Anatomical changes within the medullary dorsal horn in chronic temporomandibular disorder pain

Abstract

Accumulated evidence from experimental animal models suggests that neuroplastic changes at the dorsal horn are critical for the maintenance of various chronic musculoskeletal pain conditions. However, to date, no study has specifically investigated whether neuroplastic changes also occur at this level in humans. Using brain imaging techniques, we sought to determine whether anatomical changes were present in the medullary dorsal horn (spinal trigeminal nucleus caudalis) in subjects with the chronic musculoskeletal pain. In twenty-two subjects with painful temporomandibular disorders (TMDs) and forty pain-free controls voxel based morphometry of T1-weighted anatomical images and diffusion tensor images were used to assess regional grey matter volume and microstructural changes within the brainstem and, in addition, the integrity of ascending pain pathways. Voxel based morphometry revealed significant regional grey matter volume decreases in the medullary dorsal horn, in conjunction with alterations in diffusivity properties, namely an increase in mean diffusivity, in TMD subjects. Volumetric and mean diffusivity changes also occurred in TMD subjects in regions of the descending pain modulation system, including the midbrain periaqueductal grey matter and nucleus raphe magnus. Finally, tractography revealed altered diffusivity properties, namely decreased fractional anisotropy, in the root entry zone of the trigeminal nerve, the spinal trigeminal tract and the ventral trigeminothalamic tracts of TMD subjects. 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. These neural changes may be critical for the maintenance of pathological 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).