TMD: Identifying Pathways Involved in Chronic Pain and its Endogenous Resolution

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Integrative Biology and Infectious Diseases Branch, DER, NIDCR


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The objectives of this concept are to: 1) catalyze multi-disciplinary research addressing central and peripheral plasticity mechanisms that promote chronic temporomandibular joint disorders (TMDs) and their endogenous resolution, 2) delineate brain changes in humans and animal models that can be correlated with molecular changes in human and animal craniofacial tissues, and 3) evaluate TMD animal models to identify those that best recapitulate human pathophysiology.

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TMDs have long confounded health care providers and researchers largely due to within condition heterogeneity, lack of correlation between overt signs of injury and pain intensity, and a lack of animal models that faithfully recapitulate human pathophysiology. The absence of a firm mechanistic understanding of TMDs and clear etiological targets has precluded development of effective evidence-based treatments. As a result, patients are often exposed to a variety of treatment modalities with mixed results frequently leaving them with unrequited pain and a less than desirable quality of life.

While recent studies indicate that TMDs are multifactorial conditions influenced by genetics, sex and gender, environmental and psychological factors 1, significant gaps remain in our mechanistic understanding of peripheral and central adaptations, and psychosocial influences, that promote pain chronification or resolution of TMD pain. TMD patients can also exhibit sensory, motor 2and cognitive 3-5dysfunctions that may be related to abnormalities in brain regions associated with these functions6-9and associated ascending nociceptive pathways and/or descending pain modulatory pathways 10. Recent advances in brain imaging modalities have allowed for examination of gray and white matter volume, functional connectivity, and metabolite levels in pain-relevant areas of the brain and have provided fundamental insights into several chronic pain conditions. Nonetheless, a defining neuroimaging signature has not emerged to indicate a common central sensitization mechanism.

Rapid progress in the development of advanced imaging modalities, tools, and techniques that overcome technical hurdles associated with evaluating and perturbing intact biological systems at the molecular and cellular levels are now poised to allow a systems neuroscience approach to delineation of neural circuits and plasticity involved in chronic TMD. These advances include: tissue clearing, light sheet microscopy, near infrared spectroscopy and imaging (NIRS), radiogenetics, optogenetics, in vivo calcium imaging technologies and activated neural ensembles (CANE) capture11. These technological advances constitute powerful approaches that can be applied to increase our understanding of how central and peripheral mechanisms coalesce to promote or resolve TMD pain by enabling control and measurement of functional changes in living tissues, followed by cellular and molecular phenotyping at the whole-organ level12, relating these changes to psychological and social functioning, and quality of life.

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The NIH currently supports broad efforts in neuroimaging, such as the NIH Human Connectome Project, the Adolescent Brain Cognitive Development (ABCD) study, and the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) study. None of these studies are focused on TMD. During FY2015-2017 NIDCR has funded four human orofacial pain related neuroimaging research project grants with three having a TMD focus and, thus far, none yet in 2018. NIDCR’s 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.

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Determination of the mechanisms that sustain or promote resolution of chronic TMD pain and elucidation of strategies to intrinsically and extrinsically 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, and Stimulating Peripheral Activity to Relieve Conditions (SPARC) Initiatives are now poised to enable significant advances in our understanding of central and peripheral mechanisms underlying chronic TMD by facilitating meaningful comparison and integration of data from animal models and humans. The NIDCR has invested significantly over the years in development of TMD animal models. Additionally, NIDCR contributed to the identification of biopsychosocial and genetic factors for the onset, persistence and transition to chronic TMD through OPPERA I & II (U01DE017018). These efforts combined with the technological advances described above have set the stage for uncovering biopsychosocial mechanisms of bidirectional integration and modulation of pain processing pathways between the periphery and the brain, including environmental and social factors, within the context of craniofacial tissues and immune and circulatory systems involved in TMD.

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Examples of research suitable for this initiative include, but are not limited to:

  • Neuroimaging studies that will elucidate the underlying mechanisms that mediate maladaptive and/or adaptive plasticity changes in modulatory circuits that either promote chronic TMD pain or facilitate endogenous resolution, and their relation to psychosocial changes, including quality of life.
  • Adaptation and/or utilization of new technologies to assess brain-wide connectivity changes in TMD animal models that parallel human imaging modalities. Correlation with molecular changes in animal craniofacial tissue is desired.
  • Comparison of multiple animal models to elucidate there 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.
  • Development of new lines of research that leverage the availability of human tissue banks with advancing technologies.
  • Elucidation of interactions of the skeletal, muscular, cartilage, nervous, immune, and circulatory systems in TMD.
  • Cross-cutting strategies to address sex-based differences/influences in biopsychosocial mechanisms involved in the chronification or resolution of TMD pain.
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Office of Research in Women’s Health

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This initiative is aligned with the NIDCR Strategic Plan 2014-2019, Goals I and II. Specifically, the initiative aligns with objectives I-1 and II-1 that include “Enable basic research to advance knowledge of dental, oral, and craniofacial health”, and “Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease”. It is also aligned with the following NIDCR 2030 goal areas: “Oral Health + Overall Health” and “Autotherapies”.

This initiative is also aligned with the Federal Pain Research Strategy, published in 2017, that lists the following as research priorities: “Understand and address plasticity mechanisms that promote persistent pain and (endogenous) resolution mechanisms that may reverse persistent pain”, “Whole brain imaging in animal models compared to human models”, “Explore novel biological target and “Determine the mechanisms that sustain or resolve chronic pain and which of these elements can be intrinsically and extrinsically modulated”.

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  1. Slade, G. 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, doi:10.1016/j.jpain.2013.09.010 (2013).
  2. Svensson, P. What can human experimental pain models teach us about clinical TMD? Arch Oral Biol 52, 391-394, doi:10.1016/j.archoralbio.2006.11.015 (2007).
  3. Goldberg, M. al.Neuropsychologic deficits and clinical features of posttraumatic temporomandibular disorders. J Orofac Pain 10, 126-140 (1996).
  4. Grossi, M. L., Goldberg, M. B., Locker, D. & Tenenbaum, H. C. Reduced neuropsychologic measures as predictors of treatment outcome in patients with temporomandibular disorders. J Orofac Pain 15, 329-339 (2001).
  5. Grossi, M. L., Goldberg, M. B., Locker, D. & Tenenbaum, H. C. Irritable bowel syndrome patients versus responding and nonresponding temporomandibular disorder patients: a neuropsychologic profile comparative study. Int J Prosthodont 21, 201-209 (2008).
  6. Shibukawa, al.Cerebral cortical dysfunction in patients with temporomandibular disorders in association with jaw movement observation. Pain 128, 180-188, doi:10.1016/j.pain.2006.10.006 (2007).
  7. Shibukawa, al.Temporomandibular joint formation and condyle growth require Indian hedgehog signaling. Dev Dyn 236, 426-434, doi:10.1002/dvdy.21036 (2007).
  8. Svensson, P. & Graven-Nielsen, T. Craniofacial muscle pain: review of mechanisms and clinical manifestations. J Orofac Pain 15, 117-145 (2001).
  9. Weissman-Fogel, al.Abnormal cortical activity in patients with temporomandibular disorder evoked by cognitive and emotional tasks. Pain 152, 384-396, doi:10.1016/j.pain.2010.10.046 (2011).
  10. Lee, D. al.Chronic widespread pain is associated with slower cognitive processing speed in middle-aged and older European men. Pain 151, 30-36, doi:10.1016/j.pain.2010.04.024 (2010).
  11. Sakurai, al.Capturing and Manipulating Activated Neuronal Ensembles with CANE Delineates a Hypothalamic Social-Fear Circuit. Neuron 92, 739-753, doi:10.1016/j.neuron.2016.10.015 (2016).
  12. Greenbaum, A., Jang, M. J., Challis, C. & Gradinaru, V. Q&A: How can advances in tissue clearing and optogenetics contribute to our understanding of normal and diseased biology? BMC Biol 15, 87, doi:10.1186/s12915-017-0421-3 (2017).
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Last Reviewed
July 2018