Background

The use of brain stimulation devices provides a unique opportunity to develop novel treatments for mental health disorders. Brain stimulation devices provide both the most efficacious (electroconvulsive therapy, ECT) and one of the most recently-cleared (transcranial magnetic stimulation, TMS) treatments for depression. However, while these successes demonstrate the potential to improve clinical care, limitations of the few existing FDA approved/cleared devices (e.g., cognitive side effects of ECT, variability in response to TMS) hamper widespread clinical use. In order to develop efficacious treatments that will be widely utilized across a variety of disorders, the development of innovative brain stimulation devices and novel approaches with existing devices is urgently needed

New devices, developed with a focus on aspects unique to mental health indications, are needed to fully explore the potential of brain stimulation treatments. The majority of clinical studies using brain stimulation therapies for mental health disorders utilize existing devices developed for other neurological conditions. Deep brain stimulation (DBS) and vagal nerve stimulation (VNS) electrodes were developed for the treatment of Parkinson’s Disease and epilepsy. They have subsequently been studied, with minimal to no modification, for use in mental health disorders with mixed results. New devices, whose development is informed by basic and clinical science findings in mental health research, may provide improved treatments for patients. For example, while current DBS electrodes are limited to one or two stimulation sites, neuroimaging studies have demonstrated the distributed, network-based nature of mental health disorders. Therefore, distributed, multi-focal electrode arrays may be necessary to modulate networks back into a desired state. New forms of energy (e.g., ultrasound) also have the potential to be incorporated into the next generation of brain stimulation devices.

In addition to the development of new devices, significantly enhancing the capabilities of existing devices presents an opportunity to improve clinical care. While drug treatments become static (in terms of chemical composition) once developed, brain stimulation devices are amenable to hardware/software changes that can readily translate to improved patient care. Examples of these approaches include development of real time electric field (e-field) modeling software and augmented reality delivery systems to enable practitioners to interactively target regions of interest with TMS. The ability to close the loop with a brain stimulation device and neuroimaging/recordings could also result in improved clinical outcomes.

Improved devices that focus on developing novel approaches to delivery of previously demonstrated effective treatments are also of interest. Although ECT provides the best remission rates for depression, the widespread generalized seizure induced by the device produces cognitive side effects that limit its use. The development of novel devices that deliver more focused stimulation resulting in a smaller, controllable seizure, may produce high levels of response while minimizing side effects. Additionally, approaches that improve the focality, depth, or closed-loop delivery of TMS could improve response rates.

Research Objectives

This funding opportunity announcement (FOA) encourages the development of novel brain stimulation devices and accompanying software/hardware additions that enable improved delivery of brain stimulation treatments for mental health indications. Applications should be submitted by multi-disciplinary teams with expertise in systems neuroscience, engineering, clinical, and regulatory affairs and promote either the development of novel tools (hardware/software) or significant enhancement of existing tools (hardware/software). Applications should be engineering/pre-clinical based and focus on hardware and software development and validation. Although the application should focus on the engineering development of the tool, animal and limited human testing to demonstrate initial proof of concept is allowable. Applications that seek to study specific scientific or clinical hypotheses that utilize devices are outside the scope of this FOA.

Applications may propose to develop novel invasive or non-invasive brain stimulation devices. New devices should be designed to significantly advance the field and go beyond current stimulation and low-channel count recording/stimulating capabilities. Existing magnetic and electrical stimulation methods have limited spatial and temporal precision. To overcome these obstacles and move beyond incremental advances, collaborations between physicists, engineers, neuroscientists, and clinicians are encouraged. The perspective and expertise of such integrative teams could enable the development and testing of novel approaches that leverage other types of energy or stimulation methods in a way that can lead to novel tools for scientific discovery and for therapeutic brain stimulation. Applications that propose to improve spatiotemporal precision, stimulate at depth, enable multi-focal recording/stimulation, and utilize novel stimulation paradigms are encouraged. Appropriate modeling and preliminary data should be presented to demonstrate the feasibility of the stated approach. While the application may be in the initial stages of device development and may therefore still be in the animal testing phase, the proposed tools and methods must be designed for use in humans. Animal testing should focus on questions of safety. Industry partnership is encouraged and should be detailed in the application. The regulatory process for the new technology should be described in the application, when applicable.

Applications may also propose to develop additional capabilities for existing FDA-approved or cleared brain stimulation devices and related technologies. However, proposed improvements to existing devices and related technology should be significant and innovative, rather than incremental. Appropriate improvements may include: 1) incorporating advanced approaches to stimulation delivery, such as real-time realistic head/electric field modeling that incorporates patient-specific tractography or cellular-level resolution; 2) synchronizing behavioral recordings with brain recordings in novel ways; or 3) developing novel delivery methods, such as augmented and virtual-reality approaches. For existing devices, approaches that seek to improve the focality and depth of stimulation, controllability of the delivered dose, sham control delivery, or recording capabilities are encouraged. Software approaches that seek to develop novel approaches (e.g., machine learning) to biomarker-driven targeted delivery of stimulation are also encouraged.

Topics of interest for this FOA include, but are not limited to:

• Multi-focal electrode interfaces. These devices should demonstrate the capability to record and stimulate distributed brain regions implicated in mental health disorders.
• Devices capable of both recording and stimulating neural activity, with the ability for closed-loop control. These devices should be able to demonstrate clear capability to record oscillations of interest to mental health applications.
• Improved capabilities to synchronize behavioral data with neural data. Dense behavioral phenotyping is now possible, both in the lab and in naturalistic environments. The ability to temporally synchronize large behavioral data sets with large neural data sets is of high priority.
• Devices that enable targeted stimulation via optogenetic (or other circuit therapeutic) techniques in humans.
• Next-generation ECT devices that more focally deliver energy for controllable seizure generation.
• Validation of novel approaches, such as transcranial ultrasound for neuromodulation to stimulate the brain focally.
• A wireless, miniaturized, portable, and closed-loop EEG-stimulation system. Ideally, this should be of a size to be easily worn (i.e., fits comfortably inside a baseball cap).
• Improved portability of brain stimulation devices, without reduction in targeting capabilities.
• Pre-clinical studies necessary to obtain regulatory approval for human testing.
• Development of higher spatial resolution realistic head modeling approaches that improve the delivery of FDA-cleared treatments, such as TMS.
• Improved focality and depth of stimulation, along with controllability for FDA- approved or cleared devices for a particular indication.
• Development of closed-loop recording and stimulating for non-invasive devices, such that imaging/recording informs active stimulation.
• Software approaches, such as machine learning, that incorporate patient-specific biomarkers into brain stimulation treatment algorithms.
• New approaches to sham conditions that enable more reliable controlled trials.

Topics of low program priority include:

• Devices with low spatial resolution.
• Models that focus on standard brains and are not specific to individual patient anatomy.
• Incremental improvements to existing devices, such as operating software system updates.
• Devices with no clear potential for human application.

Innovation in this biomedical engineering FOA has a broad definition that includes development of new methods, ideas, or tools, integration of existing components into new combinations that deliver greater capabilities, new efficiencies, and/or greater effects. Applications to this FOA are not expected to be hypothesis-driven, but should propose design-directed, developmental, or discovery-driven technology research using integrative approaches. Overall impact of these advances may include reducing disparities in care, promoting wellness and independent living, increasing access to and utility of technologies to improve quality of life, reducing cost and complexity of procedures, and increasing throughput, sensitivity and specificity of diagnostic tests.

Applications seeking to explore scientific questions (in humans or animals) using novel brain stimulation devices should apply to the NIH Parent R01 and NIH Parent Clinical Trial Required R21 (PA-18-344) or NIMH R21 (PA-18-350) funding opportunities. Those seeking to assess devices as treatments in a clinical population should refer to the NIMH Policy for Submission of Applications Containing Clinical Trials NOT-MH-14-007 and NIMH Only Accepts Clinical Trial Applications Proposing Mechanistic Studies for Clinical Trial Parent R01 and R21 Announcements NOT-MH-18-004 for information on NIMH requirements.

This FOA will support mechanistic clinical trials, as defined by the NIH to include studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention. The proposed human clinical studies will meet the NIH definition of a clinical trial (see NOT-OD-15-015), but will not include studies whose primary purpose is to evaluate safety; clinical efficacy, effectiveness, and management; and/or implementation. Such trials will not be supported by this FOA. NIH Guide Notice NOT-MH-18-004 describes the types of clinical trials that NIMH supports under the NIH Parent R01 and R21 Clinical Trial FOAs. Applicants proposing clinical trials that are not supported by this FOA should refer to the NOT-MH-14-007 and NOT-MH-18-004 for the relevant FOAs and NIMH requirements.

All applicants are strongly encouraged to contact the designated Scientific/Research Contacts at NIMH prior to submission. Applicants who seek to establish proof-of-concept should respond to the R21 version of the FOA. Small businesses should consider applying to the SBIR/STTR programs to support the technology development.

Institute Staff Involvement

A grant awarded under this FOA may be converted to a cooperative agreement (U01) if substantial NIH scientific programmatic staff involvement is needed. NIH ICs routinely consider the desirability of substantial continued staff involvement in a supportive mode during the period of grant performance. Additional staff involvement may include review of the study protocol, participation on the steering committee and related meetings, and oversight of a data and safety monitoring board. If it is determined that the cooperative agreement mechanism is appropriate for an ongoing grant award, NIH program staff will consult with the grantee institution to mutually effect the conversion.

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

• Non-domestic (non-U.S.) Entities (Foreign Institutions)

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

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

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.

Other Attachments:

Intellectual Property (IP) Strategy:

Applications are expected to include an IP strategy, and the page limit must be no more than three pages. Applications that exceed this limit will not be reviewed. This attachment should be entitled "IP Strategy.pdf". Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials, if applicable.

A goal of this program initiative is to advance research towards the development of products that will benefit the public. Accordingly, applicants should describe the IP landscape surrounding their therapeutic device. This should include any known constraints that could impede the development of their therapeutic device or diagnostic (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar technologies that are under patent and/or on the market, etc.) and how these issues could be addressed as appropriate and consistent with achieving the goals of the program. If the applicant proposes using a device or technology whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should address any questions that may constrain or impede its ability to operate and move the technology forward consistent with achieving the goals of the program. If patents pertinent to the therapeutic device being developed under this application have been filed, the applicants should indicate the details of filing dates, what types of patents are filed, application status, and associated United States Patent Office (USPTO) links, if applicable.

Applicants should also discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe how IP will be shared or otherwise managed, and the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions.

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

• How the proposed approach will use the concepts from engineering, physical science, computational or other multidisciplinary methods to address the biomedical problem identified in the application.
• How the investigative team demonstrates sufficient depth and breadth of the multiple disciplines necessary to complete the project.
• Anticipated risks and limitations.

Any animal or human testing should be justified in the context of necessity for device development. Any proposed work in animals must include a description of how the methods would be scaled up for use in humans. In recognition of the fact that these methods might be in early stages of development, work with human volunteers can, but does not need to, be included.

Applications should also include the following sections in the Research Strategy:

Current State-of-the-Art:

Investigators should define the current state of technology as a benchmark against which their proposed new technology or improvements will be measured. Given that projects are likely to be early-stage and high-risk in nature, this should include the specific proof-of-concept test(s) that will indicate whether/how a proposed tool actually "works", along with alternative strategies should that effort fail to perform as expected. Tests should include a comparison against existing benchmark technologies; if a tool is truly first-in-class, comparisons may be done against a nearest neighbor technology. Investigators should briefly note how results will be used to inform future phases of tool development, such as testing in other model systems or in human brain.

Industry Partners:

Investigators should describe any relationship with industry/commercial partners. This should include details on what, if any material, partners are providing. If a memorandum of understanding (MOU), confidential disclosure agreement (CDA), or collaborative research agreement (CRA) has been signed by both parties, this should be described by the applicant.

Translational Plan:

Investigators should describe the potential translational pathway for their devices. This should include a description of the regulatory and reimbursement pathway for their device or specific type of technology. Future commercialization, implementation, and dissemination plans should be discussed.

Project Milestones and Timeline:

A timeline and milestones should be included that propose indicators of progress at critical junctures. These should be tailored to the unique scope of each project and written concretely enough to evaluate what exactly will have been achieved (e.g., crucial steps in tool making) during the course of the project. Quantitative benchmarks for success should be included.

Letters of Support:

A letter of support from any industry partners should be included.

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. There is no prescribed single license for the distribution of standards produced through grants responding to this announcement. However, the data sharing plan is expected to discuss: (1) how the standard will be made widely available; (2) transferability, i.e., ability of another individual or team to continue development as appropriate; (3) terms of availability that will enable researchers to enhance the standard and share those enhancements with colleagues

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.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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.

Applications to this FOA may propose hypothesis-driven research , but should propose design-directed, developmental, or discovery-driven technology research using integrative approaches.

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 there a strong scientific premise for the project? 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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?