(SBIR/STTR) PHS 2003-2-DHHS/NIH-NIMH/Division of Neuroscience and Basic Behavioral Science

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES PHS 2003-2
NATIONAL INSTITUTES OF HEALTH (NIH)
SBIR and STTR GRANT TOPIC(s)
NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH)

For additional information about areas of interest to the NIMH, please visit our home page at http://www.nimh.nih.gov.

Division of Neuroscience and Basic Behavioral Science

Through research in neuroscience and basic behavioral science we can gain an understanding of the fundamental mechanisms underlying thought, emotion, and behavior and an understanding of what goes wrong in the brain in mental illness. Research sponsored by the Division of Neuroscience and Basic Behavioral Science covers a broad range of neuroscience topics: from both experimental and theoretical approaches, from molecules to whole brains to populations of individuals, from single cell organisms to humans, from across the entire lifespan, and from states of health and disease. This division also supports research on the basic behavioral, psychological, and social processes that underlie normal behavioral functioning. The topics listed below reflect the NIMH interest in technologies related to this broad range, but should not be considered to be a complete list. Prospective applicants are strongly encouraged to contact Dr. Michael Huerta (listed below) with questions about the relevance of their interests to the mission of this division.

Cutting-Edge Technologies for Neuroscience Research. Most of the research topics listed after this one are posed from the Division's neuroscience and basic behavioral science mission-oriented perspective, however, the technologies that might be developed to address those mission goals might be quite fundamental. Prospective applicants familiar with such technologies, but not familiar with the mission-related use of these technologies, are strongly encouraged to contact Dr. Michael Huerta (listed below) for assistance in bridging this gap between their technical knowledge and knowledge of the neuroscience-related mission of NIMH. Technologies and approaches that might be used in products relevant to this mission include, but are not limited to:
1. Caged Molecules. These could be activated, or release an active agent, when specified bonds are broken by chemical, biochemical, photic, or other means. Among other uses, such molecules could be used to indicate biochemical or physiological processes or to deliver pharmacologic substances to highly localized brain regions.
2. Genetically Engineered Proteins. Such proteins could be put to any number of uses, including to express a fluorophore or chromophore at the occurrence of specific biochemical processes to report the time and location of such processes in brain tissue.
3. Inducible Gene Expression. Methods to turn on or off expression of particular genes in transgenic animals on the basis of time in the lifespan, location in the brain, or other factors. Such a capability would significantly advance basic brain research, and would have important implications for treatment and therapy of mental illness.
4. Combinatorial Approaches. These are high-through-put approaches that can be used to screen and synthesize molecules that affect brain cells.
5. Biocompatible Biomaterials. Such research and development relates to the chronic use of electrodes and other probes used in brain research, as well as implanted drug delivery devices.
6. Nanotechnologies. This emerging area of technology presents a wide range of opportunities for brain research, from the fabrication of probes to monitor brain physiology to novel means of delivering drugs and other substances.
7. Informatics Tools. Such technologies allow brain scientists, clinicians and theorists to make better sense and use of their data. These tools and approaches include those to acquire, store, visualize, analyze, integrate, synthesize and share data, including those for electronic collaboration.
8. Simulation Technologies. Computer-based simulations of parts of neurons, neurons, circuits or even organisms to observe the manner in which these components interact. For example, simulations of individual organisms with constellations of particular traits that vary across individuals would allow analysis of their interactions and their impact on the population as a whole.
9. Mathematical and Computer Algorithms. Such algorithms could be used to analyze large and/or complex data sets. Among other applications, these could be used to segment images (obtained from electron or light microscopes, or from volumetric imaging instruments such as confocal microscopes and magnetic resonance imagers), filter noise, visualize data or search vast data sets for specified patterns or data (e.g., use of pattern recognition algorithms to search time series data sets obtained from electrophysiological recording of neural activity, or video data obtained from behavioral analysis of genetically altered animals).
10. Telemetry. Transferring data from one point to another is important for neuroscientists monitoring the physiological signals from the brain. Telemetry, even over relatively short distances (from a few millimeters to a few meters), could, for example, provide a means to obtain data from awake, behaving animals without interfering with the behavior of interest.
11. Biosensors. Neurons communicate with each other through thousands of different chemical substances; internally, molecular pathways direct the function of the neuron. Sensors of high specificity and sensitivity for such substances would provide neuroscientists with important new ways to study the brain.
Instrumentation for Basic and Clinical Neuroscience Research. Modern equipment that uses the most recent technological advances is needed in neuroscience research so that neural substrates of mental illness can be identified and localized. The NIMH is interested in supporting research and development of new or improved approaches relevant to, but not limited to, the following:
1. Neurophysiology. Microelectrodes, smart nanoscaffolds, macroelectrodes, biocompatible coatings, interfaces to electronics, software for data analysis, visualization, etc.
2. Cell Sorting. Based on cell size, type, function, etc.
3. In Vivo Electrochemical Voltammetry. More sensitive and selective electrodes, software for data analysis, etc.
4. High Performance Liquid Chromatography. Improved reliability, specificity, sensitivity, etc.
5. Technology to support Multiple Unit Recording Electrode Arrays. Both recording techniques and analysis techniques.
6. Physiological and Behavioral Monitoring. Temperature, activity, sleep duration, neuronal activity, EEG activity, EKG, pulse rate, recording, capture and analysis of multiple single unit activity from microelectrodes.
7. Associated Software.
Macroscopic Neuroimaging. Modern technologies allow for the observation of the structure and function of the intact brain. This capability has the potential to greatly advance understanding of the brain in both health and disease, and across the lifespan. NIMH is interested in advancing this area of technology through enhancing current tools and approaches, as well as developing entirely new ways to image the brain. All modalities are of interest, including, but not limited to: magnetic resonance imaging (MRI) or spectroscopy, positron emission tomography (PET), optical imaging or spectroscopy, single photon emission computed tomography, magnetoencephalography (MEG), diffusion tensor imaging (DTI), etc. Due to its greatly increased use in recent years, technologies specifically focused on improving the utility of fMRI techniques are of particular interest.
1. Innovative agents and/or technologies to visualize brain connectivity in situ with minimal invasion.
2. Improvement in the techniques, the design and construction of devices for non-invasive imaging for any modality, for example, improving spatial resolution, quantitative accuracy, signal-to-noise ratio, and electronics.
3. Development and enhancement of non-invasive imaging techniques for evaluating alterations in brain physiology produced by drugs. These would include techniques for monitoring changes in regional blood flow; concentrations of tissue metabolites; and the distribution and activity of receptors.
4. Synthesis, or isolation from natural products, of highly selective receptor ligands or indicators of neurochemical processes, which would be labeled for imaging by one or more particular modality.
5. New approaches in radiochemistry that will permit more exact identification of the chemical changes associated with behavioral states (e.g., sleep or arousal) or mental illness as observed with any particular neuroimaging modality.
6. Better tools and approaches for producing isotopes and other chemical agents used in neuroimaging.
7. Synthesis of molecules containing stable, rarely occurring isotopes designed to be detected by non-invasive imaging techniques (e.g., fluorine-containing molecules, carbon-13 labeled substrates).
8. Automated interface systems for handling PET radiopharmaceuticals; oxygen-15 and other isotope-based radiopharmaceuticals have limited use because of the difficulty in handling the isotope.
9. Methods and associated products for quantitation of imaging data including new statistical approaches for evaluating the data.
10. Methods to integrate routines for greater and more precise computer enhancement of the images, and for combining or overlaying images obtained from multiple modalities.
11. Software needed for the precise quantitation of data obtained from these imaging techniques with emphasis on the reliable definition of discrete, anatomically distinct areas within the brain.
12. Novel agents or other tools to increase the ability to correlate features of MRI images with histological features (e.g., cytoarchitecture or chemoarchitecture) both identified and those yet to be identified.
13. Generation of physiologic measurements from images of regional radioactivity generated during PET, especially for the study of brain neurotransmitter/neuroreceptor systems.
14. Novel approaches to visualizing data obtained in neuroimaging, such as the computational "unfolding" of three-dimensional images of cerebral cortex.
15. Improved methods for pediatric brain imaging. These would include: software and database products, equipment for creating a "child-friendly" environment and for the behavioral training of children and impaired subjects for cooperation and motion reduction during neuroimaging procedures.
16. Combining of different imaging technologies (e.g., ERPs and fMRI; MEG and fMRI; MEG and EEG, etc).
17. Development of equipment, software and other tools for recording and quantifying eye movements, motion, and autonomic reactivity during scanning, applicable to all ages (including young children), particularly in the MRI environment.
18. Methods for relating changes in brain morphology and and metabolism associated with age, particularly infancy through adolescence, to changes in hemodynamic responses to neural activity and fMRI signals.
Microscopic Neuroimaging. The morphology of individual neurons and the distribution of subcellular components within them, are key to understanding the manner in which these cells function. Advances in the development of agents indicating neuronal structure and function that can be visualized microscopically are important to the NIMH's interest in brain research. This includes enhancements of current agents and ligands to be imaged (agents indicating specific biochemical processes or structures, etc.); development of novel agents and ligands; software to assist interaction with the data; and other related technologies and methods. Examples would include, but not be limited to:
1. Software and hardware for analyzing image data obtained by microscopes, including tools to automatically or semi-automatically. Identify particular profiles (e.g., labeled cell bodies), segment images, reconstruct images into three dimensional representations, perform unbiased counting and measuring, etc.
2. Synthesis and testing of novel or improved probes for microimaging the nervous system.
Molecular and Cellular Neurobiology and Neurochemistry. Manipulating and studying basic molecular, cellular and chemical processes has led to insight to understanding brain function, and has provided the foundation on which pharmacological interventions have been developed for the treatment of mental illness. NIMH is interested in supporting a wide range of new techniques and tools related to this area. These include, but are not limited to:
1. New low-cost techniques for hybridoma production of monoclonal antibodies specific for "neural antigens" (e.g., neurotransmitters, small peptides, neurotransmitter receptors).
2. Innovative methods for establishing a "monoclonal bank" (frozen cells) for each of the cell lines as a permanent, widely available, reliable, and low cost source of monoclonal antibodies for research on the nervous system.
3. Labeled antibodies or other agents that will readily identify receptors for which there are no ligands (orphan receptors) and which have low densities in the brain.
4. Automated methods for quantitating the low levels of bound ligands for quantitating receptors that are sparsely scattered in the brain.
5. New cell lines that express each of the known neurotransmitter receptors so that each cell line will be homogeneous for one receptor.
6. New cell lines that express each of the above receptors linked to some metabolic function and/or second messenger so that the functional consequences of receptor occupancy can be detected.
7. High volume, inexpensive assay methods for measuring both receptor occupancy and cellular response for each of the receptor types.
8. Develop cell culture models for neurons, including methods of purifying homogeneous populations of non-transformed cells by, for example, developing markers to identify neuronal cell types for use in characterizing cell-type-specific signaling pathways which may be useful in tracking the effects of various drugs.
9. Develop techniques for either activating or deactivating specific ion channels, receptors and signal transduction pathways.
10. Develop dynamic biochemical and imaging assays that allow measurement of variables now obtained only through electrophysiological techniques.
11. New approaches to study the multiple functions of particular proteins.
12. Tools to study post-translational changes in proteins in specified tissue compartments.
13. Technologies to study functional entities within cells (e.g., green fluorescent protein approaches).
14. Tools and approaches to study coordinate changes in genes and their functional relationship to phenotypes, including phenotypes associated with specific brain disorders.
15. New ways to assess quantitatively transcription of genes in real time in a manner that is minimally injurious to cells (e.g., non-permeabilizing approaches).
16. Novel tools and approaches to study protein-protein interactions, especially those with phosphoproteins. Further develop methods and reagents for studying the structures of membrane proteins at atomic resolution. Membrane protein systems that are of particular interest to NIMH include proteins involved in normal function and pathology of cells (neurons and glia) in the central and peripheral nervous system.
Genetic and Transgenic Technology. Advances in genetic and transgenic technologies offer many opportunities to probe fundamental questions about the brain, behavior and pathology. NIMH is broadly interested in these areas; some examples of topics relevant to the mission of this Institute include, but are not limited to:
1. Methods to perform site-directed mutagenesis in cell lines for the study of membrane proteins such as ion channels and neurotransmitter receptors.
2. Development of gene "knockout" or "knockin" animals using such approaches as homologous recombination targeting genes important in neurotransmission, development, and tropic interactions as well as in generating behavioral models of disease.
3. New methods to delete or alter targeted genes in the preparation of transgenic animals including methods that increase or decrease gene expression.
4. Development of new techniques and apparatus for delivery of antisense oligonucleotides into cells and specific tissue such as the brain.
5. Develop standardized behavioral tests to assess the gene knockouts and/or gene "knockins" affecting neurotransmission.
6. New approaches for cell-specific, tissue-specific, age-specific, transient gene activation and/or inactivation.
7. Innovative technologies to study gene function and expression.
8. Development of embryonic stem (ES) cell lines from rodent strains (rats and mice) of relevance to behavioral research.
9. Development of technologies and approaches to facilitate the collection and distribution of ES cell lines containing mutations of potential relevance to behavioral research.
10. Develop methods for long-term storage of transgenic germ cell lines.
11. Develop technologies and approaches to aid in the renewal of founder colonies of transgenic mice from repositories of transgenic germ cell lines.
12. Develop databases on neurobiological transgenic animals produced to date, including information such as the origin of the transgenic animal, key features of the biological and behavioral mutant, availability and location of germ cell lines, and existence of breeding colonies.
13. Develop gene transfer technologies such as viral vectors to produce long-term, stable gene expression in the brain.
Neuroimmunology. Research on the interplay between the brain, neuroendocrine system, and, immune system has revealed important links between these major homeostatic system components. Examples of NIMH-relevant topics in this area include, but are not limited to:
1. Development of new tools to explore the special properties of the blood-brain barrier responsible for the selective delivery or retention of cytokines, immune cells, and drugs affecting immune activity in the brain.
2. Development of assays for identifying potential autoimmune components of psychiatric disorders (other than the usual screening for "markers").
3. Identification of critical molecules, processes, and pathways mediating signals from the peripheral immune system to the brain.
4. Development of novel cytokine ligands and antagonists.
Pharmacology. Pharmacological intervention represents a major force in the treatment of mental illness, and NIMH is interested in supporting research and development in this area. Relevant topics include, but are not limited to:
1. New chemical entities with high, selective affinities for each of the receptors in the brain.
2. Methods to evaluate old and new chemical entities (including complex mixtures of crude extracts from natural products) for possible therapeutic usefulness using "in vitro" and "in vivo" assays and model systems.
3. Methods for extraction, fractionalization, and isolation of active compounds from natural products. Water-soluble compounds are of particular interest due to the difficulty of the procedures.
4. Computer algorithms that model receptors to evaluate theoretical permutations of known molecules to find the molecule with the maximum probability of having the highest affinity for a specific receptor as well as those that have the potential for the most desirable "on" and "off" rates.
5. Computer models of the blood brain barrier and evaluate potential and actual drug molecules for their ability to cross or penetrate this barrier.
6. Development of new animal tests/behavior with potential value for evaluating psychotherapeutic properties of drugs.
7. Strategies for evaluating pharmacological agents (e.g., animal behavioral testing, computer simulation) on cognitive function.
8. Behavioral "models" similar in animals and humans; behavioral pharmacological effects that may serve as "surrogate" markers in humans.
9. Development of novel drug delivery systems.
10. Tools for Drug Development including neuroimaging (e.g., radiolabeled compounds) and development of animal models.
11. Pharmacological profiling (in vitro and in vivo) for potential therapeutic drugs.
12. Methods for evaluation of long-term effects of psychotropic drug administration.
13. Improving existing, and developing new, vectors for delivery of genes to the brain.
14. Development of novel therapeutic approaches based on drug-induced changes in gene promoter activity.
15. Development of novel high throughput blood-brain barrier permeability assays.
16. Development of novel molecular targets for drug development to treat mental illnesses.
Tract Tracing Methods and Tools. Little is known about the details of the connectivity of the human nervous system, because the best tract tracing techniques are invasive and require the deposit of substances in vivo. Methods that would be applicable to post-mortem tissue would allow significant progress in connectional studies of human tissue, as well as non-human tissue, particularly with regard to the development of connections and the connections of structures not easily accessed in vivo.
Basic Behavioral Science. It is important to develop reliable methods that can correctly identify the normal and abnormal components of cognitive, emotional, and psychosocial behavior in human development. Computer-based methods of accomplishing this are also needed to increase the accessibility and reliability of information made available to the research community.
1. Methodological Research And Development. There is a need to devise new ways of data collection, analysis, management and dissemination. The goal is to encourage research that will improve the quality and scientific power of data collected in the behavioral and social sciences, relevant to the mission of NIMH. Research that addresses methodology and measurement issues in diverse populations, issues in studying sensitive behaviors, issues of ethics in research, issues related to confidential data and the protection of research subjects, and issues in developing multidisciplinary, multimethod, and multilevel approaches to behavioral and social science research is particularly encouraged.
  1. Improve or create new video devices to monitor animal and human behavior and ease analysis of behavior.
  2. Computer software to ease analysis of behavior monitored by video or telemetry systems.
  3. Innovative computer-based observation techniques, and computer software and hardware that allow on-line methods for characterization of interpersonal interactions in groups.
  4. Low cost microcomputer software for the recording and analysis of patterns and sequences in observed social interactions.
  5. Causal modeling methodology as applied to correlational longitudinal data sets.
  6. A data translation and communication package for collecting, archiving, and making available existing longitudinal behavioral sets to the scientific community for secondary or meta-analyses.
  7. Flexible user-friendly software for control of timed, multi-modal stimulus presentation and response collection for experiments on perception and cognition.
  8. There is a need for the development of hardware for time-stamped diary collecting instruments for use in actigraph studies of circadian rhythms in children and adolescents. Diaries are critical for the evaluation of activity data, and time-stamped diary collecting instruments can ensure investigators of receiving reliable information.
  9. Web-based software tools for designing, updating, sharing, linking, and searching databases containing detailed information about the methodology and results of behavioral science studies.
2. Diagnosis and assessment of emotional and psychological states such as automated methods to detect specific emotional states using behavioral and autonomic indicators.
3. Instrumentation and equipment that uses the most recent technological advances is needed so that mental disease can be related to dysfunction(s) of the CNS. Once these dysfunctions are identified and localized, rational therapies can be developed and evaluated.
  1. Physiological Monitoring. Techniques and equipment for continuous monitoring of physiological data (e.g., temperature, activity, sleep duration, EEG activity, ECG, pulse rate). Computer programs that can record, catalog, categorize and identify interrelationships between several of the above measures. Appropriate areas for behavioral clinical research would include developing:
    1. Reliable non-invasive means of chronic monitoring of physical activity and physiological measures such as body temperature.
    2. New techniques for electrophysiological images from the level of the single cell and surface EEG recording on the scalp.
    3. Small, portable automated systems to monitor eye function (e.g., pupil size, accommodation) and eye movements.
    4. Software and hardware analyzing and providing experimental control over multiple single unit recordings, on-line and in real-time.
  2. Measurements of Infant Development Using Physiological and Behavioral Measures.
    1. Psychophysiological measures to evaluate infants during the first six months of life.
    2. Miniaturized non-invasive instruments to record psychophysiological data (e.g., heart and respiration rate, galvanic skin response, and defensive motor behavior).
    3. Telemetry capability for non-invasive devices so that infants can be monitored for prolonged periods without interfering with their behavior.
    4. Computer programs and inexpensive computers that will collect, analyze and identify recurring patterns in the psychophysiological measure(s) of interest.
  3. Behavior Monitoring and Analysis.
Educational Tools. Neuroscience and basic behavioral science area compelling areas of science that not only touches upon a diverse array of disciplines, but also provides insights to the essence of what it is to be human. Products aimed at teaching the substance of these fields to students of all ages would be useful in disseminating this information and these insights. Examples include, but are not limited to: software and other interactive media used to convey fundamental concepts about the brain to children; computer simulations of neuroscience experiments; updateable media that presents state-of-the-art information on particular topics for use by experts; website or other online, interactive electronic vehicle to allow for sharing of information about the brain and its functions, including technologies for holding interactive research conferences related to basic behavioral sciences, basic neuroscience, or clinical neuroscience.
Neuroinformatics. Data generated by brain research are diverse, vast, and complex. The diversity of data is due to the fact that neuroscience data are obtained from: theoretical, experimental and clinical approaches; from levels of biological organization that span molecules to populations of individuals and from single-cell organisms to humans; and from states of health, disease, and models of disease. The quantity of data in brain research is the result of tens of thousands of neuroscience laboratories working around the world. The complexity of data reflects the high level of interconnectedness of the data, and their high dimensionality. Neuroinformatics is a new area of science that draws upon neuroscience, information science, computer science, statistics, applied mathematics, and a variety of engineering fields to develop tools that will let neuroscientists make better sense and use of their data. These tools include software and hardware for digital data acquisition, visualization, analysis, integration, and sharing (e.g., through tools for electronic scientific collaboration). Such tools can address data of any type or from any area of neuroscience; examples include, but are not limited to:
1. Databases, querying approaches, and information retrieval tools for neuroscience and neuroscience-related data.
2. Tools for neuroscience data visualization (and other forms of presentation) and manipulation (probabilistic atlases of brain structure or function, new statistical approaches for analyzing data, etc.).
3. Software for integration and synthesis of neuroscience data (computational models of neurons to integrate data about structure and function, environments to merge data from multiple imaging modalities, etc.).
4. Tools for electronic collaboration to allow neuroscientists to interact with colleagues, data, and instruments at a distance (this could include novel types of "groupware", etc.).
5. Tools that bridge existing neuroscience and biology information tools and resources, such as databases and informatics tools associated with genome mapping efforts.

For further information on basic and clinical neuroscience or basic behavioral science research topics, contact:

Margaret Grabb, Ph.D.
Chief, SBIR/STTR Program
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
6001 Executive Blvd. Room 7201
Mail Stop Code 9645
Bethesda, MD 20892 or
Rockville, MD (for Overnight/Courier)
, Fax:
Email:

Division of Neuroscience and Basic Behavioral Science

Other Research Topic(s) Within Mission of the Institute