Biology subjects

Barcsai, L.

Publications and source records attributed to Barcsai, L..

6 recordsLinked to original sources

bioRxiv2026

Phase-dependent closed-loop intersectional short-pulse stimulation reduces seizure duration: From computational modeling to clinical application

Drug-resistant epilepsy affects one-third of patients with persistent seizures despite optimal therapy. Intersectional short-pulse (ISP) stimulation is a novel transcranial electrical stimulation technique designed to deliver temporally precise, spatially targeted modulation of pathological brain activity. Here, we combined computational modeling with measurements in a rat epilepsy model and in patients with epilepsy to map the relationship between stimulation phase and seizure attenuation. In silico simulations of epileptiform networks showed that ISP stimulation significantly shortened seizure duration, with efficacy strongly depending on the phase of delivery. Phase-targeted stimulation during the rising phase and around the peaks (~45-90{degrees}) of the seizure oscillations led to the greatest reduction in seizure length. In rodents, ISP decreased seizure duration by 42.4% and shortened generalized seizure segments by 58.3%. In humans, stimulation reduced seizure length by 60.9% compared to control seizures. Phase dependence was evident across models and species, with a prominent efficacy window in the rising-to-peak portion of the ictal oscillation and model-specific secondary windows. These findings show that phase-targeted ISP can substantially shorten seizures and support phase-resolved stimulation as a precision-neuromodulation approach for epilepsy.

neuroscience↗

bioRxiv2025

Non-vectorial Integration of Intersectional Short-Pulse Stimulation Enables Enhanced Deep Brain Modulation and Effective Seizure Control

Transcranial electrical stimulation (TES) holds promise to treat neurological disorders, but its efficacy is limited by poor spatial focality and depth of penetration. Here, we examined the potential utility of Intersectional Short-Pulse (ISP) stimulation of deeper brain penetration. Using computational modeling and in vivo patch-clamp recordings in rats, we demonstrate that neurons integrate ISP-induced electric fields in a non-vectorial manner. This mechanism allows ISP to overcome some limits of conventional TES, achieving spatially limited stimulation across cortical and subcortical structures. In a rat model of temporal lobe epilepsy, closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 49% and 41% compared to sham stimulation and conventional TES and significantly reduced motor seizure severity. Our findings demonstrate that ISP stimulation can rapidly terminate hippocampal seizures, offering a potential new approach for non-invasive neuromodulation with applications across diverse neurologic and psychiatric disorders.

neuroscience↗

bioRxiv2024

Hippocampal sharp wave ripples mediate generalization and subsequent fear attenuation via closed-loop brain stimulation in rats

The balance between stimulus generalization and discrimination is essential in modulating behavioral responses across different contexts. Excessive fear generalization is linked to neuropsychiatric disorders such as generalized anxiety disorder (GAD) and PTSD. While hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are central to the consolidation of contextual memories, their involvement in non-hippocampal dependent memories remains poorly understood. Here we show that closed-loop disruption of SWRs, after the consolidation of a cued fear conditioning, leads to atypical memory discrimination that would normally be generalized. Furthermore, SWR-triggered closed-loop stimulation of the basolateral amygdala (BLA) during memory reconsolidation inhibits fear generalization and enhances subsequent extinction. Comparable effects were observed when stimulating the infralimbic cortex either post-training or after a brief memory reactivation. A consistent increase in gamma incidence within the amygdala was identified in animals subjected to closed-loop BLA or infralimbic cortex neuromodulation. Our findings highlight the functional role of hippocampal SWRs in modulating the qualitative aspects of amygdala-dependent memories. Targeting the amygdala activity via prefrontal cortex with closed-loop SWR triggered stimulation presents a potential foundation of a non-invasive therapy for GAD and PTSD.

neuroscience↗

bioRxiv2022

Higher-order thalamic nuclei facilitate the generalization and maintenance of spike-and-wave discharges in absence seizures

Spike-and-wave discharges (SWDs), generated by the cortico-thalamo-cortical (CTC) network, are pathological, large amplitude oscillations and the hallmark of absence seizures (ASs). SWDs begin in a cortical initiation network in both humans and animal models, including the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), where it is located in the primary somatosensory cortex (S1). The behavioral manifestation of an AS occurs when SWDs spread from the cortical initiation site to the whole brain, however, the mechanisms behind this rapid propagation remain unclear. Here we investigated these processes beyond the principal CTC network, in higher-order (HO) thalamic nuclei (lateral posterior (LP) and posterior (PO) nuclei) since their diffuse connectivity and known facilitation of intracortical communications make these nuclei key candidates to support SWD generation and maintenance. In freely moving GAERS, multi-site LFP in LP, PO and multiple cortical regions revealed a novel feature of SWDs: during SWDs there are short periods (named SWD-breaks) when cortical regions far from S1, such the primary visual cortex (V1), become transiently unsynchronized from the ongoing EEG rhythm. Inactivation of HO nuclei with local muscimol injections or optogenetic perturbation of HO nuclei activity increased the occurrence of SWD-breaks and the former intervention also increased the SWD propagation-time from S1. The neural underpinnings of these findings were explored further by silicon probe recordings from single units of PO which uncovered two previously unknown groups of excitatory neurons based on their burst firing dynamics at SWD onset. Moreover, a switch from tonic to burst firing at SWD onset was shown to be an important feature since it was much less prominent for non-generalized events, i.e. SWDs that remained local to S1. Additionally, one group of neurons showed a reverse of this switch during SWD-breaks, demonstrating the importance of this firing pattern throughout the SWD. In summary, these results support the view that multiple HO thalamic nuclei are utilized at SWD onset and contribute to cortical synchrony throughout the paroxysmal discharge.

neuroscience↗

bioRxiv2022

Closed-loop brain stimulation to reduce pathologic fear

Maladaptive processing of trauma related memory engrams leads to dysregulated fear reactions. In post-traumatic stress disorder (PTSD), dysfunctional extinction learning prevents discretization of trauma-related memory engrams and leads to generalized fear responses. PTSD is postulated as a mnemonic-based disorder, but we lack markers or treatments targeting pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. We demonstrate that closed-loop SWRs triggered neuromodulation of the medial forebrain bundle (MFB) can enhance the consolidation of fear extinction. It modified fear memories that became resistant to induced recall (i.e., renewal and reinstatement) and did not reemerge spontaneously as a PTSD-like phenotype. The effects are mediated by D2 receptor signaling induced synaptic remodeling in the basolateral amygdala. These results suggest that SWRs help consolidating fear extinction memories. Furthermore, enhancing the consolidation of extinction engrams by SWR-triggered induction of reward signals can alleviate pathologic fear reactions in a rodent model of PSTD. No adverse effects were seen, suggesting this potential therapy for PTSD and anxiety disorders.

neuroscience↗

bioRxiv2022

Reinstating olfactory bulb derived limbic gamma oscillations alleviates depression

Although the etiology of major depressive disorder remains poorly understood, impairment of gamma oscillations recently emerged as a potential biomarker for major depression. The olfactory bulb (OB) is a major source of brain wide gamma oscillations and bulbectomy is an animal model for depression. Here we demonstrate that chemogenetic suppression of OB neuronal activity or temporally suppressing the OB to pyriform cortex synaptic transmission decreased gamma oscillation power in multiple brain areas associated with depression-like behaviors. To assess the hypothesized link between depression and diffuse depression of gamma oscillations, we employed gamma phase-dependent closed loop neuromodulation of cortical areas, paced by the native OB output. This procedure alleviated depressive-like behaviors in animals and suggests that restoring gamma oscillations may improve depression in humans. One Sentence SummaryRole of limbic gamma oscillations in depression

neuroscience↗