Anatomical changes within the medullary dorsal horn in chronic temporomandibular disorder pain
Introduction
In many chronic pain conditions, rather than simply being a reflection of peripheral inputs or pathology, the perception of pain is thought to also dynamically reflect central neuronal alterations (Latremoliere and Woolf, 2009). In particular, it has been proposed that alterations at the first (primary) synapse, that is, between peripheral nociceptor afferents and lamina I spinal or medullary dorsal horn neurons, are critical for the maintenance of pain that was initially induced by low-level afferent input such as chronic inflammatory and musculoskeletal pain (Ikeda et al., 2006).
Both animal models and clinical conditions suggest that some forms of chronic pain are associated with alterations in neuronal activity linked to long-term structural changes in the brain (Henderson et al., 2013, Jensen et al., 2013, Sessle, 2000). In contrast, other forms may not necessarily be associated with central changes, although evidence is mixed (Moayedi et al., 2012, Younger et al., 2010). For example, we found in humans that chronic neuropathic pain is associated with thalamic and cortical structural brain changes, but musculoskeletal pain is not (Gustin et al., 2011). However, in animal models of chronic inflammatory/musculoskeletal pain, investigations of changes at the primary synapse demonstrate long-term glial up-regulation and central sensitisation (Miyagi et al., 2011, Tsuboi et al., 2011). Hence, chronic musculoskeletal pain may also be associated with structural changes, but at the level of the primary synapse, rather than higher brain regions.
To date, no study has explored the anatomy of spinal or medullary dorsal horn in humans with chronic pain. The lack of studies focussed on the spinal cord is not surprising given its extremely small size (Valsasina et al., 2012), but the brainstem can be explored using current high resolution magnetic resonance imaging (MRI) techniques. In the orofacial system, the medullary dorsal horn or spinal trigeminal nucleus caudalis (SpVc) lies within the caudal brainstem. We have previously used functional MRI to explore brainstem activation patterns during experimentally evoked acute muscle pain in healthy individuals. Indeed, we found that acute orofacial muscle pain evokes signal intensity increases within the ipsilateral SpVc (Nash et al., 2009). Given the superior spatial resolution of anatomical MRI, it is also possible to explore the anatomy of this brainstem region in humans with chronic orofacial pain conditions.
The aim of this investigation was to use anatomical MRI techniques to explore brainstem anatomy, particularly the SpVc, in individuals with painful temporomandibular disorders (TMDs), a set of chronic musculoskeletal conditions involving the masticatory muscles, the temporomandibular joints, or both (Bender, 2012). If chronic pain conditions such as TMD are maintained by central neuronal alterations, we hypothesise that this will manifest as observable anatomical changes, particularly within SpVc. Furthermore, it is likely that the degree of change will be reflected in the intensity of on-going pain. High resolution voxel-based morphometry (VBM) of T1-weighted anatomical and diffusion weighted images will be used to determine changes in regional brainstem anatomy. In addition, deterministic tractography will be used to assess the integrity of ascending orofacial pain pathways. We hypothesise that TMDs will be associated with altered SpVc anatomy and altered integrity of ascending pain pathways as a result of prolonged peripheral input (Stankewitz et al., 2013).
Section snippets
Subjects
Twenty-two subjects with painful TMDs (four males, mean [± SEM] age: 46.5 ± 2.6) and 40 pain-free controls (seven males, age: 48.3 ± 2.1) were recruited. There was no significant difference in age (t test; p > 0.05) or gender distribution (χ2 test, p > 0.05) between the two subject groups. All subjects were recruited from the Faculty of Dentistry, Westmead Hospital and University of Sydney. Individual TMD subject demographics are given in Table 1. TMD subjects were diagnosed using the research
Pain characteristics
Individual TMD subject characteristics are shown in Table 1. All TMD subjects reported myofascial muscle pain; of these eight subjects (36%) also reported TMJ athralgia. In four of the TMD subjects, pain was unilateral (right side) and the remaining subjects had pain bilaterally. Their average scan pain intensity was 4.0 ± 2.3 (moderate), the average diary pain was 3.7 ± 0.4 and their average duration of pain was 9.7 ± 1.9 years. TMD subjects most commonly described their pain as throbbing (70%),
Discussion
This study reveals that chronic musculoskeletal pain is associated with anatomical changes at multiples levels of the ascending pain pathway. In subjects with TMD, decreased FA and increased MD occurred in the REZ of the trigeminal nerve, decreased grey matter paired with increased MD occurred in the region of the medullary dorsal horn, and decreased FA occurred in the ventral trigeminothalamic tracts.
Conclusion
These data reveal that chronic musculoskeletal pain in humans is associated with discrete alterations in the anatomy of the medullary dorsal horn, as well as its afferent and efferent projections, and areas associated with descending pain modulation. These neural changes may underlie the abnormal neuronal function thought to initiate or maintain chronic musculoskeletal pain which, if so, offers a valid therapeutic target.
Acknowledgements
This research was supported by the National Health and Medical Research Council of Australia, grant #1032072, and the Australian Dental Research Foundation, Inc. (ADRF 17/2010). We wish to thank the many volunteers in this study.
Conflict of interest
The authors declare no competing financial interests.
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