Funded Awards

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Title Investigator Institute Fiscal Year FOA Number Status Project Number Priority Area Summary
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 Cellular Resolution Census of the Developing Human Brain Huang, Eric J Kriegstein, Arnold (contact) University Of California, San Francisco 2017 RFA-MH-17-210 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
Scientists have yet to achieve high-resolution classification of the billions of neurons and non-neuronal cells in the human brain. To attempt this feat, Arnold Kriegstein and Eric Huang will perform high-throughput, droplet-based single-cell RNA and transposase-accessible chromatin sequencing techniques to collect genetic and epigenetic information from individual cells, which will be sampled from multiple regions of post-mortem human brains that are developmentally between early gestation and adolescence. They will further classify living neurons cultured from select brain regions based on their calcium imaging responses to various chemical stimuli. Finally, they plan to use multiplexed single-molecule fluorescent in situ hybridization (smFISH) to identify the spatial distribution of these various cell types in the brain. After these data are compiled, we will have the most detailed picture to date of genetically and functionally defined cell types in the human brain throughout development.
A 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 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 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 Molecular and Cellular Atlas of the Marmoset Brain Feng, Guoping Massachusetts Institute Of Technology 2017 RFA-MH-17-210 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
Although rodents are a highly accessible model and relatively simple to use for genetic studies, it is unclear whether the cell types found in rodent brains match those of primates. To help fill the evolutionary gap in knowledge between rodents and humans, Feng will lead a team to classify cells across the marmoset brain. They will use high-throughput single-cell RNA sequencing to identify cell types in the prefrontal cortex, striatum, and thalamus and will then spatially map the cell types they find in the brain using multiplexed error-robust in situ hybridization (MERFISH). By combining MERFISH with viral expression of marker proteins in subsets of neurons, the team will also correlate cell morphology with genetic information. Altogether these efforts will produce a census of cell types in the marmoset brain, which will be valuable information for future work into the genetics and circuits of the primate brain.
A multimodal atlas of human brain cell types Lein, Ed Allen Institute 2017 RFA-MH-17-210 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
Because of technical limitations, most studies identifying individual cell types in the brain have focused on animal models rather than on human tissue, despite a lack of knowledge about how cell types differ between species. Ed Lein and colleagues will perform broad, high-throughput single-cell RNA sequencing techniques across the whole human brain and spinal cord, along with deep sequencing of single cells in select regions of adult post-mortem brain. They will then determine the spatial distribution of various cell types identified through these sequencing experiments by using multiplexed single-molecule fluorescent in situ hybridization (smFISH). To integrate information about neuronal function into their classifications, the team will make combined electrophysiology, morphology, and transcriptome measurements from single cells in adult human cortex obtained via live surgical resection. These efforts will lead to a much deeper understanding about the differences between cell types in the adult human brain and will facilitate future collaborations between researchers to compare cell types across species.
A 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.
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.
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.
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.
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.
Assessing the Effects of Deep Brain Stimulation on Agency Roskies, Adina L Dartmouth College 2018 RFA-MH-18-500 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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
  • Interventional Tools
  • Monitor Neural Activity
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.
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
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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.

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
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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 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
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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.

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
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

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.

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
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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.

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
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
Limited treatment options exist for emotional disorders because we do not understand the neural systems by which emotions are processed. Adolphs and colleagues will study how emotion is caused  by activity in brain networks. They will electrically stimulate emotion-related brain regions, such as the amygdala, in awake neurosurgical patients, and use concurrent fMRI to image the whole-brain networks engaged by the stimulated structures. Psychophysiological, behavioral, and self-report measures of emotion will be collected to quantify how the stimulation-induced activation patterns associate with specific components of emotion. This work could inform interventions to treat mood disorders through deep-brain stimulation.
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
  • Interventional Tools
  • Monitor Neural Activity
Traumatic brain injury (TBI) afflicts hundreds of thousands of Americans each year, producing chronic cognitive disabilities that lack effective treatment. Preliminary studies with TBI patients and non-human primates suggest that these cognitive disabilities may be due to disrupted circuit function in the brain, specifically involving impaired connections between the thalamus and the frontal cortex. Working with a group of TBI patients who can function independently but remain limited by chronic cognitive impairment, Schiff and colleagues aim to build on these studies, using the latest device technology to deliver deep brain stimulation to the thalamus. The researchers hope to obtain a variety of behavioral and electrophysiological data to inform development of a next-generation device therapy for cognitive impairment associated with TBI.
Chemogenetic Dissection of Neuronal and Astrocytic Compartment of the BOLD Signal Shih, Yen-yu Ian Univ Of North Carolina Chapel Hill 2016 RFA-MH-16-750 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
Blood oxygen level dependent (BOLD) functional MRI is widely used to study human brain function. However, the cellular and molecular mechanisms underlying the BOLD signal remain poorly understood, though many neuroscientists believe the signal reflects contributions from both neurons and astrocytes. Shih and his colleagues will employ cutting-edge tools called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to tease out the specific contributions of certain types of astrocytes and neurons to the BOLD signal by selectively activating one group while inactivating the other, and vice versa. The researchers will then repeat their experiments in animal models of chronic neuroinflammation to provide insight into how the BOLD signal is disrupted by diseases involving neuroinflammation.
Circuit mechanisms of evidence accumulation during decision-making Luo, Zhihao Princeton University 2017 RFA-MH-17-250 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity
  • Theory & Data Analysis Tools
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
  • Interventional Tools
  • Monitor Neural Activity
Blindness can have a negative impact on quality of life, and is associated with relatively high rates of depression and social isolation, and relatively low levels of employment. The IntraCortical Visual Prosthesis (ICVP) team led by Dr. Troyk has worked to develop an ICVP that can compensate for blindness by stimulating the visual centers of the brain. This project aims to provide proof of principle with a small number of human volunteers, to demonstrate that the ICVP successfully produces visual sensory perception and to assess the utility of the induced visual percepts.
Closed loop deep brain stimulation for Parkinson's disease Starr, Philip Andrew University Of California, San Francisco 2016 RFA-NS-16-010 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity
Deep brain stimulation (DBS) has an important clinical role in the management of movement disorders, including Parkinson’s disease (PD). However, current DBS therapy for PD relies on continuous stimulation, regardless of changes in brain circuit function related to changes in disease expression (i.e. oscillation between too little and too much movement). In this project, Starr and his team will use next-generation DBS devices to develop and test a method of automatically adjusting stimulation parameters based on brain signals that reflect the patient's clinical state, to optimize DBS for PD. In a small number of patients, they will measure local brain activity in each patient and use that information to develop individualized stimulation paradigms; these algorithms will then be programmed into the DBS devices, to demonstrate proof of principle for this novel, closed-loop DBS system.
Closing the Loop on Tremor: A Responsive Deep Brain Stimulator for the Treatment of Essential Tremor Foote, Kelly D Gunduz, Aysegul (contact) University Of Florida 2016 RFA-NS-16-010 Active
  • Human Neuroscience
  • Interventional Tools
  • Monitor Neural Activity

Essential tremor (ET) is an incurable, degenerative brain disorder that results in increasingly debilitating tremor. Deep Brain Stimulation (DBS) is used as an effective treatment for ET, but the continuous brain stimulation provided by current DBS methods is likely unnecessary given the intermittent nature of ET symptoms, and may underlie DBS-induced side effects such as slurred speech and difficulty walking. It also may unnecessarily hasten the need for surgery to replace depleted DBS batteries. In this project, Gunduz and Foote propose to use modern DBS devices capable of recording and stimulating simultaneously, to continuously monitor brain activity and deliver stimulation only when necessary to control tremor. This work may provide proof-of-concept for the first chronic closed-loop DBS system for the treatment of a debilitating movement disorder in humans.

Collaborative Standards for Brain Microscopy Hamilton, Carol M Research Triangle Institute 2018 RFA-MH-17-256 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience
  • Integrated Approaches
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  • Monitor Neural Activity
  • Theory & Data Analysis Tools

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
  • Interventional Tools
  • Monitor Neural Activity
4-7 million Americans suffer from obsessive-compulsive disorder (OCD), and at least half of these patients do not receive adequate relief from medication or talk therapy. Deep brain stimulation (DBS) is used as a treatment for patients with intractable OCD, but only works for about half of these patients. In an effort to improve DBS for OCD, Dougherty and Eskandar have proposed to develop and test in a small early feasibility study a next-generation, brain circuit-oriented DBS treatment for drug-refractory OCD. In their project, they will measure brain activity to test a hypothesis about the specific circuit dysfunction that underlies OCD, and they will test whether DBS stimulation can disrupt this circuit dysfunction in order to relieve OCD symptoms.
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
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

Understanding the structural basis of brain function requires spanning multiple spatial scales, from synaptic circuits to whole-brain systems, but current technology is limited in its ability to successfully integrate across these scales. Dr. Bruce Rosen and a team of investigators propose the development of a human magnetic resonance imaging (MRI) scanner that images brain structural connectivity in-vivo. Building upon previous work from the Human Connectome Project (HCP), these tools will advance brain imaging with the capability of estimating cellular and axon level microstructural brain circuits at very high resolution. The project will have the potential to significantly expand our knowledge on hierarchical anatomy and functionality of both healthy and diseased human brains, with impact on both neuroscience research and clinical applications.

Context-dependent processing in sensorimotor cortex Collinger, Jennifer UNIVERSITY OF PITTSBURGH AT PITTSBURGH 2018 RFA-NS-18-010 Active
  • Human Neuroscience
  • Integrated Approaches
  • Interventional Tools
  • Monitor Neural Activity

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

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.

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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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.

Decoding the neural basis of resting-state functional connectivity mapping Hillman, Elizabeth M Columbia University Health Sciences 2017 RFA-MH-17-235 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
Resting-state functional magnetic resonance imaging (rs-fMRI) detects how brain regions are synchronized, forming networks that support normal function. Understanding these networks may help diagnose and treat disease. Elizabeth Hillman’s team will use novel optical imaging, capturing neural activity and blood flow dynamics, to characterize cellular dependencies, pathways, behavioral correlates, and blood flow interactions of resting-state spontaneous neural activity. Data will be acquired using novel measurement and circuit manipulation techniques in awake, behaving mice, and rs-fMRI analysis of equivalent human neurovascular activity. The aggregate data will yield predictive models of network activity and the relationships between resting-state activity in specific cell types and blood flow dynamics. By optimizing and validating rs-fMRI analysis, this project could transform rs-fMRI into a reliable technique for studying the brain in health and disease.
Deep brain 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
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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
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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.
Defining Cell Type Specific Contributions to fMRI Signals Lee, Jin Hyung Stanford University 2017 RFA-MH-17-235 Active
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  • Human Neuroscience
Functional magnetic resonance imaging (fMRI) allows non-invasive study of human brain function. However, how specific cell types contribute to fMRI signals remains elusive, complicating fMRI interpretation. Jin Hyung Lee’s team will measure cell-type-specific, whole-brain network function using fMRI while using optogenetics to selectively stimulate distinct neural circuit pathways in the basal ganglia. These pathways are involved in action planning and reward, and are implicated in disorders as diverse as Parkinson’s disease, depression, and substance use disorders. Optical imaging will confirm fMRI signal sources with cell-type specificity. The group will computationally model these interaction dynamics to demonstrate how this unique approach can be used to uncover whole-brain circuit functions. This project could enable researchers to systematically design therapies to restore normal circuit function in disorders like Parkinson’s disease.
Defining Neuronal Circuits and Cellular Processes Underlying Resting fMRI Signals Milham, Michael Peter Schroeder, Charles E (contact) Nathan S. Kline Institute For Psych Res 2016 RFA-MH-16-750 Active
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  • Human Neuroscience
Methods for measuring intrinsic functional connectivity (iFC), a measure of correlation between spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal, can be used to quickly map in high detail the functional architecture of the human brain. However, the neural circuits underlying the BOLD-iFC relationship remain poorly specified. Schroeder and his colleagues propose to use a variety of measurement tools in humans and monkeys to investigate this relationship. The researchers will then employ established modeling and computational methods to help construct a comprehensive model that connects large-scale iFC to underlying microscale activity at the neural circuit level. The findings from this project may be used to improve the efficiency of iFC measurements, which could have widespread clinical implications, particularly in the discovery of biomarkers for various brain disorders.
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 and validation of empirical models of the neuronal population activity underlying non-invasive human brain measurements Devinsky, Orrin Dijkhuizen, Rick M Petridou, Natalia (contact) Ramsey, Nicolas Franciscus Winawer, Jonathan A University Medical Center Utrecht 2016 RFA-MH-16-750 Active
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  • Human Neuroscience
A major obstacle in the study of human brain function is that we currently have a limited understanding of how the measurements made by different instruments, such as fMRI and EEG, relate to one another and to the underlying neuronal circuitry. To overcome this challenge, Petridou and her colleagues will combine a number of invasive (optical imaging, ECoG) and non-invasive (functional MRI, MEG and EEG) hemodynamic and electrophysiological measurements in humans and rats. By obtaining recordings from these multiple techniques, the researchers will be able to unequivocally link electrophysiological and fMRI signals. Reconciling these different signals will lead to breakthroughs in understanding the dynamic activity of the human brain and the improvement of disease models of the nervous system.
Development of 7-T MR-compatible TOF-DOI PET Detector and System Technology for the Human Dynamic Neurochemical Connectome Scanner Catana, Ciprian MASSACHUSETTS GENERAL HOSPITAL 2018 RFA-EB-17-003 Active
  • Human Neuroscience
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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 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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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.
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.
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
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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
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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.
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
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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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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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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
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  • Human Neuroscience
Noninvasive neuromodulation technologies use a variety of electrical, magnetic, optical, and sonic techniques to stimulate the brain. The ensuing modulation of brain network dynamics can be used as a tool to study healthy brain processes, as well as for treatment of brain disorders. He’s team will develop an acousto-modulated electrophysiological source imaging (ESI) technique with improved spatial precision, and use it to monitor and image transcranial focused ultrasound (tFUS)-induced brain activity in real-time. The group will validate this integrated ESI-guided tFUS system in rats, using simultaneous intracranial recordings of neural spikes and local field potentials, and ultimately test it in human subjects. This non-invasive neuromodulation, with high spatiotemporal precision, promises stimulation which is individualized and responsive to dynamic neural activity.
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
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  • 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.
Enabling ethical participation in innovative neuroscience on mental illness and addiction: towards a new screening tool enhancing informed consent for transformative research on the human brain Roberts, Laura W Stanford University 2017 RFA-MH-17-260 Active
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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
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A comprehensive view of the brain requires quantifying multiple properties of the brain simultaneously. However, obtaining those measures with comparable levels of sensitivity and resolution remains challenging. Single-photon emission computed tomography (SPECT) utilizes multiple radiotracers that emit gamma rays at specific energies, making simultaneous measurement of multiple molecular imaging probes possible. Dr. Todd Peterson and a team of investigators will develop SPECT radiation detector technology that improves energy resolution over traditional detectors, thereby minimizing crosstalk and separating the signal that previously limited the quantitative accuracy of multi-tracer imaging studies. By aiming to improve multi-tracer SPECT technology, the researchers will deliver an imaging approach that will pave the way for simultaneous, quantitative multi-tracer imaging studies of the human brain.

Engineering optogenetic tools for studying neuropeptide activity French, Alexander Robert Purdue University 2017 RFA-MH-17-250 Active
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Dr. French will develop a high throughput screening platform to identify peptides that activate opioid receptors in response to light, creating high-resolution tools to study the function of specific opioid neural circuits in the brain.
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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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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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.
FOCUS: FUNCTIONAL OPTICAL IMAGING FEEDBACK-CONTROLLED CELLULAR-LEVEL ULTRASOUND STIMULATION Chen, Hong Washington University 2018 RFA-MH-17-240 Active
  • Human Neuroscience
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Current tools used to change neuronal activity are either noninvasive but unable to target specific cell types, or extremely precise but require invasive neurosurgery. Dr. Chen and his team plan to develop a tool called Functional Optical Imaging Feedback-Controlled Cellular-Level Ultrasound Stimulation (FOCUS), which will use a three-step process to noninvasively control specific cells. Dr. Chen’s group will identify ion channels that are activated by ultrasound and use viral vectors to deliver those channels to specific cells that will then be controlled by ultrasound. Dr. Chen’s team also plans to create an ultrasound helmet that will be worn by mice allowing control of their behavior by targeting movement- related circuits. This noninvasive, wearable tool may eventually be adapted for use in individuals affected by neurological disorders.

Foundations of MRI Corticography for mesoscale organization and neuronal circuitry Feinberg, David Alan University Of California Berkeley 2016 RFA-MH-16-750 Active
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  • Human Neuroscience
While functional MRI (fMRI) with low spatial resolution is useful for capturing a picture of dynamic activity across the entire brain, performing fMRI at high-resolution may accurately distinguish neuronal activity in cortical layers and columns. Feinberg and his colleagues plan to use recently developed high-resolution fMRI techniques with a number of other techniques, including optogenetics, transcranial magnetic stimulation, and electrocorticography, to identify and stimulate the various aspects of neural activity that drive the fMRI signal. These measurements will enable bridging neuronal activity to the level of cortical layers and columns identifiable in high-resolution fMRI signals to help better understand the underlying biology of non-invasive imaging of brain circuitry.
From ion channel dynamics to human EEG and MEG: multiscale neuronal models validated by human data Bazhenov, Maksim V (contact) Cash, Sydney S Halgren, Eric University Of California, San Diego 2018 RFA-MH-17-235 Active
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Non-invasive imaging methods, such as electroencephalography (EEG) and magnetoencephalography (MEG), are commonly used in basic research studies and in some diagnostic procedures. These methods derive neural signals by summating over the activity of millions of neurons, but the dynamics of the underlying cellular signal and circuit function remain elusive. Drs. Bazhenov, Cash, and Halgren, along with a team of investigators, will use biophysical and neural modeling to predict the cellular dynamics underlying EEG and MEG signals, which they will then confirm using extensive intracranial recording data. This bidirectional approach that generates predictions – which can then be validated with data – has the potential to identify a crucial link between neuronal and synaptic responses that subsequently give rise to macroscopic EEG and MEG recordings.

Functional Architecture of Speech Motor Cortex Chang, Edward University Of California, San Francisco 2016 RFA-NS-16-008 Active
  • Human Neuroscience
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Speaking is one example of a complex behavior that most humans can perform effortlessly, but scientists do not fully understand how the brain is able to drive speech production. Building on their prior work on the neural representation of articulatory and acoustic feature representations of speech, Chang and his team will conduct ultra high-density electrocorticography in epilepsy patients to study how the ventral sensorimotor cortex encodes the movements that produce speech, and how the prefrontal cortex is able to exert inhibitory control over speech. This work will advance our understanding of communication disorders, and refine the ability of clinicians to map speech areas of the brain in their patients.
Gated Diffuse Correlation Spectroscopy for functional imaging of the human brain Franceschini, Maria Angela Massachusetts General Hospital 2017 RFA-EB-17-001 Active
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  • 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.
Genetic analyses of complete circuit formation in Caenorhabditis elegans Cook, Steven Jay Columbia Univ New York Morningside 2017 RFA-MH-17-250 Active
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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.
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
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  • Human Neuroscience
Electroencephalography is a noninvasive method to record electrical activity in the brain, but suffers from poor resolution and inaccuracies due to blurring of electrical signals as they pass through the brain and skull. Witte and colleagues aim to overcome such deficiencies by developing a noninvasive, real-time, portable electrical human brain mapping system called the 4D Acoustoelectric Brain Imaging (ABI). ABI utilizes pulsed ultrasound to produce 4D current density images. This method holds great promise for yielding unprecedented resolution and accuracy for imaging electrical activity deep in the brain, which can help scientists decode brain function and may also be used to diagnose brain disorders.
High SNR Functional Brain Imaging using Oscillating Steady State MRI NOLL, DOUGLAS UNIVERSITY OF MICHIGAN AT ANN ARBOR 2018 RFA-EB-17-004 Active
  • Human Neuroscience
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To improve the spatial resolution of functional magnetic resonance imaging (fMRI), researchers often turn to higher magnetic field strength systems. While these systems can provide images of better quality, they require costly investment and maintenance. Dr. Douglas Noll and a team of investigators propose to improve fMRI techniques by developing a new method - Oscillating Steady State (OSS) Acquisition, for collecting MRI and fMRI data. This approach reuses magnetization to improve the signal-to-noise ratio, achieving a signal gain that is roughly equivalent to the shift from 3T to 7T, but without the practical and technical challenges and additional costs. If successful, the method can be widely and quickly disseminated to the neuroimaging community to upgrade existing 3T systems with reduced variability, noise, and improved sharpness of the images without increasing the cost of instrumentation.

High-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
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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.
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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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.

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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  • Human Neuroscience
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Molecular and cellular neuroscientists often lack the training in computer programming to fully explore “-omics” data common in the BRAIN Initiative. Drs. Hertzano and White will implement analytic software for visualization and interactive genome browsing of gene expression and RNA-seq data, including simple and complex cross-dataset analysis. These tools will be made available in the BRAIN Initiative funded Neuroscience Multi-Omic Data Archive (NeMO) which hosts multi-omic data. The software will provide an easy-to-use web-based work environment for visualization and analysis of multi-modality and multi- omic data, interrogation of relationships between epigenomic signatures and gene expression, and integration of analytical techniques for multivariate analysis, gene co- expression and other analyses.

Imaging and Analysis Techniques to Construct a Cell Census Atlas of the Human Brain Boas, David A Fischl, Bruce (contact) Massachusetts General Hospital 2018 RFA-MH-17-210 Active
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  • Human Neuroscience

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

Imaging Brain Function in Real World Environments & Populations with Portable MRI Garwood, Michael G (contact) Vaughan, John T University Of Minnesota 2014 RFA-MH-14-217 Complete
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  • Interventional Tools
  • Human Neuroscience
By employing smaller, less cumbersome magnets than used in existing MRI, Dr. Garwood and colleagues will create a downsized, portable, less expensive brain scanner.
Imaging Human Brain Function with Minimal Mobility Restrictions Garwood, Michael G University Of Minnesota 2017 RFA-EB-17-002 Active
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  • 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
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  • 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
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  • 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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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
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  • 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.
Improving Human fMRI through Modeling and Imaging Microvascular Dynamics Polimeni, Jonathan Rizzo Massachusetts General Hospital 2016 RFA-MH-16-750 Active
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  • Integrated Approaches
  • Human Neuroscience
Functional Magnetic Resonance Imaging (fMRI)—the most common technique for mapping whole brain function in humans—is based on tracking changes in blood flow that occur during brain activity. However, the temporal and spatial resolutions for this technique are fairly low. Polimeni and his colleagues will improve fMRI’s specificity by using 2-photon microscopy to create new models of the way blood flows in the brain and linking those models with highly detailed maps of human microvascular anatomy. A better understanding of how microvascular dilations and blood flow changes impact the underlying neural signals will help neuroscientists better understand fMRI signals and enable them to map human brain function at a finer scale than what is currently possible.
In Vivo Brain Network Latency Mapping BASSER, PETER J National Institute of Child Health and Human Development 2018 Active
  • Human Neuroscience
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The purpose of this project is to develop, explore, and begin implementing a new non-invasive, painless Magnetic Resonance Imaging (MRI) methodology to measure the time (latency) it takes neural impulses to travel from one functional area in the cerebral cortex to another. This project will use microstructure imaging and neurophysiological data to estimate conduction delays along white matter pathways, incorporating whole-brain diffusion MRI measurements of various white matter tract characteristics. Integrating data derived from resting state and other neurophysiological mapping approaches, these methods will yield high spatial and temporal resolution latency matrix data. Dr. Basser's website is available at https://irp.nih.gov/pi/peter-basser

In Vivo Imaging of Local Synaptic Neuromodulation by Dopamine Evans, Paul Robert Max Planck Florida Corporation 2018 RFA-MH-17-250 Active
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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.
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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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 fMRI Methods to Study Neurophysiology and Circuit Dynamics at Laminar and Columnar Level Chen, Wei University Of Minnesota 2016 RFA-MH-16-750 Active
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  • Integrated Approaches
  • Human Neuroscience
Functional MRI is a powerful technique for mapping functional brain activity. However, its low spatial resolution prevents accurate mapping of activity at the scale of cortical layers. Another long-standing limitation of fMRI has been the inability to study how neural inhibition impacts neural dynamics and networks. Chen and his colleagues propose to integrate ultrahigh-resolution high-field fMRI with the selective stimulation of groups of inhibitory neurons to study correlates of fMRI signals in neural circuits. This project has the potential to bring clarity to the relationship between structure and function at the level of individual neuronal layers, as well as shed light on the dynamics of neural activity.
Integrated multichannel system for transcranial magnetic stimulation and parallel magnetic resonance imaging Nummenmaa, Aapo Massachusetts General Hospital 2016 RFA-MH-16-810 Active
  • Interventional Tools
  • Human Neuroscience
Although the combined use of functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) is safe, noninvasive, and valuable for studying the brain and treating neurological disorders, this approach fails to uncover the spatiotemporal dynamics of distributed neural networks. Dr. Nummenmaa and colleagues will develop a new type of integrated multichannel TMS neuromodulation system with MRI parallel imaging, receive coil array, that can stimulate multiple brain regions simultaneously or in rapid succession, while simultaneously recording activity from the whole brain at high spatiotemporal resolution. This novel, integrated neuromodulation and imaging device holds great promise for clinical non-invasive brain stimulation applications, including TMS treatment of depression.
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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Even relatively simple sensory-motor decisions, such as goal-directed eye movements, exhibit sufficient flexibility and nuance to be considered a “window on cognition.” Gordon Baltuch’s team will leverage the unique opportunity provided by surgical treatment of Parkinson’s disease using deep brain stimulation, to study decision-making in the human brain at the single-neuron level. The team will simultaneously measure behavioral response time and accuracy (by asking neurosurgical patients to select a visual stimulus via eye movements) while performing brain electrophysiology. Additionally, they will conduct parallel monkey and human studies that, unlike Parkinson’s studies alone, will distinguish normal versus disrupted mechanisms in the Parkinson’s -affected brain. This project may yield a sustainable research program that probes not only neural mechanisms of decision-making, but also potential causes of, and remedies to, cognitive side effects associated with deep brain stimulation.
Invasive Approach to Model Human Cortex-Basal Ganglia Action-Regulating Networks Pouratian, Nader University Of California Los Angeles 2016 RFA-NS-16-008 Active
  • Human Neuroscience
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Circuits between the frontal cortex and basal ganglia (BG) may support the ability to suppress actions once additional information becomes available to indicate the most appropriate decision, but few studies provide the necessary spatial and temporal resolution to investigate this mechanistically. Dr. Pouratian’s group will utilize deep brain stimulation (DBS) electrodes in Parkinson’s patients to record from cortical and BG regions in multiple action-suppression tasks. In addition to investigating unit and local field potential activity during tasks, the group will use DBS coupled with functional imaging to stimulate the circuits and measure effects on brain activity, eventually developing a computational model of action suppression. Aside from informing the basic science of this circuitry, this project could expand upon how DBS influences brain networks for action, which could improve therapeutic use in various disorders.
Investigating the hypocretin to VTA circuit in memory consolidation during sleep Borniger, Jeremy Stanford University 2018 RFA-MH-17-250 Active
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Brain-computer interfaces and neuroprosthetics have provided a significant benefit to patients with cervical spinal cord injuries. However, current technology is limited in its abilities to allow the user to control how much force is exerted by the prosthesis and to provide sensory feedback from the prosthetic hand. In a public-private collaboration with Blackrock Microsystems, Dr. Boninger and colleagues are looking to improve the dexterity of neuroprostheses by incorporating microstimulation of the somatosensory cortex. This stimulation could provide tactile feedback to the user and hopefully allow the user to better control the force applied. Ultimately, this approach will improve the dexterity and control of prosthetic limbs used by patients with spinal cord injuries.

Investigating the Role of Neurotensin on Valence Assignment During Associative Learning in the Basolateral Amygdala Olson, Jacob Michael Massachusetts Institute Of Technology 2017 RFA-MH-17-250 Active
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Dr. Olson will systematically identify, manipulate, and characterize the neural projections that release the neuropeptide neurotensin to the basolateral amygdala during behavior conditioning tests in mice to identify a new circuit that regulates associative learning.
Is the Treatment Perceived to be Worse than the Disease?: Ethical Concerns and Attitudes towards Psychiatric Electroceutical Interventions Cabrera Trujillo, Laura Yenisa Michigan State University 2018 RFA-MH-18-500 Active
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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.

Large-scale monitoring of sensory transformations in the mammalian olfactory system Burton, Shawn Denver University Of Utah 2017 RFA-MH-17-250 Active
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  • Human Neuroscience
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Dr. Burton will leverage recent enhancements in calcium indicators to image pre- and post-synaptic neural activity simultaneously in the mammalian olfactory system, gaining insight into how sensory information is transformed as it moves through a neural circuit.
Lightweight, Compact, Low-Cryogen, Head-Only 7T MRI for High Spatial Resolution Brain Imaging Foo, Thomas (contact) Shu, Yunhong Xu, Duan General Electric Global Research Ctr 2018 RFA-EB-17-004 Active
  • Human Neuroscience
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Non-invasive magnetic resonance imaging (MRI) is an important tool for our understanding of the human brain. However, ultra-high field magnets are hampered by their massive size and challenging installation, limiting their accessibility to researchers and clinicians. Dr. Thomas Foo and a team of investigators propose the development of a 7T MRI system with high-performance head gradients, delivering a head-only, high-resolution MRI system that is significantly smaller and lighter in comparison to existing ultra-high field systems. The group will design, optimize, and validate a head-only 7T MRI system, piloting the system in healthy volunteers to assess the quality of the structural, functional, and metabolic data. The proposed work has the potential to open a range of scientific and clinical applications that cannot currently be achieved with existing instrumentation.

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

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

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.
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
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  • Human Neuroscience
Interest in transcranial electrical stimulation (tES) has escalated over the last decade, but the mechanisms of action of these therapies are unclear, and study results suffer from high variability. This project proposes to precisely measure where electrical energy flows in the brains of subjects and compare this with brain activity levels. Sadleir’s team will develop a technique based on MR electrical impedance tomography to measure current density and electric field distributions in the brains of healthy human subjects experiencing tES. The electrical distributions will be correlated with memory performance measures and brain activity measures using fMRI, including a specific target structure in the prefrontal cortex. This new approach will bolster explorations into the mechanisms of electrical stimulation therapies, with potential to revolutionize researchers’ understanding of tES, a technique with applications ranging from basic mechanistic studies on electrical neuromodulation to stroke and epilepsy therapy to memory enhancement.
Mechanisms of electrical stimulation of a canonical motor microcircuit Heckman, Charles NORTHWESTERN UNIVERSITY AT CHICAGO 2018 RFA-NS-18-018 Active
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  • Human Neuroscience
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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 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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The human brain can quickly “program” itself to adapt to novel situations, such as figuring out how to drive a rental car through a new city. Dr. Sheth and his colleagues plan to investigate how the brain assembles pieces of information into plans that help us manage new circumstances, and then develops a computational model of this learning. They will record from the brain’s dorso-lateral prefrontal cortex in patients with deep brain stimulation who are performing tasks to understand what information is being encoded and how it is processed. The project offers to provide a computational understanding of complex cognition. This may improve our understanding of cortical brain function and of neurological disorders that interfere with complex thinking.   

Mechanisms underlying positive and negative BOLD in the striatum Shih, Yen-yu Ian Univ Of North Carolina Chapel Hill 2018 RFA-MH-17-235 Active
  • Human Neuroscience
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A central assumption in blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging lies in the tight coupling between neuronal activity and vascular responses. To a large extent, data supporting this coupling has been based on cortical structures, but accumulating evidence suggests that the striatum exhibits a different pattern. Dr. Shih and colleagues will use a suite of cutting-edge neuroscience techniques, including optogenetics and chemogenetics, to selectively identify and target dopamine receptors, vasoactive neurotransmitters, and neuronal subtypes that underlie distinct positive and negative BOLD responses in the striatum. By using both multimodal modulation and recording techniques to simultaneously understand the vascular response to stimuli and the impact on BOLD, this project offers the potential to shed light on better understanding the function and role of the striatum in cognition and disease.

Mechanistic and causal basis of fMRI functional connectivity in non-human primates Rudebeck, Peter (contact) Russ, Brian E Icahn School Of Medicine At Mount Sinai 2018 RFA-MH-17-235 Active
  • Human Neuroscience
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Neuroscience researchers and clinicians increasingly utilize connectivity measures of functional magnetic resonance imaging (fMRI) to better understanding circuit-level mechanisms of brain function and dysfunction yet establishing causal links between fMRI functional connectivity and neural activity remains challenging. Using non-human primates, Drs. Rudebeck and Russ propose a multi-dimensional approach that combines high-resolution multi-echo fMRI, high-density neurophysiology recordings, and pathway-specific manipulations of neural activity. Collectively, these measures will help to establish a causal understanding of how connectivity and neural activity measures are related to one another at rest and during cognitive tasks. By identifying the neural mechanisms underlying fMRI, this work will both aid basic research as well as inform therapeutic approaches that target distributed brain circuits.

Mechanistic dissection of the neural basis of the resting-state fMRI signal using multi-modal approaches Drew, Patrick James Zhang, Nanyin (contact) Pennsylvania State University-univ Park 2017 RFA-MH-17-235 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
The neural basis of resting-state fMRI (rsfMRI) signal remains poorly understood. Particularly, poor understanding of cellular and circuit-level mechanisms underlying resting-state functional connectivity (RSFC) has hampered rsfMRI interpretation. Nanyin Zhang’s team will dissect the signal contributions of spiking activity from individual neuron populations. They will use multi-echo-rsfMRI (differentiates neural and non-neural rsfMRI signal components) to quantify RSFC by eliminating non-neural artifacts, and calcium-based fiber photometry to measure simultaneous neuronal and rsfMRI signals with neuron-type specificity. Finally, the group will optogenetically increase neuronal excitability and examine resulting RSFC and cortical-layer-specific electrophysiological signal changes. This project may enhance understanding of rsfMRI signal in humans, impacting brain disorder research.
Memory consolidation during sleep studied by direct neuronal recording and stimulation inside human brain FRIED, ITZHAK UNIVERSITY OF CALIFORNIA LOS ANGELES 2018 RFA-NS-18-010 Active
  • Human Neuroscience
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Sleep is important for learning and memory, but the exact mechanisms of this process are not known. Dr. Fried and his team will examine the role of sleep in memory formation in humans by recording brain activity during sleep following learning tasks. Dr. Fried’s group will identify the sleep events, such as sleep stage or changes in firing activity, that show the strongest association with memory consolidation. They will also examine whether electrical or auditory stimulation during sleep improves memory performance compared to undisturbed sleep. Greater knowledge of these mechanisms may help in the development of treatments for people suffering from memory and/or sleep disorders. 

Micro-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.
Microscopic foundation of multimodal human imaging Dale, Anders M Devor, Anna (contact) University Of California San Diego 2016 RFA-MH-16-750 Active
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  • Human Neuroscience
The computational properties of the human brain arise from an intricate interplay between billions of neurons of different types that are connected in complex networks. The hypothesis behind the project from Devor and her colleagues is that specific neuronal cell types have identifiable “signatures” in the way they contribute to large electrical signals that drive changes in the brain’s energy metabolism and blood flow. To investigate this hypothesis, the researchers will attempt to relate cell-type specific neural activity to metabolism and blood flow signals using parallel experiments in mice and humans. If successful, the proposed project will create a way to measure neuronal activity of known cell types from across the entire human brain, offering a significant enhancement to techniques such as functional MRI (fMRI).
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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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.
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
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  • 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
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  • 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-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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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.
Network Control and Functional Context: Mechanisms for TMS Response Bassett, Danielle Smith Oathes, Desmond (contact) Satterthwaite, Theodore Daniel University Of Pennsylvania 2018 RFA-MH-17-245 Active
  • Human Neuroscience
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Transcranial magnetic stimulation (TMS) is a powerful tool for non-invasively modulating brain circuits. However, the field lacks a theoretical framework to predict the effects of TMS on brain and behavior. In healthy young adults, Oathes and colleagues will test the hypothesis that brain responses to TMS are governed both by the network properties of the area stimulated and by the cognitive context, as measured by patterns of functional activation during stimulation using fMRI. The group will further test their theory during a working memory test, comparing TMS impact on performance in both healthy adults and patients with ADHD. Elucidating the mechanisms of TMS response will enhance understanding of how functional brain circuits contribute to specific cognitive functions and has the potential to accelerate personalized neuromodulatory treatments for executive dysfunction.

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.
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
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  • Human Neuroscience
A major focus of The BRAIN Initiative is to develop new tools and technologies to study circuitry of the brain. Developing methods to simultaneously modulate and image neural circuits would empower researchers to undertake such science. In this project, Caskey and his team propose to develop a next-generation method to modulate brain activity using ultrasound, while simultaneously imaging brain activity using functional magnetic resonance imaging (fMRI). The integration of highly spatially selective ultrasound neuromodulation with high field MRI has the potential to provide a unique and powerful approach to study the functional architecture of the human brain. The completion of this work will improve our understanding of the neuronal responses to ultrasound neuromodulation, establish the safety of ultrasound neuromodulation, and explore how ultrasound can be used in conjunction with MR imaging to interrogate brain circuits and diagnose brain disorders.
Neuronal and Dopaminergic Contributions to Dissimilar Evoked Hemodynamic Responses in the Striatum Walton, Lindsay Univ Of North Carolina Chapel Hill 2018 RFA-MH-17-250 Active
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Blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) is a non-invasive imaging technique that infers increased brain activity from observed increases in cerebral blood flow. A notable exception to this relationship occurs in the striatum. Walton will investigate the activity of dopamine neurons, medium spiny neurons, and dopamine receptors, under conditions that evoke either blood vessel dilatation or constriction in the striatum. She will utilize optogenetic stimulation, synthetically-derived receptors, and receptor antagonist drugs to reveal the mechanisms underlying striatal positive and negative fMRI responses. These studies are important for the accurate interpretation of BOLD fMRI signals from brain regions with atypical hemodynamic responses.
Neuronal mechanisms of human episodic memory Mamelak, Adam Nathaniel Rutishauser, Ueli (contact) Cedars-sinai Medical Center 2017 RFA-NS-17-019 Active
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No meaningful therapies for memory disorders exist, partially due to a lack of mechanistic knowledge about human memory. Ueli Rutishauser’s multi-institutional, multi-disciplinary team will study how memories of facts and events are formed and used in the human brain. The team will use electrophysiological methods to record single neurons, simultaneously in multiple brain areas, in awake patients who are implanted with electrodes to localize epileptic seizures. This work will combine single-neuron physiology, behavioral testing, electrical stimulation, and computational modeling, to address three questions: (i) how persistent activity supports memory formation, (ii) what mechanisms translate memories into decisions and judgments, and (iii) how memories are formed and recalled over time. A circuit-level understanding of memory may enable development of new treatments for memory disorders.
Neuronal Substrates of Hemodynamic Signals in the Prefrontal Cortex Howard, Matthew A. O'doherty, John P (contact) Tsao, Doris Ying California Institute Of Technology 2016 RFA-MH-16-750 Active
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  • Human Neuroscience
Functional MRI (fMRI) is the dominant technique for probing human prefrontal cortex functions such as cognition, learning, and decision-making. Yet, little is known about how fMRI signals relate to the underlying neural signals in prefrontal cortex. O’Doherty and his colleagues will examine this relationship in monkeys by first probing the region with fMRI, then recording electrical signals from individual neurons in those areas that show strong fMRI activation. The team will then follow up with dual recordings (fMRI and intracranial electrical measurements) in human patients undergoing surgical treatment for epilepsy. By combining these different recording techniques in both monkeys and humans, the team hopes to determine which aspects of underlying neural responses give rise to fMRI responses in prefrontal cortex. This work will improve the usefulness of fMRI as a diagnostic measure of disorders related to higher-order cognitive functions.
Neurons, Vessels and Voxels: Multi-modal Imaging of Layer Specific Signals Kara, Prakash Naselaris, Thomas P Olman, Cheryl A. Ugurbil, Kamil (contact) University Of Minnesota 2016 RFA-MH-16-750 Active
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  • Integrated Approaches
  • Human Neuroscience
Functional MRI (fMRI) infers the location and magnitude of neural activity from vascular signals. However, the technique has not been shown to distinguish neural activity from individual cortical layers, each of which have unique computational functions. To demonstrate ultrahigh-resolution high-field fMRI’s ability to measure layer-specific signals, Ugurbil and his colleagues will perform simultaneous 2-photon microscopy—a technique for imaging neural signals with high spatial resolution—and fMRI experiments in which cats are shown visual stimuli known to elicit responses in specific cortical layers. These experiments will seek to correlate layer-specific fMRI responses with differences in neural activity, which will ultimately enable fMRI to provide more detailed information about human brain function in both health and disease.
Neurophysiologically Based Brain State Tracking & Modulation in Focal Epilepsy Worrell, Gregory A Mayo Clinic Rochester 2015 RFA-NS-15-006 Active
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Epilepsy is a common neurological disease, and over one-third of epilepsy patients have seizures that are not controlled by conventional therapy. Surgery can be curative, but only for a subset of patients. Advances in neural engineering have produced devices that are poised to transform management of drug-resistant epilepsy; they will ultimately take the form of wireless devices that integrate the ability to measure brain activity, predict seizure onset, and deliver therapeutic stimulation to limit seizure activity. Worrell and colleagues aim first to undertake a preclinical study in dogs with naturally occurring epilepsy, to test one such device, and if this is successful then conduct a pilot clinical trial in human epilepsy patients
Neurostimulation and Recording of Real World Spatial Navigation in Humans Suthana, Nanthia A University Of California Los Angeles 2017 RFA-NS-17-019 Active
  • Human Neuroscience
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Spatial memory is thought to involve neurons in the medial temporal lobe that exhibit increased firing rates when an animal is in a specific location during spatial navigation. However, human single-neuron studies have been limited to immobile subjects viewing 2-dimensional navigational tasks. Nanthia Suthana’s team will use intracranial single-neuron and local field potential recordings, combined with deep brain stimulation (DBS), in epilepsy patients performing freely-moving spatial navigation memory tasks using state-of-the-art virtual reality headset technology and full-body motion capture. The team will record from medial temporal lobe subregions, to determine the role of single neurons and oscillations during navigation and memory, and how these neurophysiological mechanisms can be enhanced by deep brain stimulation. This work may yield insights into the neuronal correlates of real-world spatial navigation and memory.
Next-generation optical brain functional imaging platform Fang, Qianqian Northeastern University 2018 RFA-EB-17-003 Active
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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-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
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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
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Deep brain stimulation (DBS) is an important clinical option for patients with Parkinson’s disease (PD), but the optimum stimulation parameters differ from patient to patient. As a result, patient outcomes vary between individuals and across clinical trials. In this project, Walker et al. will utilize non-invasive electroencephalography (EEG) measurements of how the brain responds to DBS, to guide the activation and adjustment of next-generation DBS devices and electrodes. The researchers will test whether this personally optimized DBS is superior to conventional DBS, in terms of effectiveness and reduced side effects for patients.
Noninvasive neuromodulation via focused ultrasonic drug uncaging Airan, Raag D Stanford University 2017 RFA-MH-17-240 Active
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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.
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
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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.
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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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.

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.

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 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.
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.
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.
Rational Optimization of tACS for Targeting Thalamo-Cortical Oscillations Frohlich, Flavio Univ Of North Carolina Chapel Hill 2016 RFA-MH-16-815 Active
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  • 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.

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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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.

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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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
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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.

Resting state connectivity: Biophysical basis for and improved fMRI measurements Kleinfeld, David (contact) Rosen, Bruce R University Of California San Diego 2016 RFA-MH-16-750 Active
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  • Integrated Approaches
  • Human Neuroscience
Functional MRI (fMRI) is a unique tool that permits detailed measurements of neural activity within the entire volume of the human brain. A particularly powerful aspect of fMRI concerns measurements of coordinated fluctuations in the amplitude of blood oxygen level dependent (BOLD) signals across distant regions of the brain, referred to as “resting-state functional connections.” Kleinfeld and his colleagues plan to test the hypothesis that very subtle oscillations in the smooth muscle of arteriole walls in the brain links oscillations in with the resting-state BOLD signals. Being able to measuring resting-state connectivity by assessing arteriole movements can advance scientists’ use of fMRI to study human cognition as well as a variety of neuropsychiatric conditions.
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
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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
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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.
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.
Spatiotemporal signatures of neural activity and neurophysiology in the BOLD signal Keilholz, Shella D Emory University 2016 RFA-MH-16-750 Active
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  • Integrated Approaches
  • Human Neuroscience
Blood oxygenation level dependent (BOLD) MRI fluctuations used in mapping functional brain connectivity contain a wealth of information about neural activity. Most functional connectivity studies focus on detecting activity related to cognition and information processing, and view the presence of other contributors to the BOLD signal as a nuisance. However, evidence is growing that sources of “noise” in the BOLD signal contain clinically relevant information. Keilholz and her colleagues propose to combine a variety of imaging techniques in the rat brain in order to separate the usually discarded portions of BOLD fMRI fluctuations into four components with different spatial and temporal scales. The researchers hypothesize that each component may be affected in a different way by neurological and psychiatric disorders, so that the isolation of these components may improve the diagnosis and evaluation of brain dysfunction.
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.
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.
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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  • Circuit Diagrams
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  • Theory & Data Analysis Tools
  • Integrated Approaches
  • Human Neuroscience
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 to drastically boost photon sensitivity for brain-dedicated PET Levin, Craig S Stanford University 2017 RFA-EB-17-001 Active
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  • Interventional Tools
  • 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.
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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  • Human Neuroscience
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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
  • Cell Type
  • 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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  • Human Neuroscience
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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
  • Monitor Neural Activity
  • Interventional Tools
  • 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 Neuronal Underpinnings of Non-invasive Laminar fMRI Yacoub, Essa University Of Minnesota 2018 RFA-MH-17-235 Active
  • Human Neuroscience
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Understanding the neural circuitry of the brain behind abilities such as perception, decision-making, and language requires high-resolution neuroimaging capabilities that have, thus far, been confined to animal models. This precedent makes it difficult to study uniquely human functions, such as language. Dr. Yacoub and a team of investigators will pair high-resolution functional magnetic resonance imaging (fMRI) with electrophysical recordings within the same participants, enabling the study of different cortical layers and their contributions to cognitive function. By using these cutting-edge techniques to build a reliable and generalizable model of layer-specific neural activity, the researchers will be able to better understand the mechanisms of layer-specific activation within and across brain regions.

Toward a human adult brain cell atlas with single-cell technologies Chun, Jerold Zhang, Kun (contact) University Of California, San Diego 2018 RFA-MH-17-210 Active
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  • Circuit Diagrams
  • Human Neuroscience

Defining a complete cell atlas of the human brain, including a full molecular catalog of all its cell types and their spatial distribution, is a critical step toward understanding the human cognitive machine. Zhang’s team will expand on their previous efforts toward building a complete cell atlas of the whole human adult brain. They will systematically apply novel technologies for scalable, single-nucleus transcriptome sequencing, single-cell DNA accessibility assay, and in situ RNA imaging to MRI-scanned human brains, incorporating innovative computational approaches. If successful, the derived data will facilitate the study of molecular mechanisms underlying brain function and disorders, empowering the scientific community with a massive, readily accessible database of unprecedented scope.

Toward functional molecular neuroimaging using vasoactive probes in human subjects. Jasanoff, Alan Massachusetts Institute Of Technology 2015 RFA-MH-15-200 Complete
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  • Interventional Tools
  • 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 integrated 3D reconstruction of whole human brains at subcellular resolution Chung, Kwanghun Massachusetts Institute Of Technology 2018 RFA-MH-17-210 Active
  • Cell Type
  • Circuit Diagrams
  • Human Neuroscience

Dr. Chung’s team aims to build a three-dimensional proteomic atlas of cells and neural circuits of human brains. To do this, his team plans to develop indestructible and transparent hydrogel-tissue hybrids for multi-rounds of protein labeling and imaging at subcellular resolution. They will stain the tissue via a variety of cellular and molecular labeling techniques and then use automated imaging to visualize different brain cell types, nerve fibers and synapses. The team will also create a supercomputing cloud- based framework and algorithms to analyze petabytes of high-resolution image data. This three- dimensional human brain atlas could give researchers a rapid, low cost way to discover brain cell types and the circuit problems behind neurological and neuropsychiatric disorders.

Transcranial magnetic stimulation with enhanced focality and depth (fdTMS) Peterchev, Angel V Duke University 2017 RFA-MH-17-240 Active
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  • Interventional Tools
  • 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.
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.

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 evoked and resting-state fMRI through multi scale imaging Constable, R. Todd (contact) Crair, Michael Hyder, Dewan Syed Fahmeed Yale University 2016 RFA-MH-16-750 Active
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  • Integrated Approaches
  • Human Neuroscience
For decades, functional MRI (fMRI) has been the most powerful and ubiquitous technique for measuring whole brain activity. However, the biological activity underlying the fMRI signal is unclear. Constable and his team will probe the brain with a novel device that combines high-resolution calcium imaging—a technique that measures a proxy of electrical activity in neurons—across the entire cortex along with fMRI in mice. These measurements will identify the contributions of different cell populations (excitatory, inhibitory, and glial cells) to the fMRI signal. In addition, the team will use cutting-edge tools to knock out specific neural nodes to test the validity of fMRI-generated maps of connectivity between brain regions. This work will provide new insights into the biological basis of fMRI and improve our understanding of the functional organization of the healthy human brain.
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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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.
Understanding the synaptic, cellular and circuit events of MEG & EEG using a vertically translational cross-species approach Doiron, Brent D. Salisbury, Dean F Teichert, Tobias (contact) University Of Pittsburgh At Pittsburgh 2017 RFA-MH-17-235 Active
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  • Integrated Approaches
  • Human Neuroscience
In healthy humans, if an identical auditory stimulus is repeated within 8-12 seconds, electroencephalography/magnetoencephalography (EEG/MEG) measured response to the second occurrence is attenuated. It is unclear how this attenuation is represented at synaptic, single-cell, and circuit levels, or what it reveals about local circuit and network wiring principles. Tobias Teichert’s team will study auditory-evoked response modulation in human, rhesus monkey, and large-scale neural models, testing whether repeated-stimuli response attenuation is caused by synaptic depression at cortical synapses, and whether synaptic depression depends on circuit and network architecture. They will analyze system-level and brain-region-level EEG/MEG, circuit-level local field potentials, single-neuron firing rates, and synaptic function. Because reduced modulation of EEG/MEG amplitude by past stimuli is associated with schizophrenia, understanding the relationship between EEG/MEG and neuronal events could benefit neurological/psychiatric disease research.
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
  • Cell Type
  • Human Neuroscience
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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.

Using fMRI to Measure the Neural-level Signals Underlying Population-level Responses Cowell, Rosemary Alice (contact) Huber, David Ernest University Of Massachusetts Amherst 2017 RFA-MH-17-235 Active
  • Monitor Neural Activity
  • Integrated Approaches
  • Human Neuroscience
In spite of the ability of functional magnetic resonance imaging (fMRI) to relate neural systems to human behaviors, this relationship is indirect because it follows the neurovascular response rather than directly recording the activity of neurons. Rosemary Cowell’s team will develop and validate a technique for using fMRI in humans to determine how neural-level responses modulate with behavior. The group will model how changes in the voxel-level blood oxygenation-level dependent (BOLD) signal reflect changes in neural-level tuning functions. This research will advance the ability to accurately and precisely infer the properties of neuronal signals—associated with changes in perception, attention and cognition—underlying population-level fMRI data.
Vascular Interfaces for Brain Imaging and Stimulation Desimone, Robert Massachusetts Institute Of Technology 2014 RFA-MH-14-217 Complete
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  • 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.
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.
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
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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.

Wireless High-Density Diffuse Optical Tomography for Decoding Brain Activity Culver, Joseph P Washington University 2018 RFA-EB-17-004 Active
  • Human Neuroscience
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  • 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.