This Funding Opportunity Announcement (FOA) is issued by the National Institute of Neurological Disorders and Stroke in conjunction with the NIH Pain Consortium. This FOA for R21 applications is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel techniques, agents, methodologies, models, or applications that could have a major impact. It solicits R21 grant applications from institutions/organizations to perform innovative research that will elucidate the mechanisms underlying migraine, expand our current knowledge of the role of genetic, physiological, biopsychosocial, and environmental influences on migraine susceptibility and progression, and explore new therapeutic targets and therapies for migraine management and prevention. Episodic migraine headaches affect a large percentage of the population (17% of women and 6% of men), account for most pain-related emergency room visits, and may persist as a chronic and disabling condition that extends throughout the lifespan. Chronic migraine (15 or more headache days per month) affects 2% of the adults.
Despite the prevalence of migraine and a long history of research, many questions remain regarding the pathophysiology, progression, and the multitude of endogenous and exogenous factors that influence this complex disorder. Over the past decades the effectiveness of certain headache medications and theories of the mechanisms underlying the throbbing or pulsating pain associated with migraine drove research towards exploration of the vascular events associated with this disorder. Subsequent scientific advances led to the recognition that neural and inflammatory processes play an important role in migraine pain and associated neurological symptoms and that genetic variations, environmental effects, and psychosocial states influence susceptibility to migraines and migraine progression.
Our improved understanding of the mechanisms underlying the multiple phases of migraine and its modulators opened new and promising avenues for discovery of its causes and persistence, as well as potential therapeutic targets. The phases of migraine, including prodrome, aura, pain, and interictal periods, involve complex neurovascular mechanisms which are driven by different neurological events and influenced by numerous physiologic, genetic, and environmental factors. Exogenous factors, such as food additives, perfumes, bright lights, physical exertion, and alcohol may act to trigger this cascade of migraine phases. Sex hormone fluctuations clearly play a role in the initiation and frequency of headache attacks, but the mechanisms through which their effects are exerted and the associations between hormone levels and headache phases are unclear. Steroid hormones likely interact with other contributing factors such as stress, but here again the associations are poorly understood.
Therapeutic strategies to ameliorate hormonal exacerbation of headaches are lacking. Gene mutations for rare forms and candidate genes for more common forms of migraine have been identified recently and are ready for or are undergoing functional analysis to better understand their roles in migraine and their potential as therapeutic targets. Further advances will be facilitated through development of genetic models to assay function, to screen effective headache drugs and to test new therapeutic strategies.