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17.17: Other Neurological Disorders - Biology

17.17: Other Neurological Disorders - Biology


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There are several other neurological disorders that cannot be easily placed in the above categories. Epilepsy and stroke are discussed below.

Epilepsy

Estimates suggest that up to three percent of people in the United States will be diagnosed with epilepsy in their lifetime. While there are several different types of epilepsy, all are characterized by recurrent seizures. Epilepsy itself can be a symptom of a brain injury, disease, or other illness. For example, people who have intellectual disability or ASD can experience seizures, presumably because the developmental wiring malfunctions that caused their disorders also put them at risk for epilepsy. For many patients, however, the cause of their epilepsy is never identified and is likely to be a combination of genetic and environmental factors. Often, seizures can be controlled with anticonvulsant medications. However, for very severe cases, patients may undergo brain surgery to remove the brain area where seizures originate.

Stroke

A stroke results when blood fails to reach a portion of the brain for a long enough time to cause damage. Without the oxygen supplied by blood flow, neurons in this brain region die. This neuronal death can cause many different symptoms—depending on the brain area affected— including headache, muscle weakness or paralysis, speech disturbances, sensory problems, memory loss, and confusion. Stroke is often caused by blood clots and can also be caused by the bursting of a weak blood vessel. Strokes are extremely common and are the third most common cause of death in the United States. On average one person experiences a stroke every 40 seconds in the United States. Approximately 75 percent of strokes occur in people older than 65. Risk factors for stroke include high blood pressure, diabetes, high cholesterol, and a family history of stroke. Smoking doubles the risk of stroke. Because a stroke is a medical emergency, patients with symptoms of a stroke should immediately go to the emergency room, where they can receive drugs that will dissolve any clot that may have formed. These drugs will not work if the stroke was caused by a burst blood vessel or if the stroke occurred more than three hours before arriving at the hospital. Treatment following a stroke can include blood pressure medication (to prevent future strokes) and (sometimes intense) physical therapy.


17.17: Other Neurological Disorders - Biology

Key Dates
Release Date: July 25, 2017

Related Announcements
None

Issued by
National Institute of Neurological Disorders and Stroke (NINDS)

Excellent mentorship and superior training are critical to the development of exceptional future scientists. The National Institute of Neurological Disorders and Stroke (NINDS) will recognize the importance it places on outstanding mentorship and training through a new annual award, the NINDS Landis Award for Outstanding Mentorship. Each year, up to five (5) faculty members who are considered to be outstanding mentors and trainers will be awarded $100,000 (direct costs), to be used to foster the advancement of additional students and postdoctorates towards an independent research career. NINDS hopes that this tangible award will impress upon the scientific community as a whole, and faculty and institutional leaders in particular, the high value NINDS places on outstanding training and mentorship and the need for faculty and institutions to emphasize dedication to mentorship in addition to outstanding research accomplishments.

Selection for this new award will be based on nomination from those who have first-hand knowledge of an individual&rsquos outstanding mentorship. Current or former trainees can nominate faculty members who have served as their mentors. Faculty members nominated by two or more mentees will then be invited to submit additional information needed for the selection process. Eligible individuals for this award must be in a tenure-track or equivalent faculty position and hold an active NINDS R01, R35 or P01 with at least one year left on their grant at the time of award.

The full details of the award, and the selection process, can be found at Landis Mentor Award. Because outstanding mentors exist at each career stage, and have different levels of mentorship accomplishments, NINDS will rotate eligibility requirements each year. In the first 3 years (FY2018, 2019, 2020), NINDS will seek nominations for junior faculty mentors (in the 5th – 12th year from the start of their first tenure track or equivalent position), mid-career mentors (in the 13th – 20th year from the start of their first tenure-track or equivalent position), and senior faculty mentors (>20 years from their first tenure-track or equivalent position), respectively. NINDS will select awardees from among the nominated individuals who conduct outstanding, rigorous research and have shown a dedication to superior mentorship and training.

With this notice, NINDS invites nominations of outstanding mentors who are 5 to 12 years from the start of their first tenure-track or equivalent faculty positions. Although these nominees will not have an extensive track record of mentorship, they will have, at the earliest stage of their independent research careers, demonstrated a dedication to helping trainees towards their goal of becoming exceptional, successful, independent scientists. By making mentorship awards to these individuals, NINDS intends to send a strong message that it recognizes the time and effort they have dedicated to the careers of others and to their active training of individuals to conduct outstanding, rigorous, high-impact research. This award is meant to encourage junior faculty to dedicate themselves to strong mentorship and training of others, in addition to their own research productivity, and to encourage institutional leaders to place a high value on training and mentorship by its faculty.

Nominations for the NINDS Landis Mentor Award will be accepted ONLY from current and former trainees of the nominated individual. To nominate a current or former mentor, individuals should click on Landis Mentor Award and complete a nomination form by December 15, 2017. The following information will be requested:

  • Nominator's name and current position
  • Name of individual being nominated (the nominee)
  • Current institution and email address of nominee
  • Start date of nominee&rsquos first tenure-track or equivalent position
  • Relationship of nominator to nominee (dates of mentorship, position of nominator when mentored by nominee [e.g. Former or Current Graduate Student, Postdoctoral Fellow, etc.])
  • Statement describing the basis for the nomination. This description should include: what made/makes the nominated individual an exceptional mentor/trainer what are specific examples of extraordinary dedication to mentorship personally experienced or witnessed what does the individual do to ensure that trainees conduct the highest quality research with respect to scientific premise, experimental design and analysis what were the specific nominee activities that influenced the nominator&rsquos growth as a neuroscientist.

For a nomination to be considered, all of the above information must be provided via the nomination form found at Landis Mentor Award.


US burden of neurological disease is nearly $800 billion/year

The most common neurological diseases cost the United States $789 billion in 2014, and this figure is projected to grow as the elderly population doubles between 2011 and 2050, according to a new study published in the April issue of the Annals of Neurology. The research shows the price tag of this serious, annual financial burden for the nation, and comes at a time when the new administration has proposed significant budget cuts for federally-funded research.

Based on this demographic trend, the American Neurological Association (ANA) commissioned a study led by former ANA marketing committee and public advocacy committee chair Clifton L. Gooch, MD, currently professor and chair of the Department of Neurology at the University of South Florida's Morsani College of Medicine in Tampa. The study, The Burden of Neurological Disease in the United States: A Summary Report and Call to Action, details the annual cost of nine key neurological diseases and disorders, including Alzheimer's disease and other dementias low back pain stroke traumatic brain injury migraine epilepsy multiple sclerosis spinal cord injury and Parkinson's disease. Neurological diseases impact an estimated 100 million Americans every year, with the costs of dementia and stroke alone projected to total more than $600 billion by 2030.

A "Moonshot" for Neurology:

The huge and sustained capital investments made in cardiovascular and cancer research starting in the 1970s have increased lifespan. Ironically, these gains have increased the number of elderly who are most susceptible to neurological disease, creating a growing epidemic.

"Neurological research, like cancer, needs its own 'Moonshot' to focus substantial research investment on the neurological diseases that are impacting the mortality and quality of life of more and more Americans every year," said Gooch, referring to the $1.8 billion in funding for cancer research authorized by Congress in 2016. "We hope the findings of this report will serve as a wake-up call to

Congress to increase much needed basic and clinical research funding required to discover treatments which can mitigate, and ultimately cure, the major neurological diseases which have such profound effects in our patients and for the national economy."

"The future of funding for neurological research was a concern in 2012 when the ANA voted to support this investigation," said ANA President Barbara G. Vickrey, MD, MPH. "With the cuts currently proposed to the NIH budget by the President of the United States, it is of even greater concern today. As representatives of the scholars working to eradicate these diseases, we feel we must raise our collective voices, armed with the facts."

Researchers compiled the report through a detailed review of the world literature of the most costly and most prevalent neurological diseases in the United States. To be conservative, researchers focused on the prevalence and cost estimates they considered most comprehensive and accurate, excluding disorders like depression and chronic pain, which often have mixed etiologies beyond primary nervous system injury.

A conservative estimate:

"A full accounting of all neurological disorders, would of course, push cost estimates substantially higher," the authors wrote. Direct and indirect costs for each of the major diseases were estimated based on care norms for each disease and are detailed in the report.

Alzheimer's and other dementias accounted for $243 billion of the $789 billion total, while chronic low back pain represented $177 billion and stroke, $110 billion.

Dollar figures were converted to 2014 values using the all-items consumer price index for non-medical (indirect) costs. Direct costs were converted using the medical price index.

In addition to documenting the financial costs of neurological disease, Gooch and his USF colleagues recommend an action plan for reducing the burden through infrastructure investment in neurological research and enhanced clinical management of neurological disorders. Specifics include:


17.17: Other Neurological Disorders - Biology

A nervous system that functions correctly is a fantastically complex, well-oiled machine—synapses fire appropriately, muscles move when needed, memories are formed and stored, and emotions are well regulated. Unfortunately, each year millions of people in the United States deal with some sort of nervous system disorder. While scientists have discovered potential causes of many of these diseases, and viable treatments for some, ongoing research seeks to find ways to better prevent and treat all of these disorders.

Neurodegenerative Disorders

Neurodegenerative disorders are illnesses characterized by a loss of nervous system functioning that are usually caused by neuronal death. These diseases generally worsen over time as more and more neurons die. The symptoms of a particular neurodegenerative disease are related to where in the nervous system the death of neurons occurs. Spinocerebellar ataxia, for example, leads to neuronal death in the cerebellum. The death of these neurons causes problems in balance and walking. Neurodegenerative disorders include Huntington’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease and other types of dementia disorders, and Parkinson’s disease. Here, Alzheimer’s and Parkinson’s disease will be discussed in more depth.

Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia in the elderly. In 2012, an estimated 5.4 million Americans suffered from Alzheimer’s disease, and payments for their care are estimated at $200 billion. Roughly one in every eight people age 65 or older has the disease. Due to the aging of the baby-boomer generation, there are projected to be as many as 13 million Alzheimer’s patients in the United States in the year 2050.

Symptoms of Alzheimer’s disease include disruptive memory loss, confusion about time or place, difficulty planning or executing tasks, poor judgment, and personality changes. Problems smelling certain scents can also be indicative of Alzheimer’s disease and may serve as an early warning sign. Many of these symptoms are also common in people who are aging normally, so it is the severity and longevity of the symptoms that determine whether a person is suffering from Alzheimer’s.

Alzheimer’s disease was named for Alois Alzheimer, a German psychiatrist who published a report in 1911 about a woman who showed severe dementia symptoms. Along with his colleagues, he examined the woman’s brain following her death and reported the presence of abnormal clumps, which are now called amyloid plaques, along with tangled brain fibers called neurofibrillary tangles. Amyloid plaques, neurofibrillary tangles, and an overall shrinking of brain volume are commonly seen in the brains of Alzheimer’s patients. Loss of neurons in the hippocampus is especially severe in advanced Alzheimer’s patients. (Figure) compares a normal brain to the brain of an Alzheimer’s patient. Many research groups are examining the causes of these hallmarks of the disease.

One form of the disease is usually caused by mutations in one of three known genes. This rare form of early onset Alzheimer’s disease affects fewer than five percent of patients with the disease and causes dementia beginning between the ages of 30 and 60. The more prevalent, late-onset form of the disease likely also has a genetic component. One particular gene, apolipoprotein E (APOE) has a variant (E4) that increases a carrier’s likelihood of getting the disease. Many other genes have been identified that might be involved in the pathology.

Unfortunately, there is no cure for Alzheimer’s disease. Current treatments focus on managing the symptoms of the disease. Because decrease in the activity of cholinergic neurons (neurons that use the neurotransmitter acetylcholine) is common in Alzheimer’s disease, several drugs used to treat the disease work by increasing acetylcholine neurotransmission, often by inhibiting the enzyme that breaks down acetylcholine in the synaptic cleft. Other clinical interventions focus on behavioral therapies like psychotherapy, sensory therapy, and cognitive exercises. Since Alzheimer’s disease appears to hijack the normal aging process, research into prevention is prevalent. Smoking, obesity, and cardiovascular problems may be risk factors for the disease, so treatments for those may also help to prevent Alzheimer’s disease. Some studies have shown that people who remain intellectually active by playing games, reading, playing musical instruments, and being socially active in later life have a reduced risk of developing the disease.

Figure 1. Compared to a normal brain (left), the brain from a patient with Alzheimer’s disease (right) shows a dramatic neurodegeneration, particularly within the ventricles and hippocampus. (credit: modification of work by “Garrando”/Wikimedia Commons based on original images by ADEAR: “Alzheimer’s Disease Education and Referral Center, a service of the National Institute on Aging”)

Parkinson’s Disease

Like Alzheimer’s disease, Parkinson’s disease is a neurodegenerative disease. It was first characterized by James Parkinson in 1817. Each year, 50,000-60,000 people in the United States are diagnosed with the disease. Parkinson’s disease causes the loss of dopamine neurons in the substantia nigra, a midbrain structure that regulates movement. Loss of these neurons causes many symptoms including tremor (shaking of fingers or a limb), slowed movement, speech changes, balance and posture problems, and rigid muscles. The combination of these symptoms often causes a characteristic slow hunched shuffling walk, illustrated in (Figure). Patients with Parkinson’s disease can also exhibit psychological symptoms, such as dementia or emotional problems.

Although some patients have a form of the disease known to be caused by a single mutation, for most patients the exact causes of Parkinson’s disease remain unknown: the disease likely results from a combination of genetic and environmental factors (similar to Alzheimer’s disease). Post-mortem analysis of brains from Parkinson’s patients shows the presence of Lewy bodies—abnormal protein clumps—in dopaminergic neurons. The prevalence of these Lewy bodies often correlates with the severity of the disease.

There is no cure for Parkinson’s disease, and treatment is focused on easing symptoms. One of the most commonly prescribed drugs for Parkinson’s is L-DOPA, which is a chemical that is converted into dopamine by neurons in the brain. This conversion increases the overall level of dopamine neurotransmission and can help compensate for the loss of dopaminergic neurons in the substantia nigra. Other drugs work by inhibiting the enzyme that breaks down dopamine.

Figure 2. Parkinson’s patients often have a characteristic hunched walk.

Neurodevelopmental Disorders

Neurodevelopmental disorders occur when the development of the nervous system is disturbed. There are several different classes of neurodevelopmental disorders. Some, like Down Syndrome, cause intellectual deficits. Others specifically affect communication, learning, or the motor system. Some disorders like autism spectrum disorder and attention deficit/hyperactivity disorder have complex symptoms.

Autism

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. Its severity differs from person to person. Estimates for the prevalence of the disorder have changed rapidly in the past few decades. Current estimates suggest that one in 88 children will develop the disorder. ASD is four times more prevalent in males than females.

A characteristic symptom of ASD is impaired social skills. Children with autism may have difficulty making and maintaining eye contact and reading social cues. They also may have problems feeling empathy for others. Other symptoms of ASD include repetitive motor behaviors (such as rocking back and forth), preoccupation with specific subjects, strict adherence to certain rituals, and unusual language use. Up to 30 percent of patients with ASD develop epilepsy, and patients with some forms of the disorder (like Fragile X) also have intellectual disability. Because it is a spectrum disorder, other ASD patients are very functional and have good-to-excellent language skills. Many of these patients do not feel that they suffer from a disorder and instead think that their brains just process information differently.

Except for some well-characterized, clearly genetic forms of autism (like Fragile X and Rett’s Syndrome), the causes of ASD are largely unknown. Variants of several genes correlate with the presence of ASD, but for any given patient, many different mutations in different genes may be required for the disease to develop. At a general level, ASD is thought to be a disease of “incorrect” wiring. Accordingly, brains of some ASD patients lack the same level of synaptic pruning that occurs in non-affected people. In the 1990s, a research paper linked autism to a common vaccine given to children. This paper was retracted when it was discovered that the author falsified data, and follow-up studies showed no connection between vaccines and autism.

Treatment for autism usually combines behavioral therapies and interventions, along with medications to treat other disorders common to people with autism (depression, anxiety, obsessive compulsive disorder). Although early interventions can help mitigate the effects of the disease, there is currently no cure for ASD.

Attention Deficit Hyperactivity Disorder (ADHD)

Approximately three to five percent of children and adults are affected by attention deficit/hyperactivity disorder (ADHD). Like ASD, ADHD is more prevalent in males than females. Symptoms of the disorder include inattention (lack of focus), executive functioning difficulties, impulsivity, and hyperactivity beyond what is characteristic of the normal developmental stage. Some patients do not have the hyperactive component of symptoms and are diagnosed with a subtype of ADHD: attention deficit disorder (ADD). Many people with ADHD also show comorbitity, in that they develop secondary disorders in addition to ADHD. Examples include depression or obsessive compulsive disorder (OCD). (Figure) provides some statistics concerning comorbidity with ADHD.

The cause of ADHD is unknown, although research points to a delay and dysfunction in the development of the prefrontal cortex and disturbances in neurotransmission. According to studies of twins, the disorder has a strong genetic component. There are several candidate genes that may contribute to the disorder, but no definitive links have been discovered. Environmental factors, including exposure to certain pesticides, may also contribute to the development of ADHD in some patients. Treatment for ADHD often involves behavioral therapies and the prescription of stimulant medications, which paradoxically cause a calming effect in these patients.

Figure 3. Many people with ADHD have one or more other neurological disorders. (credit “chart design and illustration”: modification of work by Leigh Coriale credit “data”: Drs. Biederman and Faraone, Massachusetts General Hospital).

Career Connection

Neurologist
Neurologists are physicians who specialize in disorders of the nervous system. They diagnose and treat disorders such as epilepsy, stroke, dementia, nervous system injuries, Parkinson’s disease, sleep disorders, and multiple sclerosis. Neurologists are medical doctors who have attended college, medical school, and completed three to four years of neurology residency.

When examining a new patient, a neurologist takes a full medical history and performs a complete physical exam. The physical exam contains specific tasks that are used to determine what areas of the brain, spinal cord, or peripheral nervous system may be damaged. For example, to check whether the hypoglossal nerve is functioning correctly, the neurologist will ask the patient to move his or her tongue in different ways. If the patient does not have full control over tongue movements, then the hypoglossal nerve may be damaged or there may be a lesion in the brainstem where the cell bodies of these neurons reside (or there could be damage to the tongue muscle itself).

Neurologists have other tools besides a physical exam they can use to diagnose particular problems in the nervous system. If the patient has had a seizure, for example, the neurologist can use electroencephalography (EEG), which involves taping electrodes to the scalp to record brain activity, to try to determine which brain regions are involved in the seizure. In suspected stroke patients, a neurologist can use a computerized tomography (CT) scan, which is a type of X-ray, to look for bleeding in the brain or a possible brain tumor. To treat patients with neurological problems, neurologists can prescribe medications or refer the patient to a neurosurgeon for surgery.

Mental Illnesses

Mental illnesses are nervous system disorders that result in problems with thinking, mood, or relating with other people. These disorders are severe enough to affect a person’s quality of life and often make it difficult for people to perform the routine tasks of daily living. Debilitating mental disorders plague approximately 12.5 million Americans (about 1 in 17 people) at an annual cost of more than $300 billion. There are several types of mental disorders including schizophrenia, major depression, bipolar disorder, anxiety disorders and phobias, post-traumatic stress disorders, and obsessive-compulsive disorder (OCD), among others. The American Psychiatric Association publishes the Diagnostic and Statistical Manual of Mental Disorders (or DSM), which describes the symptoms required for a patient to be diagnosed with a particular mental disorder. Each newly released version of the DSM contains different symptoms and classifications as scientists learn more about these disorders, their causes, and how they relate to each other. A more detailed discussion of two mental illnesses—schizophrenia and major depression—is given below.

Schizophrenia

Schizophrenia is a serious and often debilitating mental illness affecting one percent of people in the United States. Symptoms of the disease include the inability to differentiate between reality and imagination, inappropriate and unregulated emotional responses, difficulty thinking, and problems with social situations. People with schizophrenia can suffer from hallucinations and hear voices they may also suffer from delusions. Patients also have so-called “negative” symptoms like a flattened emotional state, loss of pleasure, and loss of basic drives. Many schizophrenic patients are diagnosed in their late adolescence or early 20s. The development of schizophrenia is thought to involve malfunctioning dopaminergic neurons and may also involve problems with glutamate signaling. Treatment for the disease usually requires antipsychotic medications that work by blocking dopamine receptors and decreasing dopamine neurotransmission in the brain. This decrease in dopamine can cause Parkinson’s disease-like symptoms in some patients. While some classes of antipsychotics can be quite effective at treating the disease, they are not a cure, and most patients must remain medicated for the rest of their lives.

Depression

Major depression affects approximately 6.7 percent of the adults in the United States each year and is one of the most common mental disorders. To be diagnosed with major depressive disorder, a person must have experienced a severely depressed mood lasting longer than two weeks along with other symptoms including a loss of enjoyment in activities that were previously enjoyed, changes in appetite and sleep schedules, difficulty concentrating, feelings of worthlessness, and suicidal thoughts. The exact causes of major depression are unknown and likely include both genetic and environmental risk factors. Some research supports the “classic monoamine hypothesis,” which suggests that depression is caused by a decrease in norepinephrine and serotonin neurotransmission. One argument against this hypothesis is the fact that some antidepressant medications cause an increase in norepinephrine and serotonin release within a few hours of beginning treatment—but clinical results of these medications are not seen until weeks later. This has led to alternative hypotheses: for example, dopamine may also be decreased in depressed patients, or it may actually be an increase in norepinephrine and serotonin that causes the disease, and antidepressants force a feedback loop that decreases this release. Treatments for depression include psychotherapy, electroconvulsive therapy, deep-brain stimulation, and prescription medications. There are several classes of antidepressant medications that work through different mechanisms. For example, monoamine oxidase inhibitors (MAO inhibitors) block the enzyme that degrades many neurotransmitters (including dopamine, serotonin, norepinephrine), resulting in increased neurotransmitter in the synaptic cleft. Selective serotonin reuptake inhibitors (SSRIs) block the reuptake of serotonin into the presynaptic neuron. This blockage results in an increase in serotonin in the synaptic cleft. Other types of drugs such as norepinephrine-dopamine reuptake inhibitors and norepinephrine-serotonin reuptake inhibitors are also used to treat depression.

Other Neurological Disorders

There are several other neurological disorders that cannot be easily placed in the above categories. These include chronic pain conditions, cancers of the nervous system, epilepsy disorders, and stroke. Epilepsy and stroke are discussed below.

Epilepsy

Estimates suggest that up to three percent of people in the United States will be diagnosed with epilepsy in their lifetime. While there are several different types of epilepsy, all are characterized by recurrent seizures. Epilepsy itself can be a symptom of a brain injury, disease, or other illness. For example, people who have intellectual disability or ASD can experience seizures, presumably because the developmental wiring malfunctions that caused their disorders also put them at risk for epilepsy. For many patients, however, the cause of their epilepsy is never identified and is likely to be a combination of genetic and environmental factors. Often, seizures can be controlled with anticonvulsant medications. However, for very severe cases, patients may undergo brain surgery to remove the brain area where seizures originate.

Stroke

A stroke results when blood fails to reach a portion of the brain for a long enough time to cause damage. Without the oxygen supplied by blood flow, neurons in this brain region die. This neuronal death can cause many different symptoms—depending on the brain area affected— including headache, muscle weakness or paralysis, speech disturbances, sensory problems, memory loss, and confusion. Stroke is often caused by blood clots and can also be caused by the bursting of a weak blood vessel. Strokes are extremely common and are the third most common cause of death in the United States. On average one person experiences a stroke every 40 seconds in the United States. Approximately 75 percent of strokes occur in people older than 65. Risk factors for stroke include high blood pressure, diabetes, high cholesterol, and a family history of stroke. Smoking doubles the risk of stroke. Because a stroke is a medical emergency, patients with symptoms of a stroke should immediately go to the emergency room, where they can receive drugs that will dissolve any clot that may have formed. These drugs will not work if the stroke was caused by a burst blood vessel or if the stroke occurred more than three hours before arriving at the hospital. Treatment following a stroke can include blood pressure medication (to prevent future strokes) and (sometimes intense) physical therapy.


(p. 295) Comorbid Neurological Illness

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Cerebrovascular disease, movement disorders, epilepsy, and other neurological diseases disproportionately affect the elderly. Prevalence rates of mood disorders, particularly depression, exceed 20% in most neurological disorders. Thus, many mood disturbances in the elderly are comorbid with neurological illness. Furthermore, elderly individuals and neurological patients have high rates of mood-related morbidity and mortality. Unfortunately, mood disorders in neurological conditions are poorly recognized and under-treated. This chapter discusses the problem of mood disorders in specific neurological conditions in the elderly, and provides a general framework for approaching and treating these problems.

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What causes functional neurological disorders?

This is an area of contention because doctors can't find a definite 'cause': all blood tests, scans, and other investigations are normal. But the person certainly isn't 'making it all up': they are not malingering or faking.

One theory is that the brain, although wired up OK, doesn't control movements or receive sensations normally: hence the unusual movements like tremors, and the abnormal feelings like tingling or pain.

Many people who do not have functional neurological disorders themselves often attribute the person's symptoms to stress or emotional problems. This is valid in some cases but may be over-simplifying things. Many people with functional symptoms have had an emotional or psychological trauma in the lead-up to them developing symptoms, but others haven't. Sometimes two things coincide: a physical illness like the flu or a bad viral illness, coupled with a recent emotional trauma.

This is therefore an area where modern medicine, despite its many advances, cannot fully explain something that affects a large number of people. Another difficulty with talking about 'causes' is that the language used (with words like 'psychological', 'stress' and 'trauma') is often interpreted differently by different people.


About the book

Description

Neurobiology of Brain Disorders is the first book directed primarily at basic scientists to offer a comprehensive overview of neurological and neuropsychiatric disease. This book links basic, translational, and clinical research, covering the genetic, developmental, molecular, and cellular mechanisms underlying all major categories of brain disorders. It offers students, postdoctoral fellows, and researchers in the diverse fields of neuroscience, neurobiology, neurology, and psychiatry the tools they need to obtain a basic background in the major neurological and psychiatric diseases, and to discern connections between basic research and these relevant clinical conditions.

This book addresses developmental, autoimmune, central, and peripheral neurodegeneration infectious diseases and diseases of higher function. The final chapters deal with broader issues, including some of the ethical concerns raised by neuroscience and a discussion of health disparities. Included in each chapter is coverage of the clinical condition, diagnosis, treatment, underlying mechanisms, relevant basic and translational research, and key unanswered questions. Written and edited by a diverse team of international experts, Neurobiology of Brain Disorders is essential reading for anyone wishing to explore the basic science underlying neurological and neuropsychiatric diseases.

Neurobiology of Brain Disorders is the first book directed primarily at basic scientists to offer a comprehensive overview of neurological and neuropsychiatric disease. This book links basic, translational, and clinical research, covering the genetic, developmental, molecular, and cellular mechanisms underlying all major categories of brain disorders. It offers students, postdoctoral fellows, and researchers in the diverse fields of neuroscience, neurobiology, neurology, and psychiatry the tools they need to obtain a basic background in the major neurological and psychiatric diseases, and to discern connections between basic research and these relevant clinical conditions.

This book addresses developmental, autoimmune, central, and peripheral neurodegeneration infectious diseases and diseases of higher function. The final chapters deal with broader issues, including some of the ethical concerns raised by neuroscience and a discussion of health disparities. Included in each chapter is coverage of the clinical condition, diagnosis, treatment, underlying mechanisms, relevant basic and translational research, and key unanswered questions. Written and edited by a diverse team of international experts, Neurobiology of Brain Disorders is essential reading for anyone wishing to explore the basic science underlying neurological and neuropsychiatric diseases.


The Lancet Psychiatry: Largest study to date suggests link between COVID-19 infection and subsequent mental health and neurological conditions

One in three COVID-19 survivors received a neurological or psychiatric diagnosis within six months of infection with the SARS-CoV-2 virus, an observational study of more than 230,000 patient health records published in The Lancet Psychiatry journal estimates. The study looked at 14 neurological and mental health disorders [1].

Professor Paul Harrison, lead author of the study, from the University of Oxford, UK, said: "These are real-world data from a large number of patients. They confirm the high rates of psychiatric diagnoses after COVID-19, and show that serious disorders affecting the nervous system (such as stroke and dementia) occur too. While the latter are much rarer, they are significant, especially in those who had severe COVID-19." [2]

"Although the individual risks for most disorders are small, the effect across the whole population may be substantial for health and social care systems due to the scale of the pandemic and that many of these conditions are chronic. As a result, health care systems need to be resourced to deal with the anticipated need, both within primary and secondary care services." [2]

Since the COVID-19 pandemic began, there has been growing concern that survivors might be at increased risk of neurological disorders. A previous observational study by the same research group reported that COVID-19 survivors are at increased risk of mood and anxiety disorders in the first three months after infection [3]. However, until now, there have been no large-scale data examining the risks of neurological as well as psychiatric diagnoses in the six months after COVID-19 infection.

This latest study analysed data from the electronic health records of 236,379 COVID-19 patients from the US-based TriNetX network, which includes more than 81 million people. Patients who were older than 10 years and who became infected with the SARS-CoV-2 virus after 20 January 2020, and were still alive on 13 December 2020, were included in the analysis. This group was compared with 105,579 patients diagnosed with influenza and 236,038 patients diagnosed with any respiratory tract infection (including influenza).

Overall, the estimated incidence of being diagnosed with a neurological or mental health disorder following COVID-19 infection was 34%. For 13% of these people it was their first recorded neurological or psychiatric diagnosis.

The most common diagnoses after COVID-19 were anxiety disorders (occurring in 17% of patients), mood disorders (14%), substance misuse disorders (7%), and insomnia (5%). The incidence of neurological outcomes was lower, including 0.6% for brain haemorrhage, 2.1% for ischaemic stroke, and 0.7% for dementia (see table 2).

Risks of a neurological or psychiatric diagnosis were greatest in, but not limited to, patients who had severe COVID-19. Compared to the overall 34% incidence, a neurological or psychiatric diagnosis occurred in 38% of those who had been admitted to hospital, 46% of those in intensive care, and 62% in those who had delirium (encephalopathy) during their COVID-19 infection. This gradient of risk applied to individual disorders too. For example, 2.7% of people needing intensive care and 3.6% of people with encephalopathy had a brain haemorrhage (compared to 0.3% in people without hospitalisation) 6.9% and 9.4% had ischaemic stroke (compared to 1.3% without hospitalisation) 1.7% and 4.7% developed dementia (0.4% without hospitalisation) and 2.8% and 7% were diagnosed with a psychotic disorder (0.9% without hospitalisation) (see table 2).

The authors also looked at people who experienced flu and other respiratory tract infections over the same time frame to help understand whether these neurological and mental health complications were linked specifically to COVID-19. After taking into account underlying health characteristics, such as age, sex, ethnicity, and existing health conditions, there was overall a 44% greater risk of neurological and mental health diagnoses after COVID-19 than after flu, and a 16% greater risk after COVID-19 than with respiratory tract infections. As a result, the authors say that COVID-19 does lead to a greater risk of neurological and psychiatric disorders than these other health conditions. However, this was not seen for all conditions there was no clear evidence that COVID-19 led to an increased risk of parkinsonism or and Guillain-Barré syndrome.

Dr Max Taquet, a co-author of the study, from the University of Oxford, UK, said: "Our results indicate that brain diseases and psychiatric disorders are more common after COVID-19 than after flu or other respiratory infections, even when patients are matched for other risk factors. We now need to see what happens beyond six months. The study cannot reveal the mechanisms involved, but does point to the need for urgent research to identify these, with a view to preventing or treating them." [2]

The authors note several limitations to their study. Firstly, the completeness and accuracy of the electronic health records is not known. Secondly, many people with COVID-19 have mild or no symptoms and do not present for health care, therefore, the people studied here are likely to have been more severely affected than in the general population. Thirdly, the severity and course of the neurological and psychiatric disorders is not known.

Writing in a linked Comment article, Dr Jonathan Rogers, who was not involved in the study, from University College London (UCL), UK, said: "[this] study points us towards the future, both in its methods and implications. Researchers need to be able to observe and anticipate the neurological and psychiatric outcomes of future emerging health threats by use of massive, international, real-world clinical data. Selection biases will remain an issue, not necessarily mitigated by sample size,10 and thus the onus should be on countries with public health-care systems to enable truly comprehensive national data to be available for research. Sadly, many of the disorders identified in this study tend to be chronic or recurrent, so we can anticipate that the impact of COVID-19 could be with us for many years."

Peer reviewed / Observational / People

NOTES TO EDITORS

The study was funded by the National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre. It was conducted by researchers from the University of Oxford (UK), and TriNetX (USA).

[1] Full list of neurological and psychiatric outcomes assessed: intracranial haemorrhage ischaemic stroke parkinsonism Guillain-Barre syndrome nerve, nerve root and plexus disorders myoneural junction and muscle disease encephalitis dementia psychotic, mood and anxiety disorders (grouped and separately) substance misuse and insomnia.

[2] Quote direct from author and cannot be found in the text of the Article.

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17.17: Other Neurological Disorders - Biology

National Eye Institute (NEI)
Fogarty International Center (FIC)
National Institute on Aging (NIA)
National Institute on Deafness and Other Communication Disorders (NIDCD)
National Institute of Environmental Health Sciences (NIEHS)
National Institute of Mental Health (NIMH)
National Institute of Neurological Disorders and Stroke (NINDS)
Office of Dietary Supplements (ODS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Global Brain and Nervous System Disorders Research Across the Lifespan (R01)

  • June 19, 2018 - This PA has been reissued as PAR-18-835.
  • NOT-OD-18-009 - Reminder: FORMS-E Grant Application Forms and Instructions Must be Used for Due Dates On or After January 25, 2018.
  • September 20, 2017 - Updates to Active Funding Opportunity Announcements to Prepare for Policy Changes Impacting Due Dates On or After January 25, 2018. See NOT-OD-17-114. - Notice of NICHD's Participation in PAR-17-314. See Notice NOT-HD-17-022. - Notice of Change to Key Dates. See Notice NOT-TW-17-007.

93.989, 93.866, 93.113, 93.321, 93.853, 93.867, 93.173, 93.242 , , 93.865

This Funding Opportunity Announcement (FOA) encourages grant applications for the conduct of innovative, collaborative research projects between U.S. and low- and middle-income country (LMIC) scientists, on brain and other nervous system function and disorders throughout life, relevant to LMICs (including neurological, mental, behavioral, alcohol and substance use disorders and spanning the full range of science from basic to implementation research). Scientists in upper middle-income LMICs (UMICs) are also eligible to partner directly with scientists at other LMIC institutions with or without out a US partner. Income categories are defined by the World Bank at http://data.worldbank.org/about/country-classifications/country-and-lending-groups.

The collaborative research programs are expected to contribute to the long-term goals of building and strengthening sustainable research capacity in LMICs to address nervous system development, function and impairment throughout life and to lead to diagnostics, prevention, treatment and implementation strategies. The proposed work will also contribute to developing a base for research networking and evidence-based policy beyond the specific research project.

30 days prior to the application due date

November 7, 2017 November 7, 2018 November 7, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

November 7, 2017 November 7, 2018 November 7, 2019 by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

February 2018 February 2019 February 2020

May 2018 May 2019 May 2020

New Date June 2018

New Date June 19, 2018 per issuance of PAR-18-835. (Original Expiration Date: November 8, 2019 )

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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-17-313).

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

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 connectivity 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-17-102 and PAR-17-122).

See Section VIII. Other Information for award authorities and regulations.

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.


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