Funded Awards

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Title Investigator Institute Fiscal Year FOA Number Status Project Number Priority Area Summary
CENTER FOR EPIGENOMICS OF THE MOUSE BRAIN ATLAS (CEMBA) Ecker, Joseph R Salk Institute For Biological Studies 2017 Active
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Dr. Ecker's group will use signatures of epigenetics, the switching on-and-off of genes in response to experience, in mouse frontal cortex to help identify different classes of cells and understand their function.

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
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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
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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
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  • 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
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  • 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 5-dimensional connectomics approach to the neural basis of behavior KATZ, PAUL UNIVERSITY OF MASSACHUSETTS AMHERST 2018 Active
  • Integrated Approaches

The brain is constantly assessing information that guides decision making, which can be a matter of life or death. For example, animals can choose to go to a place filled with food or an area filled with predators. Dr. Katz and his team will examine how neural circuits allow the mollusk Berghia stephaniaedecide where to go, implementing this common decision behavior with fundamental, reductionist neural mechanisms. The group will start by creating a complete map of the Berghia nervous system, which will detail connections between neurons and sensorimotor structures, as well as gene expression in the cells, before exploring the cells and circuits involved in decision making related to navigation. This project will provide a new animal model for studying the nervous system in fundamental simplicity and will offer a broader understanding of the decision-making processes in more complex brain structures.

A Biomimetic Approach Towards a Dexterous Neuroprosthesis BONINGER, MICHAEL UNIVERSITY OF PITTSBURGH AT PITTSBURGH 2018 Active
  • Human Neuroscience
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  • 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 Circuit Program for Understanding the Sensorimotor Basis of Behavior Clandinin, Thomas Robert Dickinson, Michael H (contact) Druckmann, Shaul Mann, Richard S Murray, Richard M Tuthill, John Comber Wilson, Rachel California Institute Of Technology 2017 Active
  • Integrated Approaches
The coordination amongst components of the central nervous system to guide sensorimotor behavior requires an understanding of exactly how these modules interact, from low-level transmissions guiding individual muscles, to high-level communications for complex behavior. Michael Dickinson and a multi-disciplinary team of experts will develop a theory of Drosophila fruit fly behavior that incorporates neural processes and feedback across hierarchical levels, using methods developed from their prior BRAIN effort. Here, the team plans to use synergistic approaches – genetics, electrophysiology, imaging, biomechanics, behavior analysis, and computational methods – to understand feedback and the flow of information within and across different processing stages in the awake, intact fly brain. By investigating these hierarchical levels with parallel approaches, this project has the potential to provide a fundamental synthesis of how the central nervous system generates behavior.
A BRAIN Initiative Resource: The Neuroscience Multi-omic Data Archive White, Owen R University Of Maryland Baltimore 2017 Active
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  • Human Neuroscience
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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 Cellular Resolution Census of the Developing Human Brain Huang, Eric J Kriegstein, Arnold (contact) University Of California, San Francisco 2017 Active
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  • Human Neuroscience
Scientists have yet to achieve high-resolution classification of the billions of neurons and non-neuronal cells in the human brain. To attempt this feat, Arnold Kriegstein and Eric Huang will perform high-throughput, droplet-based single-cell RNA and transposase-accessible chromatin sequencing techniques to collect genetic and epigenetic information from individual cells, which will be sampled from multiple regions of post-mortem human brains that are developmentally between early gestation and adolescence. They will further classify living neurons cultured from select brain regions based on their calcium imaging responses to various chemical stimuli. Finally, they plan to use multiplexed single-molecule fluorescent in situ hybridization (smFISH) to identify the spatial distribution of these various cell types in the brain. After these data are compiled, we will have the most detailed picture to date of genetically and functionally defined cell types in the human brain throughout development.
A Community Resource for Single Cell Data in the Brain Gee, James C Hawrylycz, Michael (contact) Martone, Maryann E Ng, Lydia Lup-ming Philippakis, Anthony Allen Institute 2017 Active
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One major technical challenge for the BRAIN Initiative is the storage and dissemination of large amounts of data collected by different project teams. Hawrylycz and colleagues will support the cell census efforts of the BRAIN Initiative by hosting the BRAIN Cell Data Center (BCDC). Through the BCDC, they will store single-cell data on genetics, histology, electrophysiology, morphology, anatomical location, and synaptic connections from multiple species in a standardized manner. They will also develop and provide training for web-based tools to ease data visualization and analysis efforts. This will facilitate the integration of multiple data streams to better identify and characterize the different cell types in the brain.
A compact, modular two-photon fiber-coupled microscope for in vivo all-optical electrophysiology Gibson, Emily Kilborn, Karl (contact) 3 I 2019 Active
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  • 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 Comprehensive Center for Mouse Brain Cell Atlas Huang, Z Josh Cold Spring Harbor Laboratory 2017 Complete
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Identifying individual cell types in the brain is a monumental task that is complicated by the limitations of current molecular technologies. To measure genetic diversity in the whole mouse brain, Huang and Arlotta will lead a team using next-generation droplet-based single-cell transcriptome sequencing along with other highly sensitive single-cell techniques that allow for high-throughput data collection. They plan to map these data onto the spatial locations of forebrain neurons with the help of high-resolution microscopy and genetically driven cell markers. These efforts will provide the scientific community with unprecedented detail about neurons’ molecular and spatial characteristics that can be used to develop additional tools for cell-specific manipulations.

A comprehensive whole-brain atlas of cell types in the mouse Zeng, Hongkui Allen Institute 2017 Complete
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The large number of cells in the brain and the complexity of their molecular and functional characteristics make it difficult to define individual cell types. Zeng and colleagues plan to complement high throughput droplet-based transcriptome survey with deep sequencing technique and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to comprehensively characterize gene expression information from anatomically mapped cells across the entire mouse brain. Additionally, they will use patch clamp method to measure neuronal function in specific brain regions, and combine electrophysiological with transcriptomic and morphological information to provide integrative profiles of individual cell types. These efforts will refine how we define cell types and will produce a census of individual cells in the mouse brain that can then be targeted for further study.

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
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  • Human Neuroscience
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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
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  • Human Neuroscience
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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
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  • Human Neuroscience
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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
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  • Human Neuroscience
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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 Fully Ultrasonic Approach for Combined Functional Imaging and Neuromodulation in Behaving Animals Caskey, Charles F Oralkan, Omer Pinton, Gianmarco (contact) Univ Of North Carolina Chapel Hill 2019 Active
  • Interventional Tools

Although functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have unique capabilities for imaging the brain, these techniques lack the ability for brain stimulation, lack the temporal resolution compared to ultrasound, and present cost and accessibility challenges. Dr. Pinton and colleagues will create a revolutionary technology that combines ultrafast functional blood flow imaging (i.e., super resolution functional ultrasound imaging) and focused ultrasound neuromodulation in a single integrated platform. Though MR-compatible, this ultrasound system will provide direct real-time blood flow information transcranially in non-human primates, while also having the ability to simultaneously apply neuromodulatory acoustic pulses, without the need for MRI or PET.

A Functional and Selective Toolkit for Choroid Plexus Networks Lehtinen, Maria (contact) Moore, Christopher I Boston Children's Hospital 2019 Active
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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
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  • 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 genetically Encoded Method to Trace Neuronal Circuits in the Zebrafish Brain Lois, Carlos Prober, David Aaron (contact) California Institute Of Technology 2019 Active
  • Integrated Approaches

A goal of the BRAIN Initiative is to help researchers map out complete wiring diagrams of neural circuits. Recently the Prober and Lois group developed an approach called TRACT (Transcellular control of transcription) which allows researchers to map out and genetically manipulate the activity of neural circuits in Drosophila. However, it is difficult to study complex behaviors in these animals. In this project, the Prober and Lois groups plan to tailor the TRACT system for zebrafish, a vertebrates and that is easier for scientists to work with when studying complex behaviors. Their results may help scientists study, in great detail, how neural circuits control behavior under healthy and disease conditions.

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
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  • 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
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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
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  • 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
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  • Human Neuroscience
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  • 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
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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
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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 Molecular and Cellular Atlas of the Marmoset Brain Feng, Guoping Massachusetts Institute Of Technology 2017 Active
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  • Human Neuroscience
Although rodents are a highly accessible model and relatively simple to use for genetic studies, it is unclear whether the cell types found in rodent brains match those of primates. To help fill the evolutionary gap in knowledge between rodents and humans, Feng will lead a team to classify cells across the marmoset brain. They will use high-throughput single-cell RNA sequencing to identify cell types in the prefrontal cortex, striatum, and thalamus and will then spatially map the cell types they find in the brain using multiplexed error-robust in situ hybridization (MERFISH). By combining MERFISH with viral expression of marker proteins in subsets of neurons, the team will also correlate cell morphology with genetic information. Altogether these efforts will produce a census of cell types in the marmoset brain, which will be valuable information for future work into the genetics and circuits of the primate brain.
A multimodal atlas of human brain cell types Lein, Ed Allen Institute 2017 Active
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  • Human Neuroscience
Because of technical limitations, most studies identifying individual cell types in the brain have focused on animal models rather than on human tissue, despite a lack of knowledge about how cell types differ between species. Ed Lein and colleagues will perform broad, high-throughput single-cell RNA sequencing techniques across the whole human brain and spinal cord, along with deep sequencing of single cells in select regions of adult post-mortem brain. They will then determine the spatial distribution of various cell types identified through these sequencing experiments by using multiplexed single-molecule fluorescent in situ hybridization (smFISH). To integrate information about neuronal function into their classifications, the team will make combined electrophysiology, morphology, and transcriptome measurements from single cells in adult human cortex obtained via live surgical resection. These efforts will lead to a much deeper understanding about the differences between cell types in the adult human brain and will facilitate future collaborations between researchers to compare cell types across species.
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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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 Neural Systems Approach to Understanding the Dynamic Computations Underlying our Sense of Direction Taube, Jeffrey Steven (contact) Van Der Meer, Matthijs Dartmouth College 2019 Active
  • Integrated Approaches

How do you find your way around? Navigation relies on a variety of information points such as self-motion and visual landmarks, which help with our sense of direction. Using large-scale recordings, live calcium imaging, and modeling data, Dr. Taube’s group will examine where direction-related information comes from and how the brain puts it all together to determine where an animal is and where it needs to go. This project will improve understanding of how the brain collects information from the eyes, head, and body and combines it with visual landmarks to determine head direction.

A new approach to biological recording of lineage hierarchy in primate brains Brivanlou, Ali H Rockefeller University 2019 Active
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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
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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 for Cell-Type Classification and Connectivity in the Human Brain Sestan, Nenad Yale University 2014 Complete
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Dr. Sestan's group will substantially advance the profiling of cell types – their molecular identities and connections – made possible by a new method of better preserving brain tissue to maintain cell integrity.
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
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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
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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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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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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
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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
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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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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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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
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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 tool-box to control and enhance tDCS spatial precision Bikson, Marom City College Of New York 2016 Active
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The use of transcranial direct current stimulation (tDCS), which delivers low-intensity current to the brain using electrodes placed on the scalp, is being investigated for diverse applications pertaining to neuropsychiatric treatment and rehabilitation. Because electrode placement for tDCS highly influences clinical efficacy and specificity, Dr. Marom Bikson and colleagues have developed high-definition tDCS which offers the potential for more precisely targeted stimulation. In this project, the team will develop open-source software that allows researchers to more easily upload brain scans and design a brain stimulation experiment to target a specific brain region. This new toolbox for the optimization of tDCS spatial precision will enhance the rigor, efficacy, and accessibility of tDCS research aimed at understanding the brain and treating disease.
A unified cognitive network model of language Crone, Nathan E Tandon, Nitin (contact) University Of Texas Hlth Sci Ctr Houston 2016 Active
  • Human Neuroscience
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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 unified framework to study history dependence in the nervous system Santamaria, Fidel University Of Texas San Antonio 2019 Active
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A central property of the nervous system is history dependence: its ability to change reaction rates based on previous activity. Though the phenomenon is prevalent across scales of neuronal organization, sensory modalities, and species, there is no unified theory for history dependence. For this project, Dr. Fidel Santamaria and team will apply mathematical approaches to history dependence, validate the significance of that approach, and establish collaborations to test the hypothesis across species and scales. Overall, this project aims to provide a unified theoretical framework and in doing so, pave the way toward applications to study, analyze, and design experiments of history-dependent neuronal activity across multiple scales, from synaptic plasticity to complex spiking patterns in neural networks.

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
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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
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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.
Accessible technologies for high-throughput, whole-brain reconstructions of molecularly characterized mammalian neurons Miller, Michael I Mueller, Ulrich (contact) Johns Hopkins University 2019 Active
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For a complete understanding of how the brain works, there is a need for a comprehensive parts list (all of the cells in the brain) along with knowledge of how those parts are connected. Current molecular technology has advanced the inventory of cell types in the brain, but detailed information about the circuits they form is limited. Dr. Mueller’s group will develop scalable and affordable cellular imaging and neuro-informatics tools, running preliminary experiments to connect the transcriptome to anatomy, in mice. Tools will be made available to researchers, to help accelerate the creation of detailed maps at cell resolution showing circuitry in whole brains.

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.
AChMRNS: Nanosensors for Chemical Imaging of Acetylcholine Using MRI Clark, Heather NORTHEASTERN UNIVERSITY 2018 Active
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Current measurements of the brain-wide neurotransmitter acetylcholine rely on implanted electrodes or chemical sampling techniques, which offer either spatio-temporal resolution or chemical specificity. Clark and Flask will create novel magnetic resonance compatible nanosensors to measure acetylcholine across the blood brain barrier. These sensors will report acetylcholine levels in rodents by dual contrast magnetic resonance fingerprinting, producing a toolset for selective and quantitative measurement of the neurotransmitter. If successful, this project could open a new era for imaging neurotransmitter dynamics throughout the brain in animals and potentially in humans.

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 MOTEs: Injectable Microscale Optoelectronically Transduced Electrodes Molnar, Alyosha CORNELL UNIVERSITY 2018 Active
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Conventional multi-electrode recordings monitor neural activity with high temporal precision but require chronically invasive wiring. The finer spatial resolution achieved by optical imaging techniques comes at the cost of significantly worse temporal resolution. Molnar, Xu, Goldberg, and McEuen will develop a new class of neuron-sized electrophysiological recording devices by combining modern imaging with implanted optoelectronics. They will develop free-floating, implantable microscale optoelectronically transduced electrodes (MOTEs) that use light to harvest power, synchronize, and uplink measured electrophysiological data. The system should support simultaneous imaging and electrical recording of neural activity from hundreds of sites in behaving rodents, enabling minimally invasive neurobiological experiments currently unattainable.

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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  • Human Neuroscience
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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  • Human Neuroscience
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.

Anatomical characterization of neuronal cell types of the mouse brain Ascoli, Giorgio A Dong, Hong-wei (contact) Lim, Byungkook University Of Southern California 2017 Active
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Better anatomical characterization of neurons is needed if we want to identify and distinguish the different cell types in the brain. Dong and colleagues plan to classify neurons based on their spatial anatomy, connections with other neurons, and morphology using multiple neuronal retro- and anterograde tracing methods that will identify connected neurons. This team will first focus on 300 well-defined regions within the limbic system of the adult mouse, a circuit that is important for homeostasis and behavioral motivation, taking high-resolution images and creating high-throughput, three-dimensional reconstructions of these neurons. These data will provide a more complete anatomical picture of the limbic system, and this method can be applied in the future to study additional circuits throughout the brain.
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.
Automating whole brain connectomics: development, validation, and application of an open toolkit Bock, Davi University Of Vermont & St Agric College 2019 Active
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Advancements in 3D electron microscopy have provided a wealth of neuronal circuit data for the whole fruit fly brain, but current, manual analysis techniques are very slow and tedious. Dr. Bock and his team aim to disseminate their whole-brain EM data via the web-based circuit-mapping and analysis platform CATMAID, as well as develop new automated tools and software to investigate circuit structure. Fruitfly neurobiologists accessing CATMAID will be able to perform morphology-based neuron searches for segmentation-assisted circuit reconstructions, eventually using this software to guide additional infrastructure development. The proposed research should accelerate circuit mapping in the fruit fly brain, extend to other model systems, and allow individual labs to form and manage collaborations on a managed server.

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.

Axonal connectomics: dense mapping of projection patterns between cortical areas Reid, R Clay Allen Institute 2019 Active
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Macroscale connectomics lacks cellular resolution, while microscale connectomics often lacks information about the source of inputs entering, or the targets of axons exiting the studied brain volume. Dr. Reid’s lab aims to tackle this problem through the development of a high-resolution 3D imaging technique to map antibody-stained axons over long distances. Using Dual Inverted Selective Plane Illumination Microscopy (diSPIM), the researchers propose to image and analyze visual cortical areas in macaque brain to create a dense axonal connectomics data set. The approach may allow whole-brain analysis of axonal projections with microscale connectomics, advancing our knowledge of how individual neurons communicate over long distances.

Bayesian estimation of network connectivity and motifs Ringach, Dario L University Of California Los Angeles 2016 Active
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Learning how emergent behavior arises from single neurons is a key challenge in modern neuroscience. Ringach and his colleagues plan to create sophisticated algorithms and methodologies to derive the functional connectivity of neurons based on activity patterns at the single-cell level and then identify collections of neurons, or network motifs, that play important computational roles in network functions. The researchers will then validate their algorithms against a database combining functional calcium imaging data with “ground truth” estimates of direct synaptic connectivity. These tools and validation data will enable the investigation of how network motifs differ in both health and disease states.
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.
Behavioral state modulation of sensorimotor processing in cerebellar microcircuits Heiney, Shane A Baylor College Of Medicine 2017 Active
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Behavioral states affect sensorimotor processing, as sensory signals are converted into motor commands. Because these transformations are often distributed throughout the brain, it is challenging to understand the contributions of individual brain areas. Shane Heiney and colleagues are investigating how locomotion and arousal – two well-characterized behavioral states – subsequently affect cerebellar processing in mice. Using a combination of psychophysics, large-scale multiphoton imaging, and electrophysiology, Heiney plans to develop a quantitative framework for interpreting effects of behavior on cerebellar circuitry, and to study the impact of behavior on skilled movements at multiple stages of sensorimotor processing. These experiments have the potential to illuminate how a neural system and behavioral state are dynamically modulated in time.
Berkeley Course on Mining and Modeling of Neuroscience Data Sommer, Friedrich T University Of California Berkeley 2015 Complete
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In their quest to understand the brain, neuroscientists continue to improve techniques for recording simultaneously from increasingly large numbers of neurons. This generates enormously large data sets. Analysis of these data sets will require new algorithms to understand how coordinated neural activity correlates to cognitive function. The goal of the course proposed by Sommer and colleagues is to identify, teach, and disseminate the best available methods for the analysis of large-scale neuroscience data sets. Their course will build on an existing course, "Mining and modeling of neuroscience data," and addresses a critical need by bringing individuals with quantitative backgrounds into the field of neuroscience.
Beyond Diagnostic Classification of Autism: Neuroanatomical, Functional, and Behavioral Phenotypes Fletcher, Preston Thomas University Of Utah 2016 Active
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A major barrier to creating effective treatments for autism spectrum disorder (ASD), a lifelong neurological disorder characterized by stereotyped behavior and difficulties in social interactions, is the lack of understanding of the underlying brain mechanisms. Fletcher and his team propose to develop novel statistical methods for integrating the analyses of neuroimaging data (functional and structural MRI) with behavioral assessments. The resulting set of open-source tools will help relate brain networks to specific ASD behaviors, as well as those observed in other neuropsychological disorders.
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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  • Monitor Neural Activity

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.

Bidirectional optical-acoustic mesoscopic neural interface for image-guided neuromodulation in behaving animals SHOHAM, SHY et al. NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 Active
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Large-scale neural recording and perturbation technologies can help us understand brain function. At present these technologies are limited to either single-cell or whole-brain level investigations. Shoham, Razansky, and Rinberg will leverage the deep tissue penetrability of ultrasound waves to develop an integrated system combining optoacoustic imaging and ultrasound neuromodulation. With the proposed device placed on the brain surface, researchers will collect optoacoustic tomographic data and perform holographic ultrasonic neural stimulation. This system will permit access to distributed neural activity deep within the rodent brain, including during an olfactory decision-making task. Direct and/or indirect access to neural activity over large volumes at extremely high imaging rates could be achieved, enabling new deep brain experiments that currently are not possible.

 

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
  • Human Neuroscience
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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: Theories, Models and Methods for Analysis of Complex Data from the Brain Chung, Moo K University Of Wisconsin-madison 2016 Complete
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To what extents are structural and functional brain networks the product of heritability? That is the question that Chung and his colleagues will address with their proposal to develop tools to analyze in detail brain imaging scans (MRI, functional MRI, diffusion tensor imaging) they have collected from 200 pairs of monozygotic and same-sex dizygotic twins. The tools will be part of a new open-source suite of algorithms for analyzing their enormous cache of neuroimaging data, which the researchers will use to establish a baseline map for the genetic influences on brain network development in both health and disease.

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
  • Human Neuroscience
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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 a Complete, Predictive, Data-Driven Model of Action Selection During Olfactory Navigation Louis, Matthieu R. P. J. C. G. University Of California Santa Barbara 2019 Active
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We still do not understand fully how animals process sensory inputs from a noisy environment, yet this is a crucial function that the nervous system must perform to make correct behavioral decisions. Dr. Louis and colleagues propose to create a model of how the nervous system converts noisy sensory information into something that can be used to navigate the environment. Specifically, they are studying the behavior of fly larvae and their response to olfactory inputs,  i.e. their attraction to food odors, to study how environmental inputs are processed in the brain. This information will then be tested to uncover how stimuli from a noisy environment is translated into behavioral decisions.

Building analysis tools and a theory framework for inferring principles of neural computation from multi-scale organization in brain recordings Sommer, Friedrich T University Of California Berkeley 2018 Active
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Innovative recording techniques have uncovered interactions between individual neurons and cell populations that comprise complex and poorly- defined neural dynamics underlying computations and brain functions. Dr. Sommer proposes combining new tools to analyze this neuronal activity with a theoretical framework of the associated computations. After decoding behavior in mice from hippocampal recordings during exploration and replay and local field potentials from visual cortex, the group will extract “place components” or the position of the animal from the activity data. Subsequently, the team will establish a theoretical framework that, at the computational level, will describe computations underlying brain function in terms of high-dimensional representations, and at the mechanistic level will describe how the operations and representations are mapped onto biological mechanisms. Future users will be able to use this framework to design computations, explore multiple potential mechanisms, create a simulation of an experiment, and compare simulation data to a real experiment.

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 biosensors for deep-tissue imaging and spectral multiplexing Verkhusha, Vladislav Albert Einstein College Of Medicine, Inc 2017 Active
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Genetically encoded calcium indicators (GECIs) developed from fluorescent proteins (FPs) can be used to image intracellular calcium dynamics and provide a robust readout of neuronal responses to action potentials, and as a result, these proteins have revolutionized the way neural activity is recorded in the brain. Current GECIs are based on green and red fluorescent proteins, but because visible light is subject to strong scattering inside the brain, these proteins are only useful for recording activity close to the brain surface. Near-infrared (NIR) GECIs would provide a major increase in the depth at which these signals can be recorded, because they can be imaged with longer wavelength light, which is much less susceptible to scattering than light at visible wavelengths. Verkhusha’s team developed NIR GECIs that will be imaged with modern adaptive optics imaging techniques, allowing non-invasive, cellular-resolution imaging deep in the cortex and hippocampus. If successful, this research will provide highly sought-after deep-tissue optical probes and help advance researchers’ understanding of information processing in the brain.
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.
Canonical computations for motor learning by the cerebellar cortex micro-circuit Brunel, Nicolas Hull, Court A Lisberger, Stephen G (contact) Medina, Javier F Duke University 2019 Active
  • Integrated Approaches

The cerebellum plays critical roles in learning and performing coordinated, well-timed movements. The majority of research on the cerebellum has focused on Purkinje cells. This project aims to use optogenetics, machine-learning, electrophysiology, imaging, and computer modeling to investigate the entire cerebellar circuit including all relevant cell types to gain a better understanding of how the cerebellum functions to support motor learning.

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
  • Monitor Neural Activity
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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
  • Human Neuroscience
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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 atlas of mouse brain-spinal cord connectome Dong, Hong-wei Tao, Huizhong Whit Zhang, Li I (contact) University Of Southern California 2018 Active
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Systematic studies on the brain-spinal cord connectome are lacking despite great efforts to characterize neuronal cell types in the brain. Zhang’s multi- laboratories project aims to systematically characterize neuronal types in the mouse spinal cord based on their anatomy, connectivity, neuronal morphologies, molecular identities, and electrophysiological properties. Via multiple newly-developed techniques, including an anterograde/retrograde trans-synaptic tagging method to label neurons, gene expression bard coding, and a fast 3D light sheet microscopy method, the team will establish a complete cell-type based brain-spinal cord connectome database, which will be made accessible to the neuroscience community.

Cell class- or type-specific viruses for brain-wide labeling and neural circuit examination Tasic, Bosiljka Allen Institute 2019 Active
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To gain a complete understanding of how certain cell types work, researchers must be able to access those specific cells. Despite advances in single-cell transcriptomics, commonly used genetic tools and methodologies have variable expression, can lack specificity, and often take a long time to create. Dr. Tasic’s group aims to develop a set of adeno-associated viruses containing enhancers to target specific cell types following administration via an injection behind the eye to access the whole brain, in mice. The enhancers will be defined via RNA and epigenetic sequencing, before being screened for their specificity. Once made publicly available, this toolkit could offer a more efficient method to access specific cell classes, facilitating investigations into their roles in circuit function.

Cell-Specific Visualization of Endogenous Proteins Mao, Tianyi Zhong, Haining (contact) Oregon Health & Science University 2019 Active
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  • Monitor Neural Activity

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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  • Human Neuroscience
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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
  • Human Neuroscience
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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
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
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 and Synaptic Mechanisms of Visual Spatial Attention Haider, Bilal GEORGIA INSTITUTE OF TECHNOLOGY 2018 Active
  • Integrated Approaches

The role of attention in sensory perception is an important question in neuroscience, especially when trying to understand and create better treatments for disorders like schizophrenia, autism spectrum disorders, and attention deficit disorders. Dr. Haider and team will utilize transgenic mice and combine high-density local field potential and neural activity recordings in the visual cortex, patch-clamp recordings from cortical and thalamic synaptic connections, cell-type specific optogenetics, and a well-characterized spatial attention task to elucidate the neural mechanisms of attention at multiple levels: specific cells, synapses, and circuits. 

Circuit Dynamics for encoding and remembering sequence of events Jafarpour, Anna University Of Washington 2019 Active
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  • Human Neuroscience
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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 for encoding naturalistic motion in the mammalian retina Wei, Wei UNIVERSITY OF CHICAGO 2018 Active
  • Integrated Approaches

Understanding how sensory information is extracted by anatomically and functionally defined neural circuits exemplifies one of the many remaining questions surrounding neural circuit function. Using the visual direction-selective circuit in the mouse retina, Dr. Wei and colleagues will perform circuit analyses incorporating a variety of approaches: synapse-specific circuit manipulation, multiphoton calcium imaging, patch clamp electrophysiology, connectomic circuit tracing, and theoretical analysis of information encoding. Results from this work may have broad implications in understanding fundamental principles of neural computation by a well-defined neural circuit.

Circuit mechanisms of evidence accumulation during decision-making Luo, Zhihao Princeton University 2017 Active
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  • Human Neuroscience
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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.
Circuit mechanisms underlying learned changes in persistent neural activity Aksay, Emre (contact) Goldman, Mark S Seung, Hyunjune Sebastian Weill Medical Coll Of Cornell Univ 2018 Active
  • Integrated Approaches
Understanding how brain circuit-level changes mediate behavioral changes requires detailed knowledge of circuit-wide activity patterns before, during, and after learning. Aksay’s team will study the dynamics of learning by revealing the changes in circuit activity patterns underlying a newly learned behavior. Specifically, they will study the adaptive tuning of the persistent neural activity underlying visual gaze-holding behavior in the zebrafish oculomotor system. The researchers will simultaneously record throughout the oculomotor brainstem and cerebellum during learning, perform anatomical reconstructions at electron microscopic resolution of the imaged circuits, incorporate these data into computational models to make predictions for sites of plasticity, and test those predictions through optical perturbations and electrophysiology. This work could serve as a blueprint for understanding cerebellar involvement in numerous behaviors.
Circuit principles of demotivation in the decision to switch behaviors Crickmore, Michael A Boston Children's Hospital 2019 Active
  • Integrated Approaches

How is a decision made whether or not to switch behaviors? This project aims to use experimental and computational approaches to study how information from competing motivations is processed and integrated to decide whether or not to switch behavior, i.e., to stop one behavior and start another. This work conducted in the Crickmore lab will make use of the Drosophila model to study motivational regulation. The findings will be used to generate circuit and computational models that can provide better insight into motivation.

Circuitry underlying response summation in mouse and primate: Theory and experiment REYNOLDS, JOHN H et al. SALK INSTITUTE FOR BIOLOGICAL STUDIES 2018 Active
  • Integrated Approaches

Each cortical neuron in the brain receives inputs from, potentially, thousands of other cells but produces only one collective response. It is unknown how neurons combine assorted inputs, which often come from many sources -- including sensory stimuli -- into a single response.  Drs. Brunel, Miller, and Reynolds will use visual and experimental optogenetic stimulation to compare responses in the visual cortexes of mice and monkeys as the neurons receive a variety of inputs. The team will also examine how inputs from specific types of neurons influence responses elicited in the cells with which they are communicating.  These findings may increase our understanding of brain circuit function in healthy brains and may provide clues to disorders in which critical circuits are disrupted.

Classification of Cortical Neurons by Single Cell Transcriptomics Ngai, John J. University Of California Berkeley 2014 Complete
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To understand what makes neurons distinct, Dr. Ngai's team will explore one major type of mouse brain cell, pinpointing genes responsible for differentiating them into subtypes and will also test whether each subtype has unique functions, using a new technique that labels them with tagged genes.
Classifying Cortical Neurons by Correlating Transcriptome with Function Scanziani, Massimo University Of California San Diego 2014 Complete
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Dr. Scanziani's team will record neuronal responses to different visual stimuli to discover how individual brain cell activity is linked to expression of specific genes.
Clinical Testing of an Intracortical Visual Prosthesis System Troyk, Philip R Illinois Institute Of Technology 2016 Active
  • Human Neuroscience
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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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  • Monitor Neural Activity

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
  • Human Neuroscience
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  • Monitor Neural Activity
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
  • Human Neuroscience
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  • Monitor Neural Activity

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.

Coarse-graining approaches to networks, learning, and behavior Bialek, William Palmer, Stephanie E (contact) Schwab, David Jason University Of Chicago 2018 Active
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Behavioral neuroscience research produces large quantities of high- dimensional data requiring complicated interrogations. To uncover simpler underpinnings of complex neural recordings, Drs. Palmer, Bialek, and Schwab propose incorporating renormalization group (RG) techniques to a wide range of multi-unit, neural data. The statistical algorithms of their theoretical framework will be freely available and disseminated, as they should be relatively straightforward to apply regardless of discipline. This project could support tractable, efficient analysis of large datasets by enhancing future users’ ability to discern specific properties of neuronal populations critical to behaviors.

Cognitive Restoration: Neuroethics and Disability Rights Fins, Joseph J. Weill Medical Coll Of Cornell Univ 2019 Active
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  • Human Neuroscience
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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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  • Human Neuroscience
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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.

Collaboratory for atlasing cell type anatomy in the female and male mouse brain Osten, Pavel Cold Spring Harbor Laboratory 2017 Active
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Although neuronal properties have been studied for over a century, we still have an incomplete idea of how different cell types are distributed throughout the brain. Osten and colleagues will use the automated Cell Counting and Distribution Mapping (CCDM) pipeline that they developed to express specific neuronal markers in the brains of adult mice, take high-resolution images of the neurons, and then spatially map their location. They plan to identify the distribution patterns and somato-dendritic morphology of more than 80 molecularly defined cell types. These data will provide detailed anatomical information about cell circuits that can then be integrated with molecular data to better define cell types in the brain.
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
  • Human Neuroscience
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  • Monitor Neural Activity
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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  • Monitor Neural Activity

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.

Combining genetics, genomics, and anatomy to classify cell types across mammals Bejerano, Gill Lois, Carlos Mitra, Partha Pratim Nelson, Sacha B (contact) Brandeis University 2014 Complete
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To gain a deeper understanding of how cells have evolved specialized features, Dr. Nelson and colleagues will create transgenic strains of rats and mice that carry identical genetic modifications in many different cell types and see how the properties of these cells diverge across species.
Comprehensive Analysis of a Decision Circuit Pehlevan, Cengiz Samuel, Aravinthan D. Sternberg, Paul Warren (contact) Zhen, Mei California Institute Of Technology 2019 Active
  • Integrated Approaches

Past experiences often drive how an animal develops. How does the brain draw on those experiences to guide developmental choices? Dr. Sternberg’s team will take a detailed look at the C. elegans decision-making circuit during development, using state-of-the-art molecular tools, computational modeling, and functional imaging, to examine how sensory inputs influence the developmental choices an animal makes. With the help of advanced technology, Dr. Sternberg’s colleagues will see how brain circuits change before, during, and after decision making.

Comprehensive Classification Of Neuronal Subtypes By Single Cell Transcriptomics Regev, Aviv Sanes, Joshua R (contact) Schier, Alexander F Zhang, Yi Harvard University 2014 Complete
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Dr. Sanes and colleagues will use new methods of genetic screening to comprehensively catalog and distinguish different kinds of cells across species and brain regions.
Compressive Light Field microscopy for optogenetic neural activity tracking Waller, Laura University Of California Berkeley 2016 Complete
  • Monitor Neural Activity
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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 and circuit mechanisms of decision making Shadlen, Michael Neil Columbia University Health Sciences 2019 Active
  • Integrated Approaches

Many cognitive functions rely on brain mechanisms involved in decision-making. Dr. Shadlen and colleagues aim to better understand how the brain makes increasingly complex decisions by using visual processing as a model. By combining complex behavioral tasks and multichannel neural recordings from multiple brain regions in nonhuman primates, the team will explore context-dependent interactions between brain regions; changes that occur during decision-making; and the timing at which an organism must make two distinct decisions about a single object.

Computational and circuit mechanisms underlying motor control Costa, Rui M. (contact) Jessell, Thomas M. Columbia University Health Sciences 2017 Active
  • Integrated Approaches
The mechanisms by which the nervous system produces controlled movements involve interactions between cortical and subcortical regions in the brain, the spinal cord, and muscle, but a clear understanding of these interactions remains elusive. Rui Costa, Thomas Jessell, and colleagues are planning to study the functional and computational logic of connectivity between these motor centers to characterize the role of specific corticospinal neurons during movements. When investigating motor control through cell-type-specific connectivity from brain to spinal cord, the team will use optogenetic manipulations and computational modeling to obtain a clear understanding of these circuit mechanisms. This project – in addition to the use of innovative methods – will also provide an understanding of how these systems are preserved across rodent and nonhuman primate species.
Computational and Circuit Mechanisms Underlying Rapid Learning Buffalo, Elizabeth A University Of Washington 2018 Active
  • Integrated Approaches

The circuit mechanisms underlying memory consolidation allow for detailed memory formation. Impairments in these circuits negatively impact patients dramatically with myriad neurological disorders. Dr. Buffalo’s project will study the neural circuits underlying rapid learning, using single-unit and field recordings in human and nonhuman primates (NHP) during the execution of learning- dependent tasks. Alongside electrophysiological recordings in both species during naturalistic and learning task performance and during sleep, the group will perform neural network modeling and state- space analyses. The project could reveal how abstract sensorimotor representations in this circuitry enable “learning to learn” new associations to form memories in humans and NHP.

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
  • Monitor Neural Activity
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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
  • Monitor Neural Activity
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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
  • Human Neuroscience
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  • Monitor Neural Activity

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
  • Human Neuroscience
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  • Monitor Neural Activity

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
  • Monitor Neural Activity
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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.
Controlling the spatial extent of light-based monitoring and manipulation of neural activity in vivo Sabatini, Bernardo HARVARD MEDICAL SCHOOL 2018 Active
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Optogenetics has dramatically advanced neuroscience, allowing the manipulation and monitoring of activity in genetically-defined neurons in the brain using light. However, while deeper brain structures can be accessed using optical fibers, standard fibers only illuminate tissue near their tip and are invasive in small animals. The team will develop light-delivery tools—tapered fiber optics—that allow precise, flexible control of spatially separated groups of neurons. Coupling these optical devices with electrical stimulators, the group plans to interrogate the same neurons using both methods simultaneously and incorporate novel viral preparations to enable genetic change in the neurons through the device. This toolset should expand our ability to manipulate and record neuronal circuits in a less invasive manner.

Cortex-wide volumetric imaging of neuronal activity. Vaziri, Alipasha Rockefeller University 2017 Active
  • Monitor Neural Activity
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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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  • Circuit Diagrams
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  • Monitor Neural Activity
  • Theory & Data Analysis Tools
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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  • Circuit Diagrams
  • Human Neuroscience
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  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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.

Cortical Interactions Underlying Sensory Representations Chen, Jerry BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) 2018 Active
  • Integrated Approaches

Sensory perception involves the transformation of sensory input into mnemonic representations, likely through interactions within and between cortical areas. However, a challenge for neuroscientists has been to distinguish information that is processed locally versus information that is transferred to and from other cortical areas. Using whisker-based paired association tasks in the mouse, Dr. Chen will apply two-photon calcium imaging and optogenetic manipulations to provide insight into these cortical circuits and evaluate predictive models that have been proposed to explain important aspects of perception. Taken together, these efforts could broaden the understanding of sensory representations that undergird perception.

Cortical Signature and Modulation of Pain WANG, FAN et al. DUKE UNIVERSITY 2018 Active
  • Integrated Approaches

There are two components of pain perception: sensory-signal-dependent and affective-cognitive aspects. The primary somatosensory cortex (S1) has been implicated in the affective-cognitive aspect of pain. In certain chronic neuropathic pain conditions, light touch can trigger intense feelings of pain – a hypersensitivity known as mechanical allodynia. Drs. Wang and He will test the hypothesis that S1 neurons that project directly back to the spinal cord facilitate mechanical hypersensitivity, whereas S1 neurons that project intra-cortically to motor cortex suppress this hypersensitivity. The team will use viral-genetic labeling of cortical neurons, in vivo calcium imaging and electrophysiological recordings in mice, optogenetic-assisted slice physiology, trans-synaptic tracing, and computational analyses to study the sensory- and motor-cortical modulation of pain.

Cortical Spatial Processing for Solving the Cocktail Party Problem Han, Xue Sen, Kamal K (contact) Boston University (charles River Campus) 2019 Active
  • Integrated Approaches

The cocktail party syndrome describes the process by which the brain tunes into one sound while hearing many others in the background. This often happens when two people have a conversation during a noisy cocktail party. Understanding the neural basis of this cocktail party effect has been a challenge for the auditory research field. To address this, the Sen and Han labs plans to explore how the circuits of the auditory cortex of the mouse brain may play a role in controlling the cocktail party syndrome.  to use novel tools and test hypotheses involving the neural circuits of the auditory cortex, Their results may help researchers understand the circuitry behind a variety of psychological and hearing disorders that disrupt this process.

Cortico-striatal representations of multisensory decision-making Sun, Xiaonan Feinstein Institute For Medical Research 2019 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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.

CoSMo - Summer School in Computational Sensory-Motor Neuroscience Schrater, Paul R University Of Minnesota 2015 Complete
  • Theory & Data Analysis Tools
Schrater and his team will offer a two-week short course, covering cross-disciplinary training in mathematical modelling techniques to understand brain function related to sensorimotor control and dysfunction. The course aims to increase participants' understanding of the brain's working principles in health and disease, via lectures accompanied by hands-on modelling and simulation tutorials. Course participants will be better positioned to contribute successfully to the overall goals of the BRAIN Initiative.
Cracking the Olfactory Code Rinberg, Dmitry New York University School Of Medicine 2019 Active
  • Integrated Approaches

Although olfaction is an important sense used by most animals to interact with their environment, there is a lack of empirical understanding of olfactory processing. Dr. Rinberg and team will collect the first system-wide dataset of neural and perceptual responses to a large, principled set of odorants and leverage recent technical advances in molecular genetics, neural imaging, electrophysiology, opto- and chemo-genetics, human psychophysics, and machine learning to reveal the computational logic of olfaction. The goal of this project is to uncover the rules that determine how various chemical features of an odorant are represented as neural activity, how this neural activity gets transformed as it propagates from the olfactory bulb to the piriform cortex, and the relevance of various features of these olfactory bulb neural responses to eliciting behavior and perception. These experiments will create a community-wide resource with potentially wide-ranging implications for general understanding of sensory information neural processes.

CranialProgrammer: Image-Guided Directional Deep Brain Stimulation Programming Using Local-Field Potentials Duke, Austin NEXEON MEDSYSTEMS PUERTO RICO OPERATING COMPANY, INC 2018 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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.

 

CRCNS Research Proposal: Cortico-amygdalar substrates of adaptive learningRecent advances in computational psychiatry have revealed failures in using models of the reward environment to flexibly change undesired behavior in individuals with substance use SOLTANI, ALIREZA (contact); IZQUIERDO, ALICIA DARTMOUTH COLLEGE 2018 Active
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Recent advances in computational psychiatry have revealed failures in using models of the reward environment to flexibly change undesired behavior in individuals with substance use disorders (SUDs). Drs. Soltani and Izquierdo will inhibit precise brain regions and simultaneously perform calcium imaging in rodents performing an adaptive learning task to explore circuitry between the cortex and amygdala. Results from this project could lead to improved systems-level understanding of behavioral inflexibility in people with SUDs and of the precise roles of involved brain areas for better, more effective therapeutic targeting in the future.

CRCNS: Advancing Computational Methods to Reveal Human Thalamocortical Dynamics JONES, STEPHANIE RUGGIANO (contact); HAMALAINEN, MATTI BROWN UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

Advancing methods to image and interpret neural activity in humans on fine temporal-spatial scales is critical to understanding how the brain works in health and disease. However, the ability to record non-invasively from deep in the human brain with current technology is lacking. To address this issue, Drs. Hamalainen and Jones will integrate magneto-/electroencephalography (MEG/EEG), computational neural modeling, and invasive electrophysiological recording in humans to optimize methods to localize distributed deep and shallow brain sources, and to develop a computational tool to interpret the underlying cellular events. In addition to developing free open source software that will advance the ability to non-invasively study subcortical interactions in humans with MEG/EEG, this approach will provide novel insight into distributed subcortical activity that is not possible with one method alone.

CRCNS: An Integrative Study of Hippocampal-Neocortical Memory Coding during Sleep CHEN, ZHE (contact); WILSON, MATTHEW A NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 Active
  • Theory & Data Analysis Tools

<p>Sleep is critical to memory and learning, and deciphering the neural codes underlying hippocampal and sensory cortical circuits would reveal important mechanisms of memory consolidations. Therefore, the study of hippocampal-neocortical memory coding during sleep is aimed at identifying a more complete answer to the "where", "what" and "when" questions related to memory processing, where a complete understanding is currently lacking. Drs. Chen and Wilson will combine electrophysiology, population-decoding methods, optogenetics and closed-loop neural interface to uncover sleep-associated memory contents of neural codes in the hippocampus and visual cortex and to dissect the circuit mechanisms of hippocampal-neocortical interaction and memory consolidation during various stages of sleep. The proposed project will provide valuable insight into targeted memory reactivation during sleep for memory enhancement or therapeutic applications.</p>

 

CRCNS: Cholinergic contribution to hippocampal information processing CANAVIER, CARMEN CASTRO (contact); GASPARINI, SONIA LSU HEALTH SCIENCES CENTER 2018 Active
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Neuromodulation in the hippocampus is thought to guide learning and memory processes, and a thorough knowledge of the mechanisms underlying encoding and retrieval is critical towards informing clinical interventions for cognitive disorders. Drs. Canavier and Gasparini will investigate how the neurotransmitter acetylcholine controls routing in areas CA1 and CA3 of the hippocampus. Their approach uses both computational modeling and experiments to better understand the neural basis of how different oscillation frequencies can be used to route information and how acetylcholine could control this routing. The resultant improvement in understanding how information is processed and stored in the hippocampus may eventually guide therapeutic strategies for cognitive disorders.

CRCNS: CLOSED-LOOP COMPUTATIONAL NEUROSCIENCE FOR CAUSALLY DISSECTING CIRCUITS ROZELL, CHRISTOPHER JOHN GEORGIA INSTITUTE OF TECHNOLOGY 2019 Active
  • Theory & Data Analysis Tools

The neural pathways underlying sensory perception are richly structured systems, with multilayered recurrent connections between cell types within a cortical layer, between cortical laminae, between areas within a sensory pathway, and between different brain regions. Despite substantial progress characterizing neural responses, it is particularly challenging to determine causal interactions within recurrently connected circuits due to the confounding influence of the interconnections. Drs. Rozell and Stanley plan to design a closed-loop stimulation system to decouple recurrently connected elements and clamp neural ensemble activity. Notably, the system will work in real-time by analyzing neural activity and feedback to guide stimulation on a scale of milliseconds. The team proposes to test this system in the rodent whisker barrel cortex – though applications in other brain areas, as well as the development of new medical devise based on the controller architecture, could likely result.

CRCNS: Collaboration toward an experimentally validated multiscale model of rTMS QUEISSER, GILLIAN TEMPLE UNIV OF THE COMMONWEALTH 2018 Active
  • Theory & Data Analysis Tools

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that relies on electromagnetic induction. Though studied clinically for the treatment of various disorders, effective repetitive TMS (rTMS) therapies remain elusive, hampered by technical limitations and a complex parameter space. To better understand the mechanisms underlying rTMS, Dr. Queisser aims to bridge modeling and basic neuroscience to build a multi-scale computational model which combines field simulations, network/single-cell plasticity modeling, and molecular-level calcium simulations. The proposed project is a first important step towards biology-driven, computer-assisted personalized rTMS therapies to promote beneficial neural plasticity. Moreover, this molecular approach provides the perspective in testing synergistic effects of pharmacological interventions and rTMS-based therapies, which may be instrumental in informing future clinical trials to tackle mental health disease.

CRCNS: Common algorithmic strategies used by the brain for labeling points in high-dimensional space NAVLAKHA, SAKET SALK INSTITUTE FOR BIOLOGICAL STUDIES 2018 Active
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Sensory systems in simple model organisms, like olfaction in the fruit fly, are well understood but must be translated to higher level vertebrates and expanded to include computational models for full comprehension. Dr. Navlakha hopes to understand what computations are used by the mammalian olfactory system using a mouse model and extending to develop a computer algorithm for application across species. The group plans to learn what circuit mechanisms are used in the mouse olfactory system, which may help identify how disruption of these mechanisms causes circuit malfunction. Using these data to improve computational processing performance, they could uncover insights into how the brain computes more broadly in health and disease.

CRCNS: Community-supported open-source software for computational neuroanatomy GARYFALLIDIS, ELEFTHERIOS INDIANA UNIVERSITY BLOOMINGTON 2018 Active
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Diffusion-weighted Magnetic Resonance Imaging (dMRI) is the only currently available, non-invasive, method to measure the properties connections in living human brains. Widely used in clinical tests for a variety of brain disorders, dMRI helps researchers understand networks involved in perception in cognition. Dr. Garyfallidis plans to implement novel algorithms for dMRI data analysis, share benchmark data sets, and support development of cloud-computing software tools. Computational methods proposed could accelerate research using dMRI for clinical application and increase our ability to make inferences from dMRI data.

CRCNS: Computational Approach to Assess Replicability of Neurobehavior Phenotypes BOGUE, MOLLY A JACKSON LABORATORY 2018 Active
  • Theory & Data Analysis Tools

The scientific community and general public have become increasingly concerned about a lack of replicability among published discoveries, particularly in behavioral science, but extending to many areas of pre-clinical research. Dr. Bogue proposes a practical approach to the challenge of research replicability that will help circumvent extensive and costly efforts and delays in the initial reporting of important findings, while facilitating changes in how scientists evaluate and communicate research. This project will provide an approach, guidelines and publicly available data resources to reduce the number of irreproducible studies that are published and improperly used as foundational research, increasing the public health impact of NIH-funded research and ultimately restoring confidence in the public's investment in research through timely, cost-effective improvements in the scientific process.

CRCNS: Computational neuroimaging of the human RESS, DAVID B BAYLOR COLLEGE OF MEDICINE 2018 Active
  • Theory & Data Analysis Tools

The human brainstem plays a critical role in brain function, both in health and disease, yet remarkably little is known about this critical brain region. While functional magnetic resonance imaging (fMRI) of the brain has provided tremendous insight into the cerebral cortex, the depth and small size of brainstem structures, such as the superior colliculus, has made imaging of the brainstem challenging. Dr. Ress proposes to build a set of methods and modeling that will enable the use of ultra-high-field fMRI to study the brainstem. The group will demonstrate validity by performing visual response experiments in the superior colliculus of humans and, if successful, could obtain much higher resolution data that could be transformative for basic research and clinical studies alike.

CRCNS: Decision Making in Changing Environments GOLD, JOSHUA I (contact); JOSIC, KRESIMIR ; KILPATRICK, ZACHARY PETER UNIVERSITY OF PENNSYLVANIA 2018 Active
  • Theory & Data Analysis Tools

Decisions are often deliberative processes that depend on the ability to accumulate uncertain information over time, but sometimes, new information requires dynamic updates. While research has begun to examine decision-making under dynamic conditions, no studies have identified representations of this adaptive decision variable that can flexibly accumulate information to guide behavior. Dr. Gold and collaborators plan to use theoretical and experimental approaches to understand how and where the brain encodes these decision variables. Specifically, they test whether brain circuits that integrate evidence under static conditions can also implement adaptive processes under dynamic conditions. This integrated computational, behavioral, and neurophysiological approach will provide novel insights into many aspects of higher brain function and complex behaviors that depend on dynamic processing of information.

CRCNS: Deep Neural Network Approaches for Closed-Loop Deep Brain Stimulation RICHARDSON, ROBERT MARK (contact); TURNER, ROBERT STERLING UNIVERSITY OF PITTSBURGH AT PITTSBURGH 2018 Active
  • Theory & Data Analysis Tools

Deep brain stimulation (DBS) represents one of the major clinical breakthroughs in the age of translational neuroscience, though harnessing the full therapeutic potential of adaptive DBS remains a challenge. Drs. Richardson and Turner will employ artificial intelligence strategies to further elevate the therapeutic potential of DBS. The concurrent use of research electrocorticography (ECoG) during DBS surgery recently has enabled basic neuroscience investigation of human cortical-subcortical network dynamics. Therefore, the researchers will develop a computational framework for deep learning-based multi-feature decoding of behavioral and disease states from ECoG, in order to advance the evolution of aDBS. By employing artificial intelligence strategies to innovate in the field of translational, personalized, medicine, this work will inform the design of novel strategies for biomarker-responsive brain stimulation.

CRCNS: Dynamical Constraints on Neural Population Activity YU, BYRON M (contact); BATISTA, AARON PAUL CARNEGIE-MELLON UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

Cognitive and behavioral processes that unfold over time reflect, at least in part, dynamical constraints imposed by neural circuitry. Understanding these dynamics requires finely perturbing neural activity in varied ways. Drs. Batista and Yu will employ a brain-computer interface (BCI) paradigm to study neural dynamics. BCI enables perturbation of neural activity by harnessing an animal's volitional control to drive the activity of a population of neurons into specified configurations, allowing causal tests of dynamical constraints and their relation to behavior. By recording multi-neuronal activity in the motor cortex of macaque monkeys, the researchers will have a deeper insight into how movements are prepared and executed, which holds therapeutic implications for movement disorders (e.g., Parkinson’s), as well as the potential to improve the performance of BCIs that assist paralyzed patients and amputees.

CRCNS: Dynamical mechanisms of oscillation transitions in the olfactory system KAY, LESLIE M (contact); CLELAND, THOMAS A UNIVERSITY OF CHICAGO 2018 Active
  • Theory & Data Analysis Tools

The olfactory system is an excellent model for studying the role of neural oscillations within experimentally accessible tissues, but there lacks a thorough, multi-level understanding of dynamical flexibility of the cortical circuits underlying olfaction. Drs. Kay and Cleland will establish a mechanistic model of oscillations and synchronization in the mammalian olfactory system, combining electrophysiology from awake/behaving rats with recordings from acute mouse slices of the olfactory bulb. Integrating these datasets into a common network model will explicate the construction and utility of these systemwide dynamics based on their underlying cellular and network mechanisms. The proposed work takes a fairly well-characterized network and, via computational modeling, combines studies across different levels of analysis to build a mechanistic model of a complex dynamical system.

CRCNS: Dynamics of Gain Recalibration in the Hippocampal-Entorhinal Path Integration SystemThe striking organization of hippocampal place cells and grid cells have provided unique insights into how the brain constructs and uses representations of the envi KNIERIM, JAMES J (contact); COWAN, NOAH JOHN; HEDRICK, KATHRYN ; ZHANG, KECHEN JOHNS HOPKINS UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

The striking organization of hippocampal place cells and grid cells have provided unique insights into how the brain constructs and uses representations of the environment to guide behavior. These spatially selective cells are influenced by both internal signals and external stimuli. How do these two sets of information re-calibrate when positions in the environment change? Drs. Cowan, Hedrick, Knierim, and Zhang propose that visual feedback guides these updates. They will conduct a set of interactive computational and experimental studies to investigate in detail the computational mechanisms underlying this novel phenomenon. This project, combining electrophysiology, engineering, and modeling, will propel the theory forward to explain the network dynamics underlying path integration, with implications for mental health illness characterized by an inability to appropriately react to external information about the world.

CRCNS: Geometry-based Brain Connectome Analysis DUNSON, DAVID BRIAN (contact); ZHANG, ZHENGWU DUKE UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

Increasing evidence suggests that an individual's brain connectome plays a fundamental role in cognitive functioning and the risk of developing mental disorders. However, large gaps between image acquisition and in connectome construction and data analysis have limited progress in understanding the relationships between brain connectome structure and phenotypes. Drs. Dunson and Zhang will develop transformative tools to enhance understanding of how the brain connectome varies according to individual differences. The toolbox will be applied to the Human Connectome Project and UK Biobank datasets and rigorously validated. By reducing measurement errors in connectome construction, and improving the inference of relationships between connectome structure and an individual's mental health and substance use, this project can revolutionize mechanistic understanding and clinical practice in prevention and treatment of mental health disorders.

CRCNS: Improving Bioelectronic Selectivity with Intrafascicular Stimulation JUNG, RANU (contact); ABBAS, JAMES J FLORIDA INTERNATIONAL UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

Electrical stimulation technology for activating small groups of peripheral nerve fibers could form the foundation of bioelectronic systems to influence metabolic processes, enhance immune system function, regulate gastrointestinal activity, or treat a variety of medical conditions. Drs. Jung and Abbas propose to enhance the clinical viability of these techniques by developing stimulation strategies that can selectively activate small groups of fibers that produce the desired clinical effect without producing undesirable side effects. The longitudinal intrafascicular electrodes (LIFEs) produced in this international collaboration will have multiple points of contact on nerve fibers and stimulation pulse flexibility for targeted activation in anesthetized rabbits.

CRCNS: Joint coding of shape and texture in the primate brain PASUPATHY, ANITHA UNIVERSITY OF WASHINGTON 2018 Active
  • Theory & Data Analysis Tools

A fundamental capacity of the primate visual system is its ability to process both the form and texture of visual stimuli. Using a combination of primate neurophysiology experiments, behavior and computational modeling, Dr. Pasupathy hopes to achieve a new level of understanding about how the non-human primate brain integrates visual information about form and surface properties. Shared stimuli and computational approaches will permit combining the groups' electrophysiological and computational investigations in primate visual cortex with data from Japanese collaborators who perform psychophysical studies in humans. These findings could bring researchers closer to devising strategies to alleviate and treat brain disorders of impaired form and texture processing resulting from dysfunctions in the occipito-temporal pathway.

 

CRCNS: Modeling the nanophysiology of dendritic spines YUSTE, RAFAEL COLUMBIA UNIV NEW YORK MORNINGSIDE 2018 Active
  • Theory & Data Analysis Tools

Dendritic spines mediate essentially all excitatory connections and are thus critical elements in the brain, but their function is still poorly understood. In particular, a key question is whether or not they are electrical compartments. Dr. Rafael Yuste will explore the application of a broad theory to accurately model the constraints that the nanostructure of dendritic spines places on electrical current flow. Specifically, his team will combine modeling approaches to extract features from data, and experimental approaches to study how the geometry and composition of a dendritic spine affect the electrical and ionic fluxes and the coupling between the synapse and the dendrite. The work will help understand how synaptic voltages are shaped by dendritic spines, a phenomenon that is affected in many mental and neurological diseases.

CRCNS: Modeling the role of auditory feedback in speech motor control HOUDE, JOHN FRANCIS (contact); NAGARAJAN, SRIKANTAN S UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 2018 Active
  • Theory & Data Analysis Tools

The importance of auditory feedback in speaking is underscored by the many diseases with speech disorders whose etiology have been wholly or partially ascribed to underlying deficits in auditory feedback processing, including autism, stuttering, schizophrenia, dementia, and Parkinson's disease. Drs. Houde and Nagarajan propose to investigate a computational model of speech that assumes state-feedback control by the auditory system. This project could lead to better understanding of the role of auditory feedback, which may lead to improved diagnosis and treatment for these speech impairments.

CRCNS: Modulating Neural Population Interactions between Cortical Areas YU, BYRON M (contact); SMITH, MATTHEW A CARNEGIE-MELLON UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

The brain networks underlying visual attention remain poorly understood, in particular how populations of neurons communicate across regions to facilitate attention. Causal interventions, such as micro-stimulation, are a critically important way to test theories of communication between brain regions as well as to develop potential therapies. The overarching goal of Drs. Smith and Yu's project is to identify and optimize patterns of micro-stimulation in one brain region that influence another brain region, and in turn behavior. Their approach combines advanced physiological methods for simultaneous recording in multiple brain areas, a rigorous quantitative approach to understanding neuronal communication, and a novel optimization approach to using micro-stimulation to modulate neuronal activity and behavior. The implications of this work have extremely broad scope and may reveal fundamental principles by which inter-area communication supports myriad perceptual and cognitive abilities.

CRCNS: MOVE!-MOdeling of fast Movement for Enhancement via neuroprosthetics SARMA, SRIDEVI V JOHNS HOPKINS UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

Tracking fast unpredictable movements is a valuable skill, applicable in many situations (e.g., chasing prey). The sensorimotor control system (SCS) is responsible for such actions and its performance depends on neurons, communication between brains and muscles, and muscle dynamics whose contributions have not been explicitly quantified. Dr. Sridevi Sarma and a team of investigators will build upon new theory developed using feedback control principles and an appropriately simplified model of the SCS to identify how neural computing, delays, and muscles interact during the generation of fast movements. In doing so, the group will seek to restore motor performance, and more importantly restore fast and agile movements, in patients with movement disorders via neuroprosthetic devices that are designed using a validated model of the sensorimotor control system and modern control theory.

CRCNS: Multi-scale models of proprioceptive encoding for sensorimotor control TING, LENA H EMORY UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

Proprioception, or one’s relative sense of body position and strength during movement, is guided by muscle spindle sensory afferents. While altered muscle spindle function is implicated in a wide range of sensorimotor impairments and neurological disorders, the basic mechanisms of muscle spindle sensory encoding are not well understood. To address this issue, Dr. Ting will develop a novel, mechanistic model of muscle spindle sensory encoding to that will test hypotheses about the role of molecular, cellular, and circuit level mechanisms on sensorimotor control in healthy and impaired humans and animals. The model will be a useful platform to integrate classical and new findings of muscle spindle function spanning multiple levels. Importantly, the model will improve our basic understanding of how sensory impairments alter both sensing and moving, and to drive the development of new treatments.

CRCNS: Neural Basis of Planning LEE, DAEYEOL (contact); MA, WHEE KY YALE UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

Strategic planning is important for humans and other animals during learning and decision making. While mechanisms for reinforcement learning have been well studied, how the brain utilizes knowledge of the environment to plan sequential actions remains unexplored. To address this issue, Drs. Lee and Ma, PIs with complementary expertise will investigate how different subdivisions of the primate prefrontal cortex contribute to the evaluation and arbitration of different learning algorithms during strategic planning in primates. By taking advantage of recent advances in machine learning and decision neuroscience, the proposed studies will elucidate how multiple learning algorithms are simultaneously implemented and coordinated via specific patterns of activity in the prefrontal cortex. The results from these studies will transform the behavioral and analytical paradigms used to study high-order planning and their neural underpinnings in humans and animals.

CRCNS: Neural signals that maintain/refresh LTP and memory GRIFFITH, LESLIE C BRANDEIS UNIVERSITY 2018 Active
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Understanding the molecular basis of memory storage through long-term potentiation (LTP) has major implications for memory disorders and stroke. Neural signals maintain and refresh LTP and require low levels of calcium, but whether achievement of this level is dependent on spontaneous neural activity is not known. To address this issue, Dr. Griffith will use acute hippocampal slices, behavioral observations in Drosophila, and computational modeling to test the role of spontaneous neural signals in memory refresh and maintenance. This project has the potential to bear importantly on the fundamental question of whether refresh reactions are mediated by spontaneous activity, providing important information towards understanding and treatment of memory disorders.

CRCNS: NEUROCOMPUTATIONAL STUDY OF REWARD-RELATED DECISION-MAKING & UNCERTAINTY YU, ANGELA UNIVERSITY OF CALIFORNIA, SAN DIEGO 2019 Active
  • Theory & Data Analysis Tools

While important advances have been made in understanding human learning and decision-making, there is still a lack of understanding of the different motivational factors that influence decision-making. Motivational factors may include immediate and long-term rewards, as well as the idea of reducing uncertainties that inevitably and invariably arise during daily real-life navigation of the world, due to a lack of (or change in) data and information. Dr. Yu and team will use a combination of cognitive modeling, innovative behavioral experiments, fMRI data, physiological (pupillometry, cardiac, and respiratory) data, and psychiatric measures (questionnaires addressing depressiveness, anxiety, anhedonia, locus of control, pessimism, and drug abuse) to address how two forms of uncertainty – expected and unexpected – act as distinctive motivational factors in human decision making.

CRCNS: OPTIMIZATION OF CLOSED-LOOP CONTROL OF GAMMA OSCILLATIONS NAIR, SATISH S UNIVERSITY OF MISSOURI-COLUMBIA 2019 Active
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Neuronal oscillations are thought to support numerous cognitive functions, with gamma oscillations in particular supporting communication between brain regions. Gamma oscillations are expressed ubiquitously across cortical and subcortical areas, including the basolateral nucleus of the amygdala (BL), an important regulator of emotional behaviors. Dr. Nair and colleagues will use real-time local field potential (LFP) decoding of gamma oscillations and high-speed optogenetic neuromodulation in a novel and promising closed loop paradigm. The goals of this study are to develop a full-scale anatomically and physiologically constrained biophysical model of the rodent BL, and together with new signal processing routines, develop in vivo gamma modulation algorithms that are customized and optimized for each individual subject.

CRCNS: PROCESSING SPEED IN THE HUMAN CONNECTOME ACROSS THE LIFESPAN HERMES, DORA MAYO CLINIC ROCHESTER 2019 Active
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Many anatomical and neuroimaging studies have shown that the white matter pathways between brain regions – the connectome – change with development, maturation, and aging.  How these developmental changes affect the speed and variability of neural communication at the milliseconds scale is not well understood. Dr. Hermes and team plan to create a large, freely available database of cortico-cortical evoked potentials (CCEP) recorded from pre-surgical epilepsy patients. These valuable data are rarely shared, and currently, there are no standards to improve the consistency of analysis of data from different research sites. The development of a database of CCEP data in the Brain Imaging Data Structure (BIDS) format for intracranial EEG (iEEG) (a standard structure for iEEG data containing metadata that are both human and machine-readable), along with the tools to analyze it, will be an impactful resource for the BIDS developer community as well as the broader neuroscience community.

CRCNS: Real-time neural decoding for calcium imaging CHEN, RONG (contact); BHATTACHARYYA, SHUVRA S UNIVERSITY OF MARYLAND BALTIMORE 2018 Active
  • Theory & Data Analysis Tools

Real-time neural decoding predicts behavior based on neural data, provided it can do so at the same pace with which the behavior is being monitored. While miniature cellular imaging is fast becoming a powerful way to study neural circuits by recording activity with cellular spatial resolution and sub-second temporal resolution, it also generates massive amounts of high-dimensional spatiotemporal data, with which real-time neural decoding has yet to keep apace. Drs. Bhattacharyya and Chen propose to develop a software platform, called RNDC-Lab (Real-time Neural Decoding for Cellular imaging Laboratory), that will provide integrated capabilities for design of and experimentation with novel real-time neural decoding systems for miniature cellular imaging. RNDC-Lab will provide a framework and platform for cost-efficient, real-time signal processing, the success of this project carries therapeutic implications for improving precise neuromodulation systems.

CRCNS: REWARD AND MOTIVATION IN NEURAL NETWORKS KOULAKOV, ALEXEI COLD SPRING HARBOR LABORATORY 2019 Active
  • Theory & Data Analysis Tools

Animal behaviors are learned and guided toward goals defined by the values of rewards and aversive events, as described by reinforcement learning (RL) theory. On the other hand, the values are not absolute but shifted largely by internal demands, such as thirst and hunger, and the intensity of behaviors are regulated accordingly. This issue has not been successfully addressed in standard RL theories. Drs. Koulakov and Li will test the hypothesis that the neuronal interactions within the ventral pallidum (VP) – a key brain region in the reward circuit – are critical for such processes that guide motivated behaviors. They will test their hypothesis using an integrated approach that combines molecular genetic tools, optogenetics, chemogenetics, electrophysiology and imaging in behaving mice, and advanced computational analysis and modeling.

CRCNS: Rhythm generation in rodent spinal cord DOUGHERTY, KIMBERLY J DREXEL UNIVERSITY 2018 Active
  • Theory & Data Analysis Tools

Understanding the rhythm-generating mechanisms that give rise to locomotion are critical to inform therapeutic interventions following injury or motor disorders. Spinal circuitry orchestrating the rhythm and patterning of locomotion are located in the lumbar spinal cord. In a collaborative project, Dr. Dougherty will use state-of-art experimental studies of spinal neurons and neural circuits in combination with computational modeling to dissect the organization and operating mechanisms of the spinal locomotor central pattern generator. The identification of rhythm generating mechanisms and the organization of spinal flexor and extensor circuitries will provide essential insights that can be applied to treatments and recovery of function following spinal cord injury or other motor disorders involving abnormal spinal locomotor processing.

CRCNS: Sparse odor coding in the olfactory bulb RINBERG, DMITRY (contact); KOULAKOV, ALEXEI NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 Active
  • Theory & Data Analysis Tools

Animals learn about their environment through their sensory systems, and the mammalian olfactory system is ideal to understand the computations in brain areas that format this incoming information for easy and flexible extraction by downstream brain areas. Drs. Koulakov and Rinberg will utilize recently developed theoretical frameworks, new optical methods for stimulus control, and multi-neuron recordings, to carry out a collaborative project that tests the basic principles of sensory processing in the olfactory system. This project will help elucidate the general principles of olfactory information processing by demonstrating how sensory representations can be dynamically tuned to reflect particular tasks faced by the organism. Because about 1-2% of people in North America experience a smell disorder and loss in sense of smell can negatively affect quality of life, this work holds important implications for clinical and therapeutic interventions.

CRCNS: Theory and Experiments to Elucidate Neural Coding in the Reward Circuit WITTEN, DANIELA (contact); WITTEN, ILANA UNIVERSITY OF WASHINGTON 2018 Active
  • Theory & Data Analysis Tools

Dopamine neurons are implicated in a wide range of normal behavioral functions, as well as a wide range of neuropsychiatric diseases, including addiction. Dr. Witten's group will perform two-photon imaging in the midbrain of mice while they learn a complex decision-making task and incorporate a suite of statistical tools to address challenges in analyzing the activity and behavioral data. The identification of sub-populations of dopamine neurons with different functional properties could provide much-needed insight into how dopamine neurons contribute to the neurobiology of addiction.

CRCNS: Theory-guided studies of cortical mechanisms of multi-input integration MILLER, KENNETH D (contact); VAN HOOSER, STEPHEN D COLUMBIA UNIVERSITY HEALTH SCIENCES 2018 Active
  • Theory & Data Analysis Tools

Processing in cortical circuitry is critical to healthy development, underlies features of intelligence, and malfunctions during disease. Drs. Miller and Van Hooser will test the predictions of a powerful framework for understanding how the sensory cortex globally integrates multiple sources of input, bottom-up and top-down, to produce neuronal responses, and ultimately, perception. Combining a novel theory on neural responses, the stabilized supralinear network, with optical and genetic manipulations of visual cortical circuits in awake ferrets, the group will probe how the visual cortex responds to various natural stimuli. Understanding such global integration occurring in the cortex could lead to the improvement of prosthetic devices that interface with the brain to treat blindness and other disorders.

CRCNS: US-France Modeling & Predicting BCI Learning from Dynamic Networks BASSETT, DANIELLE SMITH UNIVERSITY OF PENNSYLVANIA 2018 Active
  • Theory & Data Analysis Tools

Brain-computer interfaces (BCIs) are increasingly used for control and communication, and for treatment of neurological disorders, yet despite their societal and clinical impact, many engineering challenges remain. In particular, voluntarily modulating brain activity to control a BCI requires several weeks or months to reach high performance, affecting the user’s daily life. To characterize the neural mechanisms of BCI learning and predict future performance, Dr. Danielle Bassett and a collaborative international team will leverage experimental data and interdisciplinary theoretical techniques. They will characterize brain networks at multiple scales, developing models to predict the ability to control the BCI, as well as methods to engineer BCI frameworks for adapting to neural plasticity. This project will enable a comprehensive understanding of the neural mechanisms of BCI learning, fostering the design of viable BCI frameworks that improve usability and performance.

CRCNS: US-French Research Proposal: Neurovascular coupling-democracy or oligarchy? DREW, PATRICK JAMES PENNSYLVANIA STATE UNIVERSITY-UNIV PARK 2018 Active
  • Theory & Data Analysis Tools

Hemodynamic signals, such as those measured by functional magnetic resonance imaging (fMRI), are used to non-invasively image brain activity, but it is not known whether changes in blood flow are governed by average neural activity, or the activity of the most active neurons. Drs. Drew and Charpak, along with an international collaborative team, will use in vivo two-photon imaging, in close coordination with computational analysis methods, to investigate how neural activity is coupled to changes in blood flow. The combination of these two approaches will yield a quantitative understanding of how blood flow changes relate to neural activity, and a determination of the mechanisms underlying neurovascular coupling. A deeper understanding of the conversion of these hemodynamic signals into neural activity will inform the interpretation of human imaging studies, with clinical and therapeutic implications.

CRCNS: US-Japan Research Proposal: The Computational Principles of a Neural Face Processing System FREIWALD, WINRICH ROCKEFELLER UNIVERSITY 2018 Active
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A fundamental gap remains in the understanding of how neural circuits represent complex objects like faces and permit facial recognition. The neural mechanisms of face processing are essential to human social life, and altered social perception is characteristic of many pervasive neurodevelopmental disorders. Dr. Freiwald plans to identify the neural mechanisms and computational principles underlying face recognition circuitry and explore how alterations to these circuits impair function. Integrating functional magnetic resonance imaging with electrophysiological recordings in the targeted brain regions of non-human primates, the group could uncover details of more general visual object recognition as well as advancing understanding of the circuit mechanisms for social perception.

CRCNS:Navigation Through A Memory Space in the Rodent Hippocampus HOWARD, MARC W BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) 2018 Active
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One primary function of memory is to remember the past in order to anticipate and make decisions about the future. Neurophysiological findings show that the rodent hippocampus stores representations of past events, and that hippocampal theta oscillations may provide a mechanism to imagine future paths through space. Dr. Marc Howard and collaborators will use a combination of empirical work, advanced data analyses and computational modeling to develop a hypothesis for how the hippocampus and frontal cortex cooperate to navigate memory space and inform future behavior. By bridging levels of description from behavior, to an abstract mathematical framework, to systems neuroscience, this work may shed new light on fundamental mechanisms underlying memory in the hippocampus, paving the way towards treatment of memory dysfunction in a myriad of neurological disorders.

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.
Crowdsourcing the Fly Connectome Murthy, Mala Seung, Hyunjune Sebastian (contact) Princeton University 2018 Active
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To fully map the fly brain, Seung and colleagues will develop “FlyWire,” a crowdsourcing platform designed to help scientists around the country analyze thousands of electron micrographs of brain circuits. The team will work with scientists at Janelia Research Campus, Ashburn VA, to acquire the pictures and then test the platform in their lab before making it available to the neuroscience community. The team will use this approach to study sensory circuits. Tools like “FlyWire” may one day be used to map the circuits underlying brain diseases in humans.

Customizable, Ultra-high Density Optic Fiber-paired Multielectrode Array by 3D Nanoparticle Printing Panat, Rahul Carnegie-mellon University 2019 Active
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Recording individual neuronal activity across multiple scales at high resolution and low cost is a challenge for neuroscientists. Dr. Panat and colleagues will develop highly-customizable 3D Printed MicroElectrode Arrays (3DP-MEA) for affordable, on-demand, and study-specific fabrication of neural probes. This new method of nanoparticle printing technology for 3D multi-channel, multi-functional electrode arrays should allow neuroscientists to design precise array parameters to manipulate and record the dynamics of large, multi-area neurological circuits at high resolution in in vivo experiments.

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.

Data-driven analysis for neuronal dynamic modeling Mishne, Gal Yale University 2018 Active
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The communications and interactions between neurons across the sensory-motor system require additional investigations with novel methodologies to understand dynamic activity patterns underlying behavior. Dr. Mishne will develop modular mathematical tools to automatically analyze massive amounts of high-resolution, spatiotemporal, neuronal activity data gathered from mice performing a reaching task. The proposed calcium imaging data will be processed in three modules that: develop methods for ROI (region of interest) extraction, use tensors and non-linear tools for multi-modal integration of neuronal activity with behavior, and predict future behavioral responses using a recurrent neural network approach. These methods for automated analysis, organization, and modeling of calcium imaging data gathered during behavioral tasks will be available for use by the entire community.

Decoding the neural basis of resting-state functional connectivity mapping Hillman, Elizabeth M Columbia University Health Sciences 2017 Active
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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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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 cell types, lineage, and connectivity in developing human fetal cortex Geschwind, Daniel H University Of California Los Angeles 2014 Complete
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Dr. Geschwind's group will explore the diversity of cell types in the developing human brain, and will bring to bear state-of-the-art genetic and cellular visualization technology to map and trace the relationship between cell types across the cortex.
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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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.
Defining the anatomical, molecular and functional logic of internal copy circuits involved in dexterous forelimb behaviors Azim, Eiman Salk Institute For Biological Studies 2019 Active
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Skilled control of forelimbs is one of the most important roles of the mammalian motor system and requires a circuitry in the nervous system that allow for rapid adjustments. Using molecular, anatomical, and behavioral tools, this project aims to study how a component of that circuitry, the propriospinal neurons in the spinal cord, relays information to and from the brain.

DELINEATING CELL-SPECIFIC OUTPUT PATHWAYS OF THE GPe THAT SUPPORT LONG-LASTING BEHAVIORAL RECOVERY IN DOPAMINE DEPLETED MICE Gittis, Aryn Hilary Carnegie-mellon University 2018 Active
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Deep brain stimulation in the basal ganglia system, a treatment for Parkinson’s disease, provides only transient relief of motor symptoms. Gittis and colleagues will identify which neuronal subpopulations in the external globus pallidus (GPe) within the basal ganglia are required to induce long-lasting motor rescue in dopamine-depleted mice. Optogenetics and in vivo recordings will be used to assess the impact of modulating specific neuronal subpopulations on GPe circuit dynamics and on behavior. Virally-targeted circuit mapping will elucidate the pathways through which GPe neuronal subpopulations mediate their motor effects. If successful, this work will advance the current understanding of basal ganglia circuitry, and potentially lead to better treatments for motor dysfunction.
Dendritic Computation and Representation of Head Direction in Retrosplenial Cortex Harnett, Mark Thomas Massachusetts Institute Of Technology 2019 Active
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How do individual neurons in the mammalian cortex integrate multiple streams of input to guide behavior? In this project scientists will image the dendrites and cell bodies of neurons to determine how head direction and visual information is combined by neurons in a region of the brain called the retrosplenial cortex during navigational behaviors. This research will enhance our understanding of associative cortical function and provide new insights into cellular- and circuit-level mechanisms of navigation.

Dendritome mapping of genetically-defined and sparsely-labeled cortical and striatal projection neurons Dong, Hong-wei Yang, Xiangdong William (contact) University Of California Los Angeles 2018 Active
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The precise number of neuronal cell types of about one hundred million highly-interconnected neurons in the mouse brain is unknown. Ultimately, the classification of neuronal cell types in the mammalian brain will require integrating molecular, morphological, and connectomic properties. Yang and colleagues propose to classify neuronal cell types via brain-wide comprehensive profiling of the dendritic morphology of neurons with subsequent digital reconstruction. Their transgenic mouse lines, MORF, enable sparse labeling of genetically-defined neurons in mice, which allow for the resolution and reconstruction of individual cells’ dendritic morphologies within densely populated neuronal networks. This project will help contribute to the BICCN effort to generate a reference mouse brain cell atlas, and data will be shared publicly through the BRAIN Cell Data Center.

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 a multi-modal cross-scale fMRI platform with laminar-specific cellular recordings through multi-channel tapered photonic crystal fiber array Yu, Xin Massachusetts General Hospital 2019 Active
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Large-scale, whole-brain functional magnetic resonance imaging (fMRI) signal fluctuation, including low-frequency signal fluctuation (LFF), has been linked to specific brain states, such as sleep and arousal. However, linking signals across scales (from cellular and molecular to circuit and systems levels) to behavioral outputs is a challenge. Dr. Yu and colleagues will develop an advanced multi-modal fMRI platform to study cortical, laminar-specific LFF in awake rodent models. The team will combine advanced fMRI methods for intracellular calcium and extracellular glutamate recordings, with an ultimate goal to acquire multi-site, cross-scale brain dynamic signals in both normal and diseased conditions of awake animals.

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 new tools for high throughput analysis of microcircuits and synapse ultrastructure using tagged vesicular transporters and deep learning. Boassa, Daniela Hnasko, Thomas (contact) University Of California, San Diego 2019 Active
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Understanding neuropsychiatric illness, many of which trace to synaptic dysfunction, requires uncovering the synapse connectome. Utilizing advancements in optics, genetics, computing, and engineering, Dr. Hnasko and his team aim to develop new imaging and analysis methods to better understand microcircuits and synapse structure. The team will use CRISPR/Cas9 to insert electron microscopy-compatible tags into endogenous vesicular transporters to image neurotransmitter-defined synaptic connections in 3D ultrastructure. In addition, the researchers will develop computational tools for automated segmentation and quantification of pre- and post-synaptic features. This toolkit may allow researchers to map and analyze neurotransmitter-defined circuit connections in defined cell types in 3D, improving understanding of synapse structure and function.

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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  • Human Neuroscience
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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 new photo-releasable neuropeptide nano-vesicles for studying modulation in the brain Qin, Zhenpeng (contact) Slesinger, Paul A University Of Texas Dallas 2019 Active
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Neuropeptides are widely-expressed, important neuromodulators in the brain; however, due to current limitations in neurotechnology, little is known about their actions on neural circuits. Drs. Qin, Slesinger, and colleagues will develop a novel, potentially transformative technology using nanotechnology-based photo-release of neuropeptides combined with cell-based neurotransmitter fluorescent engineered reporters to release neuropeptides at localized targets in real-time in awake animals. This project could allow, for the first time, all-optical, spatiotemporal mapping and modulation of neural circuits modulated by neuropeptides.

Development of predictive coding networks for spatial navigation Dragoi, George Yale University 2018 Active
  • Integrated Approaches
Sequential neuronal attractors (i.e., neural network patterns with stable functional dynamics) have mainly been studied in adult animals, which accumulate spatial experience during development. Therefore, the early-life development of sequential neuronal attractors for encoding future navigation experiences (i.e., predictive coding) has remained mysterious. George Dragoi and colleagues seek to elucidate the roles of innate versus experiential factors in the emergence of internally-generated (hippocampus-mediated) representations of the world. While controlling prior spatial experience, they will record chronically from hippocampal neuron ensembles in developing, freely-behaving and sleeping rats, and will identify and analyze predictive coding network properties. This project could aid the study of neuronal ensemble pattern disruptions, with implications for disorders with developmental etiologies like schizophrenia and autism.
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.
Diagnosis of Alzheimer's Disease Using Dynamic High-Order Brain Networks Shen, Dinggang (contact) Yap, Pew-thian Univ Of North Carolina Chapel Hill 2016 Active
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Despite being the most common form of dementia, Alzheimer’s disease (AD) has no known cure and current clinical diagnosis relies on subjective neuropsychological and neurobehavioral assessments. Shen and his team plan to create machine learning-based algorithms that will hone in on changes to the functional connectivity of brain networks over time—as measured by neuroimaging techniques such as diffusion MRI—as possible indicators of mild cognitive impairment (MCI), which generally occurs well before AD symptoms. The researchers will design their diagnostic tools with the flexibility to also improve the success of the early detection of other neurological disorders, including schizophrenia, autism, and multiple sclerosis.
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.
Discovering dynamic computations from large-scale neural activity recordings Engel, Tatiana Cold Spring Harbor Laboratory 2018 Active
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Dynamic neuronal activity patterns underlie behavioral and cognitive functions in healthy and disordered brains, but large-scale recordings of this activity produce massive amounts of data requiring complex computations. Dr. Engel’s project provides a novel theoretical framework for analytically modeling the process by which temporally diverse responses of single neurons contribute to population activity during decision making. The group will validate unbiased, computational methods to examine dynamic activity in primate and mouse cortices and incorporate this framework into their freely available “BrainFlow” software and visualization tools.

Dissecting circuits for local and long-range competitive inhibition in the mouse superior colliculus Mysore, Shreesh P Johns Hopkins University 2019 Active
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The superior colliculus is an area found deep inside the brain that guides the brain’s reaction to competing stimuli and is involved in spatial attention control. In this project, the Myshore group will examine the role local and long-range inhibitory neural circuits play in controlling these behaviors. Initial experiments will be performed on mice shown visual stimuli. The researchers will use optogenetics to manipulate inhibitory neurons and endoscopic calcium imaging to record any resulting changes in excitatory neuronal activity. The results may help researchers better understand the role inhibitory circuits play in behavior and brain diseases.

Dissecting distributed representations by advanced population activity analysis methods and modeling Druckmann, Shaul Stanford University 2019 Active
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Sensory information passes through multiple brain areas to ultimately lead to behavior, but there is no clear understanding of how these multiple brain areas interact. Dr. Shaul Druckmann and team will develop analytical techniques that will facilitate interpreting the interactions among brain areas by recording brain activity and studying strategic perturbations of the data patterns. Working with experimental collaborators, they will use three high-quality datasets to design analytical approaches to interpret this data. They will first develop statistical metrics, then validate dimensionality reduction approaches that capture complex data in more interpretable forms. Finally, they will adapt modeling approaches to create mechanistic models of how circuit structure supports the activity dynamics of sensory information. These approaches and tools will have the potential to reveal how brain areas interface with each other and how these interactions shape behavior.

Dissecting human brain circuits in vivo using ultrasonic neuromodulation Shapiro, Mikhail Tsao, Doris Ying (contact) California Institute Of Technology 2014 Complete
  • Monitor Neural Activity
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  • Human Neuroscience
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.
Dissecting the dual role of dopamine in context-dependent and learned behaviors Ruta, Vanessa Rockefeller University 2019 Active
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Dysfunctions in dopamine signaling underlie a number of neuropsychiatric conditions; however, the diversity of roles dopamine plays in the brain has made it difficult to study. Using Drosophila as a model, Dr. Ruta and colleagues propose to use cutting-edge techniques to study how reward and locomotor signals are translated to different patterns of dopamine release and how they engage distinct dopamine receptor signaling cascades. Specifically, the team will study the fly’s mushroom body, which is involved in olfactory processing, learning, memory, and reward. This region is especially amenable to these experiments due to its relatively simple structure and available genetic tools. The results may shed light on the role of dopamine signaling in modulating behavior.

Dose Dependent Response of Cerebellar Transcranial Magnetic Stimulation Halko, Mark A Beth Israel Deaconess Medical Center 2016 Active
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  • Human Neuroscience
Repetitive transcranial magnetic stimulation (rTMS) applied to the cerebellum has shown some promising therapeutic effects for disorders like schizophrenia and ataxia, but optimization of stimulation parameters has lagged due to uncertainty of how rTMS impacts cerebellar networks. Building upon their previous work on cerebellar connectivity and motor function in humans, Halko and colleagues will investigate the impact of a range of rTMS intensities and durations on the cerebellum and measure changes in sustained attention tasks and associated brain activity. This project will enhance understanding of network activity associated with cerebellar stimulation, and may refine rTMS parameters to improve therapeutic efficacy.
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
  • Human Neuroscience
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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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  • Monitor Neural Activity

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
  • Human Neuroscience
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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
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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
  • Human Neuroscience
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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. 

ECT current amplitude and medial temporal lobe engagement Abbott, Chris C University Of New Mexico Health Scis Ctr 2016 Active
  • Interventional Tools
  • Human Neuroscience
Electroconvulsive therapy (ECT) remains one of the most successful treatments for pharmaceutical-resistant depression, but comes at the cost of transient, debilitating cognitive side effects, such as attention and memory deficits. To better understand the mechanisms underlying successful ECT treatment and relation to cognitive deficits, Abbot and colleagues will investigate the clinical and neurocognitive impact of varying the pulse amplitude, which determines the induced electric field strength in the brain. By determining the most effective pulse amplitude that maximizes hippocampal neuroplasticity (efficacy), minimizes disrupted connectivity (cognitive stability), and creating an algorithm to predict optimal pulse amplitudes for individuals, this work will improve our understanding of ECT mechanism of action, potentially improving clinical outcomes.
EFFECTIVE CONNECTIVITY IN BRAIN NETWORKS: Discovering Latent Structure, Network Complexity and Recurrence. Hanson, Stephen Jose Rutgers The State Univ Of Nj Newark 2016 Active
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A longstanding goal of neuroscience has been matching specific functions to local brain structure and neural activity. Despite success in identifying brain areas associated with cognitive tasks such as memory, attention, and language, many areas engaged during cognitive tasks are often considered “secondary” and are consequently ignored. One weakness in current methods to associate brain regions with specific functions has been the reliance on direct correlation between increased neural activity and task performance. To identify and assess how secondary areas contribute to important cognitive tasks, Hanson and his colleagues plan to extend IMaGES and develop new functional brain imaging analysis software to search for brain areas with less intuitive, but still relevant, connections to certain tasks. This project will advance efforts to analyze information flow in the brain and determine how neural pathways are altered in both health and disease.
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.

Efficient resource allocation and information retention in working memory circuits Ching, Shinung (contact) Snyder, Lawrence H Washington University 2019 Active
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Working memory - our ability to temporarily hold information in mind - is important for many aspects of normal human cognition, but there are critical gaps in our knowledge of how the brain remembers and stores multiple items. Through a combination of behavioral tests and computational modeling, Dr. ShiNung Ching and his team will test the validity of their theory that the organization of networks optimizes efficient resource allocation. Key to this project is the integration of experimental and computation methods to tightly link observed behavioral phenomena, theory, and underlying neural mechanisms. Because dysfunction of working memory occurs in numerous neuropsychiatric illnesses, the success of this project could inform improvements in diagnosing and treating these 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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  • Human Neuroscience
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.
ELECTROPHYSIOLOGICAL SOURCE IMAGING GUIDED TRANSCRANIAL FOCUSED ULTRASOUND HE, BIN Carnegie-mellon University 2017 Active
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches

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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  • Integrated Approaches
  • Human Neuroscience
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.
Elucidating the Wiring and Rewiring of Poly-synaptic Memory Circuits by Directed Stepwise Trans-neuronal Tracing Xu, Wei Ut Southwestern Medical Center 2018 Active
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Elucidating the organization of long-range poly-synaptic neuronal pathways is essential to understanding brain functions and the pathogenesis of brain disorders. Xu’s team will develop and utilize technologies to observe hypothesized circuit rewiring during learning and memory. Modified viral vectors will enable controlled, stepwise trans-neuronal tracing, which will be used to define distinct neuronal subpopulations in the hippocampus based on their poly-synaptic inputs/outputs. The team will then manipulate specific subpopulations to determine if different neuronal groups convey distinctly sensory information and, in turn, adjust different aspects of behavior. Lastly, the connectivity of neurons of interest will be traced—before and after a learning process—to examine if learning and memory alters connectivity. This work could deepen our understanding of the neurobiology of memory in health and disease.
Embedded Ensemble Encoding Antic, Srdjan D Lytton, William W (contact) Suny Downstate Medical Center 2016 Active
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The enormous complexity of brain interactions provides numerous challenges in understanding and treating brain diseases such as autism, schizophrenia, and Alzheimer’s disease. A large part of this complexity lies in “the neural code,” which describes how cells in the brain communicate with one another. Lytton and his colleagues propose the development of a novel embedded-ensemble encoding theory for understanding the creation of ensembles of neurons that are believed to generate thoughts, perceptions, and actions. The heart of this theory states that temporary neuronal ensembles form among groups of neurons across the brain whose activity becomes synchronized. The ultimate goal of this project is to bridge the gap between single neurons and neural networks and derive fundamental insights into cortical function that may advance the understanding of a variety of neurological diseases.
Emergent dynamics from network connectivity: a minimal model Curto, Carina Pennsylvania State University-univ Park 2016 Active
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Many networks in the brain exhibit emergent dynamics: that is, they display patterns of neural activity that are shaped by the intrinsic structure of the network, rather than modified by an external input. Such dynamics are believed to underlie central pattern generators for locomotion, oscillatory activity in cortex and hippocampus, and the complex interplay between sensory-driven responses and ongoing spontaneous activity. The goal of this research by Curto and her colleague is to develop a theory of how emergent dynamics can arise solely from the structure of connectivity between neurons. Having a deeper understanding of the dynamics of neural circuits is critical for studying diseases in which those dynamics are thought to be disrupted, such as Parkinson's disease, schizophrenia, and epilepsy.
Employing subcellular calcium to control membrane voltage Hochgeschwender, Ute H (contact) Lipscombe, Diane Moore, Christopher I Central Michigan University 2015 Complete
  • Monitor Neural Activity
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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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  • Human Neuroscience
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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
  • Human Neuroscience
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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.
Ensemble neural dynamics in the medial prefrontal cortex underlying cognitive flexibility and reinforcement learning Ganguli, Surya Schnitzer, Mark J (contact) Stanford University 2017 Active
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The prefrontal cortex plays a critical role in cognitive flexibility and decision-making, but the neural circuits underlying these processes remain unclear. Mark Schnitzer and Surya Ganguli are applying reinforcement learning theory (i.e., how to select optimal future actions based on past actions) to understand how neural ensembles in prefrontal cortex guide behavior. With an innovative mini-microscope for neural calcium imaging in active mice, the team plans to use this method to acquire stable, long-term recordings of neural ensemble dynamics, then create a neural network model that tests how these dynamics affect an animal’s actions. A clear understanding of this important neural circuit has the potential to inform clinical applications for psychiatric conditions for which cognitive flexibility is compromised.
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.

Epigenomic cell-type classification and regulatory element identification in the human brain Behrens, M Margarita Ecker, Joseph R (contact) Salk Institute For Biological Studies 2019 Active
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  • Human Neuroscience

Although major categories of cell types have been identified in the human brain, less is known about the different subtypes or their locations. Drs. Ecker and Behrens’ groups will create an epigenetic atlas of the human brain focusing on DNA methylation, open chromatic patterns, and transcriptomic signatures at the single-cell level. In addition to defining new cell types and their markers, this analysis may uncover new information on genetic variants associated with psychiatric and neurological disorders.

Epigenomic mapping approaches for cell-type classification in the brain Behrens, M Margarita Ecker, Joseph R (contact) Salk Institute For Biological Studies 2014 Complete
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Dr. Ecker's group will use signatures of epigenetics, the switching on-and-off of genes in response to experience, in mouse frontal cortex to help identify different classes of cells and understand their function.
Establishing a Comprehensive and Standardized Cell Type Characterization Platform Anderson, David J Zeng, Hongkui (contact) Allen Institute 2014 Complete
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Dr. Zeng's group will characterize cell types in brain circuits controlling sensations, such as vision and emotions, as a first step to better understand information processing across circuits. The data generated will be posted as a public online resource for the scientific community.
Establishing a dose response for ultrasound neuromodulation Caskey, Charles F (contact) Chen, Li Min Vanderbilt University Medical Center 2016 Active
  • Interventional Tools
  • Human Neuroscience
Although ultrasound (US) neuromodulation is a novel, non-invasive method for modulating deep brain structures, its mechanism of action is unclear. Using a combination of in vitro patch clamp and in vivo fMRI in mice, Caskey, Chen, and colleagues will apply US neuromodulation to different neuron types under varying stimulation parameters, assessing cellular and network reactions to stimulation doses, as well as exploring spatial characteristics and limitations of US in the brains of small animals. The team will then scale up their studies to the somatosensory cortex of non-human primates, improving our understanding of how US neuromodulation influences neuronal and circuit function, as well as the spatial parameters of US.
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.

Fast volumetric imaging of large areas in deep brain HOLY, TIMOTHY WASHINGTON UNIVERSITY 2018 Active
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Rapid whole-brain imaging in small model organisms and recording from tens of thousands of neurons in explanted tissue can be achieved through light sheet microscopy. Limitations in maintaining both illumination efficiency and appropriate imaging angle have prevented widespread application to studies in awake behaving mice. Holy’s project tests a highly innovative lens system configuration that allows collection of light otherwise inaccessible with current methods. If successful, whole circuits will be viewable “in action” at single-cell resolution. The approach will then be disseminated to the broader community, potentially yielding new insights into the mechanisms of disease.

Filtered Point Process Inference Framework for Modeling Neural Data Brown, Emery N. Massachusetts General Hospital 2016 Active
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Spikes are key elements of neural computation and methods to improve the extraction of spike data from calcium imaging and other similar imaging methods are much in demand. Existing techniques are either extremely slow or susceptible to noise. Brown and his colleagues plan to develop a mathematical framework for analyzing neuronal spikes, and to apply it to the analysis of calcium imaging data in behaving mice and to neuroendocrine data related to the secretion of hormones in humans. This framework will shed light on sensory encoding in the rodent brain. It will also aid our understanding of pathological neuroendocrine states and improve the efficacy of treatments of hormonal disorders, including diabetes, obesity and osteoporosis.
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
  • Human Neuroscience
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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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  • Human Neuroscience
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 Electron Microscopy to Neural Circuit Hypotheses: Bridging the Gap Fee, Michale S Massachusetts Institute Of Technology 2018 Active
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The Fee lab will develop tools to help scientists make highly detailed maps of neural circuits from images of brain tissue taken with an electron microscope- (EM). Specifically, they will acquire and automatically segment millimeter scale EM data, identify cell types from ultrastructural fingerprints and perform virtual experiments with the dataset. They will use these tools to test theories about how songbirds learn to sing and move. Their hope is that scientists can use these tools to fully understand circuit problems behind a variety of brain disorders.
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
  • Human Neuroscience
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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.

From microscale structure to population coding of normal and learned behavior Debello, Wiliam Mcintyre Ellisman, Mark H Fischer, Brian J Pena, Jose L (contact) Albert Einstein College Of Medicine 2017 Active
  • Integrated Approaches
The mechanisms underlying how neuron populations execute auditory-driven animal behavior (i.e., sound localization), and how experience sculpts the behavior and the underlying neural representation of auditory space, are currently unknown. To better understand the relationship between activity patterns across neural populations and behavior, Jose Pena and colleagues will study the sound-driven, head-orienting responses of barn owls. The team will combine electrophysiological, anatomical, and behavioral analyses to map neuronal population activities upon presentation of sounds. They will investigate the network architecture supporting the activity patterns, as well as how the network changes with learning. The main goal of this project is to envision a complete understanding of auditory localization, from the microcircuit to population coding to behavior.
Functional Architecture of Speech Motor Cortex Chang, Edward University Of California, San Francisco 2016 Active
  • Human Neuroscience
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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 Dissection of Neural Circuitry Underlying Parenting Behavior Hong, Weizhe University Of California Los Angeles 2019 Active
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It remains unclear what accounts for differences in parenting behavior in different sexes and physiological states. Parenting behaviors in mice have been found to be governed in part by GABAergic neurons within the medial amygdala. This project will take advantage of cutting-edge functional manipulation and imaging techniques to determine the neural mechanisms and circuitry underlying these differences in parenting behaviors.

Functional dissection of thalamocortical interactions through genetically-defined TRN subnetworks Feng, Guoping (contact) Halassa, Michael M Massachusetts Institute Of Technology 2019 Active
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The thalamic reticular nucleus (TRN) is a part of the brain that is important for many activities such as sensory processing, arousal, and cognition. Disrupted TRN function could underlie behavioral deficits seen in disorders such as schizophrenia, autism, and ADHD. However, little is understood about how the circuitry in the TRN contributes to these functions. Using molecular tools, anatomical tracing, and in vivo recordings, the team for this project will study how organization of the TRN circuitry gives rise to function, specifically how distinct subgroups of TRN neurons form subnetworks that contribute to different aspects of sensory processing, arousal, and cognition.

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.

GABAergic circuit interactions within the behaving mouse dLGN Bickford, Martha E (contact) Guido, William University Of Louisville 2017 Active
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The flow of visual information from the retina to the dorsal lateral geniculate nucleus (dLGN) in the brain is regulated by behavior, but the dynamic neural circuits governing these interactions have yet to be studied in awake, behaving animals. Martha Bickford and team are determining how inhibitory elements of the dLGN coordinate in behaving animals to modulate visual responsiveness and firing mode. They plan to use both optogenetic and chemogenetic techniques to target specific activation or inactivation of inhibitory circuits in dLGN, observing both dLGN neuron responses and measures of behavioral state in the mice. By developing these methods in vivo, the group aims to develop a novel approach to answering a wide variety of questions regarding thalamic function.
Gated Diffuse Correlation Spectroscopy for functional imaging of the human brain Franceschini, Maria Angela Massachusetts General Hospital 2017 Active
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  • Human Neuroscience
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.

Genetically-targeted hemodynamic functional imaging Jasanoff, Alan Massachusetts Institute Of Technology 2017 Active
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Non-invasive neuroimaging methods (e.g., functional magnetic resonance imaging) that measure neural activity by detecting blood flow changes (hemodynamics) are limited by their lack of specificity to mechanistically-distinct components of brain activity. Jasanoff’s team will "hijack" hemodynamic signals to report on circuit- or cell type-specific activity. The group will engineer nitric oxide synthase-based protein probes delivered into the brain using viral vectors, for circuit- and/or cell-type-specific hemodynamic readout of neural activity. These genetically engineered signals will be distinguishable from endogenous hemodynamics by their differential sensitivity to pharmacological inhibition. Selective imaging of genetically-targeted brain circuits and cell types will be possible using magnetic resonance, creating a new method for non-invasive imaging with cell- and circuit-specificity.
Graph theoretical analysis of the effect of brain tumors on functional MRI networks Holodny, Andrei I Makse, Hernan (contact) City College Of New York 2016 Active
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Individuals with brain tumors often recover function after the brain has adapted to the tumor. It is difficult, however, to predict which patients will recover based solely on the location of the tumor. Makse and his colleagues propose to develop a software tool to analyze a neuroimaging database of 1500 patients with glial tumors in order to discover the relationship between brain disease states and tumor location. This project will extend and test their theoretical model of how the brain adapts to recover lost functions in the presence of a brain tumor. The researchers’ new software tool will also aid in the understanding, diagnosis, and treatment of brain disorders thought to be due to disruptions of brain connectivity, including Alzheimer's disease, ADHD, stoke and traumatic brain injury.
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
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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 density multielectrode arrays with spatially selective unidirectional and rotating fields for investigation of neuronal networks Michaeli, Shalom University Of Minnesota 2017 Active
  • Interventional Tools
Direct electrophysiological stimulation and recording of neuronal populations has led to a better understanding of the inner workings of the brain, as well as treatments for disorders such as Parkinson’s disease and major depression using deep brain stimulation (DBS). ShalomMichaeli and team will design and manufacture high-density multi-electrode arrays for selective stimulation and recordings at ultra-high spatial resolution. The innovative technology, which will be combined with fMRI and tested in rats, will selectively stimulate distinct axonal bundles, regardless of axon orientations, which will provide a new dimension for DBS and its optimization.
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
  • Interventional Tools
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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Monitor Neural Activity
  • Interventional Tools
  • 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
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

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 speed, high precision volumetric multiphoton neural control Adesnik, Hillel UNIVERSITY OF CALIFORNIA BERKELEY 2018 Active
  • Integrated Approaches
  • Interventional Tools

Dr. Adesnik will lead an interdisciplinary team of neuroscientists, engineers, and computer programmers to use holographic control of lasers to upgrade the speed, scale, and resolution of current multiphoton neural control systems to manipulate circuits using optogenetics. This will allow researchers to precisely stimulate and record the activity of many neurons that control thinking, feeling, and behavior from deep inside the brain. As part of this, they will engineer high potency, ultrafast opsin genes for stimulating neurons with light. This may help researchers to precisely explore the circuit activity behind neurological and neuropsychiatric disorders.

High Throughput Approaches for Cell-Specific Synapse Characterization Barth, Alison L Bruchez, Marcel P (contact) Carnegie-mellon University 2017 Active
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  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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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  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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
  • Monitor Neural Activity
  • Interventional Tools
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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  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
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  • Monitor Neural Activity
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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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Monitor Neural Activity
  • Interventional Tools
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.
High-throughput 3D random access three-photon calcium imaging Cui, Meng PURDUE UNIVERSITY 2018 Active
  • Interventional Tools

Though two-photon microscopy with calcium indicators achieves resolutions on the level of single action potentials, their sensitivity is limited to the top layers of mouse cortex. Cui and Gan will develop and optimize a new, deep tissue three-photon calcium imaging method that enables high-throughput 3D structural and functional imaging in rodent brains 50% deeper than current methods. Using a lower repetition rate laser to enable optimal peak intensities while minimizing tissue heating, they hope to reach deeper tissue penetration as well as faster imaging.&nbsp;&nbsp;This project could lead to improvements in calcium imaging of awake and behaving animals and, in disseminating the full system design, expand our understanding of neuronal dynamics across mammalian brains to an unprecedented degree.

 

High-throughput Physiological Micro-connectivity Mapping in Vivo Adesnik, Hillel University Of California Berkeley 2019 Active
  • Cell Type

New approaches to probe the dynamics of structural and functional synaptic connectivity may improve understanding of the neural basis for behavior and learning. Through a collaborative team effort, Dr. Adesnik, Ji, and Paninski’s groups aim to develop two new methods to uncover physiological connectivity of single neurons across cortical networks over time. The first technology combines multiphoton photo-stimulation in vivo with single cell electrophysiology and statistical algorithms for high-throughput mapping of the presynaptic connectome in mice. The second tool employs this photo-stimulation with optical reporters of single synapse activity to measure synaptic connectivity over time in the same animal. These approaches should enable measurements of synaptic strength and dynamics of discrete synaptic connections, as well as tracking changes in the micro-connectivity of cortical networks during development, learning or disease progression.

Highly specific control of neurons with photoswitchable bioluminescent optogenetics. Shaner, Nathan Christopher University Of California, San Diego 2019 Active
  • Interventional Tools
  • 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.

Highly specific, renewable, and cost-effective antibody toolbox for 3D proteomic phenotyping of the brain Chung, Kwanghun (contact) Eichinger, Daniel J Pino, Ignacio Zhu, Heng Massachusetts Institute Of Technology 2019 Active
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Recent tools have led to advances in 3-D imaging of whole brains, opening the door for proteomic imaging that can increase our understanding of how the structure and activity in cells lead to brain functions. Unfortunately, proteomic imaging is limited by antibodies currently available for this type of research. Dr. Chung’s team aims to develop a comprehensive, open-source toolbox of antibodies generated against 300 proteins that are critical for understanding how the brain works. These antibodies should be more cost-effective, targeted, and compatible with a variety of tissue processing techniques.

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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  • Monitor Neural Activity
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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.

Human Neocortical Neurosolver Hamalainen, Matti Hines, Michael L Jones, Stephanie Ruggiano (contact) Brown University 2016 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools
Magnetoencephalography (MEG) and electroencephalography (EEG) are the leading non-invasive methods for recording human brain activity with millisecond resolution. However, it is still extremely difficult to interpret the underlying cellular and circuit-level sources of these large-scale signals without simultaneous invasive recordings. This challenge limits the use of MEG and EEG in the development of treatments for neural disorders. Jones and her colleagues propose a new software tool, called the Human Neocortical Neurosolver (HNN), that allows researchers to develop and test hypotheses about the origin of non-invasively measured human brain signals obtained with MEG and EEG. The insights obtained with the HNN tool will be helpful in understanding the underpinnings of neurological and psychiatric diseases, such as autism and schizophrenia.
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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  • Monitor Neural Activity
  • Interventional Tools
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.
Identifying, manipulating, and studying a complete sensory-to-motor model behavior circuit STOWERS, LISA SCRIPPS RESEARCH INSTITUTE 2018 Active
  • Integrated Approaches

Sensory stimuli can elicit many types of behaviors, yet it remains unclear how this occurs. Dr. Stowers’ project aims to improve understanding of the link between sensory input and behavioral changes. Her team will look at a well-defined behavioral response in mice and determine the complete neural circuit responsible from olfactory input to muscle. Once the circuit is identified, Dr. Stowers’ group will study the circuit’s neuronal activity patterns to determine how behavioral information is coded within the brain. This project will help advance our understanding of how the brain converts stimuli from the environment into behavioral changes.

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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  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
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  • Monitor Neural Activity
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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
  • Monitor Neural Activity
  • Interventional Tools
  • Theory & Data Analysis Tools
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 and Analysis Techniques to Construct a Cell Census Atlas of the Human Brain Boas, David A Fischl, Bruce (contact) Massachusetts General Hospital 2018 Active
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  • Circuit Diagrams
  • Human Neuroscience

Three-dimensional human brain atlases are increasingly important for integrating complex datasets into useful community resources. Fischl’s team proposes to create a multi-scale atlas—akin to Google Earth™ for the human brain—to map hemisphere-wide networks and also zoom in to see individual, labeled cells at micron resolution. This advance will be made possible through multiple imaging technologies, including light-sheet microscopy, tissue clearing, immunohistochemistry, magnetic resonance imaging, and newly-developed techniques in Optical Coherence Tomography. The ability to probe the cellular properties and multi-scale networks of specific areas in the human brain could evolve to an automated system for visualizing across the entire human brain in health and disease.

Imaging Brain Function in Real World Environments & Populations with Portable MRI Garwood, Michael G (contact) Vaughan, John T University Of Minnesota 2014 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • 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
  • Integrated Approaches
  • Interventional Tools
  • 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
  • Monitor Neural Activity
  • Interventional Tools
  • 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
  • Monitor Neural Activity
  • 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
  • Integrated Approaches
  • Interventional Tools
  • 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.

Imaging the Neural Effects of Transcranial Direct Current Stimulation Schlaug, Gottfried Beth Israel Deaconess Medical Center 2016 Active
  • Interventional Tools
  • Human Neuroscience
The mechanism of action and optimal parameters for transcranial direct current stimulation (tDCS) remains uncertain despite its use to non-invasively modulate behavior and cognition, and mixed success in treating neurologic and psychiatric disorders. To track short- and intermediate-term effects across the brain, Schlaug and colleagues will employ quantitative magnetic resonance imaging techniques to examine the effect of tDCS stimulation parameters (current strength, duration, and electrode configuration) on correlates of neural activity, and associated behavioral activities in humans. Results from this project could provide standardized methods for imaging and quantifying neural network responses to tDCS, which would greatly facilitate further studies of non-invasive neuromodulation of circuits implicated in various disorders.
Impact of cortical feedback on odor concentration change coding Shusterman, Roman Smear, Matthew C (contact) University Of Oregon 2017 Active
  • Integrated Approaches
The brain uses both feedforward and feedback connections across many of its neural systems, but the computational role of feedback in these circuits is often unclear. Matthew Smear and Roman Shusterman are investigating cortical feedback neurons in the olfactory system through novel optogenetic strategies that can identify, record, and silence these neurons. After first determining the feedback signals that an olfactory cortical area sends to the olfactory bulb in awake mice, the team will investigate the necessity of that feedback in odor sensitivity. In the long-term, the optogenetic silencing method proposed here has the potential to facilitate a greater understanding of the role of top-down feedback in neuronal computation.
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
  • Interventional Tools
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
  • Circuit Diagrams
  • Interventional Tools
  • 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
  • Interventional Tools
  • 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
  • Monitor Neural Activity
  • 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
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
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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
  • Interventional Tools
  • Monitor Neural Activity

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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  • Circuit Diagrams
  • Human Neuroscience
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  • Monitor Neural Activity
  • Theory & Data Analysis Tools
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 Imaging of Neuroactivity in the Deep Forward Scattering Regime Using Speckle Identification and Demixing (SPID) Microscopy Gigan, Sylvain Vaziri, Alipasha (contact) Rockefeller University 2019 Active
  • Interventional Tools

A key challenge of optical recording of neuronal activity is the heterogeneous nature and scattering properties of brain tissue. After only a few hundred microns of depth within the brain, there are nearly no ballistic photons left, Thus far, all microscopy techniques rely on exploiting the ballistic component of light and extracting it from the scattered component (at the excitation level in two-photon microscopy; or at the collection level in light-field or light sheet microscopy). Drs. Vaziri, Gigan, and colleagues intend to develop a new imaging platform for in vivo deep tissue calcium imaging in the millimeter depth range in the rodent brain. This technology will include hardware and algorithmic computational tools to separate components of the signal to localize neurons and extract their activity.

In-vivo circuit activity measurement at single cell, sub-threshold resolution Forest, Craig (contact) Stanley, Garrett B. Georgia Institute Of Technology 2014 Complete
  • Cell Type
  • Circuit Diagrams
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  • Interventional Tools
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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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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  • Circuit Diagrams
  • Human Neuroscience
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  • Theory & Data Analysis Tools

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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  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
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  • Theory & Data Analysis Tools

In an effort to improve our understanding of how synaptic plas