DENOISING: Dynamic enhancement and noise overcoming in multimodal neural observations via high-density CMOS-based biosensors.

Large-scale multimodal neural recordings on high-density biosensing microelectrode arrays (HD-MEAs) offer unprecedented insights into the dynamic interactions and connectivity across various brain networks. However, the fidelity of these recordings is frequently compromised by pervasive noise, which obscures meaningful neural information and complicates data analysis. To address this challenge, we introduce DENOISING, a versatile data-derived computational engine engineered to adjust thresholds adaptively based on large-scale extracellular signal characteristics and noise levels. This facilitates the separation of signal and noise components without reliance on specific data transformations. Uniquely capable of handling a diverse array of noise types (electrical, mechanical, and environmental) and multidimensional neural signals, including stationary and non-stationary oscillatory local field potential (LFP) and spiking activity, DENOISING presents an adaptable solution applicable across different recording modalities and brain networks. Applying DENOISING to large-scale neural recordings from mice hippocampal and olfactory bulb networks yielded enhanced signal-to-noise ratio (SNR) of LFP and spike firing patterns compared to those computed from raw data. Comparative analysis with existing state-of-the-art denoising methods, employing SNR and root mean square noise (RMS), underscores DENOISING's performance in improving data quality and reliability. Through experimental and computational approaches, we validate that DENOISING improves signal clarity and data interpretation by effectively mitigating independent noise in spatiotemporally structured multimodal datasets, thus unlocking new dimensions in understanding neural connectivity and functional dynamics.

Recording and Analyzing Multimodal Large-Scale Neuronal Ensemble Dynamics on CMOS-Integrated High-Density Microelectrode Array.

Large-scale neuronal networks and their complex distributed microcircuits are essential to generate perception, cognition, and behavior that emerge from patterns of spatiotemporal neuronal activity. These dynamic patterns emerging from functional groups of interconnected neuronal ensembles facilitate precise computations for processing and coding multiscale neural information, thereby driving higher brain functions. To probe the computational principles of neural dynamics underlying this complexity and investigate the multiscale impact of biological processes in health and disease, large-scale simultaneous recordings have become instrumental. Here, a high-density microelectrode array (HD-MEA) is employed to study two modalities of neural dynamics - hippocampal and olfactory bulb circuits from ex-vivo mouse brain slices and neuronal networks from in-vitro cell cultures of human induced pluripotent stem cells (iPSCs). The HD-MEA platform, with 4096 microelectrodes, enables non-invasive, multi-site, label-free recordings of extracellular firing patterns from thousands of neuronal ensembles simultaneously at high spatiotemporal resolution. This approach allows the characterization of several electrophysiological network-wide features, including single/-multi-unit spiking activity patterns and local field potential oscillations. To scrutinize these multidimensional neural data, we have developed several computational tools incorporating machine learning algorithms, automatic event detection and classification, graph theory, and other advanced analyses. By supplementing these computational pipelines with this platform, we provide a methodology for studying the large, multiscale, and multimodal dynamics from cell assemblies to networks. This can potentially advance our understanding of complex brain functions and cognitive processes in health and disease. Commitment to open science and insights into large-scale computational neural dynamics could enhance brain-inspired modeling, neuromorphic computing, and neural learning algorithms. Furthermore, understanding the underlying mechanisms of impaired large-scale neural computations and their interconnected microcircuit dynamics could lead to the identification of specific biomarkers, paving the way for more accurate diagnostic tools and targeted therapies for neurological disorders.

High-resolution CMOS-based biosensor for assessing hippocampal circuit dynamics in experience-dependent plasticity.

Experiential richness creates tissue-level changes and synaptic plasticity as patterns emerge from rhythmic spatiotemporal activity of large interconnected neuronal assemblies. Despite numerous experimental and computational approaches at different scales, the precise impact of experience on network-wide computational dynamics remains inaccessible due to the lack of applicable large-scale recording methodology. We here demonstrate a large-scale multi-site biohybrid brain circuity on-CMOS-based biosensor with an unprecedented spatiotemporal resolution of 4096 microelectrodes, which allows simultaneous electrophysiological assessment across the entire hippocampal-cortical subnetworks from mice living in an enriched environment (ENR) and standard-housed (SD) conditions. Our platform, empowered with various computational analyses, reveals environmental enrichment's impacts on local and global spatiotemporal neural dynamics, firing synchrony, topological network complexity, and large-scale connectome. Our results delineate the distinct role of prior experience in enhancing multiplexed dimensional coding formed by neuronal ensembles and error tolerance and resilience to random failures compared to standard conditions. The scope and depth of these effects highlight the critical role of high-density, large-scale biosensors to provide a new understanding of the computational dynamics and information processing in multimodal physiological and experience-dependent plasticity conditions and their role in higher brain functions. Knowledge of these large-scale dynamics can inspire the development of biologically plausible computational models and computational artificial intelligence networks and expand the reach of neuromorphic brain-inspired computing into new applications.

Large-scale Multimodal Recordings on a High-density Neurochip: Olfactory Bulb and Hippocampal Networks.

A striking example of the brain's complexity and continued plasticity is the addition of new neuronal components to a circuit in a process called neurogenesis. Two brain regions exhibit profound circuit remodeling through this process - the olfactory bulb and hippocampus. However, how local network changes in both regions influence global circuit rewiring and dynamic network features remain largely unexplored due to the lack of spatiotemporal resolution technology and large-scale electrophysiological activity recordings. Here, we demonstrate large-scale recordings using a high-density neurochip to reveal multimodal circuit-wide electrophysiological properties and layer-specific functional connectivity in the olfactory bulb and hippocampal networks. Our findings illustrate simultaneous recordings from the entire network, which allows us to quantify synchronous electrophysiological parameter differences and layer-specific waveform markers. Examining pairwise cross-covariance between active electrode pairs reveals individual neuronal ensemble contributions to synchronous activation between layers and hub microcircuits, demonstrating network-wide rewiring. Our study suggests a novel tool to address the computational implications of large-scale activity patterns in functional multimodal neurogenic circuits.

Implementation of biohybrid olfactory bulb on a high-density CMOS-chip to reveal large-scale spatiotemporal circuit information.

Large-scale multi-site biosensors are essential to probe the olfactory bulb (OB) circuitry for understanding the spatiotemporal dynamics of simultaneous discharge patterns. Current ex-vivo biosensing techniques are limited to recording a small set of neurons and cannot provide an adequate resolution, which hinders revealing the fast dynamic underlying the information coding mechanisms in the OB circuit. Here, we demonstrate a novel biohybrid OB-CMOS biosensing platform to decipher the cross-scale dynamics of the OB electrogenesis and quantify the distinct neuronal coding properties. The approach with 4096-microelectrodes offers a non-invasive, label-free, bioelectrical imaging to decode simultaneous firing patterns from thousands of connected neuronal ensembles in acute OB slices. The platform can measure spontaneous and drug-induced extracellular field potential activity with substantially improved spatiotemporal resolution over conventional OB-based biosensors. Also, we employ our OB-CMOS recordings to perform multidimensional analysis to instantiate specific neurophysiological metrics underlying the olfactory spatiotemporal coding that emerged from the OB interconnected layers. Our results delineate the computational implications of large-scale activity patterns in functional olfactory processing. The systematic interplay of the experimental CMOS-base platform architecture and the high-content characterization of the olfactory circuit with various computational analyses endow significant functional interrogations of the OB information processing, high-spatiotemporal connectivity mapping, and global circuit dynamics. Thus, our study can inspire the design of advanced biomimetic olfactory-based biosensors and neuromorphic approaches for diagnostic biomarkers and drug discovery applications.