NIH – Global Brain and Nervous System Disorders Research Across the Lifespan (R01, R21 Clinical Trials Optional)

The following description was taken from the R01 version of this FOA.

This Funding Opportunity Announcement (FOA) encourages applications proposing innovative, collaborative research projects between United States (U.S.) and low- and middle-income country (LMIC) scientists (or direct collaborations between upper middle-income country (UMIC), and other LMIC scientists) on brain and other nervous system function and disorders throughout life, relevant to LMICs. This includes neurological, mental, behavioral, and alcohol substance use disorders and spans the full range of science from basic to implementation research. These research programs are expected to contribute to the long-term goals of building sustainable research capacity in LMICs to address nervous system development, function and impairment throughout life, which may ultimately lead to diagnostics, prevention, treatment, rehabilitation and implementation strategies.

The proposed research must be relevant to the interests of one of the participating NIH Institutes and Centers (ICs) (other than FIC) as stated in this FOA. Applications must be submitted as collaborations between U.S. (or UMIC category of LMICs) and LMIC investigators/institutions. An R01 application under this FOA must continue to build on already established research, research collaborations and research capacity building activities at the LMIC site(s). Applicants who need time and funding to develop research collaborations and capacity, and to conduct pilot studies are encouraged to apply first to the companion R21 FOA (PAR-18-836  ).

Background

During the past several decades, improvements in health care have led to a decrease in mortality (including and especially among children) and an increase in life expectancy in LMICs. These positive trends have set the stage for a complex and paradoxical epidemiology of health and disease as more children survive into adulthood and are affected by the sequelae of combined early illness, malnutrition and adverse experiences. These exposures can also advance the onset and severity of chronic diseases including cognitive and neurodegenerative disorders in later life. Similarly, socio-economic factors, such as poverty, conflict, stigma and gender inequalities, contribute to the initial causes (such as injury, psychological trauma, chronic adversity, genetic vulnerability and infection) of many nervous system disorders. These disorders, in turn create a negative feedback loop handicapping the physical and cognitive ability of individuals and their societies to address the root causes of nervous system disorders and their risk factors. The biological and cultural effects may extend for generations.

Data published in the updated Global Health Estimates for the Global Burden of Disease (GBD) (http://www.who.int/healthinfo/global_burden_disease/en/ ), continues to show that non-communicable diseases and disorders (NCDs) are rapidly becoming the dominant causes of poor health globally, including all LMIC regions with the exception of sub-Saharan Africa, where they are second only to HIV/AIDS, as defined by contribution to years lived with disability (YLD).

Disorders of the nervous system, e.g. neurodegenerative disorders such as Alzheimer’s Disease, combined with disorders affecting the nervous system, e.g. cerebral malaria, in aggregate contribute the most to the global burden of NCD disease and disability (followed by cardiovascular disease and cancer). They also contribute about a third of the burden due only to NCDs in LMICs (Global Burden of Disease and Risk Factors Report, DCP2, 2006, http://www.dcp-3.org/dcp2 and see the Global Health Estimates http://www.who.int/healthinfo/global_burden_disease/en/ ). The following nervous system disorders account for four out of the six leading causes of YLDs: mental and behavioral disorders, especially unipolar depression and bipolar affective disorder, substance-use, alcohol-use disorders, schizophrenia and dementias.

Maternal, perinatal and nutritional conditions (including anemia) along with communicable diseases still contribute disproportionately to Disability Adjusted Life Years (DALYs, a measure of overall disease burden, expressed as the number of years lost due to ill-health and disability or early death) in LMICs as compared to high-income countries. These conditions may also lead to impairment of nervous system development, function and long-term health (http://www.who.int/healthinfo/global_burden_disease/en/).

Infectious and parasitic diseases, such as HIV/AIDS, tuberculosis, malaria and other neglected tropical diseases as well as emerging diseases such as Zika, are a burden for LMICs, where they continue to be important causes of YLDs by themselves and due to their long-term effects on the nervous system, especially of children. However, very limited data is available on the epidemiology, natural history and pathogenesis of neurological problems caused by these diseases and associated opportunistic infections and co-morbidities in these settings.

Chronic pain, especially of the neck and back, is also now recognized for its large contribution to the burden of disability. Neurological disorders such as epilepsy, migraine, Parkinson’s disease, and multiple sclerosis make smaller but significant contributions. Stroke and perinatal asphyxia, with neurological complications, are also a significant problem in LMICs particularly since some of the causative factors of stroke such as hypertension are poorly treated in LMICs as compared to high-income countries.

Mental, alcohol and substance use disorders were ranked as the 3rd leading contributors to the burden of disease when the burden attributable to suicide (which is a leading cause of death in many regions) is also considered. Depression, the most common psychiatric disorder, accounts for the largest proportion of suicide-related DALYs.

The incidence of neurodevelopmental disorders and related cognitive disorders (such as mental retardation, behavioral disorders, learning disabilities and cerebral palsy) is less well characterized in LMICs. However, many of the root causes of developmental disabilities – including genetic and nutritional factors, infectious diseases, environmental toxins, and traumatic events (both pre- and post-natal) are particularly common in resource-poor countries, and their prevalence is high. Early neurodevelopmental disorders, along with disability due to postnatal injury or insult to the brain and central nervous system during infancy or childhood, are clearly a heavy burden in LMICs.

Disability from disease and injury and the need for rehabilitation and accommodation will be an increasingly heavy burden on all health systems. GBD 2010 (http://www.who.int/pmnch/media/news/2012/who_burdenofdisease/en/ )

put an important spotlight on nervous system related chronic disability (and its particularly heavy toll on women)—from, for example, mental health disorders, substance abuse, musculoskeletal disease, accidents, chronic pain and loss of vision and hearing.

Overall, the burden of neurological, mental, behavioral and substance use disorders together is expected to rise worldwide, as a proportion of the global burden of disease and disability, because of the projected increase in the number of individuals entering the ages of risk for the onset of many such disorders. Humans are living longer and birth rates are down. As recently as 1950, about 5% of the people in the world were over 65 and about 15% under 5. Those numbers are on track to reverse the years 2050. Direct attention to research on diseases and disorders of later life is therefore needed. But the rise of these disorders is expected to be steeper in LMICs, because of the continuing and long-lasting contributing effects of early life trauma, infectious disease and malnutrition, further highlighting the need for research on the influence and impact of early health/illness/treatment, experience and environment on development of those diseases and disorders, across the lifespan.

These problems pose a greater burden on vulnerable groups such as people living in poverty, those coping with disease, and those exposed to emergencies. For example, disaster, war and conflict situations are especially prevalent in many LMICs and may lead to post-traumatic stress disorder (PTSD), this affects a substantial proportion of the overall population exposed to such conditions which may lead to persistent dysfunction on top of already existing disorders. In addition, stigmatization and gender inequality amplify many of the key risk factors for nervous system disorders and contribute to poor access to and quality of treatment.

Lack of adequate prevention and treatment in LMICs is a major contributor to the burden of disease and disability. In some countries, the overall physician-patient ratio can be low as 1:20,000, with even fewer psychiatrists and neurologists. Some disabling brain disorders are readily treatable at low cost, and yet many in LMICs suffer untreated with detrimental individual, family, and societal consequences. For example, epilepsy is a common brain disorder that disproportionately affects people in LMICs (roughly 85 percent of the total number affected worldwide). Although inexpensive and effective treatments are available, epilepsy is frequently untreated and even unrecognized in LMICs, often because of stigmatization and lack of knowledge. For such disorders, implementation science that integrates social and cultural factors into education, media, policy and behavior change research is especially needed and appropriate.

Prevention of disability due to neurological impairment from adverse or toxic environmental exposures is possible in many situations with appropriate research leading to knowledge and interventions. For example, research to identify neurotoxins and their mechanisms can be combined with interventions to minimize human exposure by a reduction in use or release to the environment and by appropriate safeguards in occupational settings.

Despite their enormous burden of disease, nervous system disorders have been largely absent from the global health research agenda. In addition to research on the etiology, prevention and treatment of individual impacts, conditions and disorders, more information is needed on co-morbidities among nervous system disorders and between these disorders and other chronic NCDs. Many of these conditions exist together in LMICs and are likely to have more severe and complicated effects than any in isolation and often extend beyond the individual affected (for example maternal depression as a risk factor for infant stunting). Research on the social and economic impact of neurological, psychiatric, and developmental disorders is needed to inform interventions, implementation and policy. Research is also needed to further define the burden and identify knowledge gaps, needs, opportunities and methods to effectively reduce the burden and to lay the groundwork for developing and testing interventions.

Applicants are encouraged to refer for more background to recent publications summarizing the state of knowledge on the burden of nervous system disorders around the world including the following:  Disease Control Priorities Related to Mental, Neurological, Developmental and Substance Abuse Disorders (contains five chapters from the Disease Control Priorities in Developing Countries, second edition, World Health Organization 2006,  http://whqlibdoc.who.int/publications/2006/924156332x_eng.pdf. Also, see http://www.who.int/healthinfo/global_burden_disease/gbd/en/ and special resources at https://www.fic.nih.gov/ResearchTopics/Pages/neurological-mental-disorders-diseases.aspx  including the FIC/NIH convened series of papers: “Brain disorders across the lifespan: Research to achieve nervous system health worldwide“, Nature supplement, Nov 19, 2015

http://www.nature.com/nature/supplements/collections/npgpublications/brain-disorders/index.html).

Research Topics

Relevant research topics for this FOA are related to nervous system function and/or impairment from birth to advanced age and across generations, and must be relevant to the collaborating LMICs. Applicants are especially encouraged to propose research on co-morbidities and conditions that affect nervous system function at different life stages, as well as across the lifespan. Relevant research for these applications may range from basic science to epidemiological, clinical, health services, translational (e.g. translation of basic research to therapy and of clinical research to applications in the field) and implementation research.  Applicants may propose a research and capacity building program on some aspect of nervous system function and/or impairment at any stage of life.

Examples of nervous system disorders contributing to the burden of disease in LMICs and relevant to this FOA include, but are not limited to, neurodevelopmental disorders (including autism, cerebral palsy, fetal alcohol syndrome, learning disabilities, hydrocephaly, microcephaly), neurodegenerative diseases (such as Alzheimer’s and Parkinson’s Diseases), addictive disorders, seizure disorders (such as epilepsy), neuropsychiatric disorders (such as unipolar depression, bipolar disorder, schizophrenia), posttraumatic stress disorder, dementias, encephalopathy, peripheral neuropathies, sensory and motor neuron diseases.

Examples of influences on nervous system function across the lifespan include, but are not limited to: genetic predispositions and epigenetic  changes  in response to pre-, peri- and post-natal trauma and environmental factors (such as maternal depression, in-utero drug and alcohol exposure, neurotoxic insults, perinatal hypoxia, child abuse and neglect, inadequate environmental stimulation, and nutritional deficiencies), physical and psychological trauma (exposure to violence, sexual and  physical abuse, traumatic nervous system injury due to violence and accidents), infection of the nervous system by bacterial, viral and parasitic diseases (such as Zika, HIV/AIDS, malaria, neurocysticercosis, neonatal sepsis) and stroke. Other factors affecting healthy brain development include access to appropriate health care, environmental and socioeconomic factors.

Examples of some cross-cutting areas for research are:

  • Ethnographic studies and other areas of social science, particularly to address health systems, availability of resources, preventive or screening practices, and appropriate interventions within a given society or group;
  • Gender and socio-cultural and economic factors in the etiology, prevention and treatment of the disorders to be addressed;
  • Sex differences at all levels of brain and nervous system function and disorders;
  • The influence of socio-cultural or other environmental variables on the natural history of common neurological diseases/disorders and how this knowledge can be used for treatment and intervention;
  • Factors associated with aging affecting cognitive, emotional/mental and physical health and survival in older persons along with interventions and treatments;
  • Co-occurring risk factors or conditions, especially common in the LMIC or region (e.g. neuro-toxic or traumatic insult plus infectious disease and/or malnutrition);
  • Mechanisms (e.g. neurotoxic, epigenetic) underlying genetic, physiological, environmental, social and economic factors and interactions that affect brain function or development and result in behavioral outcomes (e.g., expression of cognitive impairment, coping, adaptation, response to intervention); and
  • Epidemiology: 1) Descriptive epidemiology to describe and define the problem in the countries in question by assessing the needs and determining the magnitude of factors involved in the problem to be addressed (e.g., research on trends in incidence, prevalence or mortality; distribution of disease; determination of population at risk; determination of case definition/disease classification). 2) Analytical epidemiology to identify potential etiological factors in the populations of interest, including factors responsible for predispositions to the neurological consequences of various infection and/or neurotoxins (e.g., identification of risk factors for neurological consequences of disease onset or progression; classification and measurement of exposure; magnitude and distribution of known risk factors).

Types of research relevant to this announcement include basic research and epidemiology, as well as translational research, research on diagnostics, early interventions, clinical treatment, prevention, and health services that are culturally appropriate, feasible, and acceptable for implementation within the LMIC. This FOA encourages the development of multidisciplinary and interdisciplinary research and the capacity in the LMIC to conduct such research, relevant to the research question. Expertise may involve, but is not limited to, fields such as genetics/epigenetics, epidemiology, neurology, cognitive neuroscience, developmental neurobiology, neuro-toxicology, neuro-endocrinology, pharmacology, psychiatry, neuro-immunology, neuro-virology, neurosurgery, neuro-rehabilitation and biotechnology (e.g., for development of diagnostic tools and treatments), as well as the behavioral and social sciences including health economics, health services and implementation science.

Research Capacity Building

The proposed collaborative exploratory/developmental research is expected to help build the capacity for full research programs by improving the research environment and strengthening LMIC individual and institutional research capabilities in the proposed research areas. The proposed work and follow up research are expected to contribute to the long-term goals of building sustainable research capacity in brain and nervous system diseases and disorders in LMICs. The proposed project may also contribute to the development of research networks and evidence-based policy.

For purposes of the research capacity building and networking encouraged in this FOA, and for background, applicants are also encouraged to use as a resource the compilation of the past awards under the past FOAs under the Brain Disorders in the Developing World: Research Across the Lifespan  program (http://www.fic.nih.gov/Programs/Pages/brain-disorders.aspx) along with the resources there including the symposium highlighting a decade of research under the program  (http://www.fic.nih.gov/News/GlobalHealthMatters/january-february-2014/Pages/brain-disorders-program-10th-anniversary.aspx ).

Specific Research Interests of the FOA Sponsors

Participating NIH Institutes and Centers (ICs) provided specific statements of interest for this FOA below. Applicants can obtain more information on research interests for each of the NIH participants in this FOA at their websites and through their Scientific/Research contact listed in this announcement.

The Fogarty International Center (FIC) is interested in all eligible applications relevant to the focus of this FOA and its mission. The FIC Strategic plan (http://www.fic.nih.gov/About/Pages/Strategic-Plan.aspx) states the following relevant goals: 1) Build research capacity through individuals, institutions, and networks to meet future and evolving global health challenges; 2) Stimulate innovation in the development and implementation of technologies and other locally relevant solutions to address global health problems; 3) Support research and research training in implementation science; 4) Advance research on prevention and control of the dual burden of communicable and non-communicable diseases and disabilities; and 5)  Build and strengthen partnerships to advance global health research and research capacity.

The National Institute on Aging (NIA) is interested in applications relevant to Alzheimer’s disease, other degenerative diseases of the nervous system in aging, and/or age-related changes in cognition, memory, sensory, and/or motor function, and in brain structural and functional connec

tivity at the cell, circuit, and network level. Of interest, also are studies on reducing disability and/or preventing or slowing additional decline among persons with cognitive, sensory, or motor disabilities as they continue to age.  The studies may be laboratory-, clinic-, or population-based.  Cross-cultural studies with data harmonization are welcome if focused on the topics above.

The National Eye Institute (NEI) is interested in applications relevant to its mission as stated on the NEI website: http://www.nei.nih.gov/about/mission.asp.

The National Institute on Deafness and Other Communication Disorders (NIDCD) conducts and supports research in 7 scientific program areas: hearing, balance/vestibular, voice, speech, language, taste and smell. The mission of the NIDCD is to reduce the burden of communicative disorders and improve public health. NIDCD is especially interested in applications that strengthen research capacity building & clinical intervention by otolaryngologists, audiologists, speech-language pathologists and related medical and health professionals. Areas focused on newborn screening of hearing ability and early identification and treatment of voice, speech, and language delay or disorders are highly desirable.

Normal hearing ability is central to the development of effective verbal expression. Communication disorders occur throughout the lifespan and can occur in isolation (e.g. hearing loss, stuttering) or may occur within the context of a hearing impairment or a neurodevelopmental disorder (e.g. autism). Communication disorders may be heritable, due to in utero exposure, or result from injury, neurologic condition (e.g. stroke), head and neck cancer, or coexist with congenital physical conditions (e.g. cleft lip/palate).  Developing research capacity of a health-related workforce fluent in the languages spoken in the LMIC is a plus. Applications from institutions within a geographic region which share the same spoken language e.g. Latin America, Middle East and North Africa would offer nodes on which to build future regional networks for communication disorders or for the development of national and regional Centers of Excellence in Communication Sciences & Disorders.

NIDCD is interested in funding the development and implementation of epidemiological studies on the incidence, prevalence, and determinants of hearing impairment and other communication disorders across the lifespan, including risks associated with behavioral, demographic, environmental, genetic, or other health factors.

The National Institute of Environmental Health Sciences (NIEHS) is interested in supporting research in LMICs to identify the causes of, and opportunities to prevent or ameliorate the consequences of neurotoxic insult to the nervous system throughout the lifespan. Research in LMICs is encouraged in how exposures to toxic environmental insults alter biologic processes, are linked to disease initiation or progression, or affect the risk of either disease development or distribution in populations. Examples of environmental exposures of interest include industrial chemicals or manufacturing byproducts, metals, pesticides, herbicides, air pollutants and other inhaled toxicants, particulates or fibers, fungal, food or bacterially derived toxins (but not infectious agents, per se) and indoor air pollutants from cooking stoves and other sources.

The National Institute of Mental Health (NIMH) encourages studies across the research spectrum, from basic through translational science to intervention development and efficacy, effectiveness, and implementation research. Mental disorders may be defined according to existing diagnostic criteria or along dimensions of neurobehavioral functioning according to the NIMH Research Domain Criteria (RDoC) framework. If existing diagnostic criteria are to be used, investigators should include plans for addressing heterogeneity within the diagnostic category or categories. Relevant research topics include, but are not limited to, research that:

  • Charts the course of neuropsychiatric disorders over the lifespan in order to: (a) understand ideal times and methods for intervention to preempt or treat mental disorders and hasten recovery; (b) examine the interactions of neurobiological systems and environmental/social factors that affect brain development, resulting in maladaptive behavioral outcomes (e.g., cognitive impairment, inability to respond to intervention); or (c) identify molecular or circuit pathways of neural function that are promising new intervention targets.

  • Seeks to understand sex, genetic, or other biological differences implicated in the presentation, course, severity, or disease burden of mental disorders or in treatment response.

  • Assesses new psychosocial and biomedical interventions, with a focus on mediators, moderators, and predictors (e.g., biological, genetic, behavioral, experiential, environmental) of intervention response and side effects in diverse patient populations.

  • Examines approaches to care for people with chronic, severe mental illnesses in institutional and community settings.

  • Examines implementation models and measures of care quality and outcomes that produce optimal results for: (a) early identification of mental disorders, (b) scaling up of training and supervision for mental health care providers, (c) integrating screening and core packages of care for mental illnesses into existing delivery platforms (e.g., primary health care, schools, HIV services, workplaces), or (d) delivering transdiagnostic interventions for mental disorders in health sector and non-health sector settings.

  • Assesses data collection and feedback models for monitoring the reach, accessibility, quality, costs, and/or effectiveness of preventive, treatment, or rehabilitative health services for mental disorders (e.g., how models enable data-driven decision-making for optimal delivery of care).

  • Targets HIV/AIDS related topics such as epidemiology, natural history and pathogenesis and genetics of HIV-associated CNS dysfunction and neuropsychiatric disorders before and after treatment initiation in adult and pediatric populations; examination of the neurobehavioral consequences, with respect to in-utero exposure to a dysregulated immune environment and/or antiretroviral medication and consequences of being born to an HIV-positive mother.  NIMH encourages development of common standardized assessment instruments with appropriate norms that can provide reliable and valid measurement of neurobehavioral consequences of HIV and its treatments throughout the age-span in low- and medium-resource environments; and develops interventions to improve neurobehavioral functioning compromised by HIV/AIDS and its associated conditions that can be implemented in LMICs. NIMH also supports research toward a cure including developing novel approaches and strategies to identify and eliminate CNS viral reservoirs that could lead toward a cure or lifelong remission of HIV infection, including studies of viral persistence, latency, reactivation, and eradication.

  • NIMH would also like to encourage the NIMH mission centered research networks option as described in this FOA

The National Institute of Neurological Disorders and Stroke (NINDS) is interested in supporting mechanistic, epidemiological, prevention, translational and clinical research across the spectrum of neurological, neuromuscular, neuroinfectious and neurovascular diseases and disorders in all ages. In addition to prevalent neurological disorders and stroke, NINDS is also interested in supporting research and capacity building in areas of rare and neglected neurological diseases that are relevant to the collaborating LMICs (NINDS Disorder Index http://www.ninds.nih.gov/disorders/disorder_index.htm). NINDS would like to encourage the development of networks in topical disease-related areas (e.g., stroke, epilepsy or other high burden neurological disorders in LMICs) or linked to existing programs or resources in LMICs (e.g., MEPI, H3Africa, or other NIH-funded projects) to share capacity building activities and conduct collaborative research. ADD:  Applicants interested in clinical trials for neurological disorders within the NINDS mission are also referred to NINDS clinical trial-specific funding announcements (PAR-18-422 and PAR-18-420).

Deadlines:  November 7, 2018; November 7, 2019 (letters of intent are due 30 days prior to the deadline)

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