A Blue Sky Vision for the Future of Neuroscience: Workshop for Invited Expert Panel

As a third source of input into a "Blue Sky" vision for the future of neuroscience, on November 13-14, 2007, the NINDS held a workshop with invited experts representing the basic and clinical neuroscience research communities, nonprofit organizations, and the pharmaceutical and biotech industries. Workshop participants discussed the future landscape of neuroscience research as well as aspirational goals and priorities for the NINDS over the next fifteen years.

The Future Landscape of Neuroscience Research

External factors that influence the landscape of neuroscience research will also shape future goals for the NINDS and its ability to meet them. Workshop participants were asked to consider major trends or developments outside of neuroscience (e.g., technological, demographic, economic, or social) that could have an impact on neuroscience research in the next fifteen years.

Demographic and economic trends:

The aging US population is leading to an increase in the burden of neurodegenerative and other age-related diseases and in their associated economic costs, making research toward treatment development ever more urgent. With healthcare costs continuing to rise and the gap between the world's rich and poor widening, workshop participants suggested that the research community consider cost-effective strategies and ways to approach disparities in access to care. Much needed advances in medical treatment are lengthening and enhancing the lives of people with neurological disorders, and more and better treatments are still lacking for many diseases and conditions. However, participants also noted potential causes for concern in an increasing acceptance and use of medications for a wide variety of indications, particularly for mental and behavioral disorders and symptoms in children.They asked what impacts the over-use or misuse of medications could have on future social and cognitive function, how it might affect future decisions about drug treatments for other problems, and whether new types of drug abuse and addiction could emerge.

Clinical research and healthcare delivery:

The participants envisioned several changes for the future of clinical research and healthcare delivery. Telemedicine may replace or augment some face-to-face clinical encounters with internet-based communication. Increased use of electronic medical records (EMRs) could create opportunities for data collected during routine clinical care to feed more easily into research. EMRs could also enable more efficient and cost-effective research by facilitating data sharing, patient recruitment and follow-up. Technological advances should also allow more continuous monitoring of disease signs and symptoms by mobile or portable devices, which could also benefit clinical research. Finally, with growing knowledge about genetic, environmental, and lifestyle factors contributing to risk for disease, participants expect the focus of healthcare to move toward prevention and education.

Globalization of science:

Intellectual capital and research funding are increasing internationally, including in countries that may have different social attitudes and policies regarding biomedical research and clinical care. Workshop participants discussed questions about the potential impacts of this globalization of science, such as whether the U.S. should aim to maintain its leadership status in the research enterprise and continue to attract the best and brightest from overseas, and how globalization can provide new sources of both partners in innovation as well as consumers.

Scientific workforce:

The participants discussed whether the current emphasis in the U.S. on translational research may appear to devalue basic science. This perception could ultimately harm both basic and translational research by discouraging careers in basic science and slowing progress toward understanding fundamental concepts that will drive future translational successes. There was also concern about the lack of sufficient numbers of trained physician-scientists to participate in basic and translational research and to undertake necessary clinical research.

Impacts of increased access to biomedical technologies and information:

The decreasing cost of genome sequencing is leading to increased use of genomic data for profiling patients and stratifying subjects for clinical research, but it has also led to the advent of "recreational genomics" and direct-to-consumer genetic testing for investigating ancestry as well as predispositions for certain diseases and traits. Participants discussed the need for the research community to do more to deal with emerging ethical issues and to ensure that these technologies be used to promote public health. Similar issues were discussed in the context of increased use and availability of advanced brain imaging technologies.

The internet and the access it provides to biomedical information will continue to empower the public, and demand on the scientific community for accountability will continue to grow. Workshop participants suggested that the faster research can deliver beneficial applications, the more convinced the public will be of its value. They also encouraged active efforts in public education, including more effective ways to track and communicate public health outcomes and other successes of biomedical research. Participants felt in general that science is undervalued in public education and that although science curricula have improved, they have not kept pace with the increasing influence of scientific issues on our everyday lives.

Workshop participants also discussed issues related to the communication of biomedical information within the scientific community, noting both increased access to different types of data, as well as an apparent decline in the readership of scientific journals. Even in individual research areas, mounting numbers of publications present an obstacle to knowledge integration, and workshop participants discussed the potential for emerging informatics tools that move beyond literature management to assist in building inferences and new hypotheses.

Identifying Grand Challenges for neuroscience research

To aid the NINDS in developing a set of aspirational goals to guide future research efforts, the participants were asked to consider which questions about the nervous system in health and disease would be most critical to ask over the next fifteen years and which capabilities would have the greatest impact on the treatment and prevention of neurological disorders. After an initial brainstorming session to generate ideas, the participants and workshop moderators selected the following three topics to discuss in terms of potential "Grand Challenges" for neuroscience research, considering such factors as what would be required meet the stated goals and how NINDS might best contriubute.

Map the connectivity of the nervous system:

A wiring diagram of the brain has long been considered a holy grail for neuroscience research. The field may finally be ripe for a large-scale "connectome" effort to map the connectivity of the nervous system.

The workshop participants discussed how a more complete understanding of neural circuitry would enable further progress on remaining questions in many areas of neuroscience research, such as how and where information is stored in the nervous system and how activity in neural circuits generates behavior and cognitive functions. In addition, a connectivity map may help explain and guide treatment development for disorders of the nervous system that may be viewed as "connectopathies," with abnormal circuit structure or activity. Workshop participants also noted analogies with the Human Genome Project in terms of the potential to accelerate progress and capture the attention and imagination of the public.

Connectivity research and neuroscience in general have previously focused heavily on excitatory neurons, and workshop participants noted a relatively limited understanding of inhibitory neurons. This diverse group of neurons shapes the balance, timing and propagation of neural circuit activity and modulates neural development and plasticity. Although disruptions in inhibition are implicated in many brain disorders, including epilepsy and schizophrenia, much remains unknown, and incorporating an emphasis on inhibitory neurons into research on brain connectivity may be one approach to learning more about their roles in nervous system function and disease. Likewise, workshop participants discussed accumulating evidence that non-neuronal cells called glia - long recognized as merely supportive for neuronal function - contribute more actively to brain circuits than previously thought. A full connectome might therefore encompass glial cell contacts in addition to connections among excitatory and inhibitory neurons. Other considerations of the eventual scope of a connectome Grand Challenge included: should it be framed as the human connectome, though progress is more likely to be made in animal models? Should the challenge extend to understanding how circuits develop or change during aging, injury or disease? Should it determine anatomical connectivity alone, or should it also link connectivity with neural circuit activity and behavioral or other outputs?

Participants also considered what would be required to meet such a challenge. A critical question is whether the field is technically prepared. Participants indicated that although it remains to be determined which tools will be best for neural circuit visualization, many new technologies are or will soon be available, and smaller-scale efforts toward a connectome are already underway. In addition to visualizing circuits, delineating the connectome will also depend on the ability to identify and classify different cell types in the nervous system. Since this effort will require the collaboration of many investigators, infrastructure and computational tools to enable data sharing and integration will also be crucial. As for potential research strategies, suggestions included a behavior-based approach that would begin with circuits underlying discrete, quantifiable behaviors, as well as a disease-based approach that would consider what disease symptoms might indicate about the nature of affected circuits.

Develop a safe, effective treatment for one or more neurodegenerative disorders:

Neurodegeneration and neuronal cell death occur in a range of neurological disorders, whether chronically as during the course of progressive degenerative diseases, or more acutely as in the aftermath of injury or stroke. Workshop participants expressed general interest in a potential Grand Challenge focused on neurodegeneration, given its ubiquity among neurological disorders as well as expected increases in the prevalence of neurodegenerative diseases as the population ages. Opinions differed as to whether to focus generally on the process of neurodegeneration, or on one or more individual disorders, and if the latter, several considerations for a selection process were discussed. Also, although the development of safe and effective treatments would be an ultimate goal, participants noted the need to define and manage expectations about future treatments and when they might become available.

Workshop participants discussed a variety of needs and strategies for accelerating progress toward interventions for neurodegenerative disorders. They also considered where in the research and drug development pipeline NINDS could best contribute, including where we might focus on partnering with other stakeholders (such as private foundations and industry) or on opportunities to catalyze transitions through current bottlenecks. For example, for disorders likely to garner significant industry interest, NINDS may contribute best by helping to identify promising targets and then facilitating their hand-off to industry, as opposed to investing in drug development from start to finish. As another suggestion, the NINDS might help to address the need to better monitor the state of research on different diseases, in order to track and communicate progress toward milestones and to identify new research opportunities. Informatics resources, including literature curation and tools for text mining, could facilitate data sharing and integration. Looking for commonalities across different disorders, including Alzheimer's disease, Parkinson's disease, ALS and others, could also reveal promising targets for research.

Develop biomarkers for predicting and monitoring disease progression and treatment outcomes:

The need for better biomarkers for predicting, diagnosing, and monitoring disease, and to serve as targets of biologic efficacy in clinical trials, extends to nearly all diseases under the NINDS mission. Workshop participants discussed a variety of strategies and operational goals for enabling progress toward biomarker development.

Many of the strategies concerned ways to take better advantage of clinical data. Suggestions included determining a standard minimal dataset that could be shared across multiple trials and areas of research, making data collection for use in research a routine part of the clinical encounter, and developing a standard consent form that would allow data collection and sharing. Workshop participants felt that the NINDS could take a leadership role in bringing researchers, industry, regulatory agencies and other stakeholders together to establish such standards. The growing use of electronic medical records should facilitate data sharing, and progress made in these areas by private foundations, in other areas of research, and outside the U.S. could serve as examples. One idea for an initial approach would be to use the Clinical and Translational Science Award (CTSA) sites as test beds for establishing data collection standards and for integrating clinical care and research. Another suggestion for increasing access to clinical data would be to make proprietary data from industry-funded trials available to the research community.

Workshop participants noted that, as with the other suggested Grand Challenges topics, biomarker development will benefit from collaboration and contributions from the broad research community. They also noted the need to involve both the FDA and industry early in the biomarker development process to facilitate meeting regulatory requirements and to agree on what data to collect. The framework developed by the Foundation for the NIH may provide opportunities for NINDS to work with the larger neuroscience community toward the development of biomarkers for neurological disorders.

Additional priority areas for the future of neuroscience

The workshop participants identified several more topics as future priority areas for neuroscience but were unable to discuss them all in the context of framing potential Grand Challenges. The descriptions below of three of these broad topics incorporate comments made during workshop discussions as well as input from both the workshop participants and NINDS staff.

The sustainable brain:

One enthusiastically received suggestion would emphasize research on the healthy brain and on ways to promote and sustain healthy brain function throughout life, including research toward understanding the effects of diet, exercise and other lifestyle factors. Identifying factors that maintain brain fitness and ward off disease should translate into preventive strategies and decreased healthcare costs, and a large population of healthy people stands to benefit. Indeed, a number of businesses have already entered this emerging market, as evidenced by brain games and other commercially available products boasting brain-sustaining powers, suggesting potential opportunities for collaborations between the NIH and the pharmaceutical and technology industries.

Workshop participants noted that the overarching nature of this "Sustainable Brain" concept could allow it to be integrated as a focus in many areas of research and other activities supported by the NINDS. For example, research on many diseases within the Institute's mission could include an increased emphasis on preventable causes. Studies of nervous system development and developmental disorders could be complemented by parallel investigations into what constitutes optimal development. Likewise, research on the aging nervous system and age-related disorders might be extended to consider factors contributing to successful aging. In this case, future efforts could build on results and recommendations from the Cognitive and Emotional Health Project (CEHP), a project with joint support from the National Institute on Aging, the NINDS and the National Institute of Mental Health (NIMH) that has assessed the state of longitudinal and epidemiological research on demographic, social and biologic determinants of cognitive and emotional health in aging adults. The CEHP has recommended adding measures of cognitive and emotional outcomes to existing large cohort clinical studies, a strategy that might be employed more generally for collecting data on factors that influence healthy brain function. Other potential activities related to a Sustainable Brain concept could include the development of biomarkers for different aspects of brain health and public education efforts to communicate what people can do to promote optimal brain function throughout life.

Biology of brain repair

The nervous system's plasticity, or capacity to change and adapt, is among the most active areas of neuroscience research, yet many questions remain about how the brain attempts to repair itself in response to injury or disease. Workshop participants suggested a focus on answering these questions, a challenge that could lead to harnessing and promoting the brain's intrinsic repair mechanisms for future therapeutic interventions.

Repairing damage due to stroke might be one target of such a focus with particular relevance to the NINDS mission, and some efforts in this area are already underway. In 2006, the NINDS Stroke Progress Review Group (PRG) identified the problem of brain repair and rehabilitation after stroke as a major priority for stroke research, and the NINDS, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIA, and National Institute on Deafness and Other Communication Disorders (NIDCD), issued a program announcement this year entitled "Mechanisms of Functional Recovery After Stroke" to encourage research on basic brain mechanisms of repair and plasticity after stroke and factors that influence these mechanisms, as well as methods and approaches to improve and enhance reparative processes for rehabilitation and functional recovery after stroke.

Like the concept of the Sustainable Brain, the biology of brain repair might be viewed as an overarching theme for NINDS research, with questions applicable to brain damage resulting from a broad range of causes in addition to stroke, such as degenerative disorders, traumatic injury, brain tumor, or infection. These goals could include understanding the relationship between functional recovery and cellular events like nerve fiber sprouting and neurogenesis observed in animal models, determining whether these same types of changes occur in the human brain, and defining the temporal profile of such changes toward identifying optimal points for potential interventions. Moreover, the problem of brain repair presents an opportunity for innovation, which could benefit from the increasingly interdisciplinary nature of neuroscience research. Brain repair of the future might include novel regenerative strategies employing bioengineered materials, prostheses and robotic devices that interface with remaining circuitry and bypass damage, or computer-aided behavioral therapies that stimulate circuit rewiring and retraining.

Bridging the divide between neurology and psychiatry

Traditionally, diseases and conditions falling into the domains of neurology and psychiatry have been separated according to whether they are accompanied by identifiable brain lesions. However, with sophisticated genetic techniques and advanced technologies for imaging and recording brain activity, neuroscience research over the past fifty years has chipped away at disciplinary boundaries by uncovering genetic, neurochemical, and neuroanatomical mechanisms contributing to a broad range of mental functions and illnesses. Moreover, many disorders traditionally considered within neurology, including epilepsy, stroke and Parkinson's disease, present with depression, psychosis or other psychiatric comorbities. The increasingly artificial divide between clinical disciplines parallels a divide in basic research between reductionist approaches to understand the component parts of neurobiological systems and behavioral and systems-level approaches to understand how these parts work together as a whole. Bridging these divides, as called for by several workshop participants, will be critical not only for gaining a more unified perspective on how best to treat brain disorders, but also for solving some of neuroscience's most fundamental mysteries, including understanding consciousness, language, and other complex brain functions.

One way to encourage integration would be to promote more programs for joint psychiatry and neurology training for medical students and interdisciplinary training for neuroscience researchers. A number of such programs already exist, including NIH's Jointly Sponsored Institutional Predoctoral Training Program in the Neurosciences, in which the NINDS participates. A major challenge for researchers and clinicians with different disciplinary backgrounds will be finding a common language to facilitate cross-talk. Workshop participants suggested that some agreed unit of function or analysis could form the basis of such a common language and help to provide an organizational structure for neuroscience concepts. Psychiatric diagnoses rely largely on subjective measures, in contrast to the physiological or structural measures used to diagnose neurological disorders, and developing more objective diagnostic tools for psychiatric disorders, perhaps rooted in their underlying mechanisms, may also help to align the two fields. Finally, in addition to the need to integrate current knowledge from data collected at different levels, a more holistic approach to neuroscience will also require the development of new methods for collecting and analyzing multimodal data.

Additional recommendations

Among remaining research areas suggested as potential future priorities but not discussed at length during the workshop were chronic pain, epigenetics, developmental disorders, the functions of sleep, improved animal models for human diseases, and the basis and evolution of factors that distinguish humans from other species. Also noted were the needs to encourage high-risk, innovative research, and to balance curiosity-driven basic research and outcome-driven translational research.

Workshop participants identified a number of operational goals that cut across research areas. Many of these were discussed in the context of the three Grand Challenge ideas above, including suggestions for ways to make better use of clinical data, to facilitate collaboration, and to enable the integration of knowledge across areas of research. Such recommendations also included providing support to centralized repositories of data and resources and increasing the availability of human nervous system tissue for research. Finally, some ideas from the workshop would represent new directions for advancing the NINDS mission. These included suggestions to develop a science of dissemination to accelerate the translation of clinical research advances to the larger public and to play a more active role in public education in neuroscience and in communicating research progress.

Blue Sky workshop participants

Robi Blumenstein (co-moderator), Managing Director and President, MRSSI, Inc./High Q Foundation
Tom Insel, MD, Director, National Institute of Mental Health
Dennis Choi, MD/PhD, Executive Director, Comprehensive Neurosciences Initiative, Emory University
Fred H. Gage, PhD, Adler Professor, Salk Institute for Biological Sciences
P. Read Montague, PhD, Director, Human Neuroimaging Laboratory, Baylor College of Medicine
Brad Margus, Executive Vice Chair, Perlegen Sciences, Inc.
Terrie Inder, MD, Associate Professor of Neurology, Washington University
Eve Marder, PhD, Professor of Biology, Brandeis University
Andres Lozano, MD/PhD, Professor of Neurosurgery, Toronto Western Hospital
Anne Young, MD/PhD, Chief of Neurology Service, Massachusetts General Hospital
Dan Lowenstein, MD, Associate Dean of Clinical and Translational Science, UCSF
Lucie Bruijn, PhD, Science Director and Vice President, The ALS Association
Joshua Sanes, PhD, Professor of Molecular and Cellular Biology, Harvard University
Gerry Fischbach, MD, Scientific Director, The Simons Foundation
David Bredt, MD/PhD, Vice Pres., Neuroscience Discovery and Clinical Investigation, Eli Lilly and Co.
Winfried Denk, PhD, Director and Scientific Member, Max Planck Institute for Medical Research
Takao Hensch, PhD/MPH, Professor of Molecular and Cellular Biology, Harvard Medical School
Clay Johnston, MD/PhD, Professor of Neurology, UCSF
Kurt Fischbeck, MD, Chief, Neurogenetics Branch, NINDS

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