May 5, 2021

By Stefan Clemens, PhD, HdR, Chair, Research Committee, RLS Foundation Scientific and Medical Advisory Board

The RLS Foundation’s Research Grant Program is a return-on-investment initiative; member contributions lead to advances in the understanding of RLS and to potential improvements in treatment options. The RLS Foundation established the Research Grant Program in 1997 under the leadership of Bob Waterman (Board of Directors member with two terms as Board Chair, 1995–2005 and 2011–2019). The idea was to award small research grants seed funding to provide the critical data necessary to secure additional research grants from national and international agencies.

The first research grant was awarded in 1999. Since then, an average of about two projects per year have been funded. To date, 48 grants have been supported by the RLS Foundation, totaling nearly $2 million in research funding. These 48 projects were carried out by 41 clinicians and researchers. Their findings have led to over 25 publications in a wide range of neurological and neurobiological journals and books. More importantly, the seed-funding grants provided by the RLS Foundation have led to over $10 million in additional grant support from other sources, thereby further strengthening research in the field of RLS.

Research grant applications are first reviewed by the RLS Foundation’s Scientific and Medical Advisory Board (SMAB); details about its members can be found at www.rls.org/SMAB. The SMAB consists of both clinicians and basic science researchers who are responsible for monitoring RLS medical and scientific research issues and bringing their respective expertise to the grant review sessions. In addition to reviewing research grant applications, the SMAB reviews all Foundation publications and advises the RLS Foundation’s Board of Directors on issues of medical or scientific interest and importance. A group of external specialists approved by the SMAB has agreed to serve as grant reviewers to strengthen the rigor of the research supported by the RLS Foundation and to provide additional guidance. Research grant proposals that receive a favorable decision by the SMAB are then presented to the RLS Foundation’s Board of Directors for funding consideration.

Since its inception, the grant program has focused on specific areas of study: genetics, epidemiology, iron regulation, neurophysiology, the development of novel treatment options and RLS animal models. Based on the findings of research in these areas, the SMAB recently developed new guidelines and funding priorities for future grant proposals that are summarized here:

Brain Iron Homeostasis: RLS is regularly associated with changes in brain iron function.

• Research Target: Elucidate the biological factors that contribute to RLS-relevant alterations in iron homeostasis in the nervous system.

Genetic/Epigenetic Factors: Multiple studies have underscored the role of specific genetic and epigenetic factors in the development of RLS. Genetic factors refer to factors that stem from familial heredity or gene mutations; epigenetic factors refer to changes in a person’s genome as a function of, for example, exposure to environmental factors.

• Research Target: Identify genetic and epigenetic factors and their interactions in RLS patients and develop animal models in which these interactions can be better explored in mechanistic detail.

Comorbidities: RLS is often associated with a wide range of other neurological and non-neurological diseases. What is the impact of RLS on other ailments such as cardiovascular disease, sleep apnea or Parkinson’s disease?

• Research Target: Identify any possible causal links between RLS and these other diseases.

Neurobiological Interactions: A variety of signaling molecules have been identified in the nervous system that are changed with RLS. It is often unclear, however, if the changes in these signaling molecules are themselves causing RLS symptoms or if they are a result of other changes.

• Research Target: Identify RLS-relevant neurotransmitters and neural pathways that may be implicated in RLS.

Therapeutics, Pharmacological Treatments and Therapeutic Responsiveness: A wide range of medications is used to treat RLS, and many of these compounds can lead to unwanted side effects, such as tolerance or augmentation.

• Research Target: Explain the pharmacology of existing RLS medications, develop novel approaches that show better efficacy or fewer side effects, and generally advance knowledge toward development of better treatments of RLS.

Nonpharmacological Treatments: In addition to current pharmacological treatment options, RLS patients may find benefit from nonpharmacological approaches. These include, but are not limited to: transcranial or spinal magnetic or electric stimulation; transcranial direct current stimulation; cognitive behavioral therapy; and intermittent compression of the lower limbs.

• Research Target: Describe the mechanisms in nonpharmacological treatments that lead to the improvement of RLS symptoms.

Novel Diagnostic Markers: Identifying RLS relies on the subjective feedback of a patient to their clinician.

• Research Target: Develop better assessment techniques or devices that will provide improved outcome measures for clinical research.

The RLS Foundation plans to open a new series of biannual calls for submissions of research grant applications with rotating main themes, in which submissions will be prioritized around the above-listed research areas. The RLS Foundation will also be seeking grant submissions from specialists in these respective areas, to increase the scientific depth and widen the breadth in RLS-related research. Additionally, the RLS Foundation has set aside funds for one predoctoral or postdoctoral fellowship grant per year to attract promising young investigators to the field. To contribute directly to that fund, go to www.rls.org/AllenFund.

These changes to the RLS Foundation’s Research Grant Program will improve our understanding of RLS in the clinic, spearhead new approaches and treatments in the lab, identify new and emerging drugs and technologies, and improve patient outcomes by engaging an increasing number of clinicians and researchers dedicated to finding a cure for RLS.