6

The Brain Mapping Initiative: Committee Conclusions and Recommendations

An environment of opportunity now exists to enhance neuroscience by a more global incorporation of computer and information technologies into the research enterprise. Yet it is also apparent from the experiences of other scientific disciplines, including the gene mapping community, that to ensure the greatest benefit, these technologies must be incorporated with care and with a clear vision of the intended goal. When such efforts are successfully realized, the benefit can be a great increase in our understanding of normal and pathological processes in biology. As in all biomedical research, increased knowledge and understanding lead to improvements in human health.

The Long-Range Goal

Neuroscience is immensely diverse in its methodology and levels of inquiry. To achieve true understanding, this diverse information must be coordinated into a meaningful picture. The burden of this coordination rests on individual neuroscientists, who necessarily spend the majority of their time investigating the many highly specific processes of the brain. Placing those detailed, specific data into the larger context of the multiple levels of brain organization and of all other relevant information is almost impossible—for several reasons. Neuroscience, like many other scientific fields, is divided into a range of specialties. The diversity of research methods generated by such specialization makes it unlikely that any one individual can achieve sufficient expertise in every method to allow for a learned interpreta-



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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH 6 The Brain Mapping Initiative: Committee Conclusions and Recommendations An environment of opportunity now exists to enhance neuroscience by a more global incorporation of computer and information technologies into the research enterprise. Yet it is also apparent from the experiences of other scientific disciplines, including the gene mapping community, that to ensure the greatest benefit, these technologies must be incorporated with care and with a clear vision of the intended goal. When such efforts are successfully realized, the benefit can be a great increase in our understanding of normal and pathological processes in biology. As in all biomedical research, increased knowledge and understanding lead to improvements in human health. The Long-Range Goal Neuroscience is immensely diverse in its methodology and levels of inquiry. To achieve true understanding, this diverse information must be coordinated into a meaningful picture. The burden of this coordination rests on individual neuroscientists, who necessarily spend the majority of their time investigating the many highly specific processes of the brain. Placing those detailed, specific data into the larger context of the multiple levels of brain organization and of all other relevant information is almost impossible—for several reasons. Neuroscience, like many other scientific fields, is divided into a range of specialties. The diversity of research methods generated by such specialization makes it unlikely that any one individual can achieve sufficient expertise in every method to allow for a learned interpreta-

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH tion of every reported finding in neuroscience. More important, the mass of detailed information being generated at every level of neural organization is impossible to grasp with conventional means. The investigator seeking information at even a single hierarchical level or in regard to a specific neurobiological mechanism is often daunted by how widely scattered that information may be throughout scores of different journals, review papers, symposia summaries, and books. Computer and information sciences have made impressive advances in the past decade. The development of database technology has given all fields of science new ways of organizing and retrieving data, and research into even more sophisticated database designs is beginning to bear fruit. Emerging object-oriented database technology, for example, will permit improved manipulation and exchange of electronic images, it is hoped, by the end of this decade. Such an advance is of particular importance to neuroscience, characterized by many as a “visual science.” Graphic imaging is another area of computer science that has grown rapidly to a high level of sophistication. Generation of two-and three-dimensional graphic images is becoming fast and simple, and the ability to interact with such images has endowed researchers with a high degree of flexibility in the use of these images. The combination of high-quality graphics capabilities and powerful data collection and analysis workstations promises to be an unprecedented resource for neuroscientists. It is already the case that substantial amounts of neuroscience data are collected and analyzed using a variety of computers and workstations, which run many different software programs and employ a wealth of utilities and tools. Further, the infrastructure is now under construction to link these and other, more highly developed computerized research environments through high-speed computer networks capable of transmitting text and image data in reasonable time frames. The capabilities afforded by the recent advances in computer science now provide the opportunity to put into context the explosion of information on the brain, its circuitry, and its functions. Therefore, the committee recommends that the Brain Mapping Initiative be established with the long-term objective of developing three-dimensional computerized maps and models of the structure, functions, connectivity, pharmacology, and molecular biology of human, rat, and monkey brains1 across developmental stages and reflecting both normal and disease states. The committee envisions this objective to be accomplished in two

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH phases, beginning with phase 1 pilot projects, which will provide an experience base for the fulfillment of phase 2. The maps and models noted above would constitute a Brain Mapping Initiative, but the committee's vision has a broader scope: not a single-entity database but a complex of interrelated, integrated databases accessible from individual laboratories. This resource would also incorporate additional tools and utilities that would allow users to interact with the data to form new associations, achieve nonstandard structural views, or otherwise change the data presentation parameters to test new hypotheses or obtain replication of specific experimental data in other systems, regions, states, or species. The committee recognizes the enormity of such an undertaking and that its successful implementation will require a transformation in the way information is acquired, communicated, and analyzed by neuroscientists. The committee views this endeavor as a long-term project to be accomplished in two phases. Phase 1 would comprise the organized initiation of seed or pilot projects with the overall goal of gaining experience in the incorporation of the required technologies and applying that experience to the long-range planning of phase 2. In addition, pilot projects would bring focus and utility to information technology research in areas useful to neuroscience research. Phase 2 would be the construction of a complete family of maps and models—all the elements necessary to provide a complex of electronic resources to enhance neuroscience research. Despite the broad scope and difficulty of such an effort, a number of reasons argue for initiating the project at this time. Aspects of the technological applications are, in fact, already being developed in a number of scattered prototype projects in individual neuroscience laboratories. These include prototype databases and three-dimensional reconstructions of brain structures and cells. Exchange of digital data files and data format standards is also evolving among certain neuroscientists from various subspecialties. To ensure the coordinated establishment of an integrated group of resources useful to the entire neuroscience community, however, the committee believes it is critical to plan the implementation fully and with great care. This planning should be based on experience with, for example, the use and development of standard data formats, methods of handling different kinds of data, methods of oversight and evaluation, and approaches to quality control and data security. In addition, this planning and the initial implementation steps should be managed and coordinated from the outset in a manner that facilitates cross-fertilization of ideas and openness to emerging technologies. Such coordination will further ensure the greatest general benefit and efficient use of fiscal

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH resources through planned integration of a variety of databases and other digital resources. Phase 1: Implementation Phase 1 projects will be the first step in approaching the challenge To achieve the long-range goals noted above, the committee formulated a number of other recommendations, the first of which relates to the initiation of phase 1. The committee recommends the establishment of pilot projects or consortia. These projects should be peer-reviewed by neuroscientists and computer scientists; they should also be investigator initiated, involve geographically dispersed laboratories, and include neuroscientists with varied levels of computer experience. The projects should develop common formats for the exchange of data and focus on different types of computer data representations (geometric, structural, image, and free text). Selection of projects should be on the basis of research quality and value to the evolution of a complex of computerized resources for mapping the brain. The phase 1 projects are intended to form a base of experience and provide the necessary infrastructure for the successful development of phase 2 of the Brain Mapping Initiative—a comprehensive brain mapping effort. Each pilot project would be a consortium of several (three to six) research groups with the primary goals of mapping brain anatomy, chemistry, and functions and forging the pathways for the integration of computer and information technology into the overall neuroscience research effort. Consortia could be organized among geographically distinct institutions or as centers housed within a single institution. If the centers approach were to be adopted, special attention should be given to involving investigators from geographically distant institutions as users of the resources being developed. Although the phase 1 projects should be individually organized around specific research interests, as a whole they should represent the diversity of neuroscience questions. (That is, the organization should include both basic and clinical neuroscientific groups.) In addition, research topics should reflect the vertical hierarchy of the brain, from behavior to cells or molecules, as well as the horizontal range of inquiry, from physiological to anatomical to chemical approaches. Finally, close collaboration with computer scientists will also be necessary. Beyond these general goals, many specific issues should

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH be addressed by the phase 1 projects, including kinds of databases, the scope of the data to be included, sociological issues, and architectural and technical requirements. These issues were discussed during task force meetings and open hearings and are summarized in Chapter 5. The kinds of databases to be explored will vary because of the broad range of information that is useful to working scientists. For example, published reports from journals are a primary source of scientific data, but other, informal interactions, including scientific meetings and individual discussions, often provide scientists with deeper understanding. The databases developed for the neuroscience field should attempt to include both kinds of information. Phase 1 projects could investigate the usefulness of the following kinds of databases: reference databases, data banks, informal databases, international registries and directories, research collaboration databases, and specialty databases (see Chapter 5 ). Each of these database forms needs to be thoroughly investigated by phase 1 projects; however, certain resources should be implemented immediately. The committee recognizes that neuroscience efforts proceed internationally and recommends that an international registry of neuroscience databases and contacts be established so that appropriate linkages can be created in the future. Such a registry, which should be available through computer networks, would help to identify what resources are currently available and also provide a mechanism by which efforts could be coordinated. Further, it would enable current investigators to develop interaction with others with whom data collection strategies, design problems and solutions, and other related issues could be discussed. It is expected that such a registry would initially contain very few groups or databases but that it would grow as the phase 1 projects proceeded. The committee recommends the establishment of an archive of public domain software, accessible through computer networks. The committee expects that phase 1 projects will have special needs for novel software. Public domain software is available at little or no cost to anyone who wants to use it, and these programs should be explored. In addition, such an archive would encourage the formation of neuroscience “news groups,” or groups of users with similar interests, who could communicate by computer bulletin boards or electronic mail. The scope of the data to be included in phase 1 projects must be

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH broad to be genuinely useful to neuroscience research, both immediately and eventually for phase 2. Although some kinds of data have universal applicability to all branches of neuroscience, other kinds are necessary only for specialized groups of investigators. In addition, the range of data covered should include normal and pathological states; it should also reflect changes that occur during development and aging. In many respects, the kinds of data to be included are relatively easy to define. The incorporation of diverse types into a unified whole, however, will present a sizable challenge to phase 1 investigators and managers. There was consensus among the task forces and support from the wider neuroscience community that anatomical data were the key data element and might well serve as the “backbone” with which other data types can be associated (see Chapter 5 ). An analogy can be made that basic brain anatomical maps or atlases are similar to LANDSAT images. Detailed information, such as precise connections, neurochemistry, cell types, and physiological response properties, can all be mapped onto those basic images in much the same way roads and other landmarks can be mapped onto LANDSAT images (Downs et al., 1990). Moreover, the level of resolution can change in both LANDSAT and brain images: it can be adjusted up or down depending on the sensitivity of the “sensors” employed. Thus, the location of pyramidal cells in a particular cortical area could be mapped from medium-magnification light microscopic examination. From higher level magnification (light or electron microscope), the differential location of neurotransmitter substances or receptors could be mapped onto a three-dimensional reconstruction of the pyramidal cell. At yet a higher level, using sensitive electrophysiological sensors, the differential locations of ion channels could be mapped. Such maps, which are prepared now largely by hand, are important contributions to the construction of computational models of neuronal function. As outlined in Chapter 5 , sociological issues present some of the most vexing problems in establishing any database or implementing any large-scale initiative. Such matters are intimately joined with how people work on a daily basis, the traditions they hold, and, often more important, how they are invested personally in their work. Understandable sensitivity exists in such areas, and careful attention to these issues is necessary for those involved with the development and planning of electronic resources. Including investigators with different levels of computer expertise in phase 1 projects will facilitate greater acceptance of computer technology by emphasizing the varied needs of the neuroscience community and opening important channels of communication. In terms of data-

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH sharing, the committee assigns no value judgment to either end of the continuum of possible actions; that a continuum exists, however, must be recognized and dealt with. The priority that phase 1 projects place on establishing collaborative groups will dictate that attention be paid to data-sharing mechanisms. As part of this effort, phase 1 projects should explore methods to ensure that preliminary data are clearly labeled and that proper credit will be given to those who contribute data for sharing. The committee also encourages examination of the effects of policies already in place—those developed by the journals devoted to gene mapping and protein and gene sequencing —that require data deposit as a condition of publication. In addition, the committee supports the concept that university tenure committees should begin to consider which kinds of data sharing should be viewed as evidence of professional competence, comparable to journal publication and teaching evaluations. If electronic resources are to be accepted and utilized, scientists must trust the accuracy of the information contained within the resource. Therefore, phase 1 projects must begin to find ways to ensure such accuracy, especially of information included in reference databases, data banks, and registries. Mechanisms are needed to ensure the appropriate use of different levels of data and to permit the deletion of information that becomes obsolete. Such mechanisms may include management of the database by an editor (or group of editors) who is an expert in the field and whose function would be analogous to that of a journal editor. Another important sociological issue facing phase 1 projects is the acceptance of standards for data representation, data entry, nomenclature, and methods of data annotation. Currently accepted methods of representing data lack the level of precision required for coordinated computer resources. The committee thus agrees with the views of task force and other study participants that such standards are needed but that they should evolve from experience and should be based on the needs of users, rather than imposed from some outside source. In terms of the proposed complex's technical and architectural requirements, definition and specification are impossible in the absence of a concerted, hands-on effort to construct a usable computer resource. The committee received valuable advice from its members, from task force participants, and from other experts with experience in these kinds of efforts (see Chapter 5 ), and this advice is encompassed in a general framework in four areas that should be explored by phase 1 investigators. Database management technology is the first: in database planning, phase 1 investigators are encouraged to seek input from such resources as the National Center for Biotechnol-

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH ogy Information at the National Library of Medicine and from national supercomputing centers, including the National Center for Super-computing Applications and the Ohio and Pittsburgh Supercomputing Centers. Particularly desirable is the involvement of established, successful university programs in biomedical computing research. Computer networks are the second technical requirement area to be considered. The future of national and international computer networks is particularly promising for the development of a brain mapping effort. The committee strongly endorses international expansion of Internet, implementation of the proposed National Research and Education Network, and the upgrades planned for existing wide area network infrastructures, such as NSFNET. Phase 1 projects should keep abreast of the developments in network capabilities and remain aware of the policies that underlie concomitant upgrades of university-controlled local area networks. Compatibility of computer hardware and operating systems is the third area for consideration in the architectural and technical requirements for a brain mapping effort. It will be important to identify the operating systems that neuroscientists use and to develop software that runs on various kinds of systems. Another approach to compatibility is the design of data interchange formats that allow for translation from one software program to another. These and other approaches should be explored; however, care should be taken not to limit compatibility by limiting access. A balance should be struck between advanced access mechanisms, such as high-speed networks, and more traditional mechanisms, such as telephone-based connections among personal computers. In addition, different kinds of data storage options should be explored. Finally, there are technical issues relating to the development of standards, as well as the sociological issues mentioned in the previous section. The identification of effective standards should be an early priority for phase 1 projects because the initial design of databases and communication protocols must take such standards into consideration. In this area, the committee encourages interaction between phase 1 investigators and the Internet Activities Board's Engineering Task Force, which conducts specific development projects for network data transmission. The committee also suggests cooperation with the National Information Standards Organization (NISO), which is responsible for the development of standards for library applications. Phase 1 projects should be centrally organized For phase 1 projects to provide the proper basis for the develop-

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH ment of a coordinated brain mapping effort, communication among the consortia and some type of central oversight are needed. The committee recommends that an administrative structure be established to coordinate phase 1 activities. This Brain Map Advisory Panel (BMAP) should be composed of neuroscientists and computer and information scientists, with additional input from funding agency administrators. The panel would be responsible for the overall direction, evaluation, and coordination of consortia and for the development of necessary policies relating to establishment of a brain mapping effort. The committee also recommends that the Advisory Panel be responsible for consideration and development of editorial functions and policies relating to the ethical and sociological issues that will arise, including, but not limited to, correctness of information and quality control, intellectual property rights, rights to privacy, and freedom of information. The panel could also coordinate action by funding agencies and other, related scientific initiatives. Finally, the panel would undertake the long-range planning of phase 2. As described earlier, the issues confronting the phase 1 projects are many and diverse, ranging from sociological to highly technical areas. Each of the consortia will need the kind of central clearinghouse for information that the proposed panel can provide. For example, the panel can examine various approaches to database design and weigh the outcomes against the scientific needs of both specialized groups and the neuroscience community as a whole. Of particular value to the coordinating function of the BMAP would be to establish contacts with other groups, including the astrophysics, earth mapping, and global change research communities, to share information and discuss common issues. An additional resource might be the Telescience Testbed Program of the National Aeronautics and Space Administration. The panel can also collate measures of the actual use of developing resources and of successful incentives for data sharing from among the various consortia to obtain a clear picture of what works and what does not. In addition, the panel could gather information from the consortia about emerging trends in the computer industry that might affect the development of phase 2, suggest more efficient datahandling methods, or facilitate more effective communication protocols. Mechanisms for integrating the developing technologies into the work practices of neuroscientists will be another area of the panel's

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH concern. Providing quality service, education, and training is essential for the sharing and effective use of research data. The panel's role in phase 1 should be to develop an infrastructure to provide these components. Appropriate services would include reliable access, distribution of data through a variety of means, and documentation of database contents. In addition, consulting support for local problems will be needed. Phase 2 efforts will also require several kinds of training at diverse sites and the development of training materials. Inclusion of panels and demonstrations at relevant scientific meetings should be explored as options. The construction of a dynamic infrastructure will promote strong interaction among development, service, and educational activities that will significantly increase the usefulness of the resource. The oversight provided by the panel should not occur in a completely “top-down” manner because such an approach could isolate the consortia from each other and slow the transfer of important findings and developments. Mechanisms should be found for organized cross-communication among the consortia and the panel. One way to accomplish this communication would be to include representatives from each consortium on the panel. Another mechanism that deserves serious consideration is to hold regular meetings of consortia investigators. Such an approach has been successful for certain genome databases. For example, the principal investigators from each consortium could meet semiannually or quarterly to present their work and identify the advances made and the barriers encountered. The meetings thus would provide the opportunity to validate data, assess needs and progress, and coordinate the exchange of software, protocols, and operational methods. They might also be used as a vehicle to obtain input from experts in neuroscience, computer science, or industry who are not involved in the phase 1 projects or on the panel but who have special skills that can be brought to bear on particular problems and issues. The panel could also participate in these meetings to offer input, receive requests for needed action, and provide a record of the proceedings. Another responsibility of the panel would be to coordinate the establishment of the international registry of neuroscience databases and contacts, and the archive of public domain software that the committee has recommended be established. In addition, the coordination of phase 1 projects with other national and international efforts is extremely important. Therefore, the committee recommends that the phase 1 and 2 projects of the Brain Mapping Initiative maintain a close relationship with the gene mapping and sequencing community and

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH the Human Genome Project, and with other scientific computing efforts, including network initiatives such as NSFNET and the proposed National Research and Education Network. As part of these efforts, the committee further recommends that linkages be established with protein sequence and genome databases to enhance access to information about brain-specific genes. Phase 1 projects will require additional funding Special challenges related to funding confront the implementation of the phase 1 projects. The first is to determine a basic funding approach. There are three ways in which federal dollars are provided for biomedical research. One is by a contract mechanism in which a government agency funds projects that it proposes, which are completed by an outside investigator according to a contract written by the government agency. The government agencies then oversee and supervise such projects. Contract mechanisms are often used by the Department of Defense to fund research, but they represent a much smaller portion of the funding provided by NIH and ADAMHA for biomedical research (ADAMHA, 1988; National Institutes of Health, 1989). The other mechanism, which is more typical of ADAMHA, NIH, and NSF funding, is that of grants to investigators or groups of investigators for research projects that are proposed, accomplished, and supervised by the investigators themselves (investigator-initiated). The third funding mechanism, cooperative agreements involving researchers and their universities, is currently used by the NSF for some projects and functions like a combination grant/contract. The committee received a great deal of input about the relative merits of these mechanisms, especially regarding grants versus contracts. Generally, it favors the use of grant mechanisms and cooperative agreements for funding the proposed initiative. This judgment is based on the committee's belief that the development of usable resources should be intricately combined with the research itself, and this dual task can best be done by scientists actively involved in the research. The limited use of contracts, however, may confer advantages during some aspects of phase 1 activities. Therefore, the committee recommends that federal funding agencies develop requests for applications and/or cooperative agreements to support the formation of consortia and the activities of the Brain Map Advisory Panel. Limited use of contract mechanisms should also be considered when appropriate to the overall goals of the initiative.

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH The second challenge is the fact that the proposed phase 1 organization is not typical of the current administrative or funding structures employed by the federal agencies responsible for the biomedical sciences. The typical structure of NIH and ADAMHA funding is that individual institutes provide funding for individual grants (R01s) or program project grants (P01s) for specific research projects related to the institute's overall research program goals. Review of such grants on the basis of scientific merit is accomplished either through the NIH Division of Research Grants' study sections or through an individual institute's scientific review groups. The proposed oversight panel and consortia, each consisting of groups of investigators (similar to program project groups), constitute a structure the committee considers essential to the success of the Brain Mapping Initiative. Such a structure, however, will require flexibility in the typical biomedical funding mechanisms noted above and cooperation among different agencies. The committee is not recommending a reorganization of the federal biomedical research complex; nevertheless, it sees a critical need for greater communication and cooperation among the components of the complex. Further, this communication and cooperation might be extended to include agencies outside the Public Health Service, such as the Departments of Defense and Energy, as well as private agencies, foundations, and universities that provide resources for biomedical science. To this end, the committee recommends that phases 1 and 2 of the Brain Mapping Initiative be international in scope and that they be funded by multiple sources in a coordinated fashion. The structure for administering the funding should ensure program stability and effectiveness. Possible funding structures include the identification of a lead agency or institute, or the establishment of formal administrative structures among two or more agencies. The committee is also sensitive to the current fiscal restraints on the entire U.S. biomedical research effort (National Academy of Sciences and Institute of Medicine, 1990; Lederman, 1991). Given this reality, there is understandable concern among scientists that large initiatives pose a threat to the survival or health of individual investigator-based research. In the case of the Brain Mapping Initiative, these fears are unfounded. The project proposed here would constitute a very small part of the entire neuroscience research effort. Moreover, the history of neuroscience abounds with examples of how technological advances have provided the tools with which major discover-

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH ies have been made, discoveries that have led directly to significant reductions in human suffering. Incorporation of computer science and information technology, to their full potential, into neuroscience research represents a technological advance that will be analogous to, and may even rival, the development of the oscilloscope and the electron microscope. It is important to reiterate that these proposals are aimed toward coordinating what would be widely separated activities into a unified effort. Only an effort of this kind can provide the kind of coordination and careful planning for the future that uses scarce resources efficiently and effectively and ensures greater use of the emerging technology by the neuroscience community as a whole. Therefore, the committee concludes that the expected benefits of the proposed Brain Mapping Initiative justify the investment of necessary resources and recommends the appropriation of additional funding to support the establishment of phase 1 projects. Phase 1 projects will require a certain amount of time and support Five years is the minimum time that should be allowed for phase 1 projects to reach the level of expertise and technological development necessary to initiate phase 2. Further, as phase 2 is initiated, the phase 1 projects should be kept in place—for a period of time to be determined by the Advisory Panel—and, possibly, phased out gradually as phase 2 begins or simply incorporated into the larger initiative. The budget for phase 1 can be estimated at $10 million per year, with an expected duration of five years. This amount is based on establishing five consortia groups, each with a $2 million-per-year funding level. The $2 million would be distributed among consortia participants; thus, individual funding levels could range from $200,000 to $400,000 annually. This funding would be used to cover the costs of investigator research support, computer systems, software and software development, establishment of necessary local area networks, and travel for consortia participants. The Advisory Panel would also require support from these funds to cover travel and administrative costs. Phase 2: Long-Term Integration and Its Potential Benefits The brain presents some of the most fascinating, complex questions in biological science. Neuroscience has amassed a substantial body of knowledge about the structures of the brain and their specific functions, but in many ways this mass of knowledge is only a begin-

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH ning. It is now time to fit the millions of pieces of the puzzle into place and bring neuroscience to a point at which it can begin to alter the course of many diseases and disabilities. The proposed Brain Mapping Initiative will allow investigators studying the brain to view data in new ways, to share data with each other, and to access needed data from any of the neuroscience subspecialties. So enabled, neuroscientists will map the brain and its functions to a degree only faintly imaginable even 20 years ago. The brain map that is thus generated can be reasonably expected to contribute greatly to the improvement of human health and the alleviation of some of the most mysterious and intractable of human diseases. Our society faces an already large and still growing burden from diseases that affect the brain. Many of these diseases are multifactorial, making them difficult to understand and difficult to treat. For example, addiction to cocaine and other drugs has reached epidemic proportions (Gerstein and Harwood, 1990). Understanding the receptor systems of the brain that mediate these drugs' effects and the brain regions that are affected is critical to achieve the kind of useful treatments that have eluded us for years. But the problem becomes exceedingly more difficult if the secondary effects of drug abuse are considered. A 1988 national household survey conducted by the Research Triangle Institute and the National Institute on Drug Abuse indicated that about 9.3 million women in high-fertility age brackets (15–35 years) had used an illicit drug at least once in the year previous to the survey. With the overall expected birth rate for a group in this age bracket taken into account, these figures suggest a probable range of 350,000 to 625,000 annual fetal exposures to one or more episodes of maternal drug consumption (Gerstein and Harwood, 1990; U.S. General Accounting Office, 1990). Not only are many of these babies born addicted to drugs, but the development of their brains has been altered, leading to attention deficits and learning disabilities, among other problems. We need desperately to understand and treat drug addiction, but we also need to understand and treat or prevent the developmental deficits it causes. The pressure to accomplish these goals is increasing rapidly. In another five years, the drug-damaged children born this year will be entering the school systems of many large cities in the United States. These schools will also be dealing with other children who have been neurologically damaged—as a result of malnutrition, lead poisoning, lack of adequate maternal prenatal care, and untreated childhood diseases (Institute of Medicine, 1989). The resulting toll on our precious human resources is obvious. Every year, half a million children and adults experience brain and spinal cord injuries (National Advisory Neurological and Communi-

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH cative Disorders and Stroke Council, 1989). Most often, these injuries lead to paralysis and lifelong disabilities. The mass of neuroscience research conducted to date has brought us to the threshold of being able to prevent the devastating effects of these injuries, but traversing that threshold will depend on the discoveries to be made in the next decade. The same conditions apply to the treatment and prevention of Alzheimer's disease. In the previous decade, we identified some of the locations of damage caused by this disease, documented some of the biochemical processes that are associated with that damage, and tested a variety of pharmacological agents for their ability to slow the disease process. Yet here again, we merely stand at the threshold. It is enlightening to remember that virtually every system of the body is affected by brain activity either through the central nervous system or the peripheral nerves that constitute the sensory systems and the autonomic nervous system. Thus, the study of neuroscience has the potential to contribute to the development of treatments for many diseases that are typically not considered neurological —for example, certain endocrine disorders, cardiac arrhythmias, and gastric ulcers. In addition, many systemic disease processes result in neurological problems that often have a metabolic basis but that are not completely understood. Examples of these problems include the chronic pain and nerve disorders that result from diabetes and the mental retardation caused by thyroid insufficiency. An excellent climate of opportunity currently prevails to expand our knowledge of brain functioning during the coming decade. Seizing this opportunity, however, requires a concerted, interdisciplinary effort on the part of basic and clinical neuroscientists worldwide. It is becoming clear that the scientific enterprise in general relies increasingly on the use of sophisticated methodologies and computer technologies. This committee has considered how the full potential of computer technologies in neuroscience research can be realized. It strongly believes that realization of this potential through the establishment of the Brain Mapping Initiative is essential to ensure the greatest benefit to society from neuroscience research. Summary of Recommendations The committee recommends that the Brain Mapping Initiative be established with the long-term objective of developing three-dimensional computerized maps and models of the structure, functions, connectivity, pharmacology, and molecular biology of human, rat, and monkey brains across developmental stages and reflecting both normal and disease states. The committee envisions this objective to

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH be accomplished in two phases, beginning with phase 1 pilot projects, which will provide an experience base for the fulfillment of phase 2. The committee recommends the establishment of pilot projects or consortia. These projects should be peer-reviewed by neuroscientists and computer scientists; they should also be investigator initiated, involve geographically dispersed laboratories, and include neuroscientists with varied levels of computer experience. The projects should develop common formats for the exchange of data and focus on dif-ferent types of computer data representations (geometric, structural, image, and free text). Selection of projects should be on the basis of research quality and value to the evolution of a complex of electronic resources for mapping the brain. The committee recognizes that neuroscience efforts proceed internationally and recommends that an international registry of neuroscience databases and contacts be established so that appropriate linkages can be created in the future. The committee recommends the establishment of an archive of public domain software, accessible through computer networks. The committee recommends that an administrative structure be established to coordinate phase 1 activities. This Brain Map Advisory Panel (BMAP) should be composed of neuroscientists and computer and information scientists, with additional input from funding agency administrators. The panel would be responsible for the overall direction, evaluation, and coordination of consortia and for the development of necessary policies relating to establishment of a brain mapping effort. The committee also recommends that the Advisory Panel be responsible for consideration and development of editorial functions and policies relating to the ethical and sociological issues that will arise, including, but not limited to, correctness of information and quality control, intellectual property rights, rights to privacy, and freedom of information. The committee recommends that the phase 1 and 2 projects of the Brain Mapping Initiative maintain a close relationship with the gene mapping and sequencing community and the Human Genome Project, and with other scientific computing efforts, including network initiatives such as NSFNET and the proposed National Research and Education Network. As part of these efforts, the committee further recommends that linkages be established with protein sequence and genome databases to enhance access to information about brain-specific genes. The committee recommends that federal funding agencies develop requests for applications and/or cooperative agreements to support the formation of consortia and the activities of the Brain

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MAPPING THE BRAIN AND ITS FUNCTIONS: INTEGRATING ENABLING TECHNOLOGIES INTO NEUROSCIENCE RESEARCH Map Advisory Panel. Limited use of contract mechanisms should also be considered when appropriate to the overall goals of the initiative. The committee recommends that phases 1 and 2 of the Brain Mapping Initiative be international in scope and that they be funded by multiple sources in a coordinated fashion. The structure for administering the funding should ensure program stability and effectiveness. Possible funding structures include the identification of a lead agency or institute, or the establishment of formal administrative structures among two or more agencies. The committee concludes that the expected benefits of the proposed Brain Mapping Initiative justify the investment of necessary resources and recommends the appropriation of additional funding to support the establishment of phase 1 projects. References Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA). 1988. ADAMHA Funding Mechanisms for Grants and Awards. Rockville, Md. : U.S. Department of Health and Human Services. Downs, A., B. Waxman, and C. Pechura. 1990. Technological Implications of Cartography and Remote Sensing for a National Neural Circuitry Database. Background paper prepared for the Committee on a National Neural Circuitry Database, Institute of Medicine. Gerstein, D. R., and H. J. Harwood, eds. 1990 . Treating Drug Problems, vol. 1. Washington, D.C. : National Academy Press Institute of Medicine. 1989. Research on Children and Adolescents with Mental, Behavioral, and Developmental Disorders: Mobilizing a National Initiative. Washington, D.C. : National Academy Press. Lederman, L. M. 1991. Science: The End of the Frontier? Science 251(Jan. 11, insert) : 1-19. National Academy of Sciences and Institute of Medicine. 1990. Forum on Supporting Biomedical Research: Near-Term Problems and Options for Action. Summary of meeting held June 27, 1990. Washington, D.C. : National Academy Press. National Advisory Neurological and Communicative Disorders and Stroke Council. 1989. Decade of the Brain: Answers Through Scientific Research. NIH Pub. No. 88-2957. Bethesda, Md. : U.S. Department of Health and Human Services, National Institutes of Health. National Institutes of Health. 1989. NIH Data Book. Pub. No. 90-1261. Bethesda, Md. : U.S. Department of Health and Human Services. U.S. General Accounting Office. 1990. Drug Exposed Infants: A Generation at Risk. Testimony before the Committee on Finance, U.S. Senate. Pub. No. GAO/T-HRD-90-46. Washington, D.C. : U.S. General Accounting Office. Note 1. These species are intended as starting points. The committee also recognizes the need to include data from other, vertebrate and invertebrate, species.

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