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In the context of focal and drug-resistant epilepsy, surgical resection of the epileptogenic zone may be the only therapeutic option for reducing or suppressing seizures. In many such patients, intracranial stereo-EEG recordings remain the gold standard for the epilepsy surgery work-up. Assessing the extent of the epileptogenic zone and its organisation is a crucial objective, and requires advanced methods of signal processing. Over the last ten years, considerable efforts have been made to develop signal analysis techniques for characterising the connectivity between spatially distributed regions. The aim of this study was to evaluate the changes in dynamic connectivity pattern under inter-ictal, pre-ictal and ictal conditions using signals derived from stereo-EEG recordings of 10 patients with Taylor-type focal cortical dysplasia. A causal linear multivariate method – partial directed coherence – and indices derived from graph theory were used to characterise the synchronisation property of the lesional zone (corresponding to the epileptogenic zone in our patients) and to distinguish it from other regions involved in ictal activity or not. The results show that a significantly different connectivity pattern (mainly in the gamma band) distinguishes the epileptogenic zone from other cortical regions not only during the ictal event, but also during the inter- and pre-ictal periods. This indicates that the lesional nodes play a leading role in generating and propagating ictal EEG activity by acting as the hubs of the epileptic network originating and sustaining seizures. Our findings also indicate that the cortical regions beyond the dysplasia involved in the ictal activity essentially act as “secondary” generators of synchronous activity. The leading role of the lesional zone may account for the good post-surgical outcome of patients with type II focal cortical dysplasia as resecting the dysplasia removes the epileptogenic zone responsible for seizure organisation. Furthermore, our findings strongly suggest that advanced signal processing techniques aimed at studying synchronisation and characterising brain networks could substantially improve the pre-surgical evaluation of patients with focal epilepsy, even in cases without an associated anatomically detectable lesion. ►Type-II focal cortical dysplasia is a model of drug-resistant epilepsy. ►PDC and graph indexes are appropriate tools to localise the epileptogenic zone. ►The lesional nodes play a leading role in the epileptogenic network. ►An abnormal connectivity characterises the inter-ictal activity of the lesional leads. ►Cortical regions outside dysplasia act as secondary sources of synchronous activity.

ABSTRACT Background Focal cortical dysplasia (FCD) is a leading cause of drug‐resistant epilepsy, characterized by cortical malformations and aberrant neuronal‐glial interactions. Recently, the role of Liver X Receptor Beta (LXRβ) in neurodevelopment has attracted considerable attention, although its involvement in FCD pathogenesis remains unclear. Methods We established a freezing lesion‐cortical dysplasia (FL‐CD) model in neonatal mice to mimic the pathological features of FCD. We evaluated the expression of LXRβ and its downstream target, brain lipid‐binding protein (BLBP), using immunohistochemistry and Western blot analysis. LXRβ activation and inhibition were pharmacologically modulated to assess their effects on glial migration, differentiation and cortical electrophysiology. Electroencephalogram (EEG) recordings were analyzed for power spectral density and functional connectivity to further investigate alterations in cortical network activity. Results LXRβ and BLBP were significantly downregulated in the lesion cortex during early developmental stages. Activation of LXRβ reduced gliosis, promoted astrocytic differentiation, and modified cortical oscillatory activity, as evidenced by enhanced α power and gamma band functional connectivity, along with adjustments in the theta/beta ratio. In contrast, inhibition of LXRβ exacerbated gliosis and disrupted cortical network synchronization. Conclusion Our findings demonstrate that LXRβ plays a critical role in regulating glial migration, differentiation and cortical network remodeling in the FL‐CD model. Pharmacological modulation of LXRβ may offer a novel therapeutic strategy for restoring neural circuit stability in FCD, highlighting its potential as a molecular target for intervention in drug‐resistant epilepsy. LXRβ activation reduces gliosis, promotes astrocytic differentiation, and enhances cortical network synchronization in fetal cortical dysplasia, while its inhibition exacerbates disruptions. Pharmacological targeting of LXRβ emerges as a therapeutic strategy to restore neural circuit stability in drug‐resistant epilepsy.

This study aims to investigate the presurgical characteristics of different types of focal cortical dysplasia (FCD) and analyze the impact of these factors on postoperative seizure outcomes. A retrospective analysis was conducted on 77 patients with histopathologically confirmed FCD, categorized into types I, II, and III. Clinical data and preoperative examinations were compared among the three groups, with significant differences analyzed using multinomial logistic regression. Cox regression was used to assess the impact of presurgical factors on postoperative seizure outcomes. Significant differences were found between FCD types I, II, and III in lesion location (p = 0.001) and the use of stereoelectroencephalography (SEEG) (p = 0.017). FCD type II lesions were more often extratemporal and unilateral (p < 0.05), while type I patients were more likely to require SEEG (p < 0.05). A trend toward a lower risk of seizure recurrence was observed in patients over 21 years old at the time of surgery (HR = 0.376, p = 0.045), although this association was not statistically significant after Benjamini-Hochberg false discovery rate (FDR) adjustment (FDR-adjusted p = 0.495). FCD type II lesions are predominantly extratemporal and unilateral, while SEEG is more commonly needed in type I cases. Additionally, surgical outcomes in adults are not inferior to those in children, indicating that epilepsy surgery is an effective treatment for both age groups.

Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy; however, the mechanisms underlying hyperexcitability in the affected cortical regions remain poorly understood. In this study, we employed a freeze-induced neocortical malformation model in rats to investigate the electrophysiological properties of pyramidal neurons surrounding the microgyrus and to evaluate changes in synaptic transmission. Using whole-cell patch-clamp recordings, we analyzed passive and active membrane properties, synaptic responses, and epileptiform activity in brain slices from rats with FCD and sham-operated controls. Our results revealed that while the intrinsic biophysical properties of neurons remained largely unchanged, the summation of excitatory and inhibitory inputs was significantly enhanced. Notably, the balance of inhibitory and excitatory synaptic currents was shifted toward excitation, making the perilesional cortex more susceptible to seizure generation. In a model of epileptiform activity induced by GABAA receptor blockade and reduced Mg2+ concentration, we observed early ictal activity originating in the microgyrus and spreading to adjacent regions. These findings demonstrate that synaptic perturbations, rather than alterations in intrinsic neuronal properties, are the primary drivers of hyperexcitability in this model. Our study highlights the importance of synaptic dysregulation in FCD-related epilepsy and suggests that targeting synaptic transmission may offer a promising therapeutic strategy for controlling seizures in patients with cortical malformations.

Focal cortical dysplasia type I (FCD I) is the most common cause of pharmaco-resistant epilepsy with the poorest prognosis. To understand the epileptogenic mechanisms of FCD I, we obtained tissue resected from patients with FCD I epilepsy, and from tumor patients as control. Using whole-cell patch clamp in acute human brain slices, we investigated the cellular properties of fast-spiking interneurons (FSINs) and pyramidal neurons (PNs) within the ictal onset zone. In FCD I epilepsy, FSINs exhibited lower firing rates from slower repolarization and action potential broadening, while PNs had increased firing. Importantly, excitatory synaptic drive of FSINs increased progressively with the scale of cortical activation as a general property across species, but this relationship was inverted towards net inhibition in FCD I epilepsy. Further comparison with intracranial electroencephalography (iEEG) from the same patients revealed that the spatial extent of pathological high-frequency oscillations (pHFO) was associated with synaptic events at FSINs. Changes in FSIN physiology and cortical E–I balance underlying pHFO generation are not fully understood. Here authors show net synaptic drive at FSINs from excitation to inhibition represents the major epileptogenic mechanism of FCD I epilepsy.

Focal cortical dysplasias (FCDs) are increasingly recognized as one of the most common causes of pharmaco-resistant epilepsies. FCDs were recently divided into various clinico-pathological subtypes due to distinct imaging, electrophysiological, and outcome characteristics. In this review, we will overview the international consensus classification of FCDs in light of more recently reported clinical, electrical, imaging and functional observations, and will also address areas of ongoing debate. In addition, we will summarize our current knowledge on pathobiology and epileptogenicity of FCDs as well as its underlying molecular and cellular mechanisms. The clinical (electroencephalographic, imaging, and functional) characteristics of major FCD subtypes and their implications on the presurgical evaluation and surgical management will be discussed in light of studies describing these characteristics and postoperative seizure outcomes in patients with medically intractable focal epilepsy due to histopathologically confirmed FCDs.

Focal cortical dysplasia (FCD) causes drug‐resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic “2‐hit” model is hypothesized. In a boy with drug‐resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second‐hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone. These findings provide new insights into the molecular and cellular correlates of FCD determining drug‐resistant epilepsy and refine conceptualization of the epileptogenic zone.

ObjectiveWe aimed to assess stereoelectroencephalography (SEEG) seizure-onset and interictal patterns associated with MRI-negative epilepsy and investigate their possible links with histology, extent of the epileptogenic zone (EZ) and surgical outcome.MethodsWe retrospectively analysed a cohort of 59 consecutive MRI-negative surgical candidates, who underwent SEEG recordings followed by cortectomy between 2000 and 2016.ResultsMost of the eight distinct seizure-onset patterns could be encountered both in confirmed focal cortical dysplasia (FCD) and in histologically non-specific or normal cases. We found strong correlation (p = 0.008) between seizure-onset pattern and histology for: (1) slow-wave/DC-shift prior to low voltage fast activity (LVFA), associated with normal/non-specific histology, and (2) bursts of polyspikes prior to LVFA, exclusively observed in FCD. Three interictal patterns were identified: periodic slow-wave/gamma burst, sub-continuous rhythmic spiking and irregular spikes. Both “periodic” patterns were more frequent in but not specific to FCD. Surgical outcome depended on the EZ complete removal, regardless electrophysiological features.ConclusionsHistologically normal and FCD-associated epileptogenic zones share distinct interictal and ictal electrophysiological phenotypes, with common patterns between FCD subtypes and between dysplastic and apparently normal brain.SignificanceSome specific seizure-onset patterns seem to be predictive of the underlying histology and may help to detect an MRI-invisible FCD.

Focal cortical dysplasia (FCD) type II is an important cause of drug-resistant epilepsy. Clinical presentation is variable, and depends on age of onset of seizures and the location and size of lesion. As FCD type II cannot be diagnosed with certainty in the clinic, in vivo identification by use of MRI is important. Diagnosis will have a major effect on management of this pathology as it should prompt referral for specialist assessment. Drug treatment commonly proves ineffective, whereas appropriate surgical treatment can be curative in many cases. The dramatic cellular anomalies of FCD seen at histopathology indicate a widespread pattern of molecular disruption underpinning the structural disorganisation of the cortex. The cause for FCD has not been firmly established, and there are no explanations for its potent intrinsic ability to cause seizures. There seem to be both neurodevelopmental abnormalities and possible premature neurodegeneration in FCD. Understanding the coordination of the abnormal processes in FCD type II might help to promote improved detection in vivo, direct treatment strategies, and perhaps help explain the development, differentiation, and loss of brain cells, with broad implications for the epilepsies and other neurological disorders.

The identification of the corticospinal tract (CST) pathway with a deterministic fiber tracking approach is limited because of crossing fibers, especially for the hand fibers of the CST due to the crossing superior longitudinal fasciculus (SLF). We examined a patient with congenital bilateral perisylvian syndrome (CBPS) who did not have the SLF, in order to visualize CST hand fibers that were not affected by crossing fibers. A 10-year-old girl without the SLF due to CBPS and three normal healthy subjects participated in this study. We used a deterministic fiber tracking algorithm, and the regions of interest (ROIs) were drawn in the posterior limb of internal capsule (PLIC) and the primary motor cortex. The apparent diffusion coefficient (ADC), fractional anisotropy (FA), relative anisotropy (RA), and volume ratio (VR) were measured based on the extracted fiber tracts. The ADC values were not different between the normal subjects and the patient with CBPS. The FA, RA, and VR values of the normal subjects were similar, but were relatively higher than those of the patient with CBPS. Our results clearly show the impact of the crossing fiber for the hand motor fibers of the CST pathway with deterministic tracking algorithms in diffusion tensor tractography.