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We are developing a two-photon miniature fiber-coupled microscope that uses electrowetting lens technology for three dimensional neural imaging in freely moving animals. We are currently working to disseminate the technology to five beta users for testing in different animal models.

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Micro-scale EMG arrays for recording single- and multi-unit activity from muscle populations, and algorithms for analyzing the resulting data.

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BCI2000 provides a portable open-source platform to implement the most common scenarios of adaptive neurotechnology research. BCI2000 acquires, synchronizes, and stores signals from a wide range of data acquisition systems, and translates these signals into useful outputs in real-time.

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CaMPARI (Calcium Modulated Photoactivatable Ratiometric Integrator) – a fluorescent protein-based integrator of calcium for permanent marking of neuronal activity, Voltron – a chemigenetic fluorescent voltage indicator for in vivo recording of electrical activity. Primary use cases are marking/monitoring of neuronal activity in vivo in model organisms. Goal is to disseminate as broadly as possible, primarily via publicly-accessible repositories, to enable new biology.

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We have developed carbon fiber electrode arrays that can be optimized for either electrophsiology or the detection of dopamine. In addition, we have implemented tip sharpening techniques for better penetration into tissue such as nerves and ganglia. We wish to continue distributing these electrodes to existing collaborators and expand to new labs, with an overall emphasis on electrode customization per the user’s needs.

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Utilizing recent 3D nanoparticle printing advances, we provide exceptionally broad, dense ephys sampling across neural volumes. The CMU Array attains previously impossible densities (>6000 electrodes/cm2). More importantly, probes are fully-customizable. Any combination of positions, lengths, and impedances are possible. One-off probes are produced in hours, not weeks – and at a fraction of the cost. Even the probe platform is customizable –including curved and flexible substrates. We are currently exploring printed optogenetic waveguides and microfluidic drug delivery.

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We have developed (1) robotic platforms for automated cranial microsurgeries. (2) transparent polymer skulls for cortex-wide neural interfacing. (1) is currently being setup at multiple groups and we are helping these groups beta test. (2) is being shared via material transfer agreement to several groups at the NIH, Stanford, MIT, Johns Hopkins, UC Boulder and Princeton. We provide starter kits – with fully assembled implants, and raw materials for making dozens more. We hope to use STTR funds soon to be provided by the BRAIN Initiative to develop commercial versions of both.

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cytoNet provides a mathematical, web-based tool to rapidly characterize multiscale networks from images. To study complex tissue, cell and subcellular topologies, cytoNet integrates vision science with graph theory to quantify environmental effects on network topology. cytoNet applications include: (1) characterizing how pain sensation alters neural circuit activity in vivo, (2) quantifying patterns in how diverse brain cells respond to neurotrophic stimuli, & (3) uncovering cell cycle synchronization of differentiating neural stem cells. Awareness of cytoNet as a resource for the BRAIN Initiative community is a dissemination goal.

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DataJoint Elements provides an efficient approach for neuroscience labs to create and manage scientific data workflows: the complex multi-step methods for data collection, preparation, processing, analysis, and modeling that scientists must perform in the course of an experimental study. The work is derived from the developments in leading neuroscience projects and uses the open-source DataJoint framework for interfacing databases and automating computations.

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We are developing genetically encoded indicators for monitoring voltage in vivo (GEVIs). Our tools can use the same wavelengths and equipment as used for imaging calcium indicators. We are open to new collaborators to deploy or benchmark these indicators for new applications, model systems, and/or imaging modalities.

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We have developed new genetically-encoded reagents for fluorescence-synapse labeling and connectivity analysis in brain tissue designed for high-throughput, compartment-specific localization of synapses across diverse neuron types in the mammalian brain. High-resolution confocal image stacks of sparsely-labeled, virally-transduced neurons can be used for 3D reconstructions of postsynaptic cells, automated detection of synaptic puncta, and multichannel fluorescence alignment of dendrites, synapses, and presynaptic neurites to assess cell-type specific connectivity. We are using these fluorescence-based reagents to quantitatively evaluate changes in synaptic connectivity during learning and in mouse models of neurological disorders. The vast number of fluorescently-labeled, input- and target-specified synapses we are collecting offers new and exciting opportunities for data analysis and machine learning.

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Gray Matter Research designs and manufactures large-scale microdrive systems to enable semi-chronic recording of neural activity from large numbers of independently moveable microelectrodes to record neural circuit activity in behaving non-human primates. Recent innovations include a larger number of electrodes and longer travel distances, flexibility to curve electrode trajectories, ability to register the electrodes to post-op scans and improved reliability. Our microdrive systems are used in over 50 laboratories worldwide. We also developed a prosthetic instrument expanding the scope and reliability of a new generation of microdrives using multi-channel laminar probes. This class of instrumentation is under development and in use in multiple laboratories. These tools provide unprecedented capabilties for reseachers to measure the activity in distributed neural circuits in behaving non-human primate performing cognitive tasks.

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Magneto- and electro-encephalography (MEG/EEG) are the two methods to non-invasively record human brain activity with millisecond temporal resolution. MEG and EEG provide reliable markers of healthy brain function and disease states. However, the difficulty of relating these macroscopic signals to the underlying cellular- and circuit-level neural generators is a major, fundamental limitation that constrains using MEG/EEG to reveal novel principles of information processing or to translate the findings into new therapies for neural pathologies. To address this problem, we built the Human Neocortical Neurosolver (HNN, https://hnn.brown.edu). HNN is a user-friendly software tool designed to help researchers, and clinicians interpret the cellular and network origins of MEG/EEG data. HNN’s core is a detailed, mechanistic neural model including canonical features of a layered neocortical circuit, with layer-specific thalamocortical and cortico-cortical drive. HNN’s model is uniquely designed to account for the biophysical origin of the electrical currents generating MEG/EEG with enough detail to connect to the underlying cellular-level activity. HNN provides a user-friendly graphical user interface so that researchers can work interactively between model and data without needing to alter the underlying mathematical model or the open-source code. Tutorials on how to simulate the most commonly measured signals, including event related potentials and brain rhythms (alpha, beta, gamma), are provided. Researchers can compare simulated signals to recorded data and easily manipulate the model parameters to develop and test alternative hypotheses for the neural origin of their signals. Micro-scale features, including layer-specific responses, cell spiking activity, and somatic voltages, can be visualized and used to guide validation of model predictions with a variety of invasive and non-invasive methods. The ability of HNN to associate signals across scales makes it a unique tool for translational neuroscience research.

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We have developed micro-coil that can be implanted into the cortex and used to magnetically stimulate cortical neurons. Coils have two important advantages over conventional micro-electrodes. First, the magnetic fields they induce are less susceptible to changes in the surrounding environment, e.g. due to foreign body responses, and second, the fields they induce can be shaped to selectively target specific types of neurons.

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BARseq and MAPseq can map long-range projections of 1000s of neurons in a single brain area at single neuron resolution, and further correlate projections to gene expression and Cre. We achieve mapping of densely labeled neurons at single neuron resolution by cellular barcoding and sequencing. Our methods allow comparison of projections across neuronal subtypes within an animal, across individual animals, and across genotypes. We offer MAPseq service through CSHL core facility, and may offer BARseq service in the future. We also welcome other labs to adopt both methods on their own.

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Our goal is to disseminate high-density micro-LED optoelectrodes for mapping circuits in the brain.

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Miniature micro-endoscope. The micro-endoscope presented here has a small footprint, weight, and cost making it almost disposable. It can be used to record brain activity in multiple brain areas simultaneously in mice.

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MoSeq (or Motion Sequencing) provides a pipeline for quantifying 3D video of freely behaving mice and discovering the underlying structure of mouse behavior. MoSeq automatically locates, tracks, and quantifies the mouse in each frame of the video. Unlike typical supervised behavioral classifiers that then require human labeling, the pipeline instead trains an unsupervised machine learning model to identify repeated motifs (or syllables) of behavior. The pipeline then offers a suite of visualization tools and statistical tests for understanding the discovered behaviors and comparing them across experimental conditions. MoSeq dramatically reduces human labor in exploring mouse behavior, discovers previously unknown behaviors, and allows neuroscientists to more completely relate neural activity to free behavior.

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Neurodata Without Borders: Neurophysiology (NWB) is a data standard for neurophysiology, providing neuroscientists with a common standard to share, archive, use, and build common analysis tools for neurophysiology data. NWB is designed to store a variety of neurophysiology data, including data from intracellular and extracellular electrophysiology experiments, data from optical physiology experiments, and tracking and stimulus data. NWB is more than just a file format; it defines an ecosystem of tools, methods, and standards for storing, sharing, and analyzing complex neurophysiology data. NWB provides software for data standardization and application programming interfaces (APIs) for reading and writing the data, and is supported by a growing ecosystem of data analysis and management tools.

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We are building a suite of bioluminescent molecular tools for controlling cells and tracking activity, as well as hardware (most notably, microscopes) to optimize their use. The NeuroNex Bioluminescence hub systematically develops and disseminates these novel and powerful tools for brain science.

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Imaging deeper, wider, and faster. Imaging multiple species using multiphoton microscope. Dissemination through meetings, campus visits, and commercial vendors.

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We have made and validated these nanoparticles (as supported by the BRAIN Initiative), and shown that after an intravenous infusion of the nanoparticles, they induce drug effects only when and where focused ultrasound is applied to the brain. We have seen that the particles may be loaded with any of a variety of neuromodulatory agents. We have also validated a production and storage scheme that will allow them to be stored long term and shipped frozen to collaborator sites. We are now working on a fool-proof protocol for any lab to easily make their own particles.

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This collection of documentation includes shared clinical protocols, IDE submission materials, FDA correspondence and meeting materials, file formats, QMS and design control background, and related reference material for groups designing and spearheading clinical studies utilizing advanced bidirectional DBS device technology.

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This collection of software tools is geared to support research using advanced deep-brain (DBS) stimulation technology (e.g. Medtronic’s Summit RC+S system) in clinical studies. The tools have been developed and shared by OpenMind Consortim member laboratories and include read-me, explanatory videos, and other material to enable use and adaptation by users to suit their research needs. The tools encompass code for data visualization and analysis, as well as code for device programming and control via device APIs. This set of resources helps to fill a critical gap in technological capacity needed to fully utilize advanced DBS device technology in clinical studies, and brings efficiencies in cost, labor, time and knowledge-sharing to the community of advanced DBS researchers.

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OpenScope opens the Allen Brain Observatory pipeline to the community, enabling theoretical, computational, and experimental scientists to test sophisticated hypotheses on brain function in a process analogous to astronomical observatories that survey the night sky. Once a year OpenScope will accept experimental proposals from external scientists, which will be reviewed by a panel of leading experts for their feasibility and scientific merit. The Allen Institute will carry out the selected experiments following verified, reproducible, and open protocols for in vivo single- and multi-area two photon calcium imaging and Neuropixels electrophysiology, making the data freely available to these scientists and to the community. This will lower barriers to testing new hypotheses about brain function, bring new computational and theoretical talents into the field, and enhance the reproducibility of results in brain research, thereby accelerating progress toward an integrated understanding of neural activity in health and disease.

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We have built a set of open-source tools for precisely locking experimental perturbations (optical/electrical/magnetic stimulation, behavioral triggering, etc.) to the phase of ongoing LFP oscillations (probably could be used with anything that has an oscillation, e.g. whisking). They are substantially more accurate than anything in the published literature and have been adapted to work with both human and animal experimental rigs. The target use case is understanding the role of oscillatory phase in cognition, e.g. altering phase relations between structures by timed perturbation.

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The Polymer Implantable Electrode (PIE) Foundry is a service which provides access to polymer-based microelectrode arrays for neuroscientists, by providing training, testing, and custom-made devices. Polymer-based electrodes offer improved device lifetime compared with conventional silicon and microwire probes, but there are few commercial options. By adapting processes from semiconductor foundries, the PIE Foundry can produce made-to-order devices with a high-degree of uniformity and precision. PIE Foundry offers BRAIN community members tools and training so they can incorporate polymer-based probes and electrodes into their own research.

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We have developed a modular recordings system with soft, flexible polymer electrodes that makes it possible to record from hundreds of neurons distributed across many brain areas, and to do so for many months. We are currently distributing these electrodes to ~20 other labs for testing, and their feedback will be used to further refine the devices. Our long term goal is to be able to disseminate these devices to the entire community.

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We develop, validate, and enhance community access to a diverse toolbox of renewable recombinant antibodies and affinity reagents for neuroscience research. Extensively characterized in mammalian brain samples (rat, mouse, human).These reagents include conventional and recombinant mouse monoclonal antibodies and miniaturized ScFV derivatives, and nanobodies (single chain miniaturized antibodies). The small size, solubility, and stability of ScFvs and nAbs facilitates their functional expression in mammalian cells, allowing for their use as intrabodies to target cargo including optogenetic reports and actuators to distinct subcellular sites in neurons. Their small size also enhances the resolution of light and electron microscope imaging when they are used as immunolabels, and their penetration into intact cleared samples.

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single-cell combinatorial indexing on Microbiopsies Assigned to Positions for the Assay for Transposase Accessible Chromatin (sciMAP-ATAC). High-throughput single cell genomic assays resolve the heterogeneity of cell states in complex tissues, however, the spatial orientation within the network of interconnected cells is lost. We present a novel method for capturing spatially-resolved epigenomic profiles of single cells within intact tissue, and apply this method to generate non-neuronal cell taxonomy atlases of human and mouse cortex. This method will be made accessible through protocols.io and all data, along with single cell analyses, will be made available through the BRAIN Initiative Cell Census Network (BICCN)

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SLEAP (Social LEAP Estimates Animal Poses) is a deep learning software framework for general purpose multi-animal limb tracking from video. This software couples a GUI for importing and annotating data with deep neural networks designed for learning to locate and associate user-specified anatomical landmarks on unmarked animals. Use cases range from kinematic studies of animal movement, to quantification of social dynamics via multi-animal part tracking.

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This resource provides the service of characterization of multiphoton absorption properties and multiphoton stability to a large number of protein engineers and neuroscientists involved in the BRAIN initiative. This information is indispensable because it makes it possible to choose the best probe and best excitation conditions (wavelength, laser power, etc.) for deep high-resolution multiphoton microscopy of the brain. Although there are few laboratories around the world that are able to quantitatively characterize the multiphoton properties of organic molecules, they are either not dealing with the probes utilized in neuroscience or they are not providing the service for all interested BRAIN researchers.

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I lead the development of the open source UCLA Miniscope project. We develop the most widely used miniature microscope for neural recording in freely behaving animals. Our system is currently in about 500 labs and we look to continue expanding access to transformative tools. New miniaturized microscopes: wireless, large field-of-view, integrated with electrophysiology. We disseminate our tools on miniscope.org

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The Floating Microelectrode Array allows stimulation and recording from the CNS and the periphery through a wireless link. This device is 5mm diameter and can interface to 16 electrodes without any wires or tethers. Power and communication is through a magnetic wireless link. The WFMA is being used for a clinical trial of cortical visual prosthesis, but has also been used for peripheral nerve (cuff) interface. Currently it is being deployed for neuroscience research through a joint effort by MicroProbes for Life Science and Sigenics, Inc.

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