further verify its effectiveness and accuracy.

Distinct connectivity patterns in human medial parietal cortices: Evidence from standardized connectivity map using cortico-cortical evoked potential

The medial parietal cortices are components of the default mode network (DMN), which are active in the resting state. The medial parietal cortices include the precuneus and the dorsal posterior cingulate cortex (dPCC). Few studies have mentioned differences in the connectivity in the medial parietal cortices, and these differences have not yet been precisely elucidated. Electrophysiological connectivity is essential for understanding cortical function or functional differences. Since little is known about electrophysiological connections from the medial parietal cortices in humans, we evaluated distinct connectivity patterns in the medial parietal cortices by constructing a standardized connectivity map using cortico-cortical evoked potential (CCEP). This study included nine patients with partial epilepsy or a brain tumor who underwent chronic intracranial electrode placement covering the medial parietal cortices. Single-pulse electrical stimuli were delivered to the medial parietal cortices (38 pairs of electrodes). Responses were standardized using the z-score of the baseline activity, and a response density map was constructed in the Montreal Neurological Institutes (MNI) space. The precuneus tended to connect with the inferior parietal lobule (IPL), the occipital cortex, superior parietal lobule (SPL), and the dorsal premotor area (PMd) (the four most active regions, in descending order), while the dPCC tended to connect to the middle cingulate cortex, SPL, precuneus, and IPL. The connectivity pattern differs significantly between the precuneus and dPCC stimulation (p<0.05). Regarding each part of the medial parietal cortices, the distributions of parts of CCEP responses resembled those of the functional connectivity database. Based on how the dPCC was connected to the medial frontal area, SPL, and IPL, its connectivity pattern could not be explained by DMN alone, but suggested a mixture of DMN and the frontoparietal cognitive network. These findings improve our understanding of the connectivity profile within the medial parietal cortices. The electrophysiological connectivity is the basis of propagation of electrical activities in patients with epilepsy. In addition, it helps us to better understand the epileptic network arising from the medial parietal cortices.

Signal processing and computational modeling for interpretation of SEEG-recorded interictal epileptiform discharges in epileptogenic and non-epileptogenic zones

Objective. In partial epilepsies, interictal epileptiform discharges (IEDs) are paroxysmal events observed in epileptogenic zone (EZ) and non-epileptogenic zone (NEZ). IEDs’ generation and recurrence are subject to different hypotheses: they appear through glutamatergic and gamma-aminobutyric acidergic (GABAergic) processes; they may trigger seizures or prevent seizure propagation. This paper focuses on a specific class of IEDs, spike-waves (SWs), characterized by a short-duration spike followed by a longer duration wave, both of the same polarity. Signal analysis and neurophysiological mathematical models are used to interpret puzzling IED generation. Approach. Interictal activity was recorded by intracranial stereo-electroencephalography (SEEG) electrodes in five different patients. SEEG experts identified the epileptic and non-epileptic zones in which IEDs were detected. After quantifying spatial and temporal features of the detected IEDs, the most significant features for classifying epileptic and non-epileptic zones were determined. A neurophysiologically-plausible mathematical model was then introduced to simulate the IEDs and understand the underlying differences observed in epileptic and non-epileptic zone IEDs. Main results. Two classes of SWs were identified according to subtle differences in morphology and timing of the spike and wave component. Results showed that type-1 SWs were generated in epileptogenic regions also involved at seizure onset, while type-2 SWs were produced in the propagation or non-involved areas. The modeling study indicated that synaptic kinetics, cortical organization, and network interactions determined the morphology of the simulated SEEG signals. Modeling results suggested that the IED morphologies were linked to the degree of preserved inhibition. Significance. This work contributes to the understanding of different mechanisms generating IEDs in epileptic networks. The combination of signal analysis and computational models provides an efficient framework for exploring IEDs in partial epilepsies and classifying EZ and NEZ.

Hyperperfusion in the cerebellum lobule VIIb in patients with epileptic seizures

BackgroundThe cerebellum plays an important role in motor control, however, its involvement in epilepsy has not been fully understood. Arterial spin labelling perfusion magnetic resonance image (ASL) is a noninvasive method to evaluate cerebral and cerebellar blood flow. We investigated cerebellar perfusion in patients with epileptic seizures using ASL.MethodsAdult patients with epileptic seizures who underwent ASL in three post labeling delay (PLD) conditions (1525, 1800, and 2500 msec) and conventional electroencephalography (EEG) on the same day were investigated. Clinical and EEG characteristics of them were retrospectively analyzed.ResultsSix patients (6 women, age; 36.2 ± 17.9 years (mean ± SD)) showed hyperperfusion in selective areas in the cerebellar paravermis of lobule VIIb. One patient with generalized epilepsy (tentative diagnosis of juvenile myoclonic epilepsy or epilepsy with myoclonic absences) showed unilateral hypoperfusion in PLD 1525 msec and hyperperfusion in PLD 1800 and 2500 msec at the area while EEG showed generalized spike-wave complexes. After successful treatment, these perfusion abnormalities disappeared. In two patients with focal epilepsy manifesting with asymmetrical motor symptoms, cerebellar hyperperfusion was found on the opposite side to the seizure focus estimated by seizure semiology. Besides hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient.ConclusionThe cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic network in humans. Cerebellar perfusion abnormalities can be associated with neurovascular coupling via capillary bed.

Immediate Effects of Vagal Nerve Stimulation in Drug-Resistant Epilepsy Revealed by Magnetoencephalographic Recordings.

Objective: Vagus nerve stimulation (VNS) has been a neuromodulatory option for treating drug-resistant epilepsy (DRE), but its mechanism remains unclear. To obtain insight into the mechanism by which VNS reduces epileptic seizures, the immediate effects of VNS in brain networks of DRE patients were investigated when the patients' vagal nerve stimulators were turned on. Methods: The brain network properties of 14 DRE patients with a vagal nerve stimulator and 14 healthy controls were evaluated using magnetoencephalography recordings for 6 main frequency bands. Results: Compared with healthy controls, DRE patients exhibited significant increases in functional connectivity in the theta, alpha, beta, and gamma bands and significant reductions in the small-world measure in the theta and beta bands. During periods when patients' vagal nerve stimulators were turned on, DRE patients showed significant reductions in functional connectivity in the theta and alpha bands and a significant increase in the small-world measure in the theta band when compared with periods when patients' vagal nerve stimulators were turned off. Conclusions: Our results indicate that the brain networks of DRE patients were pathologically hypersynchronous and instantaneous VNS can decrease the synchronization of brain networks of epileptic patients, which might play a key role in the mechanism by which VNS reduces epileptic seizures. In the theta band, instantaneous VNS can increase the network efficiency of DRE patients, and the increment in network efficiency may be helpful for improving brain cognitive function in epileptic patients. Impact statement For the first time, we investigated the immediate effects of vagus nerve stimulation (VNS) in the brain networks of drug-resistant epilepsy patients using magnetoencephalography. Our results show that instantaneous VNS can decrease the hypersynchronization of epileptic networks and increase the network efficiency of epileptic patients. Our results are helpful in understanding the mechanism of action by which VNS reduces epileptic seizures and improves the cognitive function in epileptic patients and the brain network reorganization caused by long-term VNS.

Levetiracetam Modulates EEG Microstates in Temporal Lobe Epilepsy

To determine the effects of Levetiracetam (LEV) therapy using EEG microstates analysis in a population of newly diagnosed Temporal Lobe Epilepsy (TLE) patients. We hypothesized that the impact of LEV therapy on the electrical activity of the brain can be globally explored using EEG microstates. Twenty-seven patients with TLE were examined. We performed resting-state microstate EEG analysis and compared microstate metrics between the EEG performed at baseline (EEGpre) and after 3 months of LEV therapy (EEGpost). The microstates A, B, C and D emerged as the most stable. LEV induced a reduction of microstate B and D mean duration and occurrence per second (p < 0.01). Additionally, LEV treatment increased the directional predominance of microstate A to C and microstate B to D (p = 0.01). LEV treatment induces a modulation of resting-state EEG microstates in newly diagnosed TLE patients. Microstates analysis has the potential to identify a neurophysiological indicator of LEV therapeutic activity. This study of EEG microstates in people with epilepsy opens an interesting path to identify potential LEV activity biomarkers that may involve increased neuronal inhibition of the epileptic network.

Metabolism and Intracranial Epileptogenicity in Temporal Lobe Long-Term Epilepsy-Associated Tumor.

Brain tumors are common in epilepsy surgery and frequently occur in the temporal lobe, but the optimal surgical strategies to remove the tumor and epileptogenic zone remain controversial. We aim at illustrating the positron emission tomography (PET) metabolism and the stereoelectroencephalography (SEEG) epileptogenicity of temporal lobe long-term epilepsy-associated tumors (LEAT). In this study, 70 patients and 25 healthy controls were included. Our analysis leveraged group-level analysis to reveal the whole-brain metabolic pattern of temporal lobe LEATs. The SEEG-based epileptogenicity mapping was performed to verify the PET findings in the epileptic network. Compared to controls, patients with a temporal lobe LEAT showed a more widespread epileptic network based on 18FDG-PET in patients with a mesial temporal lobe LEAT than in those with a lateral temporal lobe LEAT. The significant brain clusters mainly involved the paracentral lobule (ANOVA F = 9.731, p < 0.001), caudate nucleus (ANOVA F = 20.749, p < 0.001), putamen (Kruskal–Wallis H = 19.258, p < 0.001), and thalamus (ANOVA F = 4.754, p = 0.011). Subgroup analysis and SEEG-based epileptogenicity mapping are similar to the metabolic pattern. Our findings demonstrate the metabolic and electrophysiological organization of the temporal lobe LEAT epileptic network, which may assist in a patient-specific surgical strategy.

Epileptic networks neurosurgery: connectomes and hubs

Epileptic networks neurosurgery: connectomes and hubs

Utility of Presurgical Evaluation Using Stereoelectroencephalography(SEEG)

Precise localization of the "epileptogenic zone(EZ)" is the goal of presurgical investigations in patients with drug-resistant focal epilepsy. Intracranial electroencephalography recordings are required when noninvasive evaluation results are not consistent. Although subdural grid electrodes(SDG)have been widely used in Japan, stereoelectroencephalography(SEEG)has been recently introduced. The principle of SEEG is based on anatomo-electro-clinical correlations to investigate surgical hypotheses that are primarily driven by the analysis of seizure semiology as well as other noninvasive investigations. The most important element of the SEEG methodology is to formulate preimplantation electrode trajectories considering the anatomo-electro-clinical correlations of epileptic seizures. If the preimplantation hypotheses are insufficient or incorrect, SEEG recordings will not identify the EZ. A detailed analysis of seizure semiology with respect to anatomo-electro-clinical correlates, particularly including various deep structures, such as the insular, operculum, and cingulate cortex, forms the basis of the implantation strategy for SEEG. The strategy of implantation is not to map the lobes/lobules but the epileptic networks, which usually involve multiple lobes, indicating that the theory of SEEG is completely different from that of SDG. Herein, we introduce the basics of SEEG, especially presurgical evaluations, with a representative case presentation.

Jeavons syndrome featured with visual sensitivity existing as occipital cortex originating focal-to-generalized continuum epilepsy.

To study the relationship between eye closure sensitivity (ECLS), photosensitivity, and the mechanism of Jeavons syndrome (JS). The interictal and the ictal epileptiform discharges (EDs) of 80 patients with electroencephalograms were classified (I: focal posterior EDs; II: the posterior spread into the frontal EDs; and III: generalized EDs) and analyzed under different provoked conditions. During the interictal and the ictal period, the positive rates of ECLS were higher than those of photosensitivity (100% vs 57.5%, P=0.001; 97.5% vs 27.4%, P=0.001). After a one-year interval, eyelid-myoclonia with ECLS remitted in 16 out of 21 patients (P=0.002), and eyelid-myoclonia with photo-convulsion response (PCR) disappeared in all the previous six patients (P=0.021). For the interictal EDs with ECLS, grade I accounted for 11.2%; grade I, II, and III 51.3%; and grade III 32.5%. Interictal EDs classification of photosensitivity showed a similar trend as that of ECLS. For the ictal EDs, grade I accounted for 10.2% of patients with ECLS and 6.7% of patients with PCR; grade I, II, and III, 33.3% of patients with ECLS and 46.6% of patients with PCR; and grade III, 53.9% of patients with ECLS and 40% of patients with PCR. ECLS was more common than photosensitivity in JS. Photosensitivity was more likely to disappear than ECLS. Both eye closure and intermittent-photic-stimulation could induce three grades of EDs, confirming that visual stimuli could trigger occipital cortex originating epileptic neural network to varying degrees, which further recognizes JS as another continuum epilepsy.

Clinical validation of magnetoencephalography network analysis for presurgical epilepsy evaluation

ObjectiveTo clinically validate the connectivity-based magnetoencephalography (MEG) analyses to identify seizure onset zone (SOZ) with comparing to equivalent current dipole (ECD). MethodsThe ECD cluster was quantitatively analyzed by calculating the centroid of the cluster and maximum distance (the largest distance between all dipoles). The “primary hub” was determined by the highest eigencentrality. The distribution of nodes in the top 5% of eigenvector centrality values was quantified by generating the convex hull between each node. ResultsThirty-one patients who underwent MEG, stereotactic-EEG, and focal surgery were included. The primary hub was significantly closer to the sEEG-defined SOZ compared to ECD (p = 0.009). The seizure freedom positive and negative predictive values of complete ECD cluster and primary hub resections did not significantly differ, although complete resection of the primary hub showed slightly better negative predictive value (ECD: 50.0% NPV, hub: 64.7% NPV). Both quantitative ECD and functional connectivity analyses suggested that spatially restricted dipole distributions and higher connectivity in a smaller region correlate with better seizure outcomes. ConclusionsOur findings suggest that MEG network analysis could be a valuable complement to the ECD methods. SignificanceThe results of this study are an important step towards using non-invasive neurophysiologic recordings to accurately define the epileptic network.

Neuroimaging in the Epileptic Baboon

Characterization of baboon model of genetic generalized epilepsy (GGE) is driven both electroclinically and by successful adoption of neuroimaging platforms, such as magnetic resonance imaging (MRI) and positron emission tomography (PET). Based upon its phylogenetic proximity and similar brain anatomy to humans, the epileptic baboon provides an excellent translational model. Its relatively large brain size compared to smaller nonhuman primates or rodents, a gyrencephalic structure compared to lissencephalic organization of rodent brains, and the availability of a large pedigreed colony allows exploration of neuroimaging markers of diseases. Similar to human idiopathic generalized epilepsy (IGE), structural imaging in the baboon is usually normal in individual subjects, but gray matter volume/concentration (GMV/GMC) changes are reported by statistical parametric mapping (SPM) analyses. Functional neuroimaging has been effective for mapping the photoepileptic responses, the epileptic network, altered functional connectivity of physiological networks, and the effects of anti-seizure therapies. This review will provide insights into our current understanding the baboon model of GGE through functional and structural imaging.

Patterns of hypometabolism in frontal lobe epilepsy originating in different frontal regions.

ObjectivesAnalysis of FDG‐PET imaging commonly shows that hypometabolism extends into extra‐epileptogenic zones (extra‐EZ). This study investigates the distribution patterns of hypometabolism in frontal lobe epilepsy (FLE) originating in different frontal regions.MethodsSixty‐four patients with FLE were grouped by EZ localization according to Brodmann areas (BAs): Group 1 (the frontal motor and premotor area), BAs 4, 6, and 8; Group 2 (the inferior frontal gyrus and opercular area), BAs 44, 45, and 47; Group 3 (the dorsal prefrontal area), BAs 9, 10, 11, and 46; and Group 4 (the medial frontal and anterior cingulate gyrus), BAs 32 and 24. Regions of extra‐EZ hypometabolism were statistically analyzed between FLE groups and healthy controls. Correlation analysis was performed to identify relationships between the intensity of hypometabolism and clinical characteristics.ResultsSignificant hypometabolism in the ipsilateral (Groups 1 and 4) or bilateral (Groups 2 and 3) anterior insulae was found. Groups 1 and 4 presented with limited distribution of extra‐EZ hypometabolism, whereas Groups 2 and 3 showed widely distributed extra‐EZ hypometabolism in the rectus gyrus, cingulate gyrus, and other regions. Additionally, the intensity of hypometabolism was correlated with epilepsy duration in Groups 2 and 3.ConclusionsAll FLE groups showed hypometabolism in the anterior insula. In addition, distinct patterns of extra‐EZ hypometabolism were identified for each FLE group. This quantitative FDG‐PET analysis expanded our understanding of the topography of epileptic networks and can guide EZ localization in the future.

Unblock the Block! Preventing Inhibitory Failure to Maintain Inhibitory Restraint.

Disrupting Epileptiform Activity by Preventing Parvalbumin Interneuron Depolarization Block Călin A, Ilie AS, Akerman CJ. J Neurosci. 2021;41(45):9452-9465. doi:10.1523/JNEUROSCI.1002-20.2021. Epub 2021 Oct 5.Inhibitory synaptic mechanisms oppose epileptic network activity in the brain. The breakdown in this inhibitory restraint and propagation of seizure activity has been linked to the overwhelming of feedforward inhibition, which is provided in large part by parvalbumin-expressing (PV) interneurons in the cortex. The underlying cellular processes therefore represent potential targets for understanding and preventing the propagation of seizure activity. Here we use an optogenetic strategy to test the hypothesis that depolarization block in PV interneurons is a significant factor during the loss of inhibitory restraint. Depolarization block results from the inactivation of voltage-gated sodium channels and leads to impaired action potential firing. We used focal NMDA stimulation to elicit reproducible epileptiform discharges in hippocampal organotypic brain slices from male and female mice and combined this with targeted recordings from defined neuronal populations. Simultaneous patch-clamp recordings from PV interneurons and pyramidal neurons revealed epileptiform activity that was associated with an overwhelming of inhibitory synaptic mechanisms and the emergence of a partial, and then complete, depolarization block in PV interneurons. To counteract this depolarization block, we developed protocols for eliciting pulsed membrane hyperpolarization via the inhibitory opsin, archaerhodopsin. This optical approach was effective in counteracting cumulative inactivation of voltage-gated channels, maintaining PV interneuron action potential firing properties during the inhibitory restraint period, and reducing the probability of initiating epileptiform activity. These experiments support the idea that depolarization block is a point of weakness in feedforward inhibitory synaptic mechanisms and represents a target for preventing the initiation and spread of seizure activity.

ID:16560 Reciprocal Functional Connectivity of Amygdala in Mesial Temporal Lobe Epilepsy: A Single-Pulse Electrical Stimulation Study

The amygdala is known to be an important component of the epileptic network in patients with mesial temporal lobe epilepsy (mTLE). Using single-pulse electrical stimulation (SPES), the reciprocal functional connectivity (i.e., outward connectivity vs. inward connectivity) of the amygdala to the hippocampus has been well characterized.1 However, to our knowledge, the frequency-specific and time-varying components of amygdala reciprocal connectivity to the rest of the brain has not been well characterized with SPES.

Withdrawal seizures vs on-medication seizures: an intracranial EEG recording case report

BackgroundIt has long been an interesting question of whether withdrawal seizures in epileptic patients differ from habitual seizures in terms of semiology and electrophysiology.Case presentationHere, we addressed this issue in a 40 year-old woman with drug-resistant focal epilepsy monitored by presurgical intracranial EEG. As a part of this routine pre-operative investigation, anti-seizure medications (ASMs) were halted; as a result, multiple withdrawal seizures were recorded before ASM readministration. During 4 days of invasive monitoring, we noticed three different phases in seizure organization: Acute withdrawal seizure (AWS): The first recorded seizure 10h after the implantation; the stabilized withdrawal seizures (SWS): seven habitual seizures recorded from 24h post implantation to readministration of ASMs; and the Non-withdrawal seizures (NWS): ten seizures recorded 24h after readministration of ASMs. AWS and SWS had the same semiology and same epileptic network, but the propagation time from the temporal pole to the para-hippocampal gyrus (PHG) and hippocampus ranged from no latency in AWS to up to 50 s in SWS. NWS were electrographic seizures, without any apparent clinical manifestation. Seizure onset in this type of seizure, as in the first two types, was in the temporal pole. However, NWS could last up to 3 min without involving the PHG or hippocampus.ConclusionsWe concluded that in acute withdrawal seizures the propagation time of epileptic activity is significantly reduced without affecting ictal organization network or semiology. Furthermore, ASM in this case had a remarkable influence on propagation rather than initiation of epileptic activity.

Normative intracranial EEG maps epileptogenic tissues in focal epilepsy.

Planning surgery for patients with medically refractory epilepsy often requires recording seizures using intracranial EEG. Quantitative measures derived from interictal intracranial EEG yield potentially appealing biomarkers to guide these surgical procedures; however, their utility is limited by the sparsity of electrode implantation as well as the normal confounds of spatiotemporally varying neural activity and connectivity. We propose that comparing intracranial EEG recordings to a normative atlas of intracranial EEG activity and connectivity can reliably map abnormal regions, identify targets for invasive treatment and increase our understanding of human epilepsy. Merging data from the Penn Epilepsy Center and a public database from the Montreal Neurological Institute, we aggregated interictal intracranial EEG retrospectively across 166 subjects comprising >5000 channels. For each channel, we calculated the normalized spectral power and coherence in each canonical frequency band. We constructed an intracranial EEG atlas by mapping the distribution of each feature across the brain and tested the atlas against data from novel patients by generating a z-score for each channel. We demonstrate that for seizure onset zones within the mesial temporal lobe, measures of connectivity abnormality provide greater distinguishing value than univariate measures of abnormal neural activity. We also find that patients with a longer diagnosis of epilepsy have greater abnormalities in connectivity. By integrating measures of both single-channel activity and inter-regional functional connectivity, we find a better accuracy in predicting the seizure onset zones versus normal brain (area under the curve = 0.77) compared with either group of features alone. We propose that aggregating normative intracranial EEG data across epilepsy centres into a normative atlas provides a rigorous, quantitative method to map epileptic networks and guide invasive therapy. We publicly share our data, infrastructure and methods, and propose an international framework for leveraging big data in surgical planning for refractory epilepsy.

Real-Time &amp; Passive Localization of the Epileptic Network based on Single-Pulse Electrical Stimulation: Correlation with the standard of care and surgical outcomes UPMC HBM Lab (S7.004)

Real-Time &amp; Passive Localization of the Epileptic Network based on Single-Pulse Electrical Stimulation: Correlation with the standard of care and surgical outcomes UPMC HBM Lab (S7.004)

Double-edged Role of KNa Channels in Brain Tuning: Identifying Epileptogenic Network Micro-Macro Disconnection.

Epilepsy is commonly recognized as a disease driven by generalized hyperexcited and hypersynchronous neural activity. Sodium-activated potassium channels (KNa channels), which are encoded by the Slo 2.2 and Slo 2.1 genes, are widely expressed in the central nervous system and considered as "brakes" to adjust neuronal adaptation through regulating action potential threshold or after-hyperpolarization under physiological condition. However, the variants in KNa channels, especially gain-of-function variants, have been found in several childhood epileptic conditions. Most previous studies focused on mapping the epileptic network on the macroscopic scale while ignoring the value of microscopic changes. Notably, paradoxical role of KNa channels working on individual neuron/microcircuit and the macroscopic epileptic expression highlights the importance of understanding epileptogenic network through combining microscopic and macroscopic methods. Here, we first illustrated the molecular and physiological function of KNa channels on preclinical seizure models and patients with epilepsy. Next, we summarized current hypothesis on the potential role of KNa channels during seizures to provide essential insight into what emerged as a micro-macro disconnection at different levels. Additionally, we highlighted the potential utility of KNa channels as therapeutic targets for developing innovative anti-seizure medications.

The Optimal Target and Connectivity for Deep Brain Stimulation in Lennox-Gastaut Syndrome.

ObjectiveDeep brain stimulation (DBS) can reduce seizures in Lennox–Gastaut syndrome (LGS). However, little is known about the optimal target and whether efficacy depends on connectivity of the stimulation site. Using outcome data from the ESTEL trial, we aimed to determine the optimal target and connectivity for DBS in LGS.MethodsA total of 20 patients underwent bilateral DBS of the thalamic centromedian nucleus (CM). Outcome was percentage seizure reduction from baseline after 3 months of DBS, defined using three measures (monthly seizure diaries, 24‐hour scalp electroencephalography [EEG], and a novel diary‐EEG composite). Probabilistic stimulation mapping identified thalamic locations associated with higher/lower efficacy. Two substitute diffusion MRI datasets (a normative dataset from healthy subjects and a “disease‐matched” dataset from a separate group of LGS patients) were used to calculate structural connectivity between DBS sites and a map of areas known to express epileptic activity in LGS, derived from our previous EEG‐fMRI research.ResultsResults were similar across the three outcome measures. Stimulation was most efficacious in the anterior and inferolateral “parvocellular” CM border, extending into the ventral lateral nucleus (posterior subdivision). There was a positive association between diary‐EEG composite seizure reduction and connectivity to areas of a priori EEG‐fMRI activation, including premotor and prefrontal cortex, putamen, and pontine brainstem. In contrast, outcomes were not associated with baseline clinical variables.InterpretationEfficacious CM‐DBS for LGS is linked to stimulation of the parvocellular CM and the adjacent ventral lateral nucleus, and is associated with connectivity to, and thus likely modulation of, the “secondary epileptic network” underlying the shared electroclinical manifestations of LGS. ANN NEUROL 2022;92:61–74