Biology subjects

Mivalt, F.

Publications and source records attributed to Mivalt, F..

9 recordsLinked to original sources

bioRxiv2026

A Translational Platform for Brain-Computer Interfaces and Adaptive Neuromodulation: Technical Characterization, Long-Term Validation, and Implementation of the CorTec Brain Interchange--BCI2000 Ecosystem

Objective: Adaptive neuromodulation systems and implantable brain-computer interfaces (BCIs) are promising therapies for neurological and psychiatric disorders. However, their broader translation into research and clinical practice remains limited by technological complexity, restricted access to implantable research platforms, and the lack of standardized, reproducible experimental workflows. We therefore aimed to develop and validate an open, general-purpose translational ecosystem that enables rapid development, evaluation, and dissemination of novel neuromodulation and implantable BCI paradigms. Approach: The CorTec Brain Interchange (BIC) implantable neural sensing and stimulation device was integrated with the open-source BCI2000 platform to create a modular, extensible neuromodulation ecosystem. We established a standardized battery of quantitative assessments to characterize implantable neuromodulation systems to comprehensively evaluate the CorTec BIC device through benchtop characterization, long-term preclinical in vitro and in vivo validation, and a human proof-of-concept demonstration. Results: Benchtop and saline testing provided a comprehensive technical ex vivo characterization of the BIC device, independently validating previously reported performance while extending its characterization through quantification of the recording noise floor, stimulation and acquisition latencies and impedance measurement accuracy. Long-term in vivo validation in five canines, with the longest implantation exceeding three years, demonstrated stable chronic recordings while capturing progressive channel deterioration and its underlying mechanical causes. The ecosystem enabled active functional decoding more than two years after implantation, implementation of closed-loop stimulation using arbitrary spectral biomarkers, detection and modulation of epilepsy-associated biomarkers, and brain stimulation evoked potential recordings. In addition, we translated an established one-dimensional BCI cursor control paradigm to the BIC benchtop evaluation kit and demonstrated its feasibility in a human participant. Finally, we openly provide standardized surgical, imaging, and analysis pipelines together with datasets and software to facilitate reproducible neuromodulation research. Significance: We present a versatile, open-source translational ecosystem that supports a wide range of neuromodulation and implantable BCI applications with minimal modification. This battery of quantitative assessments can be applied generally as a blueprint for systematic characterization of implantable neuromodulation systems. By combining comprehensive hardware characterization with standardized software tools and experimental workflows, this work provides both an essential reference for researchers adopting the Brain Interchange platform. The ecosystem lowers technical barriers to implantable neurotechnology research, promotes reproducibility, and provides a foundation for accelerating the development and clinical translation of next-generation adaptive neuromodulation and implantable BCI therapies for patients with neurological and psychiatric disorders.

bioengineering↗

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↗

bioRxiv2025

Large Animal Epilepsy Model Platform: Kainic Acid Porcine Model of Mesial Temporal Lobe Epilepsy

Translational large-animal models that can accommodate human-scale implantable devices are essential for advancing neuromodulation therapies in epilepsy. This study establishes a kainic acid (KA)-induced porcine model of mesial temporal lobe epilepsy (mTLE) using clinical imaging, stereotactic surgery, and a fully implantable neural stimulation and recording (INSR) device designed for humans. Seven pigs (six KA-treated and one saline control) underwent MRI-guided stereotactic implantation of electrodes targeting bilateral hippocampus (HPC) and anterior thalamus (ANT), followed by intra-hippocampal KA or saline infusion. Local field potentials (LFP) were recorded continuously with synchronized video monitoring. Seizures and LFP interictal epileptiform-like discharges (IEDs) were quantified using validated automated detectors. Histology was performed in the saline control and the longest surviving KA-treated pig. Intra-hippocampal KA infusion induced acute status epilepticus in all (6/6) treated pigs. Four animals survived to chronic monitoring with spontaneous seizures observed in three pigs (2,733 seizures; mean duration of 27.2 {+/-} 17.6 seconds). IEDs were observed in bilateral HPC of all animals, including saline control, with higher rates in the lesioned HPC (p <0.0001). While the IED morphology is consistent with epileptiform activity; IEDs alone are not specific for epilepsy and physiological transients (e.g. sharp-wave ripples) and injury-related hyperexcitability or strain-specific hyperexcitability cannot be excluded. Histological analysis revealed patchy neuronal loss and cytoarchitectural changes in HPC. This porcine model reproduces electrophysiological features of human mTLE. This approach provides a powerful translational bridge for developing and testing next-generation INSR and neuromodulation strategies in freely behaving large animals.

neuroscience↗

bioRxiv2024

Bred for affection: The canine anterior ectosylvian gyrus responds selectively to social reinforcement

Studying mammalian brain function aids our understanding of human brain evolution. We implanted a beagle with a prototype human neuromodulation platform that measures activity from the brain surface. One year later, a set of simple sensory tasks was performed, finding visual and somatosensory representation in the canine homologs of the expected areas in humans. Surprisingly, the canine anterior ectosylvian gyrus, which is anatomically homologous to human receptive speech areas, was selectively active during independent social reinforcement tasks. This suggests that human speech understanding may have evolved from more general mammalian brain structures that are specialized for social reinforcement.

animal behavior and cognition↗

bioRxiv2023

Method for cycle detection in sparse, irregularly sampled, long-term neuro-behavioral timeseries: Basis pursuit denoising with polynomial detrending of long-term, inter-ictal epileptiform activity

Numerous physiological processes are cyclical, but sampling these processes densely enough to perform frequency decomposition and subsequent analyses can be challenging. Mathematical approaches for decomposition and reconstruction of sparsely and irregularly sampled signals are well established but have been under-utilized in physiological applications. We developed a basis pursuit denoising with polynomial detrending (BPWP) model that recovers oscillations and trends from sparse and irregularly sampled timeseries. We validated this model on a unique dataset of long-term inter-ictal epileptiform discharge (IED) rates from human hippocampus recorded with a novel investigational device with continuous local field potential sensing. IED rates have well established circadian and multiday cycles related to sleep, wakefulness, and seizure clusters. Given sparse and irregular samples of IED rates from multi-month intracranial EEG recordings from ambulatory humans, we used BPWP to compute narrowband spectral power and polynomial trend coefficients and identify IED rate cycles in three subjects. In select cases, we propose that random and irregular sampling may be leveraged for frequency decomposition of physiological signals. Author SummaryCircadian and multiday cycles are an important part of many long-term neuro-behavioral phenomena such as pathological inter-ictal epileptiform discharges (IEDs) in epilepsy. Long-term, ambulatory, neuro-behavioral monitoring in human patients involves complex recording systems that can be subject to intermittent, irregular data loss and storage limitations, resulting in sparse, irregularly sampled data. Cycle identification in sparse data or irregular data using traditional frequency decomposition techniques typically requires interpolation to create a regular timeseries. Using unique, long-term recordings of pathological brain activity in patients with epilepsy implanted with an investigational device, we developed a method to identify cycles in sparse, irregular neuro-behavioral data without interpolation. We anticipate this approach will enable retrospective cycle identification in sparse neuro-behavioral timeseries and support prospective sparse sampling in monitoring systems to enable long-term monitoring of patients and to extend storage capacity in a variety of ambulatory monitoring applications.

neuroscience↗

bioRxiv2022

Chronic modulation of human memory and thalamic-hippocampal theta activities.

Electrical stimulation is a powerful therapeutic tool for treating neurologic and neuropsychiatric disorders. Sensing and modulating electrophysiological biomarkers of memory over extended timescales is necessary for tracking and improving memory in humans. Here, we describe results from humans in their natural home environments using a novel, investigational system enabling chronic stimulation and multi-channel recording of anterior thalamic and hippocampal local field potentials during memory tasks. Four people with focal epilepsy performed a free recall verbal memory task repeatedly for up to fifty months on a touch-screen device with wireless signal acquisition with electrophysiology and behavioral data streaming to a cloud environment. Anterior thalamic-hippocampal spectral activities in the theta frequency range were found to correlate with memory processing, to predict task performance, and to be modulated by deep brain stimulation. Our results provide a new biomarker-based technology for chronic remote tracking of memory performance and modulation of the associated neural activities. One Sentence SummaryElectrical stimulation in the anterior thalamic nuclei modulates theta frequency activities and improves human verbal memory performance chronically.

neuroscience↗

bioRxiv2022

Integrated human-machine interface for closed-loop stimulation using implanted and wearable devices

Recent development in implantable devices for electrical brain stimulation includes sensing and embedded computing capabilities that enable adaptive stimulation strategies. Applications include stimulation triggered by pathologic brain activity and endogenous rhythms, such as circadian rhythms. We developed and tested a system that integrates an electrical brain stimulation & sensing implantable device with embedded computing and uses a distributed system with commercial electronics, smartphone and smartwatch for patient annotations, extensive behavioral testing, and adaptive stimulation in subjects in their natural environments. The system enables precise time synchronization of the external components with the brain stimulating device and is coupled with automated analysis of continuous streaming electrophysiology synchronized with patient reports. The system leverages a real-time bi-directional interface between devices and patients with epilepsy living in their natural environment.

neuroscience↗

bioRxiv2021

Distributed Brain Co-Processor for Neurophysiologic Tracking and Adaptive Stimulation: Application to Drug Resistant Epilepsy

Early implantable epilepsy therapy devices provided open-loop electrical stimulation without brain sensing, computing, or an interface for synchronized behavioral inputs from patients. Recent epilepsy stimulation devices provide brain sensing but have not yet developed analytics for accurately tracking and quantifying behavior and seizures. Here we describe a distributed brain co-processor providing an intuitive bi-directional interface between patient, implanted neural stimulation and sensing device, and local and distributed computing resources. Automated analysis of continuous streaming electrophysiology is synchronized with patient reports using a hand-held device and integrated with distributed cloud computing resources for quantifying seizures, interictal epileptiform spikes, and patient symptoms during therapeutic electrical brain stimulation. The classification algorithms for interictal epileptiform spikes and seizures were developed and parameterized using long-term ambulatory data from 9 humans and 8 canines with epilepsy, and then implemented prospectively in out-of-sample testing in 2 pet canines and 4 humans with drug resistant epilepsy living in their natural environments.

bioengineering↗

bioRxiv2020

Single-cell landscape of bone marrow metastases in human neuroblastoma unraveled by deep multiplex imaging

Bone marrow commonly serves as a metastatic niche for disseminated tumor cells (DTCs) of solid cancers in patients with unfavorable clinical outcome. Single-cell assessment of bone marrow metastases is essential to decipher the entire spectrum of tumor heterogeneity in these cancers, however, has previously not been performed. Here we used multi-epitope-ligand cartography (MELC) to spatially profile 20 biomarkers and assess morphology in DTCs as well as hematopoietic and mesenchymal cells of eight bone marrow metastases from neuroblastoma patients. We developed DeepFLEX, a single-cell image analysis pipeline for MELC data that combines deep learning-based cell and nucleus segmentation and overcomes frequent challenges of multiplex imaging methods including autofluorescence and unspecific antibody binding. Using DeepFLEX, we built a single-cell atlas of bone marrow metastases comprising more than 35,000 single cells. Comparisons of cell type proportions between samples indicated that microenvironmental changes in the metastatic bone marrow are associated with tumor cell infiltration and therapy response. Hierarchical clustering of DTCs revealed multiple phenotypes with highly diverse expression of markers such as FAIM2, an inhibitory protein in the Fas apoptotic pathway, which we propose as a complementary marker to capture DTC heterogeneity in neuroblastoma. The presented single-cell atlas provides first insights into the heterogeneity of human bone marrow metastases and is an important step towards a deeper understanding of DTCs and their interactions with the bone marrow niche.

cancer biology↗