Biology subjects

Berenyi, A.

Publications and source records attributed to Berenyi, A..

8 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↗

bioRxiv2026

From Scalp to Source: Precise Phase Retrieval of Intracerebral Epileptic Sources Based on Surface EEG

Accurate phase tracking of deep-brain activity is critical for effective closed-loop and phase-locked neuromodulation therapies. However, direct access to deep neural phase through intracranial recordings remains clinically restrictive due to the invasiveness. Here we validate and clinically benchmark the Gabor-Nelson (GN) dipole estimation method for reconstructing deep-brain oscillatory phase from non-invasive scalp EEG. GN is a geometry-based, imaging-independent approach that offers computationally efficient dipole reconstruction and has rarely been applied to source-level phase estimation in human neuroscience. We compared GN with an established MRI-informed Inverse Solution (IS) method using a three-stage reconstruction pipeline consisting of dipole modeling, dimensionality reduction, and frequency-dependent phase-delay correction. Validation is performed using (i) cadaveric recordings, where known ground-truth seizure waveforms were replayed through implanted deep electrodes, and (ii) simultaneous scalp EEG and SEEG recordings in human patients, where pseudo-ground truth was approximated via the intracranial contacts. GN achieved phase accuracy and signal fidelity comparable to IS across both datasets despite requiring no anatomical imaging. In cadaver recordings, phase-corrected reconstruction correlations exceeded r > 0.91 and {Delta}{Phi} < 9{degrees} in mean phase error. In patient SEEG data, GN reached up to r {approx} 0.80 with phase offsets suitable for neuromodulatory timing. GN offers a viable, low-barrier, imaging-independent alternative to traditional inverse modeling for non-invasive seizure phase tracking. This framework opens pathways for scalable, phase-locked and closed-loop stimulation therapies in epilepsy and potentially other network-based brain disorders.

neuroscience↗

bioRxiv2026

Dual thalamic drive defines the intra-amygdala wiring complexity

The amygdala plays a key role in affective behaviors by integrating incoming signals and conveying them towards subcortical output regions. Current models suggest a serial information flow within the amygdala from the lateral and basolateral towards the central subnuclei driven by incoming thalamic and cortical excitation. However, due to the lack of universally accepted parcellation principles, the precise connectivity and thus, the signal propagation within the circuit remain debated. Using a molecular-based parcellation, our subnucleus-specific anatomical and electrophysiological mapping revealed a previously overlooked complexity in the intra-amygdala wiring pattern in mice. Specifically, the intra-amygdala signal transfer relies on separate lateral thalamus-driven routes via the lateral subnucleus mostly bypassing the anterior basolateral and centrolateral subnuclei. In contrast, the anterior basolateral nucleus, innervated by the dorsal midline thalamus, supplies mostly extra-, but not intra-amygdala routes. We also demonstrated that a similar dual thalamo-cortico-amygdala organization exists in the human brain. Collectively, our findings identified unconventional amygdala wiring principles challenging the traditional serial lateral-basolateral-central stream model which can redefine our understanding of behaviorally relevant intra-amygdala computations.

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↗

bioRxiv2020

Closed-loop stimulation of the medial septum terminates epileptic seizures

Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, due to its large size and irregular shape. In contrast, the medial septum (MS) is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this proxy intervention concept and precisely timed stimulation, we report here that closed-loop MS electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell-type-specific stimulation revealed that precisely timed activation of MS GABAergic neurons underlay the effects. Our concept of phase-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and its current embodiment can be directly translated into clinical application.

neuroscience↗