Temporomandibular Disorders Priorities for Research and Care (2020) / Chapter Skim
Currently Skimming:
4 State of the Science on TMDs
4 State of the Science on TMDs
Pages 123-196
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From page 123... ...
-- most significantly in the field of m orofacial pain -- researchers have yet to unravel the etiologies and pathophysiologies of TMDs or to translate, in a meaningful way, research findings into improved clinical care practices. Over the past decade the body of research on TMDs centered on the biological mechanisms underlying the development and persistence of orofacial pain and on the structure and function of the joint and its tissues, while more recent research has begun to examine the molecular genetics, biomarkers, and biopsychosocial risk factors of TMDs and common comorbidities.
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From page 124... ...
This chapter provides the reader with an overview of recent basic science research related to the pathophysiologies of TMDs and orofacial pain, with a primary focus on the state of the evidence as it relates to the development and growth of temporomandibular joint (TMJ) tissues in health and disease and the mechanisms underpinning pain and tissue dysfunction.
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From page 125... ...
There are several major differences between the TMJ and the other synovial joints. First, the fibrocartilage of the TMJ develops from the neural crest, whereas the hyaline cartilage of the limb joints develops from mesoderm (Somoza et al., 2014)
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From page 126... ...
The roles of specific genes in driving the growth of mandibular condylar cartilage, the mandibular fossa, and the articular disc and joint cavitation have been studied to varying degrees using animal models, with two comprehensive reviews recently completed by Hinton (2014) and Scariot and collegues (2018)
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From page 127... ...
and in biological mechanisms that trigger responses. The drivers and pathways of TMJ tissue degeneration have been a focus of recent studies using animal models.
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From page 128... ...
. Similarly, considerable TMJ tissue degeneration has been seen in models using mice that over-express betacatenin (Wang et al., 2014)
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From page 129... ...
TMJ morphological and biomechanical differences between the sexes need to be identified and explored to develop an understanding of how they may contribute to a female predisposition to tissue dysfunction or chronic orofacial pain. Biomechanical Function, Joint Tissue Degeneration, and Orofacial Pain Processing The relationship between biomechanical function, joint tissue degeneration or injury, and pain processing is an expanding field of research that seeks to unravel the complex interactions between the tissues of synovial joints and the nervous system in order to understand their impact on joint function and on the initiation, maintenance, and suppression of pain.
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From page 130... ...
The connection between biomechanical function of the TMJ and oro facial pain has been established in certain animal models (Sperry et al., 2017)
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From page 131... ...
Animal Models for TMJ Tissue Engineering and Regenerative Medicine Research Those in the TMJ biomechanics and tissue engineering fields have studied a variety of animal models, including mice, rabbits, dogs, goats, pigs, minipigs, and sheep. Important factors when assessing animal models include anatomy/physiology, mechanical properties, chewing patterns, d ietary composition, cost, and ease of surgical access (Donahue et al., 2019)
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From page 132... ...
. Despite promising results, the ability to develop these engineered constructs for clinical use has been limited by an incomplete understanding of the developmental biology of the TMJ tissues -- a limitation that is further compounded by a lack of clinically relevant animal models and challenges with measuring function and forces within the joint space.
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From page 133... ...
. Biochemical and Mechanical Stimuli Stimulating bioengineered TMJ discs with growth factors, such as insulin-like growth factor I and TGF-β, has been shown to result in greater levels of collagen synthesis and improved mechanical properties (Detamore and Athanasiou, 2005)
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From page 134... ...
Moving Toward Translation Past and future research breakthroughs in TMJ bioengineering must be examined using orthotropic animal models, and once safety and effectiveness has been established, these approaches can be tested in humans. The location of the TMJ and its proximity to the brain may require more stringent safety requirements for bioengineered products (Donahue et al., 2019)
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From page 135... ...
See Box 4-1 for a list of research priorities. NEUROBIOLOGY OF OROFACIAL PAIN AND TMDs The larger field of pain research has worked to define the mechanisms of neuropathic and inflammatory pain, and, as with many complex disorders featuring acute and chronic pain, understanding the pathophysiology
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From page 136... ...
• Develop additional models for disc degeneration and the degeneration of other TMJ structures and tissues, and determine whether commonly used bio echanical models could be applied to the study of mechanisms at the m interface of orofacial pain and joint function. • Address existing challenges in the use of preclinical animal models to nhance e preclinical utility, including (1)
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From page 137... ...
The following sections will explore the findings of recent research on TMDs and orofacial pain, including: • Animal models for orofacial pain, • Overviews of peripheral and central mechanisms of acute and chronic orofacial pain, • Pain signaling and biomechanics of the TMJ, • Trigeminal versus extra-cranial pain signaling systems, and • Commonalities in neuronal pathways and central sensitization within TMDs and other chronic pain conditions. Current Animal Models of Orofacial Pain Animal models provide critical opportunities for studying the biological and cellular mechanisms of pain and help advance the development of pharmaological treatments.
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From page 138... ...
It has been argued that spontaneous pain behaviors and complex operant behaviors that involve cortical processing and decision making may be more relevant in providing insights into human orofacial pain conditions. The pain community has made significant advances in the understanding of pain through the development of diverse animal models used to examine the environmental and biological processes underlying acute and chronic pain.
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From page 139... ...
Overview of Peripheral Mechanisms of Orofacial Pain As described earlier in the chapter, the orofacial tissues are innervated by the trigeminal nerve and its nociceptive endings, which terminate in the orofacial tissues and can be activated by mechanical stimuli or injury, inflammatory processes, or exposure to an irritant or inhospitable environment. This system of mechanisms is inherently vulnerable to modulation because each component of the system interacts within and is influenced by the complex biochemical environment -- endocrine, immune, and other systems -- of the human body (Sessle, 2011)
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From page 140... ...
has been shown to be expressed by the trigeminal neurons, although the role of this expression on orofacial pain remains unclear. A study in rats by Puri and colleagues (2012)
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From page 141... ...
. Receptors and Ion Channels The role of receptors and ion channels, particularly the function of sodium ion channels like Nav1.7, has been and remains a significant focus of orofacial pain research.
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From page 142... ...
Minocycline significantly reduced the activation of microglial cells and the number of pERK-IR cells at these sites, suggesting that the activation of microglial cells in the trigeminal and upper cervical regions is involved in the increased neuronal excitability associated with the neuropathic pain. Central Mechanisms of Pain Beyond the induction of pain in the periphery, peripheral nociceptive stimuli can also affect CNS neurons (Cairns, 2010)
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From page 143... ...
. Such findings are highly relevant to understanding the experience of orofacial pain at a mechanistic level, as many individuals with orofacial pain experience increased regional sensitivity in the skin and muscles around the TMJ.
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From page 144... ...
Orofacial Pain Modulation The modification of pain on an individual level is a product of the convergence of modifiable and non-modifiable biopsychosocial factors. Current research suggests that various interacting mechanisms play a role in the generation, maintenance, and suppression of pain by the CNS, which can, as described above, signal a mismatch between the peripheral nociceptive inputs and the perception of pain by an individual.
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From page 145... ...
identified three distinct patient subgroups across an array of biopsychosocial factors. Their findings suggest that classification of individuals into clinically relevant and mechanistically based subgroups using biopsychosocial risk factors could provide a better and more personalized approach for understanding orofacial pain etiology and, in the future, for the development and application of more targeted treatments (Bair et al., 2016)
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From page 146... ...
Additionally, QST may provide further insights on the mechanisms of pain in TMDs and help predict which individuals are at higher risk of transitioning from an acute to chronic pain state after injury or inflammation. Pain and Biomechanical Function of the TMJ As discussed in a prior section, considerable work needs to be done to understand how the biomechanical function and use of the TMJ affects the health of its tissues and the generation and maintenance of orofacial pain at a mechanistic level.
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From page 147... ...
In the case of the TMJ's biomechanical function and orofacial pain, research has shown that pathological changes to joint tissues, such as the degeneration of tissues resulting from the overloading of the TMJ, alters the biochemical environment of the joint and has some degree of impact on the mediation of peripheral and central signaling processes that initiate and maintain pain (Sperry et al., 2017)
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From page 148... ...
Looking Forward: Priorities for Orofacial Pain Research As seen in other chronic pain conditions, the contribution of centralized pain mechanisms is often greater than the initial inciting trigger of the pain. As such, these pain syndromes can be difficult to replicate in animal models.
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From page 149... ...
In a model of TMDs, CGRP was also shown to stimulate neuronal and glial expression of proteins c apable of promoting peripheral and central sensitization. Additionally, in a mouse model of acute orofacial masseteric muscle pain induced by complete Freund's adjuvant injection, CGRP antagonist causes a significant reduction in spontane ous orofacial pain behaviors and a decrease in the level of Fos immunoreactivity in the trigeminal nerve (Romero-Reyes et al., 2015)
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From page 150... ...
mimicking the orofacial pain environment and orofacial pain experience in humans as well as new methods for measuring subtle behavior and responses as they relate to orofacial pain. • Develop animal models of temporomandibular disorders (TMDs)
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From page 151... ...
This is based on the concept that the circuits present in particular patients may favor a greater likelihood of chronic pain and other symptoms than appear in other patients. To apply neuroimmune interactions in a clinically meaningful way, it is critical that the genetic framework of key inflammatory, immune, and resolution pathways in patients with various subgroups of TMDs be understood.
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From page 152... ...
Regulation of the hypothalamic–pituitary–adrenal (HPA) axis is an essential part of how humans adapt to their environment and is important for the body's response to stress and to the homeostatic BOX 4-4 High-Priority Areas for Neuroimmune Research on Temporomandibular Disorders (TMDs)
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From page 153... ...
Other multi-system, chronic pain conditions such as fibromyalgia exhibit altered neuroendocrine and autonomic nervous system function, with both hypo- and hyperactive stress responses having been reported (Adler et al., 2002)
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From page 154... ...
Sex Differences and Painful TMDs Systematic reviews and meta-analyses indicate that the prevalence of TMDs is more than twice as great in women as in men (odds ratio of 2.24 for combined TMD groups) in all diagnostic groups of the esearch R Diagnostic Criteria for Temporomandibular Disorders (Axis I: groups I, II, and III)
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From page 155... ...
Looking Forward Sex differences play a significant role in the mechanisms underlying chronic pain and will require additional focused study if safe and effective treatments targeted for high-risk groups, such as females, are to be developed. Animal models specifically designed to explore sex differences in the development of chronic pain, such as the methodology used by Sannajust and colleagues (2019)
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From page 156... ...
. A more complete understanding of the genetic basis of TMDs and overlapping genetic associations with commonly comorbid conditions could provide clarity on etiology, an improved understanding of orofacial pain mechanisms, and ultimately improve clinical care.
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From page 157... ...
Targeted genotyping studies conducted over the past decade have identified a number of genetic variants that may be associated with TMDs and orofacial pain. A 2016 review of studies of genetic predictors of chronic pain conditions found 36 genes associated with TMDs, including several genes that are also associated with other pain conditions (Zorina- Lichtenwalter et al., 2016)
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From page 158... ...
. Several genetic variants associated with TMDs have also been implicated in targeted genetic association studies for other chronic pain conditions, although the meaning of these overlapping genetic variants has yet to be unraveled.
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From page 159... ...
for clinical care and research. • onitoring biomarkers are used to assess the status of a condition or M exposure over time.
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From page 160... ...
like TMDs and other chronic pain conditions. These data, with proper translation, aid in the ability to identify clinically meaningful biomarkers, stratify patients based on mechanistically relevant factors rather than by diagnoses, and identify therapeutic targets (Gazerani and Vinterhøj, 2016)
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From page 161... ...
; some of the findings of those studies hold potential value for TMD research. Proteomic analysis, which provides data on the expression, function, and regulation of proteins, can provide insights into disease patho physiology, biomarkers, and treatment response (Gazerani and Vinterhøj, 2016)
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From page 162... ...
Gazerani and Vinterhøj BOX 4-9 High-Priority Areas in Omics and Biomarker Research on Temporomandibular Disorders (TMDs) • se broad genomics approaches (e.g., genome-wide association studies U [GWASs]
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From page 163... ...
Once potential predictor, prognostic, and resilience markers have been identified in human subjects, these should be subsequently validated as therapeutic targets in animal models to aid translational research. Such translational studies act as bridging mechanisms and will be essential to pushing the research forward.
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From page 164... ...
Moayedi and colleagues (2012) found that people with painful TMDs have lower fractional anisotropy in the bilateral trigeminal nerve and diffuse abnormalities in the microstructure of white matter tracts related to sensory, motor, cognitive, and pain functions.
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From page 165... ...
. The neuroimaging of pain is also being included as a major component of large-scale, multi-site investigations that focus on idiopathic chronic pain conditions such as urological chronic pelvic pain (i.e., interstitial cystitis, chronic prostatitis, bladder pain syndrome)
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From page 166... ...
Despite acknowledgment of the contributing role of psychosocial factors in the experience of pain, this area of research remains out of balance with the comparatively large body of research on biological mechanisms. How psychosocial factors affect pain and tissue dysfunction associated with TMDs remains unknown, although the significant overlap in psychosocial risk factors between TMDs and other chronic pain conditions (see Chapter 3 for discussion of psychosocial risk factors)
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From page 167... ...
. In another study, orofacial pain response was associated with depression in participants with TMDs (Sherman et al., 2004)
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From page 168... ...
analyses, polygenic approaches, and pathway analyses to unravel the complexities of this group of disorders, identify patient subgroups, and develop safe and effective treatments. TMD RESEARCH FUNDING Current Funding for TMD Basic Research and Translation The National Institutes of Health (NIH)
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From page 169... ...
. The bulk of TMD research funding from NIH is for basic research, with clinical and translational research making up a smaller portion.
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From page 170... ...
; F33 ( ational Research Service Awards for Senior Fellows, used to provide scientists N with the opportunity to broaden scientific background and/or gain experience in an allied research field) ; and T90 (Interdisciplinary Research Training Award)
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From page 171... ...
Major areas of need, as identified in the State of the Science section above, include the biopsycho social mechanisms underpinning acute and chronic orofacial pain and tissue dysfunction; the use of new methods and tools, including the application
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From page 172... ...
A description of the role of the proposed research consortium (see Recommendations 1 and 2 in Chapter 8) and the example research framework for TMD research, which unifies research priorities within patient-centered needs, can be found below.
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From page 173... ...
This includes determining the biopsychosocial mechanisms of resilience to both orofacial pain and tissue dysfunction. Additionally, because preclinical animal models demonstrate that such mechanisms may prove to be meaningful clinical targets, addiional studies t in the translational and clinical research should be carried out to capitalize on the potential for diagnostic, prognostic, or therapeutic value.
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From page 174... ...
m Translational studies bridging mechanisms between animal and human TMD pain mechanisms will be critical to moving the field forward by identifying clinically meaningful and mechanistically based patient subgroups and developing new therapeutic approaches. Research on TMJ Development, Biomechanical Function, and Relationship with Pain To advance the understanding of TMJ function in health and disease, contemporary, multidisciplinary research focused on the biology of TMJ t issues, the interactions of these tissues, the innervation of the musculoskeletal component and vascularization of the joint, and the normal devel opmental processes and disease progression will be key research areas for expansion.
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From page 175... ...
. The available body of recent laboratory research overviewed in this chapter related to TMDs and orofacial pain illustrates this issue, with many studies focusing on only one aspect of a TMD or conducting highly discipline-specific research.
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From page 176... ...
Conclusion 4-4: The level and appropriation of funding for research on temporomandibular disorders does not reflect the complexities of these disorders, their prevalence and impact, or the need for trans disciplinary research with a focus on clinical care impacts. Role of a TMD Research Consortium and Example Research Framework for TMDs A unified, transdisciplinary research framework for TMDs developed and implemented by a national collaborative research consortium (see Figure 4-3)
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STATE OF THE SCIENCE ON TMDs 177 FIGURE 4-3 Example TMD research consortium stakeholders and goals. NOTE: NIH = National Institutes of Health; TMD = temporomandibular disorder.
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3. Increased access to funding through the alignment of research priorities across TMDs and orofacial pain research and larger clinical research initiatives.
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From page 179... ...
Research Priority 1-1: Discovery and investigation of novel biological, bio mechanical, and psychosocial targets and mechanisms relevant for the prevention and treatment of patients with TMD-related pain and tissue dysfunction. Research Priority 1-2: Translation of biological, biomechanical, and psychosocial targets and mechanisms, through the identification and use of mechanistically based and clinically meaningful subgroups of individuals with TMDs, into novel treatment approaches.
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From page 180... ...
Goal 5: Integrate primary, secondary, and tertiary prevention strategies into TMD patient care. Research Priority 5-1: Investigate the biological, biomechanical, and psycho social mechanisms of risk and resilience underlying acute and chronic orofacial pain across patient subgroups and at an individual level.
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From page 181... ...
A TMD Research Consortium would be well positioned to convene stakeholders and launch a TMD research framework. Conclusion 4-4: The level and appropriation of funding for re search on temporomandibular disorders does not reflect the com plexities of these disorders, their prevalence and impact, or the need for transdisciplinary research with a focus on clinical care impacts.
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From page 182... ...
2018. Chronic orofacial pain animal models -- Progress and challenges.
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From page 183... ...
2018. Gender differences in temporomandibular disorders in adult populational studies: A systematic review and meta-analysis.
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From page 184... ...
Presentation at the March 28, 2019, public meeting of the National Academies of Sciences, Engi neering, and Medicine's Committee on Temporomandibular Disorders (TMDs) : From Research Discoveries to Clinical Treatment, Washington, DC.
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From page 185... ...
2011. Changes in regional gray and white matter volume in patients with myofascial-type temporomandibular disorders: A voxel-based morphometry study.
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2018. Reduced corticostriatal functional connectivity in temporomandibular disorders.
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From page 187... ...
2018. Scaffold- based temporomandibular joint tissue regeneration in experimental animal models: A systematic review.
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From page 188... ...
2015. Somatosensory assessment and conditioned pain modulation in temporomandibular disorders pain patients.
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From page 189... ...
2014. Brain signature of chronic orofacial pain: A systematic review and meta- analysis on neuroimaging research of trigeminal neuropathic pain and temporo mandibular joint disorders.
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From page 190... ...
2018. Endogenous pain modulation in chronic orofacial pain: A systematic review and meta-analysis.
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From page 191... ...
2015. Dys regulation of the descending pain system in temporomandibular disorders revealed by low-frequency sensory transcutaneous electrical nerve stimulation: A pupillometric study.
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From page 192... ...
2015. Co morbidity between depression and anxiety in patients with temporomandibular disorders according to the research diagnostic criteria for temporomandibular disorders.
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From page 193... ...
2004. The relationship of somatization and depression to experimental pain response in women with temporomandibular disorders.
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2018. Temporomandibular disorders related to stress and HPA-axis regulation.
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2011. Tissue interaction is required for glenoid fossa development during temporomandibular joint formation.
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2019. Effect of a functional variant of tumor necrosis factor-β gene in temporomandibular disorders: A pilot study.
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