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 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 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 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 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 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
  • Interventional Tools
  • Theory & Data Analysis Tools
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
  • Monitor Neural Activity
  • Interventional Tools
  • 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
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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
  • Interventional Tools
  • Monitor Neural Activity

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
  • Monitor Neural Activity
  • Interventional Tools
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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  • Circuit Diagrams
  • Monitor Neural Activity
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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
  • Interventional Tools
  • Monitor Neural Activity

A major goal of neuroscience is to record the activity of all neurons in an area of an intact brain to understand the relationship between neural activity and behavior. However, current technologies do not allow direct and simultaneous access to every neuron in a three-dimensional brain area. Instead, Kuzum’s team proposes to ‘virtually’ record from neurons in a given volume of tissue with a Virtual Array. They will develop a framework to computationally increase the number of recorded neurons in data from simultaneous electrophysiology and two-photon calcium imaging (at multiple cortical depths), without the need for direct optical or electrical access to each neuron. Advanced computation will identify the time and place of action potentials. If successful, virtual arrays could lead to mapping the neural circuit dysfunctions that cause disorders and could facilitate development of targeted treatments.

Anion channelrhodopsin-based viral tools to manipulate brain networks in behaving animals Dragoi, Valentin (contact) Janz, Roger Spudich, John Lee University Of Texas Hlth Sci Ctr Houston 2015 RFA-MH-15-225 Complete
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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
  • Cell Type
  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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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  • Monitor Neural Activity

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.

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.
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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  • Monitor Neural Activity

Large-scale monitoring and modulation of brain activity using non- or minimally invasive tools with high spatiotemporal resolution remains a challenge for neuroscientists. Dr. Mehdi Kiani and colleagues will develop a new bidirectional, neural-interface platform for electrophysiological recordings and stimulation of neural activities over the entire brain. This wireless, minimally invasive technology measures micro-electrocorticography signals from 100 sites, drives ultrasonic transducers to guide a focused ultrasonic beam to stimulate a targeted brain region, and simultaneously images the neural tissue – all at <500 mm resolution. The platform functions with an external unit in a closed-loop fashion to deliver the stimulation pattern, recover the electrophysiological and imaging data, and create the neural tissue images.

Bidirectional optical-acoustic mesoscopic neural interface for image-guided neuromodulation in behaving animals SHOHAM, SHY et al. NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 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: 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 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
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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
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Genetically encoded calcium indicators (GECIs) developed from fluorescent proteins (FPs) can be used to image intracellular calcium dynamics and provide a robust readout of neuronal responses to action potentials, and as a result, these proteins have revolutionized the way neural activity is recorded in the brain. Current GECIs are based on green and red fluorescent proteins, but because visible light is subject to strong scattering inside the brain, these proteins are only useful for recording activity close to the brain surface. Near-infrared (NIR) GECIs would provide a major increase in the depth at which these signals can be recorded, because they can be imaged with longer wavelength light, which is much less susceptible to scattering than light at visible wavelengths. Verkhusha’s team developed NIR GECIs that will be imaged with modern adaptive optics imaging techniques, allowing non-invasive, cellular-resolution imaging deep in the cortex and hippocampus. If successful, this research will provide highly sought-after deep-tissue optical probes and help advance researchers’ understanding of information processing in the brain.
Calcium sensors for molecular fMRI Jasanoff, Alan Massachusetts Institute Of Technology 2014 RFA-NS-14-007 Complete
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Dr. Jasanoff's team will synthesize calcium-sensing contrast agents that will allow functional magnetic resonance imaging (fMRI) scans to reveal activity of individual brain cells.
Capabilities of MRI-Based Neural Current Imaging for Human Brain Mapping Kim, Young R Massachusetts General Hospital 2015 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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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.
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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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.
Circuit mechanisms of evidence accumulation during decision-making Luo, Zhihao Princeton University 2017 RFA-MH-17-250 Active
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Dr. Luo will use optogenetic tools to inactivate specific brain structures while simultaneously recording neuronal activity across other brain areas in the rat during evidence accumulation tasks. This research could uncover the neural circuits that support the gradual accumulation of evidence during decision making.
Clinical Testing of an Intracortical Visual Prosthesis System Troyk, Philip R Illinois Institute Of Technology 2016 RFA-NS-16-009 Active
  • Human Neuroscience
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Blindness can have a negative impact on quality of life, and is associated with relatively high rates of depression and social isolation, and relatively low levels of employment. The IntraCortical Visual Prosthesis (ICVP) team led by Dr. Troyk has worked to develop an ICVP that can compensate for blindness by stimulating the visual centers of the brain. This project aims to provide proof of principle with a small number of human volunteers, to demonstrate that the ICVP successfully produces visual sensory perception and to assess the utility of the induced visual percepts.
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
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Deep brain stimulation (DBS) has an important clinical role in the management of movement disorders, including Parkinson’s disease (PD). However, current DBS therapy for PD relies on continuous stimulation, regardless of changes in brain circuit function related to changes in disease expression (i.e. oscillation between too little and too much movement). In this project, Starr and his team will use next-generation DBS devices to develop and test a method of automatically adjusting stimulation parameters based on brain signals that reflect the patient's clinical state, to optimize DBS for PD. In a small number of patients, they will measure local brain activity in each patient and use that information to develop individualized stimulation paradigms; these algorithms will then be programmed into the DBS devices, to demonstrate proof of principle for this novel, closed-loop DBS system.
Closing the Loop on Tremor: A Responsive Deep Brain Stimulator for the Treatment of Essential Tremor Foote, Kelly D Gunduz, Aysegul (contact) University Of Florida 2016 RFA-NS-16-010 Active
  • Human Neuroscience
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Essential tremor (ET) is an incurable, degenerative brain disorder that results in increasingly debilitating tremor. Deep Brain Stimulation (DBS) is used as an effective treatment for ET, but the continuous brain stimulation provided by current DBS methods is likely unnecessary given the intermittent nature of ET symptoms, and may underlie DBS-induced side effects such as slurred speech and difficulty walking. It also may unnecessarily hasten the need for surgery to replace depleted DBS batteries. In this project, Gunduz and Foote propose to use modern DBS devices capable of recording and stimulating simultaneously, to continuously monitor brain activity and deliver stimulation only when necessary to control tremor. This work may provide proof-of-concept for the first chronic closed-loop DBS system for the treatment of a debilitating movement disorder in humans.

Collaborative Standards for Brain Microscopy Hamilton, Carol M Research Triangle Institute 2018 RFA-MH-17-256 Active
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Recent tissue-clearing techniques and advances in microscopy have made it possible to produce 3D images of intact brains. to help ensure consistency in data collection and analysis, Dr. Hamilton and her team will develop a set of standards for3D imaging of whole brains for the neuroscience research community.. Dr. Hamilton’s group will convene a Working Group of experts who will work through a consensus process to establish standards that will be distributed to the research community. These standards should help improve the efficiency of imaging research and allow comparisons across studies.

Combined Cortical and Subcortical Recording and Stimulation as a Circuit-Oriented Treatment for Obsessive-Compulsive Disorder Dougherty, Darin D (contact) Eskandar, Emad N Massachusetts General Hospital 2016 RFA-NS-16-010 Active
  • Human Neuroscience
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4-7 million Americans suffer from obsessive-compulsive disorder (OCD), and at least half of these patients do not receive adequate relief from medication or talk therapy. Deep brain stimulation (DBS) is used as a treatment for patients with intractable OCD, but only works for about half of these patients. In an effort to improve DBS for OCD, Dougherty and Eskandar have proposed to develop and test in a small early feasibility study a next-generation, brain circuit-oriented DBS treatment for drug-refractory OCD. In their project, they will measure brain activity to test a hypothesis about the specific circuit dysfunction that underlies OCD, and they will test whether DBS stimulation can disrupt this circuit dysfunction in order to relieve OCD symptoms.
Compressive Light Field microscopy for optogenetic neural activity tracking Waller, Laura University Of California Berkeley 2016 RFA-EY-16-001 Complete
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State-of-the-art techniques for measuring neural activity on a large scale still lack the ability to measure signals from across many brain regions at high speed and with cellular resolution. Borrowing from recent advances in 3D photography, Waller and her colleagues will develop an optical imaging system that will not only capture the intensity of light emitted from active, fluorescing neurons, but it will also capture the angle of the emitted light. Combining light intensity and angle allows for reconstruction of neural activity in 3D. This system, which will be relatively inexpensive and easy to set up, has the potential to record from millions of individual neurons at speeds faster than conventional imaging methods.
Computational and circuit mechanisms for information transmission in the brain Eden, Uri Tzvi Frank, Loren M Ganguli, Surya Kepecs, Adam (contact) Kramer, Mark Alan Machens, Christian Tolosa, Vanessa Cold Spring Harbor Laboratory 2015 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 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
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Deep brain stimulation (DBS) targeting the ventral internal capsule/ventral striatum (VC/VS) is being used as a treatment for those with obsessive compulsive disorder (OCD), but with inconsistent clinical results. As a tool to examine mechanisms underlying this process, Dr. Widge and colleagues will adapt the recently developed "StimVision" software suite to model DBS electrical fields that activate brain tissue, in collaboration with the McIntyre lab (Case Western Reserve University). Using data from their DBS patient cohort, the team will integrate novel algorithms to improve modeling of neural mechanisms underlying the effects of DBS. This research, using StimVision with a specific DBS patient group, will improve understanding of cortical circuits underlying the behavioral effects of DBS, potentially enhancing circuit-oriented therapies.
Concurrent multiphoton microscopy and magnetic resonance imaging (COMPMRI) Wang, Yi Xu, Chris (contact) Cornell University 2016 RFA-EY-16-001 Complete
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One of the major goals of the BRAIN Initiative is mapping neuronal function at multiple spatial scales, from synapses to the whole brain. The proposed project from Xu and Wang will deliver such maps by combining two powerful brain imaging technologies—MRI and multiphoton imaging, a deep-brain, high-resolution imaging technique that Xu has developed with the help of two previous BRAIN awards. The combined imaging device will allow studies of the relationship between neural activity at the cellular and network level.
Conducting polymer nanowires for neural modulation Payne, Christine K Georgia Institute Of Technology 2015 RFA-EY-15-001 Complete
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Microelectrodes are used to record and stimulate neuronal activity in experimental animals and in human therapeutic applications. However, the injury to tissue when they are implanted, and their mechanical mismatch with brain tissue after implantation, can trigger the brain's immune response, causing them to be encapsulated by glia and other cells and preventing current flow between neurons and the electrical contacts. Payne and her colleagues will use the latest in nanotechnology to develop ultra-thin, flexible nanowires made from a biocompatible polymer which, because of their small size and flexibility, may avoid the immune responses triggered by larger electrodes. The nanowires will be inserted into the brain with micro-capillary tubes and will connect individual neurons to external recording and/or stimulating devices. The nanowires can also be coated with specific molecules that will promote attachment to specific neuron types, allowing for precisely targeted recording or stimulation experiments.
Connectome 2.0: Developing the next generation human MRI scanner for bridging studies of the micro-, meso- and macro-connectome Basser, Peter J. Huang, Susie Yi Rosen, Bruce R (contact) Wald, Lawrence L Witzel, Thomas Massachusetts General Hospital 2018 RFA-EB-17-004 Active
  • Human Neuroscience
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Understanding the structural basis of brain function requires spanning multiple spatial scales, from synaptic circuits to whole-brain systems, but current technology is limited in its ability to successfully integrate across these scales. Dr. Bruce Rosen and a team of investigators propose the development of a human magnetic resonance imaging (MRI) scanner that images brain structural connectivity in-vivo. Building upon previous work from the Human Connectome Project (HCP), these tools will advance brain imaging with the capability of estimating cellular and axon level microstructural brain circuits at very high resolution. The project will have the potential to significantly expand our knowledge on hierarchical anatomy and functionality of both healthy and diseased human brains, with impact on both neuroscience research and clinical applications.

Context-dependent processing in sensorimotor cortex Collinger, Jennifer UNIVERSITY OF PITTSBURGH AT PITTSBURGH 2018 RFA-NS-18-010 Active
  • Human Neuroscience
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When you reach for a beverage, the way you pick up the drink depends on whether it is in a sturdy mug or a delicate champagne flute, as well as your reach configuration. Dr. Collinger and her colleagues plan to investigate the way environmental context affects motor cortex activity as the brain plans movements, such as grasping an object. Two individuals with tetraplegia will receive implants in their motor cortex to record activity while they use brain signals to control a robotic prothesis in a variety of tasks including grasping an object or grasping into empty space, picking up objects of various sizes and materials, and picking up objects for different goals. A better understanding of how the brain prepares these movements may lead to improved devices and therapies for those with sensory or motor problems. 

Controlled neuronal firing in vivo using two photon spatially shaped optogenetics Gibson, Emily Restrepo, Diego (contact) University Of Colorado Denver 2017 RFA-NS-17-004 Active
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Optical imaging techniques offer several advantages to understanding neural circuits, including the ability to interrogate a large number of neurons and genetically label specific neuronal subtypes. Diego Restrepo, Emily Gibson, and colleagues will optimize their prototype of a light-weight, two-photon, fiber-coupled, miniature confocal microscope that uses electrowetting lens technology. The new tool will be able to image and stimulate select fluorescently-labeled neurons in a 3D volume in awake-behaving animals. The device can be attached to existing commercial laser scanning microscopes – greatly expanding the number of labs who will be able to benefit from this cutting-edge technology.
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
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Optogenetics has dramatically advanced neuroscience, allowing the manipulation and monitoring of activity in genetically-defined neurons in the brain using light. However, while deeper brain structures can be accessed using optical fibers, standard fibers only illuminate tissue near their tip and are invasive in small animals. The team will develop light-delivery tools—tapered fiber optics—that allow precise, flexible control of spatially separated groups of neurons. Coupling these optical devices with electrical stimulators, the group plans to interrogate the same neurons using both methods simultaneously and incorporate novel viral preparations to enable genetic change in the neurons through the device. This toolset should expand our ability to manipulate and record neuronal circuits in a less invasive manner.

Cortex-wide volumetric imaging of neuronal activity. Vaziri, Alipasha Rockefeller University 2017 RFA-NS-17-004 Active
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Understanding how brain-wide neural network activity underlies behavior is a central goal of neuroscience, and essential to understanding neurological and psychiatric disorders. Vaziri’s group recently innovated microscopy platforms that extend the obtainable spatiotemporal resolution and volume size using calcium imaging. Here, they propose to develop, apply, and disseminate a hybrid system that enables calcium imaging of ~2 million neurons within and across layers of cortex in awake behaving rodents and marmosets. Such a system would capture functional organization and activity patterns of neuronal population dynamics. This project could enable new mechanistic insights into the computational principles of neural information processing.
Cortical circuits and information flow during memory-guided perceptual decisions Sur, Mriganka Massachusetts Institute Of Technology 2014 RFA-NS-14-009 Complete
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Dr. Sur and his team will combine a number of cutting-edge, large-scale imaging and computational techniques to determine the exact brain circuits involved in generating short term memories that influence decisions.
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
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While Deep Brain Stimulation (DBS) devices can alleviate symptomology of patients with chronic conditions like Parkinson’s disease, appropriate placement is paramount and challenging, particularly for directional stimulating leads. Dr. Austin plans to develop and test CranialProgrammer, image-guided software that uses local field potentials to help clinicians map patient brain regions for optimal placement of DBS leads. In partnership with NeuroTargeting, LLC, the software will integrate with the implanted DBS system of Parkinson’s patients to allow visualization of patient data coupled with imaging technologies. This software could dramatically improve the ability of neurologists to program directional DBS leads, providing therapeutic benefit to myriad DBS patients.

Crowd coding in the brain:3D imaging and control of collective neuronal dynamics Kanold, Patrick O (contact) Losert, Wolfgang Plenz, Dietmar Univ Of Maryland, College Park 2014 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.
DART2.0: comprehensive cell type-specific behavioral neuropharmacology Tadross, Michael R Duke University 2018 RFA-MH-17-220 Active
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Neuropharmaceuticals provide relief to millions suffering from an array of neurological and neuropsychiatric disorders. However, a barrier to identifying novel therapeutic targets can be attributed to a poor understanding of how the behavioral effects of drugs are mediated by specific neural cell types in the brain. Tadross’ team recently developed DART (Drugs Acutely Restricted by Tethering), the first and only method to date that can map the behavioral effects of clinical drugs by cell type. These tools would reveal circuit origins of desired vs harmful drug effects, explain why some drugs have higher efficacy than others, and potentially empower future rational efficacy advances. This project aims to expand the catalog of available DARTs, increase their subcellular specificity, and improve ease of use – particularly in combination with recording devices across larger brain areas. If successful, these tools will maximize utility to the neuroscience community, enabling previously intractable questions to be addressed.

Data Archive for the Brain Initiative (DABI) Duncan, Dominique Pouratian, Nader Toga, Arthur W (contact) University Of Southern California 2018 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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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.

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
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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.

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

Develop and validate novel chemogenetic tools to modulate synaptic transmission Tomita, Susumu Yale University 2017 RFA-MH-17-220 Active
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Neuronal activity modulates the strength of synaptic connections, a phenomenon known as synaptic plasticity, which is critical for forming and maintaining memories, for behavioral adaptations, and is disrupted in a variety of nervous system disorders. Tomita and colleagues will develop tools to chemically modulate excitatory synaptic transmission in vivo, mimicking synaptic plasticity. They will engineer a protein that transiently modulates synaptic activity upon addition of small chemical compounds. They will validate the protein module using a mouse fear conditioning behavioral paradigm and electrophysiology. This approach may help identify precise circuits/mechanisms underlying brain functions like learning and memory.
Developing a noninvasive method to manipulate specific cell types within the mammalian brain Chalasani, Sreekanth H. Salk Institute For Biological Studies 2016 RFA-MH-16-775 Active
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Current optogenetic techniques to manipulate cellular activity rely on an invasive light delivery method which makes control of cells deep in the brain difficult. Chalasani and colleages are developing a non-invasive method of cellular control using mechanosensitive channels that are responsive to low-intensity ultrasound - a novel technique deemed “sonogenetics.” The group can control neuronal activity in vitro by expressing these channels in target cells, and plan to test similar channels to fine-tune responsiveness to ultrasound pulses. Further, the group will develop a head device to deliver ultrasound pulses in mice, test efficacy in vivo via electrophysiological and behavioral analyses. Following development in rodents, this tool could be broadly applicable across multiple species to manipulate specific neuronal and non-neuronal cell types.
Developing drivers for neuron type-specific gene expression Hobert, Oliver Columbia University Health Sciences 2014 RFA-MH-14-216 Complete
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Dr. Hobert and colleagues will create a highly selective technology for experimentally manipulating genes in neurons, by tapping into the regulatory machinery of individual cell types.

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
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Two-photon microscopy is an important tool for neuroscience research because it enables neuronal activity to be monitored at high spatial resolution deep into the neocortex. Silver and his colleagues plan to refine and disseminate a rapid scanning technology that utilizes an acousto-optic effect, in which a crystal lens is modulated using sound waves, allowing extremely fast switching of laser light in 3D over arbitrary distances within a given scanning field. They have designed a modular system that can be integrated into current two-photon microscopes at low cost. The project design and software interface are open source and will be made available for free to non-commercial entities, and by non-exclusive licensing to commercial partners. This low-cost technology for imaging neuronal circuits in awake, behaving animals will help researchers better understand brain function.
Development and Translation of an Intracranial Auditory Nerve Implant LIM, HUBERT HYUNGIL et al. UNIVERSITY OF MINNESOTA 2018 RFA-NS-17-005 Active
  • Human Neuroscience
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Despite providing significant restoration of the ability to hear speech, cochlear implants have been limited in their ability to restore full hearing, particularly in loud environments or situations when multiple sounds are present at once. Drs. Lim, Oxenham, Franklin, Rieth, Solzbacher, and Lenarz are exploring a new, auditory nerve implant device and surgical techniques with the potential to improve upon current cochlear implants in humans. This new device will directly target the auditory nerve, which connects the cochlea to the brainstem. The researchers, who will also be developing a new surgical technique for implantation and validate efficacy and safety, hope that this will allow for improved hearing, including speech and music.

Development 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
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Systems capable of simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) are now available, but PET technology in these systems lacks the capability of tracking dynamic changes at high spatio-temporal resolution. Dr. Ciprian Catana and a team of investigators plan to develop a PET detector that can be successfully integrated with a 7-Tesla MRI scanner with high sensitivity and resolution. After designing and evaluating a scalable PET detector module, the group will investigate and address hardware challenges of developing high performance MR-compatible PET technology. The successful development of this novel PET technology will enable imaging of the human brain’s dynamic neurochemical connectome and significantly advance our understanding of human brain function, neurochemistry, and physiology.

Development of a Revolutionary MRI System for Functional Brain Imaging Wagner, Bob S Wang, Sou-tien Bert (contact) Wang Nmr, Inc. 2018 PAR-15-091 Active
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Low-cost, portable Magnetic Resonance Imaging (MRI) systems require use of small-bore magnets that are unable to capture the detail necessary to image the human brain. In this project, Drs. Wang and Wagner propose to further develop an imaging method previously funded by The BRAIN Initiative, by designing, building, and testing a portable 1.5T MRI system to image human brain activity. The novel imaging technology works with a small, lightweight (250 lb.), portable, low-cost, head-only magnet. The compactness and efficiency of this non-invasive imaging system makes the study of the human brain possible in more clinics and in subjects who previously were unable to receive an MRI scan due to constraints of standard systems.

Development of a scalable methodology for imaging neuropeptide release in the brain Anderson, David J California Institute Of Technology 2015 RFA-EY-15-001 Complete
  • Monitor Neural Activity
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Superimposed upon the brain's physical connectome is a largely invisible chemical soup of neuromodulators, including biogenic amines and neuropeptides, which exert a profound influence on the activity and function of neural networks. Yet, large-scale high-resolution techniques for measuring neuromodulators have lagged behind those for recording or imaging electrical activity. Anderson and his team plan to develop fluorescent proteins that can be attached specifically to large dense core vesicles—discrete packets of neuromodulators to be released into the synapse. This method would enable researchers to use 2-photon microscopy to image the release of neuromodulators in living animals with high spatial and temporal resolution, transforming the ability to characterize neural circuit function and facilitating the development of technologies to selectively perturb release.
Development of an integrated array for simultaneous optogenetic stimulation and electrical recording to study cortical circuit function in the non-human primate brain Angelucci, Alessandra Blair, Steven M (contact) Rieth, Loren University Of Utah 2016 RFA-NS-16-007 Active
  • Monitor Neural Activity
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Optogenetics is a potent tool for studying neural circuit function, but its application in the context of electrical recordings has been limited, especially in higher mammals beyond rodents. Blair and his colleagues propose to develop and test functional multi-optrode penetrating arrays derived from the well-established Utah electrode array. These devices, which will integrate light emitting diodes (LEDs), are designed for spatiotemporally patterned optogenetic stimulation and electrical recording of neural circuits across large volumes throughout the depth of the neocortex. This technology will allow for unprecedented optogenetic investigations of neural circuit function in higher mammals, enabling experiments that will address fundamental questions of how the brain processes information.
Development of Hybrid Adaptive Optics for Multimodal Microscopy Deep in the Mouse Brain Adie, Steven Graham Cornell University 2017 RFA-EY-17-001 Active
  • Monitor Neural Activity
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Achieving high-resolution, optical images of deep cellular brain activity with three-photon microscopy can be difficult due to technical limitations of existing methodologies. Currently, collecting a volumetric set of images uses correction sensors that require long measurement times and can damage the biological sample. Steven Adie is collaborating with Chris Xu to develop an improved hybrid imaging approach that captures high-resolution cellular imaging and outsources the correction sensor step to computational resources, reducing correction time. By enabling faster corrections to occur at greater depths than is currently possible, the group will address a standing impediment to deep-brain microscopy of brain activity. This project has the potential to be a major step towards volumetric functional imaging of neural activity in the mouse brain.
Development of Line-Scan Temporal Focusing for fast structural imaging of synapse assembly/disassembly in vivo Boivin, Josiah R Massachusetts Institute Of Technology 2017 RFA-MH-17-250 Active
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  • Human Neuroscience
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Dr. Boivin will contribute to the development of high-resolution, high-throughput Temporal Focusing (TF) two-photon microscopy to achieve real-time monitoring of synapse assembly/disassembly in developing neural circuits in vivo in the mouse brain.
Development of Protein-based Voltage Probes Pieribone, Vincent A John B. Pierce Laboratory, Inc. 2014 RFA-NS-14-008 Complete
  • Monitor Neural Activity
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Dr. Pieribone and his team will optimize fluorescent voltage probe technology, to allow scientists to measure the activity of thousands of neurons using only a camera and a microscope.
Development of tools for cell-type specific labeling of human and mouse neocortical neurons Lein, Ed Levi, Boaz Pirie (contact) Ting, Jonathan T Allen Institute 2017 RFA-MH-17-220 Active
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An important strategy for understanding the neural circuits is to identify the component cell types, then determine each cell type’s function. Currently, the characteristics of mammalian neocortical cell types are incompletely characterized, and the necessary investigative tools are lacking. Levi and colleagues will develop cross-species, cell-class-specific viral vector libraries for tagging different cell types in mouse and post-mortem human neocortex, which will be validated using single-cell RNA sequencing and electrophysiology. If successful, this project will achieve novel cell type-specific genetic tools to investigate and compare cross-species neocortical cell types.
Dexterous BMIs for tetraplegic humans utilizing somatosensory cortex stimulation Andersen, Richard A California Institute Of Technology 2016 RFA-NS-16-008 Active
  • Human Neuroscience
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As of 2016, approximately 160,000 Americans are living with partial or complete tetraplegia, a severe form of paralysis in which patients lose partial or total function and sensation in all four limbs. Many of these patients have sufficiently intact brain circuits to plan movements, but are unable to act on those plans due to paralysis at the spinal level. In this project, Andersen and his team will work with tetraplegic patients implanted with a brain machine interface (BMI) to record from and stimulate brain circuits. Their goal is to understand how the brain encodes the ability to reach for and grasp an object. They also propose to stimulate somatosensory cortex to restore sensory cues the hands would normally receive when grasping an object, and to combine these recording and stimulating efforts to design bi-directional BMIs. This work could lead to improved quality of life for patients with tetraplegia, and could inform treatment of motor impairments due to other causes including stroke and neurodegenerative diseases.
Diffuse, spectrally-resolved optical strategies for detecting activity of individual neurons from in vivo mammalian brain with GEVIs Nishimura, Nozomi Cornell University 2017 RFA-EY-17-001 Active
  • Monitor Neural Activity
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Optical recording of neural activity allows researchers to better understand the role of cells and circuits in behaviors, but distinguishing individual neurons in a population of cells is difficult with existing voltage indicators, while laser scanning methods are typically too slow to resolve action potentials from many cells at a time. Rather than using scanning methods to identify cells based on their location, Nozomi Nishimura and colleagues propose the use of spectral information to “barcode” individual neurons, using multiple colors of genetically-encoded voltage indicators to label neurons with a combination of voltage probes. After capturing the emitted fluorescence, the channels can be spectrally unmixed to sort different neurons based on their combination of colors and patterns. This novel paradigm has the potential to detect and decode action potentials in individual neurons at the imaging rates required to resolve spike timing in a population of cells.
Direct MEG/EEG detection using a novel MRI approach Bottomley, Paul A Johns Hopkins University 2017 RFA-EY-17-001 Active
  • Monitor Neural Activity
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Non-invasive measurements of neuronal electrical activity in the human brain are currently limited by the low spatial resolution of electroencephalography (EEG) and magnetoencephalography (MEG) methods. Another non-invasive method – functional magnetic resonance imaging (MRI) – provides high spatial resolution, but reports fluctuations in neural activity via the slow, indirect neurovascular response. Paul Bottomley and his team are applying spectroscopy with linear algebraic modeling (SLAM) – a method they recently developed for MR spectroscopy – to MEG-modulated MRI signals. Using SLAM, the group plans to improve the signal-to-noise ratio and demonstrate MRI-based detection of brain electrical signals in healthy human volunteers. This novel approach has the potential to deliver an MRI-based means of directly localizing EEG/MEG activity in the healthy human brain.
Dissecting human brain circuits in vivo using ultrasonic neuromodulation Shapiro, Mikhail Tsao, Doris Ying (contact) California Institute Of Technology 2014 RFA-MH-14-217 Complete
  • Monitor Neural Activity
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  • Human Neuroscience
In rodents, monkeys and eventually humans, Dr. Tsao's team will explore use of non-invasive, high resolution ultrasound to impact neural activity deep in the brain and modify behavior.
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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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
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  • 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
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The computational strategies and underlying mechanisms the brain uses to enable animals to interact flexibly with their environment are poorly understood. These researchers will use large-scale, wireless, electrical recordings from six relevant, interconnected brain regions in freely-behaving monkeys to record neuronal activity while the animals engage in foraging behavior-a natural task that involves sensory integration, spatial navigation, memory, and complex decision-making. The research team will use theoretical models of decision-making to interpret the neural activity data gathered as the animals interact with their environment, with the ambitious goal of understanding how brains create and use internal models of the world.
Dynamic Neural Mechanisms of Audiovisual Speech Perception Schroeder, Charles E Columbia University Health Sciences 2016 RFA-NS-16-008 Active
  • Human Neuroscience
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Limitations in spatial and temporal resolution with current non-invasive brain imaging technologies prevent a thorough understanding of the mechanisms of speech perception – from audio-visual (AV) integration, to encoding, and cognitive interpretation. Dr. Charles Schroeder proposes directly recording from neurons in epilepsy patients while they process AV speech using electrocorticographic (ECoG) techniques to determine how oscillations in neuronal excitability influence processing and encoding. Not only could this project improve our ability to treat neurological disorders affecting speech and language processing, but it may allow a more comprehensive investigation into the functional interactions between brain circuits and perception.
Dynamics and Causal Functions of Large-Scale Cortical and Subcortical Networks SCHALK, GERWIN WADSWORTH CENTER 2018 RFA-NS-18-010 Active
  • Human Neuroscience
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To produce a behavior, brain areas need to talk to each other. This communication has been difficult to study in humans, but novel tools provide a window into these conversations. Dr. Schalk and his colleagues plan to establish a consortium that will bring together a large cohort of study subjects and experts across scientific disciplines. They will record from state-of-the-art brain implants to investigate which regions are involved in speech, language, and music awareness; to measure how stimulating certain areas affects speech and language; and to explore how areas talk to one another during changing speech perception. These results should increase understanding of how brain regions interact, which may provide insights to treating neurological and psychiatric disorders.

Early Feasibility Clinical Trial of a Visual Cortical Prosthesis Dorn, Jessy D (contact) Greenberg, Robert Jay Pouratian, Nader Second Sight Medical Products, Inc. 2018 RFA-NS-17-006 Active
  • Human Neuroscience
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  • 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.
Electrophysiological Biomarkers to Optimize DBS for Depression Mayberg, Helen S Emory University 2017 RFA-NS-17-006 Active
  • Human Neuroscience
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  • 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.
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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
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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
  • Integrated Approaches
  • Interventional Tools
  • 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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  • Circuit Diagrams
  • Monitor Neural Activity
  • Interventional Tools
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
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • 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.
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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  • Monitor Neural Activity

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.

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
  • Integrated Approaches
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  • Monitor Neural Activity
  • Theory & Data Analysis Tools
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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Interventional Tools
  • 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.

Five-dimensional optoacoustic tomography for large-scale electrophysiology in scattering brains Razansky, Daniel Technical University Of Munich 2015 RFA-EY-15-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
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
  • Interventional Tools
  • Monitor Neural Activity

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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Monitor Neural Activity
  • Interventional Tools
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.

Functional Architecture of Speech Motor Cortex Chang, Edward University Of California, San Francisco 2016 RFA-NS-16-008 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
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.
Gated Diffuse Correlation Spectroscopy for functional imaging of the human brain Franceschini, Maria Angela Massachusetts General Hospital 2017 RFA-EB-17-001 Active
  • Monitor Neural Activity
  • 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
  • Monitor Neural Activity
  • 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
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
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  • Monitor Neural Activity
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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
  • Monitor Neural Activity
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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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Monitor Neural Activity
  • Interventional Tools
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
  • Interventional Tools
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
  • Monitor Neural Activity
  • 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.
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
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Mertz and colleagues propose two fundamental improvements to multiphoton microscopy, an important technique for imaging neural activity. The first involves modulating laser power using high speed electronics to accommodate variations in sample brightness, thus enabling recordings with much wider dynamic range. This will allow experiments where there are large differences in signal in the same sample, e.g., from axon terminals vs. cell body. The second improvement is a new method for signal multiplexing, which will enable simultaneous recordings from multiple brain regions within a large imaging area. The system is low cost and will require minimal modifications to most existing microscopes, which should contribute to ready adoption by the research community.
High resolution deep tissue calcium imaging with large field of view wavefront correction Cui, Meng (contact) Gan, Wenbiao Purdue University 2015 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
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  • Human Neuroscience
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Agency, our ability to act and experience a sense of responsibility for our actions, is central to individual identity and societal conceptions of moral responsibility. Neural devices are currently used to treat some brain disorders, such as Parkinson’s disease, and are being developed to treat others such as depression and obsessive-compulsive disorder, yet their use raises important ethical concerns about potential effects on agency. Dr. Goering, Dr. Klein and their team will investigate agency in individuals receiving brain computer interface devices for sensory, motor, communication, and psychiatric indications. They aim to build a user-centered neural agency framework, and, ultimately, to enhance the informed consent process by developing a communication tool that patient participants might use to better understand and discuss potential changes in agency associated with use of neural devices.

Identification of enhancers whose activity defines cortical interneuron types Rubenstein, John L. R. (contact) Sohal, Vikaas Singh University Of California, San Francisco 2014 RFA-MH-14-216 Complete
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  • Monitor Neural Activity
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Dr. Rubenstein and colleagues plan to identify enhancer molecules specific to particular types of interneurons – that relay neural signals – and use this information to profile distinct cell types and new ways to manipulate genes.
Illuminating Neurodevelopment through Integrated Analysis and Vizualization of Multi-Omic Data Hertzano, Ronna (contact) White, Owen R University Of Maryland Baltimore 2018 RFA-MH-17-257 Active
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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
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Human and animal research has shown that modulation of adult hippocampal neurogenesis – the generation of neurons – can lead to changes in memory and emotion, but the underlying mechanisms are not well characterized. Dr. Michael Drew and colleagues will image adult-born neurons during learning behavior via incorporating head-mounted minimicroscopes (developed with prior BRAIN Initiative support). Dr. Drew’s laboratory will perform calcium imaging experiments in awake, behaving mice during a contextual fear conditioning paradigm and, using optogenetic techniques, they will silence adult-born hippocampal neurons in order to characterize how these neurons impact the coding of context memory. These studies will enhance the understanding of the mechanisms by which changes in adult neurogenesis influences mood and cognition.
Imaging Brain Function in Real World Environments & Populations with Portable MRI Garwood, Michael G (contact) Vaughan, John T University Of Minnesota 2014 RFA-MH-14-217 Complete
  • Monitor Neural Activity
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  • Human Neuroscience
By employing smaller, less cumbersome magnets than used in existing MRI, Dr. Garwood and colleagues will create a downsized, portable, less expensive brain scanner.
Imaging Human Brain Function with Minimal Mobility Restrictions Garwood, Michael G University Of Minnesota 2017 RFA-EB-17-002 Active
  • Monitor Neural Activity
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  • Integrated Approaches
  • Human Neuroscience
Conventional magnetic resonance imaging (MRI) from whole-body magnets has become a critical tool for human neuroscience research, but there are limitations to both their usability and technical requirements. High-quality MR images typically require large magnets that maintain a static magnetic field, but in a multi-institution effort led by Michael Garwood, researchers are developing a portable MR imaging prototype that collects high-quality images with a small, light-weight magnet that also permits some degree of freedom of movement. This technological development has the potential to revolutionize MRI approaches, making it possible to collect high-quality MR images by improving scanner portability: bringing the scanner to human subjects and patients, rather than the other way around.
Imaging in vivo neurotransmitter modulation of brain network activity in realtime Gjedde, Albert Rahmim, Arman Wong, Dean Foster (contact) Johns Hopkins University 2014 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
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  • Monitor Neural Activity

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

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 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
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When neurons are electrically active they emit magnetic impulses, which can be imaged using magnetoencephalography. However, this technique requires placing a large, low-temperature detector outside the brain, which can only pick up broad signals from large numbers of neurons. Recently it has become possible to fabricate tiny magnetometers on standard substrates used in the semiconductor industry, which are ultra-sensitive, small enough to fit much closer to the brain, and don't require super-cooling. Schiff and Tadigadapa and their colleagues propose developing devices based on this technology and embedding them within the skull. They will develop active on-chip noise cancelation to allow the devices to be used outside a magnetically shielded room. If the approach is successful, it could enable use across the lifespan in animals and potentially in humans for therapeutic purposes.
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
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A fundamental challenge to achieving a mechanistic understanding of how the brain works is obtaining a systematic characterization of diverse cell types at single-cell resolution. Dulac, Regev, and Zhuang, will use Multiplexed Error Robust Fluorescent in situ Hybridization (MERFISH) to measure the transcriptome of single cells from intact brain tissue, creating a spatially informed cellular inventory of neural circuits in mouse. By expanding this method into the marmoset and coupling it with behavioral tasks, they will validate a new, unbiased imaging platform and computational toolkit that uses gene expression profiles to classify cells in the functional context of behaviorally relevant circuits.
In Vivo Brain Network Latency Mapping BASSER, PETER J National Institute of Child Health and Human Development 2018 Active
  • Human Neuroscience
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  • 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
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  • Human Neuroscience
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Dopamine is a powerful neurotransmitter that facilitates memory formation and underlies reward-related behaviors, but current techniques to assess dopamine signaling in vivo lack sufficient specificity and spatiotemporal resolution. Evans will develop new fluorescent sensors for dopamine receptors and apply them to investigate the molecular mechanisms that underlie learning in mice in vivo. The biosensors will be used to visualize the dynamic activity of specific dopamine receptors in vitro, before they are virally expressed in the motor cortex in behaving mice. Employed during motor learning, these sensors should generate a sub-micron scale map of how dopamine receptor subtypes modulate long-term structural plasticity of cortical dendritic spines. The results could help shed light on how dopaminergic modulation correlates with structural and functional plasticity.
In-vivo circuit activity measurement at single cell, sub-threshold resolution Forest, Craig (contact) Stanley, Garrett B. Georgia Institute Of Technology 2014 RFA-MH-14-216 Complete
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  • Monitor Neural Activity
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Dr. Forest's team will use a newly developed robot guided technique to measure precise changes in electrical activity from individual neurons that are connected over long distances across the brain, to understand how these connections change when our brains go into different states, such as sleeping and waking.
Increased thalamocortical connectivity in tdcs-potentiated generalization of cognitive training Lim, Kelvin O. (contact) Macdonald, Angus W University Of Minnesota 2018 RFA-MH-17-245 Active
  • Human Neuroscience
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  • Monitor Neural Activity

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

Informing Choice for Neurotechnological Innovation in Pediatric Epilepsy Surgery Illes, Judy (contact) Mcdonald, Patrick University Of British Columbia 2018 RFA-MH-18-500 Active
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More than 500,000 children in the US and Canada suffer from epilepsy and 30% of these children continue to experience seizures despite being treated with anti-seizure medication. Unmanaged, epilepsy can result in cognitive decline, social isolation, and poor quality of life, and has substantial economic impact on families and society. Novel approaches for treating epilepsy such as vagal nerve stimulation and responsive neurostimulation are being developed, but this work has been conducted predominately in adults and the outcomes of these trials are often not clearly generalizable to children. In this project, Drs. Illes and McDonald will explore ethical issues confronting families and clinicians when considering new treatment options for drug-resistant epilepsy in children. They aim to develop, evaluate, and deliver patient-directed resources in the form of infographics and informational materials and videos, and clinician resources for family decision-making, clinician counseling, and care.

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 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
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  • 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 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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  • Monitor Neural Activity
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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.
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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  • Interventional Tools
  • 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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  • Interventional Tools
  • Monitor Neural Activity
Circuits between the frontal cortex and basal ganglia (BG) may support the ability to suppress actions once additional information becomes available to indicate the most appropriate decision, but few studies provide the necessary spatial and temporal resolution to investigate this mechanistically. Dr. Pouratian’s group will utilize deep brain stimulation (DBS) electrodes in Parkinson’s patients to record from cortical and BG regions in multiple action-suppression tasks. In addition to investigating unit and local field potential activity during tasks, the group will use DBS coupled with functional imaging to stimulate the circuits and measure effects on brain activity, eventually developing a computational model of action suppression. Aside from informing the basic science of this circuitry, this project could expand upon how DBS influences brain networks for action, which could improve therapeutic use in various disorders.
Investigating the hypocretin to VTA circuit in memory consolidation during sleep Borniger, Jeremy Stanford University 2018 RFA-MH-17-250 Active
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  • Human Neuroscience
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  • Monitor Neural Activity
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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 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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  • Human Neuroscience
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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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  • Monitor Neural Activity
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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
  • Interventional Tools
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
  • Interventional Tools
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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  • Monitor Neural Activity
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Dr. Burton will leverage recent enhancements in calcium indicators to image pre- and post-synaptic neural activity simultaneously in the mammalian olfactory system, gaining insight into how sensory information is transformed as it moves through a neural circuit.
Large-scale, simultaneous intracellular recording and stimulation of neural activity London, Michael Nelken, Israel Spira, Micha E. (contact) Hebrew University Of Jerusalem 2016 RFA-NS-16-006 Active
  • Monitor Neural Activity
  • Interventional Tools
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.
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
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

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.

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
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  • Interventional Tools
Dr. Zhang's project will test a completely novel idea to assay neural activity using a blood test. It will harness the capabilities of exosomes, which are nano-scale vesicles containing protein and RNA cargo that are secreted from cells throughout the body. They readily cross the blood-brain barrier and they protect their RNA cargo from degradation in the blood. The proposal is to induce neurons to express RNA molecules that will be packaged into exosomes in response to neuronal electrical activity. Each cell's RNA molecules will have their own unique "barcode" sequences that will allow investigators to know what cells the RNA molecules came from after they are harvested from the blood. This will enable complex experiments to test neuronal circuit contributions to behaviors and to understand circuit disruptions associated with specific diseases.
Magnetic camera based on optical magnetometer for neuroscience research Alem, Orang FIELDLINE, INC. 2018 PAR-15-090 Active
  • Circuit Diagrams
  • Interventional Tools
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A camera that could image neuronal current distributions with a large array of pixels and a spatial resolution better than 1 ms resolution could dramatically enhance our understanding of neuronal circuitry. In this Phase I STTR, Fieldline, Inc. will develop a novel type of magnetographic camera, capable of providing single-shot images of electrical currents in neuronal circuits in vitro and in vivo with a millisecond time resolution. The team will first build a bench-top camera before combining it with electrode arrays, testing the ability to image neuronal connections across the circuit in vitro with turtle cerebellem. This will potentially lead to a completely portable, economical multi-pixel camera that can be produced for neuroscience research. 

Magnetic Particle Imaging (MPI) for Functional Brain Imaging in Humans Conolly, Steven M Griswold, Mark Wald, Lawrence L (contact) Massachusetts General Hospital 2014 RFA-MH-14-217 Complete
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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.
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.
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.
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
  • Interventional Tools
  • 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
  • Cell Type
  • Human Neuroscience
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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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  • Circuit Diagrams
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Dr. Brody and his colleagues will study the underlying neuronal circuitry that contributes to short-term "working" memory, using tools to record circuit activity across many brain areas simultaneously while rodents run on a track-ball through virtual mazes projected onto a screen.
Mechanisms of Rapid, Flexible Cognitive Control in Human Prefrontal Cortex Sheth, Sameer BAYLOR COLLEGE OF MEDICINE 2018 RFA-NS-18-010 Active
  • Human Neuroscience
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  • 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.   

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
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  • 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. 

Micro-coil implants for cortical activation Fried, Shelley Massachusetts General Hospital 2016 RFA-NS-16-006 Active
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Conventional stimulating electrodes are an important tool with great potential for studying neural circuits and treating brain disorders, but they have limitations, including off-target stimulation of cortical neurons and a gradual reduction in effectiveness due to scarring of surrounding brain tissue. Dr. Fried’s group will develop tiny, micro-coil based implants that stimulate neurons with a magnetic field rather than injection of electrical current. This approach promises greater spatial selectivity with less sensitivity to tissue scarring, which would be a major advance over current methods. The resulting technology could have important implications for therapies based on brain stimulation, since it would provide more selective targeting of specific circuits, longer-term stability, and minimization of unwanted side-effects.
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
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Current methods for functional brain imaging such as EEG or MEG can provide high temporal resolution, but they are limited in their spatial resolution and brain coverage. In contrast, functional MRI offers broad coverage, but it has low temporal resolution and is an indirect and incomplete measure of neural activity. Wong and his colleagues propose to combine the benefits of high-resolution electrical recordings with broad spatial coverage offered by MRI, using injected microelectronic devices that rapidly convert electric signals into magnetic fields detectable with an MRI scanner. As an intermediate goal, the researchers will record neural activity from the entire cortical surface at a sub-millimeter scale and 10 ms resolution, providing a measure of electrical activity at every cortical column simultaneously. This new approach could provide vastly richer functional data than is currently possible, and accelerate efforts to understand brain function.
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
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  • Human Neuroscience
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The startle response is disrupted (i.e., uncoordinated or weak) in several neurological and psychiatric disorders. Meserve will investigate the startle response using live imaging of neural activity in transparent larval zebrafish. The slc5a7 gene (required for acetylcholine synthesis) modulates the startle response in zebrafish, and human slc5a7 mutations are implicated in attention deficit disorder and major depression. This project will study slc5a7a’s role in neural circuit development and/or startle response. Circuit defects in slc5a7a mutants will be investigated via calcium imaging and whole-brain activity mapping of neurons known to be required for the startle response. Integrated studies on gene function, neural circuitry, and behavior will uncover the developmental stage and anatomical region where slc5a7a is required. These experiments may determine how slc5a7a promotes normal startle response, and contribute knowledge about how acetylcholine regulates behavior.
Modular High-Density Optoelectrodes for Local Circuit Analysis Buzsaki, Gyorgy Wise, Kensall David Yoon, Euisik (contact) University Of Michigan 2014 RFA-NS-14-007 Complete
  • Monitor Neural Activity
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In this project, Dr. Yoon's team will make devices for optogenetics, a technique that enables scientists to turn neurons on and off with flashes of light, more precise and diverse by integrating multiple light sources in such a way as to enable the control of specific neuronal circuits.
Modular nanophotonic probes for dense neural recording at single-cell resolution Roukes, Michael L (contact) Shepard, Kenneth L Siapas, Athanassios Tolias, Andreas California Institute Of Technology 2014 RFA-NS-14-007 Complete
  • Monitor Neural Activity
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Dr. Roukes and his team propose to build ultra-dense, light-emitting and -sensing probes for optogenetics, which could simultaneously record the electrical activity of thousands of neurons in any given region of the brain.
Modular systems for large scale, long lasting measurements of brain activity Frank, Loren UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 2018 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
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Molnar and her colleagues propose to develop a free floating, wireless microchip system for electrical recording of neural activity. The new system, called Microscale Optoelectronically Transduced Electrodes (MOTEs), will be powered by optically stimulated micro-photovoltaic cells and will use the resulting 1-2μW of electrical power to measure, amplify, and encode electrophysiological signals, up-linking the information optically through an onboard LED. Compared to standard microelectrode arrays, these free floating electrodes promise to be less damaging to neural tissue, and have potential for broader coverage of brain areas. This technology will enable many new neurobiology experiments, and provide a new, minimally invasive platform for measuring electrical signals deep in live brain tissue.
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 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-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-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-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.
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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The coordinated observation of spatial and temporal interactions of multiple signaling pathways within individual cells and across intact circuits is limited by an inability to simultaneously track dynamic molecular activity. Rizzo and colleagues will validate and further develop a new methodology, Fluorescent Anisotropy Reporters (FLAREs), for simultaneous optical imaging of multiple biosensors within single neurons of mouse brain slices during neural coding. The group will improve the optical sectioning microscopy methodology and increase the range of signaling molecules measurable with FLAREs. This technique may enhance subcellular spatial resolution and cellular temporal resolution of signaling pathways, and could scale to visualize coordinated cellular activities and neural coding in intact brain circuits.
Multiplex in vivo imaging of cell-specific and circuit-specific signaling pathways during synaptic plasticity Huganir, Richard L (contact) Zhang, Jin Johns Hopkins University 2016 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
  • Monitor Neural Activity
  • Interventional Tools
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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  • Monitor Neural Activity
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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
  • Monitor Neural Activity
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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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  • Monitor Neural Activity
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Three separate research groups are collaborating to understand in detail how three distinct areas of the brain function and work together to enable learning and decision-making behaviors. Drs. Kreitzer, Komiyama, and Lim are leveraging an impressive set of technologies to monitor and perturb different cell types in each brain region while the mice perform learning and decision-making tasks. By applying multiple recording methods across these brain regions at both the level of a single neuron and entire subpopulations of neurons, while the animals perform the same set of tasks, researchers hope to develop a single model of how vertebrate animals make choices about what to do next.

Network Control and Functional Context: Mechanisms for TMS Response Bassett, Danielle Smith Oathes, Desmond (contact) Satterthwaite, Theodore Daniel University Of Pennsylvania 2018 RFA-MH-17-245 Active
  • Human Neuroscience
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  • Monitor Neural Activity

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
  • Monitor Neural Activity
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Using optical recordings of neural activity from whole brains to reconstruct neural circuits is challenging when working with large brains or when studying behaviors that are not compatible with concurrent imaging. Laughlin and his team propose a method for making permanent recordings of neural activity that could be “read out” at a later time. The idea is that when a neuron fires during a specified time window, an enzyme genetically expressed by that neuron would interact with a genetically expressed substrate to produce a permanent record of the neuron’s activation. This innovative method will improve understanding of neural circuits.
Neural circuits in zebrafish: form, function and plasticity Cepko, Constance L Engert, Florian (contact) Lichtman, Jeff W Sompolinsky, Haim Harvard University 2014 RFA-NS-14-009 Complete
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  • Monitor Neural Activity
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Dr. Engert's team will combine a wide array of cutting-edge neuroscience techniques to watch the entire brain activity of a see-through fish while it swims, and to make detailed maps of its brain circuitry.
Neural ensembles underlying natural tracking behavior Fiete, Ila R. Huk, Alexander C Priebe, Nicholas J. (contact) University Of Texas, Austin 2015 RFA-NS-15-005 Complete
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  • Monitor Neural Activity
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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
  • Circuit Diagrams
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  • Monitor Neural Activity

Penetrating electrode arrays have an expanding application in neuroscience research as they can provide direct access to neural signals across the central and peripheral nervous system with high spatial resolution. Chronic electrode implants could revolutionize treatment for a range of medical conditions, including prosthetic motor control and proprioception for amputees, and brain-machine interfacing for paraplegics. Unfortunately, device implantation applies forces to the neural tissue resulting in significant brain compression (dimpling) at the implant site, which increases risk of implantation trauma, bleeding and inflammation. Actuated Medical, Inc. will develop a neural implant inserter, the Ultrasonic Precision Insertion of Neural Devices (UPIND) system, that will reduce the insertion force by applying ultrasonic energy to electrode arrays during insertion. This system aims to enable greater placement control of floating microware arrays, while reducing tissue trauma.

Neural Monitoring with Magnetically-Focused Electrical Impedance Tomography (mf-EIT) Freeman, Daniel Kenneth Charles Stark Draper Laboratory 2015 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.
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
  • Monitor Neural Activity
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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.
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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  • Human Neuroscience
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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
  • Human Neuroscience
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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 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.
NeuroPET HD: A low-cost high performance neuro-PET imaging system Hunter, William Coulis Jason Pet/x, Llc 2017 PAR-15-090 Active
  • Circuit Diagrams
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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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  • Monitor Neural Activity
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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  • Monitor Neural Activity
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
  • Monitor Neural Activity
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Dr. Kendall and his colleagues will develop diamond-coated electrodes to measure concentrations of the brain chemical dopamine more accurately and over long periods of time in the brain.
New approaches for better protein voltage sensors Cohen, Lawrence B Yale University 2016 RFA-NS-16-007 Active
  • Monitor Neural Activity
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Genetically coded voltage sensors represent a promising and potentially powerful avenue for recording neural activity in precisely defined neural circuits. Their fluorescence intensity responds to changes in membrane potential and action potential firing—the language the brain uses to transmit information quickly. Currently available sensors are not yet optimal for recording neural activity broadly in vivo. Cohen and his colleagues plan to develop brighter, faster, red-shifted (for deeper imaging), and more sensitive sensors for large-scale recordings of neuronal activity. The team intends to optimize their probes for detection of either spikes or subthreshold potentials, and to target them to specific subcellular domains, such as cell bodies or nerve terminals. These new sensors will enable more precise and sophisticated hypotheses to be tested for understanding the complex circuitry of the brain, in health and in animal models of brain disorders.
New Proteomic and Genome Engineering Approaches to Decipher Astrocyte Function at Synapses SODERLING, SCOTT DUKE UNIVERSITY 2018 RFA-DA-18-018 Active
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Star-shaped astrocytes are the most abundant non-neuronal cells of the brain. Their thin processes envelop neuronal synapses and critically shape their formation and function. In this project, BRAIN Initiative-funded researchers, Drs. Eroglu and Soderling, will develop and use a novel chemicogenetic approach called iBioID enabling the capture of astrocyte processes and the identification of the key proteins that form the interface between neurons and astrocytes. The team will use this technique in combination with gene editing to study how these proteins regulate the growth and maintenance of synapses in the healthy brain and explore what role they may play in neurological disorders.

New tools to target, identify and characterize astrocytes in the adult nervous system Gradinaru, Viviana Khakh, Baljit (contact) University Of California Los Angeles 2018 RFA-DA-18-018 Active
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Nearly 40 percent of the central nervous system is made up of astrocytes, star-shaped cells thought to provide synaptic support and facilitate neuronal signaling. For this project Drs. Khakh and Gradinaru plan to accelerate the development of tools for studying astrocytes. These tools include advanced methods for studying RNA and proteins, ATP biosensors for monitoring astrocyte communication, and viruses for delivering genes to astrocytes in different parts of the brain. A complement of such tools could help advance our understanding of the role of astrocytes in the healthy and diseased brain.
Next generation high-throughput random access imaging, in vivo Nedivi, Elly (contact) So, Peter T. Massachusetts Institute Of Technology 2014 RFA-NS-14-008 Complete
  • Monitor Neural Activity
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Dr. Nedivi's team proposes a new imaging technology to simultaneously record activity at each of the thousands of synapses, or communication points, on a single neuron.
Next-gen Opto-GPCRs: spatiotemporal simulation of neuromodulator signaling Bruchas, Michael R (contact) Sunahara, Roger K Washington University 2016 RFA-MH-16-775 Active
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Current tools for controlling neural activity in awake behaving animals, like optogenetics and designer receptors, are still limited in spatial and temporal control of diverse, discrete cell types. Bruchas, Sunahara, and their team will address these limitations by developing and validating a broader array of optically controlled G-protein coupled receptors with enhanced signaling dynamics and greater sensitivity and efficacy across myriad pathways. These Opto-XRs can be used in both neurons and glia, expanding the scope of experimentation in mapping brain circuitry in freely behaving animals, allowing discrete control and optodynamic stimulation of neuromodulatory signaling in brain tissues.
Next-generation optical brain functional imaging platform Fang, Qianqian Northeastern University 2018 RFA-EB-17-003 Active
  • Human Neuroscience
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  • Monitor Neural Activity

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

Non-degenerate multiphoton microscopy for deep brain imaging Devor, Anna (contact) Fainman, Yeshaiahu L University Of California, San Diego 2015 RFA-NS-15-003 Complete
  • Monitor Neural Activity
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Infra-red wavelengths, which have low attenuation in brain tissue, enhance the imaging depth of multi-photon imaging, though current use requires powerful lasers that could damage tissue. Devor and Fainman plan to use light of different wavelengths for multi-photon excitation at lower laser power, which will allow much deeper imaging than currently possible. This will be combined with an adaptive optics strategy for added gains in depth and focus, which could enable a 2-3 fold improvement in depths of imaging using two-photon microscopy.
Non-invasive neuromodulation mechanisms and dose/response metrics Oathes, Desmond University Of Pennsylvania 2016 RFA-MH-16-815 Active
  • Interventional Tools
  • Human Neuroscience
The mechanisms of action for new, non-invasive neuromodulatory techniques are not well known, particularly repetitive transcranial magnetic stimulation (rTMS), which requires capturing dynamic changes within neural networks in response to repeat stimulation. To elucidate the mechanism of rTMS in humans, Oathes and colleagues will use functional MRI to test two rTMS dose/response relationships in targeted sub-regions: 1) stimulation level and circuit activation, and 2) cumulative number of pulses and circuit communication. By recording TMS responses as well as imaging before, during, and after application of rTMS, this project will significantly advance our understanding of how rTMS affects human neural activity and will serve as an important foundation for developing novel, effective therapeutics.
Non-invasive targeted neuromodulation via focused ultrasound BBB permeabilization Livingstone, Margaret S (contact) Mcdannold, Nathan J Harvard Medical School 2018 RFA-MH-17-240 Active
  • Human Neuroscience
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  • Monitor Neural Activity

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

Noninvasive Biomarkers to Advance Emerging DBS Electrode Technologies in Parkinson's Disease Walker, Harrison Carroll University Of Alabama At Birmingham 2016 RFA-NS-16-010 Active
  • Human Neuroscience
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  • Monitor Neural Activity
Deep brain stimulation (DBS) is an important clinical option for patients with Parkinson’s disease (PD), but the optimum stimulation parameters differ from patient to patient. As a result, patient outcomes vary between individuals and across clinical trials. In this project, Walker et al. will utilize non-invasive electroencephalography (EEG) measurements of how the brain responds to DBS, to guide the activation and adjustment of next-generation DBS devices and electrodes. The researchers will test whether this personally optimized DBS is superior to conventional DBS, in terms of effectiveness and reduced side effects for patients.
Noninvasive Gene Delivery for Monitoring and Perturbing Cell Types and Circuits in Transgenic and Non-Transgenic Animals Gradinaru, Viviana California Institute Of Technology 2018 RFA-MH-17-220 Active
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  • Monitor Neural Activity

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

Noninvasive neuromodulation via focused ultrasonic drug uncaging Airan, Raag D Stanford University 2017 RFA-MH-17-240 Active
  • Monitor Neural Activity
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  • Human Neuroscience
Every millimeter of the brain is unique, yet the current standard of care for many psychiatric disorders is nonspecific (whole-body) delivery of a small-molecule drug. Airan’s team proposes spatiotemporally-precise drug delivery, by combining nanoparticle-based delivery and MRI-guided focused ultrasound. In eventual clinical usage, intravenously-infused, drug-loaded nanoparticles will permeate the blood in inactive form, and ultrasound—applied only to the brain area where drug activity is desired—will induce localized drug release. To facilitate clinical translation, Airan’s group will standardize clinically-compatible nanoparticle production, use ultrasound and EEG in rats to evaluate the dose-response and temporal kinetics of neuromodulation via localized release of the small-molecule anesthetic propofol, and use ultrasound and PET to visualize the spatial precision of neuromodulation by released propofol.
Northern Lights collaboration for better 2-photon probes Campbell, Robert E. Clack, Nathan G Drobizhev, Mikhail (contact) Hughes, Thomas E Montana State University - Bozeman 2015 RFA-NS-15-004 Complete
  • Monitor Neural Activity
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While 2-photon microscopy techniques have advanced to allow researchers to image neuronal activity at a greater depth in brain tissue, current fluorescent proteins used with indicators of cellular activity were developed under single photon parameters, which are not fully predictive of responses to 2-photon stimulation. Rebane and colleagues plan to develop a high-throughput process to screen novel fluorescent proteins for brightness and resistance to bleaching with 2-photon excitation. If successful, this high-throughput screen will deliver the next generation of brighter and more stable fluorescent proteins for incorporation into biosensors used to measure neuronal activity in deep tissue.
Novel fluorescent sensors based on GPCRs for imaging neuromodulation Hires, Samuel Andrew (contact) Li, Yulong Zhang, Li I. University Of Southern California 2017 RFA-NS-17-003 Active
  • Interventional Tools
Neuromodulators are signaling molecules that regulate cognition, mood, memory, sleep, and many other neural processes. Understanding neuromodulators’ diverse functions is challenged by a lack of tools for monitoring their release and distribution in behaving animals. Hires’ team seeks to develop a suite of new tools for chronic, non-invasive monitoring of neuromodulators in the brain at high spatiotemporal resolution during behavior. The group will produce highly specific and sensitive fluorescent sensors/indicators (for acetylcholine, serotonin, and norepinephrine) and validate their performance in behaving flies and mice. This technological advance could help researchers identify patterns of neuromodulation underlying many neural functions in behaving animals and in models of brain disorders.
Novel Genetic Strategy for Sparse Labeling and Manipulation of Mammalian Neurons Yang, Xiangdong William University Of California Los Angeles 2014 RFA-MH-14-216 Complete
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Dr. Yang's team will develop a new way to genetically target specific neurons, incorporating streamlined imaging and mapping methods that will enable the detection of sparse populations of cells that often elude existing methods.
Novel Implantable Smart Magnetoelectric NanoRFIDs for Large-Scale Neural Magnetic Recording and Modulation Sun, Nian Xiang NORTHEASTERN UNIVERSITY 2018 RFA-NS-17-003 Active
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Current systems for recording and modulating neuronal activity across spatial scales require hard wiring and are limited to linear, two dimensional planes. Sun and Cash will develop a new implantable, nanoscale, neural radio frequency identification system that both senses changes in magnetic fields induced by neurons and precisely stimulates neurons magnetically. Each independent, wireless microdevice can be incorporated into sheets so they can be distributed in high density across the brain to form a networked system for large-scale neural magnetic recording and modulation. Together, this integrated program of materials science, electrical engineering, and biology is poised to create a system that could significantly alter the landscape of brain area mapping and modulation.

Novel Neuromodulation by Transcranial Infrared Brain Stimulation with Imaging Gonzalez-lima, Francisco Liu, Hanli (contact) University Of Texas Arlington 2017 RFA-MH-17-240 Active
  • Monitor Neural Activity
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  • Human Neuroscience
This project will develop transcranial infrared brain stimulation (TIBS) as a novel, noninvasive tool to modulate human brain function. The basic premise is that infrared light will photo-oxidize cytochrome c oxidase (CCO), the mitochondrial enzyme that catalyzes oxygen metabolism. Liu’s team proposes that delivering TIBS to the prefrontal cortex increases CCO oxidation and promotes cerebral metabolism and oxygenation. In healthy participants, the group will measure TIBS penetration depth, thermal effects, spatial resolution, and mechanism. The group will create spatiotemporal maps/images to show TIBS modulation of large-scale neural circuits during and after stimulation. If successful, a new non-invasive tool will emerge for the neuromodulation of cognitive impairments, including mental disorders, brain injuries and neurodegenerative diseases.
Novel optical probe for dopamine release in neural circuits Feller, Marla (contact) Landry, Markita University Of California Berkeley 2018 RFA-EY-17-002 Active
  • Interventional Tools
  • Monitor Neural Activity

Understanding neuromodulation is key to understanding brain function. In contrast to fast synaptic transmission where one presynaptic neuron directly influences a single postsynaptic partner, neuromodulation involves a small population of neurons releasing neuromodulators that diffuse over neural circuits and affect large populations of neurons. Therefore, developing an imaging technique that directly visualizes neuromodulators is critical for characterizing their spatiotemporal gradients. Feller and Landry team will develop and test a bio-mimetic carbon nanotube whose near-infrared fluorescence increases upon exposure to the neuromodulator dopamine. The testing will involve whole- cell recording and two-photon calcium imaging in isolated mouse retinas. This project could advance our understanding of neuromodulation and its many impacts on normal and pathological circuits.

Novel optrodes for large-scale electrophysiology and site-specific stimulation Assad, John Berdondini, Luca Devittorio, Massimo Sabatini, Bernardo L (contact) Harvard Medical School 2015 RFA-NS-15-003 Complete
  • Monitor Neural Activity
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This international team (with contributors from Harvard University and the Italian Institute of Technology) proposes to develop two complementary technologies for electrical recording and optogenetic activation of neurons. The first technology is a class of high-density recording electrodes with active electronics to allow high-speed simultaneous recording from thousands of neurons in behaving animals. The second technology is a multi-point emitting optical fiber with flexibility in design to enhance spatial selectivity of optical excitation or inhibition in neural tissues using optogenetics. Cost assessments indicate that both tools will be very cheap to fabricate and thus can be made widely accessible to the neuroscience community.
Novel technologies for nontoxic transsynaptic tracing Wickersham, Ian R Massachusetts Institute Of Technology 2014 RFA-MH-14-216 Complete
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  • Monitor Neural Activity
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Dr. Wickersham and colleagues will develop nontoxic viral tracers to assist in the study of neural circuitry underlying complex behaviors.
Novel tools for cell-specific imaging of functional connectivity and circuit operations Isacoff, Ehud University Of California Berkeley 2015 RFA-MH-15-225 Complete
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  • Circuit Diagrams
  • Monitor Neural Activity
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Fundamental to understanding brain function in health and disease is the ability to relate the firing patterns of specific brain neurons to the synaptic connections they share with other neurons, and determine the strength of those connections. Isacoff and colleagues will develop novel, genetically encoded light-activated indicators in zebrafish, fruit fly, and mouse, which can selectively image neural activity in highly detailed structures of single neurons. Additional light-activated indicators will be targeted to synapses to quantify the release of neurotransmitters simultaneously at hundreds to thousands of synapses associated with a single neuron. This information can be used for tracking the strength of synapses over time in order to explore mechanisms of learning and brain adaptation.
NWB:N: A Data Standard and Software Ecosystem for Neurophysiology Ng, Lydia Lup-ming Ruebel, Oliver (contact) University Of Calif-lawrenc Berkeley Lab 2018 RFA-MH-17-256 Active
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  • Human Neuroscience
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Neurophysiology research, which focuses on recording brain cell activity, produces enormous amounts of complex data that are difficult to manage. Drs. Rubel and Ng will build upon the Neurodata Without Borders: Neurophysiology project to create a system that will allow for standardizing, sharing, and reusing neurophysiological data. The team will design an open source software system; develop methods to establish a consistent vocabulary for defining cell types, measurements, and behavioral tasks; and create tools to help the community adopt these new resources and standards. The proposed system will help accelerate neurophysiological discoveries as well as reproducibility studies.

Objective, MRI biomarkers for pre-symptomatic detection of autism spectrum disorder at 6 months old: commercial software development and optimization Bower, Bradley PRIMENEURO, INC. 2018 PAR-18-501 Active
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Magnetic Resonance Imaging (MRI) technology is being used to identify biomarkers in the central nervous system of children 6 months of age with Autism Spectrum Disorder (ASD). A potential promising group of biomarkers include data derived from both structural and functional MRI data acquired on infants. Dr. Bower’s group seeks to translate existing academic clinical research into a commercial product for potential clinical adoption by developing software that is a single, integrated, easy-to-use solution for MRI data collection, processing, and analysis for objectively evaluating a young child’s risk for ASD.

OpenNeuro: An open archive for analysis and sharing of BRAIN Initiative data Poldrack, Russell A Stanford University 2018 RFA-MH-17-255 Active
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To leverage the public investment in the BRAIN Initiative, the sharing of data produced by its myriad projects is paramount. Dr. Podrack’s project extends the recently released OpenNeuro, which was developed based on the well-established and successful OpenfMRI, for an archive of neuroimaging data. The extended archive encompasses a broader range of neuroimaging data including EEG, MEG, diffusion MRI and others. The archive also implements easy-to-use data submission, semi-automated curation and advanced data processing workflows, which run directly on the cloud platform. The archive allows to share the results alongside the data, federate with other relevant repositories, and accessible to all researchers.

Optical control of synaptic transmission for in vivo analysis of brain circuits and behavior Isacoff, Ehud Kramer, Richard H (contact) University Of California Berkeley 2014 RFA-NS-14-008 Complete
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Dr. Kramer's team will develop light-triggered chemical compounds that selectively activate or inhibit neurotransmitter receptors on neurons, to precisely control the signals sent between brain cells in behaving animals.
Optical tools for extended neural silencing Kennedy, Matthew J (contact) Tucker, Chandra L University Of Colorado Denver 2015 RFA-EY-15-001 Complete
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Blocking the activity of specific neural ensembles is a powerful approach for dissecting the circuitry underlying behavior. Brain lesion studies—either surgical or pharmacological—have provided important insights, but are limited in their specificity, reversibility, and temporal-spatial precision. Genetically encoded tools such as halorhodopsin and archearhodopsin hyperpolarize neurons with light and are spatially and temporally precise, but do not work well when extended—minutes to hours—neural silencing is required. Kennedy and Tucker propose a novel optical silencing approach in which a “split” botulinum toxin enzyme is expressed in neurons and then recombines and becomes active in response to the delivery of light, resulting in cleavage of the machinery responsible for neurotransmitter release. This tool could be applied locally with a single pulse of light to produce long-lasting, precisely targeted neural circuit disruption.
Optical Tools to Study Neuropeptide Signaling Tantama, Mathew Purdue University 2015 RFA-EY-15-001 Complete
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The lack of methods to measure neuropeptide signaling with high spatial and temporal precision represents a gap in the toolset for understanding neural circuit function in vivo. To date, no light-activatable tools have been developed for neuropeptides. Tantama proposes to develop tools for both studying and manipulating dynorphin, an opiate peptide of high functional significance for understanding pain and drug addiction. First a proposed biosensor can be expressed in specific cell populations and targeted to specific domains on the cell surface for spatially precise measurements. Second, Tantama proposes to develop an artificial dynorphin peptide targeted to specific neurons that can be activated with light for functional studies in neural circuits.
Optimal calcium imaging with shaped excitation Paninski, Liam M Peterka, Darcy S (contact) Columbia University Health Sciences 2016 RFA-EY-16-001 Complete
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Understanding information flow in the brain is dependent on simultaneously recording the activity of large neuronal populations. One problem with large-scale recordings is that the spatial and temporal resolution one can achieve typically decreases as the volume of brain to be scanned increases. Peterka and his colleagues plan to use a mix of novel software and hardware that will find creative ways to cut the amount of time needed to image each section of the brain. If successful, the new technique will enable an order of magnitude improvement in the imaged volume of brain tissue. The resulting combined software and hardware solution will be inexpensive, easy to implement and maintain, and widely applicable in the hundreds of labs currently using multiphoton imaging methods.
Optimization and distribution of high density cellular scale carbon and silicon arrays Chestek, Cynthia UNIVERSITY OF MICHIGAN AT ANN ARBOR 2018 RFA-NS-17-004 Active
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Much of our understanding of how the brain functions has come from recordings made via electrodes placed deep within the brain. However, metal electrodes can cause damage to the brain, making simultaneous visual analysis challenging. New carbon fiber electrodes developed by Dr. Chestek and her group will be much thinner and cause significantly less damage than traditional methods. Further, these new fibers can be left inside the brain tissue long-term and remain in place for analysis of placement after tissue dissection. These advances, tested in mice, will allow researchers to record from large numbers of neurons at the same time without damaging them and will help advance our understanding of how neurons communicate with each other.

Optimization of 3-photon microscopy for Large Scale Recording in Mouse Brain Xu, Chris Cornell University 2014 RFA-NS-14-008 Complete
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Dr. Xu and his collaborators will build new lasers and lenses to use three-photon microscopy to watch neuronal activity far deeper inside the brain than currently possible.
Optimization of multiphoton microscopy for large scale activity mapping in adult zebrafish Fetcho, Joseph R. Xu, Chris (contact) Cornell University 2017 RFA-NS-17-004 Active
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Monitoring the structure and function of neurons throughout living brains is vital to understanding normal and abnormal brain function. Xu’s team seeks to optimize multiphoton fluorescence microscopy to enable non-invasive imaging of the structure and function of individual neurons anywhere in the brain of an intact individual vertebrate, from embryo to adulthood. The group will develop new optical techniques to increase the number of neurons that can be imaged with reduced light exposure, facilitating repeated imaging throughout the animal’s life. These innovations will be validated by imaging novel transgenic zebrafish lines. If successful, this project will benefit future efforts to understand how behavior emerges from neuronal interactions across the brain.
Optimized dosing of repetitive transcranial magnetic stimulation for enhancement of hippocampal-cortical networks Voss, Joel L Northwestern University At Chicago 2016 RFA-MH-16-815 Active
  • Interventional Tools
  • Human Neuroscience
Although new non-invasive methods of human brain stimulation have been shown to treat memory loss, little is known about the relationships between stimulation parameters, cortical activity, and therapeutic effectiveness. Voss and colleagues aim to explore and optimize stimulation duration, frequency, and context parameters to understand the relationship between non-invasive, transcranial magnetic stimulation and the human hippocampal-cortical network activity that supports memory function. The group will measure changes in fMRI and EEG simultaneously with detailed memory testing to adjust stimulation parameters, potentially enhancing effectiveness for treatment of memory impairments caused by various conditions (i.e. schizophrenia) and disorders (i.e. brain injury).
Optimizing flexible, active electrode arrays for chronic, large-scale recording and stimulation on the scale of 100,000 electrodes Pesaran, Bijan Rogers, John Shepard, Kenneth L Viventi, Jonathan (contact) Duke University 2016 RFA-NS-16-007 Active
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To understand how the brain works in both health and disease, neuroscientists and clinicians require devices that can measure and manipulate brain activity with a high degree of precision. Viventi and his colleagues plan to develop next-generation flexible microelectrode arrays for micron-scale electrocortographic (ECoG) recordings from the surface of the cortex, and penetrating electrodes for recordings below the brain surface. Their strategy is to embed active electronics into an extremely thin silicon substrate, which will enable amplification and multiplexing directly at each electrode. Wireless data connection from the electrodes will allow extremely high number and density, and will allow the arrays to be tether free, for reduced damage to surrounding tissue. The flexibility of the silicon substrate will allow the surface ECoG arrays to conform to the irregular geometry of the brain, yielding higher fidelity signals, and reducing damage to the brain caused by penetrating arrays. Together, these innovations enable high resolution measurements over large areas of the brain while being less invasive, with fundamentally important improvements over current state-of-the-art.
Optimizing peripheral stimulation parameters to modulate the sensorimotor cortex for post-stroke motor recovery Ganguly, Karunesh University Of California, San Francisco 2016 RFA-MH-16-815 Active
  • Interventional Tools
  • Human Neuroscience
Somatsensory peripheral nerve stimulation (PNS) has had some success in improving recovery of hand motor function for stroke patients, but benefits are not consistent for all patients. PNS tailored to maximize recovery requires greater understanding of how stimulation interacts with cortical neurophysiological dynamics in the region impacted by the stroke. Ganguly and colleagues will employ a translational approach using animal model systems and human patients to study the link between PNS and changes in cortical activity in a dose-dependent manner. This work will elucidate how PNS modulates cortical activity and subsequent motor behavior, leading to the development of highly individualized PNS treatments for maximal restoration of function.
Optogenetic mapping of synaptic activity and control of intracellular signaling Kleinfeld, David Lin, John Yu-luen (contact) University Of California San Diego 2014 RFA-NS-14-007 Complete
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Dr. Lin's team will create molecules that, when they are triggered by a pulse of light, allow scientists to test for communication between neurons in specific circuits of the brain.
Optogenetic signaling inhibitors for studying brain plasticity Gan, Wenbiao Yasuda, Ryohei (contact) Max Planck Florida Corporation 2016 RFA-MH-16-775 Active
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Although the mechanisms underlying synaptic and behavioral plasticity have been widely studied, understanding spatiotemporal aspects of signaling activity via pharmacological or genetic manipulations remains limited. With their group, Yasuda and Gan will develop a new technique based on genetically encoded, cell-specific, light-inducible kinase inhibitors to improve spatiotemporal resolution of signaling required for synaptic plasticity in vivo. With this technique, they will modulate the activity of various kinases to identify the spatial and temporal window of learning-related dendritic spine turnover, including the consequences on behavioral performance post-learning.
PARALLEL ANALYSIS OF TRANSCRIPTION AND PROTEIN-DNA INTERACTIONS IN SINGLE CNS CELLS Dougherty, Joseph D (contact) Mitra, Robi D Washington University 2018 RFA-MH-17-220 Active
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The brain consists of hundreds of molecularly, physiologically, and anatomically distinct cell types. Recently-developed methods can measure gene expression in tens of thousands of single cells, to help identify and classify many new types of brain cells. However, existing technologies capture only one aspect of gene regulation – mRNA levels. Dougherty’s team will develop a method to enable the parallel analysis of transcription factor binding and mRNA expression levels in mice to create single-cell Calling Cards, generating novel data and analysis tools. If successful, this project would contribute to neuroscience by providing a broadly useful technology for understanding brain function and development, in health and disease.

Path Toward MRI with Direct Sensitivity to Neuro-Electro-Magnetic Oscillations Song, Allen W Duke University 2014 RFA-MH-14-217 Complete
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  • Human Neuroscience
Dr. Song's group will develop a scanner technology sensitive enough to image brain activity in high resolution by directly tuning in the electromagnetic signals broadcast by neurons.
Population Imaging of Action Potentials by Novel Two-Photon Microscopes and Genetically Encoded Voltage Indicators CHEN, JERRY L et al. BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) 2018 RFA-NS-17-003 Active
  • Interventional Tools

To better understand information processing by the brain, researchers must monitor electrical activity across neuronal populations while identifying the molecular and anatomical properties of individual neurons. Chen, Sander, and Pieribone will develop high speed, two-photon microscope systems with novel voltage sensors to image neuronal action potentials at single-spike resolution in awake, behaving mice. Combined with other tools to comprehensively dissect out the circuits and computations of the brain, this project could advance two-photon microscopy and genetically-encoded voltage-sensitive indicators. These techniques may enable non-invasive population-level measurements of neuronal activity across multiple timescales, uncovering how action potentials encode representations and drive behavior.

Potentiometric photoacoustic imaging of brain activity enabled by near infrared to visible light converting nanoparticles Prasad, Paras N. (contact) Xia, Jun State University Of New York At Buffalo 2015 RFA-EY-15-001 Complete
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Current techniques for recording neural activity at the cellular level use optical probes that can be imaged via fluorescence microscopy. However, a major limitation of these methods is that light in the visible spectrum cannot penetrate very far into the brain. Prasad and Xia propose alternative energy sources to address this challenge. They plan to fabricate "up-converting" nanoparticles that receive infrared light, which can reach deeper into the brain than visible light, and conjugate these nanoparticles to voltage sensitive dyes, which are chemical compounds used to image neurons' electrical activity. The dyes will be optimized for their photoacoustic properties, including their ability to give off ultrasound waves detectable from outside the brain. This method will produce high-resolution images of neural activity from deep inside the brain.
Prosthetic System for Large-Scale Recording and Manipulation of Neural Circuit Activity in Non-Human Primates Goodell, Albert Baldwin Graymatter Research 2017 PAR-15-091 Active
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Though current implantable devices which can record neuronal activity in awake, behaving animals exist, Goodell and colleagues seek to increase the size and number of brain circuits that can be both measured and manipulated long-term. The group plans to engineer and implement a system that can control hundreds of implanted electrodes to record activity from cells at any location in the brain of non-human primates, and will couple this advancement with optogenetic technologies to control neuronal firing as well. These experiments, when applied to behaviors like visual discrimination, would dramatically enhance the ability of researchers to systematically map and characterize cortical function.

Protein voltage sensors: kilohertz imaging of neural dynamics in behaving animals Lin, Michael Z. Schnitzer, Mark J (contact) Stanford University 2014 RFA-NS-14-008 Complete
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Dr. Schnitzer and his team have created a new system for developing optical voltage sensors, which will allow scientists to simultaneously record firing of large groups of neurons or electrical activity in precise locations inside of neurons, such as synapses.
Prototyping an ultrasound system for spatiotemporally precise noninvasive neuromodulatory drug uncaging and functional imaging in awake primates Caskey, Charles VANDERBILT UNIVERSITY MEDICAL CENTER 2018 RFA-NS-17-004 Active
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  • Monitor Neural Activity

Dr. Caskey and his team will develop an ultrasound brain stimulation system for noninvasively manipulating circuits. To do this, they will use magnetic resonance imaging (MRI) of brain blood flow and guided focused ultrasound modulation of brain circuits in the lateral prefrontal cortex and hippocampus of primates. In addition, they will adapt cognitive neuroscience tests to sense the effectiveness of the stimulation, and test whether focused ultrasound can precisely quiet brain cells by unlocking the anesthetic propofol from a chemical cage. One day a system like this may be used to correct circuit malfunctions that cause brain disease.

Quantitative mapping of oxygenation around neural interfaces using novel PISTOL MR imaging MUTHUSWAMY, JITENDRAN et al. ARIZONA STATE UNIVERSITY-TEMPE CAMPUS 2018 RFA-NS-17-003 Active
  • Interventional Tools

Current and emerging neural implants disrupt the local blood-brain barrier during placement into the brain, potentially leading to oxidative stress in brain tissue along the path of the implant. Muthuswamy, Kodibagkar and Sridharan will develop a novel magnetic resonance imaging technique with a siloxane contrast agent for measuring oxygen levels and potential oxidative stress. The technique will allow simultaneous monitoring of single-neuron electrophysiology and quantitative spatiotemporal mapping of oxygen levels around neural interfaces and will be scaled for use at multiple sites in the rodent brain. This technology represents an important step, as more sensitive measures of oxygen levels during typical neuronal function and after electrode placement are necessary to understand the long-term efficacy of neural implants.

Quiet TMS: A Low-Acoustic-Noise Transcranial Magnetic Stimulation System Peterchev, Angel V Duke University 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 investigating brain function and is also an approved therapy for depression. A major limitation of TMS stems from the loud noise produced by magnetic pulse delivery, which can activate off-target brain regions, can induce neuromodulation that could interfere with and confound the intended effects at the TMS target, and may pose auditory safety concerns. Dr. Peterchev and colleagues will develop a quiet TMS (qTMS) device that incorporates two key concepts: 1. the dominant frequency of the TMS pulse will be shifted to higher frequencies that are above the human hearing upper threshold, and 2. the TMS coil will be redesigned electrically and mechanically to minimize the electromagnetic energy that is converted to and emitted as acoustic energy. This novel qTMS technology could enable more precise, effective, safe, and tolerable TMS.
Rapid 3-D Nano-Printing to Create Multi-Thousand-Channel Microelectrode Arrays Panat, Rahul Yttri, Eric (contact) Carnegie-mellon University 2018 RFA-EY-17-002 Active
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  • Monitor Neural Activity

Understanding the functional connectivity of neural circuits, at the meso- and macro-scale levels requires recording the patterns of activity from sufficient volumes of brain tissue. Drs. Eric Yttri and Rahul Panat aim to develop a three-dimensional recording array, termed the massive microelectrode array (MMEA), that will be capable of recording from 5000 channels within a volume of tissue. MMEAs will be created through rapid nanoparticle printing of biocompatible materials, allowing for low-cost, resilient, and customizable probes. This technology will be tested in vivo in the mouse primary somatosensory and motor cortices, as well as the hippocampus and striatum – with an ultimate goal of providing an invaluable tool for studying circuit computations and researching and diagnosing brain disorders and dysfunction.

Rapid Electrode Multiplexing for Scalable Neural Recording Walker, Ross M University Of Utah 2016 RFA-EY-16-001 Complete
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Over the past few decades, extracellular electrodes for recording the electrical activity of individual neurons has improved to the point that an array the size of a postage stamp can record from hundreds of neurons simultaneously. What has not kept pace with the miniaturization of electrode arrays is miniaturization of the onboard computer chip that processes the incoming neuronal data. Walker and his colleagues propose a new multiplexed architecture in which each of the chip’s electrode interfaces is shared across many recording sites, enabling orders of magnitude smaller chips. These new chips, which will be able to support more than 1,000 electrodes, can improve the sensitivity of electrode arrays used for clinical applications such as deep brain stimulation and neural prosthetics.
Rational Optimization of tACS for Targeting Thalamo-Cortical Oscillations Frohlich, Flavio Univ Of North Carolina Chapel Hill 2016 RFA-MH-16-815 Active
  • Interventional Tools
  • Human Neuroscience
Although transcranial alternating current stimulation (tACS) alters cortical alpha oscillations and associated cognitive function in humans, the relationship between tACS parameters such as frequency, amplitude, and duration, and their effects of alpha oscillations remains unclear. Frohlich and colleagues will perform a series of experiments using computational modeling, in vitro and in vivo animal models, and human subjects to elucidate the relationship between tACS parameters and functional modulation of network dynamics. This work will validate tACS targeting of cortical oscillations to enable novel studies of the functional role of alpha oscillations and may provide improved therapeutic stimulation paradigms to treat individuals with psychiatric disorders.
RAVE: A New Open Software Tool for Analysis and Visualization of Electrocorticography Data Beauchamp, Michael S Baylor College Of Medicine 2018 RFA-MH-17-257 Active
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Electrocorticography (ECOG) allows the direct recording of a small population of neurons in human subjects, generating vast amounts of data. Dr. Beauchamp plans to develop the software RAVE (R Analysis and Visualization of Electrocorticography data) to help researchers explore such datasets. Incorporating established and successful informatics approaches that enable standardization, sharing, and re-use of neurophysiology data and analyses, RAVE includes rigorous statistical methodologies and seamless integration with existing analysis platforms. To facilitate user adoption and maximize impact, the developers plan to release RAVE 1.0 to the entire ECOG community within 6 months of the project start.

Realization of Optical Cell-based Reporters for in vivo Detection of Neuropeptides Kleinfeld, David Slesinger, Paul A (contact) Icahn School Of Medicine At Mount Sinai 2016 RFA-MH-16-775 Active
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Essential neuromodulators in the brain, neuropeptides control cognition and sensorimotor processing, but little is understood about when and where neuropeptides are released. Kleinfeld and colleagues developed new cell-specific fluorescent engineered reporters (CNiFERs) to optically image neurotransmitter release in real-time in vivo. The team will further develop and validate this technique for several neuropeptides, including orexin, somatostatin, and vasoactive intestinal peptide. Altered neuropeptide signals can contribute to brain dysfunction, and the expansion of this new tool will allow researchers to measure this signaling in the brains of awake, behaving animals, facilitating our understanding of complex behaviors and mental illness.
Recombinant Immunolabels for Nanoprecise Brain Mapping Across Scales Trimmer, James UNIVERSITY OF CALIFORNIA AT DAVIS 2018 RFA-NS-18-005 Active
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  • Human Neuroscience
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Studying how the brain works from the molecular to the circuit level is crucial for improving our understanding of how the brain functions normally, and what goes wrong in various disorders. Antibody probe techniques are effective tools that work at both of those levels. This project will develop a collection of validated, recombinant antibodies that are also highly renewable. In addition, antibodies will be miniaturized to increase binding efficiency and improve labeling precision. These resources will provide a cutting-edge, validated set of research tools to enable neuroscience research across a variety of resolutions from the intracellular to the neuronal network level.

Remote Neurostimulation with Ultrasound-activated Piezoelectric Nanoparticles Luke, Geoffrey P. Dartmouth College 2018 RFA-EY-17-002 Active
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  • Monitor Neural Activity

The ability to precisely stimulate neurons is currently limited to invasive and damaging technology. To overcome these hurdles, Dr. Geoffrey Luke and team will develop piezoelectric barium titanate nanoparticles (BTNPs) that will render cells (namely, cultured rat hippocampal neurons) sensitive to a secondary stimulus (i.e., ultrasound). In combination with ultrasound, BTNPs will target neuronal membranes and act as nanotransducers to precisely stimulate neuronal populations of interest. This technique builds on the emerging platforms of nanotechnology and ultrasound in neuroscience-based research, allowing for novel and non-invasive ways to study neuronal circuits.

Remote regulation of neural activity Stanley, Sarah Amy Rockefeller University 2014 RFA-MH-14-216 Complete
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The Stanley team will focus on the development of tools to instantly and precisely target cell activity deep in the brain using radio waves, nanoparticles and genetically modified viruses.
Repetitive transcranial ultrasound stimulation for modulating brain rhythms Dmochowski, Jacek City College Of New York 2018 RFA-DA-17-022 Active
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  • Monitor Neural Activity
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  • Human Neuroscience
Neural oscillations, which are temporal activity patterns in the brain, are recognized as fundamental to the brain’s information processing. Dmochowski and colleagues will evaluate the safety and efficacy of a new form of transcranial ultrasound stimulation (TUS), in which ultrasonic waves will modulate the activity of neural circuits with enhanced precision and specificity (on the order of millimeters). The team will determine whether TUS could be used to modify neural oscillations. This research may contribute foundational knowledge needed for development of new, non-surgical, ultrasonic treatments for disorders associated with abnormal brain rhythms, such as schizophrenia, Parkinson’s, and epilepsy.
Resolving Fine Architectures of Human Gray Matter with Ultra-High-Resolution Diffusion MRI Ge, Yulin Zhang, Jiangyang (contact) New York University School Of Medicine 2017 RFA-EB-17-001 Active
  • Monitor Neural Activity
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  • Human Neuroscience
Diffusion magnetic resonance imaging (dMRI) is a mainstream technique for non-invasive mapping of structural white matter connectivity tracts throughout the brain, but its low spatial resolution presents challenges for imaging gray matter (GM). Jiangyang Zhang and colleagues are developing an ultra-high-resolution dMRI technique to improve the characterization of GM microarchitecture. Zhang’s group hopes to translate the application of this approach from rodent to human brain by focusing on selective localized imaging of the human hippocampus and regional white matter tracts, and by dramatically increasing the speed of acquisition technique while accounting for motion corrections. The clinical applications of the technique could allow for unprecedented spatial resolution of GM microstructure, in which detection of architectural changes can be important for clinical diagnosis and disease monitoring.
Resource for Multiphoton Characterization of Genetically-Encoded Probes Drobizhev, Mikhail MONTANA STATE UNIVERSITY - BOZEMAN 2018 RFA-NS-18-005 Active
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Two-photon microscopy has emerged as a key technique for studying the activity of living neural networks. However, little optimization has been performed for the associated fluorescent activity probes and sensors. Dr. Drobizhev’s research group will create a resource at Montana State University to characterize the properties of two-photon probes and make that service available to the broader research community. Given increased used of this type of resource by BRAIN Initiative investigators, the research group will also organize meetings to help other labs develop their own characterization processes.

Revealing circuit control of neuronal excitation with next-generation voltage indicators Clandinin, Thomas Robert Lin, Michael Z. (contact) Stanford University 2017 RFA-MH-17-220 Active
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  • Monitor Neural Activity
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Recording real-time electrical impulses of individual neurons across multiple cells and with subcellular resolution will enable detailed understanding of neural information processing. When circuity is altered in animal models of neuropsychiatric and substance use disorders, this understanding could help explain pathogenesis and suggest treatments. Lin and colleagues will engineer brighter, more sensitive genetically-encoded voltage indicators (light-emitting proteins that report changes in membrane potential) and develop new two-photon imaging methods to determine how specific inputs affect the electrical activity of specific postsynaptic neurons deep within living fly and mouse brains. This project may open up in vivo two-photon imaging of GEVIs to researchers, potentially transforming how we measure neuronal responses in the brain.
Revealing the connectivity and functionality of brain stem circuits Berg, Darwin K Deschenes, Martin Freund, Yoav Shai Goulding, Martyn D Kleinfeld, David (contact) Knutsen, Per M University Of California San Diego 2014 RFA-NS-14-009 Complete
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Dr. Kleinfeld and his colleagues will use a variety of tools and techniques to create detailed maps of circuits in the brainstem, the region that regulates many life-sustaining functions such as breathing and swallowing, and match the circuits to actions they control.
Reversing Synchronized Brain Circuits with Targeted Auditory-Somatosensory Stimulation to Treat Phantom Percepts Shore, Susan E University Of Michigan At Ann Arbor 2017 RFA-MH-17-245 Active
  • Monitor Neural Activity
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  • Human Neuroscience
Tinnitus - hearing sound when there is no sound - emerges from abnormal functioning of the dorsal cochlear nucleus (DCN), a circuit that is amenable to long-term alterations via combined auditory and trans-dermal somatosensory stimulation. Shore’s team will implement this previously-validated bimodal sound + electrical stimulus paradigm, to study the effects of non-invasive DCN circuitry manipulations in animals and humans. The group will develop novel, optimized stimulation parameters/dosages, with the aim of weakening the circuit and ameliorating tinnitus. In addition to providing insight into auditory circuit function in normal and pathological conditions, this project could also lead to treatments for other neural disorders involving abnormal circuits, such as Parkinson’s disease.
SABER: Scalable Analytics for Brain Exploration Research using X-Ray Microtomography and Electron Microscopy Gray Roncal, William R Johns Hopkins University 2017 RFA-MH-17-257 Active
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Neuroimaging techniques are advancing at a rapid rate, resulting in high resolution images of brain tissue and large datasets that can be difficult to manage. William Gray Roncal’s team propose an integration framework called SABER: Scalable Analytics for Brain Exploration Research. With a focus on techniques (e.g., electron microscopy) that produce high resolution brain images, SABER will create a unified framework by which these data types are accessible to a broader audience, can be processed in a reproducible, portable way, and can be scaled from small data volumes to large datasets. SABER has the potential to enable discoveries from high-resolution imaging techniques, making the parsing of entire brains a new reality.

Scalar Closed-Loop STN/GPi DBS Based on Evoked and Spontaneous Potentials Turner, Dennis Alan Duke University 2017 RFA-NS-17-006 Active
  • Human Neuroscience
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The current standard of care for advanced Parkinson’s disease (PD) with motor complications is to implant a single deep brain stimulation (DBS) lead to stimulate either the subthalamic nucleus (STN) or globus pallidus interna (GPi). However, single-site stimulation can be ineffective against balance symptoms and freezing of gait, and some patients develop additional motor complications despite DBS due to disease progression. Turner’s team will implant bilateral STN + GPi/GPe electrodes in PD patients, and assess the efficacy of either STN or GPi/GPe stimulation versus dual STN + GPi stimulation. The group will also use advanced medical device technology to compare closed-loop paradigms to conventional open-loop stimulation. This project could help people with severe PD receive improved treatment options.
SCAPE microscopy for high-speed 3D imaging of cellular function in behaving animals: Continued innovation, optimization, and dissemination Hillman, Elizabeth COLUMBIA UNIVERSITY HEALTH SCIENCES 2018 RFA-NS-17-004 Active
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Dr. Hillman and her team will build on Swept Confocally Aligned Planar Excitation (SCAPE) microscopy, a groundbreaking system they developed for capturing brain cells live and in action. The second-generation SCAPE system should work better with current circuit stimulation and visualization techniques that help scientists study a variety of brains at work, from controlling how flies fly to how mice sniff out odors. They also plan to crowdsource innovation by creating ‘Open-SCAPE,’ a growing international network of SCAPE users who freely share insights on maintenance and improvements. In short, Dr. Hillman plans to make it easier for scientists to watch the circuits of the healthy and diseased brain work in real time.

SCAPE microscopy for high-speed in-vivo volumetric microscopy in behaving organisms Hillman, Elizabeth M Columbia University Health Sciences 2015 RFA-NS-15-004 Complete
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Optical imaging holds great promise for recording the activity of large numbers of neurons in the brain, but one of the challenges of this technique stems from the extended time required to focus and scan light from a laser across a given volume containing neurons of interest. Hillman's team is developing a method in which an entire plane of laser light is swept back-and-forth across the volume of interest, for much faster imaging than traditional methods. They will optimize the speed and resolution of this method in fruit flies and in mouse neocortex. The method promises a dramatic enhancement of speeds at which whole-brain volumes can be imaged, and is likely to be lower cost and more robust than competing approaches.
Selective Optogenetic Inhibition of Neuropeptide Release Blinder, Pablo (contact) Hu, Zhitao Lin, John Yu-luen Tel Aviv University 2018 RFA-EY-17-002 Active
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Similar to neurotransmitters, neuropeptides are signaling molecules involved in a variety of brain functions and behaviors, including feeding, aggression, mating, and the stress response. Currently, the neuroscience research tools for targeting neuropeptides also indirectly impact neurotransmitter activity. Drs. Pablo Blinder, John Lin, and Zhitao Hu will further develop Lin’s optogenetic technique that directly inhibits neurotransmitter release – termed InSynC ( in hibition of syn apses with c hromophore assisted light inactivation) – to selectively and reversibly target neuropeptide vesicular release in cell culture, nematodes, Drosophila , and rodents. This novel method could pave the way for studying the precise role of neuropeptides in brain function and behavior.

Self-Motile Electrodes for Three Dimensional, Non-perturbative Recording and Stimulation Melosh, Nicholas A Stanford University 2015 RFA-EY-15-001 Complete
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Current electrode arrays for recording from hundreds of neurons typically suffer from the same problem: because their substrate is stiff and inflexible, they elicit an immune response by brain tissue and over time are surrounded by protective glia that prevent them from detecting electrical activity from neurons. Melosh and his colleagues propose to develop ‘self-motile’ ultra-thin electrodes. Rather than drive the electrodes from the back, a method requiring significant mechanical stiffness, the electrodes—up to thousands emanating from a single implanted device—will ‘pull’ themselves from the front using an electro-osmotic mechanism originally developed for microfluidic pumps. The research team will also explore methods for ‘steering’ the electrodes so that they can extend throughout the brain in three dimensions and plant themselves next to individual neurons. If successful, this “front-wheel drive” technology for implantation would allow extremely thin, flexible materials to be implanted into the brain with minimal disruption.
SELF-POWERED SENSING AND DATA-LOGGING FOR LARGE-SCALE IN-VIVO MONITORING OF NEURAL ENSEMBLE ACTIVITY Chakrabartty, Shantanu Washington University 2017 RFA-EY-17-001 Active
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A major challenge in neuroscience lies in understanding the dynamics of neuron ensembles with regard to how these clusters are influenced by external stimuli, and how the network interacts internally. Exploring these interrelationships in freely-moving, awake animals is difficult because current technology typically cannot maintain continuous, large-scale monitoring of neural activity over extended time periods (weeks to months). Shantanu Chakrabartty and team are investigating the feasibility of a self-powered neural activity recorder that harvests energy from ambient thermal fluctuations and action potentials. The success of this program could pioneer the development of a suite of wireless neural recording devices for large-scale experimental studies in awake and behaving animals of varying sizes, from insects to mammals.
Sonoelectric tomography (SET): High-resolution noninvasive neuronal current tomography Hamalainen, Matti Mcdannold, Nathan J Mitra, Partha Pratim Okada, Yoshio (contact) Boston Children's Hospital 2015 RFA-MH-15-200 Complete
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  • Human Neuroscience
Okada and colleagues propose to evaluate the feasibility of developing a noninvasive method, sonoelectric tomography (SET), to "tag" specific locations in the brain using sound waves. This approach would leverage the millisecond temporal resolution of conventional scalp electroencephalography (EEG) with millimeter spatial resolution of ultrasound. This information could be used noninvasively to construct a tomographic image of neuronal currents not only in the neocortex, but in deep brain structures as well. This technology will open the door for whole-brain mapping with high temporal and spatial resolution in the human brain, not only to map the functions of brain circuits in healthy individuals, but also for understanding and potentially diagnosing complex neuropsychiatric disorders.
Space-division multiplexing optical coherence tomography for large-scale, millisecond resolution imaging of neural activity Berdichevsky, Yevgeny Zhou, Chao (contact) Lehigh University 2015 RFA-EY-15-001 Complete
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A fundamental goal of the BRAIN Initiative is to develop technologies for large-scale imaging of neural activity at the single cell level. Most optical techniques for achieving this goal require that neurons be labeled with a genetic or chemical probe that can be imaged. Zhou and Berdichevsky propose a 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, and in theory OCT should be able to detect these changes as differences in the reflected light patterns. 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.
Sparse, Strong and Large Area Targeting of Genetically Encoded Indicators Antic, Srdjan D (contact) Knopfel, Thomas University Of Connecticut Sch Of Med/dnt 2015 RFA-MH-15-225 Complete
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Electrical signals are the primary means of information processing in the brain. Recordings of electrical signals are a key means of discovering neuronal function. Genetically encoded voltage indicators (GEVI) embedded in neurons can convert electrical signals into optical signals that can be captured by powerful cameras, providing a means for observing neural activity from large populations of cells simultaneously. However, the GEVI-produced optical signals from neighboring neurons blend together and are difficult to separate. Antic and Knopfel will utilize a method for targeting GEVIs sparsely, making it possible to resolve the optical signals coming from a smaller population of individual cells.
Spatiotemporal control of large neuronal networks using high dimensional optimization Ching, Shinung Li, Jr-shin Ritt, Jason T (contact) Boston University (charles River Campus) 2016 RFA-EY-16-001 Complete
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Despite numerous recent advances in techniques for optically controlling the activity of neurons with light—a field referred to as optogenetics—neural populations are still activated or deactivated en masse. Ritt and his team will employ methods from a field of study called “control theory” to develop a toolkit for designing highly specific space and time patterns of neural stimulation and inhibition. The ability to fine tune neuronal control will greatly improve clinical applications such as deep brain stimulation, which is used to treat a variety of neurological disorders including depression, as well as to control brain-machine interfaces and neural prosthetics.
Spinal root stimulation for restoration of function in lower-limb amputees Fisher, Lee E (contact) Weber, Douglas J University Of Pittsburgh At Pittsburgh 2017 RFA-NS-17-006 Active
  • Human Neuroscience
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Despite recent advancements in prosthetics, prosthetic devices still lack a means of providing direct sensory feedback, which would improve balance control, reduce falling risk, and could significantly diminish severe phantom limb pain. In individuals with trans-tibial amputation, Fisher’s team will use spinal cord stimulator leads to electrically stimulate the dorsal root ganglia and dorsal rootlets. They intend to generate sensations of pressure and movement in the amputated limb, and reduce phantom limb pain, which correlates with greater prosthesis use. The group will use electromyography to analyze the relationship between stimulation and evoked reflexive responses, and thus optimize stimulation programming. To improve gait function, the group will study how signals from pressure/angle sensors within the prosthetics can be used to modulate sensory feedback via stimulation. These experiments could assist development of a neuroprosthesis that would improve quality of life for individuals with trans-tibial amputation.
Split RNA polymerases for sensitive, multidimensional analysis of intercellular PPIs at synapses Dickinson, Bryan (contact) Ozkan, Engin University Of Chicago 2017 RFA-MH-17-220 Active
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Deciphering the complexities of brain structure and function requires full understanding of intercellular protein-protein interactions (PPIs). Connections between neurons and other cells of the brain are orchestrated by thousands of diverse PPIs, but current methods are insufficient for studying multiple PPIs simultaneously. Dickinson and colleagues will develop new split RNA polymerase (RNAP) biosensors, capable of detecting at least four simultaneous PPIs, with novel super-resolution imaging. Because nucleic acid amplification technologies afford signal amplification and the ability to use multiple different RNAPs, RNAP-based detection could promise substantially improved sensitivity. Co-culture experiments employing primary neurons and engineered reporter cells will validate the approach. This work will initiate a new approach to probing intercellular interactions that guide synapse formation and brain signaling.
Structure guided design of photoselectable channelrhodopsins Cherezov, Vadim Hires, Samuel Andrew (contact) Katritch, Vsevolod Lin, John Yu-luen University Of Southern California 2016 RFA-EY-16-001 Complete
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For more than a decade, researchers have been able to use light to manipulate the activity of individual neurons that were genetically engineered to express light-sensitive proteins. The technique, however, has been limited to controlling neurons in confined regions of the brain. Hires and his colleagues plan to engineer a novel light-sensitive protein that would allow for the flexible, selective control of thousands of neurons distributed across large volumes of the brain. This unprecedented level of control over large swaths of neural real estate could be used to explore the roles of widespread neural circuits in complex behaviors.
Sub-micrometer x-ray tomography for neuroanatomy Jacobsen, Chris Johnson (contact) Kording, Konrad P. Northwestern University 2015 RFA-MH-15-225 Complete
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Understanding how the human brain works and how it can be healed in case of disease is heavily dependent on progress in anatomy. Jacobsen and Kording, working with researchers at Argonne National Lab, will develop a novel and powerful tool using synchrotron-based x-ray tomography to produce ultra-fine scale anatomical maps of whole mouse brains, with the possibility of scaling up the technology to study human brains. This tool will enable better research on brain anatomy and its relationship to diseases of the brain, such as Alzheimer's, schizophrenia and autism.
Subthalamic and corticosubthalamic coding of speech production Richardson, Robert Mark University Of Pittsburgh At Pittsburgh 2016 RFA-NS-16-008 Active
  • Human Neuroscience
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Evidence points to an important role for the basal ganglia (BG) in speech. For instance, deep brain stimulation (DBS) of the subthalamic nucleus (STN) within the BG can improve motor symptoms for patients with Parkinson’s disease, but often does not improve speech impairments and in fact can disrupt language function. Richardson proposes to develop a model for how the BG helps drive speech production by recording activity of individual neurons within the STN along with STN and cortical local field potentials, in patients with Parkinson’s disease undergoing surgery to implant a DBS device. This work could lead to improved treatment for speech impairments in movement disorders, and reduced speech-related side effects of DBS therapy.
SYNPLA: A scaleable method for monitoring circuit-specific learning-induced changes in synaptic strength Malinow, Roberto Zador, Anthony M (contact) Cold Spring Harbor Laboratory 2015 RFA-MH-15-225 Complete
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Learning and memory are made possible in part by a phenomenon called long-term potentiation (LTP)—the strengthening of a synapse resulting from increased firing between two neurons. To study LTP, Zador and Malinow are developing a technique they call SYNPLA, a specific, high-throughput method for marking the emergence of LTP with single synapse resolution. By attaching a fluorescent tag to a specific subtype of glutamate receptor (GluA1), which gets inserted into recently activated synapses, SYNPLA gives the researchers a way to visualize the onset of certain forms of LTP at many synapses simultaneously.
Synthetic imager to record cortical neural activity over whole cranium in freely-behaving animals Yang, Weijian University Of California At Davis 2018 RFA-EY-17-002 Active
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Deciphering how the brain works requires understanding information flow across different brain regions during behavior. This entails recording neural activities over a large neuronal population simultaneously, while maintaining spatiotemporal resolution. Conventional optical methods suffer from a tradeoff between achieving large field-of-view and spatiotemporal resolution, and many imaging systems require animals to remain in a head-fixed condition. Yang’s team will build an implantable imaging device (a <1 mm thick array of microlenses, LEDs, andphotodetectors) that records neural activity over the superficial layers of the whole cortex in freely-behaving mice. Compared to conventional systems, this technology expands the field-of-view by two orders of magnitude, while maintaining spatiotemporal resolution. This could enable neuroscientists to study the brain in unprecedented resolution and scale.

Taking DISCO Live: Dual pathway Imaging of Striatal Circuit Output in vivo Calakos, Nicole Duke University 2018 RFA-DA-17-022 Active
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Physicians currently use therapies that satisfactorily target the basal ganglia to treat movement disorders, but more effective treatments elude clinical implementation due to major gaps in our understanding of functional principles for basal ganglia circuits. Calakos and colleagues will apply in vivo electrophysiological recording, optical activity imaging, and optogenetics to study plasticity of basal ganglia circuitry. The team will develop an approach to image striatal projection neuron activity in the basal ganglia in mice during the formation of a habitual behavior. They will then monitor and manipulate the relative timing-to-fire between two classes of striatal projection neurons and test the behavioral consequences. The knowledge and methodology gained from this project could help reveal new mechanisms for striatal plasticity, which may inform future therapeutic targets for movement and neuropsychiatric disorders.
Technologies for spatiotemporally precise & closed-loop control of selected neurons to prevent epileptic seizures Ahmed, Omar Jamil University Of Michigan 2016 RFA-MH-16-725 Complete
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Although focal seizures start in subsets of neurons in specific brain regions, most anti-epileptic drugs are non-specific in their actions. Further, although optogenetics can be used to modulate cells expressing a specific genetic marker, those targeted cells may still have varying behavioral or clinical roles. When combined with two-photon imaging, recent innovations in digital holography using spatial light modulators (SLM) now make it possible to target visually-selected neurons for optogenetic interventions. Dr. Ahmed’s team will employ an SLM photoactivation module, which was newly developed by Bruker, to understand single neuron dynamics during seizures. The team will also implement closed-loop control of SLM-based optogenetics in mice to terminate seizures in real time by targeting a minimal number of neurons. The team will share this new software with the wider community.
Technologies to drastically boost photon sensitivity for brain-dedicated PET Levin, Craig S Stanford University 2017 RFA-EB-17-001 Active
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  • Human Neuroscience
The spatial resolution and signal-to-noise ratio of current positron emission tomography (PET) techniques do not permit high precision dynamic imaging of the human brain. Craig Levin’s group proposes the development of a novel PET photon detector concept that substantially enhances PET image reconstruction and permits joint PET-MR (magnetic resonance) imaging. Joint PET-MR collection would allow multi-modal, simultaneous image acquisition of neuron receptor function, functional MR, and high-resolution neuroanatomy. The device includes a portable PET ring that could be inserted into or removed from any MR system, substantially reducing costs for joint PET-MR data acquisition.
Technology for functional study of cells and circuits in large postmortem brains ex vivo Sestan, Nenad Yale University 2018 RFA-MH-17-220 Active
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Studying neural circuitry and function is particularly challenging in the human brain due to ethical considerations and the overall inherent experimental intractability of postmortem tissue. Furthermore, many aspects of human neurobiology are not fully recapitulated in small animal models, and research in large mammals is hindered by cost and experimental difficulties. Sestan’s team will optimize and validate a first-in-class neurotechnology, BrainEx, for the restoration of molecular and cellular functions of the postmortem large mammalian brain to allow connectivity and circuit tracing in myriad regions, as well as functional imaging. They aim to achieve this in the porcine model, in which brain size, complexity, and physiology are highly similar to human brains. These studies could establish the groundwork for the potential translation of this technology for conducting studies in the postmortem human brain.

The Application of Generalized Linear Models to Calcium Imaging Data for Optimal High-Dimensional Receptive Field Estimation and Identification of Latent Network Dynamics Keeley, Stephen L Princeton University 2017 RFA-MH-17-250 Active
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Dr. Keeley plans to develop and make publically available an efficient and flexible statistical framework to guide analysis of calcium imaging data, extending researchers’ ability to track the activity of hundreds or thousands of neurons at various spatial scales.
The biophysics and potential cell-type selectivity of acoustic neuromodulation Shoham, Shy NEW YORK UNIVERSITY SCHOOL OF MEDICINE 2018 RFA-NS-18-018 Active
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  • Human Neuroscience
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The NIH BRAIN Initiative aims to facilitate development of new approaches for precisely measuring and modulating brain circuit function. The high tissue penetrability of ultrasound waves presents untapped opportunities for accessing neural circuits throughout the mammalian brain and offers the possibility of transforming our ability to map brain circuit activity, test new models of brain function, and ultimately, to diagnose and treat brain diseases and disorders. This project, led by Drs. Shoham, Froemke, and Kimmel, aims to elucidate the fundamental mechanisms of ultrasound stimulation, via mathematical analyses, computational modeling, and experimental validation in a mouse model. A thorough characterization of how ultrasound affects neural cells and circuits is an essential step forward in basic neuroscience research, and may enable further development of ultrasound as a tool for both neuroscientists and clinicians.

The Brainstorm Project: A Collaborative Approach to Facilitating the Neuroethics of Bioengineered Brain Modeling Research Hyun, Insoo Case Western Reserve University 2018 RFA-MH-18-500 Active
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Organoids, grown in laboratory settings to resemble parts of the developing human brain, hold great potential for shedding light on human brain function and disease. Researchers are working to achieve key bioengineering advancements, including successful vascularization of brain organoids, generating the full complement of cell types present in a human brain, and recording and modulating neural activity in organoids. These anticipated advances in bioengineered human brain modeling research may raise ethical questions about the moral status of large, complex human brain organoids and ethical boundaries on manipulating increasingly realistic engineered brain models. In this project, Dr. Hyun will lead proactive ethical discussions among ethicists and the neuroscientists conducting this cutting-edge work to develop greater awareness and understanding of these ethical implications and to inform future management of ethical issues that may be unique to this novel area of brain research.

The Development and Human Translation of Temporal Interference Brain Stimulation Pascual-leone, Alvaro Beth Israel Deaconess Medical Center 2018 RFA-MH-17-240 Active
  • Human Neuroscience
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Deep-brain stimulation has helped many patients’ suffering from neurological disorders, but carries risks associated with neurosurgical procedures. Non-invasive brain stimulation, such as transcranial magnetic stimulation, is safer but only affects superficial brain regions. Dr. Pascual-Leone and his team have developed temporal interference stimulation, technology that combines the best of those methods, providing a noninvasive way to stimulate neurons deep in the brain by using multiple electric fields at different frequencies. Dr. Pascual-Leone and his group plan to enhance this technology, advancing it toward clinical use by testing it on specific brain structures in mice and humans. This method may provide a safe path for treating a wide range of brain disorders.

The impact of cerebellar tDCS in local and downstream brain circuits: how much is neuralactivity modulated in the resting state and during sensorimotor processing? Medina, Javier F Baylor College Of Medicine 2017 RFA-MH-17-245 Active
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  • Human Neuroscience
Cerebellar transcranial direct current stimulation (CB-tDCS) not only modulates motor circuitry, but also has an impact on cognitive function. However, the mechanisms underlying the motor and non-motor effects of CB-tDCS remain largely unknown, owing to our limited knowledge of the impact of CB-tDCS on the activity of neurons in local and downstream circuits. Medina’s team has developed a new system of delivering CB-tDCS to awake-behaving mice, while concurrently measuring neuronal responses in several brain regions. They will systematically vary the polarity and intensity of the stimulation pulse, to elucidate the dose/response relationship between CB-tDCS and cell-specific neural activity. They will examine how neurons—in the cerebellum and then other regions that receive cerebellar inputs—respond to CB-tDCS during rest, sensory processing, and motor performance. If successful, this project could demonstrate how non-invasive cerebellar stimulation affects activity in other areas of the brain.
The impact of spontaneous cortical activity on neural oscillations and behavioral performance: Evidence from high-definition tDCS and MEG Wilson, Tony W University Of Nebraska Medical Center 2018 RFA-MH-17-245 Active
  • Human Neuroscience
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Human cortical neurons exhibit spontaneous discharges and fluctuations even in the absence of activating events, giving rise to “spontaneous activity” that is ubiquitous across the human brain. The role of spontaneous activity in information processing remains largely unknown and appears to change with age. Wilson’s team will quantify the impact of transcranial direct-current stimulation (tDCS) on spontaneous rhythms, and then determine whether the strength of these rhythms at a specific frequency and location (e.g., occipital cortex) governs the behavioral performance of younger and older human adults during a visual attention task. Successful completion of this study could enhance the understanding of how tDCS and neural oscillations affect neural networks associated with visual processing and cognitive performance.

The role of patterned activity in neuronal codes for behavior Maunsell, John Hr University Of Chicago 2014 RFA-NS-14-009 Complete
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Dr. Maunsell's team will explore how large populations of neurons process visual information, using a newly developed light stimulation technique to induce brain cell activity in the visual cortex of mice.
Three Dimensional Holography for Parallel Multi-target Optogenetic Circuit Manipulation Emiliani, Valentina Picaud, Serge (contact) Pierre And Marie Curie University 2014 RFA-NS-14-008 Complete
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Dr. Picaud's team will continue its development of holographic imaging to use lasers to induce the natural electrical activity of neurons and test theories of how circuits produce behaviors in a range of animal models.
Time-Reversal Optical Focusing for Noninvasive Optogenetics Gradinaru, Viviana Yang, Changhuei (contact) California Institute Of Technology 2014 RFA-NS-14-007 Complete
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Dr. Yang's team plans to develop a light and sound system that will noninvasively shine lasers on individual cells deep within the brain and activate light-sensitive molecules to precisely guide neuronal firing.
Toward functional molecular neuroimaging using vasoactive probes in human subjects. Jasanoff, Alan Massachusetts Institute Of Technology 2015 RFA-MH-15-200 Complete
  • Monitor Neural Activity
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  • Human Neuroscience
Jasanoff and colleagues aim to develop a noninvasive neuroimaging approach in rodents and marmosets capable of mapping molecular events at a whole-brain level. If successful, the approach could potentially be used in humans to noninvasively map, for example, neurotransmitter signaling in real-time, which would revolutionize our ability to study and understand human brain function in health and disease. The team is developing new vasoactive imaging probes that will combine sensitivity approaching that of positron emission tomography (PET) with spatiotemporal resolution comparable to functional magnetic resonance imaging (fMRI), while at the same time avoiding the toxicity associated with existing imaging agents.
Towards a Complete Description of the Circuitry Underlying Memory replay. Soltesz, Ivan University Of California-irvine 2014 RFA-NS-14-009 Complete
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Dr. Soltesz's team will combine computer brain modeling and large-scale recordings of hundreds of neurons to understand how the brain generates sharp-wave-ripples, a neuronal activity pattern essential for learning and memory.
Towards deep brain monitoring with superficial EEG sensors plus neuromodulatory focused ultrasound Mourad, Pierre D University Of Washington 2016 RFA-EY-16-001 Complete
  • Monitor Neural Activity
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Existing technologies to record electrical activity on millisecond timescales either employ invasive placement of electrodes within the brain or non-invasive methods, such as subdermal electroencephalography (EEG) electrodes. However, low fidelity, sensitivity, poor spatial resolution, and susceptibility to noise all limit the use of EEG. Mourad and his colleagues plan to increase the specificity of EEG by combining it with another non-invasive method, pulsed focused ultrasound (pFU) stimulation, which will add a unique marker or tag to the electrophysiological activity within a small portion of brain. This technology may one day allow for the recording of electrical activity non-invasively from anywhere within the brain, including simultaneously from several locations, at millisecond time scales and with millimeter spatial resolution.
Tracing Brain Circuits by Transneuronal Control of Transcription Hong, Elizabeth Jennifer Lois, Carlos (contact) Zinn, Kai G California Institute Of Technology 2015 RFA-MH-15-225 Complete
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Faulty wiring of brain circuits during development could underlie the progression of many neurological diseases, such as schizophrenia and autism. Lois and colleagues propose the development and validation of a new genetically encoded system to trace brain circuits by trans-synaptic control of gene transcription. In this system, neurons expressing an artificial molecule ("emitter" neurons) activate an engineered receptor on their synaptic partners ("receiver" neurons), triggering the expression of fluorescent proteins in both partners. High-resolution imaging of the fluorescent labels will allow researchers to track the synaptic partners and other neurons in the circuit.
Trans-Sheet Illumination Microscopy (TranSIM) for decoding whole brain activity at submillisecond temporal resolution Arisaka, Katsushi (contact) Bentolila, Laurent University Of California Los Angeles 2017 RFA-EY-17-001 Active
  • Monitor Neural Activity
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Current imaging approaches typically face a tradeoff between high spatial and high temporal resolution, but a thorough understanding of cellular brain function requires developing a technology that can achieve both simultaneously. Katsushi Arisaka and team are developing TranSIM (Trans-Sheet Illumination Microscope), an optical microscope that orients a transverse beam along the z-axis, rapidly collecting high-resolution images up to 100 times faster than any existing 3D scanning microscope. By applying particle physics principles to photo-detection and optical systems, Arisaka plans to complement high-resolution spatial images with rapid collection speed, using cost-effective components that can be widely utilized in neuroscience.
Transcranial magnetic stimulation with enhanced focality and depth (fdTMS) Peterchev, Angel V Duke University 2017 RFA-MH-17-240 Active
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  • Human Neuroscience
Transcranial magnetic stimulation (TMS) is a widely-employed, non-invasive tool that uses brief magnetic pulses to probe brain function and connectivity. Peterchev’s team will use computational methods to optimize TMS’s focality and depth of stimulation. The group will develop TMS coils that out-perform existing coils, with an increase in focality of up to 100% for a given depth of stimulation or specific anatomical target. The novel coils will be compared to conventional TMS coils via computational approaches as well as studies with human subjects. This project could increase TMS’s precision, decrease its risk of side-effects (including seizures) and improve its efficacy.
Transgenic mice and multiplexed, multi-beam instrumentation for large-scale optical experiments on brain states and ensemble cellular dynamics in behaving animals SCHNITZER, MARK J et al. STANFORD UNIVERSITY 2018 RFA-NS-17-004 Active
  • Interventional Tools
  • Monitor Neural Activity

Visualizing how individual neurons and neuronal networks in the brain communicate using novel, integrative technologies is an important emphasis of the NIH BRAIN Initiative. Drs. Schnitzer and Zengare are developing a way to monitor neuronal dynamics at cellular resolution and across cortical areas by combining fluorescent molecules and state-of-the-art microscopy techniques. By using novel markers for both neuronal activity (a calcium indicator) and specific types of neurons (genetic manipulations), the researchers will be able to identify and observe specific neuronal networks in real time and see how their activity patterns are linked to behavior in awake mice. Advancements from this project could uncover new data on the function of cellular and global brain networks in the mammalian brain.

Ultra High Resolution Brain PET Scanner for in-vivo Autoradiography Imaging El Fakhri, Georges MASSACHUSETTS GENERAL HOSPITAL 2018 RFA-EB-17-004 Active
  • Human Neuroscience
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Current research and clinical positron emission tomography (PET) neuroimaging relies on whole-body scanners, with image resolution that is sub-optimal for a comprehensive, detailed look at the human brain. Drs. Georges El Fakhri, Roger Lecomte, and a team of investigators propose the development of a dedicated brain PET scanner with ultra-high resolution, to be unmatched by existing PET scanners and improving resolution and sensitivity by an order of magnitude. The group will design, build, and benchmark this next-generation PET scanner based on hardware advances by members of their collaborative team, before piloting the system in human subjects. The new system has the potential to elucidate key structures in neurotransmitter systems that currently cannot be imaged accurately with PET.

Ultra-miniaturized single fiber probe for functional brain imaging in freely moving animals Mertz, Jerome C Boston University (charles River Campus) 2015 RFA-EY-15-001 Complete
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In the ongoing quest for ever-smaller endoscopes to image neural activity in subcortical brain structures, lensless strategies may provide the next logical leap in miniaturization. Particularly attractive is the possibility of imaging through a single optical fiber. However, the direct transmission of an image through an optical fiber is difficult because spatial information is scrambled as it moves through he fiber. Mertz and his team will borrow a concept from the field of wireless communications to convert spatial information from the image into spectral codes that can be reconstructed upon arrival. Because this approach will be insensitive to movement or bending of the optical fiber, ultra-miniaturized endoscopic imaging may result in minimally invasive functional brain imaging in freely moving animals.
Ultra-Multiplexed Nanoscale In Situ Proteomics for Understanding Synapse Types Bathe, Mark Boyden, Edward S. (contact) Yin, Peng Massachusetts Institute Of Technology 2014 RFA-MH-14-216 Complete
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Dr. Boyden's team will simultaneously image both the identities and locations of multiple proteins within individual synapses – made possible by a new technique called DNA-PAINT.
Ultrasonic neuromodulation: establishing mechanisms and parameters to optimize targeted neuromodulation and control sensory side-effects Ortiz, Michael Shapiro, Mikhail (contact) Shimojo, Shinsuke Tsao, Doris Ying California Institute Of Technology 2018 RFA-MH-17-245 Active
  • Human Neuroscience
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Ultrasonic neuromodulation (UNM) is a significant new technology capable of non-invasively perturbing specific neural circuits in the brain. However, limited knowledge about its mechanism of action and recent findings of auditory sensory side effects highlight challenges to using UNM in human neuroscience. Shapiro’s team will investigate the mechanisms of both direct and off-target UNM action, and develop approaches to optimize its specificity for targeted neural circuits. Their design employs a series of experiments across levels ( in vitro to whole animal) and species (rodents and humans) to define and minimize the UMN impact off-target effects, as well as, perform dose-response mechanistic studies on isolated direct effects. This project is likely to yield important basic mechanistic understanding of focused UNM and aid the further development of UNM as a reliable, interpretable modality.

Understanding the Neural Basis of Volitional State through Continuous Recordings in Humans Cash, Sydney S Massachusetts General Hospital 2016 RFA-NS-16-008 Active
  • Human Neuroscience
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  • Monitor Neural Activity
Every day, humans make many cognitive shifts of their own volition. Examples are as diverse as changes in wakefulness to planning complex movements. Current research often explores only neural activity that is associated with behavior using fixed, externally-driven models. Dr. Sydney Cash’s team will capitalize on data from patients who already have implanted electrodes to investigate the neural basis for voluntary cognitive shifts by first examining activity during directed versus spontaneous motor acts, and then moving into language processing. The group plans to simultaneously improve and expand upon human neuronal recording technologies to enable more continuous, real-time studies, which has implications for our understanding of fundamental mechanisms underlying cognitive neuroscience, as well as various neuropsychiatric disorders and brain-machine interfaces.
Unveiling the mechanisms of ultrasound neuromodulation via spatially confined stimulation and temporally resolved recording Cheng, Ji-Xin BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) 2018 RFA-NS-18-018 Active
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  • Theory & Data Analysis Tools

The possibility of harnessing ultrasound to modulate nerve function has interested scientists for many years. Though recent work has demonstrated the feasibility of using ultrasound to stimulate the central and peripheral nervous systems, it remains unclear whether ultrasound directly affects neuronal excitability or acts indirectly on the connections between neurons at the synaptic or circuit level. In this project, Drs. Cheng, Han and colleagues will explore these questions, using cutting-edge approaches to achieve high spatial resolution of stimulation, and high temporal resolution of recording the resultant neuronal effects. This work will inform future design of ultrasound neuro-stimulators for basic neuroscience research and possible novel therapies for neurological disorders.

Use of Calcium Indicator Proteins in Spike Counting Mode Digregorio, David A Wang, Samuel Sheng-hung (contact) Princeton University 2015 RFA-EY-15-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
A principal goal of the BRAIN Initiative is to develop technologies that allow the monitoring of neural circuit activity on the time scale of milliseconds while distinguishing activity from individual neurons within a population. While fluorescent calcium indicator proteins represent a major step toward this goal, several significant problems remain, including slow signals that produce ambiguity about the number and timing of electrical impulses ("spikes"). Wang and DiGregorio and their colleagues will develop fast calcium indicators (Fast-CGaMP) that trigger fluorescence increases on a time scale of less than 1 millisecond. This time scale is quick enough that each action potential will produce an impulse-like fluorescence signal, making it possible to resolve individual spikes from one another, and to measure and assess precisely patterned signals from many different neurons within a circuit.
Validating and extending optical tools for extended neural silencing Kennedy, Matthew UNIVERSITY OF COLORADO DENVER 2018 RFA-NS-17-003 Active
  • Interventional Tools

Reversibly and selectively silencing neuronal activity helps researchers map brain circuits responsible for specific behaviors. Opsin-based tools, which silence neural activity with light, and neurotoxin/chemogenetic tools have significant limitations in terms of temporal and spatial control. Kennedy, Ford, and Tucker will address these limitations by employing a photo- and chemo-switchable system that combines fragments of Clostridium neurotoxins with light- or chemically induced silencing of neurotransmitter release. The optically controlled version attains high spatial resolution via single photons of light, whereas the chemically controlled variant can be used for widespread silencing over broad areas via a small molecule. Such multiplexed tools will allow researchers to better understand the relevance of specific neural circuits for normal brain function and their role in brain diseases and disorders.

Vascular Interfaces for Brain Imaging and Stimulation Desimone, Robert Massachusetts Institute Of Technology 2014 RFA-MH-14-217 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • Human Neuroscience
Dr. Desimone's project will access the brain through its network of blood vessels to less invasively image, stimulate and monitor electrical and molecular activity than existing methods.
Vertically integrated approach to visual neuroscience: microcircuits to behavior Euler, Thomas Huberman, Andrew D Meister, Markus Seung, Hyunjune Sebastian (contact) Wong, Rachel O Princeton University 2014 RFA-NS-14-009 Complete
  • Cell Type
  • Circuit Diagrams
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools
Dr. Seung and colleagues Thomas Euler (U Tübingen), Andrew Huberman (UC San Diego), Markus Meister (Caltech), and Rachel Wong (UW Seattle) will use state-of-the-art genetic, electrophysiological, and imaging tools to map the connectivity of the retina, the light-sensing tissue in the eye. The goal is to delineate all the retina's neural circuits and define their specific roles in visual perception and behavior.
Virtual Brain Electrode (VIBE) for Imaging Neuronal Activity Bulte, Jeff W Hugo W. Moser Res Inst Kennedy Krieger 2015 RFA-MH-15-200 Complete
  • Monitor Neural Activity
  • Interventional Tools
  • Human Neuroscience
Electroencephalography (EEG) is a non-invasive method of measuring neuronal activity in the human brain that has high temporal resolution but poor spatial resolution, making it difficult for researchers to know which area of the brain is generating the measured signals. Bulte and colleagues propose to demonstrate that by loading red blood cells with superparamagnetic iron oxide nanoparticles, local tissue conductivity can be manipulated by orienting the blood cells in an oscillating magnetic field. The new method, termed "VIBE" (Virtual Brain Electrode), would enable researchers to more precisely localize the source of an EEG signal within the brain, and help advance our understanding of how the brain works as well as be used as a tool to diagnose brain disorders.
Wavefront sensor for deep imaging of the brain Xu, Chris Cornell University 2015 RFA-EY-15-001 Complete
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  • Interventional Tools
Multiphoton microscopy—first demonstrated more than two decades ago—has dramatically extended the depth penetration of high-resolution optical imaging. Yet, imaging depth remains a primary challenge. Xu proposes a method for increasing depth penetration that will incorporate adaptive optics—a technology first developed for ground-based telescopes to counteract the effect of light scattered by the atmosphere—to correct for aberrations caused by the effect of light scattering as it passes through brain tissue. Xu and his team will design and build a novel sensor for measuring these aberrations, allowing their distortions to be corrected. This advance will double the depth at which high-resolution brain imaging is possible, thereby increasing the number and types of circuits that can be analyzed using optical techniques.
Wearable Transcranial Focused Ultrasound System for Region-specific Functional Neuromodulation Yoo, Seung-schik Brigham And Women's Hospital 2016 RFA-MH-16-810 Active
  • Interventional Tools
  • Human Neuroscience
Focused ultrasound (FUS) with image-guidance techniques allow for non-invasive, transcranial delivery of acoustic energy to superficial and deep brain regions with excellent spatial selectively. Dr. Yoo and colleagues will develop and implement a wearable, image-guided transcranial FUS (tFUS) technique to temporarily elicit or suppress region-specific cortical and thalamic brain functions of the sensorimotor pathways in sheep. This new tFUS technique will non-invasively modulate specific brain areas with enhanced depth penetration and spatial resolution, providing a unique method to study the connection between brain activity and behavior, and potentially presenting novel therapeutic opportunities for neurological and psychiatric disorders.
What are we Stimulating with Transcranial Ultrasound in Mice? Butts-pauly, Kim Butts Stanford University 2018 RFA-MH-17-245 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

Direct brain stimulation has been used to treat neurological disorders, but the most commonly used techniques involve implanting electrodes into the brain tissue. Focused ultrasound (FUS) has emerged as a potential alternative that can noninvasively stimulate targets deep within the brain, the mechanism of action is poorly understood. Using a mouse model, Dr. Butts-Pauly and colleagues will specifically look at the peripheral hearing system and the effects of FUS on that brain region. By combining behavioral changes and analyses of neuronal activity, they will determine which neurons are stimulated by FUS and the strength of FUS signal needed to cause behavioral changes. These findings could help to advance FUS as a potential treatment for patients.

Whole-brain recording into nucleic acids using template-independent polymerases Tyo, Keith NORTHWESTERN UNIVERSITY 2018 RFA-NS-17-003 Active
  • Interventional Tools

Recording neural activity densely within local circuits, yet with the flexibility to expand across large scale neural circuits, requires distributed, high bandwidth capabilities that cannot be met with current optical or electrical measurements. To address this limitation, Tyo’s team will develop DNA/RNA-based techniques that track calcium concentration fluctuations associated with neuron firing. They will then use calcium-sensitive polymerases to store that information in DNA/RNA strands to be sequenced later. Recording and storing markers of neural activity into the DNA/RNA strands of those neurons and circuits affords high spatio-temporal resolution that could provide future researchers with more complete neural activity maps than previously possible, revealing mechanisms underlying brain diseases.

Wide deployment of massively multiplexed nanosystems for brain activity mapping Roukes, Michael L (contact) Shepard, Kenneth L California Institute Of Technology 2016 RFA-NS-16-007 Active
  • Monitor Neural Activity
  • Interventional Tools
Roukes and Shepard propose next-generation, nanofabricated multielectrode arrays for recording and stimulating neural activity on a massive scale. The team will develop ultra-thin silicon probes, which will be mass-produced via partnerships with commercial grade semiconductor foundries, and will be widely disseminated to the neuroscience community. In addition to electrical recording and stimulating electrodes, arrays will be fabricated for multimodal experimental capabilities, including electrochemical sensing for neurotransmitters such as glutamate and dopamine, and nanoscale optical waveguides for optogenetic stimulation. Planar arrays of implantable shanks will be scaled to over 8,000 contact sites, establishing 3D systems with high bandwidth. The new multifunctional arrays will be tested in neuroscience research labs working on such wide-ranging topics as Parkinson's disease, the role of sleep in memory consolidation, and the function of neural circuits in different sensory systems.
Wide-field scan-less multi-photon endoscopy using spatio-temporal pulse delivery and temporal focusing Foster, Mark A Johns Hopkins University 2017 RFA-EY-17-001 Active
  • Monitor Neural Activity
  • Interventional Tools
The use of endoscopy to image neural activity deep within the brain promises to transform our understanding of circuit function. Mark Foster and his team aim to develop a high-speed, multi-photon endoscope that combines temporal focusing optics and compressive sensing, together with a novel high-energy pulse delivery scheme, potentially reaching a nearly tenfold increase in frame rate over current endoscopy methods. Successful development of this technology will provide an important tool towards understanding neural circuit function at the individual neuron level.
Wireless High-Density Diffuse Optical Tomography for Decoding Brain Activity Culver, Joseph P Washington University 2018 RFA-EB-17-004 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
Functional neuroimaging is increasingly used as a diagnostic and prognostic tool in clinical populations, but traditional brain scanners (e.g., fMRI) require patients to remain motionless as images are acquired. Dr. Joseph Culver and colleagues propose the development of a wireless and wearable high-density diffuse optical tomography (HD-DOT) system for mapping brain functions in naturalistic settings. The group will address the technical challenges of developing a lightweight, wireless system, as well as validate paradigms needed to map and decode brain function within the system, before piloting the system in patients with cerebral palsy. By creating a portable system, this work has the potential to dramatically advance optical imaging and its role in understanding brain function – particularly in situations where it is difficult for patients to remain motionless.
Wireless Photometry For In Vivo Behavorial Studies Braun, Paul (contact) Bruchas, Michael R University Of Illinois At Urbana-champaign 2016 RFA-EY-16-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
Calcium imaging is a powerful technique for assessing the activity of large populations of neurons in the brain. Rogers and his colleagues propose a wireless, injectable system that will image calcium signals in freely moving animals in any region of the brain. The miniaturized device consists of microscale light emitting diodes and inorganic photodetectors mounted on a thin flexible filament. The size reductions and purely wireless modes of operation of the new device will greatly enhance opportunities to study neural activity related to natural behaviors throughout the brain.
Wireless recording in the central nervous system with ultrasonic neural dust Carmena, Jose Miguel University Of California Berkeley 2016 RFA-EY-16-001 Complete
  • Monitor Neural Activity
  • Interventional Tools
Carmena and his colleagues plan to develop implantable sensors for neural recording, called neural dust, that are based on miniature, wireless ultrasound technology. The technology will have three components: implanted neural dust particles for detecting and reporting extracellular electrical signals from neurons, an ultrasound power source placed under the skull and an external wireless receiver. Compared to standard microelectrode arrays, this technology promises to be less damaging to tissue, and has the potential for broader coverage of brain areas.