Biology subjects

Kfir, Y.

Publications and source records attributed to Kfir, Y..

5 recordsLinked to original sources

bioRxiv2025

Exploring GPCR-mediated optogenetic modulation of seizure network in a pig model of Temporal Lobe Epilepsy

RationaleOptogenetics offers unmatched cellular specificity and control over cellular activity. Various opsins have been tested in animal models of epilepsy, each contributing to our understanding of seizure circuit dynamics. However, inhibitory optogenetic tools based on microbial rhodopsins have low light sensitivity and, thus, are less suitable for applications involving larger brains. We evaluated eOPN3, a red-shifted, highly sensitive inhibitory G-protein coupled receptor opsin in a porcine seizure model using integrated electro-optical sensing and modulation. The results demonstrated the feasibility of eOPN3 circuit modulation in a large animal epilepsy model. MethodsMRI-guided stereotactic surgery was used to deliver 20-60 {micro}L of AAV-eOPN3 (AAV5-/AAV9-CaMKII-eOPN3-mScarlet) into the hippocampus (HPC) of three Gottingen minipigs. Each hemisphere received either an active or a control viral vector (AAV5/9-CaMKII-mScarlet) with gadolinium to visualize the injection sites and diffusion volume via post-operative MRI. Two to three months post-injection, bilateral deep brain stimulation electrodes integrated with optic fibers were stereotactically implanted into the anterior nucleus of the thalamus (ANT) and HPC to assess: 1) opsin expression using fiber photometry, 2) optogenetic modulation of stimulation evoked response potentials (SERPs), 3) induction and propagation of seizure-like activity via intrahippocampal kainic acid (KA) injection, and 4) optogenetic modulation of KA-induced seizure activity. After the electrophysiology recording, brains were harvested for histological analysis to evaluate injection target precision, eOPN3 expression, and estimate eOPN3-modulated volume. ResultseOPN3 expression was confirmed during surgery via fiber photometry. ANT electrical stimulation elicited robust SERPs in the HPCs, which were attenuated by HPC light illumination. HPC stimulation similarly induced SERPs in the ipsilateral ANT and the contralateral HPC. The HPC stimulation-induced SERPs were significantly reduced by illuminating the site of the recording areas, the ipsilateral ANT and the contralateral HPC, demonstrating the optogenetic inhibition of the synaptic release from the HPC. KA injection into the HPC induced 20-30 Hz seizure-like activity. The ANT and HPC light illumination suppressed the localized KA-induced seizure activity in the early stage. However, after the generalization of KA-induced seizures, the ANT-HPC illumination lost efficacy for the control of seizures. Histological analysis confirmed eOPN3 expression in the HPC, ANT and other Papez circuit nodes. ConclusionOur pilot study highlights that eOPN3-mediated inhibition alters SERP and the latency and spread of KA-induced seizure-like activity. We developed a platform incorporating pre- and postoperative MRI for precise viral vector delivery, real-time fiber photometry for quantifying opsin expression, and integrated electro-optical sensing and stimulation to assess optogenetic efficacy in a large animal model. The large animal model provides a solid foundation for future translational research to develop electro-optical devices and cellular therapies for human epilepsy.

neuroscience↗

bioRxiv2023

DREDge: robust motion correction for high-density extracellular recordings across species

High-density microelectrode arrays (MEAs) have opened new possibilities for systems neuroscience in human and non-human animals, but brain tissue motion relative to the array poses a challenge for downstream analyses, particularly in human recordings. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm which is well suited for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from spikes in the action potential (AP) frequency band, DREDge enables automated tracking of motion at high temporal resolution in the local field potential (LFP) frequency band. In human intraoperative recordings, which often feature fast (period <1s) motion, DREDge correction in the LFP band enabled reliable recovery of evoked potentials, and significantly reduced single-unit spike shape variability and spike sorting error. Applying DREDge to recordings made during deep probe insertions in nonhuman primates demonstrated the possibility of tracking probe motion of centimeters across several brain regions while simultaneously mapping single unit electrophysiological features. DREDge reliably delivered improved motion correction in acute mouse recordings, especially in those made with an recent ultra-high density probe. We also implemented a procedure for applying DREDge to recordings made across tens of days in chronic implantations in mice, reliably yielding stable motion tracking despite changes in neural activity across experimental sessions. Together, these advances enable automated, scalable registration of electrophysiological data across multiple species, probe types, and drift cases, providing a stable foundation for downstream scientific analyses of these rich datasets.

neuroscience↗

bioRxiv2022

Robust online multiband drift estimation in electrophysiology data

High-density electrophysiology probes have opened new possibilities for systems neuroscience in human and non-human animals, but probe motion (or drift) while recording poses a challenge for downstream analyses, particularly in human recordings. Here, we improve on the state of the art for tracking this drift with an algorithm termed DREDge (Decentralized Registration of Electrophysiology Data) with four major contributions. First, we extend previous decentralized methods to exploit multiband information, leveraging the local field potential (LFP), in addition to spikes detected from the action potentials (AP). Second, we show that the LFP-based approach enables registration at sub-second temporal resolution. Third, we introduce an efficient online motion tracking algorithm, allowing the method to scale up to longer and higher spatial resolution recordings, which could facilitate real-time applications. Finally, we improve the robustness of the approach by accounting for the nonstationarities that occur in real data and by automating parameter selection. Together, these advances enable fully automated scalable registration of challenging datasets from both humans and mice.

neuroscience↗

bioRxiv2022

Flexible, Scalable, High Channel Count Stereo-Electrode for Recording in the Human Brain

Over the past decade, stereotactically placed electrodes have become the gold standard for deep brain recording and stimulation for a wide variety of neurological and psychiatric diseases. Current electrodes, however, are limited in their spatial resolution and ability to record from small populations of neurons, let alone individual neurons. Here, we report on a novel, reconfigurable, monolithically integrated human-grade flexible depth electrode capable of recording from up to 128 channels and able to record at a depth of 10 cm in brain tissue. This thin, stylet-guided depth electrode is capable of recording local field potentials and single unit neuronal activity (action potentials), validated across species. This device represents a major new advance in manufacturing and design approaches which extends the capabilities of a mainstay technology in clinical neurology. One-Sentence SummaryA human-grade thin-film depth electrode offers new opportunities in spatial and temporal resolution for recording brain activity.

neuroscience↗

bioRxiv2021

Large-scale neural recordings with single-cell resolution in human cortex using high-density Neuropixels probes

Recent advances in multi-electrode array technology have made it possible to monitor large neuronal ensembles at cellular resolution. In humans, however, current approaches either restrict recordings to only a few neurons per penetrating electrode or combine the signals of thousands of neurons in local field potential (LFP) recordings. Here, we describe a new probe variant and set of techniques which enable simultaneous recording from over 200 well-isolated cortical single units in human participants during intraoperative neurosurgical procedures using silicon Neuropixels probes. We characterized a diversity of extracellular waveforms with eight separable single unit classes, with differing firing rates, positions along the length of the linear electrode array, spatial spread of the waveform, and modulation by LFP events such as inter-ictal discharges and burst suppression. While some additional challenges remain in creating a turn-key recording system, high-density silicon arrays provide a path for studying human-specific cognitive processes and their dysfunction at unprecedented spatiotemporal resolution.

neuroscience↗