NOT-AT-21-002: Notice of Special Interest (NOSI): Promoting Research on Interoception and Its Impact on Health and Disease

Notice of Special Interest (NOSI): Promoting Research on Interoception and Its Impact on Health and Disease

Notice Number:

NOT-AT-21-002

Key Dates

Release Date:

January 22, 2021

First Available Due Date:

February 25, 2021

Expiration Date:

May 07, 2024

Related Announcements

NOT-HL-21-037 - Notice of NHLBI Participation in NOT-AT-21-002 "Notice of Special Interest (NOSI): Promoting Research on Interoception and Its Impact on Health and Disease (R01).

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-184 - Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

PA-20-183 - Research Project Grant (Parent R01 Clinical Trial Required)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-20-196 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)

PA-20-194 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)

Issued by

National Center for Complementary and Integrative Health (NCCIH)

National Institute on Aging (NIA)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute on Drug Abuse (NIDA)

National Institute of Environmental Health Sciences (NIEHS)

National Institute of Mental Health (NIMH)

National Cancer Institute (NCI)

All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Office of Behavioral and Social Sciences Research (OBSSR)

Office of Research on Women's Health (ORWH)

Purpose

The purpose of this NOSI is to promote innovative and rigorous research on interoception and its impact on health and disease. This initiative is broadly supported by many participating NIH institutes, centers, and offices (ICOs). For this NOSI, interoception includes the processes by which an organism senses, interprets, integrates, and regulates signals originating from within itself and represents its internal states. This NOSI encourages basic and clinical research projects that 1) combine diverse expertise; 2) develop and use innovative technologies and approaches to delineate interoceptive mechanisms at the molecular, cellular, circuit, functional, and/or behavioral levels; 3) assess pathophysiological processes of interoception in the context of diseases and disorders; 4) determine the impact of interventions and therapies to manipulate interoceptive processes on health and/or disease; and 5) develop and validate predictive biomarkers, computational models, or artificial intelligence models relevant to interoception and its impact on health and disease.

Background

Neuroscience has gained a tremendous understanding of how we sense and interact with our external world through research into the primary exteroceptive sensory systems of vision, audition, olfaction, taste, and somatosensation. We know less about the interoceptive system the nervous system’s ability to sense and regulate our own internal milieu. From April 16 to 17, 2019, the NIH Blueprint for Neuroscience Research convened a workshop on The Science of Interoception and Its Roles in Nervous System Disorders. At the workshop, a distinguished group of investigators highlighted recent findings and discussed a wide range of topics critical to the future of interoception research. This workshop addressed some of the key issues in interoception research, including the definition of interoception, the scope of interoception science, interoceptive signaling via specialized interoceptors, ascending and descending neuroanatomical pathways that are essential for interoception, normative functions and disease implications, and potential interventions, as well as the integration of internal and external representations of the world from an experimental and computational modeling perspective. Workshop videos and program book can be accessed through: Day 1 Video; Day 2 Video; Workshop Program Book.

The workshop also identified many critical knowledge gaps and challenges not currently tackled by major NIH research initiatives such as the BRAIN Initiative and the NIH Common Fund Stimulating Peripheral Activity to Relieve Conditions (SPARC) Initiative or by individual NIH neuroscience institutes and centers via their regular programmatic activities. These critical areas include: 1) characterization of functional circuits and interaction dynamics between central and peripheral nervous systems in physiological conditions; 2) delineation of the interaction between interoceptive networks involved in basic physiological processes (e.g., respiration, thirst, feeding, urination, metabolism) and other sensory, motor, reward, emotional, cognitive/memory, and social circuits to regulate brain diseases and disorders; 3) determination of the impact of central or peripheral disorders on interoceptive networks and the effects of modulating interoceptive processes on associated diseases and disorders; and 4) the need for objective and quantitative assessments of interoception as well as effective technologies and approaches to measure and modulate interoceptive processes.

Since the workshop, the NIH Blueprint ICOs published a funding opportunity RFA-AT-21-003 support interoception research focused on functional neural circuit analysis of interoceptive processes in animal models. In addition, the workshop committee members worked together and published a review article on "The Emerging Science of Interoception: Sensing, Integrating, Interpreting, and Regulating Signals within the Self in Trends in Neuroscience.

Terminology for Interoception Research

We encourage applicants to incorporate and define the following terms in their applications:

Interoceptive signals are signals that originate within an organism and include at least three major types: 1) biochemical signals ranging from inorganics, such as acidic ions, to organic molecules and small peptides; 2) mechanical forces altering structures, such as cellular shape, through stretch or tissue extension; and 3) thermal and electromagnetic signals, which may be delivered in various forms across the electromagnetic spectrum.

Interoception includes the processes by which an organism senses, interprets, integrates, and regulates internal signals. Here, the action of sensing denotes communication from physiological systems outside of the central nervous system (CNS) to the CNS, through the commonly called ascending or afferent pathways, whereas the action of regulating refers to the communication from the brain to other physiological systems via descending or efferent pathways. The CNS, especially the brain, is primarily responsible for interpreting and integrating these signals into a representation of the internal world. The systems involved in processing signals about the internal environment include not only the peripheral nervous system and the CNS but also components of the vascular, endocrine, and immune systems.

Interoceptors are molecular sensors or receptors in neurons that directly detect these various internal signals and transduce them into electrical, hormonal, or other non-neural signals to be integrated and interpreted by the brain. Interoceptors include chemoreceptors, humoral receptors, specialized mechanoreceptors, and free nerve endings or nociceptors. The location of the interoceptors may determine whether the interoceptive signals are transmitted through the peripheral nervous system or the non-neural humoral pathway.

Central interpreters and integrators of interoception include neurons in the CNS (spinal cord and brain) involved in processing, interpreting, and/or integrating interoceptive signals. They may include substructures throughout the brain, including within the brainstem, hypothalamus, thalamus, insula, and other cortical regions.

Central regulators of interoception include neurons in the CNS (spinal cord and brain) involved in generating signals to regulate interoceptive processes.

Regulating signals refer to signals generated by the CNS to regulate interoceptive processes. The regulating signal can be transmitted via non-neural (e.g. humoral) pathways or descending neural pathways (cranial/vagal or spinal efferents) to effector organs/tissues to modulate their function or their interoceptive signaling. Most regulating signals may be biochemical or electrical.

Peripheral interoceptive neural pathways include both ascending and descending neural connections between the peripheral organs/tissues and the CNS. The ascending connections primarily transmit interoceptive signals from the periphery to the brain via two major types of peripheral sensory ganglia. One type resides in the cranial/vagal pathways, such as nodose or jugular ganglia, and often projects to nucleus tractus solitarii of the brainstem. The other type consists of dorsal root ganglia that project into the brain through the spinal cord. The descending connections primarily transmit regulating signals from the brain to the peripheral organs/tissues via cranial/vagal or spinal efferents. In the descending neural pathways, the final effecting neurons or effectors are also commonly called sympathetic or parasympathetic ganglion neurons and directly synapse with the peripheral organ/tissue non-neural cells.

Research Objectives and Participating ICO Interests

The scope of research to be supported through this NOSI is very broad and encourages research that will develop innovative technologies, identify mechanisms underlying interoception, investigate the role of interoception in health and diseases, or develop and validate predictive biomarkers, computational models, and/or artificial intelligence based models and applications.

Applicants are strongly encouraged to consult the Scientific/Research Contact listed below to discuss the alignment of their proposed work with the goals of this funding opportunity announcement (FOA) and the participating ICO interests.

National Center for Complementary and Integrative Health (NCCIH)

NCCIH is broadly interested in research on understanding the fundamental mechanisms of interoception or the development and validation of innovative methods, tools, and technologies to assess interoceptive processes, which are relevant to complementary and integrative health approaches with preclinical models and/or with human volunteers. Topics of high program priorities include: 1) studies focusing on evaluating multiple organ systems (e.g., brain-heart, brain-gut, brain-myofascial tissues, brain-lymphatics) and their interactions in the context of complementary and integrative health approaches; and 2) studies with relevance to health outcomes such as pain, anxiety, mild-to-moderate depression, sleep, and cardiovascular or digestive dysfunctions, well-being, resilience, health restoration, or disease prevention. Complementary and integrative health approaches include natural products (including botanicals, probiotics and microbial-based therapies, dietary supplements, and special diets) and mind and body approaches (such as acupuncture, meditation, spinal manipulation, yoga, massage, hypnosis, music and art-based therapies). Applications proposing a clinical trial must follow the Consolidated Notice on NCCIH Clinical Trials Policies at https://grants.nih.gov/grants/guide/notice-files/NOT-AT-20-001.html as only mechanistic clinical trials will be accepted by NCCIH through this NOSI.

National Cancer Institute (NCI)

NCI is interested in research on interoceptive processes as they may relate to cancer prevention and control. How do disrupted interoceptive networks contribute to obesity? What is the role of interoception in addiction to carcinogenic substances such as tobacco and alcohol? How might cancer and/or cancer treatments disrupt interoceptive function to create the late effects suffered by cancer survivors? How can we intervene to improve interoceptive function to ameliorate any of these conditions?

National Institute on Aging (NIA)

The National Institute on Aging encourages applications that examine changes in interoceptive processes across the lifespan and how these changes manifest in normal aging and/or in Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD). Applications are encouraged at all levels of analysis from molecular to social. Topics of interest include but are not limited to:

How changes in interoceptive processes might lead to changes in perception, motor function, physical function, cognition, affect, motivation, and social behavior in normative aging
How disruptions in interoceptive processes might lead to, accelerate onset of, or exacerbate symptoms of cognitive decline, MCI, and AD/ADRD
How age-related neurodegenerative processes might impact interoceptive systems
How age-related changes in sympathetic tone differentially impact multiple peripheral organs and tissues or change the trajectory of endocrine and cytokine signaling in peripheral tissues.

National Institute of Dental and Craniofacial Research (NIDCR)

The National Institute of Dental and Craniofacial Research (NIDCR) is interested in research that significantly enhances our understanding of interoceptive processes in Dental, Oral, and Craniofacial (DOC) tissues and their role in craniofacial health and disease. Areas of interest include but are not limited to: 1) delineation of interoceptive mechanisms at the molecular, cellular, circuitry, functional and/or behavior levels that promote resilience, maintain homeostasis, or are dysregulated in DOC diseases and disorders, 2) studies focused on brain/DOC tissue interoceptive processes as well as studies focused on the interaction/integration of interoceptive processes across brain/DOC tissues and other organs/systems/tissues (e.g. nervous, lymphatic, immune, endocrine, digestive, cardiovascular systems, etc) and 3) studies focusing on orofacial pain conditions including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain, and other conditions. 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. However, Basic Experimental Studies with Humans (BESH) are allowed. 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.

National Institute on Drug Abuse (NIDA)

NIDA is interested in the processes of interoception as they relate to substance use and substance use disorder (SUD), at the clinical and pre-clinical levels. NIDA also supports fundamental studies on interoception as it relates to circuits and cognitive processes associated with SUD; while such projects need not include clinical SUD populations, they should clearly relate to a better mechanistic understanding of the role of interoception in SUD.

Topics of interest include but are not limited to:

The role of processes underlying interoceptive awareness or interoceptive dysfunction in establishing, sustaining, or enhancing the performance of motivated and compulsive behaviors
Computational modeling towards establishing causal mechanisms linking interoception and substance use outcomes
The role of interoception in modulating dysphoric/allostatic states
- Role of interoceptive signaling in positive and negative reinforcement
- State-based mediation of interoceptive processing at a circuit or mechanistic level
The effects of drugs of abuse on relevant interoceptive processes and associated brain circuits/networks
The characterization of interoceptive sensory neurons and their signaling mechanisms (biochemical, electrical) that promote or attenuate drug use, or that are disrupted by drug misuse
The study of internal physiological and hormonal state sensations in SUD
The identification of internal state coding networks associated with SUD

Applicants are strongly encouraged to consult NIDA Program staff prior to submission of an application.

National Institute of Environmental Health Sciences (NIEHS)

The mission of the NIEHS is to discover how the environment affects people to promote healthier lives. The NIEHS has broad interest in supporting research projects that address or seek to understand how exposures to toxic environmental insults alter interoceptive biological mechanisms and are linked to disease initiation, progression, or morbidity. Examples of environmental exposures relevant to the mission of the NIEHS include, but are not limited to, industrial chemicals or manufacturing byproducts, e-waste, metals, pesticides, herbicides, and inhaled toxicants including indoor air pollutants from cooking and other sources, climate variability, and the environmental impacts of natural and man-made disasters.

National Institute of Mental Health (NIMH)

NIMH is interested in mechanistic research studies aiming to understand the role of interoception in cognitive, affective, and social processing under normative functioning and in the context of mental illness.

High-interest topics:

Causal experimental designs seeking to enhance a mechanistic understanding of the effect of interoceptive pathways on cognitive, emotional, and social processing domains using behavioral assessment methods relevant to Research Domain Criteria (RDoC) domains and constructs (see Behavioral Assessment Methods for RDoC Constructs Report)
Development and empirical testing of computational models of interoceptive processing.

Low-interest topics:

Studies focusing solely on peripheral organs, peripheral interoceptive processes and their interaction that do not include CNS measures
Studies interrogating interoceptive networks involved in basic physiological processes (e.g., hunger, thirst, respiration, urination, metabolism, reproduction) including sensory and motor functions
Studies focusing on lymphatic and immune system interactions with CNS.

Studies involving the use of animal models should adhere to guidelines specified in NOT-MH-19-053, and proposals that contain stress biology research should refer to NOT-MH-18-058. Applicants are strongly encouraged to consult NIMH staff while developing applications.

Office of Behavioral and Social Sciences (OBSSR)

The OBSSR does not accept assignment of applications or manage awards that are funded. Please contact one of the ICs listed below for inquiries regarding the suitability of the proposed project for the FOA and the IC's research portfolio.

Office of Research on Women’s Health (ORWH)

The mission of the ORWH is to improve the quality of women’s lives, reduce their disease burden across the life course, and address health disparities among populations of women in the United States. In support of this initiative, ORWH is interested in applications that promote innovative and rigorous research on interoception and its impact on women’s health and/or sex and gender influences on health. There is a growing recognition that the quality and generalizability of biomedical research findings depend on the consideration of sex as a biological variable to advance science for the health of women and men. The 2019 2023 Trans-NIH Strategic Plan for the Health of Women Advancing Science for the Health of Women identifies the guiding principles, research goals, and objectives to advance the health of women.

Applicants interested in interoception research related to neurological disorders and/or stroke not covered by the participating ICOs in this NOSI are encouraged to consider PAS-18-483.

Application and Submission Information

This notice applies to due dates on or after February 25, 2021, and subsequent receipt dates through May 7, 2024.

Submit applications for this initiative using one of the following FOAs or any reissues of these announcements through the expiration date of this notice.

PA-20-185 NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-20-184 Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
PA-20-183 Research Project Grant (Parent R01 Clinical Trial Required)
PA-20-195 NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
PA-20-196 NIH Exploratory/Developmental Research Grant Program (Parent R21 Basic Experimental Studies with Humans Required)
PA-20-194 NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Required)

All instructions in the SF424 (R&R) Application Guide and the FOA used for submission must be followed, with the following additions:

For funding consideration, applicants must include NOT-AT-21-002 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Although NCCIH, NCI, NIMH, NIDCR are not listed as a Participating Organization in all the FOAs listed above, applications for this initiative will be accepted.

Applications nonresponsive to terms of this NOSI will be withdrawn from consideration for this initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Wen G. Chen, M.MSc, Ph.D.

National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-451-3989
Email: chenw@mail.nih.gov

Todd S. Horowitz, Ph.D.
National Cancer Institute (NCI)
Phone: 240-276-6963
Email: todd.horowitz@mail.nih.gov

Coryse St. Hillaire-Clarke, Ph.D.
National Institute on Aging (NIA)

Phone: 301-496-9350
Email:coryse.sthillaire-clarke@nih.gov

Janine M. Simmons, M.D., Ph.D.

National Institute on Aging (NIA)

Phone: 301-480-8959

Email: Janine.Simmons@nih.gov

Melissa Ghim, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-496-7853
Email: melissa.ghim@nih.gov

John R. Fedota, Ph.D.