Molecular and Cellular Neuroscience Program
Center for Integrative Craniofacial Research
OBJECTIVE: The objective of this Initiative is to stimulate research on discovering etiological and pathophysiological mechanisms underlying a set of chronic, comorbid conditions associated with temporomandibular joint and muscle disorder (TMJD). TMJD is a complex disease involving one or more tissues of the joint. Primary symptoms include chronic pain in facial muscles and limited and painful movement of the jaw. In addition, these and other symptoms of TMJD occur together with other chronic illnesses such as fibromyalgia, atypical face pain, trigeminal neuralgia, chronic fatigue syndrome, multiple chemical sensitivity, irritable bowel syndrome, migraine headache, speech and hearing disorders, and certain cardiovascular diseases. This Initiative will seek research applications that use state-of-the-art, multidisciplinary and interdisciplinary approaches to discover molecular, physiological, and behavioral mechanisms responsible for the overlapping symptoms manifested in the set of disorders that co-exist with TMJD. The outcome of this Initiative will be a better understanding of how TMJD and these other comorbid disorders interact to influence the development, course, and persistence of TMJD. An additional outcome will be a better appreciation of the etiology and pathology of TMJD itself.
BACKGROUND: TMJD is a complex heterogeneous disease. It likely represents a collection of disorders with varying etiologies, affecting the tissues of the TMJ. Due to this complexity and our lack of a complete understanding of the underlying mechanisms of disease onset and progression, the treatment of some patients with TMJD currently is less than satisfactory. The etiology of complex disorders like TMJD may involve pre-disposing genetic factors, environmental influences, and the interactions of these genetic and environmental factors. In addition, it may be appropriate to view TMJD as a biopsychosocial disorder, not only when considering diagnosis and treatment, but also in the context of pathological mechanisms associated with disease and comorbidities. Peripheral defects in muscle function, abnormal neurotransmission, aberrant central integration of sensory and motor inputs, and the societal and cognitive influences on these processes, probably all interact and influence the disease process and expression of the associated comorbidities.
The major symptoms of TMJD are chronic myofacial pain particularly in the muscles of mastication, restricted range of jaw motion and jaw locking, and abnormal popping and clicking noises in the TMJ. In addition, other symptoms are known to occur in this disorder such as pain in the joint itself and in the area surrounding and radiating from the joint including the ear, neck, shoulder, and back; vertigo; diminished hearing or ringing in the ear; chronic headache; blurred or double vision; sleep disturbances; and difficulty in swallowing. Besides these symptoms, certain psychiatric disturbances are associated with TMJD and may include depression, anxiety disorders, and substance abuse. While these other symptoms and conditions are clearly not diagnostic of TMJD, they are associated with other chronic painful disorders. For example, similar psychiatric disorders are associated with TMJD, fibromyalgia (FM), chronic fatigue syndrome (CFS), and irritable bowel syndrome (IBS). TMJD patients present with symptoms of other chronic painful conditions, such as FM, CFS, IBS, multiple chemical sensitivities, and cardiovascular abnormalities to name a few. The degree of overlapping symptoms and comorbid conditions is not trivial. While some of the apparent comorbidity may be due to diagnostic ambiguity, it is clear that patients with these disorders have similar and multiple symptoms that characterize the various disorders.
The etiological and pathological mechanisms linking the multiple symptoms of TMJD and these comorbid conditions are unclear; however, in general they may involve abnormal responses of common homeostatic mechanisms, i.e. processes that are engaged to return the body to original set points after a disruptive stressor. Alternatively, or in addition, the mechanisms may relate to allostatic processes, i.e. the adaptation to new set points in the continued presence of a stressor or an altered environment. In addition, failed or repeated allostatic processes, i.e. the allostatic load, may account for these comorbidities. Most of these regulatory systems control a systemic, physiological response and a central behavioral response. The concept of faulty adaptive processes is in agreement with a shift in thinking in recent years to a more central nervous system focus as the cause of TMJD (excluding TMJD associated with traumatic injury) rather than simply a peripheral one employing local homeostatic mechanisms. An additional consideration is that there is an increased prevalence of these comorbid disorders in females, indicating that sex steroids may play an important, but complex role in the common pathophysiology. For example, there is an increased prevalence of TMJD and FM in women, yet TMJD patients are usually in their childbearing years while FM is usually diagnosed around mid-life. Regardless of the mechanisms responsible for the comorbidities associated with TMJD, a more precise determination of the phenotypes of the diseases will be critical in order to clearly identify subsets of TMJD patients and the specific comorbid conditions associated with TMJD.
While several distinct pathological mechanisms may account for the comorbidities seen in association with TMJD, many seem to ultimately involve abnormal functioning of feedback circuits (both positive and negative). These may include disturbances in the following: the hypothalamic-pituitary-adrenal (HPA) axis, the classical stress-response system; immune and neuroimmune function; centrally regulated biological clocks; autonomic nervous system function; and specific neurotransmitter system regulation. These and other mechanisms may work alone or in concert to cause the collection of comorbid conditions associated with TMJD.
In order to approach this comorbidity problem effectively, the cooperation of researchers with a common interest in TMJD and specific expertise in research areas related to the overlapping comorbid conditions and symptoms found in TMJD is needed. Information from the fields of neurology, psychiatry, cardiology, genomics, endocrinology, rheumatology, and communicative disorders, to name a few, will be required to develop and test hypotheses relating to the mechanisms that can account for the cluster of comorbidities. Technical expertise in behavioral science, genomic and proteomic approaches, biomedical imaging, electrophysiology, and molecular biology will be necessary to carry out cutting-edge experiments designed to uncover biological mechanisms responsible for overlapping symptoms and comorbid conditions associated with TMJD.
Current Portfolio Overview: The NIDCR currently supports almost all research grants related to TMJD at the NIH. Only a few of these directly explore comorbidities associated with TMJD. Other NIH Institutes and Centers have research programs that support the individual diseases and disorders associated with TMJD but, for the most part, do not support studies on comorbid conditions that cross Institute boundaries. Therefore, this Initiative represents an area that is underrepresented in both the NIDCR and NIH research portfolios and will likely encourage cross-Institute collaborations on this important orofacial disorder.
Collaborative Activities: The scope of this Initiative is broad and will require scientific knowledge of scientists from many disciplines. The NIDCR therefore will solicit the participation of several other Institutes and Centers at NIH and draw on their collective expertise to enhance the quality of the science garnered from this Initiative.
Funding Mechanisms: This Initiative will utilize the R01 and R21 mechanisms