Background

Music has the remarkable ability to enhance child development, improve adult function and well-being, and optimize the quality of life during aging. Many studies have shown that music can also ameliorate the symptoms of a broad range of diseases and disorders that occur throughout the lifespan and be utilized effectively in delivering palliative care during serious advanced illness and at the end of life. Recent scientific breakthroughs, including the development of new technologies, are providing the community with opportunities to understand the mechanisms through which music acts, and to develop new music interventions for a variety of human conditions. To capitalize on these opportunities, the NIH is issuing three related funding initiatives intended to: i) promote our understanding of the basic mechanisms through which music is processed by the brain and body; ii) explore how music can impact health and disease, and iii) facilitate rigorous music intervention studies to help treat disease.

In 2016, the NIH, John F. Kennedy Center for the Performing Arts (KC), and National Endowment for the Arts (NEA) formed a collaborative partnership ( Sound Health) and in early 2017 organized a workshop to evaluate the state of basic and applied music research ( Music and the Brain). In this meeting, a diverse panel of experts discussed three overlapping periods of life (childhood, adulthood and aging) and made recommendations for enhancing research in each of these domains ( NIH report). The group developed a set of recommendations intended to highlight research opportunities and promote the rigor of future research. These recommendations centered around four broad areas: 1) Basic and Mechanistic Research, 2) Translational and Clinical Research, 3) Methods and Outcomes and 4) Capacity Building and Infrastructure.

In 2017, a trans-NIH Music and Health working group was formed to capitalize on these recommendations and promote their implementation. To achieve this, the NIH is issuing three related announcements. The first two FOAs are related and will support R01 and R21 awards respectively that are within the interests of the participating NIH components (see below) and that address the recommendations of the 2017 workshop. This R21 FOA emphasizes exploratory projects which may have a unique potential for moving an important aspect of the science of music and health. The companion FOA utilizes the R01 mechanism and is intended to support studies with a sound premise and potentially strong impact on the science of music and health. Projects for either the R01 or R21 FOAs could potentially range from basic foundational studies to clinical trials that provide a basis for better therapeutic interventions. The third FOA will utilize a phased R61/R33 mechanism to support research that can best be facilitated through milestone-driven awards on music and health geared towards music intervention. While no preliminary data is needed for the R61 phase, transition to the R33 phase is contingent on successful completion of agreed upon Go/No-Go milestones.

Potential applicants for any of the three FOAs are strongly encouraged to reach out to the chief contact listed near the end of announcement to discuss any questions about the most suitable FOA, as well as questions about scope and clinical trials. For questions about the specific interests of a participating institute, center or office, applicants should contact the appropriate contact listed at the end of the appropriate document.

Investigators are expected to participate in an annual meeting held at the National Institutes of Health to review progress of the funded research and highlight advances on the science of music and health and should therefore budget accordingly.

Scope of Research

This R01 FOA proposes to build upon the rapidly expanding evidence base linking music and health and to address the broad research recommendations that emerged from the NIH workshop referenced above. Both basic and applied studies are within the scope of this RFA. Applications that propose multidisciplinary research and collaborative studies involving musicians, music therapists, biomedical, behavioral, and/or social scientists are encouraged.

All proposed projects should have the potential to increase our understanding of the science of music and health, and inform music interventions to enhance normal function and improve health.

All projects should be rigorously designed, reproducible and within the mission of the participating institutes, centers and offices. Projects that are responsive to this FOA include but are not limited to categories and bullets below from the NIH workshop that produced research recommendations for the field.

Basic and Mechanistic studies

• Defining which neural circuits are involved in the interaction between music and the brain or body
• Investigating which physiological pathways are enhanced by both active and passive musical training
• Examine commonalities between music and language processing

Translational and Clinical studies

• Integrating mechanistic understanding with music therapy approaches
• Developing and validating biomarkers for music interventions
• Better defining the issue of dosing in music interventions
• Developing methods to better understand and predict individual differences in response to music interventions

Methods and Outcomes

• Developing methods that integrate brain- and other relevant organ system-based measurements with musical activities
• Conducting longitudinal and ancillary studies to assess outcomes of music interventions.
• Establishing standardized and/or personalized outcome measures
• Establishing evidence-based best practices for music interventions intended to enhance wellness or treat/ameliorate specific health conditions

Critical Notes for Applicants Proposing Clinical Trials or Work with Human Subjects

Potential applicants are strongly encouraged to interact with the scientific contacts listed below to discuss possible clinical trials and other clinical studies. Applicants are also encouraged to see the current NIH Definition of a Clinical Trial, the sub-definition of an intervention, and the numerous case studies provided. For example, administering a stimulus (such as music) for the purposes of measuring or describing brain activity but NOT to modify it, is not considered an intervention under the NIH definition, and would thus not be a clinical trial (see case study 18b as an example). The NIH sub-definition of an intervention states that an intervention is a manipulation of a subject or their environment with the intent to modify a health-related outcome.

Health-related outcome is defined very broadly and ranges from changes in protein levels to changes in behavioral outcomes for example, and essentially covers most of the NIH’s research portfolio. The type of health-related outcomes that will be assessed determines what type of clinical trial the application would be considered, and this is critical to know and understand prior to submission, as not all participating institutes and centers support all types of trials under this FOA. There are two main types of clinical trials relevant to this FOA: Mechanistic clinical trials and Clinical Outcome Clinical Trials.

Mechanistic clinical trials are studies with primary outcomes designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention. Clinical outcome clinical trials are studies with primary outcomes designed to assess the safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, surgical, or device interventions.

It is imperative for an applicant to determine whether they are proposing a clinical trial, and if so, which of the above categories it falls within. The scientific contacts listed can help with this determination, and ascertain whether the application would fit within the requirements listed by the relevant participating institutes, centers, and offices below.

IC and NIH Office Interest Areas and Specific Requirements:

Understanding the basic science of music and exploring its potential to enhance health and treat disease is relevant to the mission of the NIH Institutes participating in this FOA. Below is a list of areas that are of particular interest to participating ICs:

NINDS: The National Institute of Neurological Disorders and Stroke (NINDS) is interested in supporting basic and applied research that is within its mission and focused on understanding the effects of music on the brain. This includes investigating the effects of music on neural circuits and pathways, sensorimotor processing, proprioception, motor function, and skill learning. Approaches involving either music listening or music production, in the contexts of music experience, training, or practice are welcome. NINDS is also interested in studies that inform the understanding, management, and/or treatment of neurological diseases and disorders, and/or accompanying symptoms. This includes studies to facilitate recovery processes (e.g. after injury or stroke) or maintain function (e.g. slow cognitive decline). Music interventions may be studied alone, in conjunction with, or in comparison to other interventions.

NCCIH: The National Center for Complementary and Integrative Health (NCCIH) is broadly interested in supporting research aimed at understanding the mechanisms by which music and music interventions impact symptom management in high-priority topics such as pain, stress-related disorders, sleep disorders. NICCH is also interested in how music and music intervention could be used to address opioid misuse and enhancement of emotional well-being. In addition to basic animal model work, NCCIH supports mechanistic clinical trials under this FOA. However, NCCIH will not support grant applications proposing efficacy or effectiveness research with primary clinical outcomes under this FOA. Investigators who are ready to propose a fully powered efficacy or effectiveness clinical trials can apply to PAR-18-662 with a companion application to PAR-18-663 for an independent data coordinating center. Investigators are strongly encouraged to contact program staff to discuss their aims prior to submission.

NEI: The National Eye Institute (NEI) supports research that addresses blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind. Under this FOA, NEI will accept applications that propose to examine how music affects the fundamental mechanisms of visual function or loss of vision, which may inform development of music-based interventions for the visually impaired. Topics of interest include, but are not restricted to, the role of music in neural reorganization and plasticity in the visually impaired; the impact of music on sensory substitution, navigation/mobility, and functional strategies in the visually impaired; and music integration in low vision rehabilitation.

NIAAA: The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is interested in supporting research within the mission of NIAAA. Example research areas of interest to NIAAA include 1) How does music modulate negative emotion states associated with alcohol dependence and withdrawal? What are the biological and neurological underpinnings of the modulation? 2) How does alcohol exposure across the life span, during early development, adolescent stage, adult, and aging, impact music processing? 3) Can music facilitate cognitive recovery following heavy chronic alcohol use, and what are the underlying neurocircuit mechanisms? 4) How does music impact recovery from alcohol use disorders? Which types of music might promote sustained abstinence?

NIA: The National Institute on Aging (NIA) is interested in research to increase our basic understanding of how music affects the brain, body and behavior with aging. Of specific interest is research to investigate the neural pathways and circuits involved in music processing and how these may be altered in aging, the mechanisms by which the experience of music may affect brain structure and function in aging and the potential for music to induce neural and behavioral plasticity in aging and the underlying mechanisms. NIA is also interested in behavioral intervention development, in accordance with the NIH Stage Model (please see https://www.nia.nih.gov/research/dbsr/stage-model-behavioral-intervention-development) that capitalizes on and integrates basic research on music to inform the development of efficacious interventions for individuals as they age. The purpose of the interventions to be developed may be, for example, to promote health and well-being, promote behaviors associated with health and well-being (e.g., exercise), cope with stress (e.g., dementia caregivers), improve the emotional/behavioral status of care providers of individuals with dementia, help individuals deal with age-related disorders (e.g., Parkinson s), help older individuals with declining memory improve their memory. Applications to NIA proposing behavioral intervention development research are encouraged to use NIH Science of Behavior Change experimental medicine methodology (for more information about the SOBC program, please see: https://commonfund.nih.gov/behaviorchange).

NIDCD: The National Institute on Deafness and Other Communication Disorders (NIDCD) seeks to conduct and support biomedical and behavioral research in the normal and disordered processes of hearing, balance, taste, smell, voice, speech, and language. With respect to this RFA, NIDCD is particularly interested in supporting research to investigate the neuroscience of music as a complex auditory stimulus, and to understand the basic processing mechanisms as they relate to communication disorders through voice, speech, and language processing. Well-designed and controlled investigations of music interventions, and interactions, on areas such as voice, speech, language, balance, or the processing of complex sounds may also be of interest. These studies could result in clinical outcomes and/or explore the mechanisms underlying music interventions through human studies. The immediate or long-term focus of these investigations should be to ameliorate conditions such as disordered communication, poor hearing, or balance disorders. Applicants are strongly encouraged to contact NIDCD program staff to discuss their aims prior to submission.

NIDCR: The National Institute of Dental and Craniofacial Research (NIDCR) is interested in music research that has the potential to improve dental, oral, and craniofacial health. Areas of interest include, but are not limited to, investigations of mechanisms by which music may: i) Decrease anxiety, stress, and/or fear levels at the pre-treatment and treatment stages as well as influence levels of these during recall (memory) of the experience in pediatric and adult dental patients; including special needs populations, and ii) Modulate the experience of acute and chronic orofacial pain conditions including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain, and other conditions. The effects of music on neuroplasticity, connectivity, endogenous opioids, and differences in affective states that may exist between healthy individuals and those that suffer from chronic orofacial pain conditions are of interest. Clinical trials designed to answer specific questions about the safety, tolerability, efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device interventions will only be supported by NIDCR if submitted to an NIDCR clinical trials-specific FOA https://www.nidcr.nih.gov/research/clinical-trials. Awardees will be required to comply with the NIDCR Clinical Terms of Award for activities that involve human subjects. Investigators are encouraged to contact NIDCR program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.

NIMH: The National Institute of Mental Health (NIMH) supports neuroscience research to discover the causes of mental illness and to develop more effective and safer treatments. For applications proposing clinical trials, the NIMH only accepts applications proposing mechanistic studies that meet NIH’s definition of a clinical trial (see NOT-OD-15-015) through this FOA. A mechanistic study is designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention. NIMH is interested in applications proposing to develop and test novel potential biomarkers of treatment response to advance understanding of the neurobiological effect of target engagement in healthy subjects and/or in patients. However, trials that include as goals the determination of safety or clinical efficacy of interventions are outside of the scope of this FOA. Applicants interested in evaluating treatments for clinical efficacy should apply through one of the FOAs listed at the NIMH clinical trials website, which includes links to the NIMH CT FAQs. NIMH strongly encourages applicants to consult with NIMH Program Officials when developing plans for an application. This early contact will provide an opportunity to clarify NIMH policies and guidelines and identify whether the proposed project is consistent with NIMH program priorities, and to determine which available FOA would best support the proposed research. This is particularly important if there is doubt as to whether or not the submission is determined to be an NIH-defined clinical trial, and if found to be a clinical trial, whether it is a mechanistic study as described by NIMH.

Data Sharing

To support the goal of advancing research through widespread data sharing among researchers, investigators funded under this FOA by NIMH are expected to share those data via the National Institute of Mental Health Data Archive (NDA; https://data-archive.nimh.nih.gov). Established by the NIMH, NDA is a secure informatics platform for scientific collaboration and data sharing that enables the effective communication of detailed research data, tools, and supporting documentation. A cost estimation tool for data sharing is available at https://ndct.nimh.nih.gov/preplanning/budget and can be used when preparing budgets for applications.

Recruitment Reporting

NIMH requires reporting of recruitment milestones for participants in all NIMH extramural-funded clinical research studies proposing to enroll 150 or more subjects per study, and all clinical trials, regardless of size (see https://grants.nih.gov/grants/guide/notice-files/NOT-MH-16-013.html). All NIMH funded mechanistic clinical trials funded under this FOA must report recruitment milestones, including those with fewer than 150 subjects. This expectation will be stated in the notice of grant award.

NINR: The National Institute of Nursing Research (NINR) supports research in areas that explore strategies to prevent, reduce, or comfort the symptoms of advanced illness across the lifespan, particularly developing and testing strategies to minimize the physical and psychological burdens on individuals and their caregivers. In doing so, NINR promotes and improves the health of individuals, families, and communities across the lifespan, in a variety of clinical settings and within diverse populations.

As the lead NIH Institute for end of life research, NINR recognizes palliative care as a critical component of high-quality, evidence-based care that includes advanced symptom management and informed decision-making support for both individuals and their family caregivers.

NINR will consider studies involving the evaluation of the efficacy or effectiveness of music-based interventions in the clinical management of individuals with serious, advanced illness and their families/caregivers that are consistent with the NINR's research goals. Of particular interest are studies in end-of-life and hospice care, palliative care, pediatric palliative care, diverse populations, and settings.

OBSSR: The Office of Behavioral and Social Sciences Research (OBSSR) is interested in behavioral neuroscience and social science research that:

• Investigates how music affects the brain and behavior and/or the pathways/neural circuits involved in the interaction between music, brain, and behavior
• The mechanisms that underlie music-based interventions for the improvement and/or maintenance of health and well-being, or the prevention and/or treatment of behavioral and/or neurological disorders
• Develops methods and measures that integrate brain and behavioral measurements with musical activities/interventions
• Performs longitudinal and ancillary studies to assess outcomes of music interventions
• Establishes standardized and/or personalized outcome measures
• Is multidisciplinary research and capacity building through collaborative studies involving neuroscientists, music therapists, musicians, and biomedical, behavioral, or social scientists
• Establishes evidence-based best practices for music interventions intended to enhance wellness or treat/ameliorate specific health conditions.

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Robert Riddle, PhD

National Institute of Neurological Disorders and Stroke (NINDS)

Telephone:301-496-5745

Email: [email protected]

All instructions in the SF424 (R&R) Application Guide must be followed.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

In addition, for applications involving clinical trials:

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?