Biennial Report of the Director

Research in Diseases, Disorders, and Health Conditions

Composed of the brain, spinal cord, sensory organs, and nerves of the body, the nervous system underlies perception, movement, emotions, learning, and memory, and other functions essential to individual and societal well-being. The nervous system interacts with all other organ systems and is affected by countless diseases, conditions, and environmental factors. Moreover, with limited capacity for self-repair, the nervous system is particularly vulnerable to damage due to injury or infection, and its repair mechanisms are poorly understood. Neuroscience research seeks to understand the nervous system and its functions in health and disease. Given its intrinsic complexity and central role in physiology and behavior, this understanding must necessarily come from multiple perspectives. Accordingly, neuroscience research spans many disciplines, from genetics to physiology to psychology, and applies tools from areas such as molecular biology, anatomy, computer science, and imaging technologies.

Neuroscience is a unifying theme in NIH research. The intramural and extramural programs of several ICs have a major focus on the nervous system, but the full scope of NIH neuroscience activities extends to components of research portfolios across most of the Agency, reflecting the multidisciplinary nature of the field and the importance of the nervous system to many aspects of human health, development, and disease. These activities often involve collaborative efforts combining the unique strengths and expertise of individual ICs. To reinforce such collaborations, NIH established the Blueprint for Neuroscience Research, which accelerates neuroscience research through training programs, the development of shared tools and resources, and initiatives to address challenges in neuroscience that transcend the mission of any single IC.

The principal aim of NIH research in neuroscience is to reduce the burden of diseases that affect the nervous system, including a broad range of neurological disorders; disorders affecting cognitive, emotional, and behavioral function; diseases and conditions that impair the primary senses; and developmental and age-related disorders. Whether led by single investigators or conducted through centers and consortia, NIH neuroscience research includes basic science studies of normal function and development in both humans and animal models, translational research that develops medications or other therapies, and clinical trials that test interventions in patients.

Nervous system disorders include common killers and major causes of disability like stroke, multiple sclerosis, and epilepsy, as well as hundreds of less common diseases, such as lysosomal storage disorders, spinal muscular atrophy, muscular dystrophies, inherited neuropathies, neurofibromatosis, tuberous sclerosis, and Rett and Tourette syndromes. Many neurological disorders have genetic or developmental origins. Others result from trauma to the nerves, spinal cord, or brain; from autoimmune, infectious, or systemic disease; from tumor growth in nervous system tissues; or from neurodegenerative processes as in Parkinson’s disease, glaucoma, frontotemporal dementia, and amyotrophic lateral sclerosis (ALS). Still others are known or suspected of resulting from environmental exposure to substances, such as pesticides, solvents, PCBs, and metals. NIH research on neurological diseases, largely supported by NINDS, seeks to uncover their causes and mechanisms and to develop drugs and other treatments or preventive strategies. This research also aims to understand the multiple aspects of the nervous system that disease can affect and has shared support across NIH for basic science studies of the cerebral vasculature, electrochemical signaling in neurons and other cells, mechanisms of development and cell death, neuromuscular function and motor control, and behavior and cognition. In addition, NIH works to enhance the lives of those disabled by stroke, traumatic brain injury, spinal cord injury, and other neurological conditions through research supported by NICHD’s National Center for Medical Rehabilitation Research and other ICs on neuroplasticity, recovery and repair of motor and cognitive function, and rehabilitative and assistive strategies and devices.

Brain disorders affecting cognitive, emotional, and behavioral function include schizophrenia and psychoses; autism spectrum disorder and other developmental disorders; mood and anxiety disorders; addiction to nicotine, alcohol, and other substances; and post-traumatic stress disorder, eating disorders, attention deficit hyperactivity disorder (ADHD), and others. Through research efforts led by NIAAA, NIDA, NIMH, NIEHS, and other ICs, NIH focuses on understanding the causes of these conditions (e.g., the underlying neural and behavioral bases) and their effects (e.g., the acute and long-term effects of abused substances on the nervous system) so as to develop effective therapies and interventions for treatment and prevention.

Communication disorders make it challenging for a person to sense, interpret, and respond to environmental stimuli. Not only do communication disorders compromise a person’s physical health, but they also affect that person’s emotional, social, recreational, educational, and vocational life. One such disorder, aphasia, results from damage to portions of the brain that are responsible for language. This disorder usually occurs suddenly, often as the result of a stroke or head injury, but it may also develop slowly, as in the case of a brain tumor, an infection, or dementia. NIDCD, NINDS, NICHD, NIMH, and NIA support research on this disorder. The goal of this research is to develop therapies to improve an individual's ability to communicate by helping the person use remaining abilities, to restore language abilities as much as possible, to compensate for language problems, and to learn other methods of communicating.

Sight, smell, hearing and balance, and our other primary senses, require specialized nerve cells that respond to specific features of the external or internal environment and send signals to the brain. For example, light coming through the lens of the eye projects onto photoreceptor neurons in the retina. Absorption of light causes the protein structure within these cells to twist, triggering a cascade of molecular and electrical changes in the photoreceptor cell, which then send signals to the brain for further processing. NEI funds research on basic visual neuroscience in the eye and brain, and on diseases and conditions that affect vision. NIDCD conducts and supports biomedical and behavioral research, as well as research training in the normal and disordered processes of hearing, balance, taste, smell, voice, speech, and language related to answering fundamental scientific questions and to prevent, screen, diagnose, and treat disorders of human communication.

Although vital to survival, the sensation of pain also is symptomatic of many diseases with origins in and outside the nervous system, such as migraine and other headaches and cancer-related pain. NIH pain research is led by NINDS and the NIH Pain Consortium, which coordinates research across NIH in this area with the guidance of an Executive Committee comprised of the NINDS, NIDCR, NINR, NCCAM, and NIDA Directors.

NIH-supported research also studies the many ways the nervous system interacts with and regulates changes in the body’s internal environment. This research, including efforts supported by NHLBI and NIDDK, focuses on areas such as circadian rhythms and sleep disorders; neuroendocrine processes that regulate stress responses, hormone levels, and motivational states; and the neural basis of appetite and feeding, which is of key relevance to slowing the increasing rates of obesity worldwide.

Nervous system disorders may arise during early development, strike young adults, or emerge late in life. NICHD, NIEHS, and other ICs sponsor research on the development of the nervous system and its functions. This research encompasses studies of structural birth defects, including spina bifida and other neural tube defects, and associated conditions such as hydrocephalus, cerebral palsy, Down syndrome, and other causes of intellectual and learning disabilities. Nervous system development continues into early adulthood in humans, and developmental processes and external influences contribute to mental fitness and disease risk later in life, including the risk for addiction, which often begins in childhood or adolescence. At the other end of the lifespan, with key support from NIA, NIH research on the aging nervous system includes studies of age-related disorders such as Alzheimer’s disease (AD) and other dementias, as well as environmental and lifestyle factors affecting neurological, cognitive, and emotional health in aging populations.

Across all ages, the nervous system is a common target of exposure to toxins, pollutants, metals, food constituents, and other agents, the effects of which range from acute reactions to developmental disruption to neurodegeneration. NIH-sponsored research on the consequences of such environmental exposures for nervous system development, function, and disease is a particular focus of NIEHS.

NIH also considers diseases of the nervous system from a global point of view. Coordinated in part by FIC, NIH supports neuroscience-related research around the world in unique populations and environments and on factors contributing to disparities in disease vulnerability and treatment quality and access, such as socioeconomic conditions and infectious disease.

Nervous system disorders take an enormous toll on human health and the economy. Even rare disorders carry a substantial collective burden, as they often have an early onset and long duration, and the stigma commonly attached to neurological and mental disorders further compounds individual and societal impact. According to 2005 estimates, neurological disorders strike more than 1 billion people worldwide, accounting for 12 percent of total deaths.76 Exit Disclaimer In the U.S., stroke is the fourth leading killer of adults and results in annual medical and disability costs totaling more than $34 billion and estimated to reach almost $96 billion by 2030.77 Each year, another 1.7 million Americans sustain traumatic brain injury (TBI), the leading cause of death and long-term disability in young adults,78 with direct and indirect costs reaching approximately $76.5 billion in 2000.79 Head injury also accounts for an estimated 20 percent of combat-related injuries in modern wars, and blasts are a leading cause of TBI in military personnel.80 According to the Department of Veterans Affairs, tinnitus (ringing in the ears) is the most prevalent service-connected disability of American veterans, with more than 744,000 veterans receiving disability compensation for tinnitus as of the end of FY 2010.

In a given year, approximately 12.5 million American adults (or one in every 17) suffer a debilitating mental illness.81 Mental disorders result in more disability for U.S. adults than any other class of medical illness,82 and a conservative estimate places the total direct and indirect annual costs of mental illness at more than $300 billion.83 In 2011, among persons in the U.S. ages 12 years or older, 16.7 million were classified with dependence on or abuse of alcohol, and 6.5 million with dependence on or abuse of illicit drugs.84 The overall social and economic burden of substance abuse continues to rise, with annual costs related to alcohol, tobacco, and illicit drug abuse totaling more than $600 billion.85

Mental illness and neurological disorders affect people of all ages. An estimated 17 percent of U.S. children have a developmental or behavioral disorder such as autism spectrum disorder, intellectual disability, or ADHD.86 Current demographic trends project a growing burden from age-related diseases of the nervous system as populations benefit from increased longevity. One in seven U.S. adults ages 72 years and older has dementia, and estimates of the prevalence of Alzheimer’s disease range from 2.4 million to 5.1 million, a number expected to rise to as many as 13.2 million by 2050 unless effective interventions are developed.87

76For more information, see https://www.who.int/mediacentre/news/releases/2007/pr04/en/index.html.
77Roger V, et al. Circulation. 2012; 125(1):e2–e220. PMID: 22179539. Heidenreich PA, et al. Circulation. 2011; 123(8)933–44. PMID: 21262990.
78For more information, see https://www.cdc.gov/traumaticbraininjury/statistics.html.
79Finkelstein E, et al. The Incidence and Economic Burden of Injuries in the United States. New York: Oxford University Press, 2006.
80Ling G, et al. J Neurotrauma. 2009;26(6):815–25. PMID: 19397423.
81Kessler RC, et al. Arch Gen Psychiatry. 2005;62:617–27. PMID: 15939839. For additional information, see https://www.census.gov/popest/national/asrh.
82World Health Organization. World Health Statistics 2006. Geneva, Switzerland: World Health Organization, 2006.
83Insel TR. Am J Psychiatry. 2008;165(6):663–5. PMID: 18519528.
84Substance Abuse and Mental Health Services Administration. Results from the 2011 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-44, HHS Publication No. (SMA) 12-4713 (2012). Rockville, MD. Available at: https://www.samhsa.gov/data/NSDUH/2k11Results/NSDUHresults2011.pdf.
85Rehm J, et al. Lancet. 2009 Jun 27;373(9682):2223–33. PMID: 19560604. Centers for Disease Control and Prevention. Best Practices for Comprehensive Tobacco Control Programs—2007. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2007. National Drug Intelligence Center. The Economic Impact of Illicit Drug Use on American Society. Washington D.C.: United States Department of Justice, 2011. Product No. 2011-Q317-002.
86U.S. Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Bureau. The National Survey of Children with Special Health Care Needs Chartbook 2001. Rockville, MD, 2004. For more information, see https://mchb.hrsa.gov/chscn/.
87Plassman BL, et al. Neuroepidemiology. 2007;29:125–32. PMID: 17975326. Hebert LE, et al. Arch Neurol. 2003;60:1119–22. PMID: 12925369.

NIH Funding for Neuroscience and Disorders of the Nervous System

NIH funding for research in neuroscience and disorders of the nervous system was $5,515 million in FY 2010, and $5,548 million in FY 2011 for non-ARRA (regular appropriations) and $794 million in FY2010 for ARRA appropriations.88

Summary of NIH Activities

Neurodevelopment, neuroplasticity, and neurodegeneration are common themes that reflect shared biological processes found in many aspects of nervous system function and disease. In this section, these themes will serve to highlight selected examples of activities and progress in neuroscience research enabled by NIH, as well as challenges and future opportunities. Additional activities and initiatives exemplify how collaborative approaches are facilitating advances in basic, translational, and clinical neuroscience.

Neurodevelopment: Periods of Growth, Maturation, and Vulnerability

Complex interactions between gene expression and function, endocrine and other physiological processes, neuronal activity, and external influences guide the development of the nervous system. From the early differentiation of its many neuronal and other cell types to the establishment of billions of connections between neurons, each step in nervous system development is vulnerable to disruption by disease, injury, or environmental exposures. NIH research across all stages of neurodevelopment is leading to a better understanding of neurological, mental, and behavioral function in health and disease throughout life, as well as to new treatments and preventive strategies.

During early human embryonic development, a flat surface of cells destined to become the brain and spinal cord rolls into a structure called the neural tube. Defects resulting from improper neural tube formation, including spina bifida and anencephaly, are among the most common birth defects. A randomized clinical trial supported by NICHD recently showed that prenatal fetal surgery to repair the spinal opening in the most common form of spina bifida resulted in improved outcomes as compared to standard postnatal surgery.89 NICHD and NINDS are supporting a follow up study to determine the effects of prenatal repair on adaptive behavior, cognitive and motor function, brain morphology and microstructure, urologic health, and other outcomes at school age. Other NIH-funded studies explore the developmental mechanisms of neural tube closure, including structural, genetic, and dietary influences in animal models and in humans, which may identify targets for intervention or prevention.

NINDS also supports a broad portfolio of research on hydrocephalus, a condition that often develops in people with spina bifida and other developmental brain malformations. Shunts to drain excess cerebrospinal fluid are the most common treatment for hydrocephalus, but they often fail due to blockage or infection. In 2009, NINDS and NICHD issued a funding opportunity announcement for small business research to improve the design, operation, and monitoring of CSF shunts. The initiative brought increased small business attention to this applied research need, and the awards made so far are supporting the development of implantable and non-invasive diagnostic and monitoring devices, novel materials for preventing shunt infection and blockage, and a new shunt design with feedback control.

Developmental disability is a severe, long-term disability that can affect cognitive ability, physical functioning, or both. According to the CDC, there are an estimated 35–43 million people with physical and mental disabilities in the U.S. The Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers support projects that address cerebral connectivity; genetics and environmental influences on brain development; efforts to prevent and treat conditions ranging from brain injury in premature infants to autism spectrum disorder; and research programs in genetic/genomic disorders, inborn errors of metabolism, and mitochondrial disorders. In addition, NIH is supporting the development of new technologies for newborn screening and an infrastructure to promote newborn screening research. The goals are to develop fast, reliable, and cost-effective means to screen newborns and to expand the number of conditions these tests can assess. Such screening makes it possible to begin treatment early, when chances for success are greatest.

Both genetic and environmental factors influence nervous system development and function, and a growing area of neuroscience research focuses on how genes and the environment interact to influence both disease course and treatment for a range of disorders including multiple sclerosis, Parkinson’s disease, depression and other mood and anxiety disorders, addiction, and autism spectrum disorder. NIAAA- and NIDA-supported researchers examined the role that variability in genes that encode a specific receptor for the neurotransmitter (neurotransmitters are chemicals involved in transmitting signals from one nerve cell to another) dopamine may play in improving outcomes of a substance use prevention intervention in a case control study of African American rural adolescents. The study, which focused on parenting behavior, found that youth carrying one variation of this gene (DRD4) not only were more responsive to the intervention than youth with another variation, but also that they reduced past month alcohol or marijuana use over a 29-month period. Taken together with the previous finding that variation in a gene that regulates the actions of the neurotransmitter serotonin influences initiation of adolescent substance use, the results suggest different genes may influence different phases of substance use and highlights potential opportunities to match individuals to prevention programs based on genotype.

NIH supports broad efforts to understand how autism spectrum disorder may arise from combined effects of genetic vulnerabilities and exposure to potentially harmful environmental agents during key periods of development. Recent research suggests that environmental factors may play a much greater role in autism risk than previously suspected and could even be more influential than genetic factors. These findings stem from a study in twins90 designed to model the genetic and environmental factors that contribute to the development of autism. Using mathematical modeling, the researchers propose that environmental factors accounted for 55 percent of autism risk, while genetic heritability contributed less than 40 percent. The difference in rates among fraternal twins and siblings, who share similar amounts of DNA, suggests that environmental factors in the womb may be an important area of future study.

Although all forms of autism spectrum disorder are characterized by challenges in three core domains of functioning (social impairments; communication difficulties; and restricted, repetitive, or stereotyped patterns of behavior), considerable heterogeneity exists across individuals with autism spectrum disorder in these and other clinical features, suggesting the contribution of multiple developmental trajectories and causal factors. One cross-cutting theme highlighted in the Interagency Autism Coordinating Committee’s (IACC) Strategic Plan for autism spectrum disorder research is the need to understand this heterogeneity, which could lead to new insights into the causes of autism spectrum disorder, improved diagnosis, and more targeted intervention strategies. To examine the genetic basis of autism, researchers sequenced the protein-coding region of the genome (called exome) of 20 people with autism and their parents, and identified 21 spontaneous or de novo mutations.91 Of the 21 mutations, four were determined to be potentially causative (FOXP1, GRIN2B, SCN1A, and LAMC3). Three of the four genes identified in the study had previously been associated with autism, intellectual disability without autism, and epilepsy. The fourth mutation, LAMC3, had never before been linked to autism and represents a potential new avenue of research. Furthermore, within the study, two of the four children had been hit with a "genetic double-whammy"—both inheriting a harmful gene mutation from their parents and having a de novo mutation. These two cases support the “multi-hit” theory of autism—that a combination of mutations in the same pathway is necessary to cause severe autism or related disorders. The authors note that the study supports the role of de novo mutations as a major genetic contributor to autism.

The human brain continues to mature into early adulthood, and understanding normal nervous system development is essential to knowing when, where, and how developmental processes can go wrong. In the NIH Magnetic Resonance Imaging (MRI) Study of Normal Brain Development, NIH-supported researchers at seven collaborating institutions collected brain scans and clinical and behavioral data from more than 500 healthy infants, children, and adolescents over the course of seven years, providing important baseline information that could identify signs of atypical brain development. The data gathered and analytical tools developed for this longitudinal study are available to the broader research community in an online, searchable database. An improved understanding of the normal course of human brain development also is yielding insights into behavioral and cognitive development and function across the lifespan. For example, previous brain imaging studies have shown that one of the last brain areas to fully mature is the prefrontal cortex, an area important for decision-making and impulse control. This aspect of brain development may contribute to impulsive behavior in teenagers and help explain their increased susceptibility to substance abuse and addiction. A number of human and animal studies have suggested that the developing brain is vulnerable to heavy alcohol use in adolescence; however, it is unclear whether the structural and functional deficits that were observed predated the onset of alcohol use or occurred as a consequence. To further elucidate how alcohol impacts the developing adolescent brain in both the short and long term, NIAAA is supporting multisite longitudinal studies of youth ages 12­–21, capturing them before they begin to drink. The studies are using advanced neuroimaging technology as well as neuropsychological and behavioral measures to assess alcohol’s effects on brain development and the associated cognitive, affective and behavioral processes.

NIH investigators already are using knowledge about human brain and behavioral development to guide research on interventions to treat nervous system disorders, or to reduce their risk of occurrence later in life. For example, researchers reporting delayed development of the prefrontal cortex in ADHD are now studying the effects of ADHD treatment on the rate of cortical maturation. Research has established that substance abuse is a developmental disease beginning in childhood and adolescence. Therefore, prevention strategies must focus on developmentally appropriate interventions for youth. In fact, universal prevention approaches that teach all children (regardless of risk) problem-solving, refusal, and coping skills have proven successful not just in reducing future drug abuse risk but other related risk behaviors, as well. The NIH Underage Drinking Initiative similarly supports research on prevention of underage drinking and its risk factors, as well as efforts to develop and implement effective interventions within a developmental framework.

88For funding of various Research, Condition, and Disease Categories (RCDC), see https://report.nih.gov/categorical_spending.aspx.
88 Adzick NS, et al. NEJM. 2011;364(11):993–1004. PMID: 21306277.
89Hallmayer J, et al. Arch Gen Psychiatry. 2011;68(11):1095–102. PMID: 21727249.
90O’Roak BJ, et al. Nat. Genet. 2012;44(4):471. PMID: 21572417.

Neuroplasticity: Substrates for Change and Repair

Throughout development, and even once its basic structure and circuitry have been established, the nervous system retains a remarkable capacity to adapt to changes in the body’s internal environment and external conditions and events. This capacity, known as plasticity, reshapes the function and activity of neuronal networks, and it occurs at many levels of the nervous system. Plasticity enables beneficial adaptations, generally associated with a gain in function, including acquiring new knowledge, improving performance, and adjusting behavior.

One project funded by NEI provides a unique opportunity to study neuroplasticity and visual processing while also providing humanitarian benefit. Project Prakash operates in India, which has the largest population of blind children, many of whom live in poor, remote villages with limited access to professional eye care. The project screens thousands of children for treatable conditions, such as dense congenital cataracts that are routinely removed in the U.S. and has provided vision to hundreds. The treated children are old enough to describe the objects they are beginning to see and learning to recognize after gaining sight. Using behavioral tests and neuroimaging to study how the brain turns visual input into recognizable images, the results have provided remarkable insights. For example, contrary to previous theories, Project Prakash is showing that even after years of being blind since birth, children can still acquire complex visual abilities, providing hope for restoring functional vision to many children.

However, neuroplasticity also can lead to maladaptive changes, associated with negative consequences, which contribute to a range of conditions, including mood disorders, addiction, chronic pain, and cognitive impairment. Neuroplastic changes also are intrinsically connected to biological events like neurogenesis, neurodegeneration, neuronal sprouting, and changes in signal transduction pathways, which all play a role in several neurological disorders. Maladaptive plasticity can also arise as a consequence of long-term drug exposure, as in the case of drugs of abuse and levodopa-induced uncontrolled movements (dyskinesias) in Parkinsonian patients. By better understanding the underlying mechanisms of neuroplastic changes in the nervous system, researchers may be able to both harness their therapeutic potential and limit their deleterious consequences.
Plasticity-related processes in brain circuits contribute to many of the underlying causes of epilepsy, which include developmental malformations, genetic mutations, trauma such as stroke or head injury, brain tumor, and central nervous system infection and inflammation. In 2010 and 2011, NINDS announced several new initiatives that aim to better understand the causes of epilepsy and to develop new ways to treat or prevent its development in those at risk.

Mental and addictive disorders are known to have a strong neurodevelopmental component and are associated with functional changes in highly plastic brain areas, such as the prefrontal cortex, which play a key role in cognition and impulse control. Recent studies suggest that putative schizophrenia risk genes are involved in regulating neuroplasticity, and alterations in their expression and function may contribute to the abnormal pattern of cortical connectivity observed in schizophrenia.

NIH will continue to support research on treatments for mood disorders through clinical trial networks and the Innovative Approaches to Personalizing the Treatment of Depression Program. Ongoing studies include investigations on susceptibility genes and associations with brain structural changes in major depressive disorders; analysis of biomarker predictions of outcome based on quantitative electroencephalographic features that change during a week of exposure to antidepressant medications; and observational studies using longitudinal data from large population-based samples to identify patterns of response to multiple treatments.

Neuroplasticity also underlies a range of changes in brain function and behavior involved in the development and persistence of addiction. For example, a landmark NIDA-funded study in mice identified a biological mechanism that could help explain how tobacco products could act as gateway drugs, increasing a person’s future likelihood of abusing cocaine and perhaps other drugs as well. Mice that were exposed to nicotine for a week showed an increased response to cocaine. This effect depended on nicotine-induced changes in the structure of the tightly packaged DNA molecule that reprogram the expression pattern of specific genes, including a gene linked to the switch from acute to chronic drug effects. If nicotine is found to have similar effects in humans, these findings suggest that effective smoking prevention efforts would not only prevent the negative health consequences associated with smoking but could also decrease the risk of progression and addiction to cocaine and possibly other illicit drugs.

Several examples of maladaptive plasticity have been observed in pain disorders. Opioid analgesics are the most powerful medications currently available to treat chronic pain, but they can unfortunately result in addiction, tolerance, and physical dependence, limiting their value in some patients. Scientists are working toward the development of a morphine-like drug that will have the analgesic qualities of morphine, but without the drug's negative side effects. Another focus of NIH-supported research to develop new pain treatments is the cannabinoid signaling system. Just as the brain produces natural opioid-like compounds, it also produces natural compounds that act on the same receptors as the neuroactive component in the cannabis plant (marijuana). Cannabinoid signaling modulates neuronal activity and plasticity and also plays a role in modulating pain. Research suggests that selective activation of cannabinoid signaling pathways may provide pain relief with minimal mind-altering effects.

NIH funds research on understanding and identifying the multiple and varied contributions of dysfunctional changes in the central nervous system that lead to and maintain persistent pain. For example, work supported by NIH is exploring the role of increased activity of neurotransmitters in enhancing neuronal activity in response to pain. NIH- funded research has also demonstrated the role of increased activity in certain brain structures in amplifying pain signals or causing or maintaining persistent pain. For instance, repeated activation of certain brainstem neurons (neurons in an area of the brain that regulates basic functions such as breathing and heart rate) causes an increase in their activity associated with a transition from episodic to chronic daily headaches. 

NIH-supported researchers also have reported new findings on the mechanisms that lead to neuropathic pain induced by nerve injury. Following injury, the nervous system undergoes a tremendous reorganization. Thus, therapies directed at preventing these long-term changes may prevent the development of chronic pain conditions. Most available treatments for neuropathic pain target neurons. In contrast, the new findings highlight the role of certain enzymes released by non-neuronal cells called glia, which are involved in immune and inflammatory responses to nerve injury. Future treatments targeting glia may provide a way to halt the maladaptive signaling cascade that results in neuropathic pain. NIH also supports efforts to exploit adaptive plasticity at the level of brain networks for therapeutic pain intervention. Using real-time brain imaging, researchers have shown that patients with chronic pain can learn to exert voluntary control over activation of a particular brain region involved in pain perception and its regulation, effectively reducing the impact of their painful sensations. Future research will focus on the question of whether neuroimaging profiles can be used as a biomarker that would allow for an objective diagnosis of different pain conditions, and for the prediction of individual responses to specific therapies.

NIH is playing a key role in the new Interagency Pain Research Coordinating Committee, which includes biomedical researchers, representatives from nonprofit public advocacy organizations, and representatives of six federal government organizations that deal with pain research and patient care. The committee will work to identify critical gaps in basic and clinical research on the symptoms, causes, and treatment of pain, and coordinate pain research activities across the federal government with the goals of stimulating pain research collaboration.

Although plasticity can lead to changes in neural activity patterns throughout life, the adult human brain and spinal cord have a limited capacity to replace or repair neurons that are lost or damaged by injury or disease. An exciting area of neuroscience research focuses on ways to overcome these limitations and to harness neuroplasticity mechanisms to promote recovery and restore function. For example, spinal cord injury often leads to permanent paralysis and loss of sensation below the site of injury, because damaged nerve fibers are unable to regrow across the injury site. NIH supports research to understand the mechanisms that restrict such regrowth and to design strategies that integrate new nerve fibers into spinal circuitry. In one study, researchers showed that the vitamin folate (also known as vitamin B9) promotes healing in damaged rat spinal cord tissue by stimulating DNA modifications. The concern for U.S. Representative Gabrielle Giffords following a brain injury resulting from a gunshot, as well as the high rate of TBI among military personnel, has also increased attention on recovery, rehabilitation, and brain plasticity. Recently published data on TBI patients suggest that gene polymorphisms related to neuroplasticity may play a role in the variability of recovery. Ongoing TBI research projects supported by NIH are investigating the mechanisms of cognitive, attentional, memory, and motor problems and exploring how plasticity contributes to recovery. Examples include investigations on dietary interventions to correct metabolic changes following TBI; the beneficial effects of exercise on plasticity; and brain imaging studies addressing how forced-use behavioral therapy affects the brain reorganization that underlies motor recovery. ARRA-funded research grants in this area include testing standards for data collection and outcome research from rehabilitation centers, and assessing a home stroke rehabilitation system that includes user-friendly home therapy robots and a tele-rehabilitation system. A National Center for Medical Rehabilitation Research-funded project is studying the effects of home-based care for pediatric TBI patients in Latin America, where the incidence of TBI is three times the world average. The same project is also developing a data registry and improving the research infrastructure for future pediatric TBI research in Latin America.

92 For more information, see https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-11-007.html and https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-11-006.html.
93For more information, see https://grants.nih.gov/grants/guide/pa-files/PAR-10-144.html and https://grants1.nih.gov/grants/guide/pa-files/PAR-10-143.html.
94For more information, see https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-12-005.html and https://grants.nih.gov/grants/guide/rfa-files/RFA-NS-11-003.html.

Neurodegeneration: Fighting the Effects of Age, Exposure, and Disease

The progressive loss of neurons is a common endpoint of many diseases and insults to the nervous system. Such degeneration presents challenges to developing strategies to slow and prevent cell death, protect remaining neurons, and possibly replenish those that are lost. Aging is the most consistent risk factor for many disabling neurodegenerative disorders. As the number of older people in the U.S. is projected to increase dramatically between 2010 and 2030, it is imperative to discover new and more effective ways to improve the health and productivity of this segment of the population.

NIH research on neurodegenerative diseases focuses on understanding their biological and environmental causes, and on efforts to develop interventions that not only alleviate their symptoms, but that may slow or even stop disease progression. Initially supported through ARRA funds, the iPS Cell Consortium is developing induced pluripotent stem (iPS) cells in three neurodegenerative diseases (Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS)) for use in disease mechanism studies and preclinical therapy. In FY 2011, NINDS announced continued support for the iPS cell consortia through a public-private partnership with industry, non-government organizations, and the California Institute for Regenerative Medicine.

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, though some inherited forms of the disease become symptomatic in middle age. AD slowly impairs memory, thinking skills and, eventually, the ability to carry out the simplest tasks of daily living. NIH-supported basic research on AD mechanisms has contributed in recent years to the development of new drug treatments. Although these treatments can help to manage symptoms in some people, they cannot cure this devastating disease.

NIH, with NIA taking the lead, supports a comprehensive research portfolio on AD, including basic research, epidemiological studies and clinical trials, to better diagnose, prevent, and treat AD. Ongoing research initiatives include:

NIH currently supports over 35 clinical trials investigating a wide range of interventions to prevent, slow, or treat AD and/or cognitive decline. Many of these trials are coordinated through the long running AD Cooperative Study. Examples of highly promising studies include a pilot trial on a nasal-spray form of insulin to delay memory loss and preserve cognition, a study of brain amyloid deposits in healthy people as a predictor of AD risk, and the ADNI cerebrospinal fluid biomarker study, which may aid the development of a diagnostic test for the early stages of AD. Finally, a joint effort between NIA and the Alzheimer’s Association has made possible the first revision of the clinical diagnostic criteria for AD in 27 years. The new guidelines address the use of imaging and biomarkers to determine whether changes in the brain and body fluids are due to AD.

Parkinson’s disease (PD) ranks among the most common late-life neurodegenerative diseases, with a prevalence of 1 percent in individuals over the age of 60. NIH-supported research has identified 10 new genetic mutations as risk factors for PD, revealed the benefits and risks of deep brain stimulation in PD patients, determined that tai chi improves balance and stability in patients with PD more than resistance training or stretching, and developed a novel strategy for deriving dopamine neurons from human pluripotent stem cells. Ongoing research efforts continue to uncover new gene mutations associated with increased risk for PD. NINDS is establishing the PD Biomarkers Program, which will support clinical and laboratory-based research projects, as well as bio-repository and data management resources to accelerate biomarker discovery. NINDS also supports numerous investigator-initiated grants covering a variety of research priority areas, including the detection of genetic and environmental risk factors, identification of molecular and neurophysiological determinants of PD, and the development of technologies and therapeutics to improve symptoms or halt the progression of the disease. In addition, NINDS and NIEHS support numerous PD-related resources, research centers and clinical trials. For example:

Many of the leading causes of blindness are due to neurodegenerative diseases. In retinitis pigmentosa, genetic mutations in key proteins cause light-sensitive photoreceptor cells to die. NEI researchers are testing gene therapy to treat some of these diseases, and have published very promising gene replacement clinical trial results for a form of Leber’s congenital amaurosis, a retinal degenerative disease caused by a mutant enzyme. Stargardt’s disease and age-related macular degeneration (AMD) are neurodegenerative diseases in which atrophy of the retinal pigment epithelium (RPE), a tissue that supports and nourishes the photoreceptors, ultimately causes the neurons to die as well. In a clinical trial started in 2011, Advanced Cell Technology, Inc. transplanted RPE derived from human embryonic stem cells in patients with Stargardt’s and AMD. Although many neurodegenerative diseases may be caused by rare mutations, NEI is funding research on more general therapy options using neurotrophins, factors that function to protect neurons from degeneration and may be able to rescue neurons at risk of loss through neurodegeneration, no matter the cause.

Moreover, neurons are not unique in their vulnerability to degenerative diseases. Muscular dystrophies (MD) are a class of neuromuscular disorders that lead to progressive muscle weakness and degeneration. NIH support for research on MD includes funding for six congressionally-mandated Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers95 (also see the section on Wellstone MD Cooperative Research Centers in Chapter 4), as well as several initiatives for translational research. A public-private partnership funded by NIH, Parent Project MD, and PTC Therapeutics has made significant progress in identifying and optimizing small molecules that alter the levels of target proteins involved in the pathophysiology of MD. Other translational projects with public-private funding include a study focused on developing the peptide, biglycan, as a therapeutic for MD, and the first translational cooperative agreement for therapy development in myotonic dystrophy, the most common adult form of MD. The NIH Therapeutics for Rare and Neglected Diseases (TRND) Program has also accepted two MD projects for therapeutic co-development with biotech partners.

Other projects supported by NINDS and NIAMS focus on non-invasive imaging methods to track disease progression, and on understanding the molecular mechanisms underlying those forms of MD that are not yet at the stage of therapy development, such as congenital MD. NIAMS has recently funded a new Center of Research Translation of Systemic Exon-Skipping in MD, which will test the therapeutic potential of molecules that promote the production of a modified, but functional, form of the protein dystrophin. NHLBI also funds a number of basic and translational projects to investigate the basis for cardiac muscle disease in MD, and develop and evaluate novel therapies to prevent or restore dystrophin expression.

Multiple sclerosis (MS) is the most common of a number of diseases that lead to the degeneration of myelin, a fatty substance that sheathes many nerve fibers in the brain and the peripheral nervous system, causing a variety of symptoms including impaired mobility, spasticity, chronic pain, and depression. Despite tremendous efforts, the cause(s) of MS are still elusive. NIH-funded research covers a wide range of topics including studies on genetic and environmental risk factors; basic research on myelination, demyelination, and neuron degeneration; the blood-brain-barrier breakdown in MS; the immune system function in the central nervous system; optic neuritis (visual impairment due to inflammation or demylenation of the optic nerve); mechanisms underlying gender differences in the incidence of MS; and development of better strategies to diagnose MS and monitor disease progression. For example, NINDS supports a randomized, double-blind Phase III trial comparing the efficacy of treatment combining two FDA-approved MS medications (beta-interferon and glatiramer acetate) versus treatment with either agent alone for relapsing-remitting MS (CombiRx). Preliminary results showed that the combined treatment decreases the rate of brain lesions but was no more effective than either agent alone for reducing the risk of relapse. An ancillary study of CombiRx aims to identify gene and protein biomarkers of disease progression and treatment response in patients with relapsing-remitting MS. In addition, other Phase I/II clinical trials, including studies conducted at the NIH Clinical Center, are investigating the safety and efficacy of immunotherapies, mesenchymal stem cells, nutritional supplements, and hormonal treatments.

Advancing Neuroscience Research through Collaboration

Federal neuroscience research involves collaboration across NIH, HHS, and several other executive branch departments, including the Department of Defense (DoD), the Department of Veterans Affairs (VA), and the Department of Education (ED). For example, NIH ICs have a long history of collaboration with DoD and the VA on TBI research, including a long-term study of the neuropsychological outcomes associated with TBI among Vietnam War veterans and the development of the Federal Interagency TBI Research informatics repository.

Since its inception in 2004, the NIH Blueprint for Neuroscience Research has been a successful model of trans-NIH collaboration, bringing together 16 NIH ICs and Offices that support neuroscience research. The Blueprint continues to support clinical assessment tools for neurological and behavioral function, and widely used neuroimaging, neuroinformatics, and genetics and animal model resources. The NIH Blueprint also supports training programs for neuroscience researchers, including programs focused on interdisciplinary research training, computational neuroscience, neuroimaging, and translational research. In addition, the Blueprint has announced new Grand Challenges initiatives focused on understanding the connectivity of the human brain, neuropathic pain, and the development of treatments for brain disorders.

Other recent NIH Blueprint for Neuroscience Research initiatives include:

Other NIH collaborative activities for neuroscience research include collecting and sharing clinical research data, which requires large investments in time and resources. However, currently there is no uniform way to help investigators implement NIH data-sharing policies for research on neurological disorders. In 2006, NINDS initiated an effort called Common Data Elements96 to address this issue for many different disease areas. NINDS has worked with disease-specific experts and other stakeholders as part of this effort to develop standards to facilitate data collection, analysis and sharing across the research community. To date, this effort has led to the development of a set of core data elements, and disease-specific elements for headache, spinal cord injury, stroke, epilepsy, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Friedrich’s ataxia, and multiple sclerosis, all of which are available on the website for use by investigators. A working group is currently developing data elements for several neuromuscular diseases, such as spinal muscle atrophy, Duchenne muscular dystrophy, traumatic brain injury, and myasthenia gravis.

Using FY 2009 ARRA funds, NIH is constructing the 293,839 square feet Porter Neuroscience Research Center Phase II, which will host cross-disciplinary researchers for seven ICs generating discoveries in structural biology, synaptic processing, sensory systems and sensory development, neuroenvironments, neurodevelopment and neurodegeneration, behavior, genetics, and high resolution microscopy.

The Joint NSF/NIH Initiative to Support Collaborative Research in Computational Neuroscience is a joint initiative among seven NSF Directorates and Offices, nine participating NIH ICs, and the German Federal Ministry of Education and Research. The program supports innovative, collaborative science and engineering research on brain function, integrating computational models and methods with neuroscience, emphasizing data sharing.

NIH IC Directors participate in the Institute of Medicine Forum on Neuroscience and Nervous System Disorders, which focuses on building partnerships to further understand the brain and nervous system, disorders in their structure and function, as well as effective clinical prevention and treatment strategies.

NIMH has partnered with the U.S. Army and DoD to carry out the Army Study to Assess Risk and Resilience in Service members (Army STARRS), the largest study of suicide and mental health among military personnel ever undertaken. The rate of suicide among Army soldiers has exceeded the civilian rate. This initiative seeks to identify risk and protective factors, including neurobiological factors that will help the Army develop effective strategies for reducing rising suicide rates.

NIH, in partnership with DOD, is building a central database for traumatic brain injury (TBI) research designed to promote data sharing and accelerate comparative effectiveness research on brain injury treatment and diagnosis. The Federal Interagency TBI Research database will serve as a central repository for new data, link to existing databases, and allow valid comparisons of results across studies. By collecting uniform and high-quality data on TBI, including brain imaging scans and neurological test results, the database will help to address current challenges associated with wide variation across studies in how data are collected and described.

The National Action Alliance for Suicide Prevention is a public-private partnership that includes representatives from NIH, CDC, the Substance Abuse and Mental Health Services Administration, the U.S. Army, and other federal entities. The Alliance’s mission is to help guide the implementation of the goals and objectives set forth in the National Strategy for Suicide Prevention. NIMH is co-chairing an Alliance taskforce that aims to identify gaps in suicide research, including neuroscience research, that demonstrate promise in advancing the goal of reducing suicide through prevention.

NIMH provides leadership to the HHS Interagency Autism Coordinating Committee and works with other ICs, multiple HHS agencies, ED, and private research foundations to coordinate a national strategy for research on autism spectrum disorder. Each year, the Committee releases an updated Strategic Plan for Autism Spectrum Disorder Research.

Pain research activities at NIH are coordinated in large part by the NIH Pain Consortium—a joint undertaking across 25 ICs and Offices that identifies and facilitates implementation of key opportunities in collaborative pain research. In 2010–2011, the Consortium was proactive in coordinating a number of pain research initiatives and activities at NIH, which included identifying key opportunities in pain research and education, convening conferences and workshops to highlight recent advances and needs in the field, and building collaborations with other federal agencies, such as the FDA, and academic institutions involved in pain research.

95For more information, see https://www.nichd.nih.gov/research/supported/mdcrc.cfm.
96 For more information, see https://www.commondataelements.ninds.nih.gov/#page=Default.