Funded Awards

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Title Investigator Institute Fiscal Year FOA Number Status Project Number Priority Area Summary
3D neonatal Photoacoustic Tomography (3D-nPAT) to detect Hypoxic-Ischemic brain injury in preterm neonates Nasiriavanaki, Mohammadreza Wayne State University 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Hypoxic-ischemic brain injury (HII) is a severe condition caused by a lack of oxygen to the brain at or near the time of birth in preterm and low birth weight newborns. Unfortunately, there is a lack of high quality, non-invasive imaging technologies that allow for bed-side imaging of brain hypoxia and monitoring of early brain development in newborn children. Dr. Nasiriavanaki and colleagues will develop a novel, portable, point-of-care 3D neonatal photoacoustic tomography (3D-nPAT) system to detect hypoxic ischemic brain regions in preterm neonates. Unlike current imaging options, this technology will not require sedation, radiation, or radionuclides. 3D-nPAT aims to provide an accurate 3D map of brain tissue oxygen levels within the neonatal cranium, which will improve the diagnostic information of HII.

3D Printed Multifunctional Brain Windows for Simultaneous Optical Imaging and Electrophysiology Kodandaramaiah, Suhasa B (contact) Mcalpine, Michael Applied Universal Dynamics Corporation 2019 Active
  • Circuit Diagrams
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  • Monitor Neural Activity

A mechanistic understanding of the neuronal underpinnings of sensory perception, action, emotion, and cognition requires measuring activities of these neuronal circuits at single cell resolution across several millimeters, and at multiple temporal scales. However, methods providing high spatial resolution often lack concurrent high temporal resolution and vice versa, creating technical challenges. Working with Applied Universal Dynamics Corporation, Dr. Kodandaramaiah and team plan to engineer and commercially disseminate digitally generated, functionalized cranial prostheses (“brain windows”) that combine wide‐field optical imaging with concurrent electrical recordings of neuronal activities for widefield activity mapping of the whole cortex during behavior. These developments will inform fundamentally new experimental paradigms in mice and enable new insights into the neuronal computations that underlie sensory perception, action and cognitive processes.

3D-Fast Optical Interface for Rapid Volumetric Neural Sensing and Modulation Gibson, Emily Welle, Cristin G (contact) University Of Colorado Denver 2018 Active
  • Interventional Tools
  • Monitor Neural Activity

To further our understanding of how neural circuits function, we need tools that can collect simultaneous measurements from large populations of neurons involved in a common neural computation and provide precise functional modulation. Current optical imaging in awake animals expressing calcium indicators provides spatial and temporal precision, but limitations include small fields-of-view (encompassing single brain regions) and head-fixation requirements that prevents naturalistic behavior. Welle and Gibson propose an optical interface that uses novel hardware and computational strategies to allow for fast 3D-imaging (3D-FAST), precisely-patterned optogenetic stimulation, and closed-loop recording in freely-moving animals. They will test the technology in rodents and record from and modulate thousands of neurons to lay the ground for additional behavioral experiments in untethered animals.

4D Transcranial Acoustoelectric Imaging for High Resolution Functional Mapping of Neuronal Currents Witte, Russell S (contact) University Of Arizona 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Achieving high spatiotemporal resolution with non-invasive electrophysiology measurements continues to be a challenge for human neuroscience. One promising method is transcranial acoustoelectric brain imaging (tABI), which uses an ultrasound beam to safely and briefly alter brain tissue conductivity. The rapid detection of these modulations overcomes limitations in conventional electroencephalography that can result in signal blurring. Here, Dr. Witte and a multidisciplinary team of investigators aim to develop, validate and implement tABI for noninvasive functional mapping of neural currents deep in the human brain through the skull. The success of this approach would demonstrate a safe and revolutionary modality for mapping brain electrical activities, enabling future work to transform our understanding of brain function.

A 100MM Scale Single Unit Neural Recording Probe Using IR-Based Powering and Communication Blaauw, David University Of Michigan At Ann Arbor 2018 Active
  • Interventional Tools
  • Monitor Neural Activity

Wireless, small, injectable neural recording modules have been a long-standing goal in neuroscience. Blaauw’s team presents a new approach for recording and transmitting neural signals at the single- neuron level, using fully-wireless, 100x100μm-sized micro-probe implants (mProbes). mProbes can be injected into the brain at nearly unlimited locations in the sub-arachnoid space. The fully wireless nature afforded by near-infra-red transmitters and receivers of the mProbes reduces implant complexity and risk of complications (e.g., infection and cerebrospinal leakage), and enables mechanical isolation of the implanted probe that is critical for minimizing tissue damage. Functional testing will be done in the rat motor cortex. This technology will allow controlled placement of large numbers of independent wireless neural interfaces that could be useful for brain-machine interface applications.

A Biomimetic Approach Towards a Dexterous Neuroprosthesis BONINGER, MICHAEL UNIVERSITY OF PITTSBURGH AT PITTSBURGH 2018 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

Brain-computer interfaces and neuroprosthetics have provided a significant benefit to patients with cervical spinal cord injuries. However, current technology is limited in its abilities to allow the user to control how much force is exerted by the prosthesis and to provide sensory feedback from the prosthetic hand. In a public-private collaboration with Blackrock Microsystems, Dr. Boninger and colleagues are looking to improve the dexterity of neuroprostheses by incorporating microstimulation of the somatosensory cortex. This stimulation could provide tactile feedback to the user and hopefully allow the user to better control the force applied. Ultimately, this approach will improve the dexterity and control of prosthetic limbs used by patients with spinal cord injuries.

A BRAIN Initiative Resource: The Neuroscience Multi-omic Data Archive White, Owen R University Of Maryland Baltimore 2017 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

A thorough understanding of the complexities of the brain’s different cell types requires the sharing and integration of myriad genomic information generated from various data sources. Owen White proposes creating a Neuroscience Multi-Omic (NeMO) Archive, a cloud-based data repository for -omic data. White and his team of researchers will establish an archive for multi-omic data and metadata of the BRAIN Initiative. The group will document and archive data processing workflows to ensure standardization, as well as create resources for user engagement and data visualization. The NeMO Archive will provide an accessible community resource for raw -omics data and for other BRAIN Initiative project data, making them available for computation by the general research community.

A compact, modular two-photon fiber-coupled microscope for in vivo all-optical electrophysiology Gibson, Emily Kilborn, Karl (contact) 3 I 2019 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

Studies with freely-moving animals often encounter technical impediments that prevent the recording and perturbation of neural activity at cellular resolution. Working with Intelligent Imaging Innovations Inc (3I), Dr. Karl Kilborn and team will evaluate the feasibility of constructing a compact, stand-alone system that uses a laser source to perform fast, volumetric interrogation of cortical circuits in awake, behaving animals. They will validate the use of a two-photon, fiber-coupled microscope that can transmit light to optogenetically-targeted brain areas, as well as record biochemical signals from the same (or even different) brain areas. The success of this project will greatly increase the types of experiments that can be conducted in freely-moving animals, leading to a better understanding of the links between complex neural activity and behavior.

A Computational Miniature Mesoscope for Large-Scale Brain Mapping in Behaving Mice Boas, David A Davison, Ian Gordon Tian, Lei (contact) Boston University (charles River Campus) 2019 Active
  • Interventional Tools
  • Monitor Neural Activity

Watching the brain in action can help advance our knowledge of how neuronal activity produces behaviors but currently, long-term brain monitoring systems have a limited field of view. Here, the multidisciplinary collaborative group will create a novel head-mounted miniscope that will image large areas of the cortex in freely moving mice. Based on their novel computational imaging framework, the researchers aim to develop the Computational Miniature Mesoscope (CM2), which uses parallel sampling with single lightweight microlens array to simplify the optical path, producing an increased field of view with maximized light-throughput, resolution and signal-to-noise ratio. The team will develop novel optical designs for ‘wearable’ cellular-resolution Ca2+ imaging throughout neocortex and then validate and optimize the CM2 for cortex-wide functional imaging in behaving mice. This new technology aims to expand researchers’ ability to probe neuronal activity over large areas of the brain, furthering our understanding of the neural basis of behavior.

A Confocal Fluorescence Microscopy Brain Data Archive Bruchez, Marcel P Ropelewski, Alexander J (contact) Watkins, Simon C Carnegie-mellon University 2017 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

Advances in microscopy and imaging have created new possibilities in many fields of research, but these advances have also generated large amounts of data that can overwhelm traditional data management systems. Along with collaborators at Carnegie Mellon University and the University of Pittsburgh, Alexander Ropelewski plans to establish a BRAIN Imaging Archive that takes advantages of infrastructure and personnel resources at the Pittsburgh Supercomputing Center. The Archive will include a pipeline for data submission, user access and support, and BRAIN Initiative community engagement through an online presence, workshops, and hackathons. This unique resource will provide an accessible and cost-effective way for the research community to analyze, share, and interact with large image datasets of the BRAIN Initiative.

A data science toolbox for analysis of Human Connectome Project diffusion MRI Rokem, Ariel Shalom University Of Washington 2019 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
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  • Monitor Neural Activity
  • Theory & Data Analysis Tools

The Human Connectome Project provides one of the largest publicly available datasets of diffusion MRI from a sample of healthy individuals. Dr. Rokem and team will create an end-to-end pipeline for analysis of human white matter connections by using “tractometry” methods to analyze the diffusion MRI dataset from the Human Connectome Project. In tractometry, tissue properties are estimated in the long-range connections between remote brain regions. This project aims to generate a normative distribution of tissue properties in the major white matter connections, develop novel statistical methods to connect the properties of white matter connections to cognitive abilities, and create visualization tools to further explore and communicate the data. These tools may create an easily accessible platform that could be applied to other important neuroscience datasets.

A Facility to Generate Connectomics Information Lichtman, Jeff HARVARD UNIVERSITY 2018 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

Connectomics describes a field of study that builds maps of the connections within the brain. Dr. Lichtman and colleagues have developed a facility for generating high-resolution, large-volume serial section electron microscopy data that can be used to generate connectomic maps. In this project, access to the facility, techniques, and analytical software will be provided to the broader neuroscience community. This will allow other research groups who may be inexperienced in these techniques to generate data in projects aimed at mapping brain circuitry, a high priority goal in the BRAIN 2025 report. By providing this resource, Dr. Lichtman and colleagues will help researchers classify the cell types within healthy and diseased brains or model systems, which will improve our understanding of brain function and neurological disorders.

A Fast, Accurate and Cloud-based Data Processing Pipeline for High-Density, High-Site-Count Electrophysiology Kimmel, Bruce VIDRIO TECHNOLOGIES, LLC 2018 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

The community’s need for an integrated open-source analysis platform is rapidly growing due to the increasing capacity of extracellular electrodes and the limited number of new and validated spike- sorting methods. JRCLUST, a free, open-source, standalone spike sorting software, offers a scalable, automated and well-validated spike sorting workflow for analysis of data generated by large multielectrode arrays. The software can tolerate experimental recording conditions from behaving animals, and it can handle a wide range of datasets using a set of pre-optimized parameters making it practical for wide use in the community. JRCLUST has been adopted in 20+ labs worldwide since its inception less than a year ago. Drs. Kimmel and Nathan seek to expand and maintain JRCLUST, thus empowering researchers to elucidate how functionally defined subpopulations of neurons mediate specific information-processing functions at key moments during behavior.

A fully biological platform for monitoring mesoscale neural activity Dzirasa, Kafui Duke University 2018 Active
  • Interventional Tools
  • Monitor Neural Activity

A barrier to understanding the brain is its geometry. When electrodes are implanted to access deep subcortical structures, brain tissue at the surface is often destroyed in the process. Dzirasa’s team will develop a technology to ‘functionally’ change the geometry of the brain by biologically projecting neural activity onto a flat surface for real-time imaging. In awake-behaving animals, the team will grow (rather than implant) a ‘biological electrode’ into the brain with engineered proteins, then convert the electrical activity into fluorescent light that can be imaged on a flat surface atop the brain. This approach will be scalable to allow recording of 100,000s of neurons simultaneously throughout the entire depth of the brain, revolutionizing neural recordings across model species and humans.

A Functional and Selective Toolkit for Choroid Plexus Networks Lehtinen, Maria (contact) Moore, Christopher I Boston Children's Hospital 2019 Active
  • Cell Type
  • Circuit Diagrams
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  • Monitor Neural Activity

Composed of epithelial cells and primary non-neuronal cells, the choroid plexus (ChP) produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Studies of the ChP have been limited by a lack of tools to target and characterize ChP cells in vivo. Leveraging new single-cell transcriptomic data, Dr. Lethinen and her team aim to engineer genetic driver lines in mice that will allow precision monitoring and control of specific ChP cell types. In collaboration with the Andermann and Moore labs, the team will develop new 3D two-photon imaging methods to observe and control calcium activity, as well as visualize motility, of defined ChP cells, before developing opto- and chemogenetic protocols for ChP regulation. This toolkit aims to improve access and control of cells within the choroid plexus, advancing the knowledge of this deep brain tissue.

A General Approach for the Development of New Cell-Type-Specific Viral Vectors Greenberg, Michael E Harvard Medical School 2017 Active
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
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The limited ability to genetically access specific neural cell types, based on distinctive gene expression patterns, impedes brain function probing and therapy development. Greenberg and colleagues will generate recombinant viral reagents that target specific cortical cell types, using recent advances in genetics and a novel application of single-cell transcriptome analysis. They propose to identify genetic drivers specific for excitatory and inhibitory mouse cortical neuronal subtypes. If successful, this may establish a general method for identifying cell-type-specific genetic elements that can be used in viral vectors to drive gene expression, could be applied to other brain regions and mammalian species, and may assist cell-type-specific applications like neuronal activity monitoring, optogenetic and chemogenetic manipulation, axonal tracing, gene delivery, and genome editing.
A high-performance unshielded wearable brain-computer interface based on microfabricated total-field OPMs Contreras-vidal, Jose Luis (contact) Knappe, Svenja University Of Houston 2018 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Non-invasive imaging methods, such as magnetoencephalography (MEG), are powerful in their ability to image brain dynamics without contacting the skull and scalp, but MEG is limited by the requirement of a magnetic shielding environment. In this proof-of-concept project, Drs. Jose Contreras-Vidal, Svenja Knappe, and a team of investigators will develop a wearable, compact, and noninvasive MEG system that can operate without external shielding, while maintaining high performance. The group will then validate the prototype system in a small-scale human study through a closed-loop MEG-based brain-computer interface system. The successful creation of a wearable MEG system will enable behaviorally active human neuroimaging that allows flexible movement in time and space, while providing high-quality sensitivity to neuronal sources.

A high-speed volumetric multiphoton microscope for the study of developing neural circuits in retina Feller, Marla University Of California Berkeley 2016 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • Theory & Data Analysis Tools
Spontaneous neuronal activity plays a role in the wiring of retinal circuits during development. Current imaging techniques are unable to capture such activity accurately. Dr. Feller’s team will assemble a system containing a resonant scanner-based two-photon microscope with the ability to achieve three-dimensional imaging of a single spontaneous firing event in vivo. Her team will utilize this high-speed volumetric two-photon imaging during visual stimulation to study the formation of functional neuronal circuits in the developing mouse retina.
A magnetic particle imager (MPI) for functional brain imaging in humans Wald, Lawrence L Massachusetts General Hospital 2017 Active
  • Monitor Neural Activity
  • Interventional Tools
  • Integrated Approaches
  • Human Neuroscience
A complete understanding of human brain network structure and functional activation requires non-invasive imaging tools that generate high-resolution functional maps with dramatically increased sensitivity. Lawrence Wald and his team believe that achieving the next level of sensitivity of neuroimaging technology will occur through functional magnetic particle imaging (MPI). Unlike functional magnetic resonance imaging (fMRI) which indirectly detects blood oxygenation level, fMPI can directly detect this iron concentration with no intermediate step. Because MPI shares a technological foundation with MRI, the researchers can validate the fMPI method in animals and human simulations before assessing its sensitivity in humans. The development of fMPI could provide brain function information over an order of magnitude more sensitive than fMRI.
A Massive Library of AAVs to Target Transcriptionally-Defined Primate Cell Types Stauffer, William Richard University Of Pittsburgh At Pittsburgh 2019 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

Development of targeted gene therapeutics to treat neurological and psychiatric disorders requires improved tools to probe circuit-specific functions. Dr. Stauffer and collaborators plan to combine single-cell RNA-Seq (scRNA-Seq) with high-throughput screening of engineered adeno-associated viruses (AAVs) to create a toolbox to minimally invasively monitor and manipulate of neurons in macaques. The researchers plan to create large libraries of mutated AAV vectors and synthetic regulatory elements, in which each variant is paired with a unique DNA barcode and use scRNA-Seq to capture the transcriptome for each cell, as well as quantify barcode expression. The team will then perform validation studies using the optimized AAVs to explore and inventory cell type-specific circuits for mood, learning, and vision in non-human primates, potentially producing a toolkit that could be applied to other large brains.

A method for anterograde trans-synaptic tracing Arnold, Donald B University Of Southern California 2018 Active
  • Cell Type
  • Circuit Diagrams
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  • Monitor Neural Activity

To understand how the activation of individual neurons in the brain leads to particular behaviors, it is necessary to identify synaptic connections to downstream neurons. Although considerable information about neuronal circuits has been generated using rabies virus to trace trans-synaptic connections in the retrograde direction, there is no comparable technique for trans-synaptic tracing in the anterograde direction. In rodent brains, Arnold and colleagues will optimize a non-toxic method for anterograde monosynaptic tracing from single neurons to virtually any postsynaptic receptor. Their method labels only active synapses, ensuring the technique’s physiological relevance.

A microscope optimized for brain-scale 2-photon imaging Pesaran, Bijan New York University 2017 Active
  • Monitor Neural Activity
  • Interventional Tools
Two-photon optical imaging of large populations of genetically-modified neurons is a powerful tool for studying neuronal circuits. Developed primarily for rodent models, use of this technology in primates is currently very challenging, in part due to the restricted imaging fields of traditional microscopes. Bijan Pesaran and a team of neuroscientists and engineers will develop an automated platform to enable imaging across multiple imaging fields situated over broad areas of the primate neocortex with micrometer precision. The group will leverage a recently developed two-photon random-access mesoscope with a very large field of view for optimal neural recordings. Their goal is to provide a unique perspective into the neural dynamics of the primate brain.
A multimodal platform to bridge the experimental gap between behavioral, neuronal, and molecular studies Cai, Dawen (contact) Cui, Meng University Of Michigan At Ann Arbor 2019 Active
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  • Monitor Neural Activity

Despite the success in technology development in neuroscience, there currently lacks a method to directly link activity, connectivity, and molecular identity of individual neurons in a functional circuit at the single cell resolution. Here, Drs. Cai, Cui, and teams aim to use coMAAP, a method that combines Brainbow AAV labeling, calcium imaging, innovative sample preparation, and light-sheet microscopy, to acquire correlative optical mapping of activity, anatomy, and molecular identity of the same neurons in the same animal. After optimizing and validating the coMAAP experimental paradigm, they plan to utilize coMAAP to uncover the heterogenous neuronal populations that are activated in the mouse ventral tegmental area during arousal. Improved understanding of the cellular and circuitry components could accelerate the identification of specific neuronal targets in psychiatric disorders.

A new approach to biological recording of lineage hierarchy in primate brains Brivanlou, Ali H Rockefeller University 2019 Active
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  • Monitor Neural Activity

Current genetic lineage recorders are limited to a finite number of recording events, making them unsuitable for the study of prolonged development. Here, Dr. Brivanlou’s lab plans to use a new approached called CHRONICLE to enable continuous, dynamic lineage-tracing in non-human primates. CHRONICLE (Cellular Hierarchy Recording in Organisms by Nucleotide Interconversion with Cas9 Linked Editors) combines base-editing with self-targeting guide RNA arrays to generate a large collection of sequence variants that can be used to trace cellular hierarchy lineages. The researchers aim to trace lineages in vitro human and marmoset cortical organoids, as well as in vivo marmoset early embryos, compare developmental lineage trees of the marmoset cortex in projection neurons, interneurons, and glia using single cell RNA analysis. Understanding novel lineage relationships of the primate brain may improve our ability to use developmental principles to restore function in diseased and damaged tissues.

A new strategy for cell-type specific gene disruption in flies and mice Clandinin, Thomas Robert (contact) Shah, Nirao Mahesh Stanford University 2015 Complete
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
The ability to inactivate targeted genes only in relevant cell types is critical for understanding how specific genes contribute to circuit function and dysfunction. Clandinin's team will generate novel tools to inactivate genes in specific cell-types, and will validate these tools with imaging experiments and behavioral tests in live fruit flies. They will then adapt the tools for use in mice to directly manipulate genes controlling neuronal excitation and inhibition.
A novel approach to examine slow synaptic transmission in vivo Mao, Tianyi Zhong, Haining (contact) Oregon Health & Science University 2015 Complete
  • Monitor Neural Activity
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Neuromodulation events, which regulate neuronal excitability and plasticity, have been extensively studied from the standpoint of individual neurons, but their actions and effects in behaving animals are poorly understood because of the absence of a toolset for recording these events in vivo. Zhong and Maowill develop in vivo sensors of cyclic AMP/protein kinase A (cAMP/PKA) signaling, which is an important intracellular target of neuromodulators such as norepinephrine and dopamine. The investigators will optimize cAMP/PKA sensors for 2-photon fluorescent lifetime imaging, which is predicted to be more robust to tissue scattering and differences in probe concentration than traditional methods.
A novel optically pumped magnetometer (OPM) system for high resolution magnetocorticography Nugent, Allison C. (contact); Robinson, Stephen E. U.s. National Institute Of Mental Health 2019 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Magnetoencephalography (MEG) is a non-invasive imaging technology that measures the magnetic field outside the head produced by electrophysiological activity in the brain. Currently available MEG systems, which are based on superconducting quantum interference devices (SQUIDs), often lack spatial resolution because the sensors cannot be placed directly on the scalp. Drs. Nugent, Robinson, and team will develop a new system based on an optically pumped magnetometer (OPM) for non-invasive human brain imaging.  By minimizing the standoff distance, this new magnetocorticography technology will be capable of providing millimeter resolution mapping of cortical brain function in healthy and diseased brains.

A novel platform for genetically-encoded optical neuropeptide sensors (NEONS) Banghart, Matthew Ryan (contact) Chang, Geoffrey A University Of California, San Diego 2017 Active
  • Monitor Neural Activity
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Neuropeptides, a special class of neuromodulator, can initiate biochemical signaling events that change neuronal physiology in diverse and subtle ways, but current methodologies to study them lack spatiotemporal precision. Matthew Banghart and Geoffrey Chang are developing genetically-encoded optical sensors that can quantify the presence of neuropeptides in brain tissue. Their strategy is to fuse fluorescent reporters to nanobodies that bind neuropeptides and generate an optical signal. By overcoming the challenge of converting peptide binding to an optical signal, this novel approach will improve spatiotemporal precision by permitting micron- and millisecond-scale measurements. After first testing the method in brain slices, the team ultimately plans to use the resulting probes in vivo to identify behaviors linked to peptide release.
A novel platform for the investigation of human microglia Blurton-jones, Mathew Mark Gandhi, Sunil (contact) Spitale, Robert C University Of California-irvine 2019 Active
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  • Monitor Neural Activity

Recent work has revealed the need for a robust system to accurately model the dynamic nature of human microglia in the brain in health and disease. Dr. Gandhi and team aim to validate a novel mouse xenotransplantation platform, XMG, using human induced pluripotent stem cell-derived microglia as a promising model system which they intend to disseminate publicly. The group will compare the transcriptional landscape of XMG to endogenous microglia from mice and humans, as well as use cutting edge multiphoton imaging technique to measure calcium activity and insulin response of XMG following acute insult. Further, the group will query changes in the function of XMG in the context of a pathological state resembling Alzherimer’s disease in the mouse. Developing this novel XMG system may advance the ability to study human microglia in vivo and provide far-reaching insights into microglial biology.

A platform for high-throughput production of targeting systems for cell-type-specific transgene expression in wild-type animals Wickersham, Ian R Massachusetts Institute Of Technology 2016 Active
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  • Circuit Diagrams
  • Monitor Neural Activity
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In vivo genetic modification within a specific cell type generally requires production of transgenic or knockout animal models, a time- and resource-consuming process. Wickersham and colleagues will use high-throughput techniques to develop a novel set of viral vectors to allow selective transgene expression in targeted neuronal subpopulations in wild-type mammals. These tools will expand the possibility of optogenetic control, recording, and genomic modification of neural circuits to uncover their organization in healthy and dysfunctional brains, with potential therapeutic use in humans for mental and neurological disorders.
A robust ionotropic activator for brain-wide manipulation of neuronal function Ellington, Andrew D (contact) Zemelman, Boris V University Of Texas, Austin 2015 Complete
  • Monitor Neural Activity
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The ability to manipulate defined neuron populations has revolutionized in vivo investigations of brain circuitry. Although optogenetics has captured much of the attention in this realm, so-called "chemical genetic" strategies utilizing artificial receptor-ligand pairs have been highly successful, and have the advantage that they can access cell populations scattered across the brain. Using such strategies, specific neural populations that are genetically modified to express an artificial receptor can be manipulated by administering the corresponding chemical ligand to the animal, providing control of specific brain circuits. Ellington and Zemelman propose a new class of artificial receptors that directly couple ion channel activation to receptor binding, and unlike the most popular designer receptor techniques, do not rely on the intracellular signaling pathways of the host organism for their effects.
A SAFE AND COMPACT NEONATE TO ADULT NEUROIMAGING MRI SYSTEM Srinivasan, Ravi Advanced Imaging Research, Inc. 2019 Active
  • Circuit Diagrams
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Magnetic resonance imaging (MRI) is an established diagnostic tool. However, while mapping dynamic anatomical and functional connectivity in the human brain is essential, adult MRI systems are not well-suited for clinical use in infants and children. Working with Advanced Imaging Research Inc., Dr. Ravi Srinivasan and team propose to create a compact MRI system that provides MRI systems to infants, children, and adults in any hospital department. The group will develop, test, and refine a compact MRI system with strong connectome gradients, thus alleviating cost and safety burdens that can be posed by large adult whole-body MRIs. The success of the project could stimulate development of mobile mental health and stroke assessment systems, thereby improving accessibility to MRI systems.

A system for whole-brain recording and control of activated neurons with near-infrared light Shcherbakova, Daria Albert Einstein College Of Medicine, Inc 2019 Active
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  • Monitor Neural Activity

Observing activity across the entire brain should help increase understanding of how it responds to stimuli and leads to behavior. Available technology limits what can be seen by restricting observations to small areas, slowly recording activity, and damaging the brain. Dr. Shcherbakova’s team will develop novel technology that will allow for recording of neuronal activity in the entire mouse brain using noninvasive near-infrared light (NIR). The researchers will develop a NIR optogenetic system of light-inducible protein-protein interaction (PPI), combining a calcium-induced PPI and a NIR-induced PPI to drive gene expression of fluorescent proteins or other optogenetic tools in activated neurons. The system will be optimized in cultured cells and primary neurons, then validated in vivo, targeting the primary motor cortex of mice. This tool will allow researchers to study circuit activity during behavior in freely moving animals, advancing our understanding of how the brain processes information in health and disease.

A Technology Resource for Polymer Microelectrode Arrays Meng, Ellis (contact); Song, Dong University Of Southern California 2019 Active
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  • Human Neuroscience
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Polymer microelectrode arrays are electrical recording devices made of flexible materials. These materials reduce tissue damage and improve the long-term stability of the recording setup. The Meng and Song labs aim to establish a service that will manufacture and test out arrays that are customized to researchers’ needs. The service may help researchers use the latest electrical recording devices for studying a variety of neurological disorders.

A TOF, DOI, MRI compatible PET detector to support sub-millimeter neuroPET imaging Dolinsky, Sergei Miyaoka, Robert S (contact) University Of Washington 2018 Active
  • Human Neuroscience
  • Integrated Approaches
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  • Monitor Neural Activity
Currently, body imaging systems perform brain imaging, making it difficult to provide the necessary level of spatial and temporal resolution needed to understand brain function. Brain-only imaging systems include positron emission tomography (PET) and are referred to as neuroPET. Drs. Robert Miyaoka, Sergei Dolinsky, and a team of investigators seek to develop improvements in both image resolution and signal-to-noise ratio of neuroPET technology. The researchers will characterize neuroPET parameters, validate them through machine learning methods, and characterize performance of a prototype detector that is compatible with magnetic resonance imaging (MRI). By improving detector imaging technology that facilitates compatibility between PET and MRI, this work will improve image resolution to advance research into the development, function, and aging of the human brain.
A unified cognitive network model of language Crone, Nathan E Tandon, Nitin (contact) University Of Texas Hlth Sci Ctr Houston 2016 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
Current non-invasive methodologies limit our ability to understand the neural basis of cognitive processes due to poor temporal or spatial resolution, and typical intracranial EEG (icEEG) approaches provide fragmentary information. To address these limitations, Drs. Tandon and Crone will study human language function, working with epilepsy patients who have intracranial electrodes in place. The group will then modulate activity at identified nodes of brain activity using closed-loop direct cortical stimulation. This project could provide insight into language processing and organization in the brain using a novel method of modeling neural computation, and provide insight into the language impairments that can affect patients with a range of neurologic and psychiatric illnesses.
A viral system for light-dependent trapping of activated neurons Drew, Michael R Martin, Stephen Zemelman, Boris V (contact) University Of Texas, Austin 2015 Complete
  • Monitor Neural Activity
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Zemelman and colleagues will develop a system to label activated cell ensembles within the same animal in response to different behaviorally relevant stimuli over time. The system entails activity-dependent tagging of neurons based on the expression of select genes controlled by administering different antibiotic compounds at different times in the experiment. The antibiotics bind to and regulate specific "repressor proteins," giving them the ability to control gene expression. The team will also develop "caged" versions of each antibiotic, which can be uncaged via pulses of light for fast control of gene expression during rodent behaviors. This novel design will allow for faster temporal resolution of neuronal activation across brain regions and functions.
A wearable functional-brain-imaging system with full-head coverage and enhanced spatiotemporal-resolution to study complex neural circuits in human subjects Schwindt, Peter D. D. Sandia Corp-sandia National Laboratories 2019 Active
  • Human Neuroscience
  • Integrated Approaches
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Comprehensively studying the brain requires non-invasive neuroimaging methods at high spatiotemporal resolution that can capture the functions in naturalistic behaviors. Magnetoencephalography (MEG) is a promising approach, but its operation uses rigid helmet hardware that compromises signal and spatial resolution. Dr. Schwindt and a team of investigators plan to address these challenges by improving MEG sensors to develop a wearable, conformable, full-head coverage MEG system. After developing the sensor array, the group aims to enhance spatial resolution of the MEG system while accounting for heterogeneity in head shape, and finally validate the performance of the new system against traditional approaches. By providing a whole-head MEG system for people of all head sizes, this advance will enable the study of brain dynamics in increasingly naturalistic environments with cortical spatial resolution rivaling functional MRI.

A wearable high-density MEG system with uOPMs Alem, Orang Fieldline, Inc. 2019 Active
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Magnetoencephalography (MEG) is a powerful tool for non-invasive imaging of cortical activity with high temporal and spatial resolution. Unfortunately, MEG locations are sparse, largely because of high costs, maintenance, and limited usability due to rigid helmet configuration. To generate a high-density, high-performance, and wearable MEG helmet, Dr. Orang Alem and team will work with FieldLine Inc. on a few key innovations. The group will address technical challenges such as cross-talk between sensors, background field noise, and sensor calibration and localization. The success of this project could move this technology beyond the laboratory to the larger community of neuroscientists and clinicians, providing a turnkey high-density system that will have a significant impact in the field of biomagnetic research and diagnostics.

A whole-brain ultrasonic neural stimulation and photoacoustic recording system in behaving animals Oralkan, Omer (contact) Sahin, Mesut North Carolina State University Raleigh 2017 Active
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Understanding neural networks and communication between brain regions requires the decoding of electrical and chemical signals, but current methods often face a tradeoff in spatiotemporal precision. Omer Oralkan and Mesut Sahin propose the development of a tool that combines ultrasound neural stimulation and photo-acoustic recording of hemodynamic activity to monitor awake and behaving animals. Under this approach, high-frequency ultrasound allows for high stimulation precision, and a fast-repeating laser source permits high-resolution imaging of neurovascular responses that report neural activity. The success of this technological advance could pave the way for implantable, wireless dual-mode ultrasound/photoacoustic imaging devices that provide high spatiotemporal resolution of the entire brain using a minimally invasive approach.
Accessing the Neuronal Scale: Designing the Next Generation of Compact Ultra High Field MRI Technology for Order-of-Magnitude Sensitivity Increase in Non-Invasive Human Brain Mapping Rutt, Brian Keith Stanford University 2017 Active
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Non-invasive methods for imaging the human brain are currently limited in spatial resolution, hindering our understanding of neuronal connectivity by blurring responses across millions of neurons. Brian Rutt proposes the development of next-generation, ultra-high-field (UHF) magnetic resonance imaging (MRI), allowing for the mapping of neural activations and connections containing only a few thousand neurons. To overcome obstacles of cost, size, and technical/physical limitations, he is partnering with General Electric and Tesla Engineering to design a UHF MRI prototype that is capable of acquiring whole-brain maps at microscopic spatial resolution. The development of a low-cost, compact UHF MRI system would allow for unprecedented spatial resolution of the human brain, providing a fine-grained window into the underlying principles by which brain networks give rise to human cognition.
Accurate and reliable computational dosimetry and targeting for transcranial magnetic stimulation Gomez, Luis Javier Duke University 2019 Active
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Transcranial magnetic stimulation (TMS) is a noninvasive technique used to study brain function and can be used to treat some brain disorders. Researchers use computational simulations of TMS electrical fields to gain a better understanding of how TMS affects the brain. Existing simulations, however, are inherently variable due to factors that impact the accuracy and precision of the technique, such as differences in experimental set-up and coil placement. Dr. Gomez proposes to use a novel computational framework to measure and address the uncertainty and variability of TMS electrical fields. The project will increase the fidelity and reliability of TMS simulations. The results will benefit researchers and clinicians by enabling more precise control of the technique and may help improve medical uses of TMS.

Achieving ethical integration in the development of novel neurotechnologies Chiong, Winston University Of California, San Francisco 2017 Active
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Novel neurotechnologies hold promise for treating neuropsychiatric disorders, but also raise profound neuroethics issues including self-ownership of our thoughts, emotions, and actions. Engaging patients and researchers in the early stages of neurotechnology research and clinical translation can help ensure ethical development of the field. This research study will be embedded in one of two projects funded by the DARPA BRAIN Initiative to develop implantable brain stimulation devices that both monitor and adaptively stimulate brain areas involved in mood and behavior regulation. Dr. Chiong and an interdisciplinary team with expertise in neuroscience, clinical care, law, philosophy, and social science will assess neuroethics issues associated with the DARPA-funded brain stimulation project. The overall goal is to enable acceptability and adoption of new treatments for neuropsychiatric disorders, by recognizing and incorporating the perspectives of patients, researchers, and other stakeholders into the design of these novel neurotechnological therapies.
Acoustically targeted molecular control of cell type specific neural circuits in non-human primates Shapiro, Mikhail (contact) Tsao, Doris Ying California Institute Of Technology 2019 Active
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Controlling specific neural circuits across large-scale areas is vital to improve our understanding of the nervous system. Drs. Shapiro, Tsao, and collaborators aim to further develop Acoustically Targeted Chemogenetics (ATAC) to modulate neural circuits non-invasively in non-human primates (NHPs) with spatiotemporal and cell-type specificity, starting in the visual cortex of macaques. The group will develop AAV viruses optimized for chemogenetic receptor delivery using in vivo evolution in mice and NHP, in addition to the development of ultrasound methods to target focused ultrasound-blood brain barrier opening in NHPs. ATAC will then be used to modulate face recognition neurons and sensorimotor circuits in NHPs.  Successful development of ATAC for NHPs will improve the study of neural circuits, and potentially help uncover new therapies for neuropsychiatric disease.

Adaptive DBS in Non-Motor Neuropsychiatric Disorders: Regulating Limbic Circuit Imbalance Goodman, Wayne K Baylor College Of Medicine 2016 Active
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Deep brain stimulation (DBS) is currently a treatment option for patients with obsessive-compulsive disorder (OCD), but there is room for improvement both in terms of increasing treatment effectiveness and reducing unwanted side effects. In this project, Goodman and his team aim to utilize next-generation DBS systems that can record, stimulate, and make real-time adjustments to stimulation parameters based on the patient’s brain activity. Specifically, they propose to develop a stimulation paradigm that will allow the DBS system to automatically adjust stimulation to better control OCD-related distress while minimizing unwanted DBS-induced hypomania, which they will test in an early feasibility study with a small number of OCD patients. This work may help refine DBS therapy for neuropsychiatric and neurological diseases and disorders more broadly.
ADVANCED NEXT GEENRATION RADIO FREQUENCY COILS FOR MAGNETIC RESONANCE IMAGING Srinivasan, Ravi Advanced Imaging Research, Inc. 2019 Active
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Magnetic resonance imaging (MRI) is a safe, non-invasive diagnostic imaging tool that provides detailed information about major organs of the body, including the brain. But, effective diagnosis depends on the quality of the MR image, and increasing magnet field strength or receiver channels can be burdensome in cost and maintenance. In a collaboration with Advanced Imaging Research Inc., Dr. Srinivasan and team propose to maximize MRI image quality with the intention of alleviating the burden placed on high-cost, high-magnet field-based MRI systems. The group plans to improve the signal-to-noise ratio within MRI systems by increasing the radio-frequency (RF) coil efficiency. The success of the project could significantly reduce scan time and facilitate disease diagnosis.

Advancing MRI & MRS Technologies for Studying Human Brain Function and Energetics Chen, Wei (contact) Yang, Qing X University Of Minnesota 2014 Complete
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Dr. Chen's team will achieve unprecedented higher resolution magnetic resonance imaging and spectroscopy scanning by integrating ultra-high dielectric constant material and ultra-high-field techniques.
All-Optical Methods for Studying Sequential Motor Behaviors Roberts, Todd F Ut Southwestern Medical Center 2016 Complete
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The execution of learned sequential motor behaviors is thought to be supported by precise sequences of neuronal activity in the brain. Dr. Roberts seeks to identify brain circuits important for learning vocal behaviors, and has pioneered several techniques in songbirds, including viral vector methods, two-photon microscopy, optogenetic studies, and in vivo calcium imaging. The Roberts Lab will employ a newly developed two-photon digital holographic system for optogenetic stimulation, along with targeted whole-cell recordings, to map the functional organization of circuits. This all-optical interrogation of circuits involved in generating precisely timed sequential vocal behaviors could be used to identify how sequences of neuronal activity underlying complex learned behaviors are generated in the brain.
An academic industrial partnership for the development of high frame-rate transcranial super resolution ultrasound imaging Dayton, Paul A Pinton, Gianmarco (contact) Univ Of North Carolina Chapel Hill 2017 Active
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To achieve real-time imaging of the human brain, improvements to ultrasound technology must overcome the challenge of penetrating the thick skull barrier. In a public-private partnership, Gianmarco Pinton and researchers at the University of North Carolina in Chapel Hill are partnering with Verasonics to develop transcranial contrast enhanced super-resolution imaging (TCESR). TCESR corrects for skull-induced aberrations, allowing for ultrasound imaging of in-vivo animal microvasculature and local blood flow. These advancements have the potential to unlock ambulatory ultrasound monitoring of real-time brain blood flow, something that is currently impossible with other neuroimaging methodologies. TCESR could have significant clinical and scientific applications by enabling visualization of microvasculature deep within the brain.
AN INDUCIBLE MOLECULAR MEMORY SYSTEM TO RECORD TRANSIENT STATES OF CNS CELLS Mitra, Robi D Washington University 2015 Complete
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Currently, methods that seek to link transient gene expression events to specific brain functions typically require genomic analysis of a population of cells, resulting in the destruction of those cells. This makes it difficult to directly connect molecular changes in a neuron with knowledge of subsequent biological outcomes, such as memory formation, brain development, or neurodegeneration. Mitra and his colleagues will develop a transformative technology called "Calling Cards" that provides a permanent genetic record of molecular events associated with gene expression, which can be read out by DNA sequencing at a later time after relevant biological outcomes have occurred. The data collected with this technique will deepen the understanding of processes such as brain development, memory formation and the progression of neurodegenerative disease.
An open software solution to integrate non-invasive brain stimulation with functional imaging data Opitz, Alexander University Of Minnesota 2019 Active
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Non-invasive brain stimulation methods, like transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS), modulate brain activity in a safe and painless manner. Several BRAIN Initiative projects are combining these non-invasive brain stimulation methods with neuroimaging methods. Dr. Opitz and team will develop a computational tool that integrates empirically validated finite element method (FEM) models with imaging data, by extending and scaling the SimNIBS (Simulation of Non-Invasive Brain Stimulation) software platform. The SimNIBS is the leading open source software platform for generating FEM-based models of the electric field distribution produced by TMS, tDCS, and tACS. The resultant analysis package will allow rapid visualization and analysis of non-invasive brain stimulation (NIBS) BRAIN Initiative data, which could be more broadly used by the general neuroscience community.

An open source, wireless, miniature microscope for monitoring neuronal activity BASSO, MICHELE A et al. UNIVERSITY OF CALIFORNIA LOS ANGELES 2018 Active
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Drs. Basso and Golshani will design, manufacture, optimize, and test a two-channel, wireless miniaturized microscope for monitoring primate brain cell activity in real time. The system will be based on the miniaturized microscopes, called Miniscopes, they developed for studying mouse brains in action. To do this, they will increase the size and sensitivity of imaging sensors and objective lenses, increase battery power, develop a microscope synchronization system, and incorporate drug and light delivery systems.  All innovations will be shared freely with the community of Miniscope users. With these microscopes, Drs. Basso and Golshani hope to help scientists move one step closer to understanding the neural circuit problems underlying human brain diseases.

An optical-genetic toolbox for reading and writing neural population codes in functional maps Geisler, Wilson S Seidemann, Eyal J (contact) Zemelman, Boris V University Of Texas, Austin 2016 Active
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Advanced optical methods for reading and writing neural information using genetically-encoded reporters and actuators have become powerful tools for studying neural circuits. However, these tools are generally optimized for rodents, which provide a suboptimal model for human perception because of their vastly different sensory representations and perceptual capabilities. The goal of this proposal by Seidemann and his colleagues is to develop and optimize an optical-genetic toolbox for reading and writing neural population codes in brains of awake, behaving higher mammals. As part of this project, the researchers will test new genetic methods for cell-type and activity dependent targeting of transgenes to specific neurons, design a two-photon microscope that will cover a larger area of the cortex, and develop methods for patterned optical stimulation to mimic neuronal population codes in the visual cortex. This new set of tools will pave the way for optogenetic studies in higher mammals, which will enable a deeper understanding of how the human brain processes information.
An optogenetic brain implant with EEG monitoring and response for mice Hashemi, Kevan Open Source Instruments, Inc. 2019 Active
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Epileptic seizures can be halted or reduced by optogenetic activation of selected inhibitory neurons. By monitoring electroencephalography (EEG) data in real time, seizures can be identified at their onset and correcting pulses of optogenetic stimulation may be applied. Working with Open Source Instruments Inc., Dr. Kevan Hashemi and team propose the development of a fully implantable, wireless EEG monitor that can detect EEG events in real-time and apply correcting pulses of closed-loop optogenetic stimulation. The group will develop the necessary hardware, adapt an algorithm to classify EEG events, and test the device's ability to detect seizures in mice. The success of the project could inform creation of a medical instrument that aborts focal seizures in humans who suffer from epilepsy.

An optogenetic toolkit for the interrogation and control of single cells. Hannon, Gregory J Cold Spring Harbor Laboratory 2014 Complete
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Dr. Hannon's group will develop optogenetic techniques that use pulses of light to control genes and isolate proteins in specific cell types in the brain for molecular studies.
An Ultra High-Density Virtual Array with Nonlinear Processing of Multimodal Neural Recordings Kuzum, Duygu University Of California, San Diego 2018 Active
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A major goal of neuroscience is to record the activity of all neurons in an area of an intact brain to understand the relationship between neural activity and behavior. However, current technologies do not allow direct and simultaneous access to every neuron in a three-dimensional brain area. Instead, Kuzum’s team proposes to ‘virtually’ record from neurons in a given volume of tissue with a Virtual Array. They will develop a framework to computationally increase the number of recorded neurons in data from simultaneous electrophysiology and two-photon calcium imaging (at multiple cortical depths), without the need for direct optical or electrical access to each neuron. Advanced computation will identify the time and place of action potentials. If successful, virtual arrays could lead to mapping the neural circuit dysfunctions that cause disorders and could facilitate development of targeted treatments.

Anion channelrhodopsin-based viral tools to manipulate brain networks in behaving animals Dragoi, Valentin (contact) Janz, Roger Spudich, John Lee University Of Texas Hlth Sci Ctr Houston 2015 Complete
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Examining neural circuits requires the ability to activate and silence individual neurons and subsequently assess the impact on circuit function and the circuit's overall influence on behavior. While genetically encoded molecular tools for selectively controlling the activity of neurons with light have been successfully implemented in mice, these tools have had limited success in non-human primates (NHPs). The researchers plan to modify a new class of recently discovered, light-activated molecular tools with superior light sensitivity to work well in NHPs. In addition, they will test a new, possibly more efficient, method of delivering these molecular tools via viral vectors into the neurons of awake, behaving NHPs.
Anterograde monosynaptic tracing Wickersham, Ian R Massachusetts Institute Of Technology 2015 Complete
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Using a modified rabies virus, neuroscientists can identify and manipulate neurons directly upstream from any targeted group of neurons in the brain. However, while this retrograde monosynaptic tracing system is now well established, an anterograde counterpart—one that would allow identification and manipulation of neurons directly downstream from a target cell group—has never been constructed. Wickersham and his team propose three different methods for creating an anterograde tracing system. Any one of the methods would greatly expand the types of anatomical and functional studies that can be performed in a large variety of animals, including primates.
Assessing the Effects of Deep Brain Stimulation on Agency Roskies, Adina L Dartmouth College 2018 Active
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Deep brain stimulation (DBS), a method of modulating brain circuit function, is FDA-approved for certain brain disorders such as Parkinson’s Disease. The NIH BRAIN Initiative aims to launch neurotechnological developments that include new ways of directly affecting brain circuit function. Use of these novel interventions warrants careful consideration about ways in which brain stimulation may affect personal identity, autonomy, authenticity and, more generally, agency. In this project, Dr. Roskies and her team will develop an assessment tool to measure changes in agency due to direct brain interventions, and establish a database to catalogue these changes in agency in various patient populations receiving DBS. These efforts have the potential to facilitate improvements in therapeutic approaches and informed consent and will be used to develop a framework for further neuroethical thought about brain interventions, allowing us to better identify, articulate, and measure effects on agency.

Asynchronous distributed multielectrode neuromodulation for epilepsy Devergnas, Annaelle Gross, Robert E (contact) Gutekunst, Claire-anne N Mahmoudi, Babak Emory University 2016 Active
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Dominant hemisphere mesial temporal lobe epilepsy (MTLE) is a form of epilepsy for which it is particularly difficult to control seizures. In this project, Gross and colleagues will test a next-generation deep brain stimulation (DBS) device and a novel stimulation paradigm in a non-human primate model of MTLE. If they are successful in controlling seizures in this model, the team will advance to an early clinical feasibility study in a small number of MTLE patients, measuring seizure reduction and memory testing for safety. Success in this small clinical study could lay the foundation for a clinical trial utilizing this novel DBS method in patients with MTLE, and possibly other forms of epilepsy.
Autonomously-activating bioluminescent reporters to enable continuous, real-time, non-invasive brain cell imaging Sayler, Gary S 490 Biotech, Inc. 2018 Active
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To understand brain function, we need to be able to able to monitor cellular activity in the brain noninvasively over time.  To overcome these limitations Dr. Sayler's group will develop a set of self-exciting, continuously bioluminescent, optical imaging reporters that, unlike existing systems, are pre-engineered to support genetically encoded, autonomous, metabolically-neutral, neuron- or astrocyte-specific fluorescence that can be monitored with common laboratory equipment.

BCI2000: Software Resource for Adaptive Neurotechnology Research Brunner, Peter Schalk, Gerwin (contact) Wadsworth Center 2019 Active
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Changes occur to the central nervous system (CNS) throughout life due to activity-dependent plasticity as we learn new behaviors. Adaptive neurotechnologies are systems that can interact with the CNS in ways that produce beneficial neural plasticity. The group led by Schalk and Brunner has created a software platform, BCI2000, that can be used in a variety of adaptive neurotechnology applications. However, the current BCI2000 system requires considerable expertise in programming for successful implementation. This project will produce a configuration of BCI2000 that can be more easily used for adaptive neurotechnology experiments, as well as an introductory course and online training for scientists, engineers, and clinicians using the system. These new resources will allow deployed neurotechnologies to be more quickly used in the study, diagnosis, and treatment of brain disorders.

Behavioral readout of spatiotemporal codes dissected by holographic optogenetics Rinberg, Dmitry (contact) Shoham, Shy New York University School Of Medicine 2014 Complete
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Dr. Rinberg's team aims to understand how the brain turns odors into nerve signals by activating and recording neurons in the olfactory bulbs of mice as they detect a variety of odors.
Bidirectional Hybrid Electrical-Acoustic Minimally Invasive Implants for Large-Scale Neural Recording and Modulation Kiani, Mehdi PENNSYLVANIA STATE UNIVERSITY-UNIV PARK 2018 Active
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Large-scale monitoring and modulation of brain activity using non- or minimally invasive tools with high spatiotemporal resolution remains a challenge for neuroscientists. Dr. Mehdi Kiani and colleagues will develop a new bidirectional, neural-interface platform for electrophysiological recordings and stimulation of neural activities over the entire brain. This wireless, minimally invasive technology measures micro-electrocorticography signals from 100 sites, drives ultrasonic transducers to guide a focused ultrasonic beam to stimulate a targeted brain region, and simultaneously images the neural tissue – all at 500 mm resolution. The platform functions with an external unit in a closed-loop fashion to deliver the stimulation pattern, recover the electrophysiological and imaging data, and create the neural tissue images.

BIDS-Derivatives: A data standard for derived data and models in the BRAIN Initiative Poldrack, Russell A Stanford University 2017 Active
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The proliferation and heterogeneity of magnetic resonance imaging (MRI) experiments, data analysis pipelines, and statistical modeling procedures presents a challenge for effective data sharing and collaboration. Russell Poldrack and colleagues propose expansion of the Brain Imaging Data Structure (BIDS), which standardizes the description and collection of imaging data/metadata for MRI, with development plans for other neuroimaging types as well. Under BIDS, the group will develop standards for pre-processing data pipelines, computational modeling results, and statistical modeling, using quick validation of any implemented standard so that researchers can assess whether their data fit within BIDS guidelines. These standardization goals will facilitate sharing of data, modeling, and results, ensuring their usability and engaging the greater research community in developing highly useable data standards.

Bilateral Closed Loop Deep Brain Stimulation for Freezing of Gait using Neural and Kinematic Feedback Bronte-stewart, Helen Stanford University 2019 Active
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Gait impairment and freezing of gait (FOG) lead to falls, loss of independent living, and injury (even death) in patients with Parkinson’s disease (PD). These symptoms have limited treatment options that are not well addressed by current deep brain stimulation (DBS) methods. Dr. Bronte-Stewart and colleagues will test the feasibility of subthalamic nucleus (STN) neural and kinematic adaptive DBS (NaDBS and KaDBS, respectively) in PD patients, as well as the safety and tolerability of the use of dopaminergic medication in coordination with adaptive stimulation. This innovative approach using neuro-biomechanical features may enable the first clinical studies of bilateral STN aDBS for FOG, laying the groundwork for improved gait therapy in PD and other neurological disorders.

Biological 'Living Electrodes' Using Tissue Engineered Axonal Tracts to Probe and Modulate the Nervous System Cullen, Daniel Kacy University Of Pennsylvania 2015 Complete
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Traditional non-organic micro-electrodes can record and stimulate from many brain areas, but they produce inflammation, exhibit signal degradation, and lack specificity in neuronal cell type targeting. Cullen's project will develop "living electrodes" composed of neurons transfected with optogenetic reagents that can record and stimulate neural circuits. The neurons will be grown in tiny glass tubes and inserted into rodent cortex. If they make connections to cortical neurons, they could be used for selective recording and modulation of the native cortical circuits, which would enable targeting of specific host neuronal subtypes using custom tissue engineering to increase specificity to target neuronal populations.
BioLuminescent OptoGenetics (BL-OG): A Novel and Versatile Strategy for Neuromodulation Hochgeschwender, Ute H (contact) Moore, Christopher I Shaner, Nathan Christopher Central Michigan University 2016 Active
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Optogenetics and chemigenetics are powerful tools for precise control over neural activity in specific circuits. Hochgeschwender and her colleagues will develop and optimize a new class of hybrid opto-/chemi- genetic probes. Their strategy entails tethering a bioluminescent enzyme from fireflies (luciferase) to channel opsins that respond to light. Administration of a chemical substrate (luciferin) induces the opsins to either enhance or inhibit neuronal action potential firing, depending on the type of opsin to be used. With the continued development of new opsin and luciferase variants, this approach promises more flexibility and precision in experimental systems for testing circuit contributions to behavioral function and dysfunction in a variety of brain and psychiatric disorders.
Biophysical Design Strategies for Next-Generation Maquette-based Genetically Encoded Voltage Indicators (GEVIs) Chow, Brian Y Discher, Bohdana (contact) University Of Pennsylvania 2016 Complete
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A key goal for the BRAIN Initiative is to be able to image neural activity from identified cell types in the brain. Discher and her colleagues propose a new strategy for genetically coded voltage sensors that exploits electron transport across protein domains rather than conformational shifts in protein structure. If this strategy is successful, the new indicators will report voltage changes on the order of microseconds, potentially matching the time-scale of fast action potentials in neurons. Once developed, these sensors will greatly advance optical imaging of neural activity, thereby accelerating progress toward understanding how brain activity governs human behavior, cognition, and brain disorders.
Boss: A cloud-based data archive for electron microscopy and x-ray microtomography Wester, Brock A. Johns Hopkins University 2018 Active
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Technological advancements in high-resolution imaging of brain volumes permits the accumulation of huge quantities of data that requires solution for storage and archiving. Dr. Brock’s project develops an open, accessible, and cloud-based data archive for electron microscopy and X-ray microtomography data by leveraging the proven architecture of the existing BossDB database. Allowing for petabyte scale data storage, curation, sharing, visualization and analysis, the archive is scalable and allows for a fast in- memory spatial data store, seamless migration of data between low cost and durable object storage (i.e. S3), and rapid access to the enormous datasets. The system enables computing data quality metrics on large datasets and metadata stores through a standardized interface. The archive is developed through an agile process that actively folds in community stakeholders for regular reviews and continuous opportunities for design input.

Brain circuit mapping using light inducible recombinase systems Cetin, Ali Haydar Allen Institute 2017 Active
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Studying vast numbers of functioning neurons in the brain requires precise spatio-temporal tools. Toward this end, researchers are interested in genetically modifying specifically selected cells in vivo, for neuronal subtype-specific, single-cell-level analysis. Cetin and colleagues will modify current genomic manipulation enzymes, making them light inducible, to achieve high-throughput single-cell genomic modification in response to brief pulses of light in the brain. They will generate transgenic mouse lines with these recombinases, use light to trigger site-specific DNA modification, and study the connections, morphology, function, and genetic identity of individual neurons within the brain. This approach may break technical barriers and has a range of potential applications, enabling enhanced precision in analyzing mammalian brain circuitry.
BRAIN INITIATIVE RESOURCE: DEVELOPMENT OF A HUMAN NEUROELECTROMAGNETIC DATA ARCHIVE AND TOOLS RESOURCE (NEMAR) Delorme, Arnaud Majumdar, Amitava Makeig, Scott (contact) Poldrack, Russell A University Of California, San Diego 2019 Active
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Dr. Makeig et al. have identified the need for the creation of data archives and standards for specifying, identifying, and annotating the data deposited. Specifically, they aim to create a gateway from the OpenNeuro.org archive for human neuroelectromagnetic data such as EEG and MEG data. This gateway will also provide tools to users for quality evaluation and data visualization. This resource will further allow machine learning methods to be applied to human brain activity data.

BRAIN Initiative: Integrated Multimodal Analysis of Cell and Circuit-Specific Processes in Hippocampal Function Sweedler, Jonathan V. University Of Illinois At Urbana-champaign 2015 Complete
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Individual cell types contain specific combinations of chemical constituents that directly affect cell behavior. However, detailed knowledge of these constituents, as well as a precise method for identifying them, is currently lacking. Sweedler and colleagues will combine two methods for probing the chemical makeup of living tissue—mass spectrometry of individual cells, and stimulated Raman scattering microscopy (SRSM) from unlabeled tissue in brain slices. The combined analyses will be deployed in the dentate gyrus region of the hippocampus to identify the region’s many different cell types and chemical characteristics, and to investigate how this wealth of information relates to functions involved in memory formation.
BRAIN power: expanding reproducibility, quality control, and visualization in AFNI/SUMA COX, ROBERT WILLIAM (contact); NIELSON, DYLAN MILES U.S. NATIONAL INSTITUTE OF MENTAL HEALTH 2018 Active
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AFNI (Analysis of Functional NeuroImages) is an open-source software package for neuroimaging analysis and visualization of both functional and structural MRI as well as other modalities. Drs. Cox and Nielson propose to extend this widely used software package by offering containerization, cloud accessibility and web-accessible visualization. The software extension could support evolving BRAIN Initiative standards for human neuroimaging data organization and experiment specification. The project makes it possible for public integration testing of the software package, thus enabling end-user feedback and wider adoption and dissemination within the neuroimaging community.

Brain-wide correlation of single-cell firing properties to patterns of gene expression Cohen, Adam Ezra Harvard University 2018 Active
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Different neurons show widely varying patterns of gene expression and widely varying patterns of electrical spiking. It is not currently possible to predict the electrical spiking properties of a cell from its pattern of gene expression. Cohen’s team seeks to develop tools to record gene expression and spiking patterns in thousands of neurons by combining two novel technologies: all-optical electrophysiology and BRAIN Initiative-funded fluorescent in situ hybridization, MERFISH. They will create correlated brain-wide maps of gene expression and neuronal firing, first in rodent acute brain slices and then in the zebrafish spinal cord in vivo . These maps may ultimately help elucidate the roles of genes in governing neural function in health and disease.

Breaking Spatiotemporal Barriers of MR Imaging Technologies to Study Human Brain Function and Neuroenergetics Chen, Wei (contact) Zhu, Xiao-hong University Of Minnesota 2018 Active
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Advancing the image sensitivity and resolution of magnetic resonance (MR) imaging technologies is fundamental towards capturing a comprehensive view of the healthy human brain. Dr. Wei Chen and colleagues propose the development and validation of radiofrequency (RF) coil technology, combining it with spatiospectral CorrElation (SPICE) technique to improve the quality of MR imaging (MRI) and MR- spectroscopic imaging (MRSI) for human brain studies. Their approach aims to improve image sensitivity, while minimizing absorption of RF power in neural tissue, as well as exploit their previously developed SPICE technique to boost signal-to-noise ratio and image resolution. By pioneering this neuroengineering solution to improve the quality and resolution of these MR imaging technologies, these researchers will enable ultrahigh-resolution mapping of neural activity, circuits, and dynamics.

Breaking the Barriers to Microscale fMRI Vu, An Northern California Institute 2019 Active
  • Human Neuroscience
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The need for improved non-invasive imaging is paramount in order to reveal the underpinnings of both the diseased and healthy human brain. Dr. Vu and colleagues will develop a Stimulus-Locked K-Space (SLIK) approach to achieve meso-resolution imaging for whole human brain fMRI. They will incorporate and evaluate commercially available motion mitigation and navigator-based dynamic B0 correction techniques. This novel technology will build upon existing commercialized 7 Tesla scanners, and therefore, following its development, could be readily disseminated to the neuroscience community.

Bridging structure, dynamics, and information processing in brain networks Choi, Hannah University Of Washington 2019 Active
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The mammalian brain has unique abilities to process various sensory inputs from the environment, based on efficient and complex brain network structures and dynamics. However, the precise connections between the brain’s intricate wiring and its rich network dynamics are unclear, as is our understanding of how the brain’s connectivity and dynamics relate to underlying neural coding principles. Leveraging the Allen Institute’s Mouse Brain Connectivity Atlas, Dr. Choi will explore these issues, ultimately aiming to help close the gap between brain biophysiology and neural coding principles, with a focus on predictive coding theory using data-driven mathematical models.

Bringing laser focus to voltage imaging: Enhanced indicators and advanced scanning methods for two-photon recording of dense networks in vivo Dieudonne, Stephane Lin, Michael Z. (contact) Stanford University 2017 Active
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Genetically encoded voltage indicators (GEVIs) are light-emitting proteins that report neuronal action potentials with high spatiotemporal precision, but they have limitations, including the fact that their kinetics are too fast for typical two-photon laser scanning microscopy. Improvements to GEVI brightness, responsivity, wavelengths, and localization would facilitate action potential detection, as would enhanced imaging capabilities that are matched to the properties of specific GEVIs of interest. Lin’s team proposes to integrate the above-mentioned GEVI improvements with development of a new generation of multiphoton optical hardware that will dramatically accelerate targeted scanning, enabling high-speed imaging of hundreds of individual, genetically-defined neurons. The group will apply these improved technologies to study patterns of fast neuronal activity in vivo, during behavior. This project could enable new insights into neural circuit function in health and disease.
Building and sharing next generation open-source, wireless, multichannel miniaturized microscopes for imaging activity in freely behaving mice Golshani, Peyman (contact) Khakh, Baljit Markovic, Dejan Silva, Alcino J. University Of California Los Angeles 2015 Complete
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Currently, technologies to image large populations of neurons over time in awake, behaving animals are limited, as commercial microscopes require animals to be tethered, have only one imaging channel, and are prohibitively expensive. Golshani and colleagues propose to develop and test a new, miniaturized wireless microscope with two channels to measure and optogenetically manipulate activity of genetically labeled neurons in behaving animals. The system design and coding will be made open source immediately, allowing other researchers to probe neuronal activity across model systems with higher specificity at low costs as the project progresses.
C-PAC: A configurable, compute-optimized, cloud-enabled neuroimaging analysis software for reproducible translational and comparative Craddock, Richard Cameron Milham, Michael Peter (contact) Child Mind Institute, Inc. 2018 Active
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Novel neuromodulation, recording, and imaging techniques applied to human and non- human primate brains generate datasets that require tools for organizing, processing and analyzing data that are widely available and easy to use. Drs. Milham and Craddock plan to extend C-PAC (Configurable Pipeline for the Analysis of Connectomes), building a configurable data analysis pipeline that incorporates various statistical analysis, machine learning, and network analytic techniques. In addition to adapting methods used in human imaging for non-human primate data, the project will implement a toolbox for alignment of electrophysiological data with brain imaging data. The resulting software enables high- throughput, semiautomated and end-to-end processing and analysis of structural and functional MRI data that are accessed locally or via the cloud.

Calcium sensors for molecular fMRI Jasanoff, Alan Massachusetts Institute Of Technology 2014 Complete
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Dr. Jasanoff's team will synthesize calcium-sensing contrast agents that will allow functional magnetic resonance imaging (fMRI) scans to reveal activity of individual brain cells.
Capabilities of MRI-Based Neural Current Imaging for Human Brain Mapping Kim, Young R Massachusetts General Hospital 2015 Complete
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Non-invasive imaging of human brain activity relies either on the correlation between neuronal activity and blood flow (for functional MRI) or on measurements of the activity of broad neural populations from fields that are generated very near the surface of the brain (for electroencephalography and magnetoencephalography). Kim proposes a new direct-detection method based on the ability of a "spinlock" MRI sequence that increases sensitivity to select magnetic fields, allowing direct access to neural population activity without relying on blood flow measurements as a proxy. This approach involves carefully controlled animal experiments to provide proof-of-concept, using optogenetics to induce synchronous neuronal firing with simultaneous silencing of blood flow signals to test the new stimulus-induced rotary saturation (SIRS) technique to directly image activity.
Carbon Thread Arrays for High Resolution Multi-Modal Analysis of Microcircuits Berke, Joshua D Chestek, Cynthia Anne (contact) University Of Michigan At Ann Arbor 2015 Complete
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Chestek and Berke will develop dense arrays of 8 micron carbon-fiber electrodes, which are stiff enough to insert into the brain, but sufficiently small to avoid damage which plagues research using traditional recording electrode arrays. In addition to use in electrical recording, the electrodes will be developed for voltammetric measurements of transmitters such as dopamine. Together, these technological advancements could allow multi-site, real-time simultaneous electrophysiological and transmitter measurements in behaving animals, providing a novel method to monitor neural microcircuits.
Causal mapping of emotion networks with concurrent electrical stimulation and fMRI Adolphs, Ralph (contact) Howard, Matthew A. Poldrack, Russell A California Institute Of Technology 2018 Active
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Limited treatment options exist for emotional disorders because we do not understand the neural systems by which emotions are processed. Adolphs and colleagues will study how emotion is caused  by activity in brain networks. They will electrically stimulate emotion-related brain regions, such as the amygdala, in awake neurosurgical patients, and use concurrent fMRI to image the whole-brain networks engaged by the stimulated structures. Psychophysiological, behavioral, and self-report measures of emotion will be collected to quantify how the stimulation-induced activation patterns associate with specific components of emotion. This work could inform interventions to treat mood disorders through deep-brain stimulation.
Cell-Specific Visualization of Endogenous Proteins Mao, Tianyi Zhong, Haining (contact) Oregon Health & Science University 2019 Active
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Monitoring endogenous synaptic proteins in neuronal subtypes of behaving animals is needed to better understand neural circuits underlying behavior, but current visualization methods can produce altered protein function and off-target effects. Here, Dr. Zhong, Mao, and labs aim to develop a novel genetic strategy called endogenous labeling via exon duplication (ENABLED) to label endogenous synaptic proteins for in vivo imaging. Expanding on their success of labeling PSD-95 in neurons, the team will optimize the ENABLED method to label several additional synaptic proteins in mice, with the goal of generating ENABLED mice in which synaptic proteins are labeled with different colors for simultaneous imaging. This work could provide new tools for researchers to advance our understanding of synaptic connectivity and plasticity under physiological conditions in behaving animals.

Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation Voss, Joel L (contact); Disterhoft, John F Northwestern University At Chicago 2019 Active
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Alzheimer’s disease, epilepsy and other neurological disorders can cause problems with how the brain learns. In this project, researchers in the Disterhoft and Voss labs will perform experiments on rodents and human subjects designed to understand the cellular effects of electrical stimulation on the hippocampus, a region known to be involved in learning and memory. As part of this project, they will examine the relationship between stimulation and hippocampal neuronal synchrony during theta activity rhythms. Their results may help researchers understand the underlying circuitry associated with the memory problems common in many brain disorders.

Central thalamic stimulation for traumatic brain injury Butson, Christopher R Giacino, Joseph Thomas Henderson, Jaimie M Machado, Andre Guelman Schiff, Nicholas D (contact) Weill Medical Coll Of Cornell Univ 2015 Active
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Traumatic brain injury (TBI) afflicts hundreds of thousands of Americans each year, producing chronic cognitive disabilities that lack effective treatment. Preliminary studies with TBI patients and non-human primates suggest that these cognitive disabilities may be due to disrupted circuit function in the brain, specifically involving impaired connections between the thalamus and the frontal cortex. Working with a group of TBI patients who can function independently but remain limited by chronic cognitive impairment, Schiff and colleagues aim to build on these studies, using the latest device technology to deliver deep brain stimulation to the thalamus. The researchers hope to obtain a variety of behavioral and electrophysiological data to inform development of a next-generation device therapy for cognitive impairment associated with TBI.
Cerebellar network mapping with a high-throughput TEM platform Lee, Wei-chung Allen Harvard Medical School 2017 Active
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Understanding cell type-specific neuronal connectivity may help indicate how the brain is altered in nervous system disorders. Lee’s team will use a high-throughput technology for electron microscopy volume image acquisition—capable of up to two orders of magnitude faster acquisition compared to current methods—and comprehensively characterize the cell types and connectivity within the cerebellum. They will reconstruct cerebellar network anatomy computationally and explore the organizational principles underlying cerebellar circuits. The tools and datasets will be released publicly, and may help uncover the role of specific circuit elements in nervous system function.
Chemogenetic Dissection of Neuronal and Astrocytic Compartment of the BOLD Signal Shih, Yen-yu Ian Univ Of North Carolina Chapel Hill 2016 Active
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Blood oxygen level dependent (BOLD) functional MRI is widely used to study human brain function. However, the cellular and molecular mechanisms underlying the BOLD signal remain poorly understood, though many neuroscientists believe the signal reflects contributions from both neurons and astrocytes. Shih and his colleagues will employ cutting-edge tools called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to tease out the specific contributions of certain types of astrocytes and neurons to the BOLD signal by selectively activating one group while inactivating the other, and vice versa. The researchers will then repeat their experiments in animal models of chronic neuroinflammation to provide insight into how the BOLD signal is disrupted by diseases involving neuroinflammation.
Chromatin Plasticity, Transcriptional Activity and Kinetics in Developing and Adult Human Astrocyte and Oligodendroglial Lineages Tsankova, Nadejda Mincheva Icahn School Of Medicine At Mount Sinai 2019 Active
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To better understand human-specific glial diversity, Dr. Tsankova’s lab has endeavored to improve isolation methods of glial cells from human brain tissue, via cell-specific immunotagging techniques to isolate nuclear RNA and chromatin from frozen brain. Building off this work, the team aims to profile the epigenetic and molecular features of developing and adult human astrocyte and oligodenroglial lineages. They will use high throughput technologies like Tn5-HiC, ChIP-, RNA-, and ATAC-seq to characterize the chromatin structure, transcriptional factor binding activity, and differentiation kinetics across different developmental stages of human astrocytes and oligodenroglial progenitors. These epigenetic and functional datasets should enable the creation of an integrated map of glial plasticity, providing a reference tool for comparative studies of human health and disease.

Circuit Dynamics for encoding and remembering sequence of events Jafarpour, Anna University Of Washington 2019 Active
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Typically, we experience the world as a continuous sequence of events; but when recalling memories, we remember segmented episodes. The hippocampus and prefrontal cortex (PFC) play a role in segmenting, linking, and retrieving memories of associated events, but the neural circuit mechanism of this process is not well understood. Dr. Jafarpour aims to use intracranial encephalography (iEEG) to identify the neural dynamics in the hippocampal-PFC circuit that support the encoding of sequences of words. By combining iEEG with advanced analytical techniques, natural language processing models, and research with patients with hippocampal lesions, this project will offer insights into the neural basis of speech encoding and memory formation. The work may inform the development of neural prosthetics for use by patients with memory impairments.

Circuit mechanisms of evidence accumulation during decision-making Luo, Zhihao Princeton University 2017 Active
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Dr. Luo will use optogenetic tools to inactivate specific brain structures while simultaneously recording neuronal activity across other brain areas in the rat during evidence accumulation tasks. This research could uncover the neural circuits that support the gradual accumulation of evidence during decision making.
Clinical Testing of an Intracortical Visual Prosthesis System Troyk, Philip R Illinois Institute Of Technology 2016 Active
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Blindness can have a negative impact on quality of life, and is associated with relatively high rates of depression and social isolation, and relatively low levels of employment. The IntraCortical Visual Prosthesis (ICVP) team led by Dr. Troyk has worked to develop an ICVP that can compensate for blindness by stimulating the visual centers of the brain. This project aims to provide proof of principle with a small number of human volunteers, to demonstrate that the ICVP successfully produces visual sensory perception and to assess the utility of the induced visual percepts.
Close-loop, spatially addressable multiphoton functional imaging Xu, Chris Cornell University 2019 Active
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The Xu lab aims to help researchers use multiphoton microscopy for watching electrical neural circuit activity in real time. In this project, they plan to develop an adaptive excitation source that will make multiphoton microscopy much faster at imaging activity. They will work with researchers at Cornell and Stanford Universities and at the HHMI Janelia Research Campus to test out and fine tune this new system. The system may help researchers explore how circuits control the brain under healthy and disease conditions.

Closed loop deep brain stimulation for Parkinson's disease Starr, Philip Andrew University Of California, San Francisco 2016 Active
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Deep brain stimulation (DBS) has an important clinical role in the management of movement disorders, including Parkinson’s disease (PD). However, current DBS therapy for PD relies on continuous stimulation, regardless of changes in brain circuit function related to changes in disease expression (i.e. oscillation between too little and too much movement). In this project, Starr and his team will use next-generation DBS devices to develop and test a method of automatically adjusting stimulation parameters based on brain signals that reflect the patient's clinical state, to optimize DBS for PD. In a small number of patients, they will measure local brain activity in each patient and use that information to develop individualized stimulation paradigms; these algorithms will then be programmed into the DBS devices, to demonstrate proof of principle for this novel, closed-loop DBS system.
Closing the Loop on Tremor: A Responsive Deep Brain Stimulator for the Treatment of Essential Tremor Foote, Kelly D Gunduz, Aysegul (contact) University Of Florida 2016 Active
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Essential tremor (ET) is an incurable, degenerative brain disorder that results in increasingly debilitating tremor. Deep Brain Stimulation (DBS) is used as an effective treatment for ET, but the continuous brain stimulation provided by current DBS methods is likely unnecessary given the intermittent nature of ET symptoms, and may underlie DBS-induced side effects such as slurred speech and difficulty walking. It also may unnecessarily hasten the need for surgery to replace depleted DBS batteries. In this project, Gunduz and Foote propose to use modern DBS devices capable of recording and stimulating simultaneously, to continuously monitor brain activity and deliver stimulation only when necessary to control tremor. This work may provide proof-of-concept for the first chronic closed-loop DBS system for the treatment of a debilitating movement disorder in humans.

Cognitive Restoration: Neuroethics and Disability Rights Fins, Joseph J. Weill Medical Coll Of Cornell Univ 2019 Active
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Many traumatic brain injury (TBI) patients often experience chronic cognitive impairments that disrupt functioning and can interfere with societal reentry – current efforts aim to rapidly restore cognitive function to TBI patients. In doing so, a thorough understanding of the opportunities and challenges posed by rapid cognitive restoration is critical. To address this need, Dr. Joseph Fins and his team will interview patients and family members before implantation of thalamic deep brain stimulation (DBS) devices. These interviews will collect perspectives on risks and benefits, expectations and fears, as well as factors that are weighed during decision making. After implantation, interviews will collect perspectives on the impact of cognitive impairment and restoration. The project aims to develop legal theory that supports social reentry for TBI subjects who have achieved cognitive restoration, paving the way for maximizing patient-centered benefits of any therapeutic advance.

Collaborative Standards for Brain Microscopy Hamilton, Carol M Research Triangle Institute 2018 Active
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Recent tissue-clearing techniques and advances in microscopy have made it possible to produce 3D images of intact brains. to help ensure consistency in data collection and analysis, Dr. Hamilton and her team will develop a set of standards for3D imaging of whole brains for the neuroscience research community.. Dr. Hamilton’s group will convene a Working Group of experts who will work through a consensus process to establish standards that will be distributed to the research community. These standards should help improve the efficiency of imaging research and allow comparisons across studies.

Combined Cortical and Subcortical Recording and Stimulation as a Circuit-Oriented Treatment for Obsessive-Compulsive Disorder Dougherty, Darin D (contact) Eskandar, Emad N Massachusetts General Hospital 2016 Active
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4-7 million Americans suffer from obsessive-compulsive disorder (OCD), and at least half of these patients do not receive adequate relief from medication or talk therapy. Deep brain stimulation (DBS) is used as a treatment for patients with intractable OCD, but only works for about half of these patients. In an effort to improve DBS for OCD, Dougherty and Eskandar have proposed to develop and test in a small early feasibility study a next-generation, brain circuit-oriented DBS treatment for drug-refractory OCD. In their project, they will measure brain activity to test a hypothesis about the specific circuit dysfunction that underlies OCD, and they will test whether DBS stimulation can disrupt this circuit dysfunction in order to relieve OCD symptoms.
Combined Cortical and Subcortical Recording and Stimulation as a Circuit-Oriented Treatment for Obsessive-Compulsive Disorder Dougherty, Darin D (contact) Widge, Alik S Massachusetts General Hospital 2018 Active
  • Human Neuroscience
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4-7 million Americans suffer from obsessive-compulsive disorder (OCD), and at least half of these patients do not receive adequate relief from medication or talk therapy. Deep brain stimulation (DBS) is used as a treatment for patients with intractable OCD, but only works for about half of these patients. In an effort to improve DBS for OCD, Dougherty and Eskandar have proposed to develop and test in a small early feasibility study a next-generation, brain circuit-oriented DBS treatment for drug-refractory OCD. In their project, they will measure brain activity to test a hypothesis about the specific circuit dysfunction that underlies OCD, and they will test whether DBS stimulation can disrupt this circuit dysfunction in order to relieve OCD symptoms.

Compressive Light Field microscopy for optogenetic neural activity tracking Waller, Laura University Of California Berkeley 2016 Complete
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State-of-the-art techniques for measuring neural activity on a large scale still lack the ability to measure signals from across many brain regions at high speed and with cellular resolution. Borrowing from recent advances in 3D photography, Waller and her colleagues will develop an optical imaging system that will not only capture the intensity of light emitted from active, fluorescing neurons, but it will also capture the angle of the emitted light. Combining light intensity and angle allows for reconstruction of neural activity in 3D. This system, which will be relatively inexpensive and easy to set up, has the potential to record from millions of individual neurons at speeds faster than conventional imaging methods.
Computational and circuit mechanisms for information transmission in the brain Eden, Uri Tzvi Frank, Loren M Ganguli, Surya Kepecs, Adam (contact) Kramer, Mark Alan Machens, Christian Tolosa, Vanessa Cold Spring Harbor Laboratory 2015 Complete
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Dr. Kepecs and colleagues are investigating how information is integrated into decision making, and then further transformed into behavior. This project focuses on understanding information flow across specific regions of the brain in trained rats. By performing parallel, large-scale, simultaneous electrical recordings of neural activity in these different brain regions while the animals perform two different types of decision-making tasks, these researchers hope to observe how activity in one area influences activity in a downstream area. In addition, there are plans to identify and manipulate the activity of neurons that connect these brain areas to understand the causal relationships governing information flow among these regions. Gaining such mechanistic insights into how the brain processes information will provide insights into how both the normal and disordered brain operates.
Computational Modeling of Deep Brain Stimulation of the Ventral Striatum Dougherty, Darin D Widge, Alik S (contact) Massachusetts General Hospital 2016 Complete
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Deep brain stimulation (DBS) targeting the ventral internal capsule/ventral striatum (VC/VS) is being used as a treatment for those with obsessive compulsive disorder (OCD), but with inconsistent clinical results. As a tool to examine mechanisms underlying this process, Dr. Widge and colleagues will adapt the recently developed "StimVision" software suite to model DBS electrical fields that activate brain tissue, in collaboration with the McIntyre lab (Case Western Reserve University). Using data from their DBS patient cohort, the team will integrate novel algorithms to improve modeling of neural mechanisms underlying the effects of DBS. This research, using StimVision with a specific DBS patient group, will improve understanding of cortical circuits underlying the behavioral effects of DBS, potentially enhancing circuit-oriented therapies.
Concurrent multiphoton microscopy and magnetic resonance imaging (COMPMRI) Wang, Yi Xu, Chris (contact) Cornell University 2016 Complete
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One of the major goals of the BRAIN Initiative is mapping neuronal function at multiple spatial scales, from synapses to the whole brain. The proposed project from Xu and Wang will deliver such maps by combining two powerful brain imaging technologies—MRI and multiphoton imaging, a deep-brain, high-resolution imaging technique that Xu has developed with the help of two previous BRAIN awards. The combined imaging device will allow studies of the relationship between neural activity at the cellular and network level.
Conducting polymer nanowires for neural modulation Payne, Christine K Georgia Institute Of Technology 2015 Complete
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Microelectrodes are used to record and stimulate neuronal activity in experimental animals and in human therapeutic applications. However, the injury to tissue when they are implanted, and their mechanical mismatch with brain tissue after implantation, can trigger the brain's immune response, causing them to be encapsulated by glia and other cells and preventing current flow between neurons and the electrical contacts. Payne and her colleagues will use the latest in nanotechnology to develop ultra-thin, flexible nanowires made from a biocompatible polymer which, because of their small size and flexibility, may avoid the immune responses triggered by larger electrodes. The nanowires will be inserted into the brain with micro-capillary tubes and will connect individual neurons to external recording and/or stimulating devices. The nanowires can also be coated with specific molecules that will promote attachment to specific neuron types, allowing for precisely targeted recording or stimulation experiments.
Connectome 2.0: Developing the next generation human MRI scanner for bridging studies of the micro-, meso- and macro-connectome Basser, Peter J. Huang, Susie Yi Rosen, Bruce R (contact) Wald, Lawrence L Witzel, Thomas Massachusetts General Hospital 2018 Active
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Understanding the structural basis of brain function requires spanning multiple spatial scales, from synaptic circuits to whole-brain systems, but current technology is limited in its ability to successfully integrate across these scales. Dr. Bruce Rosen and a team of investigators propose the development of a human magnetic resonance imaging (MRI) scanner that images brain structural connectivity in-vivo. Building upon previous work from the Human Connectome Project (HCP), these tools will advance brain imaging with the capability of estimating cellular and axon level microstructural brain circuits at very high resolution. The project will have the potential to significantly expand our knowledge on hierarchical anatomy and functionality of both healthy and diseased human brains, with impact on both neuroscience research and clinical applications.

Context-dependent processing in sensorimotor cortex Collinger, Jennifer UNIVERSITY OF PITTSBURGH AT PITTSBURGH 2018 Active
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When you reach for a beverage, the way you pick up the drink depends on whether it is in a sturdy mug or a delicate champagne flute, as well as your reach configuration. Dr. Collinger and her colleagues plan to investigate the way environmental context affects motor cortex activity as the brain plans movements, such as grasping an object. Two individuals with tetraplegia will receive implants in their motor cortex to record activity while they use brain signals to control a robotic prothesis in a variety of tasks including grasping an object or grasping into empty space, picking up objects of various sizes and materials, and picking up objects for different goals. A better understanding of how the brain prepares these movements may lead to improved devices and therapies for those with sensory or motor problems. 

Controlled neuronal firing in vivo using two photon spatially shaped optogenetics Gibson, Emily Restrepo, Diego (contact) University Of Colorado Denver 2017 Active
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Optical imaging techniques offer several advantages to understanding neural circuits, including the ability to interrogate a large number of neurons and genetically label specific neuronal subtypes. Diego Restrepo, Emily Gibson, and colleagues will optimize their prototype of a light-weight, two-photon, fiber-coupled, miniature confocal microscope that uses electrowetting lens technology. The new tool will be able to image and stimulate select fluorescently-labeled neurons in a 3D volume in awake-behaving animals. The device can be attached to existing commercial laser scanning microscopes – greatly expanding the number of labs who will be able to benefit from this cutting-edge technology.
Cortex-wide volumetric imaging of neuronal activity. Vaziri, Alipasha Rockefeller University 2017 Active
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Understanding how brain-wide neural network activity underlies behavior is a central goal of neuroscience, and essential to understanding neurological and psychiatric disorders. Vaziri’s group recently innovated microscopy platforms that extend the obtainable spatiotemporal resolution and volume size using calcium imaging. Here, they propose to develop, apply, and disseminate a hybrid system that enables calcium imaging of ~2 million neurons within and across layers of cortex in awake behaving rodents and marmosets. Such a system would capture functional organization and activity patterns of neuronal population dynamics. This project could enable new mechanistic insights into the computational principles of neural information processing.
Cortical circuits and information flow during memory-guided perceptual decisions Sur, Mriganka Massachusetts Institute Of Technology 2014 Complete
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Dr. Sur and his team will combine a number of cutting-edge, large-scale imaging and computational techniques to determine the exact brain circuits involved in generating short term memories that influence decisions.
Cortical dynamics underlying visual working memory Resulaj, Arbora University Of California, San Francisco 2019 Active
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Working memory is crucial to many human functions, and a better understanding of its underlying mechanisms could improve our understanding of memory abnormalities in advanced age. Current hypotheses suggest that working memory is maintained by a hierarchy of interconnected cortical areas, but more work is needed to understand the unique role of each area. Dr. Resulaj aims to study visual working memory at the systems and cellular level in the mouse. Utilizing novel behavior assays, a laser scanning galvo system, and optogenetics, this work ultimately will develop a computational model of visual working memory in the mouse cortex.

Cortico-striatal representations of multisensory decision-making Sun, Xiaonan Feinstein Institute For Medical Research 2019 Active
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Activity in the striatum is known to be linked to perceptual decision-making processes orchestrated by the cortex. Dr. Sun proposes to use genetically-encoded calcium indicators to examine cortex-wide activity patterns in mice performing perceptual decision tasks. This will be combined with wide-field calcium imaging in order to correlate behavior with changes in neural activity. The research will enhance our understanding of how activity in the cortico-striatal pathway supports decision-making.

CranialProgrammer: Image-Guided Directional Deep Brain Stimulation Programming Using Local-Field Potentials Duke, Austin NEXEON MEDSYSTEMS PUERTO RICO OPERATING COMPANY, INC 2018 Active
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While Deep Brain Stimulation (DBS) devices can alleviate symptomology of patients with chronic conditions like Parkinson’s disease, appropriate placement is paramount and challenging, particularly for directional stimulating leads. Dr. Austin plans to develop and test CranialProgrammer, image-guided software that uses local field potentials to help clinicians map patient brain regions for optimal placement of DBS leads. In partnership with NeuroTargeting, LLC, the software will integrate with the implanted DBS system of Parkinson’s patients to allow visualization of patient data coupled with imaging technologies. This software could dramatically improve the ability of neurologists to program directional DBS leads, providing therapeutic benefit to myriad DBS patients.

 

Crowd coding in the brain:3D imaging and control of collective neuronal dynamics Kanold, Patrick O (contact) Losert, Wolfgang Plenz, Dietmar Univ Of Maryland, College Park 2014 Complete
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Dr. Kanold and his team propose cutting edge methods to stimulate neurons at different depths in the auditory cortex, and will use new computational methods to understand complex interactions between neurons in mice while testing their ability to hear different sounds.
DANDI: Distributed Archives for Neurophysiology Data Integration Ghosh, Satrajit Sujit (contact) Halchenko, Yaroslav O Massachusetts Institute Of Technology 2019 Active
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Dr. Ghosh and colleagues propose to develop a new computer infrastructure for scientists to share, collaborate, and process neurophysiological data. The data will be open to both scientists and also be used to engage high school and college students. The team will also develop tools to facilitate data submission and access and to encourage adoption of the Neurodata Without Borders data standard.

DART2.0: comprehensive cell type-specific behavioral neuropharmacology Tadross, Michael R Duke University 2018 Active
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Neuropharmaceuticals provide relief to millions suffering from an array of neurological and neuropsychiatric disorders. However, a barrier to identifying novel therapeutic targets can be attributed to a poor understanding of how the behavioral effects of drugs are mediated by specific neural cell types in the brain. Tadross’ team recently developed DART (Drugs Acutely Restricted by Tethering), the first and only method to date that can map the behavioral effects of clinical drugs by cell type. These tools would reveal circuit origins of desired vs harmful drug effects, explain why some drugs have higher efficacy than others, and potentially empower future rational efficacy advances. This project aims to expand the catalog of available DARTs, increase their subcellular specificity, and improve ease of use – particularly in combination with recording devices across larger brain areas. If successful, these tools will maximize utility to the neuroscience community, enabling previously intractable questions to be addressed.

Data Archive for the Brain Initiative (DABI) Duncan, Dominique Pouratian, Nader Toga, Arthur W (contact) University Of Southern California 2018 Active
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This project develops DABI (Data Archive for the Brain Initiative) to aid the dissemination of human neurophysiological data generated through the BRAIN Initiative. Incorporating infrastructure from a pre- existing hub for delivering effective informatics and analytics solutions for major projects in the study of neurological diseases, Drs. Toga, Duncan, and Pouratian will aggregate data related to human electrophysiology, making the data broadly available and accessible to the research community. The group plans to incorporate analysis tools with user interfaces, implement tools for data management and use, and link metadata across different data modalities. The overarching goal of this project is to secure, link, and disseminate BRAIN Initiative data with all pertinent recording and imaging parameters coming from participating sites

Data interface and apps for systems neurophysiology and imaging Van Hooser, Stephen D Brandeis University 2018 Active
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Many labs develop unique software to manage and interpret their findings, but those programs are often specific for certain types of datasets, making them difficult to share among researchers. Dr. Van Hooser’s team plans to create an interface standard that establishes a common set of processes for accessing neurophysiological and imaging data. The standard will be tested, and revised accordingly, based on feedback from graduate students and postdoctoral researchers during data access events, or “hack-a-thons.” The interface standard will help increase the speed of research and make data widely available, allowing individuals outside of the neuroscience and research communities to make discoveries.

Decoding the neural basis of resting-state functional connectivity mapping Hillman, Elizabeth M Columbia University Health Sciences 2017 Active
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  • Human Neuroscience
Resting-state functional magnetic resonance imaging (rs-fMRI) detects how brain regions are synchronized, forming networks that support normal function. Understanding these networks may help diagnose and treat disease. Elizabeth Hillman’s team will use novel optical imaging, capturing neural activity and blood flow dynamics, to characterize cellular dependencies, pathways, behavioral correlates, and blood flow interactions of resting-state spontaneous neural activity. Data will be acquired using novel measurement and circuit manipulation techniques in awake, behaving mice, and rs-fMRI analysis of equivalent human neurovascular activity. The aggregate data will yield predictive models of network activity and the relationships between resting-state activity in specific cell types and blood flow dynamics. By optimizing and validating rs-fMRI analysis, this project could transform rs-fMRI into a reliable technique for studying the brain in health and disease.
Deep brain photoacoustic tomography at single-neuron resolution using arrays of photonic emitters and high-frequency ultrasound transducers Roukes, Michael L Shepard, Kenneth L Wang, Lihong (contact) California Institute Of Technology 2016 Active
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Photoacoustic tomography, an imaging technique that relies on ultrasonic thermal responses to absorption of light pulses, has the potential for faster and deeper imaging than other modalities such as multiphoton microscopy. It can be applied for imaging neurovascular responses, and in principle should be suitable for imaging activity of calcium and voltage reporters. Dr. Wang and colleagues will develop a high-frequency version of the technique using implantable photonic emitter and ultrasound detector arrays. This technology will improve the scale, resolution, contrast, and penetration of imaging in the mouse brain in vivo, providing neuroscientists with a powerful new tool for understanding complex brain circuitry.
Deep brain stimulation for depression using directional current steering an individualized network targeting Goodman, Wayne K Pouratian, Nader Sheth, Sameer Anil (contact) Columbia University Health Sciences 2017 Active
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Deep brain stimulation (DBS) for treatment-resistant depression (TRD) has shown promise, but has delivered inconsistent results. Sheth’s team hypothesizes that patient-specific, network-guided neuromodulation is critical, and that lack of clinical success is partly due to off-target stimulation (i.e., a failure to modulate appropriate brain networks). Using next-generation, precision DBS with directional steering capability in patients with TRD, the team will delineate patient-specific, depression-relevant networks and demonstrate behavioral changes with network-targeted stimulation. They will target the subgenual cingulate and ventral capsule/ventral striatum, along with other TRD-implicated regions, then identify and engage symptomatic networks. In addition to managing TRD, this study may have implications for understanding neurocircuit dysfunction in other neuropsychiatric conditions.
Deep cerebellar electrical stimulation for post-stroke motor recovery Baker, Kenneth B Machado, Andre Guelman (contact) Cleveland Clinic Lerner Com-cwru 2016 Active
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Despite current efforts at rehabilitation, one third of stroke patients have long-term motor deficits severe enough to require assistance with the activities of daily life. Machado and colleagues are working to develop therapies that promote recovery of motor function and improve quality of life for such individuals. Specifically, the goal of this project is to demonstrate proof of principle of a next-generation, multi-electrode, closed-loop system for deep brain stimulation in the cerebellum’s dentate nucleus. It is hoped that such stimulation can facilitate motor recovery for patients with persistent, moderate-to-severe, upper extremity hemiparesis due to stroke.
DEEPHIPPO: Ultra-thin lensless endoscope for the visualization of deep hippocampus neuronal functional activity. Rigneault, Herve AIX-MARSEILLE UNIVERSITY 2018 Active
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Optical imaging methods have emerged to measure and control neuronal signals with unprecedented spatial resolution and genetic specificity. Two‐photon excitation (2PE) microscopy and the development of genetically-encoded activity sensors have supported numerous discoveries about nervous system function. However, 2PE signal intensity decreases exponentially with tissue depth. To circumvent the depth-limit imaging problem, Rigneault’s team has developed a very small (150µm to 200µm diameter) endoscope for two‐photon calcium imaging in the hippocampus of freely-moving (navigating) mice. Compared to other minimally-invasive probes , this system has a smaller, more flexible, lensless design and the ability to support multi-photon operation. This project could improve the ability to image deep brain structures in behaving animals.

Defining Cell Type Specific Contributions to fMRI Signals Lee, Jin Hyung Stanford University 2017 Active
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  • Human Neuroscience
Functional magnetic resonance imaging (fMRI) allows non-invasive study of human brain function. However, how specific cell types contribute to fMRI signals remains elusive, complicating fMRI interpretation. Jin Hyung Lee’s team will measure cell-type-specific, whole-brain network function using fMRI while using optogenetics to selectively stimulate distinct neural circuit pathways in the basal ganglia. These pathways are involved in action planning and reward, and are implicated in disorders as diverse as Parkinson’s disease, depression, and substance use disorders. Optical imaging will confirm fMRI signal sources with cell-type specificity. The group will computationally model these interaction dynamics to demonstrate how this unique approach can be used to uncover whole-brain circuit functions. This project could enable researchers to systematically design therapies to restore normal circuit function in disorders like Parkinson’s disease.
Defining Neuronal Circuits and Cellular Processes Underlying Resting fMRI Signals Milham, Michael Peter Schroeder, Charles E (contact) Nathan S. Kline Institute For Psych Res 2016 Active
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  • Human Neuroscience
Methods for measuring intrinsic functional connectivity (iFC), a measure of correlation between spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal, can be used to quickly map in high detail the functional architecture of the human brain. However, the neural circuits underlying the BOLD-iFC relationship remain poorly specified. Schroeder and his colleagues propose to use a variety of measurement tools in humans and monkeys to investigate this relationship. The researchers will then employ established modeling and computational methods to help construct a comprehensive model that connects large-scale iFC to underlying microscale activity at the neural circuit level. The findings from this project may be used to improve the efficiency of iFC measurements, which could have widespread clinical implications, particularly in the discovery of biomarkers for various brain disorders.
Designing and deploying an expanded color palette of voltage indicators engineered for multiphoton microscopy St-pierre, Francois (contact) Tolias, Andreas Baylor College Of Medicine 2019 Active
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Genetically encoded voltage indicators (GEVIs) are fluorescent proteins designed to help researchers watch electrical activity in neurons. Changes in voltage change the brightness that GEVIs shine. The St. Pierre and Tolias labs plan to develop an array of GEVIs that can measure different types of electrical activity using multi-photon microscopy. To do this, they will make a microscope designed to rapidly search for new GEVIs; create GEVI’s that can detect electrical spikes or synaptic communication between neurons; and tailor the fluorescent colors of GEVI for multi-photon microscopy. Results from this project may help researchers watch brain circuits spark and fire in real time.

Designing low-cost, customizable high-density probes for acute and chronic neural recordings in rodents Van Welie, Ingrid Neural Dynamics Technologies, Llc 2018 Active
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To advance our understanding of the function of dynamical neural circuits, there is a need for technologies that can record the activity of hundreds to thousands of neurons simultaneously within and across brain regions in intact brains. Through Neural Dynamics Technologies, LLC, Drs. van Welie, Scholvin, and Boyden propose one way to resolve this issue by developing customizable high-density neural probes for use in acute or chronic recordings of neural population activity with a spatial and temporal resolution that is required for studying neural circuit activity.

Determination of olfactory bulb cell identity through the integration of single cell epigenomic and transcriptomic data Doyle, Wayne University Of California, San Diego 2019 Active
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Olfaction is an extremely important sensory modality across species, and it is one of the first to be disrupted in many neurodegenerative diseases. Dr. Doyle will conduct a full census of all cell types in the mouse olfactory bulb, to better understand information integration and processing in the olfactory system. This approach will utilize transcriptomic (single cell RNA-sequencing) and epigenomic (single nucleus methylome- and single nucleus ATAC-sequencing) data generated by members of the BRAIN Initiative Cell Census Network (BICCN). Overall, this will allow for a fuller understanding of the roles of cell diversity, regulatory elements, and transcription factors in the mouse olfactory system.

Determining the role of muscle afferent signals in cortical proprioceptive representation Blum, Kyle Northwestern University At Chicago 2019 Active
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While it is known that proprioception plays an important role in movement, how the brain translates proprioceptive information into information for movement in the somatosensory cortex (S1) is poorly understood. Dr. Blum aims to study how active and passive movements of limbs elicit different responses from muscle spindles and Golgi tendon organs, especially as reflected in area 3a of S1. Using electrophysiological data, arm kinematic measurements, and EMGs in monkeys trained to perform an arm-reaching task, this research aims to model afferent proprioceptive signals and motor outputs in a neural network model. These results will improve our understand of the neural control of movement.

Develop and validate novel chemogenetic tools to modulate synaptic transmission Tomita, Susumu Yale University 2017 Active
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Neuronal activity modulates the strength of synaptic connections, a phenomenon known as synaptic plasticity, which is critical for forming and maintaining memories, for behavioral adaptations, and is disrupted in a variety of nervous system disorders. Tomita and colleagues will develop tools to chemically modulate excitatory synaptic transmission in vivo, mimicking synaptic plasticity. They will engineer a protein that transiently modulates synaptic activity upon addition of small chemical compounds. They will validate the protein module using a mouse fear conditioning behavioral paradigm and electrophysiology. This approach may help identify precise circuits/mechanisms underlying brain functions like learning and memory.
Developing a noninvasive method to manipulate specific cell types within the mammalian brain Chalasani, Sreekanth H. Salk Institute For Biological Studies 2016 Active
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Current optogenetic techniques to manipulate cellular activity rely on an invasive light delivery method which makes control of cells deep in the brain difficult. Chalasani and colleages are developing a non-invasive method of cellular control using mechanosensitive channels that are responsive to low-intensity ultrasound - a novel technique deemed “sonogenetics.” The group can control neuronal activity in vitro by expressing these channels in target cells, and plan to test similar channels to fine-tune responsiveness to ultrasound pulses. Further, the group will develop a head device to deliver ultrasound pulses in mice, test efficacy in vivo via electrophysiological and behavioral analyses. Following development in rodents, this tool could be broadly applicable across multiple species to manipulate specific neuronal and non-neuronal cell types.
Developing drivers for neuron type-specific gene expression Hobert, Oliver Columbia University Health Sciences 2014 Complete
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Dr. Hobert and colleagues will create a highly selective technology for experimentally manipulating genes in neurons, by tapping into the regulatory machinery of individual cell types.

Developing genetically-encoded detectors for neuropeptide release based on class B G-protein coupled peptide receptors Pang, Zhiping P. Rbhs-robert Wood Johnson Medical School 2019 Active
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Due to their chemically inert nature and delayed signaling pathways, neuropeptides have been difficult to study by conventional electrophysiology or with oxidizable probes. To overcome this, Dr. Pang’s group aims to develop genetically encoded optical sensors for neuropeptides, named Chimeric Detectors for Neuropeptide Release (CDNRs), using unique structural features of neuropeptide-recognizing receptors. To validate the new probes, the researchers will express CDNRs in defined glucagon-like peptide-1 (GLP-1) and corticotropin-releasing hormone/factor (CRF) circuitry using viral transduction in mice and perform high-resolution optical recording to detect the release of endogenous GLP-1 and CRF, ex vivo and in vivo. This work may lay a foundation for the development of other neuropeptides detectors to advance our understanding of neuropeptide functional connectivity in the brain.

Developing novel chemo-optogenetic tools for in vivo applications Lam, Pui Ying University Of Utah 2019 Active
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Optogenetics and chemo-optogenetics are emerging tools for neuroscience research, providing ways to modulate cell function with light. However, current limitations for these tools include limited ability to target cells deep in the brain, the relatively small effects they elicit, and safety concerns over long-term use. Dr. Lam proposes to develop new chemo-optogenetic tools to address these issues, based on the TRPA1 and TRPV1 receptor channels. Further, she will develop this technology for in vivo use, testing its utility in behavioral assays of zebrafish. The work will improve our ability to understand brain circuit function, and will create a platform for the discovery of other novel chemo-optogenetic approaches that mimic natural cell activity.

Development and dissemination of high speed 3D acousto-optic lens two-photon microscopy for in vivo imaging Digregorio, David A Hausser, Michael Mrsic-flogel, Thomas O'keefe, John Silver, Robin Angus (contact) University College London 2016 Active
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Two-photon microscopy is an important tool for neuroscience research because it enables neuronal activity to be monitored at high spatial resolution deep into the neocortex. Silver and his colleagues plan to refine and disseminate a rapid scanning technology that utilizes an acousto-optic effect, in which a crystal lens is modulated using sound waves, allowing extremely fast switching of laser light in 3D over arbitrary distances within a given scanning field. They have designed a modular system that can be integrated into current two-photon microscopes at low cost. The project design and software interface are open source and will be made available for free to non-commercial entities, and by non-exclusive licensing to commercial partners. This low-cost technology for imaging neuronal circuits in awake, behaving animals will help researchers better understand brain function.
Development and Translation of an Intracranial Auditory Nerve Implant LIM, HUBERT HYUNGIL et al. UNIVERSITY OF MINNESOTA 2018 Active
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Despite providing significant restoration of the ability to hear speech, cochlear implants have been limited in their ability to restore full hearing, particularly in loud environments or situations when multiple sounds are present at once. Drs. Lim, Oxenham, Franklin, Rieth, Solzbacher, and Lenarz are exploring a new, auditory nerve implant device and surgical techniques with the potential to improve upon current cochlear implants in humans. This new device will directly target the auditory nerve, which connects the cochlea to the brainstem. The researchers, who will also be developing a new surgical technique for implantation and validate efficacy and safety, hope that this will allow for improved hearing, including speech and music.

Development and validation of AAV vectors to manipulate specific neuronal subtypes and circuits involved in epilepsy and psychiatric disorders across mammalian species. Deverman, Benjamin E Dimidschstein, Jordane Fishell, Gordon J (contact) Broad Institute, Inc. 2019 Active
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The ability to genetically target specific neuron populations in non-human primates (NHPs) and humans is needed to understand neural circuits in epilepsy and psychiatric disorders. Here, Drs. Fishell, Dimidschstein, and Deverman and collaborators aim to develop a Cre-based, high-throughput screening platform to identify AAV-enhancer vectors that could target specific disease-relevant neuronal populations. The team plans to evaluate the performance of promising AAV vectors across model systems (mice, NHPs, and human cell-derived organoids), before mapping the functional connectivity of inhibitory and disinhibitory interneurons in prefrontal cortex of NHPs. This work may provide a validated toolkit of AAV vectors to investigate the brain activity of specific neuronal cell populations to further our understanding of disease-relevant circuits.

Development and validation of empirical models of the neuronal population activity underlying non-invasive human brain measurements Devinsky, Orrin Dijkhuizen, Rick M Petridou, Natalia (contact) Ramsey, Nicolas Franciscus Winawer, Jonathan A University Medical Center Utrecht 2016 Active
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A major obstacle in the study of human brain function is that we currently have a limited understanding of how the measurements made by different instruments, such as fMRI and EEG, relate to one another and to the underlying neuronal circuitry. To overcome this challenge, Petridou and her colleagues will combine a number of invasive (optical imaging, ECoG) and non-invasive (functional MRI, MEG and EEG) hemodynamic and electrophysiological measurements in humans and rats. By obtaining recordings from these multiple techniques, the researchers will be able to unequivocally link electrophysiological and fMRI signals. Reconciling these different signals will lead to breakthroughs in understanding the dynamic activity of the human brain and the improvement of disease models of the nervous system.
Development of 7-T MR-compatible TOF-DOI PET Detector and System Technology for the Human Dynamic Neurochemical Connectome Scanner Catana, Ciprian MASSACHUSETTS GENERAL HOSPITAL 2018 Active
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Systems capable of simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) are now available, but PET technology in these systems lacks the capability of tracking dynamic changes at high spatio-temporal resolution. Dr. Ciprian Catana and a team of investigators plan to develop a PET detector that can be successfully integrated with a 7-Tesla MRI scanner with high sensitivity and resolution. After designing and evaluating a scalable PET detector module, the group will investigate and address hardware challenges of developing high performance MR-compatible PET technology. The successful development of this novel PET technology will enable imaging of the human brain’s dynamic neurochemical connectome and significantly advance our understanding of human brain function, neurochemistry, and physiology.

 

Development of a Revolutionary MRI System for Functional Brain Imaging Wagner, Bob S Wang, Sou-tien Bert (contact) Wang Nmr, Inc. 2018 Active
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Low-cost, portable Magnetic Resonance Imaging (MRI) systems require use of small-bore magnets that are unable to capture the detail necessary to image the human brain. In this project, Drs. Wang and Wagner propose to further develop an imaging method previously funded by The BRAIN Initiative, by designing, building, and testing a portable 1.5T MRI system to image human brain activity. The novel imaging technology works with a small, lightweight (250 lb.), portable, low-cost, head-only magnet. The compactness and efficiency of this non-invasive imaging system makes the study of the human brain possible in more clinics and in subjects who previously were unable to receive an MRI scan due to constraints of standard systems.

Development of a scalable methodology for imaging neuropeptide release in the brain Anderson, David J California Institute Of Technology 2015 Complete
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Superimposed upon the brain's physical connectome is a largely invisible chemical soup of neuromodulators, including biogenic amines and neuropeptides, which exert a profound influence on the activity and function of neural networks. Yet, large-scale high-resolution techniques for measuring neuromodulators have lagged behind those for recording or imaging electrical activity. Anderson and his team plan to develop fluorescent proteins that can be attached specifically to large dense core vesicles—discrete packets of neuromodulators to be released into the synapse. This method would enable researchers to use 2-photon microscopy to image the release of neuromodulators in living animals with high spatial and temporal resolution, transforming the ability to characterize neural circuit function and facilitating the development of technologies to selectively perturb release.
Development of an integrated array for simultaneous optogenetic stimulation and electrical recording to study cortical circuit function in the non-human primate brain Angelucci, Alessandra Blair, Steven M (contact) Rieth, Loren University Of Utah 2016 Active
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Optogenetics is a potent tool for studying neural circuit function, but its application in the context of electrical recordings has been limited, especially in higher mammals beyond rodents. Blair and his colleagues propose to develop and test functional multi-optrode penetrating arrays derived from the well-established Utah electrode array. These devices, which will integrate light emitting diodes (LEDs), are designed for spatiotemporally patterned optogenetic stimulation and electrical recording of neural circuits across large volumes throughout the depth of the neocortex. This technology will allow for unprecedented optogenetic investigations of neural circuit function in higher mammals, enabling experiments that will address fundamental questions of how the brain processes information.
Development of Hybrid Adaptive Optics for Multimodal Microscopy Deep in the Mouse Brain Adie, Steven Graham Cornell University 2017 Active
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Achieving high-resolution, optical images of deep cellular brain activity with three-photon microscopy can be difficult due to technical limitations of existing methodologies. Currently, collecting a volumetric set of images uses correction sensors that require long measurement times and can damage the biological sample. Steven Adie is collaborating with Chris Xu to develop an improved hybrid imaging approach that captures high-resolution cellular imaging and outsources the correction sensor step to computational resources, reducing correction time. By enabling faster corrections to occur at greater depths than is currently possible, the group will address a standing impediment to deep-brain microscopy of brain activity. This project has the potential to be a major step towards volumetric functional imaging of neural activity in the mouse brain.
Development of Line-Scan Temporal Focusing for fast structural imaging of synapse assembly/disassembly in vivo Boivin, Josiah R Massachusetts Institute Of Technology 2017 Active
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Dr. Boivin will contribute to the development of high-resolution, high-throughput Temporal Focusing (TF) two-photon microscopy to achieve real-time monitoring of synapse assembly/disassembly in developing neural circuits in vivo in the mouse brain.
Development of Protein-based Voltage Probes Pieribone, Vincent A John B. Pierce Laboratory, Inc. 2014 Complete
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Dr. Pieribone and his team will optimize fluorescent voltage probe technology, to allow scientists to measure the activity of thousands of neurons using only a camera and a microscope.
Development of tools for cell-type specific labeling of human and mouse neocortical neurons Lein, Ed Levi, Boaz Pirie (contact) Ting, Jonathan T Allen Institute 2017 Active
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An important strategy for understanding the neural circuits is to identify the component cell types, then determine each cell type’s function. Currently, the characteristics of mammalian neocortical cell types are incompletely characterized, and the necessary investigative tools are lacking. Levi and colleagues will develop cross-species, cell-class-specific viral vector libraries for tagging different cell types in mouse and post-mortem human neocortex, which will be validated using single-cell RNA sequencing and electrophysiology. If successful, this project will achieve novel cell type-specific genetic tools to investigate and compare cross-species neocortical cell types.
Dexterous BMIs for tetraplegic humans utilizing somatosensory cortex stimulation Andersen, Richard A California Institute Of Technology 2016 Active
  • Human Neuroscience
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As of 2016, approximately 160,000 Americans are living with partial or complete tetraplegia, a severe form of paralysis in which patients lose partial or total function and sensation in all four limbs. Many of these patients have sufficiently intact brain circuits to plan movements, but are unable to act on those plans due to paralysis at the spinal level. In this project, Andersen and his team will work with tetraplegic patients implanted with a brain machine interface (BMI) to record from and stimulate brain circuits. Their goal is to understand how the brain encodes the ability to reach for and grasp an object. They also propose to stimulate somatosensory cortex to restore sensory cues the hands would normally receive when grasping an object, and to combine these recording and stimulating efforts to design bi-directional BMIs. This work could lead to improved quality of life for patients with tetraplegia, and could inform treatment of motor impairments due to other causes including stroke and neurodegenerative diseases.
Diffuse, spectrally-resolved optical strategies for detecting activity of individual neurons from in vivo mammalian brain with GEVIs Nishimura, Nozomi Cornell University 2017 Active
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Optical recording of neural activity allows researchers to better understand the role of cells and circuits in behaviors, but distinguishing individual neurons in a population of cells is difficult with existing voltage indicators, while laser scanning methods are typically too slow to resolve action potentials from many cells at a time. Rather than using scanning methods to identify cells based on their location, Nozomi Nishimura and colleagues propose the use of spectral information to “barcode” individual neurons, using multiple colors of genetically-encoded voltage indicators to label neurons with a combination of voltage probes. After capturing the emitted fluorescence, the channels can be spectrally unmixed to sort different neurons based on their combination of colors and patterns. This novel paradigm has the potential to detect and decode action potentials in individual neurons at the imaging rates required to resolve spike timing in a population of cells.
Direct MEG/EEG detection using a novel MRI approach Bottomley, Paul A Johns Hopkins University 2017 Active
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Non-invasive measurements of neuronal electrical activity in the human brain are currently limited by the low spatial resolution of electroencephalography (EEG) and magnetoencephalography (MEG) methods. Another non-invasive method – functional magnetic resonance imaging (MRI) – provides high spatial resolution, but reports fluctuations in neural activity via the slow, indirect neurovascular response. Paul Bottomley and his team are applying spectroscopy with linear algebraic modeling (SLAM) – a method they recently developed for MR spectroscopy – to MEG-modulated MRI signals. Using SLAM, the group plans to improve the signal-to-noise ratio and demonstrate MRI-based detection of brain electrical signals in healthy human volunteers. This novel approach has the potential to deliver an MRI-based means of directly localizing EEG/MEG activity in the healthy human brain.
Dissecting human brain circuits in vivo using ultrasonic neuromodulation Shapiro, Mikhail Tsao, Doris Ying (contact) California Institute Of Technology 2014 Complete
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In rodents, monkeys and eventually humans, Dr. Tsao's team will explore use of non-invasive, high resolution ultrasound to impact neural activity deep in the brain and modify behavior.
DREADD2.0: AN ENHANCED CHEMOGENETIC TOOLKIT Jin, Jian Kash, Thomas L. Roth, Bryan L. (contact) Univ Of North Carolina Chapel Hill 2014 Complete
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Dr. Roth and colleagues will build second generation technology that uses artificial neurotransmitters and receptors to manipulate brain activity simultaneously across select cells and pathways to understand their functions and potentially treat brain disorders.
DUAL LEAD THALAMIC DBR-DBS INTERFACE FOR CLOSED LOOP CONTROL OF SEVERE ESSENTIAL TREMOR OWEISS, KARIM G UNIVERSITY OF FLORIDA 2019 Active
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Essential Tremor (ET) is a progressive disease that leads to significant disability and markedly diminished quality of life. Deep brain stimulation (DBS) in the ventralis intermedius (VIM) thalamus has been an effective treatment for ET, but is associated with problematic side effects (e.g., slurred/slow speech, muscle imbalance) and may lose efficacy over time in people with severe ET. Drs. Oweiss, Foote, and colleagues will utilize the Medtronic Summit RC+S DBS system to investigate how limb movement and tremor relate to neural activity in the VIM and ventralis oralis thalamus, then use this information to develop a dual-lead, closed-loop stimulation approach for people with severe ET who are refractory to open loop VIM DBS.

Dual-channel Sub-millisecond Resolution Neural Imaging System Zhao, Youbo Physical Sciences, Inc 2018 Active
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Dr. Zhao's project aims to build a highly innovative and low-cost imaging tool that addresses a technological gap in neuroscience research for non-invasive recording of large neuron populations with high spatial and temporal resolution. The team plan to build and validate a fluorescent imaging system that enables parallel recording of multiple neuron populations with sub-cellular and sub-millisecond resolution. The system will include optimization of a benchtop microscope with two detection channels, and subsequent development of a head-mounted device for imaging in rodents. Successful development and commercialization of this technology could significantly advance neuroscience research, and thus improve our understanding of brain function.

Dynamic network computations for foraging in an uncertain environment Angelaki, Dora (contact) Dragoi, Valentin Pitkow, Zachary Samuel Schrater, Paul R Baylor College Of Medicine 2015 Complete
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The computational strategies and underlying mechanisms the brain uses to enable animals to interact flexibly with their environment are poorly understood. These researchers will use large-scale, wireless, electrical recordings from six relevant, interconnected brain regions in freely-behaving monkeys to record neuronal activity while the animals engage in foraging behavior-a natural task that involves sensory integration, spatial navigation, memory, and complex decision-making. The research team will use theoretical models of decision-making to interpret the neural activity data gathered as the animals interact with their environment, with the ambitious goal of understanding how brains create and use internal models of the world.
Dynamic Neural Mechanisms of Audiovisual Speech Perception Beauchamp, Michael S (contact) Schroeder, Charles E Baylor College Of Medicine 2019 Active
  • Human Neuroscience
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Speech perception often lies at the heart of our interactions with other people. By nature, it is multisensory, combining auditory information from the voice with visual information from the face. However, there is a large gap in our knowledge about this critical cognitive skill because most experimental techniques available in humans have poor spatiotemporal resolution. In this strategic opportunity to study patients undergoing clinically-indicated brain surgery, Dr. Michael Beauchamp and his team will use intracranial recording (iEEG) in humans to study the neural mechanisms of speech perception. In addition to high-resolution intracranial electrode grids, the group will also leverage non-penetrating electrodes that are safely placed on the cortical surface of the brain. This multi-pronged approach will enable the group to study the organization and operation of the brain during audiovisual speech perception, providing a better understanding of this important human skill.

Dynamic Neural Mechanisms of Audiovisual Speech Perception Schroeder, Charles E Columbia University Health Sciences 2016 Active
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Limitations in spatial and temporal resolution with current non-invasive brain imaging technologies prevent a thorough understanding of the mechanisms of speech perception – from audio-visual (AV) integration, to encoding, and cognitive interpretation. Dr. Charles Schroeder proposes directly recording from neurons in epilepsy patients while they process AV speech using electrocorticographic (ECoG) techniques to determine how oscillations in neuronal excitability influence processing and encoding. Not only could this project improve our ability to treat neurological disorders affecting speech and language processing, but it may allow a more comprehensive investigation into the functional interactions between brain circuits and perception.
Dynamics and Causal Functions of Large-Scale Cortical and Subcortical Networks SCHALK, GERWIN WADSWORTH CENTER 2018 Active
  • Human Neuroscience
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To produce a behavior, brain areas need to talk to each other. This communication has been difficult to study in humans, but novel tools provide a window into these conversations. Dr. Schalk and his colleagues plan to establish a consortium that will bring together a large cohort of study subjects and experts across scientific disciplines. They will record from state-of-the-art brain implants to investigate which regions are involved in speech, language, and music awareness; to measure how stimulating certain areas affects speech and language; and to explore how areas talk to one another during changing speech perception. These results should increase understanding of how brain regions interact, which may provide insights to treating neurological and psychiatric disorders.

Early Feasibility Clinical Trial of a Visual Cortical Prosthesis Dorn, Jessy D (contact) Greenberg, Robert Jay Pouratian, Nader Second Sight Medical Products, Inc. 2018 Active
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Currently, a recently developed retinal prosthesis, the Argus® II, restores vision to over 200 patients with retinitis pigmentosa. Argus II electrically stimulates the retina, inducing visual perception. However, retinal implants can only help a small subset of the millions of people suffering from profound blindness. In this early feasibility clinical trial, Greenberg’s team will implant (and test) a prosthesis on the medial surface of the visual cortex. Building on the platform of the Argus II, the proposed prosthesis will electrically stimulate the visual cortex, to restore visual perception. This project could help restore useful vision to many people with blindness from disorders like diabetic retinopathy or glaucoma, or damage to the eyes, optic nerve, or thalamus. 

Effects of standard fMRI calibrations on the diverse microvascular blood flow and oxygenation responses in cortical layers Sencan, Ikbal Massachusetts General Hospital 2019 Active
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Various improvements are being considered to create next generation biophysical models of blood oxygenation and fMRI measurements in brain. Dr. Sencan plans to quantify spatial and temporal diversity in cortical metabolism in order to inform these scientific advancements. By measuring processes of cortical oxygenation, metabolic rate, and blood flow responses at microvascular scales, she aims to understand how these processes contribute to brain function and vary across age, region, and depth in the awake, mouse brain. To achieve these goals, she will use novel experimental techniques, related to faster, deeper, and more realistic imaging of oxygen concentration. This work may support better interpretation of clinical results derived through imaging technologies like fMRI.

Efficiency and Safety of Microstimulation Via Different Electrode Materials Cui, Xinyan Tracy University Of Pittsburgh At Pittsburgh 2019 Active
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Microstimulation electrodes help neurologists examine the brains of patients suffering from epileptic seizures and other neural circuit problems. The Cui team aims to develop standardized in vivo and in vitro model systems for testing the safety and efficiency of novel microstimulation devices made with newly designed t materials. Experiments in mice and cultured neurons will examine the short- and long-term effects of stimulation on the health of the tissue and the integrity of the electrodes. This system may help researchers develop better microstimulation devices for treating a variety of neurological disorders.

Electrophysiological Biomarkers to Optimize DBS for Depression Mayberg, Helen S Emory University 2017 Active
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Deep brain stimulation of subcallosal cingulate (DBS-SCC) white matter is an emerging new therapy for treatment resistant depression (TRD). An important next step is to develop biomarkers for guiding lead placement and titrating stimulation parameters during ongoing care. Mayberg’s team will develop and test electrophysiological biomarkers for device configuration in individuals receiving DBS-SCC for TRD. They aim to optimize and standardize treatment based on functional anatomy and electrophysiological variables, replacing current methods that rely on? depression severity scores and psychiatric assessments. If successful, this work will impact future clinical trial design and provide a new approach to long-term management of symptoms in patients receiving this treatment.
Electrophysiological source imaging guided transcranial focused ultrasound He, Bin University Of Minnesota 2017 Complete
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Noninvasive neuromodulation technologies use a variety of electrical, magnetic, optical, and sonic techniques to stimulate the brain. The ensuing modulation of brain network dynamics can be used as a tool to study healthy brain processes, as well as for treatment of brain disorders. He’s team will develop an acousto-modulated electrophysiological source imaging (ESI) technique with improved spatial precision, and use it to monitor and image transcranial focused ultrasound (tFUS)-induced brain activity in real-time. The group will validate this integrated ESI-guided tFUS system in rats, using simultaneous intracranial recordings of neural spikes and local field potentials, and ultimately test it in human subjects. This non-invasive neuromodulation, with high spatiotemporal precision, promises stimulation which is individualized and responsive to dynamic neural activity.
Elementary Neuronal Ensembles to Whole Brain Networks: Ultrahigh Resolution Imaging of Function and Connectivity in Humans Ugurbil, Kamil University Of Minnesota 2017 Active
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Obtaining a comprehensive view of the human brain – from neuronal circuitry up to whole-brain functional and structural connectivity – requires advances in current magnetic resonance imaging (MRI) methods that span spatial and temporal scales. Kamil Ugurbil and a team of multi-institution researchers are improving on the technologies required to generate a previously unavailable, 10.5 Tesla, high-quality MR image. Ugurbil aims to develop methods that exploit the signal-to-noise ratios available at ultrahigh fields, improve image reconstruction, and use these technological developments to create a publicly available dataset for novel computational modeling. These developments will permit investigation of brain function and connectivity in order to reach and span currently unavailable spatial scales, going from neuronal ensembles composed of few thousand neurons to the entire human brain networks, enabling the integration of animal and human studies.
Employing subcellular calcium to control membrane voltage Hochgeschwender, Ute H (contact) Lipscombe, Diane Moore, Christopher I Central Michigan University 2015 Complete
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This is an interdisciplinary team that plans to develop a new class of optogenetic tools for modulating neural activity, with potential applications that could one day be employed to treat disorders such as epilepsy or chronic pain. The team will use luciferase, a light-producing enzyme best known for its expression in fireflies, tethered to an opsin-a light-triggered ion channel. The researchers will make the luciferase sensitive to calcium ions, which enter neurons when they fire action potentials. If the luciferase is tethered to an inhibitory opsin, it will prevent neurons from being too active, and if it is tethered to an excitatory opsin, it will provide a boost to neural activity. The end result will be a set of tools with subtle regulatory capabilities that can be selectively expressed in specific neural circuits.
Enabling ethical participation in innovative neuroscience on mental illness and addiction: towards a new screening tool enhancing informed consent for transformative research on the human brain Roberts, Laura W Stanford University 2017 Active
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The NIH BRAIN Initiative aims to accelerate the development of innovative neurotechnologies and their application to reduce the burden of brain disorders, including mental illnesses and substance use disorders. However, because the brain is central to our humanity, this kind of research raises profound neuroethics issues, including questions about personal identity, and socially acceptable limits on novel neurotechnologies. Further, research involving participants with brain disorders is complex because these disorders can affect cognition, emotion, behavior, and decision-making capacity. In this project, Dr. Roberts and colleagues will assess the neuroethics issues encountered in neuroscience research related to mental illness and addiction through interviews with neuroscientists, neuroethicists, and institutional review board members. They will also study factors that influence research decision-making by people with mental illness and addiction, as compared with healthy controls and people with diabetes. Finally, they will develop a screening tool to enhance informed consent, as an evidence-informed practice to facilitate ethically sound cutting-edge human neuroscience research.
Enabling Multi-Tracer SPECT Studies of the Human Brain Peterson, Todd VANDERBILT UNIVERSITY MEDICAL CENTER 2018 Active
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A comprehensive view of the brain requires quantifying multiple properties of the brain simultaneously. However, obtaining those measures with comparable levels of sensitivity and resolution remains challenging. Single-photon emission computed tomography (SPECT) utilizes multiple radiotracers that emit gamma rays at specific energies, making simultaneous measurement of multiple molecular imaging probes possible. Dr. Todd Peterson and a team of investigators will develop SPECT radiation detector technology that improves energy resolution over traditional detectors, thereby minimizing crosstalk and separating the signal that previously limited the quantitative accuracy of multi-tracer imaging studies. By aiming to improve multi-tracer SPECT technology, the researchers will deliver an imaging approach that will pave the way for simultaneous, quantitative multi-tracer imaging studies of the human brain.

 

Engineered viral tropism for cell-type specific manipulation of neuronal circuits Schmidt, Daniel (contact) Thomas, Mark John University Of Minnesota 2015 Complete
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Revealing how specific cell types contribute to different neural circuits that underlie cognition, behavior, and disease pathology remains a longstanding goal in neuroscience. Current methods for investigating cell-types are limited, and typically require genetically engineered animal models. Schmidt and his team propose a completely different approach that relies on natural toxins from venomous organisms, which have evolved to bind to specific receptors and ion channels residing on neuronal cell surfaces. The toxin binding domains will be attached to the surface of viruses as a means for them to gain entry into specific cell-types. This method will make it possible to study specific cell types in a wider range of animals than is currently possible.
Engineering optogenetic tools for studying neuropeptide activity French, Alexander Robert Purdue University 2017 Active
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Dr. French will develop a high throughput screening platform to identify peptides that activate opioid receptors in response to light, creating high-resolution tools to study the function of specific opioid neural circuits in the brain.
Epigenetic tools and resources for cell-type and spatial analysis of individual mammalian non-neuronal cells Adey, Andrew OREGON HEALTH & SCIENCE UNIVERSITY 2018 Active
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Dr. Adey’s team will use advanced single cell analysis techniques to explore the epigenetic properties of non-neuronal brain cells. Techniques will include performing chromatin access assays and genome-wide profiling of DNA methylation, along with studying how a cell’s chromatin folds. Some of their methods will be used to profile and compare glial and vascular cells across brain regions in both rodents and humans. To help further understand the role of non-neuronal cells in the brain, the group plans to make these tools and data available to the research community for additional analyses.

Ethical Safeguards for Exit and Withdrawal from Implanted Neurotechnology Research Sankary, Lauren Cleveland Clinic Lerner Com-cwru 2017 Active
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Dr. Sankary will combine an assessment of the experience of research participants exiting from research studies involving implanted neurological devices with a critical evaluation of existing research practices and regulations that protect these subjects. The goal of this research is to determine the responsiveness of these safeguards to patient concerns and lay the groundwork for development of evidence-based guidelines for the ethical conduct of this research.
Ethics of Patients and Care Partners Perspectives on Personality Change in Parkinsons disease and Deep Brain Stimulation Kubu, Cynthia M. S. Cleveland Clinic Lerner Com-cwru 2017 Active
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The nature and extent of personality changes following deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD) are unclear. Dr. Kubu and colleagues will analyze patients’ and caregivers’ perspectives on personality characteristics (e.g., extroversion, humility) at different stages of PD and over the course of DBS (patients within one year of diagnosis, within 5 -7 years of diagnosis, and those undergoing DBS). This study will shed light on participant's most valued personality characteristics, and whether those characteristics are captured in the existing informed consent process; the influence of PD and/or DBS on personality; and the extent of agreement between patients’ and caregivers’ perceptions of personality change. These data will facilitate an enhanced, iterative informed consent process that includes systematic assessment of patients’ perceived personality changes, values, and goals; will inform understanding of identity and autonomy in the context of DBS; and may allow clinicians to ease the fears of patients receiving DBS.
Expanding access to open-source data acquisition software for next-generation silicon probes Siegle, Joshua H Allen Institute 2019 Active
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Determining how brain cells communicate with each other bolsters understanding of the causes of disorders. The new Neuropixels probe allows for highly detailed recordings of neurons communicating; however, sophisticated software is required to use this tool and to understand the data it generates, which include nearly 1000 recording sites from a single probe. For other labs to use this system, a support network is needed to address user requests, maintain the software code, and improve documentation. Through this project, Dr. Siegle and colleagues will support other labs that wish to use Neuropixel probes to better understand the underpinnings of neurological and mental disorders.

Expanding field-of-view with reduced tissue displacement in micro-endoscopic computational imaging Blair, Steven M (contact) Menon, Rajesh Shepherd, Jason D University Of Utah 2019 Active
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To improve understanding of the brain, it will be critical to image far beneath the surface. However, it is difficult to achieve high-resolution and fast imaging of deeper brain structures due to limitations in current technology. Drs. Blair, Menon, and Shepherd intend to develop new technology that uses an array of narrow probes, optrodes, to minimize tissue damage when looking at deeper structures in mouse brain, including a unique plan for computational imaging to recreate a large imaging field. This system, sized for small micro-endoscope arrays, may provide a new and more detailed look at deep brain structures, which are currently not easily accessible.

Exploring the role of reactive astrocytes in brain inflammation using a novel combinatorial strategy Fiacco, Todd A (contact) Riccomagno, Martin Miguel Wilson, Emma Harriet University Of California Riverside 2019 Active
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FAST HIGH-RESOLUTION DEEP PHOTOACOUSTIC TOMOGRAPHY OF ACTION POTENTIALS IN BRAINS Wang, Lihong Washington University 2014 Complete
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Dr. Wang and his collaborators will test a way to image the electrical activity of neurons deep inside the brain, using a variation on ultrasound imaging he invented called photoacoustic tomography.
Fast Spatial Light Modulators for Neuronal Excitation and Imaging Faraon, Andrei California Institute Of Technology 2018 Active
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Progress in the study of brain disorders has been limited by the availability of tools to investigate neuronal circuits with spatio-temporal specificity, until the recent development of genetically-encoded optical probes. To maximize the impact of these optical probes, Faraon’s team will develop devices— fast spatial light modulators (SLM)—that allow for ultra-fast delivery of optical signals for patterned optogenetic excitation of specific sets of neurons in the brain. SLM components enable steering of optical beams, and the group intends to achieve speeds exceeding 10 MHz operating at near infrared wavelengths. To improve upon current state-of-the-art SLMs, the team will replace silicone with gallium arsenide to achieve very high speeds of precise, patterned excitation in two-photon microscopy. This project could prove transformative for optogenetic applications.

Five-dimensional optoacoustic tomography for large-scale electrophysiology in scattering brains Razansky, Daniel Technical University Of Munich 2015 Complete
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Due to the potential of photoacoustic tomography to image much deeper than current optical approaches while maintaining cellular-level resolution, there is a great deal of interest in developing the technique for imaging neural activity. Razansky's team will develop and apply a high-speed photoacoustic imaging system that can stimulate and rapidly record from thousands of neurons at the cellular level to reveal individual instances of neuronal activity. They will validate the system by imaging neural activity in zebrafish and mice, and they will screen for neural activity probes with optimal photoacoustic properties.
FlatScopes for Implantable and Scalable Optical Imaging of Neural Activity Kemere, Caleb Robinson, Jacob T. (contact) Veeraraghavan, Ashok Rice University 2018 Active
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Current tools for fluorescence microscopy in freely-moving animals are incapable of recording from more than a few hundred cells at a time, due to the large microscope size and small field of view (FOV). Robinson and colleagues will develop a new class of miniature, large-FOV, flat microscopes that can be arrayed in sheets that lie flat on top of the brain surface of a freely-moving animal. These ‘FlatScopes’ exploit emerging computational imaging technologies to provide a more than one-hundred-fold increase in the number of neurons that can be simultaneously imaged using fluorescence microscopy. If successful, this project will aid in the understanding of brain activity with cellular resolution, for potential scaling to calcium- or voltage-sensor fluorescent imaging of thousands of neurons at the single cell level.

Flexible active electrodes for frequency-multiplexed large-scale neural recording Johnston, Matthew L (contact) Minot, Ethan D Oregon State University 2019 Active
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Current devices for brain cell recording are designed with one wire for each electrode and have been successfully used to measure activity in small areas of the brain. For larger scale recording, devices will require more electrodes and, with the existing technology, many more wires, which may interfere with data collection. Dr. Johnston’s team will develop a flexible device using graphene that will contain over 22,000 recording sites with only 300 wires, that allows frequency-based multiplexing and shared sensor wires at the recording site. This device could allow researchers to record from many more surface neurons at once, with great resolution and high speed.

Flexible neural probe arrays for large-scale cortical and subcortical recording Meng, Ellis University Of Southern California 2016 Active
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Implantable neural electrodes have been an important tool for studying the brain and treating neurological disorders. However, most electrodes are currently made from stiff materials such as silicon, which can induce scarring that limits their useful lifetime for recordings in vivo. Dr. Meng’s team will fabricate and test high-density, flexible polymer-based electrodes with the potential to overcome this challenge and produce stable recordings over many months to years. In addition, a new integrated circuit design will greatly reduce the number of external wire connections and the overall footprint for the device. Future plans involve incorporating stimulation, wireless operation, electrochemical sensing into this new technology, and ultimately improve neural prosthetic platforms with potential for treating human neuropsychiatric disorders.
Fluidic microdrives for minimally invasive actuation of flexible electrodes Robinson, Jacob T. Rice University 2017 Active
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Implantation of neural electrodes into the brain allows for the recording of nearby neurons, but the implantation process and electrode characteristics cause acute neural damage and chronic scarring that degrade neural recordings over time. Use of electrodes that are very thin and/or very flexible can minimize these effects, but their insertion into the brain is difficult and time-consuming. Jacob Robinson and team propose a novel electrode implantation technology that utilizes fluidic microdrives to insert flexible polymer probes into the brain. With this technique, fluid flow in contact with the electrode above the neural tissue creates a viscous drag force that prevents electrode buckling during implantation. This novel implantation method has the potential to increase the quality and longevity of neural recordings.
Fluorescent Sensors for Imaging External Potassium in the Brain Kobertz, William R Univ Of Massachusetts Med Sch Worcester 2015 Complete
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Proper termination of a neuronal action potential requires the efflux of potassium ions from the neuron. Problems with potassium permeability may be associated with various neurological disorders, ranging from epilepsy and episodic ataxia to congenital deafness and migraines. Existing methods of visualizing potassium release use single electrodes that are invasive, time consuming, and provide minimal spatiotemporal information on potassium efflux. Kobertz and his team will develop near infrared sensors that can attach themselves to the outer surface of neurons. The fluorescence response of the sensors will change when the potassium concentration goes up as the ions move from the inside to the outside of a cell. Because the sensors can be attached to a large numbers of neurons, this approach has the potential to enable large-scale visualization of potassium release with an unprecedented level of detail.
FOCUS: FUNCTIONAL OPTICAL IMAGING FEEDBACK-CONTROLLED CELLULAR-LEVEL ULTRASOUND STIMULATION Chen, Hong Washington University 2018 Active
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Current tools used to change neuronal activity are either noninvasive but unable to target specific cell types, or extremely precise but require invasive neurosurgery. Dr. Chen and his team plan to develop a tool called Functional Optical Imaging Feedback-Controlled Cellular-Level Ultrasound Stimulation (FOCUS), which will use a three-step process to noninvasively control specific cells. Dr. Chen’s group will identify ion channels that are activated by ultrasound and use viral vectors to deliver those channels to specific cells that will then be controlled by ultrasound. Dr. Chen’s team also plans to create an ultrasound helmet that will be worn by mice allowing control of their behavior by targeting movement- related circuits. This noninvasive, wearable tool may eventually be adapted for use in individuals affected by neurological disorders.

Foundations of MRI Corticography for mesoscale organization and neuronal circuitry Feinberg, David Alan University Of California Berkeley 2016 Active
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While functional MRI (fMRI) with low spatial resolution is useful for capturing a picture of dynamic activity across the entire brain, performing fMRI at high-resolution may accurately distinguish neuronal activity in cortical layers and columns. Feinberg and his colleagues plan to use recently developed high-resolution fMRI techniques with a number of other techniques, including optogenetics, transcranial magnetic stimulation, and electrocorticography, to identify and stimulate the various aspects of neural activity that drive the fMRI signal. These measurements will enable bridging neuronal activity to the level of cortical layers and columns identifiable in high-resolution fMRI signals to help better understand the underlying biology of non-invasive imaging of brain circuitry.
From ion channel dynamics to human EEG and MEG: multiscale neuronal models validated by human data Bazhenov, Maksim V (contact) Cash, Sydney S Halgren, Eric University Of California, San Diego 2018 Active
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Non-invasive imaging methods, such as electroencephalography (EEG) and magnetoencephalography (MEG), are commonly used in basic research studies and in some diagnostic procedures. These methods derive neural signals by summating over the activity of millions of neurons, but the dynamics of the underlying cellular signal and circuit function remain elusive. Drs. Bazhenov, Cash, and Halgren, along with a team of investigators, will use biophysical and neural modeling to predict the cellular dynamics underlying EEG and MEG signals, which they will then confirm using extensive intracranial recording data. This bidirectional approach that generates predictions – which can then be validated with data – has the potential to identify a crucial link between neuronal and synaptic responses that subsequently give rise to macroscopic EEG and MEG recordings.

Functional Architecture of Speech Motor Cortex Chang, Edward University Of California, San Francisco 2016 Active
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Speaking is one example of a complex behavior that most humans can perform effortlessly, but scientists do not fully understand how the brain is able to drive speech production. Building on their prior work on the neural representation of articulatory and acoustic feature representations of speech, Chang and his team will conduct ultra high-density electrocorticography in epilepsy patients to study how the ventral sensorimotor cortex encodes the movements that produce speech, and how the prefrontal cortex is able to exert inhibitory control over speech. This work will advance our understanding of communication disorders, and refine the ability of clinicians to map speech areas of the brain in their patients.
Functional implications of a patch/matrix-like compartmental organization in the mouse inferior colliculus Lesicko, Alexandria Marie University Of Pennsylvania 2019 Active
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The brain’s inferior colliculus is described to have a patch- or matrix-like “modular” anatomical organization, with various nuclei and distinct chemical boundaries. However, the functional implications of this organization are unknown. Dr. Lesicko’s experiments aim to determine whether this modularity underlies distinct streams of information processing in the inferior colliculus. Using a combination of two-photon calcium imaging, clustering analysis, optogenetics, and behavioral assays in mice performing a behavioral task, the work will examine distinctions in neural activity and mechanisms for auditory and somatosensory signaling in the inferior colliculus.

Gated Diffuse Correlation Spectroscopy for functional imaging of the human brain Franceschini, Maria Angela Massachusetts General Hospital 2017 Active
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Advancements in non-invasive imaging technology – such as functional near-infrared spectroscopy (fNIRS) – allow for more accurate measurements of human brain function. Maria Franceschini and her team are developing a wearable (and potentially wireless) device that advances fNIRS by employing functional diffuse correlation spectroscopy (fDCS). Current fNIRS methods quantify blood flow by measuring light attenuation, but Franceschini’s DCS method captures both hemoglobin concentration and blood flow, leading to better temporal and spatial estimates of neuronal activity, as well as improve spatial resolution by distinguishing between brain and superficial scalp and skull. Development of this fDCS prototype could lead to more accurate and cost-effective methods of imaging human brain function.
Generating a formal set of collaborative standards for sharing behavioral data and task designs to enable reproducibility in neuroscience Edwards, Stephen Anthony; Kepecs, Adam (contact) Cold Spring Harbor Laboratory 2019 Active
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Different laboratories use different behavioral systems, hardware, and software, which makes it difficult to standardize, communicate, and replicate experiments. Dr. Kepecs et al. have led the creation of a laboratory consortium to address this problem by developing requirements for behavioral data formats and an open source software suite for editing, executing, and visualizing behavioral tasks. They will also engage the scientific community to promote the adoption of these standards and tools.

Generating Multiple Circuit and Neuron Type Specific AAV Vectors With Cross-Species Applicability He, Zhigang Boston Children's Hospital 2015 Complete
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Tools to investigate and manipulate brain functions in a cell-type or circuit-specific manner are critical for understanding how different neurons and circuits underlie cognition and behavior. So far, this capability has primarily been available only for the mouse, and only for a limited number of cell types. Dr. He and his team will screen DNA sequences from ultra-conserved regions of the genome known as "enhancer elements," and test their ability to control region- and cell-type specific gene expression in the brain, as well as for expression that is dependent on neurons' electrical activity. The goal is to produce an expanded, universal tool set consisting of vectors for cell- and circuit-specific gene expression that can be used across a wide variety of species.
Genetic analyses of complete circuit formation in Caenorhabditis elegans Cook, Steven Jay Columbia Univ New York Morningside 2017 Active
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Using the model system C. elegans, which has a simple, well characterized nervous system, Dr. Cook will develop new tools to create an exquisitely detailed map of a circuit in live animals and reveal the genetic factors that orchestrate assembly of a complete neural circuit.
Genetic tools and imaging technology for mapping cholinergic engrams of anxiety Role, Lorna W State University New York Stony Brook 2015 Complete
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Neuronal circuits are widely modulated by neurotransmitters such as acetylcholine. To explore in detail how acetylcholine impacts neural circuits, Role's team will use gene-activity mapping of neurons involved in a specific cognitive function in mice - recall of anxiety-provoking experiences. During recall, the team's mapping technique will track activity-related gene expression in basal forebrain neurons expressing acetylcholine and the neurons they project to in the hippocampus, amygdala, and cortex. In addition the team will make improvements to an imaging system called 3D SPIM that can be used to track neuronal activity. These improvements have the potential to reduce the time it takes to collect and analyze the imaging data by a factor of 50.
Genetically Encoded Activity Sensors for Photoacoustic Imaging of the Brain Griesbeck, Oliver (contact) Razansky, Daniel Max Planck Institute For Neurobiology 2017 Active
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Current fluorescence imaging of neural activity is limited in volume rate and penetration depth, thereby preventing large-scale volumetric imaging of deep neuronal structures. Photoacoustic methods, which rely on absorbance of light to produce an acoustic response, could overcome these challenges by enabling 3D volumetric imaging at speeds and depths not possible using traditional fluorescence methods. Oliver Griesbeck and Daniel Razansky propose to develop new photo-acoustic calcium sensors that report neural activity by absorbing in the near-infrared portion of the light spectrum, minimizing the background noise that impedes photoacoustic signals in live tissue. To accomplish this, the researchers will engineer bacterial phytochrome proteins, which naturally fluoresce in the infrared, into photo-acoustic probes that absorb light rather than emitting fluorescence. They will fuse these probes to calcium binding domain motifs that have been successfully used in fluorescent calcium indicators, before validating the sensors in mouse visual cortex in vivo. Successful development of this technology could provide high performance activity sensors that permit large scale, photo-acoustic imaging of the brain at unprecedented speed and depth.
Genetically encoded indicators for large-scale sensing of neuromodulatory signaling in behaving animals Nimmerjahn, Axel Tian, Lin (contact) Vonzastrow, Mark E Williams, John T University Of California At Davis 2017 Active
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Alterations in neuromodulators such as dopamine, norepinephrine, and serotonin characterize many neurological, psychiatric, and substance use disorders, yet little is known about how these modulators spread and exert their function. Tian’s group seeks to engineer genetically-encoded fluorescent proteins for large-scale optical measurement of neuromodulator signaling. The group will endow their own previously-developed serotonin, norepinephrine, and dopamine sensors with improved signal-to-noise ratio, affinity, kinetics, and specificity. They will also develop novel neuromodulator sensors, and validate them in behaving mice. Combined with calcium and voltage imaging, these sensors promise to reveal how individual cells and circuits respond to neuromodulators, and how genetically-defined populations of neurons and glia communicate. This work could enable neuromodulator signaling measurement in normal brains and in a host of models of brain disorders.
Genetically Encoded Localization Modules for Targeting Activity Probes to Specific Subcellular Sites in Brain Neurons Trimmer, James S University Of California At Davis 2016 Active
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The use of genetic constructs offers the potential to target subcellular regions of neurons, which would enhance the quality of recordings and permit more precise modulation of brain activity. Dr. Trimmer and colleagues propose to develop and test a set of protein domains that will function as a toolbox for genetically encoded “localization modules,” which can be fused to diverse molecular reporters and modulators of neural activity to direct their localization to precise subcellular sites in neurons. Their strategy is to develop two types of modules, one consisting of fragments derived from naturally occurring proteins that themselves are localized to specific subcellular domains, and the other using nanobody affinity modules that bind to such protein targets and carry the tethered reporter/modulator construct with them. This new toolkit will be made widely available to enable new experiments with enhanced precision and providing deeper understanding of neural circuit function.
Genetically encoded reporters of integrated neural activity for functional mapping of neural circuitry Lam, Kit S (contact) Trimmer, James S University Of California At Davis 2014 Complete
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Dr. Lam's team plans to develop fluorescent sensors that will mark ion channels, molecules that help control information flow in the brain, and enable scientists to observe the neurons that are activated during a specific behavior, such as running.
Genetically encoded sensors for the biogenic amines: watching neuromodulation in action Tian, Lin University Of California At Davis 2014 Complete
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Dr. Tian and her colleagues will create sensors that will allow researchers to see how molecules like dopamine, norepinephrine and serotonin regulate activity of neural circuits and behavior in living animals.
Genetically engineered anterograde monosynaptic viral tracers for multi-species neural circuit analysis Horwitz, Gregory D Luo, Min-hua Sandri-goldin, Rozanne M. Xu, Xiangmin (contact) University Of California-irvine 2019 Active
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Due to the relatively poor performance of current anterograde viral tracers, Drs. Xu, Horwitz, Luo, Sandri-Goldin and teams aim to engineer improved anterograde monosynaptic tracers with increased labeling efficacy and reduced toxicity for the analysis of neural circuits. Using a bacterial artificial chromosome-based engineering system, the team will generate recombinant Herpes simplex virus type 1 strain 129 (H129) vectors for targeted expression in multiple neural circuits. The researchers will then validate their anterograde tracers in the visual system, hippocampus, and stress-relevant hypothalamus circuits of rodents and non-human primates. The tools developed here will be disseminated through a service platform with the goal of improving the ability to study neuronal projection networks.

Genetically targeted high sensitivity voltage sensitive dyes Loew, Leslie M University Of Connecticut Sch Of Med/dnt 2019 Active
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Brain cells primarily communicate through electrical signals and the ability to measure these ‘conversations’ in real time could help advance our understanding of how the brain works. However, currently available tools for looking at electrical activity are not sensitive or sufficiently specific. Dr. Loew’s group will develop a novel type of hybrid voltage sensor that binds a fluorescent protein to the cell’s surface and is connected to a quenching molecule that moves across the membrane, producing a large florescence signal during electrical activity. The new sensors should be bright, sensitive, and allow researchers to look at specific brain areas or circuits.

Head-mounted miniature microscopes for combined calcium imaging and electrophysiological measurement of neural circuit function in deep brain regions of behaving macaques Nassi, Jonathan J Inscopix, Inc. 2019 Active
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The ability to record the activity patterns of genetically-defined neuronal populations in freely behaving animals is transforming neural circuits research. To advance our understanding of higher-cognitive function, complex behavior and mental health, a critical need remains to translate such capabilities to research using non-human primates. Working with Inscopix Inc., Dr. Jonathan Nassi and team will build on the success of nVista for rodents, Inscopix's flagship product, to develop and commercialize a next-generation platform for integrated calcium imaging and electrophysiology in behaving macaques. The group will prototype and validate a system that enables cellular-resolution, large-scale recordings deep and distributed throughout the macaque brain. Success of the project could produce a commercial-ready, next-generation platform for neural circuit research in behaving macaques.

High dynamic range multiphoton microscopy for large-scale imaging Davison, Ian Gordon Mertz, Jerome C (contact) Boston University (charles River Campus) 2016 Complete
  • Monitor Neural Activity
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Mertz and colleagues propose two fundamental improvements to multiphoton microscopy, an important technique for imaging neural activity. The first involves modulating laser power using high speed electronics to accommodate variations in sample brightness, thus enabling recordings with much wider dynamic range. This will allow experiments where there are large differences in signal in the same sample, e.g., from axon terminals vs. cell body. The second improvement is a new method for signal multiplexing, which will enable simultaneous recordings from multiple brain regions within a large imaging area. The system is low cost and will require minimal modifications to most existing microscopes, which should contribute to ready adoption by the research community.
High resolution deep tissue calcium imaging with large field of view wavefront correction Cui, Meng (contact) Gan, Wenbiao Purdue University 2015 Complete
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While neural imaging and activity measurements have advanced to a resolution that captures events at single synapses, they are still limited to the outer surface of the cortex in behaving rodents. Cui's team will develop new methods in adaptive optics to correct for imaging aberrations caused by tissue, which will enable much deeper optical imaging of neural activity and, in some cases, allow for non-invasive imaging through the skull. Their proposed innovations to adaptive optics stand to improve imaging resolution as well as increase imaging speed and the total volume that can be measured.
High resolution electrical brain mapping by real-time and portable 4D Acoustoelectric Imaging Witte, Russell S University Of Arizona 2015 Complete
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  • Human Neuroscience
Electroencephalography is a noninvasive method to record electrical activity in the brain, but suffers from poor resolution and inaccuracies due to blurring of electrical signals as they pass through the brain and skull. Witte and colleagues aim to overcome such deficiencies by developing a noninvasive, real-time, portable electrical human brain mapping system called the 4D Acoustoelectric Brain Imaging (ABI). ABI utilizes pulsed ultrasound to produce 4D current density images. This method holds great promise for yielding unprecedented resolution and accuracy for imaging electrical activity deep in the brain, which can help scientists decode brain function and may also be used to diagnose brain disorders.
High SNR Functional Brain Imaging using Oscillating Steady State MRI NOLL, DOUGLAS UNIVERSITY OF MICHIGAN AT ANN ARBOR 2018 Active
  • Human Neuroscience
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To improve the spatial resolution of functional magnetic resonance imaging (fMRI), researchers often turn to higher magnetic field strength systems. While these systems can provide images of better quality, they require costly investment and maintenance. Dr. Douglas Noll and a team of investigators propose to improve fMRI techniques by developing a new method - Oscillating Steady State (OSS) Acquisition, for collecting MRI and fMRI data. This approach reuses magnetization to improve the signal-to-noise ratio, achieving a signal gain that is roughly equivalent to the shift from 3T to 7T, but without the practical and technical challenges and additional costs. If successful, the method can be widely and quickly disseminated to the neuroimaging community to upgrade existing 3T systems with reduced variability, noise, and improved sharpness of the images without increasing the cost of instrumentation.

High Throughput Approaches for Cell-Specific Synapse Characterization Barth, Alison L Bruchez, Marcel P (contact) Carnegie-mellon University 2017 Active
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Understanding the wiring principles within the cerebral cortex will benefit understanding of cognitive function, and how experiences are encoded into long-term memory. Bruchez and colleagues will develop molecular genetic tools using fluorogen activating proteins (FAPs), a system enabling fluorescence identification of synapses and cell-type specific connectivity, in mice. They will perform pre- and post-synaptic targeting of fluorescent and FAP proteins, respectively, allowing selective detection of connections between genetically selected cell populations. Through cell-type-specific synapse detection via high-throughput 3D imaging and analysis, this project may transform researchers’ ability to study synaptic connectivity.
High throughput mapping of neuronal circuitry using DNA sequencing Zador, Anthony M Cold Spring Harbor Laboratory 2017 Active
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  • Monitor Neural Activity
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Neurons transmit information to distant brain regions via axonal projections. Current neuroanatomical techniques for tracing these projections are expensive and labor intensive. Zador and his team will use high-throughput DNA sequencing to map neuronal circuitry cheaply and efficiently. Their goal is to tag each neuron in the mouse neocortex with many copies of a unique RNA barcode. Because the barcode will be present throughout the neuron, projections can be mapped across brain regions. By converting circuit mapping into a DNA sequencing task, this model will leverage the remarkable advances in high-throughput sequencing. This project could provide a new method for understanding normal neuronal circuitry and a new tool for studying animal models of neural circuit disorders.
High Throughput of Protein-based Voltage Probes Pieribone, Vincent A John B. Pierce Laboratory, Inc. 2017 Active
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Genetically encoded voltage indicators (light-emitting proteins that report neuronal electrical activity), combined with fluorescence microscopy imaging, enable activity measurements in large numbers of specific neurons within intact brain circuits. Advancement of such studies relies on developing improved indicators. Building on their successful high-throughput workflow for creating and screening indicators, Pieribone’s team proposes to scale up and improve their platform. To develop indicators with improved response properties, the group will screen ~8000 novel constructs per week. Additionally, they will include random mutagenesis in the process, to improve identification of characteristics that enhance indicator function (i.e., directed evolution). This project is likely to produce useful probes for neural activity imaging, enabling insights into circuit function in health and disease.
High-Bandwidth Wireless Interfaces for Continuous Human Intracortical Recording Hochberg, Leigh R (contact) Nurmikko, Arto Massachusetts General Hospital 2015 Active
  • Human Neuroscience
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  • Monitor Neural Activity
More than 100,000 people in the United States suffer from quadriplegia, with the most extreme cases resulting in loss of all voluntary movement, including speech. Dr. Hochberg has led development of BrainGate, a brain implant system designed to allow users to control an external device, such as a prosthetic arm, by thought alone. In this project, Dr. Hochberg and his team aim to push the envelope with BrainGate to make a fully implanted medical treatment system, freeing patients from externally tethered components, and giving them greater control over their home environments and daily lives. Ultimately, the goal is to transition from a device that is used occasionally under medical supervision to one that patients can use independently on an ongoing basis.
High-density microfiber interfaces for deep brain optical recording and stimulation Gardner, Timothy James Boston University (charles River Campus) 2016 Complete
  • Monitor Neural Activity
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Recording from neurons deep in the brain using optical fibers is limited due to tissue damage that occurs during implantation. In this project, Gardner and his colleagues propose an implantable optical interface consisting of microfibers whose cross section is two to three orders of magnitude smaller than optical fibers now in use for recording and stimulating neural activity. During insertion into the brain, the bundle of microfibers, each 7 microns wide, splays such that each fiber follows a distinct path into the brain as it is deflected by brain tissue. If successful, this will enable recordings from many more neurons in deep brain regions critical for brain function.
High-density microgrid development for human neural interface devices Cleary, Daniel R University Of California, San Diego 2019 Active
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  • Human Neuroscience
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Brain-computer interfaces (BCI) show promising potential in treating symptoms of various brain diseases. A collaborative group at the University of California, San Diego, has developed a high-density array of microgrid electrodes that are thin, non-destructive, and sit lightly on the surface of the brain, for improved decoding and resolution of neural activity. This study will implement this technology to study cortical physiology and organization in the rat somatosensory cortex. Dr. Cleary aims to test the capabilities of these surface microgrids for discriminating cortical columns in the rat “barrel cortex,” representing innervation of the whiskers. He also will study how surface stimulation of the cortex affects neural activity in different layers of the cortex, initially in rats and subsequently in human neurosurgical patients. This work may improve BCI technology, providing additional treatment strategies for various brain diseases.

High-Density Recording and Stimulating Microelectrodes Gardner, Timothy James Boston University (charles River Campus) 2014 Complete
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Dr. Gardner and his colleagues will develop ultrathin electrodes that minimize tissue damage and are designed for long-term recording of neural electrical activity.
High-speed Deep Brain Imaging and Modulation with Ultrathin Minimally Invasive Probes Piestun, Rafael University Of Colorado 2015 Complete
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A major challenge for recording the patterns of electrical activity in brain circuits is the inability to image individual neurons deep in the brain. One potential strategy for overcoming this hurdle is inserting ultrathin endoscope probes - based on fiber optic technology developed by the telecom industry-into deep brain structures to optically image their activity. The light that comes out of the fibers is scrambled and cannot be imaged directly, so Piestun and his colleagues propose to unscramble the signals using holographic methods. If they are successful, the new fiber optic probes could be much thinner and less invasive than current endoscopes, making it possible to use them in many different brain structures.
High-speed volumetric imaging of neural activity throughout the living brain Ji, Na University Of California Berkeley 2017 Active
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A fundamental goal of the BRAIN Initiative is to develop mechanistic understanding of neural circuit functions in healthy brains and brain diseases, which necessitates the ability to monitor neural activity in 3D at high spatiotemporal resolution. Existing 3D imaging in behaving animals suffers from insufficient volume-imaging speed and brain-motion-induced image artifacts, as well as complex hardware and software implementation. Ji’s group will combine their recently-developed Bessel focus scanning technology (BEST) with traditional optics and with microendoscopy to achieve volumetric imaging of deeply buried neurons for the first time. The team will develop a method to record dense populations of neurons, both near the surface of the brain and in deeper structures such as the basal ganglia and hypothalamus, to monitor entire subpopulations of neurons in behaving mice. This project could help overcome existing 3D imaging barriers and open new opportunities for neurobiological enquiries.
High-speed volumetric imaging of neuronal network activity at depth using Multiplexed Scanned Temporal Focusing (MuST) Vaziri, Alipasha Rockefeller University 2015 Complete
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Capturing the functional behavior of neural networks requires tools to record activity of neurons across entire circuits at precise and relevant time scales. Vaziri's project involves high-speed optical imaging of neural activity using temporal focusing, a multi-photon approach that allows neural volumes, rather than focal points, to be scanned, and will enhance imaging speed and resolution of the volumetric field. In addition, a 3-photon implementation will be incorporated to enable high-speed optical imaging at greater depths of rodent brain tissue.
Highly specific control of neurons with photoswitchable bioluminescent optogenetics. Shaner, Nathan Christopher University Of California, San Diego 2019 Active
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  • Monitor Neural Activity

Optogenetics allows researchers to turn brain cells on and off to study how they work and identify neurons that may play a role in specific behaviors. Dr. Shaner’s group will develop bioluminescent molecules to improve existing optogenetics technology to create more targeted activation and allow maintained stimulation in the absence of an external light source. The researchers will fuse luciferases to reversible photoswitchable or photoactivatable fluorescent proteins, using directed evolution to optimize the constructs for enhanced on-off contrast, switching efficiency, and kinetics. The optimized constructs will then be combined with optogenetic elements to generate probes for targeted chemogenetic control of selected neurons. The tools will be tested ex vivo, in vitro, and in vivo in mouse neocortex. The development of these bioluminescent probes will allow high-precision “reprogrammable” activation of neurons, which may further our understanding of brain function and neurodegenerative disease.

Human Agency and Brain-Computer Interfaces: Understanding users? experiences and developing a tool for improved consent Goering, Sara (contact) Klein, Eran University Of Washington 2018 Active
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  • Human Neuroscience
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Agency, our ability to act and experience a sense of responsibility for our actions, is central to individual identity and societal conceptions of moral responsibility. Neural devices are currently used to treat some brain disorders, such as Parkinson’s disease, and are being developed to treat others such as depression and obsessive-compulsive disorder, yet their use raises important ethical concerns about potential effects on agency. Dr. Goering, Dr. Klein and their team will investigate agency in individuals receiving brain computer interface devices for sensory, motor, communication, and psychiatric indications. They aim to build a user-centered neural agency framework, and, ultimately, to enhance the informed consent process by developing a communication tool that patient participants might use to better understand and discuss potential changes in agency associated with use of neural devices.

Identification of enhancers whose activity defines cortical interneuron types Rubenstein, John L. R. (contact) Sohal, Vikaas Singh University Of California, San Francisco 2014 Complete
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Dr. Rubenstein and colleagues plan to identify enhancer molecules specific to particular types of interneurons – that relay neural signals – and use this information to profile distinct cell types and new ways to manipulate genes.
Illuminating Neurodevelopment through Integrated Analysis and Vizualization of Multi-Omic Data Hertzano, Ronna (contact) White, Owen R University Of Maryland Baltimore 2018 Active
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  • Human Neuroscience
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Molecular and cellular neuroscientists often lack the training in computer programming to fully explore “-omics” data common in the BRAIN Initiative. Drs. Hertzano and White will implement analytic software for visualization and interactive genome browsing of gene expression and RNA-seq data, including simple and complex cross-dataset analysis. These tools will be made available in the BRAIN Initiative funded Neuroscience Multi-Omic Data Archive (NeMO) which hosts multi-omic data. The software will provide an easy-to-use web-based work environment for visualization and analysis of multi-modality and multi- omic data, interrogation of relationships between epigenomic signatures and gene expression, and integration of analytical techniques for multivariate analysis, gene co- expression and other analyses.

Imaging adult-born neurons in action using head-mounted minimicroscopes Drew, Michael R University Of Texas, Austin 2016 Complete
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Human and animal research has shown that modulation of adult hippocampal neurogenesis – the generation of neurons – can lead to changes in memory and emotion, but the underlying mechanisms are not well characterized. Dr. Michael Drew and colleagues will image adult-born neurons during learning behavior via incorporating head-mounted minimicroscopes (developed with prior BRAIN Initiative support). Dr. Drew’s laboratory will perform calcium imaging experiments in awake, behaving mice during a contextual fear conditioning paradigm and, using optogenetic techniques, they will silence adult-born hippocampal neurons in order to characterize how these neurons impact the coding of context memory. These studies will enhance the understanding of the mechanisms by which changes in adult neurogenesis influences mood and cognition.
Imaging Brain Function in Real World Environments & Populations with Portable MRI Garwood, Michael G (contact) Vaughan, John T University Of Minnesota 2014 Complete
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  • Human Neuroscience
By employing smaller, less cumbersome magnets than used in existing MRI, Dr. Garwood and colleagues will create a downsized, portable, less expensive brain scanner.
Imaging Brain Function with Biomechanics Patz, Samuel (contact) Sinkus, Ralph Brigham And Women's Hospital 2019 Active
  • Human Neuroscience
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  • Monitor Neural Activity

Functional magnetic resonance imaging (fMRI) measures the blood-oxygenation-level dependent (BOLD) response to neuronal activity. Although it has become a ubiquitous tool for high spatial resolution mapping of whole-brain function, the quest for breaking the barrier on temporal resolution has never stopped. Drs. Patz, Sinkus, and team will develop a novel technique, functional magnetic resonance elastography (fMRE), that measures brain tissue stiffness change in response to neural activity. This state-of-the-art, ground-breaking non-invasive imaging technology is poised to provide an order of magnitude improvement of temporal resolution over fMRI, which could potentially provide a new window for assessing brain circuits and function.

Imaging Human Brain Function with Minimal Mobility Restrictions Garwood, Michael G University Of Minnesota 2017 Active
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  • Integrated Approaches
  • Human Neuroscience
Conventional magnetic resonance imaging (MRI) from whole-body magnets has become a critical tool for human neuroscience research, but there are limitations to both their usability and technical requirements. High-quality MR images typically require large magnets that maintain a static magnetic field, but in a multi-institution effort led by Michael Garwood, researchers are developing a portable MR imaging prototype that collects high-quality images with a small, light-weight magnet that also permits some degree of freedom of movement. This technological development has the potential to revolutionize MRI approaches, making it possible to collect high-quality MR images by improving scanner portability: bringing the scanner to human subjects and patients, rather than the other way around.
Imaging in vivo neurotransmitter modulation of brain network activity in realtime Gjedde, Albert Rahmim, Arman Wong, Dean Foster (contact) Johns Hopkins University 2014 Complete
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  • Interventional Tools
  • Human Neuroscience
Dr. Wong and colleagues will explore the possibility that newly developed infrared chemical tags may be used for minimally invasive imaging of rapidly changing human brain chemical messenger activity – with greater time resolution.
Imaging the Brain in Motion: The Ambulatory Micro-Dose, Wearable PET Brain Imager Brefczynski-lewis, Julie Ann West Virginia University 2014 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • Human Neuroscience
Dr. Brefczynski-Lewis and co-workers will engineer a wearable PET scanner that images activity of the human brain in motion – for example, while taking a walk in the park.
Imaging the D2/A2A Heterodimer with PET Mach, Robert H University Of Pennsylvania 2018 Active
  • Human Neuroscience
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  • Monitor Neural Activity

Dr. Robert Mach and team propose to develop PET imaging agents that have a potential to visualize dimeric dopamine D2/adenosine A2A receptors. This proof-of-concept study could provide a new methodology for imaging G protein coupled receptors (GPCR) heterodimers in vivo with PET. Current methods for imaging single GPCRs are not adequate to fully understand the complexity of brain function, thus new strategies are needed to image them to understand the change in receptor mechanism that can occur with disease.

Impact of Timing, Targeting, and Brain State on rTMS of Human and Non-Human Primates Sommer, Marc A Duke University 2017 Active
  • Monitor Neural Activity
  • Interventional Tools
  • Human Neuroscience
Transcranial magnetic stimulation in sequences of pulses (i.e., repetitive TMS (rTMS)) has not reached its therapeutic potential due to limited knowledge of the temporal, spatial, and state-dependency factors governing its effects. Sommer’s team will investigate how these factors influence rTMS neuromodulation, in human and non-human primates, during performance of a visual motion task. The project will employ the diverse methods of single cell recording, fMRI, and EEG in a coordinated manner, with a focus on one homologous region – area MT – and its interconnected circuits. The group will stimulate the middle temporal visual area and assess how the frequency and number of pulses influence inhibitory vs. excitatory effects of rTMS. Then, they will examine how the TMS coil location/orientation affects neural pathway recruitment, using single-cell recordings, functional magnetic resonance imaging, and electroencephalography. Finally, simultaneous neural and cognitive effects of rTMS will be quantified, during active (i.e., motion task), less active, and resting states. This work will enhance our understanding of the mechanisms of neurostimulation, and could provide new opportunities for treating psychiatric and motor disorders.
Implantable Brain Microelectromechanical Magnetic Sensing and Stimulation (MEMS-MAGSS) Schiff, Steven J. (contact) Tadigadapa, Srinivas Pennsylvania State Univ Hershey Med Ctr 2015 Complete
  • Monitor Neural Activity
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When neurons are electrically active they emit magnetic impulses, which can be imaged using magnetoencephalography. However, this technique requires placing a large, low-temperature detector outside the brain, which can only pick up broad signals from large numbers of neurons. Recently it has become possible to fabricate tiny magnetometers on standard substrates used in the semiconductor industry, which are ultra-sensitive, small enough to fit much closer to the brain, and don't require super-cooling. Schiff and Tadigadapa and their colleagues propose developing devices based on this technology and embedding them within the skull. They will develop active on-chip noise cancelation to allow the devices to be used outside a magnetically shielded room. If the approach is successful, it could enable use across the lifespan in animals and potentially in humans for therapeutic purposes.
IMPLANTABLE MICROARRAY PROBE FOR REAL-TIME GLUTAMATE AND GABA DETECTION MOLDOVAN, NICOLAIE ANDREI ALCORIX 2019 Active
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  • Monitor Neural Activity

Neurotransmitter (NT) sensors that are versatile, selective, sensitive and reliable can facilitate investigation of the neurobiological mechanisms of behavior and disease symptoms. However, existing monitoring methods suffer from the inability to measure NT dynamics continuously, in real time. Working with Alcorix, Dr. Moldovan and team will develop a novel implantable probe for real-time detection of excitatory and inhibitory NTs. The group plans to create the next generation of their biosensor microelectrode array probe, capable of higher sensitivity, selectivity, and reliability, with no need for external reagents. The multiplexing and in vivo capabilities of the probe will facilitate a fundamental understanding of NT homeostasis that can inform more effective animal models and therapeutics for brain diseases and disorders.

Implantable Recording and Integrated Stimulation (IRIS) device for cortical experiments Wilder, Andrew Ripple, Llc 2019 Active
  • Circuit Diagrams
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  • Monitor Neural Activity

Understanding the dynamics of neural activity requires new tools to record and manipulate neural signals in real-time. However, current cortical electrophysiological recording and stimulation implant systems puncture the skin, present a constant danger of infection and irritation, and require extensive attention from investigators to clean and maintain. Working with Ripple LLC, Dr. Andrew Wilder and a team of investigators will develop the Grapevine IRIS (Implantable Recording with Integrated Stimulation) system. IRIS will be a fully implantable system capable of both recording and stimulation on a large number of channels, enabling closed-loop experiments while mitigating the need for skin puncture. The success of IRIS will provide a research platform to enable longer, safer, and better chronic animal studies.

Improving Human fMRI through Modeling and Imaging Microvascular Dynamics Polimeni, Jonathan Rizzo Massachusetts General Hospital 2016 Active
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  • Integrated Approaches
  • Human Neuroscience
Functional Magnetic Resonance Imaging (fMRI)—the most common technique for mapping whole brain function in humans—is based on tracking changes in blood flow that occur during brain activity. However, the temporal and spatial resolutions for this technique are fairly low. Polimeni and his colleagues will improve fMRI’s specificity by using 2-photon microscopy to create new models of the way blood flows in the brain and linking those models with highly detailed maps of human microvascular anatomy. A better understanding of how microvascular dilations and blood flow changes impact the underlying neural signals will help neuroscientists better understand fMRI signals and enable them to map human brain function at a finer scale than what is currently possible.
In situ transcriptional analysis of brain circuits at single cell resolution Dulac, Catherine G (contact) Regev, Aviv Zhuang, Xiaowei Harvard University 2016 Active
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A fundamental challenge to achieving a mechanistic understanding of how the brain works is obtaining a systematic characterization of diverse cell types at single-cell resolution. Dulac, Regev, and Zhuang, will use Multiplexed Error Robust Fluorescent in situ Hybridization (MERFISH) to measure the transcriptome of single cells from intact brain tissue, creating a spatially informed cellular inventory of neural circuits in mouse. By expanding this method into the marmoset and coupling it with behavioral tasks, they will validate a new, unbiased imaging platform and computational toolkit that uses gene expression profiles to classify cells in the functional context of behaviorally relevant circuits.
In Vivo Brain Network Latency Mapping BASSER, PETER J National Institute of Child Health and Human Development 2018
Active
  • Human Neuroscience
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The purpose of this project is to develop, explore, and begin implementing a new non-invasive, painless Magnetic Resonance Imaging (MRI) methodology to measure the time (latency) it takes neural impulses to travel from one functional area in the cerebral cortex to another. This project will use microstructure imaging and neurophysiological data to estimate conduction delays along white matter pathways, incorporating whole-brain diffusion MRI measurements of various white matter tract characteristics. Integrating data derived from resting state and other neurophysiological mapping approaches, these methods will yield high spatial and temporal resolution latency matrix data. Dr. Basser's website is available at https://irp.nih.gov/pi/peter-basser

In Vivo Imaging of Local Synaptic Neuromodulation by Dopamine Evans, Paul Robert Max Planck Florida Corporation 2018 Active
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  • Human Neuroscience
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Dopamine is a powerful neurotransmitter that facilitates memory formation and underlies reward-related behaviors, but current techniques to assess dopamine signaling in vivo lack sufficient specificity and spatiotemporal resolution. Evans will develop new fluorescent sensors for dopamine receptors and apply them to investigate the molecular mechanisms that underlie learning in mice in vivo. The biosensors will be used to visualize the dynamic activity of specific dopamine receptors in vitro, before they are virally expressed in the motor cortex in behaving mice. Employed during motor learning, these sensors should generate a sub-micron scale map of how dopamine receptor subtypes modulate long-term structural plasticity of cortical dendritic spines. The results could help shed light on how dopaminergic modulation correlates with structural and functional plasticity.
In-vivo circuit activity measurement at single cell, sub-threshold resolution Forest, Craig (contact) Stanley, Garrett B. Georgia Institute Of Technology 2014 Complete
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Dr. Forest's team will use a newly developed robot guided technique to measure precise changes in electrical activity from individual neurons that are connected over long distances across the brain, to understand how these connections change when our brains go into different states, such as sleeping and waking.
Increased thalamocortical connectivity in tdcs-potentiated generalization of cognitive training Lim, Kelvin O. (contact) Macdonald, Angus W University Of Minnesota 2018 Active
  • Human Neuroscience
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  • Monitor Neural Activity

Transcranial direct current stimulation (tDCS) represents a therapeutic tool for non-invasive neuromodulation of brain circuitry, yet little is understood about how it changes cognition. Lim and colleagues will study how tDCS, coupled with cognitive training, impacts a particular neural circuit: the connectivity between the thalamus and prefrontal cortex. They will assess the effects of location of tDCS, treatment duration, and an individual’s modeled dosage, on functional connectivity and cognitive performance in both healthy controls and schizophrenia patients. These represent the first experiments to examine how tDCS-augmented cognitive training alters brain circuitry in both health and psychopathology, which could guide future research and/or interventions for cognitive impairments.

Informing Choice for Neurotechnological Innovation in Pediatric Epilepsy Surgery Illes, Judy (contact) Mcdonald, Patrick University Of British Columbia 2018 Active
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More than 500,000 children in the US and Canada suffer from epilepsy and 30% of these children continue to experience seizures despite being treated with anti-seizure medication. Unmanaged, epilepsy can result in cognitive decline, social isolation, and poor quality of life, and has substantial economic impact on families and society. Novel approaches for treating epilepsy such as vagal nerve stimulation and responsive neurostimulation are being developed, but this work has been conducted predominately in adults and the outcomes of these trials are often not clearly generalizable to children. In this project, Drs. Illes and McDonald will explore ethical issues confronting families and clinicians when considering new treatment options for drug-resistant epilepsy in children. They aim to develop, evaluate, and deliver patient-directed resources in the form of infographics and informational materials and videos, and clinician resources for family decision-making, clinician counseling, and care.

Input-specific imaging and manipulation of synaptic plasticity underlying social memory Phillips, Mary L Max Planck Florida Corporation 2019 Active
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  • Human Neuroscience
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In an effort to improve our understanding of how synaptic plasticity contributes to social memory, Dr. Phillips aim to create a tool to modulate synaptic plasticity in specific circuits during behavior. Using advanced imaging techniques and various innovative biochemical assays, she plans to create a photo-activatable inhibitor of presynaptic plasticity and will use this tool to understand the circuitry of social memory. The researcher will develop constructs of a photo-activatable PKA inhibitor and screen the constructs using 2-photon fluorescence lifetime imaging in HeLa cells. The optimized inhibitor constructs will then be expressed in the dCA2-vCA1, vCA1-PL, and PL-dPAG projections in mice and used to block presynaptic plasticity during social learning in either aggressive or neutral contexts.  Successful development of these tools will enable investigation of neural circuitry to better our understanding of behavior and neuropsychiatric diseases.

Integrated Biophysical and Neural Model of Electrical Stimulation Effects Bazhenov, Maksim V Halgren, Eric (contact) University Of California, San Diego 2019 Active
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  • Human Neuroscience
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Electrical stimulation devices are used for neuroscience research and the treatment of brain disorders. To make the procedures more predictable, researchers in the Halgren and Bazhenov labs aim to develop a novel computational approach for predicting which neuron type will be activated by stimulation. Models will be based on neuron type, shape, brain location, and connectivity. The validity of these models will be tested in mice and humans using advanced imaging and microscopic techniques that will help the researchers observe neuronal responses.

Integrated compressive sensing microscope for high-speed functional biological imaging Chin , Sang Peter Boston University (charles River Campus) 2017 Active
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The development of optical voltage sensors promises a direct readout of electrical activity in large populations of neurons and in subcellular domains such as axon terminals and dendritic spines. However, because these electrical events occur on millisecond timescales, this new class of optical reporters requires novel approaches to high-speed imaging. Sang (Peter) Chin and his team have developed an innovative high-speed camera design with pixelwise exposure control, which they propose to incorporate into a wireless miniature microscope to image voltage sensors in the brains of awake, behaving animals. Their new camera will incorporate compressive sensing principles to enable long camera exposure and slow readout, saving power, reducing system size, and increasing signal-to-noise ratios, while maintaining action potential detectability. This work has the potential to provide an alternative to microelectrode-based recordings, enabling high speed voltage imaging in freely-moving mammals.
Integrated fMRI Methods to Study Neurophysiology and Circuit Dynamics at Laminar and Columnar Level Chen, Wei University Of Minnesota 2016 Active
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  • Human Neuroscience
Functional MRI is a powerful technique for mapping functional brain activity. However, its low spatial resolution prevents accurate mapping of activity at the scale of cortical layers. Another long-standing limitation of fMRI has been the inability to study how neural inhibition impacts neural dynamics and networks. Chen and his colleagues propose to integrate ultrahigh-resolution high-field fMRI with the selective stimulation of groups of inhibitory neurons to study correlates of fMRI signals in neural circuits. This project has the potential to bring clarity to the relationship between structure and function at the level of individual neuronal layers, as well as shed light on the dynamics of neural activity.
Integrating flexible neural probes with a giant cranial window for combined electrophysiology and 2-photon calcium imaging of cortex-hippocampal interactions Golshani, Peyman University Of California Los Angeles 2016 Complete
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Learning and memory retrieval may rely upon coordinated network activation in regions of the neocortex during 150-250 Hz neuronal oscillations, or ripples, in the hippocampus. Golshani’s team will implant flexible electrode arrays developed by BRAIN-funded investigators into mouse hippocampus, and will combine this technology with their large cranial window preparation. This setup should allow for long-lasting, low-noise calcium imaging of neurons across brain regions, extending from frontal to occipital cortex, bilaterally, during a memory retrieval task. The group plans to identify neurons co-activated during ripple oscillations to explore interactions between the hippocampus and neocortex, which could improve understanding of memory dysfunctions in neurodegenerative and neuropsychiatric diseases.
Integrative approach to classifying neuronal cell types of the mouse hippocampus Dong, Hong-wei (contact) Zhang, Li I University Of Southern California 2017 Active
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Identifying the diversity of nervous system cell types may enable their selective manipulation and reveal their functions in health and disease. Dong and his team propose state-of-the-art techniques in viral circuit tracing and molecular and electrophysiological profiling, to classify neuronal cell types of the mouse hippocampus and subiculum. Combined with CLARITY (a tissue-clearing technique), expansion microscopy, and multiphoton imaging, their approach will report the anatomical location, connectivity, morphology, molecular profile, and electrophysiological characteristics of each cell type. Raw and analyzed data will be publicly shared on the Mouse Connectome Project website. If successful, this work can be applied toward characterizing neuronal cell types of the entire brain.
Integrative Functional Mapping of Sensory-Motor Pathways Dickinson, Michael H (contact) Holmes, Philip J Mann, Richard S Wilson, Rachel California Institute Of Technology 2014 Complete
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Dr. Dickinson will lead an interdisciplinary team to study how the brain uses sensory information to guide movements, by recording the activity of individual neurons from across the brain in fruit flies, as they walk on a treadmill and see and smell a variety of sights and odors.
Intercellular TWEAK/Fn14 Cytokine Signaling in Sensory-Dependent Circuit Refinement Cheadle, Lucas M Harvard Medical School 2019 Active
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Neurodevelopmental disorders can arise from impairments in sensory-dependent refinement or strengthening of synapses during postnatal brain development. However, treatment strategies focused on addressing such impairments lack an advanced understanding of the cellular and molecular mechanisms of this process. Building on prior results showing that expression of the gene Fn14 is driven by visual experience and encodes a receptor required for synaptic refinement, Dr. Cheadle aims to use slice electrophysiology and bioinformatics to study how microglia-to-neuron signaling is involved in refinement via examining the role of TWEAK, an Fn14 receptor ligand, in healthy and neurodevelopmentally-impaired mice. The results may offer insights into the development of treatments for neurodevelopmental disorders.

Interneurons differentially regulate discrete pathways from ventral hippocampus Donegan, Jennifer University Of Texas Hlth Science Center 2019 Active
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Hippocampal microcircuits include excitatory pyramidal cells, which integrate information and signal to downstream brain regions, and inhibitory interneurons, which function locally to regulate pyramidal cell activity. Circuit dysfunction in the ventral hippocampus (vHipp) has been associated with various brain disorders. Dr. Donegan will use techniques including mammalian GFP reconstitution across synaptic partners (mGRASP), fiber photometry, in vivo electrophysiology, and optogenetics, to test the hypothesis that different types of interneurons in the vHipp differentially regulate the function of ventral hippocampus pyramidal cells depending on their projection target. She will also test whether vHipp microcircuit anatomy and function are altered by chronic stress, shedding light on the potential link between circuit dysfunction in the hippocampus and brain disorders.

Interrogating Biophysical Mechanisms of Magnetogenetic Cell Stimulation at Radio Frequencies Liu, Chunlei University Of California Berkeley 2019 Active
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Magnetogenetics refers to a promising new method for wirelessly stimulating brain circuits. Initial reports suggest that neurons can be genetically modified to express magnetically sensitive ion channels, allowing the neurons to be activated by exposure to electromagnetic fields. The Liu group aims to systematically explore the full potential and limitations of this technology. Their results may help neuroscientists noninvasively examine the role of brain circuits in a variety of behaviors and disorders.

Intrabody-dependent activation of cell-specific gene expression in CNS Blackshaw, Seth Johns Hopkins University 2015 Complete
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Techniques for inducing specific cell types to express certain proteins typically require using genetically engineered animals, which are limited primarily to rodents and can take years to develop. Blackshaw and colleagues are developing tools that will allow specific cells to be labeled and manipulated without complex genetic approaches. If successful, this technology would enable the labeling and modification of multiple types of specific neurons in nearly any animal, at a fraction of the cost and time of current techniques.
Intraoperative studies of flexible decision-making Baltuch, Gordon H (contact) Gold, Joshua I University Of Pennsylvania 2017 Active
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Even relatively simple sensory-motor decisions, such as goal-directed eye movements, exhibit sufficient flexibility and nuance to be considered a “window on cognition.” Gordon Baltuch’s team will leverage the unique opportunity provided by surgical treatment of Parkinson’s disease using deep brain stimulation, to study decision-making in the human brain at the single-neuron level. The team will simultaneously measure behavioral response time and accuracy (by asking neurosurgical patients to select a visual stimulus via eye movements) while performing brain electrophysiology. Additionally, they will conduct parallel monkey and human studies that, unlike Parkinson’s studies alone, will distinguish normal versus disrupted mechanisms in the Parkinson’s -affected brain. This project may yield a sustainable research program that probes not only neural mechanisms of decision-making, but also potential causes of, and remedies to, cognitive side effects associated with deep brain stimulation.
Invasive Approach to Model Human Cortex-Basal Ganglia Action-Regulating Networks Pouratian, Nader University Of California Los Angeles 2016 Active
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Circuits between the frontal cortex and basal ganglia (BG) may support the ability to suppress actions once additional information becomes available to indicate the most appropriate decision, but few studies provide the necessary spatial and temporal resolution to investigate this mechanistically. Dr. Pouratian’s group will utilize deep brain stimulation (DBS) electrodes in Parkinson’s patients to record from cortical and BG regions in multiple action-suppression tasks. In addition to investigating unit and local field potential activity during tasks, the group will use DBS coupled with functional imaging to stimulate the circuits and measure effects on brain activity, eventually developing a computational model of action suppression. Aside from informing the basic science of this circuitry, this project could expand upon how DBS influences brain networks for action, which could improve therapeutic use in various disorders.
Investigating the hypocretin to VTA circuit in memory consolidation during sleep Borniger, Jeremy Stanford University 2018 Active
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Brain-computer interfaces and neuroprosthetics have provided a significant benefit to patients with cervical spinal cord injuries. However, current technology is limited in its abilities to allow the user to control how much force is exerted by the prosthesis and to provide sensory feedback from the prosthetic hand. In a public-private collaboration with Blackrock Microsystems, Dr. Boninger and colleagues are looking to improve the dexterity of neuroprostheses by incorporating microstimulation of the somatosensory cortex. This stimulation could provide tactile feedback to the user and hopefully allow the user to better control the force applied. Ultimately, this approach will improve the dexterity and control of prosthetic limbs used by patients with spinal cord injuries.

Investigating the molecular, cellular and circuit effects of transcranial magnetic stimulation Falchier, Arnaud Y Opitz, Alexander (contact) Vlachos, Andreas University Of Minnesota 2019 Active
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Transcranial magnetic stimulation (TMS) has the potential to non-invasively treat brain circuit disorders. Nevertheless, scientists do not completely understand how it may work. Researchers in the Falchier, Opitz, and Vlachos labs plan to use electrical and optical recording techniques to examine the molecular and cellular effects of TMS on neurons in brain slices from rodents and nonhuman primates. Their goal is to develop computational models that will help researchers understand and predict the effects of TMS. Ultimately, the results may help researchers devise improved TMS based treatments for a variety of neurological disorders.

Investigating the response of CNS neurons to electric and magnetic stimulation Fried, Shelley Massachusetts General Hospital 2019 Active
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To help improve nerve stimulation devices, the Fried team will explore the fundamental neurophysiological principles that guide how retinal and cortical neurons respond to artificial electrical and magnetic stimulation. Neural responses to stimulation will be recorded in individual retinal ganglion cells from rodents or nonhuman primates. The scientists will then map the sensitivity of different parts of each neuron. The results may be used to create models of neuronal activity that may inform the development of more efficient nerve stimulation devices for treating neurological disorders.

Investigating the Role of Neurotensin on Valence Assignment During Associative Learning in the Basolateral Amygdala Olson, Jacob Michael Massachusetts Institute Of Technology 2017 Active
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Dr. Olson will systematically identify, manipulate, and characterize the neural projections that release the neuropeptide neurotensin to the basolateral amygdala during behavior conditioning tests in mice to identify a new circuit that regulates associative learning.
Is the Treatment Perceived to be Worse than the Disease?: Ethical Concerns and Attitudes towards Psychiatric Electroceutical Interventions Cabrera Trujillo, Laura Yenisa Michigan State University 2018 Active
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The NIH BRAIN Initiative aims to catalyze novel tools and technologies to modulate brain circuit function, paving the way for new treatment options for brain disorders. However, such interventions also have the potential to cause unintended changes in aspects of cognition, behavior, and emotion. These changes, in turn, raise concerns regarding autonomy, personal identity, and capacity for informed consent. In this study, Dr. Cabrera Trujillo and her team will study ethical concerns, beliefs, and attitudes about the use of novel bioelectric approaches among clinicians, patients, and the broader public. The work will provide stakeholder perspectives that will be valuable for informing the responsible development and use of these novel neurotechnologies.

Label-free 4D optical detection of neural activity Bazhenov, Maksim V Binder, Devin K Park, Boris Hyle (contact) University Of California Riverside 2015 Complete
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Development of technologies for large-scale imaging of neural activity at the single cell level is a fundamental goal of the BRAIN Initiative. Most optical techniques for achieving this goal require labeling neurons with a genetic or chemical probe that can be imaged. Park and his colleagues propose a novel method for achieving this goal by adapting a technique called optical coherence tomography (OCT), which captures light as it reflects off the surface of living tissue, and doesn't require that neurons be labeled. When neurons fire action potentials they undergo ultra-small changes in size and shape that Park and his team will measure by examining the intensity and phase of the OCT signal. If OCT is successful in living animals, it could produce label-free and depth-resolved images of activity from thousands of neurons with micron-scale spatial resolution and sub-millisecond temporal resolution.
Lagging or Leading? Linking Substantia Nigra Activity to Spontaneous Motor Sequences Adams, Ryan Prescott Datta, Sandeep R Sabatini, Bernardo L (contact) Harvard Medical School 2015 Complete
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One of the goals of the BRAIN Initiative is to understand how the brain generates behaviors. These researchers are utilizing a novel 3D machine vision technology to automate classification of spontaneous behavior when freely-moving mice are confronted with stimuli; they are then correlating that information with dense recordings of neural activity in key regions of the brain implicated in movement disorders. Researchers are then manipulating the activity of specific neurons in this brain region with light to test their role in the animal’s behavior. Dr. Sabatini and colleagues offer an innovative ‘grammatical’ structure to understanding how the brain produces complex, systematic behavior.
Large-Scale Electrophysiological Recording and Optogenetic Control System Goodell, Albert Baldwin Graymatter Research 2014 Complete
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Dr. Goodell and his colleagues aim to develop optrodes, which are implantable columns of lights and wires for simultaneous electrical recording of neurons and delivery of light flashes to multiple brain areas.
Large-scale monitoring of sensory transformations in the mammalian olfactory system Burton, Shawn Denver University Of Utah 2017 Active
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Dr. Burton will leverage recent enhancements in calcium indicators to image pre- and post-synaptic neural activity simultaneously in the mammalian olfactory system, gaining insight into how sensory information is transformed as it moves through a neural circuit.
Large-scale, simultaneous intracellular recording and stimulation of neural activity London, Michael Nelken, Israel Spira, Micha E. (contact) Hebrew University Of Jerusalem 2016 Active
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Current in vivo multi-electrode recording devices monitor extracellular spiking activity from multiple neurons, but they do not capture the full range of neural activity that is available from intracellular recordings. Intracellular recordings are commonly obtained from brain slices or cultured neurons, but are very difficult to acquire in freely moving animals where it is typically only possible to record from one neuron at a time. Dr. Spira and colleagues will apply a novel method using arrays of micron-size, gold electrodes that are shaped like mushrooms and coated with bioactive materials to form a tight seal with the plasma membrane, allowing intracellular electrode access. If successful, the arrays will enable in vivo long-term intracellular recordings of action potentials and subthreshold activity from dozens to hundreds of individual neurons.
Leveraging ethical dissension among capacity, beneficence and justice in clinical trials of neurotherapeutics in the severely disabled: lessons from schizophrenia Davis, Rachel A Gault, Judith Morse (contact) Saks, Elyn R. University Of Colorado Denver 2019 Active
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Individuals with severe, disabling, chronic mental illness, such as treatment-refractory schizophrenia/schizoaffective disorder (TRS), have often been excluded from research, leading to challenges in developing treatment for their illnesses as well as access to that treatment. Here, Dr. Judith Gault will examine the ethical issues that will lay a foundation for conducting clinical research in TRS patients who have traditionally been excluded in studies. These ethical principles will include transparency, accessibility and safety of clinical trials testing neurosurgical intervention in TRS patients who are in urgent need of effective novel interventions. The team will explore the ethical implications of excluding individuals based on their capacity to consent, surgical risks, and severity of symptoms for a planned clinical trial to treat TRS. Successful completion of the project could revolutionize our understanding of how to overcome research disparities among severely disabled individuals by improving transparency, accessibility, and safety of clinical trials.

Lightweight, Compact, Low-Cryogen, Head-Only 7T MRI for High Spatial Resolution Brain Imaging Foo, Thomas (contact) Shu, Yunhong Xu, Duan General Electric Global Research Ctr 2018 Active
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Non-invasive magnetic resonance imaging (MRI) is an important tool for our understanding of the human brain. However, ultra-high field magnets are hampered by their massive size and challenging installation, limiting their accessibility to researchers and clinicians. Dr. Thomas Foo and a team of investigators propose the development of a 7T MRI system with high-performance head gradients, delivering a head-only, high-resolution MRI system that is significantly smaller and lighter in comparison to existing ultra-high field systems. The group will design, optimize, and validate a head-only 7T MRI system, piloting the system in healthy volunteers to assess the quality of the structural, functional, and metabolic data. The proposed work has the potential to open a range of scientific and clinical applications that cannot currently be achieved with existing instrumentation.

Linking neuronal, metabolic, and hemodynamic responses across scales Ghose, Geoffrey M University Of Minnesota 2018 Active
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Previous work on blood oxygenation level dependent (BOLD) signals underlying functional magnetic resonance imaging (fMRI) has typically focused on improvements in spatial resolution. Emerging data suggest that when fast fMRI designs are used, rich information can be extracted from the temporal aspects of BOLD fMRI. Dr. Ghose and colleagues will simultaneously measure and compare neuronal, metabolic, and hemodynamic responses that underlie the BOLD signal as a function of stimulus strength, behavioral state, and brain network state using fast optical and MR imaging techniques. By integrating imaging and stimulation technologies that span the scale from neurons to voxels across species, this multi-modal approach will enable temporally precise inferences to be drawn regarding the relationship between neuronal activity and fMRI measurements.

LIPS: A novel technology for spatial and temporal control of protein synthesis in dendritic spines Gan, Wenbiao Jaffrey, Samie R (contact) Weill Medical Coll Of Cornell Univ 2015 Complete
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Synaptic plasticity involves changes in protein expression that are precisely localized to dendrites and synaptic spines, but current techniques for manipulating gene expression are not able to approach these small scales. Jaffrey and colleagues propose a method called light-induced protein synthesis (LIPS), using RNA transcripts under control of plant-derived phytochrome proteins that can be activated by microscopic laser spots. The ability to directly manipulate the protein content at specific synapses and spines may greatly enhance efforts to decipher the roles of synaptic proteins in learning, memory, behavior, and disease.
LOCATER: Large-scale Observation of Cellular Activity Through Exosomal Reporters Zhang, Feng Broad Institute, Inc. 2015 Complete
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Dr. Zhang's project will test a completely novel idea to assay neural activity using a blood test. It will harness the capabilities of exosomes, which are nano-scale vesicles containing protein and RNA cargo that are secreted from cells throughout the body. They readily cross the blood-brain barrier and they protect their RNA cargo from degradation in the blood. The proposal is to induce neurons to express RNA molecules that will be packaged into exosomes in response to neuronal electrical activity. Each cell's RNA molecules will have their own unique "barcode" sequences that will allow investigators to know what cells the RNA molecules came from after they are harvested from the blood. This will enable complex experiments to test neuronal circuit contributions to behaviors and to understand circuit disruptions associated with specific diseases.
Magnetic camera based on optical magnetometer for neuroscience research Alem, Orang FIELDLINE, INC. 2018 Active
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A camera that could image neuronal current distributions with a large array of pixels and a spatial resolution better than 1 ms resolution could dramatically enhance our understanding of neuronal circuitry. In this Phase I STTR, Fieldline, Inc. will develop a novel type of magnetographic camera, capable of providing single-shot images of electrical currents in neuronal circuits in vitro and in vivo with a millisecond time resolution. The team will first build a bench-top camera before combining it with electrode arrays, testing the ability to image neuronal connections across the circuit in vitro with turtle cerebellem. This will potentially lead to a completely portable, economical multi-pixel camera that can be produced for neuroscience research. 

Magnetic Particle Imaging (MPI) for Functional Brain Imaging in Humans Conolly, Steven M Griswold, Mark Wald, Lawrence L (contact) Massachusetts General Hospital 2014 Complete
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The Wald team plans to use an iron-oxide contrast agent to track blood volume, which will permit dramatically more sensitive imaging of human brain activity than existing methods.
Mapping and controlling gene expression in inhibitory interneurons mammals Fishell, Gordon J New York University School Of Medicine 2016 Complete
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In order to better understand what influences normal brain development, it is necessary to track changes in gene expression over time and in different contexts, including learning and development. Fishell and colleagues modified DNA Adenine Methyltransferase Identification technology (DamID) to make it inducible in forebrain interneurons at particular developmental time points to measure gene activation. The new DamID will provide a transcriptome timestamp in a diverse cell population without requiring transgenic tools. The group intends to use transcriptome data and computational programming to expand into viral vectors to modulate interneuron subgroups in mice and non-human primates.
Mapping cerebellar granule cell function with novel genetic and optical tools Broussard, Gerard Joey Princeton University 2019 Active
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Small, tightly-packed granule cells (GrCs) in the cerebellum have been associated with sensory and motor events, but their specific roles remain unclear due to their close packing.  Dr. Broussard aims to precisely record from and perturb GrCs and measure the resulting effects on neural firing patterns and activity in mice. The researcher will develop a spike-counting method for genetically encoded indicators by optimizing the kinetics of the calcium sensor GCaMP. After developing a cleared skull preparation to access the full posterior cerebellum in mice, the new indicator will be used to map the neocortical drivers of GrC activity across the cerebellum, and rodent behavioral tasks will be used to disambiguate sensory, motor and internal-state contributions to granule cell activity patterns. Better knowledge of GrCs activity will further our understanding of neural circuits that guide sensory processing and plays roles in neurological disorders.

Mapping neuronal chloride microdomains Staley, Kevin J. Massachusetts General Hospital 2014 Complete
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Using protein engineering technology to monitor the movement of chloride through inhibitory neurotransmitter receptor channels, Dr. Staley's group aims to understand the role of chloride microdomains in memory.
Massive scale electrical neural recordings in vivo using commercial ROIC chips Kording, Konrad P. (contact) Schaefer, Andreas Rehabilitation Institute Of Chicago 2015 Complete
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Increasing the number and density of electrically recorded neurons in behaving animals is an important goal for achieving a nuanced and accurate rendering of neural circuit function. To date, efforts to achieve this goal have relied on specialized hardware developed for neural recordings. Kording and Schaefer and their colleagues propose a radically different approach that uses readout integrated circuit (ROIC) arrays taken from commercial infrared camera chips, which they will bind to bundles of glass-insulated gold microwires. In principle, this should enable recordings from tens- to hundreds-of-thousands of neurons in rodent brain tissue. Since commercial camera array electronics are continuing to improve in speed and scale, successful implementation could just be a starting point for this approach.
Massively Multiplexed Gold Microprobe Arrays for Whole-Mouse-Brain Recording Fang, Hui (contact) Walker, Ross M Northeastern University 2019 Active
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Simultaneously recording from tens of thousands of neurons involved in a circuit may help increase understanding of brain function, but current technology is invasive and only allows for surface recording. Drs. Fang and Walker’s teams will develop hair-thin, deep penetrating (up to 1mm), gold microprobes in combination with a thin, CMOS electronic router to record from thousands of neurons in rat cortex. This new, multiplexed technology of 1000 electrodes may eventually be scaled up to include 10,000-100,000 microprobes, enabling recording from multiple brain areas.

Mechanism and dosimetry exploration in transcranial electrical stimulation using magnetic resonance current mapping methods. Sadleir, Rosalind J Arizona State University-tempe Campus 2017 Active
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Interest in transcranial electrical stimulation (tES) has escalated over the last decade, but the mechanisms of action of these therapies are unclear, and study results suffer from high variability. This project proposes to precisely measure where electrical energy flows in the brains of subjects and compare this with brain activity levels. Sadleir’s team will develop a technique based on MR electrical impedance tomography to measure current density and electric field distributions in the brains of healthy human subjects experiencing tES. The electrical distributions will be correlated with memory performance measures and brain activity measures using fMRI, including a specific target structure in the prefrontal cortex. This new approach will bolster explorations into the mechanisms of electrical stimulation therapies, with potential to revolutionize researchers’ understanding of tES, a technique with applications ranging from basic mechanistic studies on electrical neuromodulation to stroke and epilepsy therapy to memory enhancement.
Mechanism underlying Nerve Conduction Block by High Frequency (kHz) Biphasic Stimulation Tai, Changfeng University Of Pittsburgh At Pittsburgh 2019 Active
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High frequency biphasic stimulation (HFBS) of the spinal cord is a new and highly effective method for treating lower back pain, but little is known about why it works. Here the Tai group will perform experiments in animals to explore how HFBS blocks nerve signal conduction along spinal cord axons. They will focus on changes in axonal ion gradients, ion channels, and ion pumps in response to stimulation. Their results may help researchers not only understand how HFBS works but also refine the way it is used to treat pain.

Mechanisms of Active Sensing in Drosophila Suver, Marie New York University School Of Medicine 2019 Active
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To process information about the world, the nervous system must distinguish external stimuli from internally generated sensory stimuli, but the mechanisms underlying the cellular basis of internally generated sensation and movement are not well understood. Here, Dr. Suver plans to develop a small circuit model of this process using the antennae of the fruit fly as a model system. Using electrophysiological recordings, optogenetics, and immunohistochemistry, she will develop the neural circuits controlling and sensing antennal movement as a cellular model for studying principles of active sensing. The insights gained from a tractable genetic circuit model may improve understanding of active sensation, as well as how these mechanisms might fail in disease.

Mechanisms of electrical stimulation of a canonical motor microcircuit Heckman, Charles NORTHWESTERN UNIVERSITY AT CHICAGO 2018 Active
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A central goal of the NIH BRAIN Initiative is to develop new and improved methods for modulating the activity of specific neural cells and circuits, including those of the spinal cord. Dr. Heckman and his team will study the effect of dorsal electrical stimulation (DES) on motor circuits of the lumbar spinal cord. Specifically, they will investigate how DES affects two functions of descending inputs from the brain to the spinal cord – the generation of movements and the control of spinal neuron excitability. This work will help define the potential of DES for selective control of spinal motor circuits and may inform efforts to restore movement after spinal cord injury via DES.

Mechanisms of neural circuit dynamics in working memory Bialek, William Brody, Carlos D (contact) Seung, Hyunjune Sebastian Tank, David W Wang, Samuel Sheng-hung Witten, Ilana Princeton University 2014 Complete
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Dr. Brody and his colleagues will study the underlying neuronal circuitry that contributes to short-term "working" memory, using tools to record circuit activity across many brain areas simultaneously while rodents run on a track-ball through virtual mazes projected onto a screen.
Mechanisms of Rapid, Flexible Cognitive Control in Human Prefrontal Cortex Sheth, Sameer BAYLOR COLLEGE OF MEDICINE 2018 Active
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The human brain can quickly “program” itself to adapt to novel situations, such as figuring out how to drive a rental car through a new city. Dr. Sheth and his colleagues plan to investigate how the brain assembles pieces of information into plans that help us manage new circumstances, and then develops a computational model of this learning. They will record from the brain’s dorso-lateral prefrontal cortex in patients with deep brain stimulation who are performing tasks to understand what information is being encoded and how it is processed. The project offers to provide a computational understanding of complex cognition. This may improve our understanding of cortical brain function and of neurological disorders that interfere with complex thinking.

Mechanisms underlying large-scale coordination of cortical activity during perceptual decisions Pinto, Lucas Princeton University 2019 Active
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Evidence suggests that both spontaneous and learned behaviors engage activity in various regions of the cortex. However, for perceptual decision-making, more complex and demanding tasks involve decorrelated cortical activity as a more distributed, widespread process throughout the cortex. Dr. Pinto aims to understand this phenomenon, using cutting-edge technology to study how distributed cortical acitivity mediates complex decision-making and the mechanisms of task-induced changes in large-scale cortical dynamics. The research will utilize two-photon calcium imaging, virtual reality behavioral tasks, pharmacogenetics, optogenetics, and modelling, increasing our understanding of the neural basis of decision-making.

Mechanisms underlying positive and negative BOLD in the striatum Shih, Yen-yu Ian Univ Of North Carolina Chapel Hill 2018 Active
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A central assumption in blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging lies in the tight coupling between neuronal activity and vascular responses. To a large extent, data supporting this coupling has been based on cortical structures, but accumulating evidence suggests that the striatum exhibits a different pattern. Dr. Shih and colleagues will use a suite of cutting-edge neuroscience techniques, including optogenetics and chemogenetics, to selectively identify and target dopamine receptors, vasoactive neurotransmitters, and neuronal subtypes that underlie distinct positive and negative BOLD responses in the striatum. By using both multimodal modulation and recording techniques to simultaneously understand the vascular response to stimuli and the impact on BOLD, this project offers the potential to shed light on better understanding the function and role of the striatum in cognition and disease.

Mechanistic and causal basis of fMRI functional connectivity in non-human primates Rudebeck, Peter (contact) Russ, Brian E Icahn School Of Medicine At Mount Sinai 2018 Active
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Neuroscience researchers and clinicians increasingly utilize connectivity measures of functional magnetic resonance imaging (fMRI) to better understanding circuit-level mechanisms of brain function and dysfunction yet establishing causal links between fMRI functional connectivity and neural activity remains challenging. Using non-human primates, Drs. Rudebeck and Russ propose a multi-dimensional approach that combines high-resolution multi-echo fMRI, high-density neurophysiology recordings, and pathway-specific manipulations of neural activity. Collectively, these measures will help to establish a causal understanding of how connectivity and neural activity measures are related to one another at rest and during cognitive tasks. By identifying the neural mechanisms underlying fMRI, this work will both aid basic research as well as inform therapeutic approaches that target distributed brain circuits.

Mechanistic dissection of the neural basis of the resting-state fMRI signal using multi-modal approaches Drew, Patrick James Zhang, Nanyin (contact) Pennsylvania State University-univ Park 2017 Active
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  • Human Neuroscience
The neural basis of resting-state fMRI (rsfMRI) signal remains poorly understood. Particularly, poor understanding of cellular and circuit-level mechanisms underlying resting-state functional connectivity (RSFC) has hampered rsfMRI interpretation. Nanyin Zhang’s team will dissect the signal contributions of spiking activity from individual neuron populations. They will use multi-echo-rsfMRI (differentiates neural and non-neural rsfMRI signal components) to quantify RSFC by eliminating non-neural artifacts, and calcium-based fiber photometry to measure simultaneous neuronal and rsfMRI signals with neuron-type specificity. Finally, the group will optogenetically increase neuronal excitability and examine resulting RSFC and cortical-layer-specific electrophysiological signal changes. This project may enhance understanding of rsfMRI signal in humans, impacting brain disorder research.
Memory consolidation during sleep studied by direct neuronal recording and stimulation inside human brain FRIED, ITZHAK UNIVERSITY OF CALIFORNIA LOS ANGELES 2018 Active
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Sleep is important for learning and memory, but the exact mechanisms of this process are not known. Dr. Fried and his team will examine the role of sleep in memory formation in humans by recording brain activity during sleep following learning tasks. Dr. Fried’s group will identify the sleep events, such as sleep stage or changes in firing activity, that show the strongest association with memory consolidation. They will also examine whether electrical or auditory stimulation during sleep improves memory performance compared to undisturbed sleep. Greater knowledge of these mechanisms may help in the development of treatments for people suffering from memory and/or sleep disorders. 

Micro-coil implants for cortical activation Fried, Shelley Massachusetts General Hospital 2016 Active
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Conventional stimulating electrodes are an important tool with great potential for studying neural circuits and treating brain disorders, but they have limitations, including off-target stimulation of cortical neurons and a gradual reduction in effectiveness due to scarring of surrounding brain tissue. Dr. Fried’s group will develop tiny, micro-coil based implants that stimulate neurons with a magnetic field rather than injection of electrical current. This approach promises greater spatial selectivity with less sensitivity to tissue scarring, which would be a major advance over current methods. The resulting technology could have important implications for therapies based on brain stimulation, since it would provide more selective targeting of specific circuits, longer-term stability, and minimization of unwanted side-effects.
Microdevice mediated functional brain imaging with high temporal and spatial resolution Wong, Eric C University Of California San Diego 2016 Complete
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Current methods for functional brain imaging such as EEG or MEG can provide high temporal resolution, but they are limited in their spatial resolution and brain coverage. In contrast, functional MRI offers broad coverage, but it has low temporal resolution and is an indirect and incomplete measure of neural activity. Wong and his colleagues propose to combine the benefits of high-resolution electrical recordings with broad spatial coverage offered by MRI, using injected microelectronic devices that rapidly convert electric signals into magnetic fields detectable with an MRI scanner. As an intermediate goal, the researchers will record neural activity from the entire cortical surface at a sub-millimeter scale and 10 ms resolution, providing a measure of electrical activity at every cortical column simultaneously. This new approach could provide vastly richer functional data than is currently possible, and accelerate efforts to understand brain function.
Microscopic foundation of multimodal human imaging Dale, Anders M Devor, Anna (contact) University Of California San Diego 2016 Active
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The computational properties of the human brain arise from an intricate interplay between billions of neurons of different types that are connected in complex networks. The hypothesis behind the project from Devor and her colleagues is that specific neuronal cell types have identifiable “signatures” in the way they contribute to large electrical signals that drive changes in the brain’s energy metabolism and blood flow. To investigate this hypothesis, the researchers will attempt to relate cell-type specific neural activity to metabolism and blood flow signals using parallel experiments in mice and humans. If successful, the proposed project will create a way to measure neuronal activity of known cell types from across the entire human brain, offering a significant enhancement to techniques such as functional MRI (fMRI).
Model behavior in zebrafish: characterization of the startle response Meserve, Joy Hart University Of Pennsylvania 2018 Active
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The startle response is disrupted (i.e., uncoordinated or weak) in several neurological and psychiatric disorders. Meserve will investigate the startle response using live imaging of neural activity in transparent larval zebrafish. The slc5a7 gene (required for acetylcholine synthesis) modulates the startle response in zebrafish, and human slc5a7 mutations are implicated in attention deficit disorder and major depression. This project will study slc5a7a’s role in neural circuit development and/or startle response. Circuit defects in slc5a7a mutants will be investigated via calcium imaging and whole-brain activity mapping of neurons known to be required for the startle response. Integrated studies on gene function, neural circuitry, and behavior will uncover the developmental stage and anatomical region where slc5a7a is required. These experiments may determine how slc5a7a promotes normal startle response, and contribute knowledge about how acetylcholine regulates behavior.
Modular High-Density Optoelectrodes for Local Circuit Analysis Buzsaki, Gyorgy Wise, Kensall David Yoon, Euisik (contact) University Of Michigan 2014 Complete
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In this project, Dr. Yoon's team will make devices for optogenetics, a technique that enables scientists to turn neurons on and off with flashes of light, more precise and diverse by integrating multiple light sources in such a way as to enable the control of specific neuronal circuits.
Modular nanophotonic probes for dense neural recording at single-cell resolution Roukes, Michael L (contact) Shepard, Kenneth L Siapas, Athanassios Tolias, Andreas California Institute Of Technology 2014 Complete
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Dr. Roukes and his team propose to build ultra-dense, light-emitting and -sensing probes for optogenetics, which could simultaneously record the electrical activity of thousands of neurons in any given region of the brain.
Modular systems for large scale, long lasting measurements of brain activity Frank, Loren UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 2018 Active
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Led by Dr. Frank, this team of Drs. Adesnik, Brainard, Buffalo, Denes, Haque, Karlsson, and Tooker aims to fine tune a high-density electrode recording system developed for long-lasting recordings of brain activity. The team plans to make their flexible polymer technology systems smaller, lighter, and capable of containing a higher density of probes. The team also will actively help distribute the probes to the research community. These tools will be used by researchers who are trying to understand how the firing patterns of brain circuits can control the healthy and diseased brain.

Modular systems for measuring and manipulating brain activity Frank, Loren M (contact) Harrison, Reid Tolosa, Vanessa University Of California, San Francisco 2014 Complete
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Dr. Frank and his colleagues will engineer a next-generation, all-in-one neural recording and stimulating system, which can simultaneously monitor thousands of neurons in the brain for several months while also delivering drugs, light or electrical pulses.
Molecular Functional Ultrasound for Non-Invasive Imaging and Image-Guided Recording and Modulation of Neural Activity Shapiro, Mikhail California Institute Of Technology 2016 Active
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Functional ultrasound (fUS) is a recently developed Doppler-based technique for imaging neurovascular responses. Compared to fMRI, it has greater spatiotemporal resolution and can be implemented in more diverse experimental settings. To enhance this technology, Dr. Shapiro has developed a system utilizing genetically engineered gaseous nanovesicles, which are hollow protein structures derived from buoyant microbes that are permeable to gases, but not to water. He is collaborating with the inventor of fUS, Michael Tanner, to use the nanovesicles in two ways: first as blood-borne contrast reagents for high resolution imaging of neurovascular responses (analogous to fMRI), and second as a means to detect calcium changes in genetically selected neurons for a readout of neuronal action potential firing. The system will be developed for multiple species to enable a flexible neural recording method able to reach deep into the brain, covering large areas with high temporal resolution.
MOTES: Micro-scale Opto-electronically Transduced Electrode Sites Goldberg, Jesse Heymann Mceuen, Paul Molnar, Alyosha Christopher (contact) Cornell University 2016 Complete
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Molnar and her colleagues propose to develop a free floating, wireless microchip system for electrical recording of neural activity. The new system, called Microscale Optoelectronically Transduced Electrodes (MOTEs), will be powered by optically stimulated micro-photovoltaic cells and will use the resulting 1-2μW of electrical power to measure, amplify, and encode electrophysiological signals, up-linking the information optically through an onboard LED. Compared to standard microelectrode arrays, these free floating electrodes promise to be less damaging to neural tissue, and have potential for broader coverage of brain areas. This technology will enable many new neurobiology experiments, and provide a new, minimally invasive platform for measuring electrical signals deep in live brain tissue.
Motion Sequencing for All: pipelining, distribution and training to enable broad adoption of a next-generation platform for behavioral and neurobehavioral analysis Datta, Sandeep R Harvard Medical School 2019 Active
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Despite the ability of scientists to record from and modulate the activity of individual neurons and neuronal circuits, it has been difficult to translate those observations into a readout of behavior. Dr. Datta and colleagues have developed a technology called Motion Sequencing (MoSeq) that captures, in three dimensions, the behavior of a freely moving mouse and then, using machine learning, turns that data into standard “syllables” of behavior. While MoSeq could have broad applications for several research projects, the complex math makes it difficult for non-expert users to implement. This project will adapt the MoSeq system to make it more accessible for researchers and will provide a training course on how to set up and use MoSeq. This will enable a wider range of research projects to use the technology, which could improve our ability to study the effects of drugs or genetic and neuronal changes on behavior.

MRI Corticography (MRCoG): Micro-scale Human Cortical Imaging Feinberg, David Alan (contact) Liu, Chunlei Mukherjee, Pratik Setsompop, Kawin University Of California Berkeley 2014 Complete
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To image the activity and connections of the brain's cortex on a micro scale – with dramatically higher resolution than existing scanners – Dr. Feinberg's group will employ high sensitivity MRI coils that focus exclusively on the brain's surface.
MRI CORTICOGRAPHY: DEVELOPING NEXT GENERATION MICROSCALE HUMAN CORTEX MRI SCANNER Feinberg, David Alan (contact) Liu, Chunlei Mukherjee, Pratik Setsompop, Kawin Wald, Lawrence L University Of California Berkeley 2017 Active
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The macroscopic scale of current magnetic resonance imaging (MRI) scanners makes it challenging to link neural circuitry to human cognition and behavior. David Feinberg and his team are developing MR Corticography (MRCoG), a new tool for studying neuronal circuitry that improves resolution by an order of magnitude, making it possible to visualize cortical layers and microcircuit columns throughout the whole brain. By expanding on scanner hardware and image acquisition software that Feinberg has previously developed, the team intends to improve image sensitivity while reducing sources of signal distortion. With these tools, they plan to explore the clinical potential of MRCoG in patients with epilepsy and autism spectrum disorder. MRCoG has the potential to be a major advance in human neuroscience, providing researchers with a tool to connect cortical visualization to clinical and cognitive neuroscience.
Multi-area two-photon microscopy for revealing long-distance communication between multiple local brain circuits Helmchen, Fritjof University Of Zurich 2014 Complete
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Dr. Helmchen and his colleagues propose a system to simultaneously record neuronal activity in four different areas of the neocortex and discover how brain cells in different regions interact during specific behaviors.
Multi-channel MR-compatible flexible microelectrode for recording and stimulation Franklin, Robert Kyle Shih, Yen-yu Ian (contact) Blackrock Microsystems 2016 Active
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Given the increasing use of magnetic resonance imaging (MRI) in brain research, understanding of what MRI signals really represent has become a fundamental yet fully elusive research topic. Recent neuroscience/neuroimaging research has also emphasized the importance of using multi-modal approaches, in which the data are acquired by multiple techniques to combine higher temporal resolution with spatial resolution of brain activity.  Drs. Shih and Franklin aim to bridge two of the most powerful and widely used research/clinical tools used in neuroscience – MRI and electrophysiology – by creating a novel MR-compatible 16-channel microelectrode array. This microelectrode array addresses two major applications: high resolution electrophysiology and deep brain stimulation. Both of which, in combination with simultaneous MRI, comprise a highly innovative platform which is intended to improve our understanding of brain function and neural circuit connectivity.

Multi-channel MR-compatible flexible microelectrode for recording and stimulation Shih, Yen-Yu BLACKROCK MICROSYSTEMS 2018 Active
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Given the increasing use of magnetic resonance imaging (MRI) in brain research, understanding of what MRI signals really represent has become a fundamental yet fully elusive research topic. Recent neuroscience/neuroimaging research has also emphasized the importance of using multi-modal approaches, in which the data are acquired by multiple techniques to combine higher temporal resolution with spatial resolution of brain activity.  Drs. Shih and Franklin aim to bridge two of the most powerful and widely used research/clinical tools used in neuroscience – MRI and electrophysiology – by creating a novel MR-compatible 16-channel microelectrode array. This microelectrode array addresses two major applications: high resolution electrophysiology and deep brain stimulation. Both of which, in combination with simultaneous MRI, comprise a highly innovative platform which is intended to improve our understanding of brain function and neural circuit connectivity.

Multi-context software for robust and reproducible neuroscience image analysis Papademetris, Xenophon (contact) Scheinost, Dustin Yale University 2017 Active
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A thorough understanding of brain function requires the integration of neuroscience data across species and scales. While current software can verify data quality within one or a handful of data sources, reproducibility across multiple data sources is limited. Xenophon Papademetris and colleagues are developing software tools with cross-scale, cross-species reproducibility analysis in mind. By leveraging data created by two other BRAIN Initiative projects at Yale University, Papademetris will extend current software algorithms to incorporate data from multiple sources, design the software to be cross-platform compatible, validate the software through rigorous testing, and finally, distribute it to the community. The potential for a set of software tools to reliably and reproducibly analyze multiple heterogeneous neuroscience data types will help to break down data barriers for the greater neuroscience community.

Multielectrode Arrays for Neurotransmitter Detection with Fast Scan Cyclic Voltammetry Zestos, Alexandros George Microprobes For Life Science, Inc. 2019 Active
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To monitor brain states under various conditions, multielectrode arrays can sense neurotransmitters across distributed parts of the brain. However, the brain's complexity and heterogeneity - coupled with technological limitations of these arrays - have created challenges for this approach. Working with Microprobes for Life Science, Dr. Alexander Zestos and a team of investigators will develop and commercialize multielectrode arrays for neurotransmitter detection with fast scan cyclic voltammetry. Multielectrode arrays will be either constructed with carbon fibers or carbon-modified metal microelectrodes and coupled with multichannel hardware to measure neurotransmitter changes in multiple brain regions simultaneously. The success of this project will meet a crucial and currently unmet need in the greater neuroscience community by providing multielectrode arrays with neurotransmitter sensing capabilities.

Multiparametric Biosensor Imaging in Brain Slices Blanpied, Thomas A Meredith, Andrea L Rizzo, Mark A (contact) University Of Maryland Baltimore 2016 Active
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The coordinated observation of spatial and temporal interactions of multiple signaling pathways within individual cells and across intact circuits is limited by an inability to simultaneously track dynamic molecular activity. Rizzo and colleagues will validate and further develop a new methodology, Fluorescent Anisotropy Reporters (FLAREs), for simultaneous optical imaging of multiple biosensors within single neurons of mouse brain slices during neural coding. The group will improve the optical sectioning microscopy methodology and increase the range of signaling molecules measurable with FLAREs. This technique may enhance subcellular spatial resolution and cellular temporal resolution of signaling pathways, and could scale to visualize coordinated cellular activities and neural coding in intact brain circuits.
Multiplex in vivo imaging of cell-specific and circuit-specific signaling pathways during synaptic plasticity Huganir, Richard L (contact) Zhang, Jin Johns Hopkins University 2016 Active
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Kinase signaling pathways that regulate synaptic plasticity help integrate multiple types of synaptic inputs to control neuronal circuit adaptation during behavior. However, monitoring more than one of these pathways simultaneously in awake behaving animals remains a challenge. Huganir and Zhang plan to develop and validate new genetically encoded fluorescent biosensors and use two-photon microscopy to image activity of multiple kinase signaling pathways in awake, behaving mice. This tool will improve rapid (seconds to minutes) detection of dynamic signaling pathways during physiologically relevant sensory experiences and learning tasks, greatly improving our ability to visualize cell-specific and circuit-specific signaling pathways.
Multiplexed Multiphoton Interrogation of Brain Connectomics Han, Xue Ramachandran, Siddharth (contact) Boston University (charles River Campus) 2015 Complete
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Optical imaging of living mammalian brains has been limited by tissue scattering. Imaging deep neuronal targets, such as mouse hippocampus, in a non-invasive fashion requires deep-tissue light penetration. New methods such as 3-photon imaging promise to achieve such depths, but they are only beginning to be explored. To date, 3-photon microscopy has only been tested with single input wavelengths, even though theoretical predictions suggest that using inputs with different wavelengths could achieve greater depth of penetration. Ramachandran and Han propose using a novel tunable laser to explore input wavelength combinations to optimize penetration depth.
MULTISCALE ANALYSIS OF SENSORY-MOTOR CORTICAL GATING IN BEHAVING MICE Jaeger, Dieter (contact) Stanley, Garrett B. Emory University 2015 Complete
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The neural circuitry underlying how animals make motor decisions, especially in response to sensory or environmental cues, is not well understood. Many motor disorders, including Parkinson’s and Huntington’s disease, are linked to faulty circuits in a region of the brain called the basal ganglia. Researchers will use a variety of advanced methods to image, record, and manipulate the activity of neurons in this area as well as in the areas of the brain involved in sensory perception and movement. By employing these methods at multiple scales – from the individual neuron to neuronal networks – and then correlating these data with the behavior of awake, behaving mice, researchers hope to reveal how sensory information is integrated with input from the basal ganglia to result in the decision to initiate or suppress movement.
Multiscale Imaging of Spontaneous Activity in Cortex: Mechanisms, Development and Function Constable, R. Todd Crair, Michael (contact) Yale University 2015 Complete
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Being able to observe the activity of a single neuron while simultaneously observing the activity of entire brain regions is a critical step in bridging the gap in understanding of how a collection of nerve cells ultimately generates an organized behavior. Dr. Crair and colleagues will develop and use two different imaging techniques to measure the activity of individual neurons, regions of the brain, and the whole brain, during different behavior states, such as REM and non-REM sleep, in developing mice. Bridging their analyses and insights between and within scales will allow these researchers to examine neural circuits and networks in different brain states and determine how they are modulated through development.
Nano-switches for optogenetic control of neuronal proteins with ultra-specificity Wang, Lei University Of California, San Francisco 2017 Active
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Optogenetics is a powerful tool for controlling the activity of neurons with light, but it currently cannot be readily applied on any protein of choice, and lacks specificity. Wang and his team propose a nano-switch technology, in which unnatural amino acids (UAA) will be incorporated into neuronal proteins at single sites, achieving reversible optical control of the protein. Compared with existing methods using large, light-sensitive proteins, this method uses only a single UAA for light sensitivity, and can photo-modulate a protein without knowing its function in advance. This project’s success in model organisms will introduce vast opportunities for investigating previously-inaccessible neuronal processes at the molecular level.
Near Infrared Genetically Encoded Voltage Indicators (NIR-GEVIs) for All-Optical Electrophysiology (AOE) Antic, Srdjan D Knopfel, Thomas (contact) Verkhusha, Vladislav U Of L Imperial Col Of Sci/technlgy/med 2016 Active
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Genetically-coded voltage indicators are a promising tool for imaging electrical activity of specifically targeted neurons. Dr. Knopfel and colleagues propose to develop voltage sensors that excite and emit fluorescence in the near-infrared part of the spectrum, which is less susceptible to scattering than visible light, and thus can be imaged far deeper in the brain. To do this they will use near-infrared phytochrome-based fluorescent proteins developed in Dr. Verkhusha’s lab, and they will test them in neurons expressing genetically coded opsins. This will ultimately enable fully optical approaches to measuring and manipulating neural activity at cellular and subcellular scales, including in awake, behaving animals.
Network basis of action selection Komiyama, Takaki Kreitzer, Anatol (contact) Lim, Byungkook J. David Gladstone Institutes 2015 Complete
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Three separate research groups are collaborating to understand in detail how three distinct areas of the brain function and work together to enable learning and decision-making behaviors. Drs. Kreitzer, Komiyama, and Lim are leveraging an impressive set of technologies to monitor and perturb different cell types in each brain region while the mice perform learning and decision-making tasks. By applying multiple recording methods across these brain regions at both the level of a single neuron and entire subpopulations of neurons, while the animals perform the same set of tasks, researchers hope to develop a single model of how vertebrate animals make choices about what to do next.

Network Control and Functional Context: Mechanisms for TMS Response Bassett, Danielle Smith Oathes, Desmond (contact) Satterthwaite, Theodore Daniel University Of Pennsylvania 2018 Active
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Transcranial magnetic stimulation (TMS) is a powerful tool for non-invasively modulating brain circuits. However, the field lacks a theoretical framework to predict the effects of TMS on brain and behavior. In healthy young adults, Oathes and colleagues will test the hypothesis that brain responses to TMS are governed both by the network properties of the area stimulated and by the cognitive context, as measured by patterns of functional activation during stimulation using fMRI. The group will further test their theory during a working memory test, comparing TMS impact on performance in both healthy adults and patients with ADHD. Elucidating the mechanisms of TMS response will enhance understanding of how functional brain circuits contribute to specific cognitive functions and has the potential to accelerate personalized neuromodulatory treatments for executive dysfunction.

Neural activity integration during user defined epochs with modular reporters Laughlin, Scott T. State University New York Stony Brook 2016 Complete
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Using optical recordings of neural activity from whole brains to reconstruct neural circuits is challenging when working with large brains or when studying behaviors that are not compatible with concurrent imaging. Laughlin and his team propose a method for making permanent recordings of neural activity that could be “read out” at a later time. The idea is that when a neuron fires during a specified time window, an enzyme genetically expressed by that neuron would interact with a genetically expressed substrate to produce a permanent record of the neuron’s activation. This innovative method will improve understanding of neural circuits.
Neural circuits in zebrafish: form, function and plasticity Cepko, Constance L Engert, Florian (contact) Lichtman, Jeff W Sompolinsky, Haim Harvard University 2014 Complete
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Dr. Engert's team will combine a wide array of cutting-edge neuroscience techniques to watch the entire brain activity of a see-through fish while it swims, and to make detailed maps of its brain circuitry.
Neural ensembles underlying natural tracking behavior Fiete, Ila R. Huk, Alexander C Priebe, Nicholas J. (contact) University Of Texas, Austin 2015 Complete
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Animals move their eyes to track the movement of objects around them. These researchers will measure and manipulate the activity of populations of identified neurons in marmosets during pursuit eye movements. This work will allow a detailed understanding of how the pursuit circuit integrates information from a large number regions is a critical step in bridging the gap in understanding of how a collection of nerve cells ultimately generates an organized behavior. Dr. Crair and colleagues will develop and use two different imaging techniques to measure the activity of individual neurons, regions of the brain, and the whole brain, during different behavior states, such as REM and non-REM sleep, in developing mice. Bridging their analyses and insights between and within scales will allow these researchers to examine neural circuits and networks in different brain states and determine how they are modulated through development.
Neural Implant Insertion System using Ultrasonic Vibration to Reduce Tissue Dimpling and Improve Insertion Precision of Floating Arrays in the Neocortex Mulvihill, Maureen L. Actuated Medical, Inc. 2018 Active
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Penetrating electrode arrays have an expanding application in neuroscience research as they can provide direct access to neural signals across the central and peripheral nervous system with high spatial resolution. Chronic electrode implants could revolutionize treatment for a range of medical conditions, including prosthetic motor control and proprioception for amputees, and brain-machine interfacing for paraplegics. Unfortunately, device implantation applies forces to the neural tissue resulting in significant brain compression (dimpling) at the implant site, which increases risk of implantation trauma, bleeding and inflammation. Actuated Medical, Inc. will develop a neural implant inserter, the Ultrasonic Precision Insertion of Neural Devices (UPIND) system, that will reduce the insertion force by applying ultrasonic energy to electrode arrays during insertion. This system aims to enable greater placement control of floating microware arrays, while reducing tissue trauma.

Neural Monitoring with Magnetically-Focused Electrical Impedance Tomography (mf-EIT) Freeman, Daniel Kenneth Charles Stark Draper Laboratory 2015 Complete
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Electrical impedance tomography (EIT) detects impedance changes associated with neural activity by injecting small currents through scalp electrodes. However, this technique, which has the advantage of being non-invasive, has poor spatial resolution. Freeman proposes to address the problem of spatial resolution by using magnetic field-based current steering—a method commonly used in particle accelerators—to precisely target the current through the brain. If successful, the approach could enable a non-invasive method for imaging brain activity with greater spatial and temporal resolution than current technologies.
Neural signatures of learning complex environments in the amygdala-prefrontal network Barack, David Columbia University Health Sciences 2019 Active
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The ability to learn, think, and make decisions in complex environments is extremely important to critical life functions across species, but the neural correlates of external and internal representative states are largely unstudied. Recent studies suggest activity in the amygdala and orbitofrontal cortex correlate to state representation, but their exact roles are unknown. Dr. Barack aims to investigate how monkeys learn these state representations, using a complex, sequential decision-making task. During this novel behavioral task, similar to the boardgame “Battleship,” the team with elucidate learning in a complex environment, measuring associated neural mechanisms of circuits in the amygdala and orbitofrontal cortex activated in learning and decision-making. These results could promote the creation of computational models that may provide insights about animal and human interactions with the world.

Neuro-glio-vascular interactions in vivo probed with optical imaging Du, Congwu Pan, Yingtian (contact) State University New York Stony Brook 2019 Active
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With the goal of understanding the interplay between astrocyte, neuronal activities, and regional neurovascular response, Dr. Pan and his team aim to develop an optical platform to image synchronized activity, via genetically encoded calcium indicators, alongside local cerebral blood flow dynamics. The team plans to develop multimodality fluorescence – swept-source optical Doppler microscopy (fl-ssODM) to image large-scale astrocyte/neuronal calcium fluorescence and cerebral blood flow velocities in the cortex of mice. fl-ssODM will provide real-time spatiotemporal dynamics of astrocyte/neural calcium activity and vascular responses at rest and during activation of the cortex. The researchers will employ inhibition of astrocyte signaling using designer receptor exclusively activated by designer drugs to further validate fl-ssODM as a useful tool to investigate the interactions of astrocytic and neuronal activities and local cerebral blood flow in the brain.

Neuroethics of aDBS Systems Targeting Neuropsychiatric and Movement Disorders Goodman, Wayne K Lazaro-munoz, Gabriel (contact) Mcguire, Amy Lynn Baylor College Of Medicine 2017 Active
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A technological advance beyond traditional, open-loop DBS devices, adaptive deep brain stimulation (aDBS) devices monitor local neural activity to adjust stimulation in real time when treating certain movement and neuropsychiatric disorders. However, because aDBS devices autonomously record neural data and provide neuromodulation to affect motor function and mood, these systems raise important neuroethics issues, including changes in perception of autonomy and personal identity; risk-taking propensity; and privacy, use, and ownership of neural data. In this project, Dr. Lazaro-Munoz and colleagues will gather data from participants in existing aDBS clinical trials, their caregivers, people who declined to receive aDBS, and the aDBS researchers, to identify and assess the most pressing neuroethics issues related to aDBS research and translation. The long-term goal of this research program is to develop an empirically-informed and ethically-justified framework for the responsible development and clinical translation of aDBS systems, which will help maximize the social utility of this type of novel neurotechnology.
NeuroGrid: a scalable system for large-scale recording of action potentials from the brain surface Buzsaki, Gyorgy (contact) Devinsky, Orrin New York University School Of Medicine 2016 Active
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Buzaki and his colleagues propose to optimize a novel scalable electrode array to record the activity of thousands of individual neurons using a “NeuroGrid” of high density microelectrodes resting on the surface of the neocortex. The proposed grid is scalable and flexible, conforming to the brain’s curvature. An important development of this project is that the device will allow recordings from individual neurons using surface electrodes, something currently only possible with brain-penetrating electrodes. Experiments will assess the nature of the neural signals and will establish their cellular origin in animal model systems, as well as in human patients undergoing surgery for epilepsy. If successful, this work will establish a new paradigm for recording neural activity that is more stable and less invasive than penetrating electrodes, and can be scaled across brain areas with high density.
Neuromodulation approaches for restoring dexterous control following cortical stroke. Khanna, Preeya University Of California, San Francisco 2019 Active
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Despite physical therapy, about 50% of stroke survivors must live with impaired hand function, impacting daily activities for the remainder of their life. However, recent studies in rats have suggested that low-frequency cortical stimulation may help alleviate such symptoms. In order to translate this work to humans, Dr. Khanna aims to use a multiscale model of electrophysiological recording to monitor motor and somatosensory activity during dexterous control, comparing affected and unaffected hemispheres in non-human primates (NHP) recovering from a stroke. The results may inform development of therapeutic techniques for stroke-related motor dysfunction, while improving our understanding of neuromodulation.

Neuron selective modulation of brain circuitry in non-human primates Caskey, Charles F (contact) Chen, Li Min Grissom, William A Vanderbilt University 2015 Complete
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A major focus of The BRAIN Initiative is to develop new tools and technologies to study circuitry of the brain. Developing methods to simultaneously modulate and image neural circuits would empower researchers to undertake such science. In this project, Caskey and his team propose to develop a next-generation method to modulate brain activity using ultrasound, while simultaneously imaging brain activity using functional magnetic resonance imaging (fMRI). The integration of highly spatially selective ultrasound neuromodulation with high field MRI has the potential to provide a unique and powerful approach to study the functional architecture of the human brain. The completion of this work will improve our understanding of the neuronal responses to ultrasound neuromodulation, establish the safety of ultrasound neuromodulation, and explore how ultrasound can be used in conjunction with MR imaging to interrogate brain circuits and diagnose brain disorders.
Neuronal and Dopaminergic Contributions to Dissimilar Evoked Hemodynamic Responses in the Striatum Walton, Lindsay Univ Of North Carolina Chapel Hill 2018 Active
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Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) is a non-invasive imaging technique that infers increased brain activity from observed increases in cerebral blood flow. A notable exception to this relationship occurs in the striatum. Walton will investigate the activity of dopamine neurons, medium spiny neurons, and dopamine receptors, under conditions that evoke either blood vessel dilatation or constriction in the striatum. She will utilize optogenetic stimulation, synthetically-derived receptors, and receptor antagonist drugs to reveal the mechanisms underlying striatal positive and negative fMRI responses. These studies are important for the accurate interpretation of BOLD fMRI signals from brain regions with atypical hemodynamic responses.
Neuronal mechanisms of human episodic memory Mamelak, Adam Nathaniel Rutishauser, Ueli (contact) Cedars-sinai Medical Center 2017 Active
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No meaningful therapies for memory disorders exist, partially due to a lack of mechanistic knowledge about human memory. Ueli Rutishauser’s multi-institutional, multi-disciplinary team will study how memories of facts and events are formed and used in the human brain. The team will use electrophysiological methods to record single neurons, simultaneously in multiple brain areas, in awake patients who are implanted with electrodes to localize epileptic seizures. This work will combine single-neuron physiology, behavioral testing, electrical stimulation, and computational modeling, to address three questions: (i) how persistent activity supports memory formation, (ii) what mechanisms translate memories into decisions and judgments, and (iii) how memories are formed and recalled over time. A circuit-level understanding of memory may enable development of new treatments for memory disorders.
Neuronal Substrates of Hemodynamic Signals in the Prefrontal Cortex Howard, Matthew A. O'doherty, John P (contact) Tsao, Doris Ying California Institute Of Technology 2016 Active
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  • Human Neuroscience
Functional MRI (fMRI) is the dominant technique for probing human prefrontal cortex functions such as cognition, learning, and decision-making. Yet, little is known about how fMRI signals relate to the underlying neural signals in prefrontal cortex. O’Doherty and his colleagues will examine this relationship in monkeys by first probing the region with fMRI, then recording electrical signals from individual neurons in those areas that show strong fMRI activation. The team will then follow up with dual recordings (fMRI and intracranial electrical measurements) in human patients undergoing surgical treatment for epilepsy. By combining these different recording techniques in both monkeys and humans, the team hopes to determine which aspects of underlying neural responses give rise to fMRI responses in prefrontal cortex. This work will improve the usefulness of fMRI as a diagnostic measure of disorders related to higher-order cognitive functions.
Neuronal voltage tracers for photoacoustic imaging in the deep brain Sack, Jon Thomas University Of California At Davis 2015 Complete
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Photoacoustic imaging presents a new, non-invasive method to image brain activity at a cellular resolution much deeper than current methods, but it requires the development of biosensors. Sack and his colleagues recently developed a first-generation probe for imaging neural activity, which uses a fragment from a tarantula toxin that has evolved to selectively bind a specific ion channel on the surface of mammalian neurons. They will develop this probe for use in photoacoustic tomography. They will screen, optimize, and validate the probe for imaging in deep brain areas, and potentially expand it to formulate other similar peptides to target additional ion channels.
Neurons, Vessels and Voxels: Multi-modal Imaging of Layer Specific Signals Kara, Prakash Naselaris, Thomas P Olman, Cheryl A. Ugurbil, Kamil (contact) University Of Minnesota 2016 Active
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  • Integrated Approaches
  • Human Neuroscience
Functional MRI (fMRI) infers the location and magnitude of neural activity from vascular signals. However, the technique has not been shown to distinguish neural activity from individual cortical layers, each of which have unique computational functions. To demonstrate ultrahigh-resolution high-field fMRI’s ability to measure layer-specific signals, Ugurbil and his colleagues will perform simultaneous 2-photon microscopy—a technique for imaging neural signals with high spatial resolution—and fMRI experiments in which cats are shown visual stimuli known to elicit responses in specific cortical layers. These experiments will seek to correlate layer-specific fMRI responses with differences in neural activity, which will ultimately enable fMRI to provide more detailed information about human brain function in both health and disease.
NeuroPET HD: A low-cost high performance neuro-PET imaging system Hunter, William Coulis Jason Pet/x, Llc 2017 Active
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Positron Emission Tomography (PET) has the potential to be an important tool in understanding the human brain. However, current PET systems used in oncology are expensive and lack the level of resolution necessary for human neuroimaging studies. Drs. Hunter and Coulis plan to combine a novel detector technology with innovative system architecture for commercial production of a cost-effective PET brain imaging system (Neuro-PET HD). In the Phase I STTR, PET/X LLC will create and validate the performance of a new PET detector ring system before generating a full commercial prototype. The goal is to reduce system cost, while providing a significantly more compact, mobile system that provides rigorously accurate images of brain function.

Neurophysiologically Based Brain State Tracking & Modulation in Focal Epilepsy Worrell, Gregory A Mayo Clinic Rochester 2015 Active
  • Human Neuroscience
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Epilepsy is a common neurological disease, and over one-third of epilepsy patients have seizures that are not controlled by conventional therapy. Surgery can be curative, but only for a subset of patients. Advances in neural engineering have produced devices that are poised to transform management of drug-resistant epilepsy; they will ultimately take the form of wireless devices that integrate the ability to measure brain activity, predict seizure onset, and deliver therapeutic stimulation to limit seizure activity. Worrell and colleagues aim first to undertake a preclinical study in dogs with naturally occurring epilepsy, to test one such device, and if this is successful then conduct a pilot clinical trial in human epilepsy patients
NeuropixelsUltra: Dense arrays for stable, unbiased, and cell type-specific electrical imaging Harris, Timothy D Olsen, Shawn R. Steinmetz, Nicholas (contact) University Of Washington 2019 Active
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Despite recent advances, electrophysiological techniques to measure the activity of dispersed neuron populations remain unable to detect certain cell types or record stably in the presence of brain motion. Drs. Harris, Olsen, Steinmetz and colleagues aim to develop a high-density electrode array that will increase the number of recording sites by 10-fold, using probes that provide imaging of ‘electro-morphological’ shapes. Based on the Neuropixel infrastructure, they will test the systems’ ability to record electrical currents from a variety of mouse neuron cell types and during motion. The new system will be disseminated for beta testing and may help researchers perform high-resolution studies on the activity of brain circuits in freely-moving animals.

Neurostimulation and Recording of Real World Spatial Navigation in Humans Suthana, Nanthia A University Of California Los Angeles 2017 Active
  • Human Neuroscience
  • Integrated Approaches
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Spatial memory is thought to involve neurons in the medial temporal lobe that exhibit increased firing rates when an animal is in a specific location during spatial navigation. However, human single-neuron studies have been limited to immobile subjects viewing 2-dimensional navigational tasks. Nanthia Suthana’s team will use intracranial single-neuron and local field potential recordings, combined with deep brain stimulation (DBS), in epilepsy patients performing freely-moving spatial navigation memory tasks using state-of-the-art virtual reality headset technology and full-body motion capture. The team will record from medial temporal lobe subregions, to determine the role of single neurons and oscillations during navigation and memory, and how these neurophysiological mechanisms can be enhanced by deep brain stimulation. This work may yield insights into the neuronal correlates of real-world spatial navigation and memory.
Neurotransmitter Absolute Concentration Determination with Diamond Electrode Lee, Kendall H. (contact) Manciu, Felicia S. Tomshine, Johnathan R Mayo Clinic Rochester 2014 Complete
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Dr. Kendall and his colleagues will develop diamond-coated electrodes to measure concentrations of the brain chemical dopamine more accurately and over long periods of time in the brain.
New approaches for better protein voltage sensors Cohen, Lawrence B Yale University 2016 Active
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Genetically coded voltage sensors represent a promising and potentially powerful avenue for recording neural activity in precisely defined neural circuits. Their fluorescence intensity responds to changes in membrane potential and action potential firing—the language the brain uses to transmit information quickly. Currently available sensors are not yet optimal for recording neural activity broadly in vivo. Cohen and his colleagues plan to develop brighter, faster, red-shifted (for deeper imaging), and more sensitive sensors for large-scale recordings of neuronal activity. The team intends to optimize their probes for detection of either spikes or subthreshold potentials, and to target them to specific subcellular domains, such as cell bodies or nerve terminals. These new sensors will enable more precise and sophisticated hypotheses to be tested for understanding the complex circuitry of the brain, in health and in animal models of brain disorders.
New approaches for single cell tagging, editing and profiling of glial cells in vivo Hong, Weizhe University Of California Los Angeles 2019 Active
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Despite their vital roles in the brain, glial cells have been understudied in the past due to a lack of tools to precisely target and manipulate these cells. Drs. Hong and Chen plan to combine a new single-cell RNA sequencing tool, Act-seq with novel AAV-based CRISPR techniques to build a toolbox for profiling and manipulating specific mouse glial populations in vivo. Act-seq will permit transcriptional profiling of diverse glial cells, as well tracking of changes following perturbation. AAV-based CRISPR will enable tagging, labeling, and functional manipulations. By combining their expertise, the groups hope to open new avenues to study glial cell composition, function and interaction with neurons for better understanding of myriad neural circuits and complex behaviors.

New Proteomic and Genome Engineering Approaches to Decipher Astrocyte Function at Synapses SODERLING, SCOTT DUKE UNIVERSITY 2018 Active
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Star-shaped astrocytes are the most abundant non-neuronal cells of the brain. Their thin processes envelop neuronal synapses and critically shape their formation and function. In this project, BRAIN Initiative-funded researchers, Drs. Eroglu and Soderling, will develop and use a novel chemicogenetic approach called iBioID enabling the capture of astrocyte processes and the identification of the key proteins that form the interface between neurons and astrocytes. The team will use this technique in combination with gene editing to study how these proteins regulate the growth and maintenance of synapses in the healthy brain and explore what role they may play in neurological disorders.

New tools to target, identify and characterize astrocytes in the adult nervous system Gradinaru, Viviana Khakh, Baljit (contact) University Of California Los Angeles 2018 Active
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Nearly 40 percent of the central nervous system is made up of astrocytes, star-shaped cells thought to provide synaptic support and facilitate neuronal signaling. For this project Drs. Khakh and Gradinaru plan to accelerate the development of tools for studying astrocytes. These tools include advanced methods for studying RNA and proteins, ATP biosensors for monitoring astrocyte communication, and viruses for delivering genes to astrocytes in different parts of the brain. A complement of such tools could help advance our understanding of the role of astrocytes in the healthy and diseased brain.
Next generation all-optical toolkits for functional analysis of neuropeptide dynamics in neural circuits Banghart, Matthew Ryan (contact) Sabatini, Bernardo L Tian, Lin University Of California, San Diego 2019 Active
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Neuropeptides are effective modulators of brain circuit activity, but measuring the timing and impact of these effects is difficult. Researchers in the Banghart, Sabatini, and Tian labs aim to develop a toolkit that will help neuroscientists study neuropeptides in real time. This kit will include photoactivatable agents to deliver neuropeptides to particular mammalian brain circuits and genetically-encoded sensors that will indicate the best timing for detecting neuropeptides. With these tools, neuroscientists may be able to manipulate neuropeptide effects and gain fundamental insights into how they modulate healthy and diseased brain circuits.

Next Generation Cell-Type-Specific Viral Vectors for Non-Neuronal Brain Cell Types Greenberg, Michael E Harvard Medical School 2019 Active
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Our ability to genetically target diverse non-neuronal cell types in research and therapeutics has remained quite limited due to a lack of specific genetic tools. Dr. Greenberg and his team aim to advance the development of cell type-specific adeno-associated viral (AAV) drivers for non-neuronal cell populations and their distinct subtypes in mice. This group will use single-cell profiling, high-throughput screening, and validation with in vivo characterization to develop AAVs that expand genetic access to astrocytes, oligodendrocytes, microglia, and endothelial cells. The AAV drivers should retain utility across species for future experimental studies.

Next generation high-throughput random access imaging, in vivo Nedivi, Elly (contact) So, Peter T. Massachusetts Institute Of Technology 2014 Complete
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Dr. Nedivi's team proposes a new imaging technology to simultaneously record activity at each of the thousands of synapses, or communication points, on a single neuron.
Next-gen Opto-GPCRs: spatiotemporal simulation of neuromodulator signaling Bruchas, Michael R (contact) Sunahara, Roger K Washington University 2016 Active
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Current tools for controlling neural activity in awake behaving animals, like optogenetics and designer receptors, are still limited in spatial and temporal control of diverse, discrete cell types. Bruchas, Sunahara, and their team will address these limitations by developing and validating a broader array of optically controlled G-protein coupled receptors with enhanced signaling dynamics and greater sensitivity and efficacy across myriad pathways. These Opto-XRs can be used in both neurons and glia, expanding the scope of experimentation in mapping brain circuitry in freely behaving animals, allowing discrete control and optodynamic stimulation of neuromodulatory signaling in brain tissues.
Next-generation high-resolution diffusion MRI resolving cortical columns and layers in vivo Song, Allen W (contact) Truong, Trong-kha Duke University 2019 Active
  • Human Neuroscience
  • Integrated Approaches
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Development of next generation non-invasive imaging techniques could help clinicians identify neuronal markers of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Drs. Song, Truong, and colleagues will develop ultrahigh resolution (sub-millimeter) diffusion MRI acquisition methodologies to map white and gray matter neuronal cortical tracts, columns, and layers in the human brain. They will create a new 48-channel iPRES (integrated parallel reception, excitation, and shimming) AIRcoil array (a new generation of radiofrequency coils based on GE Healthcare’s AIR TechnologyTM), integrated with 3 Tesla magnetic field strength, to allow for deep brain penetration with high spatial fidelity. This novel technology will be able to detect subtle, microstructural changes in very early stage neurodegenerative diseases, when interventions can be most effective.

Next-generation optical brain functional imaging platform Fang, Qianqian Northeastern University 2018 Active
  • Human Neuroscience
  • Integrated Approaches
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  • Monitor Neural Activity

Non-invasive imaging techniques are restricted by their lack of portability, which leads to limited, lab-based experiments. Advancing neuroscience research requires improvements in emerging optical methods, such as functional near-infrared spectroscopy (fNIRS), to continually assess brain dynamics in natural environments. Dr. Qianqian Fang and a team of investigators will design wearable optical imaging headgear and develop an imaging analysis pipeline that improves image resolution and contrast. Through validation of their platform in a small-scale clinical study, the group will create an advanced optical brain imaging platform that is wireless and compact. This proposed work has the potential to reduce cost and weight of optical imaging systems, while providing improved image resolution and accuracy, paving the way for optical methods as an important monitoring tool.

Non-degenerate multiphoton microscopy for deep brain imaging Devor, Anna (contact) Fainman, Yeshaiahu L University Of California, San Diego 2015 Complete
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Infra-red wavelengths, which have low attenuation in brain tissue, enhance the imaging depth of multi-photon imaging, though current use requires powerful lasers that could damage tissue. Devor and Fainman plan to use light of different wavelengths for multi-photon excitation at lower laser power, which will allow much deeper imaging than currently possible. This will be combined with an adaptive optics strategy for added gains in depth and focus, which could enable a 2-3 fold improvement in depths of imaging using two-photon microscopy.
Non-Invasive Nanoparticle Platform for Tool Delivery to the Brain Hochgeschwender, Ute H Rossignol, Julien (contact) Sharma, Ajit Central Michigan University 2019 Active
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  • Monitor Neural Activity

Many molecular tools have been created in the past few years for recording and regulating neuronal activity, but non-invasive delivery of such tools remains a challenge. Drs. Rossignol, Hochgeschwender, and Sharma will use their expertise in nanoparticle research to develop tools to noninvasively transport DNA materials into the brain. The team hopes to improve DNA packaging capacity and optimized surface features for crossing the blood-brain-barrier, enhancing efficient cellular uptake and intracellular release of cargo. The researchers will test their new nanoparticles in vitro before validating in vivo, testing delivery and expression in mice brains.  The successful development of non-invasive nanoparticles should reduce current delivery barriers of new tools for imaging and manipulation of neural activity, helping to rapidly propel the field of tool development and therapeutic discovery.

Non-invasive targeted neuromodulation via focused ultrasound BBB permeabilization Livingstone, Margaret S (contact) Mcdannold, Nathan J Harvard Medical School 2018 Active
  • Human Neuroscience
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  • Monitor Neural Activity

Recent studies have shown that combining ultrasound with a microbubble contrast agent can temporarily break apart the protective blood-brain barrier (BBB), providing brief, direct access to brain tissue. Dr. Livingstone and her colleagues will use this technique to deliver GABA, a molecule that inhibits brain cells and normally does not cross the BBB, into the macaque brain before examining resulting changes in neuronal activity using fMRI. To determine clinical potential of the ultrasound method, Dr. Livingstone’s team proposes to use the ultrasound technology in a primate model of Parkinson’s disease to test whether GABA lessens tremors and akinesia in the animals. Using ultrasound for targeted drug delivery may benefit individuals suffering from a wide range of brain disorders.

Noninvasive Biomarkers to Advance Emerging DBS Electrode Technologies in Parkinson's Disease Walker, Harrison Carroll University Of Alabama At Birmingham 2016 Active
  • Human Neuroscience
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Deep brain stimulation (DBS) is an important clinical option for patients with Parkinson’s disease (PD), but the optimum stimulation parameters differ from patient to patient. As a result, patient outcomes vary between individuals and across clinical trials. In this project, Walker et al. will utilize non-invasive electroencephalography (EEG) measurements of how the brain responds to DBS, to guide the activation and adjustment of next-generation DBS devices and electrodes. The researchers will test whether this personally optimized DBS is superior to conventional DBS, in terms of effectiveness and reduced side effects for patients.
Noninvasive Gene Delivery for Monitoring and Perturbing Cell Types and Circuits in Transgenic and Non-Transgenic Animals Gradinaru, Viviana California Institute Of Technology 2018 Active
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  • Monitor Neural Activity

When used in conjunction with transgenic animals to restrict expression to cell populations of interest, adeno-associated viruses (AAVs) can provide well-tolerated, targeted transgene expression enabling long-term behavioral, in vivo imaging, and physiological experiments. From previous BRAIN Initiative funding, Gradinaru’s team developed a method that allows systemic delivery of viral vectors capable of crossing the blood brain barrier, circumventing the need for transgenic animals. Here the team proposes to improve on this methodology by enabling select AAV variants to anterogradely cross synapses. This will be achieved through targeted evolution of AAVs. This ability to cross synapses with cell-specificity will also provide neural connectivity information. One could envision eventually being able to deliver therapeutics systemically that target disrupted circuitry with cell-specificity.

Noninvasive neuromodulation via focused ultrasonic drug uncaging Airan, Raag D Stanford University 2017 Active
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  • Human Neuroscience
Every millimeter of the brain is unique, yet the current standard of care for many psychiatric disorders is nonspecific (whole-body) delivery of a small-molecule drug. Airan’s team proposes spatiotemporally-precise drug delivery, by combining nanoparticle-based delivery and MRI-guided focused ultrasound. In eventual clinical usage, intravenously-infused, drug-loaded nanoparticles will permeate the blood in inactive form, and ultrasound—applied only to the brain area where drug activity is desired—will induce localized drug release. To facilitate clinical translation, Airan’s group will standardize clinically-compatible nanoparticle production, use ultrasound and EEG in rats to evaluate the dose-response and temporal kinetics of neuromodulation via localized release of the small-molecule anesthetic propofol, and use ultrasound and PET to visualize the spatial precision of neuromodulation by released propofol.
Northern Lights collaboration for better 2-photon probes Campbell, Robert E. Clack, Nathan G Drobizhev, Mikhail (contact) Hughes, Thomas E Montana State University - Bozeman 2015 Complete
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While 2-photon microscopy techniques have advanced to allow researchers to image neuronal activity at a greater depth in brain tissue, current fluorescent proteins used with indicators of cellular activity were developed under single photon parameters, which are not fully predictive of responses to 2-photon stimulation. Rebane and colleagues plan to develop a high-throughput process to screen novel fluorescent proteins for brightness and resistance to bleaching with 2-photon excitation. If successful, this high-throughput screen will deliver the next generation of brighter and more stable fluorescent proteins for incorporation into biosensors used to measure neuronal activity in deep tissue.
Novel fluorescent sensors for imaging neuromodulation Dan, Yang (contact) Ding, Jun Li, Yulong Lin, Dayu University Of California Berkeley 2019 Active
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Neurolipids, like endocannabinoids, and neuropeptides, such as oxytocin, can alter brain circuit activity and behavior. To study these molecules, researchers in the Dan, Ding, Li, and Lin labs will optimize the ability of fluorescent sensors for detecting neuropeptide and neurolipid activity. The sensors are based on G protein-coupled receptors for a variety of neuropeptides and neurolipids, including endocannabinoids, vasopressin, and oxytocin. The effectiveness of these sensors will be tested on neural circuit activity recorded in both mouse brain slices and   in vivo in the mouse brain. The tools may help neuroscientists explore the roles neuropeptides and neurolipids play in modulating activity in healthy and diseased brain circuits.

Novel Genetic Strategy for Sparse Labeling and Manipulation of Mammalian Neurons Yang, Xiangdong William University Of California Los Angeles 2014 Complete
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Dr. Yang's team will develop a new way to genetically target specific neurons, incorporating streamlined imaging and mapping methods that will enable the detection of sparse populations of cells that often elude existing methods.
Novel Neuromodulation by Transcranial Infrared Brain Stimulation with Imaging Gonzalez-lima, Francisco Liu, Hanli (contact) University Of Texas Arlington 2017 Active
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  • Interventional Tools
  • Human Neuroscience
This project will develop transcranial infrared brain stimulation (TIBS) as a novel, noninvasive tool to modulate human brain function. The basic premise is that infrared light will photo-oxidize cytochrome c oxidase (CCO), the mitochondrial enzyme that catalyzes oxygen metabolism. Liu’s team proposes that delivering TIBS to the prefrontal cortex increases CCO oxidation and promotes cerebral metabolism and oxygenation. In healthy participants, the group will measure TIBS penetration depth, thermal effects, spatial resolution, and mechanism. The group will create spatiotemporal maps/images to show TIBS modulation of large-scale neural circuits during and after stimulation. If successful, a new non-invasive tool will emerge for the neuromodulation of cognitive impairments, including mental disorders, brain injuries and neurodegenerative diseases.
Novel optical probe for dopamine release in neural circuits Feller, Marla (contact) Landry, Markita University Of California Berkeley 2018 Active
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Understanding neuromodulation is key to understanding brain function. In contrast to fast synaptic transmission where one presynaptic neuron directly influences a single postsynaptic partner, neuromodulation involves a small population of neurons releasing neuromodulators that diffuse over neural circuits and affect large populations of neurons. Therefore, developing an imaging technique that directly visualizes neuromodulators is critical for characterizing their spatiotemporal gradients. Feller and Landry team will develop and test a bio-mimetic carbon nanotube whose near-infrared fluorescence increases upon exposure to the neuromodulator dopamine. The testing will involve whole- cell recording and two-photon calcium imaging in isolated mouse retinas. This project could advance our understanding of neuromodulation and its many impacts on normal and pathological circuits.

Novel optrodes for large-scale electrophysiology and site-specific stimulation Assad, John Berdondini, Luca Devittorio, Massimo Sabatini, Bernardo L (contact) Harvard Medical School 2015 Complete
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This international team (with contributors from Harvard University and the Italian Institute of Technology) proposes to develop two complementary technologies for electrical recording and optogenetic activation of neurons. The first technology is a class of high-density recording electrodes with active electronics to allow high-speed simultaneous recording from thousands of neurons in behaving animals. The second technology is a multi-point emitting optical fiber with flexibility in design to enhance spatial selectivity of optical excitation or inhibition in neural tissues using optogenetics. Cost assessments indicate that both tools will be very cheap to fabricate and thus can be made widely accessible to the neuroscience community.
Novel technologies for nontoxic transsynaptic tracing Wickersham, Ian R Massachusetts Institute Of Technology 2014 Complete
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Dr. Wickersham and colleagues will develop nontoxic viral tracers to assist in the study of neural circuitry underlying complex behaviors.
Novel tools for cell-specific imaging of functional connectivity and circuit operations Isacoff, Ehud University Of California Berkeley 2015 Complete
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Fundamental to understanding brain function in health and disease is the ability to relate the firing patterns of specific brain neurons to the synaptic connections they share with other neurons, and determine the strength of those connections. Isacoff and colleagues will develop novel, genetically encoded light-activated indicators in zebrafish, fruit fly, and mouse, which can selectively image neural activity in highly detailed structures of single neurons. Additional light-activated indicators will be targeted to synapses to quantify the release of neurotransmitters simultaneously at hundreds to thousands of synapses associated with a single neuron. This information can be used for tracking the strength of synapses over time in order to explore mechanisms of learning and brain adaptation.
Novel tools for spatiotemporal modulation of astrocytes in neuronal circuits Sur, Mriganka Massachusetts Institute Of Technology 2019 Active
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Dr Sur’s lab plans to develop innovative tools to probe astrocyte gene expression, intracellular signal transduction, and glutamate uptake with enhanced spatiotemporal regulation. The team will use CRISPR/Cas9 to target multiple genes using a single virus Multi-gRNA, Cys4-mediated, Universal Targeting System (MRCUTS) in cultured astrocytes, comparing its efficacy to CRE-LoxP methods. The team will also develop optogenetically activated G-protein receptors to probe astrocyte signal transduction in vitro and in vivo.  In addition, the researchers will develop an in vivo method to optogenetically disrupt astrocytic glutamate uptake using a light-gated ion channel, ChromeQ in mouse brain slices. The tools developed may further our ability to investigate and understand astrocyte-neuron crosstalk with enhanced spatial and temporal precision.

NWB:N: A Data Standard and Software Ecosystem for Neurophysiology Ng, Lydia Lup-ming Ruebel, Oliver (contact) University Of Calif-lawrenc Berkeley Lab 2018 Active
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  • Human Neuroscience
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  • Theory & Data Analysis Tools

Neurophysiology research, which focuses on recording brain cell activity, produces enormous amounts of complex data that are difficult to manage. Drs. Rubel and Ng will build upon the Neurodata Without Borders: Neurophysiology project to create a system that will allow for standardizing, sharing, and reusing neurophysiological data. The team will design an open source software system; develop methods to establish a consistent vocabulary for defining cell types, measurements, and behavioral tasks; and create tools to help the community adopt these new resources and standards. The proposed system will help accelerate neurophysiological discoveries as well as reproducibility studies.

Objective, MRI biomarkers for pre-symptomatic detection of autism spectrum disorder at 6 months old: commercial software development and optimization Bower, Bradley PRIMENEURO, INC. 2018 Active
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Magnetic Resonance Imaging (MRI) technology is being used to identify biomarkers in the central nervous system of children 6 months of age with Autism Spectrum Disorder (ASD). A potential promising group of biomarkers include data derived from both structural and functional MRI data acquired on infants. Dr. Bower’s group seeks to translate existing academic clinical research into a commercial product for potential clinical adoption by developing software that is a single, integrated, easy-to-use solution for MRI data collection, processing, and analysis for objectively evaluating a young child’s risk for ASD.

 

OpenNeuro: An open archive for analysis and sharing of BRAIN Initiative data Poldrack, Russell A Stanford University 2018 Active
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To leverage the public investment in the BRAIN Initiative, the sharing of data produced by its myriad projects is paramount. Dr. Podrack’s project extends the recently released OpenNeuro, which was developed based on the well-established and successful OpenfMRI, for an archive of neuroimaging data. The extended archive encompasses a broader range of neuroimaging data including EEG, MEG, diffusion MRI and others. The archive also implements easy-to-use data submission, semi-automated curation and advanced data processing workflows, which run directly on the cloud platform. The archive allows to share the results alongside the data, federate with other relevant repositories, and accessible to all researchers.

Optical control of synaptic transmission for in vivo analysis of brain circuits and behavior Isacoff, Ehud Kramer, Richard H (contact) University Of California Berkeley 2014 Complete
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Dr. Kramer's team will develop light-triggered chemical compounds that selectively activate or inhibit neurotransmitter receptors on neurons, to precisely control the signals sent between brain cells in behaving animals.
Optical tools for extended neural silencing Kennedy, Matthew J (contact) Tucker, Chandra L University Of Colorado Denver 2015 Complete
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Blocking the activity of specific neural ensembles is a powerful approach for dissecting the circuitry underlying behavior. Brain lesion studies—either surgical or pharmacological—have provided important insights, but are limited in their specificity, reversibility, and temporal-spatial precision. Genetically encoded tools such as halorhodopsin and archearhodopsin hyperpolarize neurons with light and are spatially and temporally precise, but do not work well when extended—minutes to hours—neural silencing is required. Kennedy and Tucker propose a novel optical silencing approach in which a “split” botulinum toxin enzyme is expressed in neurons and then recombines and becomes active in response to the delivery of light, resulting in cleavage of the machinery responsible for neurotransmitter release. This tool could be applied locally with a single pulse of light to produce long-lasting, precisely targeted neural circuit disruption.
Optical Tools to Study Neuropeptide Signaling Tantama, Mathew Purdue University 2015 Complete
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The lack of methods to measure neuropeptide signaling with high spatial and temporal precision represents a gap in the toolset for understanding neural circuit function in vivo. To date, no light-activatable tools have been developed for neuropeptides. Tantama proposes to develop tools for both studying and manipulating dynorphin, an opiate peptide of high functional significance for understanding pain and drug addiction. First a proposed biosensor can be expressed in specific cell populations and targeted to specific domains on the cell surface for spatially precise measurements. Second, Tantama proposes to develop an artificial dynorphin peptide targeted to specific neurons that can be activated with light for functional studies in neural circuits.
Optimal calcium imaging with shaped excitation Paninski, Liam M Peterka, Darcy S (contact) Columbia University Health Sciences 2016 Complete
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Understanding information flow in the brain is dependent on simultaneously recording the activity of large neuronal populations. One problem with large-scale recordings is that the spatial and temporal resolution one can achieve typically decreases as the volume of brain to be scanned increases. Peterka and his colleagues plan to use a mix of novel software and hardware that will find creative ways to cut the amount of time needed to image each section of the brain. If successful, the new technique will enable an order of magnitude improvement in the imaged volume of brain tissue. The resulting combined software and hardware solution will be inexpensive, easy to implement and maintain, and widely applicable in the hundreds of labs currently using multiphoton imaging methods.
Optimization and Delivery of Bioactive Coating for High Yield and Stable Neural Recording Cui, Xinyan Tracy University Of Pittsburgh At Pittsburgh 2019 Active
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The Cui lab has developed a biomimetic coating for multi-electrode arrays. The coating has been shown to reduce chemical degradation caused by the body’s natural defenses in response to implantation, a response that causes problems with long-term electrode implantation in the brain. Working with researchers across the United States, this group will perform preclinical studies in rodents aimed at optimizing protocols for the sterilization, packaging, and delivery of coated electrodes. The results may help further understanding of the brain’s immune response to the coating, and may one day have clinical relevance to the types of electrodes used in the human brain.

Optimization and dissemination of non-linear Acousto-Optic Lens two-photon microscopy for high speed multiscale 3D imaging Cardin, Jessica A Diamond, Jeffrey S Peterka, Darcy S Silver, Robin Angus (contact) University College London 2019 Active
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Two-photon microscropy is a technique that scientists use to watch neuronal circuit activity deep within brain tissue. However, it can only detect slower signals. Non-linear acousto-optic lens 3D microscopy is a new high-resolution imaging technique developed by Dr. Silver and colleagues that allows scientists to watch faster signals as brain circuits communicate in real time. In this project, the team aims to improve upon the older technology by enabling ultrafast line-scanning, and disseminating this technology to other researchers. The results may help neuroscientists make fundamental discoveries about brain circuit function.

Optimization of 3-photon microscopy for Large Scale Recording in Mouse Brain Xu, Chris Cornell University 2014 Complete
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Dr. Xu and his collaborators will build new lasers and lenses to use three-photon microscopy to watch neuronal activity far deeper inside the brain than currently possible.
Optimization of multiphoton microscopy for large scale activity mapping in adult zebrafish Fetcho, Joseph R. Xu, Chris (contact) Cornell University 2017 Active
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Monitoring the structure and function of neurons throughout living brains is vital to understanding normal and abnormal brain function. Xu’s team seeks to optimize multiphoton fluorescence microscopy to enable non-invasive imaging of the structure and function of individual neurons anywhere in the brain of an intact individual vertebrate, from embryo to adulthood. The group will develop new optical techniques to increase the number of neurons that can be imaged with reduced light exposure, facilitating repeated imaging throughout the animal’s life. These innovations will be validated by imaging novel transgenic zebrafish lines. If successful, this project will benefit future efforts to understand how behavior emerges from neuronal interactions across the brain.
Optimizing flexible, active electrode arrays for chronic, large-scale recording and stimulation on the scale of 100,000 electrodes Pesaran, Bijan Rogers, John Shepard, Kenneth L Viventi, Jonathan (contact) Duke University 2016 Active
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  • Interventional Tools
To understand how the brain works in both health and disease, neuroscientists and clinicians require devices that can measure and manipulate brain activity with a high degree of precision. Viventi and his colleagues plan to develop next-generation flexible microelectrode arrays for micron-scale electrocortographic (ECoG) recordings from the surface of the cortex, and penetrating electrodes for recordings below the brain surface. Their strategy is to embed active electronics into an extremely thin silicon substrate, which will enable amplification and multiplexing directly at each electrode. Wireless data connection from the electrodes will allow extremely high number and density, and will allow the arrays to be tether free, for reduced damage to surrounding tissue. The flexibility of the silicon substrate will allow the surface ECoG arrays to conform to the irregular geometry of the brain, yielding higher fidelity signals, and reducing damage to the brain caused by penetrating arrays. Together, these innovations enable high resolution measurements over large areas of the brain while being less invasive, with fundamentally important improvements over current state-of-the-art.
Optogenetic mapping of synaptic activity and control of intracellular signaling Kleinfeld, David Lin, John Yu-luen (contact) University Of California San Diego 2014 Complete
  • Monitor Neural Activity
  • Interventional Tools
Dr. Lin's team will create molecules that, when they are triggered by a pulse of light, allow scientists to test for communication between neurons in specific circuits of the brain.
Optogenetic signaling inhibitors for studying brain plasticity Gan, Wenbiao Yasuda, Ryohei (contact) Max Planck Florida Corporation 2016 Active
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Although the mechanisms underlying synaptic and behavioral plasticity have been widely studied, understanding spatiotemporal aspects of signaling activity via pharmacological or genetic manipulations remains limited. With their group, Yasuda and Gan will develop a new technique based on genetically encoded, cell-specific, light-inducible kinase inhibitors to improve spatiotemporal resolution of signaling required for synaptic plasticity in vivo. With this technique, they will modulate the activity of various kinases to identify the spatial and temporal window of learning-related dendritic spine turnover, including the consequences on behavioral performance post-learning.
PARALLEL ANALYSIS OF TRANSCRIPTION AND PROTEIN-DNA INTERACTIONS IN SINGLE CNS CELLS Dougherty, Joseph D (contact) Mitra, Robi D Washington University 2018 Active
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  • Monitor Neural Activity

The brain consists of hundreds of molecularly, physiologically, and anatomically distinct cell types. Recently-developed methods can measure gene expression in tens of thousands of single cells, to help identify and classify many new types of brain cells. However, existing technologies capture only one aspect of gene regulation – mRNA levels. Dougherty’s team will develop a method to enable the parallel analysis of transcription factor binding and mRNA expression levels in mice to create single-cell Calling Cards, generating novel data and analysis tools. If successful, this project would contribute to neuroscience by providing a broadly useful technology for understanding brain function and development, in health and disease.

Path Toward MRI with Direct Sensitivity to Neuro-Electro-Magnetic Oscillations Song, Allen W Duke University 2014 Complete
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  • Interventional Tools
  • Human Neuroscience
Dr. Song's group will develop a scanner technology sensitive enough to image brain activity in high resolution by directly tuning in the electromagnetic signals broadcast by neurons.
Pediatric Deep Brain Stimulation: Neuroethics and Decision Making Blumenthal-barby, Jennifer Lazaro-munoz, Gabriel (contact) Storch, Eric A. Baylor College Of Medicine 2019 Active
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  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
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  • Theory & Data Analysis Tools

Deep brain stimulation (DBS) is currently used in children with dystonia, epilepsy, and Tourette Syndrome, and this use is expanding to other neuropsychiatric conditions. In doing so, there are several challenging ethical issues, and no consistent guidance on the use of DBS in pediatric populations. To address this challenge, Dr. Gabriel Lazaro-Munoz and team will examine neuroethics issues and decisional and informational needs of families by conducting interviews with pDBS stakeholders (minors, caregivers, and clinicians). These interviews will inform the development of a decision aid for caregivers considering DBS for dystonia, the most common use of pDBS. This project will provide key information about the ethical issues facing families, minors, and clinicians alike when considering pDBS, as well as develop a clinical decision aid for making informed, patient-centered decisions surrounding the clinical use of invasive neuromodulation in minors.

Potentiometric photoacoustic imaging of brain activity enabled by near infrared to visible light converting nanoparticles Prasad, Paras N. (contact) Xia, Jun State University Of New York At Buffalo 2015 Complete
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  • Interventional Tools
Current techniques for recording neural activity at the cellular level use optical probes that can be imaged via fluorescence microscopy. However, a major limitation of these methods is that light in the visible spectrum cannot penetrate very far into the brain. Prasad and Xia propose alternative energy sources to address this challenge. They plan to fabricate "up-converting" nanoparticles that receive infrared light, which can reach deeper into the brain than visible light, an