Funded Awards

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Title Investigator Institute Fiscal Year FOA Number Status Project Number Priority Area Summary
3D-Fast Optical Interface for Rapid Volumetric Neural Sensing and Modulation Gibson, Emily Welle, Cristin G (contact) University Of Colorado Denver 2018 RFA-EY-17-002 Active
  • Interventional Tools
  • Monitor Neural Activity

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

A 100MM Scale Single Unit Neural Recording Probe Using IR-Based Powering and Communication Blaauw, David University Of Michigan At Ann Arbor 2018 RFA-EY-17-002 Active
  • Interventional Tools
  • Monitor Neural Activity

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

A 5-dimensional connectomics approach to the neural basis of behavior KATZ, PAUL UNIVERSITY OF MASSACHUSETTS AMHERST 2018 RFA-NS-18-008 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 RFA-NS-17-006 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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

A Brain 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 RFA-NS-17-018 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 RFA-MH-17-255 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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

A Cellular Resolution Census of the Developing Human Brain Huang, Eric J Kriegstein, Arnold (contact) University Of California, San Francisco 2017 RFA-MH-17-210 Active
  • Cell Type
  • Circuit Diagrams
  • 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 RFA-MH-17-215 Active
  • Cell Type
  • Circuit Diagrams
  • Theory & Data Analysis Tools
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 Comprehensive Center for Mouse Brain Cell Atlas Huang, Z Josh Cold Spring Harbor Laboratory 2017 RFA-MH-17-225 Complete
  • Cell Type
  • Circuit Diagrams

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 RFA-MH-17-225 Complete
  • Cell Type
  • Circuit Diagrams

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 Confocal Fluorescence Microscopy Brain Data Archive Bruchez, Marcel P Ropelewski, Alexander J (contact) Watkins, Simon C Carnegie-mellon University 2017 RFA-MH-17-255 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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

A Facility to Generate Connectomics Information Lichtman, Jeff HARVARD UNIVERSITY 2018 RFA-NS-18-005 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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

A Fast, Accurate and Cloud-based Data Processing Pipeline for High-Density, High-Site-Count Electrophysiology Kimmel, Bruce VIDRIO TECHNOLOGIES, LLC 2018 RFA-MH-17-257 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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

A fully biological platform for monitoring mesoscale neural activity Dzirasa, Kafui Duke University 2018 RFA-EY-17-002 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 General Approach for the Development of New Cell-Type-Specific Viral Vectors Greenberg, Michael E Harvard Medical School 2017 RFA-MH-17-220 Active
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
The limited ability to genetically access specific neural cell types, based on distinctive gene expression patterns, impedes brain function probing and therapy development. Greenberg and colleagues will generate recombinant viral reagents that target specific cortical cell types, using recent advances in genetics and a novel application of single-cell transcriptome analysis. They propose to identify genetic drivers specific for excitatory and inhibitory mouse cortical neuronal subtypes. If successful, this may establish a general method for identifying cell-type-specific genetic elements that can be used in viral vectors to drive gene expression, could be applied to other brain regions and mammalian species, and may assist cell-type-specific applications like neuronal activity monitoring, optogenetic and chemogenetic manipulation, axonal tracing, gene delivery, and genome editing.
A high-performance unshielded wearable brain-computer interface based on microfabricated total-field OPMs Contreras-vidal, Jose Luis (contact) Knappe, Svenja University Of Houston 2018 RFA-EB-17-003 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

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

A high-speed volumetric multiphoton microscope for the study of developing neural circuits in retina Feller, Marla University Of California Berkeley 2016 RFA-MH-16-725 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • Theory & Data Analysis Tools
Spontaneous neuronal activity plays a role in the wiring of retinal circuits during development. Current imaging techniques are unable to capture such activity accurately. Dr. Feller’s team will assemble a system containing a resonant scanner-based two-photon microscope with the ability to achieve three-dimensional imaging of a single spontaneous firing event in vivo. Her team will utilize this high-speed volumetric two-photon imaging during visual stimulation to study the formation of functional neuronal circuits in the developing mouse retina.
A magnetic particle imager (MPI) for functional brain imaging in humans Wald, Lawrence L Massachusetts General Hospital 2017 RFA-EB-17-002 Active
  • Monitor Neural Activity
  • Interventional Tools
  • Integrated Approaches
  • Human Neuroscience
A complete understanding of human brain network structure and functional activation requires non-invasive imaging tools that generate high-resolution functional maps with dramatically increased sensitivity. Lawrence Wald and his team believe that achieving the next level of sensitivity of neuroimaging technology will occur through functional magnetic particle imaging (MPI). Unlike functional magnetic resonance imaging (fMRI) which indirectly detects blood oxygenation level, fMPI can directly detect this iron concentration with no intermediate step. Because MPI shares a technological foundation with MRI, the researchers can validate the fMPI method in animals and human simulations before assessing its sensitivity in humans. The development of fMPI could provide brain function information over an order of magnitude more sensitive than fMRI.
A method for anterograde trans-synaptic tracing Arnold, Donald B University Of Southern California 2018 RFA-MH-17-220 Active
  • Cell Type
  • Circuit Diagrams
  • Interventional Tools
  • 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 RFA-NS-17-004 Active
  • Monitor Neural Activity
  • Interventional Tools
Two-photon optical imaging of large populations of genetically-modified neurons is a powerful tool for studying neuronal circuits. Developed primarily for rodent models, use of this technology in primates is currently very challenging, in part due to the restricted imaging fields of traditional microscopes. Bijan Pesaran and a team of neuroscientists and engineers will develop an automated platform to enable imaging across multiple imaging fields situated over broad areas of the primate neocortex with micrometer precision. The group will leverage a recently developed two-photon random-access mesoscope with a very large field of view for optimal neural recordings. Their goal is to provide a unique perspective into the neural dynamics of the primate brain.
A Molecular and Cellular Atlas of the Marmoset Brain Feng, Guoping Massachusetts Institute Of Technology 2017 RFA-MH-17-210 Active
  • Cell Type
  • Circuit Diagrams
  • 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 RFA-MH-17-210 Active
  • Cell Type
  • Circuit Diagrams
  • 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 new strategy for cell-type specific gene disruption in flies and mice Clandinin, Thomas Robert (contact) Shah, Nirao Mahesh Stanford University 2015 RFA-MH-15-225 Complete
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
The ability to inactivate targeted genes only in relevant cell types is critical for understanding how specific genes contribute to circuit function and dysfunction. Clandinin's team will generate novel tools to inactivate genes in specific cell-types, and will validate these tools with imaging experiments and behavioral tests in live fruit flies. They will then adapt the tools for use in mice to directly manipulate genes controlling neuronal excitation and inhibition.
A Novel Approach for Cell-Type Classification and Connectivity in the Human Brain Sestan, Nenad Yale University 2014 RFA-MH-14-215 Complete
  • Cell Type
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 RFA-NS-15-003 Complete
  • Monitor Neural Activity
  • Interventional Tools
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 platform for genetically-encoded optical neuropeptide sensors (NEONS) Banghart, Matthew Ryan (contact) Chang, Geoffrey A University Of California, San Diego 2017 RFA-EY-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
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 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 RFA-MH-16-775 Active
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-EY-15-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
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 TOF, DOI, MRI compatible PET detector to support sub-millimeter neuroPET imaging Dolinsky, Sergei Miyaoka, Robert S (contact) University Of Washington 2018 RFA-EB-17-003 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
Currently, body imaging systems perform brain imaging, making it difficult to provide the necessary level of spatial and temporal resolution needed to understand brain function. Brain-only imaging systems include positron emission tomography (PET) and are referred to as neuroPET. Drs. Robert Miyaoka, Sergei Dolinsky, and a team of investigators seek to develop improvements in both image resolution and signal-to-noise ratio of neuroPET technology. The researchers will characterize neuroPET parameters, validate them through machine learning methods, and characterize performance of a prototype detector that is compatible with magnetic resonance imaging (MRI). By improving detector imaging technology that facilitates compatibility between PET and MRI, this work will improve image resolution to advance research into the development, function, and aging of the human brain.
A tool-box to control and enhance tDCS spatial precision Bikson, Marom City College Of New York 2016 RFA-MH-16-810 Active
  • Interventional Tools
  • Human Neuroscience
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 RFA-NS-16-008 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
Current non-invasive methodologies limit our ability to understand the neural basis of cognitive processes due to poor temporal or spatial resolution, and typical intracranial EEG (icEEG) approaches provide fragmentary information. To address these limitations, Drs. Tandon and Crone will study human language function, working with epilepsy patients who have intracranial electrodes in place. The group will then modulate activity at identified nodes of brain activity using closed-loop direct cortical stimulation. This project could provide insight into language processing and organization in the brain using a novel method of modeling neural computation, and provide insight into the language impairments that can affect patients with a range of neurologic and psychiatric illnesses.
A viral system for light-dependent trapping of activated neurons Drew, Michael R Martin, Stephen Zemelman, Boris V (contact) University Of Texas, Austin 2015 RFA-EY-15-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
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 whole-brain ultrasonic neural stimulation and photoacoustic recording system in behaving animals Oralkan, Omer (contact) Sahin, Mesut North Carolina State University Raleigh 2017 RFA-EY-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
Understanding neural networks and communication between brain regions requires the decoding of electrical and chemical signals, but current methods often face a tradeoff in spatiotemporal precision. Omer Oralkan and Mesut Sahin propose the development of a tool that combines ultrasound neural stimulation and photo-acoustic recording of hemodynamic activity to monitor awake and behaving animals. Under this approach, high-frequency ultrasound allows for high stimulation precision, and a fast-repeating laser source permits high-resolution imaging of neurovascular responses that report neural activity. The success of this technological advance could pave the way for implantable, wireless dual-mode ultrasound/photoacoustic imaging devices that provide high spatiotemporal resolution of the entire brain using a minimally invasive approach.
Accessing the Neuronal Scale: Designing the Next Generation of Compact Ultra High Field MRI Technology for Order-of-Magnitude Sensitivity Increase in Non-Invasive Human Brain Mapping Rutt, Brian Keith Stanford University 2017 RFA-EB-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
  • Human Neuroscience
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.
Achieving ethical integration in the development of novel neurotechnologies Chiong, Winston University Of California, San Francisco 2017 RFA-MH-17-260 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools
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 RFA-NS-17-003 Active
  • Interventional Tools

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.

Adaptive DBS in Non-Motor Neuropsychiatric Disorders: Regulating Limbic Circuit Imbalance Goodman, Wayne K Baylor College Of Medicine 2016 RFA-NS-16-010 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity
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 RFA-NS-17-003 Active
  • Interventional Tools

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.

Advancing MRI & MRS Technologies for Studying Human Brain Function and Energetics Chen, Wei (contact) Yang, Qing X University Of Minnesota 2014 RFA-MH-14-217 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • 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 RFA-MH-16-725 Complete
  • Monitor Neural Activity
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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 RFA-EB-17-001 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 RFA-MH-15-225 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 source, wireless, miniature microscope for monitoring neuronal activity BASSO, MICHELE A et al. UNIVERSITY OF CALIFORNIA LOS ANGELES 2018 RFA-NS-17-004 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 RFA-NS-16-007 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 toolkit for the interrogation and control of single cells. Hannon, Gregory J Cold Spring Harbor Laboratory 2014 RFA-MH-14-216 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 RFA-EY-17-002 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 RFA-MH-17-230 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 RFA-MH-15-225 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 RFA-MH-15-225 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 RFA-MH-18-500 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 RFA-NS-16-009 Active
  • Human Neuroscience
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Dominant hemisphere mesial temporal lobe epilepsy (MTLE) is a form of epilepsy for which it is particularly difficult to control seizures. In this project, Gross and colleagues will test a next-generation deep brain stimulation (DBS) device and a novel stimulation paradigm in a non-human primate model of MTLE. If they are successful in controlling seizures in this model, the team will advance to an early clinical feasibility study in a small number of MTLE patients, measuring seizure reduction and memory testing for safety. Success in this small clinical study could lay the foundation for a clinical trial utilizing this novel DBS method in patients with MTLE, and possibly other forms of epilepsy.
Autonomously-activating bioluminescent reporters to enable continuous, real-time, non-invasive brain cell imaging Sayler, Gary S 490 Biotech, Inc. 2018 PAR-15-091 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.

Bayesian estimation of network connectivity and motifs Ringach, Dario L University Of California Los Angeles 2016 RFA-EB-15-006 Active
  • Integrated Approaches
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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.
Behavioral readout of spatiotemporal codes dissected by holographic optogenetics Rinberg, Dmitry (contact) Shoham, Shy New York University School Of Medicine 2014 RFA-NS-14-009 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 RFA-NS-17-015 Active
  • Integrated Approaches
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 RFA-MH-15-215 Complete
  • Theory & Data Analysis Tools
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 RFA-EB-15-006 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 RFA-EY-17-002 Active
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Large-scale monitoring and modulation of brain activity using non- or minimally invasive tools with high spatiotemporal resolution remains a challenge for neuroscientists. Dr. Mehdi Kiani and colleagues will develop a new bidirectional, neural-interface platform for electrophysiological recordings and stimulation of neural activities over the entire brain. This wireless, minimally invasive technology measures micro-electrocorticography signals from 100 sites, drives ultrasonic transducers to guide a focused ultrasonic beam to stimulate a targeted brain region, and simultaneously images the neural tissue – all at <500 mm resolution. The platform functions with an external unit in a closed-loop fashion to deliver the stimulation pattern, recover the electrophysiological and imaging data, and create the neural tissue images.

Bidirectional optical-acoustic mesoscopic neural interface for image-guided neuromodulation in behaving animals SHOHAM, SHY et al. NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 RFA-NS-17-003 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 RFA-MH-17-256 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.

Biological 'Living Electrodes' Using Tissue Engineered Axonal Tracts to Probe and Modulate the Nervous System Cullen, Daniel Kacy University Of Pennsylvania 2015 RFA-NS-15-003 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 RFA-NS-16-007 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 RFA-EY-16-001 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 RFA-MH-17-255 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 RFA-MH-17-220 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: Theories, Models and Methods for Analysis of Complex Data from the Brain Chung, Moo K University Of Wisconsin-madison 2016 RFA-EB-15-006 Complete
  • Integrated Approaches
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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 RFA-MH-15-225 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 RFA-MH-17-257 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 RFA-MH-17-220 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 RFA-EB-17-004 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.

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 RFA-NS-17-004 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 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 RFA-EB-17-005 Active
  • Integrated Approaches
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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 RFA-NS-15-004 Complete
  • Monitor Neural Activity
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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 RFA-MH-17-257 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 RFA-NS-17-003 Active
  • Interventional Tools
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 RFA-NS-14-007 Complete
  • Monitor Neural Activity
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Dr. Jasanoff's team will synthesize calcium-sensing contrast agents that will allow functional magnetic resonance imaging (fMRI) scans to reveal activity of individual brain cells.
Capabilities of MRI-Based Neural Current Imaging for Human Brain Mapping Kim, Young R Massachusetts General Hospital 2015 RFA-EY-15-001 Complete
  • Monitor Neural Activity
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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 RFA-NS-15-003 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 RFA-NS-17-019 Active
  • Human Neuroscience
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  • Monitor Neural Activity
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 RFA-MH-17-230 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.

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 RFA-NS-15-008 Active
  • Human Neuroscience
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  • Monitor Neural Activity
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 RFA-MH-17-220 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 RFA-MH-16-750 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.
Circuit and Synaptic Mechanisms of Visual Spatial Attention Haider, Bilal GEORGIA INSTITUTE OF TECHNOLOGY 2018 RFA-NS-18-009 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 mechanisms for encoding naturalistic motion in the mammalian retina Wei, Wei UNIVERSITY OF CHICAGO 2018 RFA-NS-18-009 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 RFA-MH-17-250 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 RFA-NS-17-014 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.
Circuitry underlying response summation in mouse and primate: Theory and experiment REYNOLDS, JOHN H et al. SALK INSTITUTE FOR BIOLOGICAL STUDIES 2018 RFA-NS-18-008 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 RFA-MH-14-215 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 RFA-MH-14-215 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 RFA-NS-16-009 Active
  • Human Neuroscience
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  • Monitor Neural Activity
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.
Closed loop deep brain stimulation for Parkinson's disease Starr, Philip Andrew University Of California, San Francisco 2016 RFA-NS-16-010 Active
  • Human Neuroscience
  • Interventional Tools
  • 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 RFA-NS-16-010 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 RFA-EB-17-005 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.

Collaborative Standards for Brain Microscopy Hamilton, Carol M Research Triangle Institute 2018 RFA-MH-17-256 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 RFA-MH-17-230 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 RFA-NS-16-010 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 RFA-MH-14-215 Complete
  • Cell Type
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 Classification Of Neuronal Subtypes By Single Cell Transcriptomics Regev, Aviv Sanes, Joshua R (contact) Schier, Alexander F Zhang, Yi Harvard University 2014 RFA-MH-14-215 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 RFA-EY-16-001 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 RFA-NS-15-005 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 underlying motor control Costa, Rui M. (contact) Jessell, Thomas M. Columbia University Health Sciences 2017 RFA-NS-17-018 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 RFA-NS-17-018 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 RFA-MH-16-725 Complete
  • Monitor Neural Activity
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  • Theory & Data Analysis Tools
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 RFA-EY-16-001 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 RFA-EY-15-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-EB-17-004 Active
  • Human Neuroscience
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  • Interventional Tools
  • 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 RFA-NS-18-010 Active
  • Human Neuroscience
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  • Interventional Tools
  • 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 RFA-NS-17-004 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-NS-17-003 Active
  • Interventional Tools

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 RFA-NS-17-004 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-NS-14-009 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 Interactions Underlying Sensory Representations Chen, Jerry BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) 2018 RFA-NS-18-009 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 RFA-NS-18-009 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. 

CoSMo - Summer School in Computational Sensory-Motor Neuroscience Schrater, Paul R University Of Minnesota 2015 RFA-MH-15-215 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.
CranialProgrammer: Image-Guided Directional Deep Brain Stimulation Programming Using Local-Field Potentials Duke, Austin NEXEON MEDSYSTEMS PUERTO RICO OPERATING COMPANY, INC 2018 RFA-NS-17-007 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 PAR-18-804 Active
  • Theory & Data Analysis Tools

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 PAR-18-804 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 PAR-18-804 Active
  • Theory & Data Analysis Tools

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.

CRCNS: Cholinergic contribution to hippocampal information processing CANAVIER, CARMEN CASTRO (contact); GASPARINI, SONIA LSU HEALTH SCIENCES CENTER 2018 PAR-17-804 Active
  • Theory & Data Analysis Tools

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: Collaboration toward an experimentally validated multiscale model of rTMS QUEISSER, GILLIAN TEMPLE UNIV OF THE COMMONWEALTH 2018 PAR-18-804 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 PAR-18-804 Active
  • Theory & Data Analysis Tools

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 PAR-18-804 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 PAR-17-804 Active
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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 PAR-18-804 Active
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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 PAR-17-804 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 PAR-18-804 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 PAR-17-804 Active
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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 PAR-14-804 Active
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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 PAR-18-804 Active
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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 PAR-18-804 Active
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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 PAR-18-804 Active
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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 PAR-18-804 Active
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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 PAR-18-804 Active
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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 PAR-18-804 Active
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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 PAR-18-804 Active
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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 PAR-18-804 Active
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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 PAR-16-804 Active
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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 PAR-18-804 Active
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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 PAR-16-804 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: Real-time neural decoding for calcium imaging CHEN, RONG (contact); BHATTACHARYYA, SHUVRA S UNIVERSITY OF MARYLAND BALTIMORE 2018 PAR-18-804 Active
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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: Rhythm generation in rodent spinal cord DOUGHERTY, KIMBERLY J DREXEL UNIVERSITY 2018 PAR-15-804 Active
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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 PAR-14-804 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 PAR-18-804 Active
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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 PAR-18-804 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 PAR-15-804 Active
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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 PAR-15-804 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 PAR-18-804 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 PAR-16-804 Active
  • Theory & Data Analysis Tools

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 RFA-NS-14-009 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 RFA-MH-18-505 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.

DART2.0: comprehensive cell type-specific behavioral neuropharmacology Tadross, Michael R Duke University 2018 RFA-MH-17-220 Active
  • Cell Type
  • Circuit Diagrams
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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 RFA-MH-17-255 Active
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  • Human Neuroscience
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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 RFA-MH-17-256 Active
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  • Circuit Diagrams
  • Human Neuroscience
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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 RFA-EB-17-005 Active
  • Integrated Approaches
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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 RFA-MH-17-235 Active
  • Monitor Neural Activity
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  • Human Neuroscience
Resting-state functional magnetic resonance imaging (rs-fMRI) detects how brain regions are synchronized, forming networks that support normal function. Understanding these networks may help diagnose and treat disease. Elizabeth Hillman’s team will use novel optical imaging, capturing neural activity and blood flow dynamics, to characterize cellular dependencies, pathways, behavioral correlates, and blood flow interactions of resting-state spontaneous neural activity. Data will be acquired using novel measurement and circuit manipulation techniques in awake, behaving mice, and rs-fMRI analysis of equivalent human neurovascular activity. The aggregate data will yield predictive models of network activity and the relationships between resting-state activity in specific cell types and blood flow dynamics. By optimizing and validating rs-fMRI analysis, this project could transform rs-fMRI into a reliable technique for studying the brain in health and disease.
Deep brain photoacoustic tomography at single-neuron resolution using arrays of photonic emitters and high-frequency ultrasound transducers Roukes, Michael L Shepard, Kenneth L Wang, Lihong (contact) California Institute Of Technology 2016 RFA-NS-16-006 Active
  • Monitor Neural Activity
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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 RFA-NS-17-006 Active
  • Human Neuroscience
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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 RFA-NS-16-010 Active
  • Human Neuroscience
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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 RFA-EY-17-002 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 RFA-MH-17-235 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
Functional magnetic resonance imaging (fMRI) allows non-invasive study of human brain function. However, how specific cell types contribute to fMRI signals remains elusive, complicating fMRI interpretation. Jin Hyung Lee’s team will measure cell-type-specific, whole-brain network function using fMRI while using optogenetics to selectively stimulate distinct neural circuit pathways in the basal ganglia. These pathways are involved in action planning and reward, and are implicated in disorders as diverse as Parkinson’s disease, depression, and substance use disorders. Optical imaging will confirm fMRI signal sources with cell-type specificity. The group will computationally model these interaction dynamics to demonstrate how this unique approach can be used to uncover whole-brain circuit functions. This project could enable researchers to systematically design therapies to restore normal circuit function in disorders like Parkinson’s disease.
Defining cell types, lineage, and connectivity in developing human fetal cortex Geschwind, Daniel H University Of California Los Angeles 2014 RFA-MH-14-215 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 RFA-MH-16-750 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
Methods for measuring intrinsic functional connectivity (iFC), a measure of correlation between spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal, can be used to quickly map in high detail the functional architecture of the human brain. However, the neural circuits underlying the BOLD-iFC relationship remain poorly specified. Schroeder and his colleagues propose to use a variety of measurement tools in humans and monkeys to investigate this relationship. The researchers will then employ established modeling and computational methods to help construct a comprehensive model that connects large-scale iFC to underlying microscale activity at the neural circuit level. The findings from this project may be used to improve the efficiency of iFC measurements, which could have widespread clinical implications, particularly in the discovery of biomarkers for various brain disorders.
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 RFA-NS-17-014 Active
  • Integrated Approaches
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.
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 RFA-MH-17-230 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 low-cost, customizable high-density probes for acute and chronic neural recordings in rodents Van Welie, Ingrid Neural Dynamics Technologies, Llc 2018 PAR-15-091 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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.

Develop and validate novel chemogenetic tools to modulate synaptic transmission Tomita, Susumu Yale University 2017 RFA-MH-17-220 Active
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  • Monitor Neural Activity
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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 RFA-MH-16-775 Active
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  • Monitor Neural Activity
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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 RFA-MH-14-216 Complete
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  • Interventional Tools
  • Monitor Neural Activity

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.

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 RFA-NS-16-007 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-NS-17-005 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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 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 RFA-MH-16-750 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
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 RFA-EB-17-003 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

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 PAR-15-091 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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 RFA-EY-15-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-NS-16-007 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-EY-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-MH-17-250 Active
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  • Human Neuroscience
  • Integrated Approaches
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  • Monitor Neural Activity
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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 predictive coding networks for spatial navigation Dragoi, George Yale University 2018 RFA-NS-17-014 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 RFA-NS-14-008 Complete
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-MH-17-220 Active
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  • Monitor Neural Activity
  • Interventional Tools
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 RFA-NS-16-008 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
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 RFA-EB-15-006 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools
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 RFA-EY-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-EY-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-EB-17-005 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools

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 human brain circuits in vivo using ultrasonic neuromodulation Shapiro, Mikhail Tsao, Doris Ying (contact) California Institute Of Technology 2014 RFA-MH-14-217 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • 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.
Dose Dependent Response of Cerebellar Transcranial Magnetic Stimulation Halko, Mark A Beth Israel Deaconess Medical Center 2016 RFA-MH-16-815 Active
  • Interventional Tools
  • 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 RFA-MH-14-216 Complete
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  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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-channel Sub-millisecond Resolution Neural Imaging System Zhao, Youbo Physical Sciences, Inc 2018 PAR-15-091 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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 RFA-NS-15-005 Complete
  • Cell Type
  • Circuit Diagrams
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools
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 Schroeder, Charles E Columbia University Health Sciences 2016 RFA-NS-16-008 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
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 RFA-NS-18-010 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

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 RFA-NS-17-006 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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 RFA-MH-16-815 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 RFA-EB-15-006 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools
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.
Electrophysiological Biomarkers to Optimize DBS for Depression Mayberg, Helen S Emory University 2017 RFA-NS-17-006 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity
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 RFA-MH-17-240 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • 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.
Elementary Neuronal Ensembles to Whole Brain Networks: Ultrahigh Resolution Imaging of Function and Connectivity in Humans Ugurbil, Kamil University Of Minnesota 2017 RFA-EB-17-002 Active
  • Monitor Neural Activity
  • Interventional Tools
  • 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 RFA-NS-17-014 Active
  • Integrated Approaches
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 RFA-EB-15-006 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools
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 RFA-EB-15-006 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools
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 RFA-EY-15-001 Complete
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This is an interdisciplinary team that plans to develop a new class of optogenetic tools for modulating neural activity, with potential applications that could one day be employed to treat disorders such as epilepsy or chronic pain. The team will use luciferase, a light-producing enzyme best known for its expression in fireflies, tethered to an opsin-a light-triggered ion channel. The researchers will make the luciferase sensitive to calcium ions, which enter neurons when they fire action potentials. If the luciferase is tethered to an inhibitory opsin, it will prevent neurons from being too active, and if it is tethered to an excitatory opsin, it will provide a boost to neural activity. The end result will be a set of tools with subtle regulatory capabilities that can be selectively expressed in specific neural circuits.
Enabling ethical participation in innovative neuroscience on mental illness and addiction: towards a new screening tool enhancing informed consent for transformative research on the human brain Roberts, Laura W Stanford University 2017 RFA-MH-17-260 Active
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  • Circuit Diagrams
  • 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 RFA-EB-17-003 Active
  • Human Neuroscience
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  • Monitor Neural Activity

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 RFA-MH-15-225 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 RFA-MH-17-250 Active
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  • Human Neuroscience
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  • Theory & Data Analysis Tools
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 RFA-NS-17-015 Active
  • Integrated Approaches
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 RFA-DA-18-018 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 mapping approaches for cell-type classification in the brain Behrens, M Margarita Ecker, Joseph R (contact) Salk Institute For Biological Studies 2014 RFA-MH-14-215 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.
Epigenomic mapping approaches for cell-type classification in the brain Ecker, Joseph R Salk Institute For Biological Studies 2017 RFA-MH-17-225 Complete
  • Cell Type
  • Circuit Diagrams

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 RFA-MH-14-215 Complete
  • Cell Type
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 RFA-MH-16-815 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 RFA-MH-17-250 Active
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  • Human Neuroscience
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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 RFA-MH-17-260 Active
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  • Human Neuroscience
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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.
FAST HIGH-RESOLUTION DEEP PHOTOACOUSTIC TOMOGRAPHY OF ACTION POTENTIALS IN BRAINS Wang, Lihong Washington University 2014 RFA-NS-14-007 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 RFA-EY-17-002 Active
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  • Monitor Neural Activity

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 RFA-NS-17-003 Active
  • Interventional Tools

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 RFA-EB-15-006 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 RFA-EY-15-001 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 RFA-EY-17-002 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 neural probe arrays for large-scale cortical and subcortical recording Meng, Ellis University Of Southern California 2016 RFA-NS-16-006 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 RFA-EY-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-EY-15-001 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 RFA-MH-17-240 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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 RFA-MH-16-750 Active
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  • Integrated Approaches
  • 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 RFA-MH-18-505 Active
  • Cell Type
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 RFA-MH-17-235 Active
  • Human Neuroscience
  • Integrated Approaches
  • Monitor Neural Activity

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 RFA-NS-17-014 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 RFA-NS-16-008 Active
  • Human Neuroscience
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  • Interventional Tools
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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.
GABAergic circuit interactions within the behaving mouse dLGN Bickford, Martha E (contact) Guido, William University Of Louisville 2017 RFA-NS-17-015 Active
  • Integrated Approaches
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 RFA-EB-17-001 Active
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  • Interventional Tools
  • 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 Multiple Circuit and Neuron Type Specific AAV Vectors With Cross-Species Applicability He, Zhigang Boston Children's Hospital 2015 RFA-MH-15-225 Complete
  • Cell Type
  • Circuit Diagrams
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  • Interventional Tools
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 RFA-MH-17-250 Active
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  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
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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 RFA-MH-15-225 Complete
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  • Circuit Diagrams
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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 RFA-EY-17-001 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 RFA-NS-17-004 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 RFA-NS-16-006 Active
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-NS-14-007 Complete
  • Monitor Neural Activity
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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 RFA-NS-14-007 Complete
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  • Interventional Tools
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-targeted hemodynamic functional imaging Jasanoff, Alan Massachusetts Institute Of Technology 2017 RFA-NS-17-003 Active
  • Interventional Tools
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 RFA-EB-15-006 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools
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.
High density multielectrode arrays with spatially selective unidirectional and rotating fields for investigation of neuronal networks Michaeli, Shalom University Of Minnesota 2017 RFA-NS-17-003 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 RFA-EY-16-001 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 RFA-NS-15-004 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 RFA-MH-15-200 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 RFA-EB-17-004 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 RFA-NS-17-004 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 RFA-MH-17-220 Active
  • Cell Type
  • 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 RFA-MH-17-220 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 RFA-NS-17-004 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 RFA-NS-15-006 Active
  • Human Neuroscience
  • Interventional Tools
  • 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 RFA-EY-16-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
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 Recording and Stimulating Microelectrodes Gardner, Timothy James Boston University (charles River Campus) 2014 RFA-NS-14-007 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 RFA-EY-15-001 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 RFA-NS-17-004 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 RFA-NS-15-004 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 RFA-NS-17-003 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.  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.

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 RFA-MH-18-500 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • 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 RFA-EB-15-006 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 RFA-MH-14-216 Complete
  • Cell Type
  • Circuit Diagrams
  • 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 RFA-NS-18-009 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 RFA-MH-17-257 Active
  • Cell Type
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  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • 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 RFA-MH-16-725 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 RFA-MH-17-210 Active
  • Cell Type
  • 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 RFA-MH-14-217 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 Human Brain Function with Minimal Mobility Restrictions Garwood, Michael G University Of Minnesota 2017 RFA-EB-17-002 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 RFA-MH-14-217 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 RFA-MH-14-217 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 RFA-EB-17-003 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 RFA-MH-16-815 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 RFA-NS-17-015 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 RFA-MH-17-245 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 RFA-EY-15-001 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.
Improving Human fMRI through Modeling and Imaging Microvascular Dynamics Polimeni, Jonathan Rizzo Massachusetts General Hospital 2016 RFA-MH-16-750 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 RFA-MH-16-775 Active
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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 RFA-MH-17-250 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • 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 circuit activity measurement at single cell, sub-threshold resolution Forest, Craig (contact) Stanley, Garrett B. Georgia Institute Of Technology 2014 RFA-MH-14-216 Complete
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • 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 RFA-MH-17-245 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

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

Informing Choice for Neurotechnological Innovation in Pediatric Epilepsy Surgery Illes, Judy (contact) Mcdonald, Patrick University Of British Columbia 2018 RFA-MH-18-500 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • 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.

Integrated compressive sensing microscope for high-speed functional biological imaging Chin , Sang Peter Boston University (charles River Campus) 2017 RFA-EY-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
The development of optical voltage sensors promises a direct readout of electrical activity in large populations of neurons and in subcellular domains such as axon terminals and dendritic spines. However, because these electrical events occur on millisecond timescales, this new class of optical reporters requires novel approaches to high-speed imaging. Sang (Peter) Chin and his team have developed an innovative high-speed camera design with pixelwise exposure control, which they propose to incorporate into a wireless miniature microscope to image voltage sensors in the brains of awake, behaving animals. Their new camera will incorporate compressive sensing principles to enable long camera exposure and slow readout, saving power, reducing system size, and increasing signal-to-noise ratios, while maintaining action potential detectability. This work has the potential to provide an alternative to microelectrode-based recordings, enabling high speed voltage imaging in freely-moving mammals.
Integrated fMRI Methods to Study Neurophysiology and Circuit Dynamics at Laminar and Columnar Level Chen, Wei University Of Minnesota 2016 RFA-MH-16-750 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
Functional MRI is a powerful technique for mapping functional brain activity. However, its low spatial resolution prevents accurate mapping of activity at the scale of cortical layers. Another long-standing limitation of fMRI has been the inability to study how neural inhibition impacts neural dynamics and networks. Chen and his colleagues propose to integrate ultrahigh-resolution high-field fMRI with the selective stimulation of groups of inhibitory neurons to study correlates of fMRI signals in neural circuits. This project has the potential to bring clarity to the relationship between structure and function at the level of individual neuronal layers, as well as shed light on the dynamics of neural activity.
Integrated multichannel system for transcranial magnetic stimulation and parallel magnetic resonance imaging Nummenmaa, Aapo Massachusetts General Hospital 2016 RFA-MH-16-810 Active
  • Interventional Tools
  • Human Neuroscience
Although the combined use of functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) is safe, noninvasive, and valuable for studying the brain and treating neurological disorders, this approach fails to uncover the spatiotemporal dynamics of distributed neural networks. Dr. Nummenmaa and colleagues will develop a new type of integrated multichannel TMS neuromodulation system with MRI parallel imaging, receive coil array, that can stimulate multiple brain regions simultaneously or in rapid succession, while simultaneously recording activity from the whole brain at high spatiotemporal resolution. This novel, integrated neuromodulation and imaging device holds great promise for clinical non-invasive brain stimulation applications, including TMS treatment of depression.
Integrating flexible neural probes with a giant cranial window for combined electrophysiology and 2-photon calcium imaging of cortex-hippocampal interactions Golshani, Peyman University Of California Los Angeles 2016 RFA-MH-16-725 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • Theory & Data Analysis Tools
Learning and memory retrieval may rely upon coordinated network activation in regions of the neocortex during 150-250 Hz neuronal oscillations, or ripples, in the hippocampus. Golshani’s team will implant flexible electrode arrays developed by BRAIN-funded investigators into mouse hippocampus, and will combine this technology with their large cranial window preparation. This setup should allow for long-lasting, low-noise calcium imaging of neurons across brain regions, extending from frontal to occipital cortex, bilaterally, during a memory retrieval task. The group plans to identify neurons co-activated during ripple oscillations to explore interactions between the hippocampus and neocortex, which could improve understanding of memory dysfunctions in neurodegenerative and neuropsychiatric diseases.
Integrative Analysis of Long-range Top-down Cortical Circuit for Attentional Behavior Morishita, Hirofumi Icahn School Of Medicine At Mount Sinai 2017 RFA-NS-17-015 Active
  • Integrated Approaches
Thought to be driven by regions in frontal cortex, attentional behavior underlies many core cognitive behaviors, yet its precise neural circuit mechanisms remain poorly understood. Hirofumi Morishita and collaborators plan to investigate the role of cortical circuits between the frontal and sensory cortex while dynamically modulating attentional behavior in mice. Through an innovative combination of technologies including viral mapping, electrophysiology, fiber photometry, miniscope imaging, and optogenetics, the team plans to identify when these circuits are activated, how they affect attentional behavior, and whether modulation of these circuits can improve attentional behavior. Having a strong basis for the causal role of this frontal-sensory cortical circuit will pave the way for analysis of other circuits in the brain, as well as potential examination of this circuit in pre-clinical applications.
Integrative approach to classifying neuronal cell types of the mouse hippocampus Dong, Hong-wei (contact) Zhang, Li I University Of Southern California 2017 RFA-MH-17-220 Active
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Identifying the diversity of nervous system cell types may enable their selective manipulation and reveal their functions in health and disease. Dong and his team propose state-of-the-art techniques in viral circuit tracing and molecular and electrophysiological profiling, to classify neuronal cell types of the mouse hippocampus and subiculum. Combined with CLARITY (a tissue-clearing technique), expansion microscopy, and multiphoton imaging, their approach will report the anatomical location, connectivity, morphology, molecular profile, and electrophysiological characteristics of each cell type. Raw and analyzed data will be publicly shared on the Mouse Connectome Project website. If successful, this work can be applied toward characterizing neuronal cell types of the entire brain.
Integrative Functional Mapping of Sensory-Motor Pathways Dickinson, Michael H (contact) Holmes, Philip J Mann, Richard S Wilson, Rachel California Institute Of Technology 2014 RFA-NS-14-009 Complete
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Dr. Dickinson will lead an interdisciplinary team to study how the brain uses sensory information to guide movements, by recording the activity of individual neurons from across the brain in fruit flies, as they walk on a treadmill and see and smell a variety of sights and odors.
Interdisciplinary Training in Computational Neuroscience for Researchers from Graduate and Medical Students to Junior Faculty Nair, Satish S University Of Missouri-columbia 2015 RFA-MH-15-215 Complete
  • Theory & Data Analysis Tools
A longstanding goal of neuroscience research is to understand how activity of individual neurons and within neural circuits gives rise to outputs ranging from movement to thought. Integrative and interdisciplinary training in neuroscience is necessary to help develop scientists who can work together to address this goal by using approaches from diverse fields including biology, psychology, computer science, electrical engineering, and physics. Nair and colleagues propose to develop a new training course designed to strengthen the quantitative skills of students with biological backgrounds and increase the knowledge of neuroscience concepts for those students from quantitative backgrounds. This will fill a training gap at the pre- and post-doctoral and junior faculty levels.
Intrabody-dependent activation of cell-specific gene expression in CNS Blackshaw, Seth Johns Hopkins University 2015 RFA-MH-15-225 Complete
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Techniques for inducing specific cell types to express certain proteins typically require using genetically engineered animals, which are limited primarily to rodents and can take years to develop. Blackshaw and colleagues are developing tools that will allow specific cells to be labeled and manipulated without complex genetic approaches. If successful, this technology would enable the labeling and modification of multiple types of specific neurons in nearly any animal, at a fraction of the cost and time of current techniques.
Intracellular calcium sensing with molecular fMRI Jasanoff, Alan MASSACHUSETTS INSTITUTE OF TECHNOLOGY 2018 RFA-NS-17-003 Active
  • Interventional Tools

Minimally invasive direct readouts of neural activity could be obtained by combining whole-brain MRI with the molecular specificity of calcium sensors. Jasanoff’s team will build on prior BRAIN-funded work to develop contrast agents with calcium sensors for direct readout of neural activity by MRI, as opposed to indirect fMRI methods. They will develop small molecule calcium binding agents that are cell permeable in their synthesized form but remain inside the cell following cleavage by endogenous enzymes. The team will engineer sensors with increased sensitivity, that are selectively retained in defined cell populations, and perform in vivo validation in rats. This project could achieve non-invasive, cellular-level characterization of functional neuroarchitecture throughout the brain that may help to advance the study and diagnosis of neurological diseases. 

Intraoperative studies of flexible decision-making Baltuch, Gordon H (contact) Gold, Joshua I University Of Pennsylvania 2017 RFA-NS-17-019 Active
  • Human Neuroscience
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  • Monitor Neural Activity
Even relatively simple sensory-motor decisions, such as goal-directed eye movements, exhibit sufficient flexibility and nuance to be considered a “window on cognition.” Gordon Baltuch’s team will leverage the unique opportunity provided by surgical treatment of Parkinson’s disease using deep brain stimulation, to study decision-making in the human brain at the single-neuron level. The team will simultaneously measure behavioral response time and accuracy (by asking neurosurgical patients to select a visual stimulus via eye movements) while performing brain electrophysiology. Additionally, they will conduct parallel monkey and human studies that, unlike Parkinson’s studies alone, will distinguish normal versus disrupted mechanisms in the Parkinson’s -affected brain. This project may yield a sustainable research program that probes not only neural mechanisms of decision-making, but also potential causes of, and remedies to, cognitive side effects associated with deep brain stimulation.
Invasive Approach to Model Human Cortex-Basal Ganglia Action-Regulating Networks Pouratian, Nader University Of California Los Angeles 2016 RFA-NS-16-008 Active
  • Human Neuroscience
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Circuits between the frontal cortex and basal ganglia (BG) may support the ability to suppress actions once additional information becomes available to indicate the most appropriate decision, but few studies provide the necessary spatial and temporal resolution to investigate this mechanistically. Dr. Pouratian’s group will utilize deep brain stimulation (DBS) electrodes in Parkinson’s patients to record from cortical and BG regions in multiple action-suppression tasks. In addition to investigating unit and local field potential activity during tasks, the group will use DBS coupled with functional imaging to stimulate the circuits and measure effects on brain activity, eventually developing a computational model of action suppression. Aside from informing the basic science of this circuitry, this project could expand upon how DBS influences brain networks for action, which could improve therapeutic use in various disorders.
Investigating information processing in parallel circuits that link external chemical signals to social behavior Meeks, Julian P Ut Southwestern Medical Center 2017 RFA-NS-17-015 Active
  • Integrated Approaches
Understanding the contributions of sensory circuits to perception, emotions, and behavior is a critical task in neuroscience, but for the accessory olfactory system in mice – an ideal-model sensory circuit – technical barriers have prevented a thorough investigation. Julian Meeks’ team aims to overcome these barriers by expanding the capacity to measure olfactory chemosensory encoding and integration ex vivo through stereolithography and volumetric imaging methods. They also plan to evaluate how the accessory olfactory system sorts information in the olfactory bulb and its immediate downstream targets through retrograde labeling and multi-site multi-electrode recordings. Success with this ambitious project will improve our understanding of the mechanisms by which mammalian neural circuits decode environmental information and use that information to guide behaviors.
Investigating the hypocretin to VTA circuit in memory consolidation during sleep Borniger, Jeremy Stanford University 2018 RFA-MH-17-250 Active
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Brain-computer interfaces and neuroprosthetics have provided a significant benefit to patients with cervical spinal cord injuries. However, current technology is limited in its abilities to allow the user to control how much force is exerted by the prosthesis and to provide sensory feedback from the prosthetic hand. In a public-private collaboration with Blackrock Microsystems, Dr. Boninger and colleagues are looking to improve the dexterity of neuroprostheses by incorporating microstimulation of the somatosensory cortex. This stimulation could provide tactile feedback to the user and hopefully allow the user to better control the force applied. Ultimately, this approach will improve the dexterity and control of prosthetic limbs used by patients with spinal cord injuries.

Investigating the neurocircuitry of sleep duration regulation Fu, Ying-hui University Of California, San Francisco 2018 RFA-NS-17-014 Active
  • Integrated Approaches
Gene variations have been identified (called ADRB1 and DEC2) that enable individuals expressing these variations to sleep fewer hours per day without health detriments. Fu’s team seeks to demonstrate that there are unique neurocircuits for sleep duration/efficiency, separate from sleep/wake-promoting circuits. First, the team will systematically search for ADRB1-positive and DEC2-positve cells in the brains of transgenic mice. To confirm that ADRB1/DEC2-expressing networks are critical for regulating sleep duration/efficiency, they will pharmacogenetically and optogenetically manipulate ADRB1/DEC2-expressing neurons/circuits and evaluate the resulting effects on sleep. To understand mechanistic relationships, they will examine ADRB1/DEC2-positive cell activities while monitoring sleep state with EEG/EMG recording. This project may lead to a better understanding of the neurocircuitry of sleep regulation.
Investigating the Role of Neurotensin on Valence Assignment During Associative Learning in the Basolateral Amygdala Olson, Jacob Michael Massachusetts Institute Of Technology 2017 RFA-MH-17-250 Active
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Dr. Olson will systematically identify, manipulate, and characterize the neural projections that release the neuropeptide neurotensin to the basolateral amygdala during behavior conditioning tests in mice to identify a new circuit that regulates associative learning.
Is the Treatment Perceived to be Worse than the Disease?: Ethical Concerns and Attitudes towards Psychiatric Electroceutical Interventions Cabrera Trujillo, Laura Yenisa Michigan State University 2018 RFA-MH-18-500 Active
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  • Human Neuroscience
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The NIH BRAIN Initiative aims to catalyze novel tools and technologies to modulate brain circuit function, paving the way for new treatment options for brain disorders. However, such interventions also have the potential to cause unintended changes in aspects of cognition, behavior, and emotion. These changes, in turn, raise concerns regarding autonomy, personal identity, and capacity for informed consent. In this study, Dr. Cabrera Trujillo and her team will study ethical concerns, beliefs, and attitudes about the use of novel bioelectric approaches among clinicians, patients, and the broader public. The work will provide stakeholder perspectives that will be valuable for informing the responsible development and use of these novel neurotechnologies.

kHz-rate in vivo imaging of neural activity througout the living brain Ji, NA UNIVERSITY OF CALIFORNIA BERKELEY 2018 RFA-NS-17-003 Active
  • Interventional Tools

A foundational goal of the BRAIN Initiative is to monitor neural activity at the “speed of thought,” which requires fundamentally-new technologies like multiphoton fluorescent microscopy to obtain millisecond-resolution signals from extended volumes of brain tissue. The Tsia lab’s innovative laser scanning technique (Free-space Angular-Chirp-Enhanced Delay, FACED) bypasses mechanical scanning mirrors to achieve line-scanning rates that are significantly faster than current state-of-the-art. Working with Ji and colleagues, the team will leverage this method with multiphoton imaging and computational modeling for kHz-rate in vivo imaging of neural activity throughout the brains of behaving mice on a millisecond scale.

Label-free 4D optical detection of neural activity Bazhenov, Maksim V Binder, Devin K Park, Boris Hyle (contact) University Of California Riverside 2015 RFA-EY-15-001 Complete
  • Monitor Neural Activity
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Development of technologies for large-scale imaging of neural activity at the single cell level is a fundamental goal of the BRAIN Initiative. Most optical techniques for achieving this goal require labeling neurons with a genetic or chemical probe that can be imaged. Park and his colleagues propose a novel method for achieving this goal by adapting a technique called optical coherence tomography (OCT), which captures light as it reflects off the surface of living tissue, and doesn't require that neurons be labeled. When neurons fire action potentials they undergo ultra-small changes in size and shape that Park and his team will measure by examining the intensity and phase of the OCT signal. If OCT is successful in living animals, it could produce label-free and depth-resolved images of activity from thousands of neurons with micron-scale spatial resolution and sub-millisecond temporal resolution.
Lagging or Leading? Linking Substantia Nigra Activity to Spontaneous Motor Sequences Adams, Ryan Prescott Datta, Sandeep R Sabatini, Bernardo L (contact) Harvard Medical School 2015 RFA-NS-15-005 Complete
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One of the goals of the BRAIN Initiative is to understand how the brain generates behaviors. These researchers are utilizing a novel 3D machine vision technology to automate classification of spontaneous behavior when freely-moving mice are confronted with stimuli; they are then correlating that information with dense recordings of neural activity in key regions of the brain implicated in movement disorders. Researchers are then manipulating the activity of specific neurons in this brain region with light to test their role in the animal’s behavior. Dr. Sabatini and colleagues offer an innovative ‘grammatical’ structure to understanding how the brain produces complex, systematic behavior.
Large-scale analysis of functional synapses during circuit plasticity with novel optogenetic sensors Zito, Karen University Of California At Davis 2017 RFA-NS-17-003 Active
  • Interventional Tools
Altered synaptic transmission has been associated with a variety of brain disorders, including epilepsy, schizophrenia, autism, and addiction. Karen Zito and colleagues will develop glutamate sensors for monitoring individual synapses over larger fields-of-view, incorporating slower kinetics for large-scale monitoring, in awake zebrafish and mice. These novel sensors may then be applied to a variety of advanced imaging techniques, such as wide-field, confocal, and two-photon microscopy, to ultimately lead to a better understanding of mechanisms underlying neuronal plasticity, circuit dynamics, and behavior.
Large-scale cellular-resolution voltage imaging of the zebrafish brain Gong, Yiyang DUKE UNIVERSITY 2018 RFA-NS-17-003 Active
  • Interventional Tools

Genetically-encoded voltage indicators (GEVIs) can detect single action potentials with millisecond precision at large spatial scales; however, voltage imaging techniques have not yet matched the temporal resolution of GEVIs. Dr. Yiyang Gong will develop a set of novel optical, electronic, and protein tools to broaden voltage imaging technology with GEVIs. He will create a hybrid light-sheet/light-field microscope that will use volumetric light-sheet excitation to illuminate multiple depths, and light-field imaging to reconstruct the images at the illuminated depths. In addition, he will engineer a new camera system for the implementation of the microscope that will be able to read out a sensor chip at fast speeds with low noise. This toolkit will be developed in zebrafish with the goal of expanding and/or adapting to other model systems to better understand brain circuit dynamics.

Large-Scale Electrophysiological Recording and Optogenetic Control System Goodell, Albert Baldwin Graymatter Research 2014 RFA-NS-14-008 Complete
  • Monitor Neural Activity
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Dr. Goodell and his colleagues aim to develop optrodes, which are implantable columns of lights and wires for simultaneous electrical recording of neurons and delivery of light flashes to multiple brain areas.
Large-scale monitoring of sensory transformations in the mammalian olfactory system Burton, Shawn Denver University Of Utah 2017 RFA-MH-17-250 Active
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  • Human Neuroscience
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Dr. Burton will leverage recent enhancements in calcium indicators to image pre- and post-synaptic neural activity simultaneously in the mammalian olfactory system, gaining insight into how sensory information is transformed as it moves through a neural circuit.
Large-scale Network Modeling for Brain Dynamics: Statistical Learning and Optimization Luo, Xi Brown University 2016 RFA-EB-15-006 Active
  • Integrated Approaches
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Functional MRI (fMRI) is a useful technique for examining brain-wide networks involved in tasks that involve perceiving stimuli and behaviorally responding to those stimuli. Luo and his colleagues are applying machine learning approaches for modeling whole-brain networks using fMRI and behavioral response data captured during the performance of specific tasks. The algorithms the team develops will facilitate the analysis of a wide array of neuroimaging and behavioral data, which may lead to the discovery of pharmacological targets for treating neurological and psychiatric disorders.
Large-scale recording of population activity during social cognition in freely moving non-human primates DRAGOI, VALENTIN et al. UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON 2018 RFA-NS-18-008 Active
  • Integrated Approaches

Humans are social creatures. Positive interactions with others, such as cooperation and altruism, are important for our species’ health and survival, but not much is known about the mechanisms underlying these behaviors. Drs. Aazhang, Dragoi, and Wright plan to identify specific brain regions involved in social cognition and investigate how brain activity changes as animals determine whether to cooperate with each other. The team will record brain activity in freely interacting monkeys as they participate in social cognition tasks, including working with one another to obtain food. Increased knowledge about complex social behaviors may help understand collective interactions among individuals and could improve treatments for certain mental health disorders.

Large-scale, simultaneous intracellular recording and stimulation of neural activity London, Michael Nelken, Israel Spira, Micha E. (contact) Hebrew University Of Jerusalem 2016 RFA-NS-16-006 Active
  • Monitor Neural Activity
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Current in vivo multi-electrode recording devices monitor extracellular spiking activity from multiple neurons, but they do not capture the full range of neural activity that is available from intracellular recordings. Intracellular recordings are commonly obtained from brain slices or cultured neurons, but are very difficult to acquire in freely moving animals where it is typically only possible to record from one neuron at a time. Dr. Spira and colleagues will apply a novel method using arrays of micron-size, gold electrodes that are shaped like mushrooms and coated with bioactive materials to form a tight seal with the plasma membrane, allowing intracellular electrode access. If successful, the arrays will enable in vivo long-term intracellular recordings of action potentials and subthreshold activity from dozens to hundreds of individual neurons.
Learning spatio-temporal statistics from the environment in recurrent networks Brunel, Nicolas Shouval, Harel Zeev (contact) University Of Texas Hlth Sci Ctr Houston 2016 RFA-EB-15-006 Active
  • Integrated Approaches
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Learning new tasks and interacting with new environments leads to changes in the dynamics of brain circuits. The ability of animals to incorporate the statistical properties of the environment into decision-making brain circuits is necessary for survival. Shouval and his colleagues plan to develop a theoretical model for how brain circuits implement these statistics. This model may provide novel insights into the basis of a variety of neurophysiological processes, including learning and memory.
Lightweight, Compact, Low-Cryogen, Head-Only 7T MRI for High Spatial Resolution Brain Imaging Foo, Thomas (contact) Shu, Yunhong Xu, Duan General Electric Global Research Ctr 2018 RFA-EB-17-004 Active
  • Human Neuroscience
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Non-invasive magnetic resonance imaging (MRI) is an important tool for our understanding of the human brain. However, ultra-high field magnets are hampered by their massive size and challenging installation, limiting their accessibility to researchers and clinicians. Dr. Thomas Foo and a team of investigators propose the development of a 7T MRI system with high-performance head gradients, delivering a head-only, high-resolution MRI system that is significantly smaller and lighter in comparison to existing ultra-high field systems. The group will design, optimize, and validate a head-only 7T MRI system, piloting the system in healthy volunteers to assess the quality of the structural, functional, and metabolic data. The proposed work has the potential to open a range of scientific and clinical applications that cannot currently be achieved with existing instrumentation.

Linking neuronal, metabolic, and hemodynamic responses across scales Ghose, Geoffrey M University Of Minnesota 2018 RFA-MH-17-235 Active
  • Human Neuroscience
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  • Monitor Neural Activity

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

Linking Plasticity of Hippocampal Representation across the Single Neuron and Circuit Levels BASU, JAYEETA et al. NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 RFA-NS-18-009 Active
  • Integrated Approaches

Functional circuits between the entorhinal cortex and hippocampus are known to play a major role in spatial navigation and episodic memories. To develop a theoretical model of studying neural plasticity at both the single cell and circuit levels, Drs. Basu and Clopath will target specific cortico-hippocampal circuits using in vivo two-photon calcium imaging, slice electrophysiology, and optogenetic manipulation, in newly-developed transgenic mice. The knowledge gained from these experiments will aid in the understanding of neural circuits of functional memory and may influence treatments for diseases with neurological dysfunctional states, such as Alzheimer’s disease. 

LIPS: A novel technology for spatial and temporal control of protein synthesis in dendritic spines Gan, Wenbiao Jaffrey, Samie R (contact) Weill Medical Coll Of Cornell Univ 2015 RFA-MH-15-225 Complete
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Synaptic plasticity involves changes in protein expression that are precisely localized to dendrites and synaptic spines, but current techniques for manipulating gene expression are not able to approach these small scales. Jaffrey and colleagues propose a method called light-induced protein synthesis (LIPS), using RNA transcripts under control of plant-derived phytochrome proteins that can be activated by microscopic laser spots. The ability to directly manipulate the protein content at specific synapses and spines may greatly enhance efforts to decipher the roles of synaptic proteins in learning, memory, behavior, and disease.
LOCATER: Large-scale Observation of Cellular Activity Through Exosomal Reporters Zhang, Feng Broad Institute, Inc. 2015 RFA-EY-15-001 Complete
  • Monitor Neural Activity
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Dr. Zhang's project will test a completely novel idea to assay neural activity using a blood test. It will harness the capabilities of exosomes, which are nano-scale vesicles containing protein and RNA cargo that are secreted from cells throughout the body. They readily cross the blood-brain barrier and they protect their RNA cargo from degradation in the blood. The proposal is to induce neurons to express RNA molecules that will be packaged into exosomes in response to neuronal electrical activity. Each cell's RNA molecules will have their own unique "barcode" sequences that will allow investigators to know what cells the RNA molecules came from after they are harvested from the blood. This will enable complex experiments to test neuronal circuit contributions to behaviors and to understand circuit disruptions associated with specific diseases.
MACHINE LEARNING APPROACHES FOR ELECTROPHYSIOLOGICAL CELL CLASSIFICATION Barth, Alison L Carnegie-mellon University 2017 RFA-NS-17-015 Active
  • Integrated Approaches
Recordings of neural spike activity produce high-density, temporally precise patterns of neural firing that researchers aim to deconstruct into meaningful accounts of information processing in the brain. As the amount of generated data increases, neuroscientists need to decode more information than neuronal firing – they must be able to identify which specific cell-types are firing. Alison Barth is teaming up with computer scientists to develop a machine-learning classifier that can differentiate between inhibitory neuron subtypes in somatosensory cortex by using information from features such as rate of spontaneous firing, response to stimulation, and covariance of activity. By developing algorithms for cell identification that can identify specific neuron subtypes from spike train data in vivo, this project has the potential to build bridges between local circuit computations and cognitive processes.
Magnetic camera based on optical magnetometer for neuroscience research Alem, Orang FIELDLINE, INC. 2018 PAR-15-090 Active
  • Circuit Diagrams
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  • Monitor Neural Activity

A camera that could image neuronal current distributions with a large array of pixels and a spatial resolution better than 1 ms resolution could dramatically enhance our understanding of neuronal circuitry. In this Phase I STTR, Fieldline, Inc. will develop a novel type of magnetographic camera, capable of providing single-shot images of electrical currents in neuronal circuits in vitro and in vivo with a millisecond time resolution. The team will first build a bench-top camera before combining it with electrode arrays, testing the ability to image neuronal connections across the circuit in vitro with turtle cerebellem. This will potentially lead to a completely portable, economical multi-pixel camera that can be produced for neuroscience research. 

Magnetic Particle Imaging (MPI) for Functional Brain Imaging in Humans Conolly, Steven M Griswold, Mark Wald, Lawrence L (contact) Massachusetts General Hospital 2014 RFA-MH-14-217 Complete
  • Monitor Neural Activity
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  • Human Neuroscience
The Wald team plans to use an iron-oxide contrast agent to track blood volume, which will permit dramatically more sensitive imaging of human brain activity than existing methods.
Manifold-valued statistical models for longitudinal morphometic analysis in preclinical Alzheimer's disease (AD) Johnson, Sterling C Singh, Vikas (contact) University Of Wisconsin-madison 2016 RFA-EB-15-006 Active
  • Integrated Approaches
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In light of the profound public health issues Alzheimer’s disease (AD) represents, there is a tremendous need for methods to identify the onset of the disease as early as possible. Singh and his colleague propose to develop novel methods for analyzing Cauchy deformation tensors (CDTs) in brain images. These methods will enable the identification of structural changes in healthy midlife adults that are predictive of AD onset. The proposed analysis will be conducted on the largest preclinical AD cohort assembled to date and will help inform how telltale clinical biomarkers of AD emerge in asymptomatic individuals at risk for the disease. These preclinical biomarkers may be used in the design of clinical trials for new therapies.
Mapping and controlling gene expression in inhibitory interneurons mammals Fishell, Gordon J New York University School Of Medicine 2016 RFA-MH-16-775 Complete
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In order to better understand what influences normal brain development, it is necessary to track changes in gene expression over time and in different contexts, including learning and development. Fishell and colleagues modified DNA Adenine Methyltransferase Identification technology (DamID) to make it inducible in forebrain interneurons at particular developmental time points to measure gene activation. The new DamID will provide a transcriptome timestamp in a diverse cell population without requiring transgenic tools. The group intends to use transcriptome data and computational programming to expand into viral vectors to modulate interneuron subgroups in mice and non-human primates.
Mapping neuronal chloride microdomains Staley, Kevin J. Massachusetts General Hospital 2014 RFA-MH-14-216 Complete
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Using protein engineering technology to monitor the movement of chloride through inhibitory neurotransmitter receptor channels, Dr. Staley's group aims to understand the role of chloride microdomains in memory.
Mapping neurotransmitter receptors onto the connectome Zipursky, S. Lawrence University Of California Los Angeles 2018 RFA-MH-18-505 Active
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The Zipursky team plans to develop a system for finding postsynaptic neurotransmitter receptors on high-resolution pictures of synapses. By combing expansion microscopy with CRISPR-based and stochastic single-cell labeling techniques the team aims to tag receptors found at the synapses of Drosophila visual system circuits. With minor adjustments, these techniques may one day be used to map receptors in the human brain.

Mapping of spatiotemporal code features to neural and perceptual spaces RINBERG, DMITRY et al. NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 RFA-NS-18-009 Active
  • Integrated Approaches

Sensory systems neuroscience investigates how stimuli are represented by the activity of populations of neurons, as well as how neural circuits process this information, resulting in behavioral outcomes. After varying patterns of optogenetic stimulation and recording both neural activity and behavioral output, Drs. Rinberg and Panzeri will develop a mathematical model of neural coding for odor discrimination in mice. Their model may determine the specialized spatiotemporal neural code involved in olfactory processing which could be further applied to other neural circuits.  

Mapping the Developing Human Neocortex by Massively Parallel Single Cell Analysis Kriegstein, Arnold University Of California, San Francisco 2014 RFA-MH-14-215 Complete
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By combining genetic, molecular and physiological techniques at the single cell level, Dr. Kriegstein and colleagues will classify diverse cell types in the prefrontal cortex of developing human brain tissue.
Massive scale electrical neural recordings in vivo using commercial ROIC chips Kording, Konrad P. (contact) Schaefer, Andreas Rehabilitation Institute Of Chicago 2015 RFA-NS-15-003 Complete
  • Monitor Neural Activity
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Increasing the number and density of electrically recorded neurons in behaving animals is an important goal for achieving a nuanced and accurate rendering of neural circuit function. To date, efforts to achieve this goal have relied on specialized hardware developed for neural recordings. Kording and Schaefer and their colleagues propose a radically different approach that uses readout integrated circuit (ROIC) arrays taken from commercial infrared camera chips, which they will bind to bundles of glass-insulated gold microwires. In principle, this should enable recordings from tens- to hundreds-of-thousands of neurons in rodent brain tissue. Since commercial camera array electronics are continuing to improve in speed and scale, successful implementation could just be a starting point for this approach.
Measuring, Modeling, and Modulating Cross-Frequency Coupling Eden, Uri Tzvi Kramer, Mark Alan (contact) Boston University (charles River Campus) 2018 RFA-EB-17-005 Active
  • Integrated Approaches
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Cross-frequency coupling (CFC) is a phenomenon through which brain rhythms of different frequencies (fast vs. slow oscillations) coordinate to enable efficient communication between and among neural networks. Current methods measure a single type of CFC related to a given research question, but do not necessarily account for different interactions or combinations between phase and amplitude in fast and slow frequency bands. Drs. Kramer and Eden will develop a more general statistical inferential framework to estimate CFC in rats by creating a method to acquire real-time phase and amplitude data for estimation of CFC to accommodate dynamic manipulations. The team will incorporate computational modeling studies to simulate CFC between the amygdala and the frontal cortex and test via in vivo experiments. This framework will allow future users to explore the basis of network communication in the brain and evaluate the causal role of cross-frequency coupling.

Mechanism and dosimetry exploration in transcranial electrical stimulation using magnetic resonance current mapping methods. Sadleir, Rosalind J Arizona State University-tempe Campus 2017 RFA-MH-17-245 Active
  • Monitor Neural Activity
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  • Human Neuroscience
Interest in transcranial electrical stimulation (tES) has escalated over the last decade, but the mechanisms of action of these therapies are unclear, and study results suffer from high variability. This project proposes to precisely measure where electrical energy flows in the brains of subjects and compare this with brain activity levels. Sadleir’s team will develop a technique based on MR electrical impedance tomography to measure current density and electric field distributions in the brains of healthy human subjects experiencing tES. The electrical distributions will be correlated with memory performance measures and brain activity measures using fMRI, including a specific target structure in the prefrontal cortex. This new approach will bolster explorations into the mechanisms of electrical stimulation therapies, with potential to revolutionize researchers’ understanding of tES, a technique with applications ranging from basic mechanistic studies on electrical neuromodulation to stroke and epilepsy therapy to memory enhancement.
Mechanisms of electrical stimulation of a canonical motor microcircuit Heckman, Charles NORTHWESTERN UNIVERSITY AT CHICAGO 2018 RFA-NS-18-018 Active
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  • Human Neuroscience
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  • Monitor Neural Activity
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A central goal of the NIH BRAIN Initiative is to develop new and improved methods for modulating the activity of specific neural cells and circuits, including those of the spinal cord. Dr. Heckman and his team will study the effect of dorsal electrical stimulation (DES) on motor circuits of the lumbar spinal cord. Specifically, they will investigate how DES affects two functions of descending inputs from the brain to the spinal cord – the generation of movements and the control of spinal neuron excitability. This work will help define the potential of DES for selective control of spinal motor circuits and may inform efforts to restore movement after spinal cord injury via DES.

Mechanisms of neural circuit dynamics in working memory Bialek, William Brody, Carlos D (contact) Seung, Hyunjune Sebastian Tank, David W Wang, Samuel Sheng-hung Witten, Ilana Princeton University 2014 RFA-NS-14-009 Complete
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Dr. Brody and his colleagues will study the underlying neuronal circuitry that contributes to short-term "working" memory, using tools to record circuit activity across many brain areas simultaneously while rodents run on a track-ball through virtual mazes projected onto a screen.
Mechanisms of neural circuit dynamics in working memory anddecision-making Brody, Carlos D (contact) Pillow, Jonathan William Seung, Hyunjune Sebastian Tank, David W Wang, Samuel Sheng-hung Witten, Ilana Princeton University 2017 RFA-NS-17-018 Active
  • Integrated Approaches
Intense research efforts have focused on understanding working memory and decision-making, but technical and theoretical limitations have prevented a thorough understanding of these cognitive processes. Building on a previous BRAIN award, Carlos Brody and a team of experts are now aiming to outline a multi-brain-region, biophysical circuit model of the mechanisms that underlie working memory and decision-making. While mice complete a working memory task, the group will employ a variety of advanced imaging methods and optogenetic inactivation approaches to inform computational methods of incorporating these data into an integrative circuit model of the central nervous system. This combination of innovative methods can provide a mechanistic understanding of how the brain works with information.
Mechanisms of Rapid, Flexible Cognitive Control in Human Prefrontal Cortex Sheth, Sameer BAYLOR COLLEGE OF MEDICINE 2018 RFA-NS-18-010 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

The human brain can quickly “program” itself to adapt to novel situations, such as figuring out how to drive a rental car through a new city. Dr. Sheth and his colleagues plan to investigate how the brain assembles pieces of information into plans that help us manage new circumstances, and then develops a computational model of this learning. They will record from the brain’s dorso-lateral prefrontal cortex in patients with deep brain stimulation who are performing tasks to understand what information is being encoded and how it is processed. The project offers to provide a computational understanding of complex cognition. This may improve our understanding of cortical brain function and of neurological disorders that interfere with complex thinking.   

Mechanisms underlying positive and negative BOLD in the striatum Shih, Yen-yu Ian Univ Of North Carolina Chapel Hill 2018 RFA-MH-17-235 Active
  • Human Neuroscience
  • Integrated Approaches
  • Monitor Neural Activity

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

Mechanistic and causal basis of fMRI functional connectivity in non-human primates Rudebeck, Peter (contact) Russ, Brian E Icahn School Of Medicine At Mount Sinai 2018 RFA-MH-17-235 Active
  • Human Neuroscience
  • Integrated Approaches
  • Monitor Neural Activity

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

Mechanistic dissection of the neural basis of the resting-state fMRI signal using multi-modal approaches Drew, Patrick James Zhang, Nanyin (contact) Pennsylvania State University-univ Park 2017 RFA-MH-17-235 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
The neural basis of resting-state fMRI (rsfMRI) signal remains poorly understood. Particularly, poor understanding of cellular and circuit-level mechanisms underlying resting-state functional connectivity (RSFC) has hampered rsfMRI interpretation. Nanyin Zhang’s team will dissect the signal contributions of spiking activity from individual neuron populations. They will use multi-echo-rsfMRI (differentiates neural and non-neural rsfMRI signal components) to quantify RSFC by eliminating non-neural artifacts, and calcium-based fiber photometry to measure simultaneous neuronal and rsfMRI signals with neuron-type specificity. Finally, the group will optogenetically increase neuronal excitability and examine resulting RSFC and cortical-layer-specific electrophysiological signal changes. This project may enhance understanding of rsfMRI signal in humans, impacting brain disorder research.
Memory consolidation during sleep studied by direct neuronal recording and stimulation inside human brain FRIED, ITZHAK UNIVERSITY OF CALIFORNIA LOS ANGELES 2018 RFA-NS-18-010 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Sleep is important for learning and memory, but the exact mechanisms of this process are not known. Dr. Fried and his team will examine the role of sleep in memory formation in humans by recording brain activity during sleep following learning tasks. Dr. Fried’s group will identify the sleep events, such as sleep stage or changes in firing activity, that show the strongest association with memory consolidation. They will also examine whether electrical or auditory stimulation during sleep improves memory performance compared to undisturbed sleep. Greater knowledge of these mechanisms may help in the development of treatments for people suffering from memory and/or sleep disorders. 

Mental, measurement, and model complexity in neuroscience Balasubramanian, Vijay Gold, Joshua I (contact) University Of Pennsylvania 2018 RFA-EB-17-005 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools

Three specific challenges for neuroscience data include: 1) identifying the relevant spatial, temporal, and computational scales in which the underlying information-processing dynamics are best understood, 2) identifying the best ways to design and select models to account for these dynamics, and 3) inferring what the data tells us about how the brain itself processes complex information. Drs. Gold and Balasubramanian will develop theoretical tools for understanding how the brain integrates information across large temporal and spatial scales, using definitions of complexity to facilitate the analysis and interpretation of complex neural and behavioral data sets. This formal, mathematical assessment of data complexity could be used by the community for other data-driven model building and for comparisons of existing neuroscience models.

Methodologically-Integrated Approaches Linking Cell Types to Neural Circuits and Function Callaway, Edward M Salk Institute For Biological Studies 2017 RFA-NS-17-015 Active
  • Integrated Approaches
Cortical circuits in the mouse are relatively well understood, but the extent they generalize to phylogenetically higher species remains unclear. Edward Callaway and colleagues are developing a suite of methods that will record neurons in non-human primate cortex, to better understand principles and functions of neural circuits in this model organism. Through molecular, genetic, viral, and large scale optical and electrical tools - including high-density electrode arrays and two-photon calcium imaging, Callaway’s team will investigate the levels of selectivity at which visually-evoked activity can be linked to circuits in terms of their cell types, connections, and functions. This novel approach in macaque monkeys has the potential to characterize large ensembles of simultaneously recorded neurons in important ways, a critical step in understanding neural circuitry across species.
Methods from Computational Topology and Geometry for Analysing Neuronal Tree and Graph Data Mitra, Partha Pratim (contact) Wang, Yusu Cold Spring Harbor Laboratory 2016 RFA-EB-15-006 Active
  • Integrated Approaches
  • Theory & Data Analysis Tools
The complex tree shapes of neurons are important for their role in neuronal circuitry, but they are mathematically challenging to characterize and analyze. Mitra and his colleagues are applying advanced methods from computational topology and geometry to classify neuronal structure and its role in the function of circuits. The resulting tools will be made available to neuroscientists studying normal and diseased brain circuitry.
Micro-coil implants for cortical activation Fried, Shelley Massachusetts General Hospital 2016 RFA-NS-16-006 Active
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  • Interventional Tools
Conventional stimulating electrodes are an important tool with great potential for studying neural circuits and treating brain disorders, but they have limitations, including off-target stimulation of cortical neurons and a gradual reduction in effectiveness due to scarring of surrounding brain tissue. Dr. Fried’s group will develop tiny, micro-coil based implants that stimulate neurons with a magnetic field rather than injection of electrical current. This approach promises greater spatial selectivity with less sensitivity to tissue scarring, which would be a major advance over current methods. The resulting technology could have important implications for therapies based on brain stimulation, since it would provide more selective targeting of specific circuits, longer-term stability, and minimization of unwanted side-effects.
Micro-TMS Technology for Ultra-Focal Brain Stimulation Bonmassar, Giorgio Massachusetts General Hospital 2016 RFA-MH-16-810 Active
  • Interventional Tools
  • Human Neuroscience
Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that is widely used for studying the brain and treating a number of neuropsychiatric disorders, such as stroke and depression. TMS can be used to investigate the functional role of specific brain cortical areas in implementing a particular cognitive or behavioral function. However the precision of this approach is limited by the spatial resolution of TMS. Micromagnetic stimulation (μMS) is an emerging technology that uses small coils to focally stimulate neural activity. Dr. Giorgio Bonmassar and colleagues will incorporate μMS technology into novel, miniaturized TMS (μTMS) elements to non-invasively increase the precision and depth of TMS stimulation. Their ultra-small size will allow for stimulatiion and mapping of the human cortex with unprecedented resolution, with elements that could be adapted into arrays on a helmet-like device that will allow, for the first time, simultaneous multi-focal stimulation of the human brain.
Microdevice mediated functional brain imaging with high temporal and spatial resolution Wong, Eric C University Of California San Diego 2016 RFA-EY-16-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
Current methods for functional brain imaging such as EEG or MEG can provide high temporal resolution, but they are limited in their spatial resolution and brain coverage. In contrast, functional MRI offers broad coverage, but it has low temporal resolution and is an indirect and incomplete measure of neural activity. Wong and his colleagues propose to combine the benefits of high-resolution electrical recordings with broad spatial coverage offered by MRI, using injected microelectronic devices that rapidly convert electric signals into magnetic fields detectable with an MRI scanner. As an intermediate goal, the researchers will record neural activity from the entire cortical surface at a sub-millimeter scale and 10 ms resolution, providing a measure of electrical activity at every cortical column simultaneously. This new approach could provide vastly richer functional data than is currently possible, and accelerate efforts to understand brain function.
Microscopic foundation of multimodal human imaging Dale, Anders M Devor, Anna (contact) University Of California San Diego 2016 RFA-MH-16-750 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
The computational properties of the human brain arise from an intricate interplay between billions of neurons of different types that are connected in complex networks. The hypothesis behind the project from Devor and her colleagues is that specific neuronal cell types have identifiable “signatures” in the way they contribute to large electrical signals that drive changes in the brain’s energy metabolism and blood flow. To investigate this hypothesis, the researchers will attempt to relate cell-type specific neural activity to metabolism and blood flow signals using parallel experiments in mice and humans. If successful, the proposed project will create a way to measure neuronal activity of known cell types from across the entire human brain, offering a significant enhancement to techniques such as functional MRI (fMRI).
MINIMALLY-INVASIVE NANO-DIALYSIS NEURAL PROBE FOR MULTIPLEXED MONITORING OF NEUROCHEMICALS WITH HIGH SPATIO-TEMPORAL RESOLUTION VLASOV, YURII A et al. UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN 2018 RFA-NS-17-003 Active
  • Interventional Tools

Correlating neural circuit functionality to behavior can be aided by monitoring local concentrations of neurochemicals in the brain in vivo. Limitations in current methods for detecting neurochemicals include low temporal and/or spatial resolution and low sensitivity, and invasiveness. Vlasov, Bashir, and Sweedler will develop an implantable device that integrates nanoscale dialysis functionality with electrophysiological recordings and optogenetic stimulation on a single neural probe. The probe will be a minimally-invasive, microfabricated device with recording, optogenetic manipulation, and stimulation capabilities, with nano-dialysis built-in to sense multiple neurochemicals by mass-spectroscopy. The team will test the probe in vitro and in behaving-animal experiments to confirm increased sensitivity and resolution with reduced tissue damage. The ability to sense multiple neurochemicals at a high spatio-temporal resolution in precise brain regions could accelerate fundamental understanding of systems neuroscience.

Model behavior in zebrafish: characterization of the startle response Meserve, Joy Hart University Of Pennsylvania 2018 RFA-MH-17-250 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
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The startle response is disrupted (i.e., uncoordinated or weak) in several neurological and psychiatric disorders. Meserve will investigate the startle response using live imaging of neural activity in transparent larval zebrafish. The slc5a7 gene (required for acetylcholine synthesis) modulates the startle response in zebrafish, and human slc5a7 mutations are implicated in attention deficit disorder and major depression. This project will study slc5a7a’s role in neural circuit development and/or startle response. Circuit defects in slc5a7a mutants will be investigated via calcium imaging and whole-brain activity mapping of neurons known to be required for the startle response. Integrated studies on gene function, neural circuitry, and behavior will uncover the developmental stage and anatomical region where slc5a7a is required. These experiments may determine how slc5a7a promotes normal startle response, and contribute knowledge about how acetylcholine regulates behavior.
Models and Methods for Calcium Imaging Data with Application to the Allen Brain Observatory Buice, Michael Witten, Daniela (contact) University Of Washington 2018 RFA-EB-17-005 Active
  • Integrated Approaches
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Though calcium imaging permits single-cell observations in behaving animals, variation between trials and complexities in activity-dependent calcium dynamics and fluorescent read-out create challenging data analyses. Motivated by a large-scale, publicly-available repository of calcium imaging data obtained from mouse models at the Allen Brain Observatory, Drs. Witten and Buice will develop novel statistical models, methods, and software to improve analysis techniques comparing extracellular electrophysiology and calcium imaging recordings in the context of behavior. Creating new, open, online algorithms to interpret fluorescent traces of firing neurons and building models that account for variations in neuronal activity, could improve researchers’ ability to draw rigorous and replicable conclusions on the basis of calcium imaging data.

Modular High-Density Optoelectrodes for Local Circuit Analysis Buzsaki, Gyorgy Wise, Kensall David Yoon, Euisik (contact) University Of Michigan 2014 RFA-NS-14-007 Complete
  • Monitor Neural Activity
  • Interventional Tools
In this project, Dr. Yoon's team will make devices for optogenetics, a technique that enables scientists to turn neurons on and off with flashes of light, more precise and diverse by integrating multiple light sources in such a way as to enable the control of specific neuronal circuits.
Modular nanophotonic probes for dense neural recording at single-cell resolution Roukes, Michael L (contact) Shepard, Kenneth L Siapas, Athanassios Tolias, Andreas California Institute Of Technology 2014 RFA-NS-14-007 Complete
  • Monitor Neural Activity
  • Interventional Tools
Dr. Roukes and his team propose to build ultra-dense, light-emitting and -sensing probes for optogenetics, which could simultaneously record the electrical activity of thousands of neurons in any given region of the brain.
Modular systems for large scale, long lasting measurements of brain activity Frank, Loren UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 2018 RFA-NS-17-004 Active
  • Interventional Tools
  • Monitor Neural Activity

Led by Dr. Frank, this team of Drs. Adesnik, Brainard, Buffalo, Denes, Haque, Karlsson, and Tooker aims to fine tune a high-density electrode recording system developed for long-lasting recordings of brain activity. The team plans to make their flexible polymer technology systems smaller, lighter, and capable of containing a higher density of probes. The team also will actively help distribute the probes to the research community. These tools will be used by researchers who are trying to understand how the firing patterns of brain circuits can control the healthy and diseased brain.

Modular systems for measuring and manipulating brain activity Frank, Loren M (contact) Harrison, Reid Tolosa, Vanessa University Of California, San Francisco 2014 RFA-NS-14-007 Complete
  • Monitor Neural Activity
  • Interventional Tools
Dr. Frank and his colleagues will engineer a next-generation, all-in-one neural recording and stimulating system, which can simultaneously monitor thousands of neurons in the brain for several months while also delivering drugs, light or electrical pulses.
Molecular Functional Ultrasound for Non-Invasive Imaging and Image-Guided Recording and Modulation of Neural Activity Shapiro, Mikhail California Institute Of Technology 2016 RFA-NS-16-006 Active
  • Monitor Neural Activity
  • Interventional Tools
Functional ultrasound (fUS) is a recently developed Doppler-based technique for imaging neurovascular responses. Compared to fMRI, it has greater spatiotemporal resolution and can be implemented in more diverse experimental settings. To enhance this technology, Dr. Shapiro has developed a system utilizing genetically engineered gaseous nanovesicles, which are hollow protein structures derived from buoyant microbes that are permeable to gases, but not to water. He is collaborating with the inventor of fUS, Michael Tanner, to use the nanovesicles in two ways: first as blood-borne contrast reagents for high resolution imaging of neurovascular responses (analogous to fMRI), and second as a means to detect calcium changes in genetically selected neurons for a readout of neuronal action potential firing. The system will be developed for multiple species to enable a flexible neural recording method able to reach deep into the brain, covering large areas with high temporal resolution.
MOTES: Micro-scale Opto-electronically Transduced Electrode Sites Goldberg, Jesse Heymann Mceuen, Paul Molnar, Alyosha Christopher (contact) Cornell University 2016 RFA-EY-16-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
Molnar and her colleagues propose to develop a free floating, wireless microchip system for electrical recording of neural activity. The new system, called Microscale Optoelectronically Transduced Electrodes (MOTEs), will be powered by optically stimulated micro-photovoltaic cells and will use the resulting 1-2μW of electrical power to measure, amplify, and encode electrophysiological signals, up-linking the information optically through an onboard LED. Compared to standard microelectrode arrays, these free floating electrodes promise to be less damaging to neural tissue, and have potential for broader coverage of brain areas. This technology will enable many new neurobiology experiments, and provide a new, minimally invasive platform for measuring electrical signals deep in live brain tissue.
MR-guided Focused Ultrasound Neuromodulation of Deep Brain Structures Butts-pauly, Kim Butts Stanford University 2016 RFA-MH-16-810 Active
  • Interventional Tools
  • Human Neuroscience
Focused ultrasound (FUS) has been shown to be noninvasive, safe, and spatially specific in various animal models, and more recently for therapeutic applications in the human brain. To calibrate the focal spot, computed tomography (CT) scans capture an associated rise in temperature to help guide FUS to a specific brain target. A safe, repeatable alternative that does not use repeat CT exposure or temperature increase is needed. Dr. Butts-Pauly and colleagues will develop technology that combines FUS and magnetic resonance imaging (MRI) in vivo in pigs to accurately predict ultrasound intensities and temperatures at the target site and throughout the brain. This will lead to a much better understanding of the mechanism of FUS neuromodulation and will enhance the safety of FUS for studying both normal and diseased populations.
MRI Corticography (MRCoG): Micro-scale Human Cortical Imaging Feinberg, David Alan (contact) Liu, Chunlei Mukherjee, Pratik Setsompop, Kawin University Of California Berkeley 2014 RFA-MH-14-217 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • Human Neuroscience
To image the activity and connections of the brain's cortex on a micro scale – with dramatically higher resolution than existing scanners – Dr. Feinberg's group will employ high sensitivity MRI coils that focus exclusively on the brain's surface.
MRI CORTICOGRAPHY: DEVELOPING NEXT GENERATION MICROSCALE HUMAN CORTEX MRI SCANNER Feinberg, David Alan (contact) Liu, Chunlei Mukherjee, Pratik Setsompop, Kawin Wald, Lawrence L University Of California Berkeley 2017 RFA-EB-17-002 Active
  • Monitor Neural Activity
  • Interventional Tools
  • Integrated Approaches
  • Human Neuroscience
The macroscopic scale of current magnetic resonance imaging (MRI) scanners makes it challenging to link neural circuitry to human cognition and behavior. David Feinberg and his team are developing MR Corticography (MRCoG), a new tool for studying neuronal circuitry that improves resolution by an order of magnitude, making it possible to visualize cortical layers and microcircuit columns throughout the whole brain. By expanding on scanner hardware and image acquisition software that Feinberg has previously developed, the team intends to improve image sensitivity while reducing sources of signal distortion. With these tools, they plan to explore the clinical potential of MRCoG in patients with epilepsy and autism spectrum disorder. MRCoG has the potential to be a major advance in human neuroscience, providing researchers with a tool to connect cortical visualization to clinical and cognitive neuroscience.
Multi-area two-photon microscopy for revealing long-distance communication between multiple local brain circuits Helmchen, Fritjof University Of Zurich 2014 RFA-NS-14-008 Complete
  • Monitor Neural Activity
  • Interventional Tools
Dr. Helmchen and his colleagues propose a system to simultaneously record neuronal activity in four different areas of the neocortex and discover how brain cells in different regions interact during specific behaviors.
Multi-channel MR-compatible flexible microelectrode for recording and stimulation Franklin, Robert Kyle Shih, Yen-yu Ian (contact) Blackrock Microsystems 2016 PAR-15-090 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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

Multi-channel MR-compatible flexible microelectrode for recording and stimulation Shih, Yen-Yu BLACKROCK MICROSYSTEMS 2018 PAR-15-090 Active
  • Circuit Diagrams
  • Interventional Tools
  • Monitor Neural Activity

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

Multi-context software for robust and reproducible neuroscience image analysis Papademetris, Xenophon (contact) Scheinost, Dustin Yale University 2017 RFA-MH-17-257 Active
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  • Human Neuroscience
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  • Monitor Neural Activity
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A thorough understanding of brain function requires the integration of neuroscience data across species and scales. While current software can verify data quality within one or a handful of data sources, reproducibility across multiple data sources is limited. Xenophon Papademetris and colleagues are developing software tools with cross-scale, cross-species reproducibility analysis in mind. By leveraging data created by two other BRAIN Initiative projects at Yale University, Papademetris will extend current software algorithms to incorporate data from multiple sources, design the software to be cross-platform compatible, validate the software through rigorous testing, and finally, distribute it to the community. The potential for a set of software tools to reliably and reproducibly analyze multiple heterogeneous neuroscience data types will help to break down data barriers for the greater neuroscience community.

Multi-regional neural circuit dynamics underlying short-term memory Druckmann, Shaul Li, Nuo (contact) Baylor College Of Medicine 2017 RFA-NS-17-015 Active
  • Integrated Approaches
Short-term memory is involved in many core cognitive behaviors, but it remains unclear whether its neural circuitry is mediated by a single distributed circuit or by many distinct parallel representations, and whether causal relations exist between regions. Nuo Lui and Shaul Druckmann are using optogenetic approaches to selectively perturb brain regions, observing whether this disruption in persistent activity in mouse frontal cortex also results in transient and/or lasting disruptions in behavior. By developing new analysis and modeling techniques to convert neural recordings and perturbations into circuit models, this work could provide a comprehensive investigation of the multi-region circuits that mediate short-term memory.
Multi-Site Non-Invasive Magnetothermal Excitation and Inhibition of Deep Brain Structures Anikeeva, Polina O (contact) Pralle, Arnd Massachusetts Institute Of Technology 2016 RFA-MH-16-810 Active
  • Interventional Tools
  • Human Neuroscience
Current tools for modulating specific populations of cell types, such as DREADDs and optogenetics, either have poor temporal resolution or they require implanted hardware. Non-invasive tools like electromagnetic induction and ultrasound have limited resolution and lack cell-type specificity. Dr. Polina Anikeeva and colleagues will develop a “magnetothermal toolbox” technology that combines magnetic nanoparticles and heat sensitive ion channels to activate and inhibit individual neurons in both deep and superficial brain regions in mice. This novel approach for controlling specific cell types is wireless and implant-free, allowing for a potential pathway to human clinical use in the future.
Multimodal modeling framework for fusing structural and functional connectome data Nagarajan, Srikantan S. Raj, Ashish (contact) Weill Medical Coll Of Cornell Univ 2016 RFA-EB-15-006 Active
  • Integrated Approaches
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Recent advances in the development of imaging tools are allowing researchers to both measure brain function (i.e., EEG, fMRI, PET) and the underlying structure of brain connections (i.e., diffusion MRI). Integrating functional brain activity data across imaging platforms, each of which provide unique information, has been tricky, as has been combining that data with structural connectivity data. Raj and his team are developing sophisticated modeling programs that combine this wealth of data across multiple spatial scales. These programs will provide insight into the relationship between brain function and structure and how the relationship is altered in cases of injury and disease.
Multiparametric Biosensor Imaging in Brain Slices Blanpied, Thomas A Meredith, Andrea L Rizzo, Mark A (contact) University Of Maryland Baltimore 2016 RFA-MH-16-775 Active
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  • Monitor Neural Activity
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The coordinated observation of spatial and temporal interactions of multiple signaling pathways within individual cells and across intact circuits is limited by an inability to simultaneously track dynamic molecular activity. Rizzo and colleagues will validate and further develop a new methodology, Fluorescent Anisotropy Reporters (FLAREs), for simultaneous optical imaging of multiple biosensors within single neurons of mouse brain slices during neural coding. The group will improve the optical sectioning microscopy methodology and increase the range of signaling molecules measurable with FLAREs. This technique may enhance subcellular spatial resolution and cellular temporal resolution of signaling pathways, and could scale to visualize coordinated cellular activities and neural coding in intact brain circuits.
Multiplex imaging of neuronal activity and signaling dynamics underlying learning in discrete amygdala circuits of behaving mice. Li, Bo Mao, Tianyi Zhong, Haining (contact) Oregon Health & Science University 2018 RFA-NS-17-014 Active
  • Integrated Approaches
Dysfunction in the amygdala circuitry has large ramifications for myriad actions including those driven by threat or reward, and is essential for both learned behaviors - and for mood. How individual learning tasks differentially change this circuit to produce different behaviors remains largely unknown. Haining Zhong’s team will perform two-photon, multiplex imaging using a tiny GRIN lens, which allows optical access to deep brain structures, to image calcium activity as a proxy for neuronal firing in the amygdalae of behaving mice. Simultaneously, they will image the activity dynamics of the biochemical cAMP/PKA signaling pathway, as a readout for stress-/reward-induced neuromodulation. The team aims to discover and characterize, with cell-type specificity, functional subdivisions of the amygdala. This work may improve understanding of neuropsychiatric diseases associated with amygdala dysfunction.
Multiplex in vivo imaging of cell-specific and circuit-specific signaling pathways during synaptic plasticity Huganir, Richard L (contact) Zhang, Jin Johns Hopkins University 2016 RFA-MH-16-775 Active
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  • Monitor Neural Activity
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Kinase signaling pathways that regulate synaptic plasticity help integrate multiple types of synaptic inputs to control neuronal circuit adaptation during behavior. However, monitoring more than one of these pathways simultaneously in awake behaving animals remains a challenge. Huganir and Zhang plan to develop and validate new genetically encoded fluorescent biosensors and use two-photon microscopy to image activity of multiple kinase signaling pathways in awake, behaving mice. This tool will improve rapid (seconds to minutes) detection of dynamic signaling pathways during physiologically relevant sensory experiences and learning tasks, greatly improving our ability to visualize cell-specific and circuit-specific signaling pathways.
Multiplexed Multiphoton Interrogation of Brain Connectomics Han, Xue Ramachandran, Siddharth (contact) Boston University (charles River Campus) 2015 RFA-EY-15-001 Complete
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Optical imaging of living mammalian brains has been limited by tissue scattering. Imaging deep neuronal targets, such as mouse hippocampus, in a non-invasive fashion requires deep-tissue light penetration. New methods such as 3-photon imaging promise to achieve such depths, but they are only beginning to be explored. To date, 3-photon microscopy has only been tested with single input wavelengths, even though theoretical predictions suggest that using inputs with different wavelengths could achieve greater depth of penetration. Ramachandran and Han propose using a novel tunable laser to explore input wavelength combinations to optimize penetration depth.
MULTISCALE ANALYSIS OF SENSORY-MOTOR CORTICAL GATING IN BEHAVING MICE Jaeger, Dieter (contact) Stanley, Garrett B. Emory University 2015 RFA-NS-15-005 Complete
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  • Monitor Neural Activity
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The neural circuitry underlying how animals make motor decisions, especially in response to sensory or environmental cues, is not well understood. Many motor disorders, including Parkinson’s and Huntington’s disease, are linked to faulty circuits in a region of the brain called the basal ganglia. Researchers will use a variety of advanced methods to image, record, and manipulate the activity of neurons in this area as well as in the areas of the brain involved in sensory perception and movement. By employing these methods at multiple scales – from the individual neuron to neuronal networks – and then correlating these data with the behavior of awake, behaving mice, researchers hope to reveal how sensory information is integrated with input from the basal ganglia to result in the decision to initiate or suppress movement.
Multiscale Imaging of Spontaneous Activity in Cortex: Mechanisms, Development and Function Constable, R. Todd Crair, Michael (contact) Yale University 2015 RFA-NS-15-005 Complete
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Being able to observe the activity of a single neuron while simultaneously observing the activity of entire brain regions is a critical step in bridging the gap in understanding of how a collection of nerve cells ultimately generates an organized behavior. Dr. Crair and colleagues will develop and use two different imaging techniques to measure the activity of individual neurons, regions of the brain, and the whole brain, during different behavior states, such as REM and non-REM sleep, in developing mice. Bridging their analyses and insights between and within scales will allow these researchers to examine neural circuits and networks in different brain states and determine how they are modulated through development.
Nano-switches for optogenetic control of neuronal proteins with ultra-specificity Wang, Lei University Of California, San Francisco 2017 RFA-MH-17-220 Active
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Optogenetics is a powerful tool for controlling the activity of neurons with light, but it currently cannot be readily applied on any protein of choice, and lacks specificity. Wang and his team propose a nano-switch technology, in which unnatural amino acids (UAA) will be incorporated into neuronal proteins at single sites, achieving reversible optical control of the protein. Compared with existing methods using large, light-sensitive proteins, this method uses only a single UAA for light sensitivity, and can photo-modulate a protein without knowing its function in advance. This project’s success in model organisms will introduce vast opportunities for investigating previously-inaccessible neuronal processes at the molecular level.
Near Infrared Genetically Encoded Voltage Indicators (NIR-GEVIs) for All-Optical Electrophysiology (AOE) Antic, Srdjan D Knopfel, Thomas (contact) Verkhusha, Vladislav U Of L Imperial Col Of Sci/technlgy/med 2016 RFA-NS-16-006 Active
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Genetically-coded voltage indicators are a promising tool for imaging electrical activity of specifically targeted neurons. Dr. Knopfel and colleagues propose to develop voltage sensors that excite and emit fluorescence in the near-infrared part of the spectrum, which is less susceptible to scattering than visible light, and thus can be imaged far deeper in the brain. To do this they will use near-infrared phytochrome-based fluorescent proteins developed in Dr. Verkhusha’s lab, and they will test them in neurons expressing genetically coded opsins. This will ultimately enable fully optical approaches to measuring and manipulating neural activity at cellular and subcellular scales, including in awake, behaving animals.
Network basis of action selection Komiyama, Takaki Kreitzer, Anatol (contact) Lim, Byungkook J. David Gladstone Institutes 2015 RFA-NS-15-005 Complete
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Three separate research groups are collaborating to understand in detail how three distinct areas of the brain function and work together to enable learning and decision-making behaviors. Drs. Kreitzer, Komiyama, and Lim are leveraging an impressive set of technologies to monitor and perturb different cell types in each brain region while the mice perform learning and decision-making tasks. By applying multiple recording methods across these brain regions at both the level of a single neuron and entire subpopulations of neurons, while the animals perform the same set of tasks, researchers hope to develop a single model of how vertebrate animals make choices about what to do next.

Network Connectivity Modeling of Heterogeneous Brain Data to Examine Ensembles of Activity Across Two Levels of Dimensionality Gates, Kathleen Univ Of North Carolina Chapel Hill 2016 RFA-EB-15-006 Active
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Functional MRI (fMRI) is currently the most ubiquitous imaging technique for measuring whole brain activity in humans. The usefulness of fMRI in both research and clinical settings, however, has been limited by the availability of computational tools for analyzing the data. Most tools allow researchers to track activity in brain regions within a known network, without the ability to simultaneously examine connections between various networks. Gates and her colleagues have proposed a set of software tools that enable the simultaneous analysis of within- and between-network connectivity. The tools will also make it easier to combine fMRI data across individuals in order to learn more about how whole brain activity differs across people in both health and disease.
Network Control and Functional Context: Mechanisms for TMS Response Bassett, Danielle Smith Oathes, Desmond (contact) Satterthwaite, Theodore Daniel University Of Pennsylvania 2018 RFA-MH-17-245 Active
  • Human Neuroscience
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Transcranial magnetic stimulation (TMS) is a powerful tool for non-invasively modulating brain circuits. However, the field lacks a theoretical framework to predict the effects of TMS on brain and behavior. In healthy young adults, Oathes and colleagues will test the hypothesis that brain responses to TMS are governed both by the network properties of the area stimulated and by the cognitive context, as measured by patterns of functional activation during stimulation using fMRI. The group will further test their theory during a working memory test, comparing TMS impact on performance in both healthy adults and patients with ADHD. Elucidating the mechanisms of TMS response will enhance understanding of how functional brain circuits contribute to specific cognitive functions and has the potential to accelerate personalized neuromodulatory treatments for executive dysfunction.

Neural activity integration during user defined epochs with modular reporters Laughlin, Scott T. State University New York Stony Brook 2016 RFA-EY-16-001 Complete
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Using optical recordings of neural activity from whole brains to reconstruct neural circuits is challenging when working with large brains or when studying behaviors that are not compatible with concurrent imaging. Laughlin and his team propose a method for making permanent recordings of neural activity that could be “read out” at a later time. The idea is that when a neuron fires during a specified time window, an enzyme genetically expressed by that neuron would interact with a genetically expressed substrate to produce a permanent record of the neuron’s activation. This innovative method will improve understanding of neural circuits.
Neural circuits for spatial navigation Maimon, Gaby Rockefeller University 2018 RFA-NS-17-014 Active
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A circuit-level understanding of how brains perform quantitative, navigation-related computations would be a major advance for neuroscience. Gaby Maimon’s team will study how brains construct navigational signals and how these signals guide behavior. Using physiological recordings in active fruit flies, they seek to identify a circuit by which sensory information arrives at the central brain (where neurons respond to sensory-motor signals) to update the head-direction when flies turn in darkness. To investigate whether the fly’s internal heading/compass signal is needed for them to keep a straight bearing, the researchers will take recordings after impairing this system. Finally, they will test whether flies have forward speed-sensitive neurons that enable 2D navigation. Such discoveries could elucidate how model brain machinery can perform day-to-day navigation tasks, and how to approach conditions in which these abilities are impaired, such as Alzheimer’s disease.
Neural circuits in zebrafish: form, function and plasticity Cepko, Constance L Engert, Florian (contact) Lichtman, Jeff W Sompolinsky, Haim Harvard University 2014 RFA-NS-14-009 Complete
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Dr. Engert's team will combine a wide array of cutting-edge neuroscience techniques to watch the entire brain activity of a see-through fish while it swims, and to make detailed maps of its brain circuitry.
Neural circuits underlying thirst and satiety regulation Oka, Yuki CALIFORNIA INSTITUTE OF TECHNOLOGY 2018 RFA-NS-18-009 Active
  • Integrated Approaches

The neural circuits involved in the regulation of thirst and satiety remain poorly understood. Classical models postulate that water deficits drive appetite, which is sated when the internal environment is rehydrated. Using viral tracing studies, in vivo optical recording in mice, retrograde labeling, and single-cell RNA-seq analysis, Dr. Oka and team will test the hypothesis that ingestive behavior itself directly modulates appetite in the brain before the body is satiated. This work will bring new understanding to the role of thirst circuits and drinking behavior.

Neural ensembles underlying natural tracking behavior Fiete, Ila R. Huk, Alexander C Priebe, Nicholas J. (contact) University Of Texas, Austin 2015 RFA-NS-15-005 Complete
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Animals move their eyes to track the movement of objects around them. These researchers will measure and manipulate the activity of populations of identified neurons in marmosets during pursuit eye movements. This work will allow a detailed understanding of how the pursuit circuit integrates information from a large number regions is a critical step in bridging the gap in understanding of how a collection of nerve cells ultimately generates an organized behavior. Dr. Crair and colleagues will develop and use two different imaging techniques to measure the activity of individual neurons, regions of the brain, and the whole brain, during different behavior states, such as REM and non-REM sleep, in developing mice. Bridging their analyses and insights between and within scales will allow these researchers to examine neural circuits and networks in different brain states and determine how they are modulated through development.
Neural Implant Insertion System using Ultrasonic Vibration to Reduce Tissue Dimpling and Improve Insertion Precision of Floating Arrays in the Neocortex Mulvihill, Maureen L. Actuated Medical, Inc. 2018 PAR-15-091 Active
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Penetrating electrode arrays have an expanding application in neuroscience research as they can provide direct access to neural signals across the central and peripheral nervous system with high spatial resolution. Chronic electrode implants could revolutionize treatment for a range of medical conditions, including prosthetic motor control and proprioception for amputees, and brain-machine interfacing for paraplegics. Unfortunately, device implantation applies forces to the neural tissue resulting in significant brain compression (dimpling) at the implant site, which increases risk of implantation trauma, bleeding and inflammation. Actuated Medical, Inc. will develop a neural implant inserter, the Ultrasonic Precision Insertion of Neural Devices (UPIND) system, that will reduce the insertion force by applying ultrasonic energy to electrode arrays during insertion. This system aims to enable greater placement control of floating microware arrays, while reducing tissue trauma.

Neural mechanisms and behavioral consequences of non-Gaussian likelihoods in sensorimotor learning Nemenman, Ilya M. (contact) Sober, Samuel Emory University 2016 RFA-EB-15-006 Active
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A central goal of neuroscience is to understand how learning is implemented by the nervous system. However, despite years of studies in animals and humans, our knowledge of both the computational basis of learning and its implementation by the brain is still rudimentary. This project by Nemenman and his colleagues will spawn a unified mathematical theory explaining how the brain learns complex skills. The researchers will validate their theory in songbirds, with the goal of understanding sensorimotor learning of a single acoustic parameter, pitch, which is precisely regulated by the songbird brain. A better understanding of the mechanisms underlying sensorimotor learning could guide rehabilitative strategies that exploit the plasticity of complex behavior.
Neural mechanisms of active avoidance behavior Castro-alamancos, Manuel A Drexel University 2018 RFA-NS-17-014 Active
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Maladaptive, active avoidance behavior is present in most forms of pathological anxiety. To better understand this process, Castro-Alamancos and colleagues will study freely-behaving, genetically-modified mice performing active avoidance (e.g., withdrawing from aversive noise or mild electrical foot shocks). They will employ behavioral, electrophysiological, optogenetic, chemogenetic, pharmacological, and histological procedures to test some of specific hypotheses: 1) The substantia nigra pars reticulata (SNr) mediates active avoidance behavior via projections to midbrain locomotor regions. and 2) Specific regions of the striatum control SNr activity during avoidance via connections projecting from the striatum to the substantia nigra. This project will provide understanding about the neural circuits responsible for active avoidance behavior.
Neural Monitoring with Magnetically-Focused Electrical Impedance Tomography (mf-EIT) Freeman, Daniel Kenneth Charles Stark Draper Laboratory 2015 RFA-EY-15-001 Complete
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Electrical impedance tomography (EIT) detects impedance changes associated with neural activity by injecting small currents through scalp electrodes. However, this technique, which has the advantage of being non-invasive, has poor spatial resolution. Freeman proposes to address the problem of spatial resolution by using magnetic field-based current steering—a method commonly used in particle accelerators—to precisely target the current through the brain. If successful, the approach could enable a non-invasive method for imaging brain activity with greater spatial and temporal resolution than current technologies.
Neural sequences for planning and production of learned vocalizations Cooper, Brenton G. Hahnloser, Richard Roberts, Todd F (contact) Ut Southwestern Medical Center 2018 RFA-NS-18-009 Active
  • Integrated Approaches

To understand how the brain controls voluntary movements via sequences of neuronal activity, Dr. Roberts and colleagues intend to study how the brains of songbirds control singing, a natural behavior. For this project they will use calcium imaging, electrophysiological recordings, and optogenetic manipulations in a cell-type specific manner to investigate how specific circuits help songbirds plan, prepare, and sing their songs. The work could improve our understanding of how patterns of neuronal activity integrate to allow voluntary, skilled actions, which may help researchers understand how the breakdown of these circuits can cause movement disorders, like Parkinson’s disease.

Neuroethics of aDBS Systems Targeting Neuropsychiatric and Movement Disorders Goodman, Wayne K Lazaro-munoz, Gabriel (contact) Mcguire, Amy Lynn Baylor College Of Medicine 2017 RFA-MH-17-260 Active
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A technological advance beyond traditional, open-loop DBS devices, adaptive deep brain stimulation (aDBS) devices monitor local neural activity to adjust stimulation in real time when treating certain movement and neuropsychiatric disorders. However, because aDBS devices autonomously record neural data and provide neuromodulation to affect motor function and mood, these systems raise important neuroethics issues, including changes in perception of autonomy and personal identity; risk-taking propensity; and privacy, use, and ownership of neural data. In this project, Dr. Lazaro-Munoz and colleagues will gather data from participants in existing aDBS clinical trials, their caregivers, people who declined to receive aDBS, and the aDBS researchers, to identify and assess the most pressing neuroethics issues related to aDBS research and translation. The long-term goal of this research program is to develop an empirically-informed and ethically-justified framework for the responsible development and clinical translation of aDBS systems, which will help maximize the social utility of this type of novel neurotechnology.
NeuroGrid: a scalable system for large-scale recording of action potentials from the brain surface Buzsaki, Gyorgy (contact) Devinsky, Orrin New York University School Of Medicine 2016 RFA-NS-16-007 Active
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Buzaki and his colleagues propose to optimize a novel scalable electrode array to record the activity of thousands of individual neurons using a “NeuroGrid” of high density microelectrodes resting on the surface of the neocortex. The proposed grid is scalable and flexible, conforming to the brain’s curvature. An important development of this project is that the device will allow recordings from individual neurons using surface electrodes, something currently only possible with brain-penetrating electrodes. Experiments will assess the nature of the neural signals and will establish their cellular origin in animal model systems, as well as in human patients undergoing surgery for epilepsy. If successful, this work will establish a new paradigm for recording neural activity that is more stable and less invasive than penetrating electrodes, and can be scaled across brain areas with high density.
Neuromodulation by Transcranial Current Stimulation Krekelberg, Bart Rutgers The State Univ Of Nj Newark 2016 RFA-MH-16-815 Active
  • Interventional Tools
  • Human Neuroscience
Transcranial current stimulation (TCS) modulates neural activity via small electrical fields and is portable, inexpensive, and easily deployed in the clinic or at home. However, little is known about its mechanism of action and dose-response relationships with neural activity. Krekelberg and colleagues will use intracranial recordings in non-human primate visual cortex to study neuromodulatory effects from three different types of currents (direct, transcranial random noise, and alternating). By also varying parameters such as current strength, electrode configuration, and stimulation duration for each of the 3 types of TCS, discoveries from this work will support the rational design of electrotherapies for neurological disorders such as depression or epileptic seizure.
Neuromodulation of Brain States Luo, Liqun Stanford University 2018 RFA-NS-17-014 Active
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Abnormalities of the serotonin neuromodulatory system contribute to mood disorders. In rodents, Luo’s team will use their recently-developed viral-genetic tools to dissect the complexities of the serotonin system into specific sub-systems. They will anatomically characterize the organization of the dorsal raphe (DR)-serotonin sub-systems, identifying how each sub-system divides up the projections of the entire DR-serotonin system, as well as the input-output relationship for each sub-system. Sub-system behavioral functions will be determined by manipulating and recording serotonin neuron subtypes in anxiety- and depression-like states. Finally, the team will explore the circuit and cellular mechanisms by which serotonin regulates thirst-motivated behavior, using a technique to genetically manipulate thirst-activated neurons. This work could elucidate how serotonin modulates diverse physiological functions and behaviors.
Neuromodulatory control of collective circuit dynamics in C. elegans Flavell, Steven Willem Massachusetts Institute Of Technology 2017 RFA-NS-17-014 Active
  • Integrated Approaches
The neural mechanisms that allow animals to initiate, maintain, and terminate long-lasting behavioral states (e.g., sleep/wake, emotional, and cognitive states) are unknown. Steven Flavell’s team aims to identify, in freely-moving C. elegans, the circuit-wide neural dynamics that define roaming and dwelling behavioral states, and to examine how specific neuromodulators coordinate the activity of their target neurons to organize whole-circuit activity patterns over long stretches of time. The team will combine their own newly-developed calcium imaging technology, which can simultaneously monitor every neuron in a circuit, with genetic/optogenetic manipulations (e.g., neuromodulator deletions and inter-neuron functional connectivity perturbations) and with novel analysis/modeling methods. These studies could help reveal how neuromodulators orchestrate whole-circuit changes in activity to influence animal behavior.
Neuron selective modulation of brain circuitry in non-human primates Caskey, Charles F (contact) Chen, Li Min Grissom, William A Vanderbilt University 2015 RFA-MH-15-200 Complete
  • Monitor Neural Activity
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  • Human Neuroscience
A major focus of The BRAIN Initiative is to develop new tools and technologies to study circuitry of the brain. Developing methods to simultaneously modulate and image neural circuits would empower researchers to undertake such science. In this project, Caskey and his team propose to develop a next-generation method to modulate brain activity using ultrasound, while simultaneously imaging brain activity using functional magnetic resonance imaging (fMRI). The integration of highly spatially selective ultrasound neuromodulation with high field MRI has the potential to provide a unique and powerful approach to study the functional architecture of the human brain. The completion of this work will improve our understanding of the neuronal responses to ultrasound neuromodulation, establish the safety of ultrasound neuromodulation, and explore how ultrasound can be used in conjunction with MR imaging to interrogate brain circuits and diagnose brain disorders.
Neuronal and Dopaminergic Contributions to Dissimilar Evoked Hemodynamic Responses in the Striatum Walton, Lindsay Univ Of North Carolina Chapel Hill 2018 RFA-MH-17-250 Active
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Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) is a non-invasive imaging technique that infers increased brain activity from observed increases in cerebral blood flow. A notable exception to this relationship occurs in the striatum. Walton will investigate the activity of dopamine neurons, medium spiny neurons, and dopamine receptors, under conditions that evoke either blood vessel dilatation or constriction in the striatum. She will utilize optogenetic stimulation, synthetically-derived receptors, and receptor antagonist drugs to reveal the mechanisms underlying striatal positive and negative fMRI responses. These studies are important for the accurate interpretation of BOLD fMRI signals from brain regions with atypical hemodynamic responses.
Neuronal mechanisms of human episodic memory Mamelak, Adam Nathaniel Rutishauser, Ueli (contact) Cedars-sinai Medical Center 2017 RFA-NS-17-019 Active
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No meaningful therapies for memory disorders exist, partially due to a lack of mechanistic knowledge about human memory. Ueli Rutishauser’s multi-institutional, multi-disciplinary team will study how memories of facts and events are formed and used in the human brain. The team will use electrophysiological methods to record single neurons, simultaneously in multiple brain areas, in awake patients who are implanted with electrodes to localize epileptic seizures. This work will combine single-neuron physiology, behavioral testing, electrical stimulation, and computational modeling, to address three questions: (i) how persistent activity supports memory formation, (ii) what mechanisms translate memories into decisions and judgments, and (iii) how memories are formed and recalled over time. A circuit-level understanding of memory may enable development of new treatments for memory disorders.
Neuronal population dynamics within and across cortical areas Doiron, Brent UNIVERSITY OF PITTSBURGH AT PITTSBURGH 2018 RFA-EB-17-005 Active
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Drs. Doiron, Smith, and Yu will develop a method that combines large-scale network modeling, large-scale neural recordings, and neural population analyses to understand the key network principles that drive behavior. The team proposes to validate their methods using data recorded from macaque prefrontal cortex to the visual area, V4. A toolkit called Balance BEAM (Brains, Experiments, Analysis and Models), implemented in Matlab, will include a graphical user interface for designing balanced, optimized network models. If successful, Balance BEAM will allow future users to better research how neural circuits give rise to transient activity, steady-state activity, and neural variability.

Neuronal Substrates of Hemodynamic Signals in the Prefrontal Cortex Howard, Matthew A. O'doherty, John P (contact) Tsao, Doris Ying California Institute Of Technology 2016 RFA-MH-16-750 Active
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  • Human Neuroscience
Functional MRI (fMRI) is the dominant technique for probing human prefrontal cortex functions such as cognition, learning, and decision-making. Yet, little is known about how fMRI signals relate to the underlying neural signals in prefrontal cortex. O’Doherty and his colleagues will examine this relationship in monkeys by first probing the region with fMRI, then recording electrical signals from individual neurons in those areas that show strong fMRI activation. The team will then follow up with dual recordings (fMRI and intracranial electrical measurements) in human patients undergoing surgical treatment for epilepsy. By combining these different recording techniques in both monkeys and humans, the team hopes to determine which aspects of underlying neural responses give rise to fMRI responses in prefrontal cortex. This work will improve the usefulness of fMRI as a diagnostic measure of disorders related to higher-order cognitive functions.
Neuronal voltage tracers for photoacoustic imaging in the deep brain Sack, Jon Thomas University Of California At Davis 2015 RFA-EY-15-001 Complete
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Photoacoustic imaging presents a new, non-invasive method to image brain activity at a cellular resolution much deeper than current methods, but it requires the development of biosensors. Sack and his colleagues recently developed a first-generation probe for imaging neural activity, which uses a fragment from a tarantula toxin that has evolved to selectively bind a specific ion channel on the surface of mammalian neurons. They will develop this probe for use in photoacoustic tomography. They will screen, optimize, and validate the probe for imaging in deep brain areas, and potentially expand it to formulate other similar peptides to target additional ion channels.
Neurons, Vessels and Voxels: Multi-modal Imaging of Layer Specific Signals Kara, Prakash Naselaris, Thomas P Olman, Cheryl A. Ugurbil, Kamil (contact) University Of Minnesota 2016 RFA-MH-16-750 Active
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  • Human Neuroscience
Functional MRI (fMRI) infers the location and magnitude of neural activity from vascular signals. However, the technique has not been shown to distinguish neural activity from individual cortical layers, each of which have unique computational functions. To demonstrate ultrahigh-resolution high-field fMRI’s ability to measure layer-specific signals, Ugurbil and his colleagues will perform simultaneous 2-photon microscopy—a technique for imaging neural signals with high spatial resolution—and fMRI experiments in which cats are shown visual stimuli known to elicit responses in specific cortical layers. These experiments will seek to correlate layer-specific fMRI responses with differences in neural activity, which will ultimately enable fMRI to provide more detailed information about human brain function in both health and disease.
NeuroPET HD: A low-cost high performance neuro-PET imaging system Hunter, William Coulis Jason Pet/x, Llc 2017 PAR-15-090 Active
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Positron Emission Tomography (PET) has the potential to be an important tool in understanding the human brain. However, current PET systems used in oncology are expensive and lack the level of resolution necessary for human neuroimaging studies. Drs. Hunter and Coulis plan to combine a novel detector technology with innovative system architecture for commercial production of a cost-effective PET brain imaging system (Neuro-PET HD). In the Phase I STTR, PET/X LLC will create and validate the performance of a new PET detector ring system before generating a full commercial prototype. The goal is to reduce system cost, while providing a significantly more compact, mobile system that provides rigorously accurate images of brain function.

Neurophysiologically Based Brain State Tracking & Modulation in Focal Epilepsy Worrell, Gregory A Mayo Clinic Rochester 2015 RFA-NS-15-006 Active
  • Human Neuroscience
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Epilepsy is a common neurological disease, and over one-third of epilepsy patients have seizures that are not controlled by conventional therapy. Surgery can be curative, but only for a subset of patients. Advances in neural engineering have produced devices that are poised to transform management of drug-resistant epilepsy; they will ultimately take the form of wireless devices that integrate the ability to measure brain activity, predict seizure onset, and deliver therapeutic stimulation to limit seizure activity. Worrell and colleagues aim first to undertake a preclinical study in dogs with naturally occurring epilepsy, to test one such device, and if this is successful then conduct a pilot clinical trial in human epilepsy patients
Neurostimulation and Recording of Real World Spatial Navigation in Humans Suthana, Nanthia A University Of California Los Angeles 2017 RFA-NS-17-019 Active
  • Human Neuroscience
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Spatial memory is thought to involve neurons in the medial temporal lobe that exhibit increased firing rates when an animal is in a specific location during spatial navigation. However, human single-neuron studies have been limited to immobile subjects viewing 2-dimensional navigational tasks. Nanthia Suthana’s team will use intracranial single-neuron and local field potential recordings, combined with deep brain stimulation (DBS), in epilepsy patients performing freely-moving spatial navigation memory tasks using state-of-the-art virtual reality headset technology and full-body motion capture. The team will record from medial temporal lobe subregions, to determine the role of single neurons and oscillations during navigation and memory, and how these neurophysiological mechanisms can be enhanced by deep brain stimulation. This work may yield insights into the neuronal correlates of real-world spatial navigation and memory.
Neurotransmitter Absolute Concentration Determination with Diamond Electrode Lee, Kendall H. (contact) Manciu, Felicia S. Tomshine, Johnathan R Mayo Clinic Rochester 2014 RFA-NS-14-007 Complete
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Dr. Kendall and his colleagues will develop diamond-coated electrodes to measure concentrations of the brain chemical dopamine more accurately and over long periods of time in the brain.
New approaches for better protein voltage sensors Cohen, Lawrence B Yale Univers