TMD Collaborative for IMproving PAtient-Centered Translational Research (TMD IMPACT)

Goal

The goal of this concept is to establish a national, interdisciplinary trans-NIH patient-centered research consortium or network (henceforth termed the Collaborative) to advance Temporomandibular Disorders (TMDs) basic and clinical research, research training, and translation to evidence-based treatments and improved clinical care. The primary objectives of this Collaborative are to: 1) support robust and rigorous basic, translational, and clinical research to generate clinically meaningful knowledge, improve diagnosis and prevention of acute to chronic pain, identify effective treatments, and improve quality of care; 2) strengthen population-based research on the public health burden and costs of TMDs to improve prevention and management of TMDs; 3) bolster clinical and implementation research efforts for safe and effective treatments; and 4) train the next generation of interdisciplinary TMD researchers, ensuring a diversity of career stages, disciplines, and investigators.

Background

TMDs are a set of more than 30 heterogeneous health disorders¹ associated with the temporomandibular joint (TMJ), muscles of mastication, and surrounding tissues. The TMJ’s skeletal and connective tissues originate from the neural crest during early development, rather than from the mesoderm, indicating different genetic drivers and pathways than in other joints. TMDs are considered to be pain conditions with multifactorial components, that can range from acute to chronic, and from mild to severe, compromising quality of life for many individuals. They affect between 5-10% of the U.S. population with an annual incidence rate that is greater in females compared to males (~2:1) and often lack correlation between overt signs of injury and pain intensity ratings (nociplastic pain). TMDs may also present with other systemic and comorbid medical conditions and overlapping or frequently co-occurring pain conditions (COPCs) such as fibromyalgia, back pain, headache, and irritable bowel syndrome—indicating changes in central processes. The heterogeneous etiologies and clinical presentations of TMDs make accurate, clinically relevant and mechanistically based phenotyping difficult. TMDs have long confounded medical and dental health care providers, often resulting in misdiagnosis and delayed or ineffective treatment.

Recent studies indicate that TMDs are multifactorial conditions influenced by genetics, sex and gender, environmental and psychological factors²; however, significant gaps remain in our mechanistic understanding of peripheral and central adaptations, and psychosocial influences, that promote pain chronification or resolution of TMD pain. While our mechanistic understanding of TMDs has been advanced through human and animal studies, progress has been hampered by limited emphasis on changes in affected human target tissues and few integrated analyses combining findings in multiple cells and tissues. The absence of a firm mechanistic understanding of TMDs has precluded stratification of patients into clinically meaningful and mechanistically based subgroups and identification of clear etiological targets for development of effective evidence-based treatments or their clinical endpoints.

Determination of the mechanisms that sustain or promote resolution of chronic TMD pain and technologies and approaches to modulate these mechanisms are crucial to development of successful precision medicine pain management approaches. Recent technological advances and resources developed through the NIH BRAIN, Blueprint, HEAL, and Common Fund Initiatives can now be utilized or adapted to the context of TMD to enable significant advances in our understanding of central and peripheral mechanisms.

Gaps and Opportunities

The Collaborative will be expected to use coordinated, multi-level, interdisciplinary and integrated approaches to address TMD comprehensively from the whole-person perspective, which includes systems biology approaches, single-cell multi-omics, and biopsychosocial determinants of health. Active engagement with relevant stakeholders including patient advocacy groups, regulatory agencies, and the private sector will be encouraged.

Although the Collaborative’s research agenda will be flexible and responsive to the changing research, regulatory, and treatment landscape, the compelling research priorities that initiated/spurred this concept are the following:

Stratification of patients into clinically meaningful and mechanistically based subgroups and identification and validation of etiological targets for diagnosis, treatments, or their clinical endpoints.
Research focused on discerning mechanisms of molecular pathogenesis or resilience, in target tissue, that correlate with stratification approaches and TMD clinical heterogeneity, as well as mechanisms that sustain or promote endogenous resolution of chronic TMD pain.
Comparison of multiple animal models to elucidate their capitulation of human TMD pathophysiology by these models.
Identification and anatomic, genetic, molecular, pharmacological, and physiological characterization of deep nociceptors (e.g., bone/joint, muscle, etc.) involved in TMD pain and its resolution.
Systems biology, whole-organ, and whole-person approaches that include biopsychosocial mechanisms.
Biomechanical, tissue engineering, and regeneration studies.
Adaptation and utilization or development of new tools and technologies to facilitate access to the TMJ and the unique orofacial physiology, and/or to advance current standards of detection and measurement.
Harness the potential of artificial intelligence and computational methods for large datasets for purposes such as integration of data from various animal models, distinguishing disease subtypes, developing individualized clinical decision support, and predicting patient responses.
Strengthening the evidence-base for existing treatments, including mechanistic studies, pragmatic trials, and comparative effectiveness trials, as well as the development and dissemination of new evidence-based treatments.

Impact

The Collaborative will develop and implement a Strategy or Approach for identifying and prioritizing research topics and projects of high clinical relevance that best address gaps in knowledge or the evidence-base and is highly likely to lead ultimately to improved TMD patient care. The scope of research priorities should be broad, for example ranging from basic mechanistic to behavioral to population-based to clinical trials and implementation research. The Collaborative will also be expected to facilitate coordination across research teams and research projects, as well as coordinate data, repositories, and other resources according to FAIR Data Principles and establishment of common data elements where appropriate. The Collaborative will also be expected to train the next generation of interdisciplinary TMD researchers via a formal structure to ensure a common curriculum and collaborative and interdisciplinary research training projects.

Current Portfolio Overview

The NIH currently supports broad efforts in pain and/or opioid use and disorders, for example the Early Phase Pain Investigation Clinical Network (EPPIC-Net), Back Pain Consortium (BACPAC) Research Program, Patient-Reported Outcomes Measurement Information System (PROMIS), and the NIH Common Fund program Acute to Chronic Pain (A2CPS); however, none of these studies are focused on TMD. Recent NIDCR and HEAL FOAs and concepts related to TMDs include the 1) Feasibility Studies that Explore Healthy and Diseased Temporomandibular Joints (TMJ) using Single Cell Multi-Omic Analyses; 2) HEAL Initiative: Developing Quantitative Imaging and Other Relevant Biomarkers of Myofascial Tissues for Clinical Pain Management; and 3) Joint Pain and Innervation Research concept (still under development). These are too recent to have generated awards but could inform the research conducted under the Collaborative. Two additional trans-NIH FOAs have yielded NIDCR-supported awards (Mechanisms, Models, Measurement, & Management in Pain Research; and Research on Chronic Overlapping Pain Conditions). However, these FOAs are either expired or expiring soon and there are currently only two active NIDCR-supported grant awards stemming from these programs that specifically pertain to TMDs. NIDCR’s complete portfolio contains a total of 32 awards that focus on TMDs or the TMJ, which includes the 2 aforementioned grants. Of the 32 awards, 5 are training or early career awards, 6 are regeneration projects, 3 pertain to biomechanics of the TMJ, 6 focus on mechanisms of TMJ development, degeneration, or remodeling, and the remainder (12) pertain to TMD pain. This portfolio does not currently have any animal studies seeking to measure changes in brain activity/connectivity associated with TMD that could serve as translational models and it has no TMD-focused grants utilizing advanced techniques such as tissue clearing.

References

Schiffman E, et al. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache 28(1), 6-27 (2014).
Slade GD, et al. Summary of findings from the OPPERA prospective cohort study of incidence of first-onset temporomandibular disorder: implications and future directions. J Pain 14, T116-124 (2013).
National Academies of Sciences, Engineering, and Medicine. Temporomandibular Disorders: Priorities for Research and Care. The National Academies Press (2020).

Last Reviewed
April 2024