Epilepsy

This investigators workshop examines adeno-associated virus gene therapies for epilepsy from design and animal testing through clinical translation. Research examples concern Lafora disease, SCN1B-related Dravet syndrome and SLC6A1-related neurodevelopmental disorder. The panel considers treatment efficacy, seizure-associated adverse effects and AAV toxicity, alongside strategies for overcoming current limitations. Discussion also covers biomarkers, scalability and the evidence needed to advance candidates beyond preclinical studies. Sunday 6 December, 14:00–15:30 Mountain Standard Time (Amer

Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from abnormal electrical activity in the brain. All experimental models for seizure generation are based on the administration of drugs (e.g. pilocarpine), on artificial increase in the concentrations of extracellular K+ (Ko) or on direct electric stimulation, to name a few. However, all these approaches may not accurately reflect the in vivo conditions, where otherwise normal neuronal activity can generate occasional seizures. It is thus important to better understand the pathological changes that may be

…bursts in the brains of patients with epilepsy. IEDs represent an important disease biomarker for tracking seizure risk and they also convey direct pathophysiological impacts including on cognitive function. While most work in human IED mechanisms has targeted the population-level neural activity using macro-electrode recordings, the single-neuron mechanisms of IEDs across the depth of human cortical lamina in vivo are largely unknown. We leveraged high-density Neuropixels probes to evaluate single-neuron acti

There are over 30 million people with drug-resistant epilepsy worldwide. When neuroimaging and non-invasive neural recordings fail to localise seizure onset zones (SOZ), intracranial recordings become the best chance for localisation and seizure-freedom in those patients. However, intracranial neural activities remain hard to visually discriminate across recording channels, which limits the success of intracranial visual investigations. In this presentation, I present methods which quantify intracranial neural time series and combine them with explainable machine learning algorithms to localis

…accompany pathological states such as epilepsy [5]. While heterog

…the seizure frequency in patients with epilepsy. This therapy greatly benefits from designing personalized electrode montages (electrode positions and currents) that target the appropriate areas of the brain. In the state-of-the-art pipelines, a specialized physician selects these areas and a biophysical model of the patient’s head is used to find an optimal electrode montage that inhibits them. In the Galvani project, we aim to go a step forward and develop a pipeline that uses personalized Neurotwins for mo

…activity, treating conditions like Epilepsy [1]. Using synthetic micro-electrode array (MEA) signals as stimuli in a DBS system enables electrical impulses that mimic natural brain activity, improving precision and effectiveness [2]. This can reduce side effects and enhance therapeutic outcomes [3]. This study introduces Time-Series Generative Denoising Diffusion Transformers (TSG-DDT), an architecture for generating high-fidelity synthetic MEA data [4]. TSG-DDT combines denoising diffusion models [5] w

…marked by intellectual disability and epilepsy, resulting from haploinsufficiency of KANSL1. This gene encodes a scaffolding protein within the non-specific lethal (NSL) complex which is crucial for histone modifications. The NSL complex regulates the expression of housekeeping, DNA repair, and autophagy genes. Autophagy, a pivotal process delivering cytoplasmic material to the lysosome for degradation, plays a key role in brain development and homeostasis maintenance; defects in autophagy have been linked to neurodevelopmental disorde

Epilepsy is a chronic neurological disorder that affects 1% of the world's population and is often linked with notable comorbidities and higher risks of mortality. Around 30% of epilepsies are considered pharmacoresistant (PRE). Resection surgery provides around remission in only 30-40% of eligible patients, leaving the remainder without alternative treatment options. Transcranial current stimulation (tCS) is a new safe and noninvasive approach that is increasingly being used in treating brain disorders. In the context of PRE, tCS seems to be a promising solution that aims to reduce cortical e

Epilepsy, a neurological disorder affecting approximately 60 million individuals globally, poses a significant medical challenge with a substantial unmet need. Temporal lobe epilepsy is the most prevalent form, often triggered by traumatic incidents or status epilepticus (SE), resulting in hippocampal damage characterized by neuronal loss, astro- and microgliosis and neuroinflammation preceding the spontaneous recurrent seizures. Recently, an AAV-PHP.B-GFAP-interleukin-2 (IL-2) gene therapy exhibited impressive neuroprotective and anti-inflammatory effects in mouse models of traumatic brain in

Astrocytic dysfunctions have increasingly been recognized as a significant element in epilepsy pathophysiology. The prominent expression of connexin channels is one of the key features of astrocytes, essential for their extensive intercellular coupling. It is currently debated whether astrocytic connexins have pro- or anti-epileptic effects. The existence of two types of connexins, namely Cx30 and Cx43, which display different properties as well as several functions beyond gap junction formation, such as hemichannel constituents or signaling elements, further makes it more complex to investig

Virtual brain modeling is a data-driven approach that combines personalized anatomical information with mathematical models of brain activity to generate spatiotemporal patterns as observed in brain imaging signals. In this study our aim is to conduct inference and prediction on the local and global dynamics using virtual brain models, affected by disorders. Inference algorithms are necessary to efficiently estimate the unknown parameters (such as regional excitability parameters and global scaling factor on connectome), ideally incorporating measures of uncertainty. In this work, we provide f

Introduction: The rational polytherapy of epilepsy during pregnancy is challenging. VPA represents an old antiepileptic with broad spectrum indications and LEV is relatively new antiepileptic used for the treatment of generalized tonic-clonic and juvenile myoclonic epilepsy and adjunctive therapy for focal seizures. Combination of these two antiepileptics during pregnancy, according to the cohort study (Gašparović at al., 2020), was the most common. Aim: The aim of the present study was to assesse the behavioral performance of the mice whose mothers were treated with combination of VPA and LEV

【Aims】Epilepsy, a recurrent neurological disease with abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter dynamics and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. We aimed to investigate the dynamics of neurotransmitters during convulsive seiz

Epilepsy, affecting over 70 million individuals worldwide, poses a significant risk of sudden death, known as SUDEP. The DEPDC5 gene is a common factor in familial focal epilepsy, with or without cortical malformations, and its pathogenic variants increase the susceptibility to SUDEP. This study aims to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for high-risk patients, and develop preventive interventions.Methods involved the targeted deletion of Depdc5 in nucleus tractus solitarius (NTS) neurons in the mouse brainstem, followed by the administra

Epilepsy provides a unique opportunity to study human cellular electrophysiology through in vivo and in vitro approaches. In vivo recordings offer advantages in action potential pattern reconstruction and connection preservation, while in vitro studies allow broader tissue exploration within a confined space of cut connections, yet coherent investigation in these distinct conditions is lacking. This study compared single-neuron firing properties in four epileptic patients using identical 24-channel laminar microelectrodes with 150 μm inter-contact distance for both their in vivo and in vitro i

…to neurodevelopmental syndromes with epilepsy and intellectual disability. To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for CACNA1A haploinsufficiency, by differentiating isogenic induced pluripotent stem cell lines into glutamatergic neurons, and investigated the effect of CACNA1A haploinsufficiency on mature neuronal

…of neurodegenerative diseases such as epilepsy underscores the importance of further elucidating its biophysical mechanism. In this study, the effects of IR neuromodulation on cortical neurons in vivo were investigated using high-density laminar recordings. The neocortex of anesthetized rats was exposed

…The term EA originates from epilepsy research, where interictal EA appears in EEG between seizures. Importantly, EA occurs not only in epilepsy but also in various pathologies, possibly contributing to cognitive impairment. EA has been observed in neurodegenerative disorders like Alzheimer's and Parkinson's diseases. However, a direct causal link between EA and cognitive impairment remains elusive. A significant issue is the lack of a pure EA model for invest

…associated with severe childhood-onset epilepsy, global developmental delay, intellectual disability, and autistic-like features. Here, we characterized the epileptic and behavioral phenotypes of a mouse model with Chd2 haploinsufficiency (Chd2+/m and Chd2m/m mice). Interestingly, we discovered th

Epilepsy is a common neurological disorder that affects 1% of the global population and significantly burdens patients and society. Many epilepsies are acquired following brain injury and no effective prophylaxis or cure exists. Accumulating evidence suggests that oxidative stress plays a critical role in the development of epilepsy, and that pharmacological targeting of oxidative stress can prevent spontaneous seizures. However, non-specific antioxidant therapies may disrupt the physiological balance of oxidants/antioxidants, highlighting the need for targeted intervention. Here, we used AAV

Epilepsy and autism spectrum disorder have a high degree of comorbidity, likely due to shared underlying predisposing factors. Loss of αV and β3 integrin subunits have been implicated in the onset of epilepsy and autism, respectively. However, the role of the αVβ3 integrin receptor in these disorders remains unclear. Integrins are heterodimeric receptors involved in mechanotransduction between the extracellular matrix and the intracellular cytoskeleton. In the brain, β3 integrin forms heterodimers with αV integrin, regulating the synaptic localization of GluA2-containig AMPA receptors (AMPARs)

Transcranial direct current stimulation (tDCS) is a clinical technique employed in the treatment of multiple pathological conditions such as chronic pain, stroke, and among others. Nonetheless, a comprehensive exploration of the impact of electric fields on cortical circuits is still necessary. Studies by Frohlich and McCormick (2010) and D’Andola et al. (2018) have revealed the effect of direct current (DC) exogenous fields to modulate emergent activity patterns in cortical slices exhibiting spontaneous slow oscillations (SO).Considering the potential of tDCS as a treatment option for epileps

The sudden emergence of dangerous seizures is the defining feature of epilepsy, but how and when the brain changes dynamics remains enigmatic. From the perspective of dynamical systems theory, such critical transitions occur upon inconspicuous perturbations in highly interconnected systems presenting positive feedback loops and can be modeled as mathematical bifurcations between alternative regimes. Here, we sought to characterize dynamical signatures of impending seizures. We systematically verified the predictions of the model called ‘Epileptor’ that captures seizure dynamics in five differe