Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder
Research Highlights
►TMD patients had cortical thickening in somatosensory and frontal regions. ►TMD pain intensity negatively correlated with M1 and cingulate cortical thickness. ►TMD unpleasantness and neuroticism contribute to orbitofrontal cortical thickness. ►TMD duration positively correlated with thalamic gray matter. ►We report that TMD chronic pain and neuroticism contribute to abnormal gray matter.
Introduction
Temporomandibular disorder (TMD) is a common chronic orofacial pain that is more prevalent in women than in men (Ramírez et al., 2005). TMD can be idiopathic in that there may not be any clear peripheral etiological factors identifiable (Dworkin, 1994, Dworkin and Massoth, 1994, Dworkin et al., 1994, Ohrbach and Dworkin, 1998). In this scenario, it is thought that the CNS may initiate and/or maintain the pain (Sarlani and Greenspan, 2005).
Although a clear pattern of change has yet to be determined, previous structural MRI studies of chronic pain populations have found both increases and decreases in gray matter (GM). For instance, some studies of headache and chronic facial pain populations have found that patients with chronic pain had GM increases in regions likely associated with pain perception (DaSilva et al., 2007, May, 2008, Obermann et al., 2009, Younger et al., 2010). Additionally, most studies of chronic pain patients have found reduced GM in cortical regions likely associated with pain modulation and limbic function (Blankstein et al., 2010, Geha et al., 2008, May, 2008). Interestingly, some studies have also reported GM loss in cortical and subcortical motor areas (Apkarian et al., 2009, May, 2008, Schmidt-Wilcke et al., 2010). However, the increases are not limited to regions thought by some to be associated with pain perception, and the decreases are not limited to regions typically associated with pain modulation. Although the role of motor regions in pain is not fully established, there is evidence suggesting these areas play a role in pain modulation (Adachi et al., 2008, Brown and Barbaro, 2003, Craig and Dostrovsky, 1997, Garcia-Larrea et al., 2009, Garcia-Larrea et al., 1999, Lima and Fregni, 2008). In support of this concept are the motor abnormalities that can accompany chronic pain (Chen et al., 2009, Juottonen et al., 2002, Kirveskari et al., 2010, Svensson and Graven-Nielsen, 2001, Weissman-Fogel et al., 2011), possibly related to nocifensive behaviour (Murray and Peck, 2007).
There are two main routes by which the CNS may contribute to the development and/or maintenance of chronic pains such as TMD. One possibility is that long-term nociceptive input into the brain induces maladaptive brain plasticity, which may play a role in maintaining pain (Albanese et al., 2007, Woolf and Salter, 2000). For example, a recent study demonstrated that experimental pain that increased GM in nociceptive regions (Teutsch et al., 2008), induced pain habituation over time that was accompanied by decreased activity within nociceptive areas and increased activity within the antinociceptive system (Bingel et al., 2007). Chronic pain patients, however, may not be able to adapt in this way to nociceptive activity. For example, neuroimaging studies of chronic pain have shown hyperactivity in nociceptive regions, and hypoactivity in antinociceptive regions (Apkarian et al., 2005, Lev et al., 2010). Chronic pain patients' inability to habituate to increased nociceptive activity may be related to a reduced capacity of the brain to dampen pain by descending (top–down) controls (Bingel and Tracey, 2008). Indeed, many structural MRI studies have found GM differences in chronic pain populations associated with pain-related characteristics (intensity, unpleasantness, or duration) (Apkarian et al., 2004, Blankstein et al., 2010, May, 2008, Rodriguez-Raecke et al., 2009, Younger et al., 2010).
The second route by which the CNS may contribute to the development and/or maintenance of chronic pain relates to inherent personality-related factors that reduce the brain's capacity to modulate nociceptive input. This poor pain control represents a vulnerability to develop chronic pain. For example, there is evidence that neuroticism may be associated with pain-related suffering (Harkins et al., 1989), pain sensitivity (Costa, 1987, Goubert et al., 2004, Wade et al., 1992), nerve injury outcomes and neuropathic pain (Taylor et al., 2010) and inhibition of negative thoughts (Costa and McCrae, 1992). However, not all chronic pain patients have high neuroticism scores, and not all persons with neuroticism have chronic pain (Costa et al., 1986). Therefore, neuroticism alone is not sufficient to develop chronic pain. Rather, the normal relationship between neuroticism and brain structure and function may be disrupted within regions involved in pain modulation, such as the orbitofrontal cortex (OFC) (Wright et al., 2006) or the medial prefrontal cortex (mPFC) (DeYoung et al., 2010, Haas et al., 2008) and this could facilitate or maintain chronic pain.
Thus, in the current study we examined GM abnormalities in patients with idiopathic TMD and focused our investigation on the contribution of pain-related characteristics and neuroticism. Towards this goal, we measured GM in patients who had suffered from TMD over a range of pain intensities, unpleasantness and for varying durations, and neuroticism scores. Based on the aforementioned behavioural and neuroimaging studies, we specifically tested the hypotheses that TMD patients will have: 1) increased GM in areas associated with pain perception; 2) reduced GM in areas associated with pain modulation and motor function; 3) GM positively correlates with pain intensity, unpleasantness and TMD duration within areas associated with pain perception areas and negatively correlates with GM in areas associated with antinociception; 4) negative correlation between neuroticism and GM in regions implicated in pain modulation, and positive correlation in regions implicated in the affective dimension of pain, because of the interaction between affective processing and pain modulation in TMD (Turner et al., 2001).
Section snippets
Subjects
A group of 17 females with idiopathic TMD (mean age ± SD: 33.1 ± 11.9 years) and 17 healthy females (mean age ± SD: 32.2 ± 10.1 years) provided informed written consent to procedures approved by the University Health Network and Mount Sinai Hospital Research Ethics Boards. All subjects were right-handed. Patients with TMD were screened using TMD research diagnostic criteria (TMD-RDC) (Dworkin and Leresche, 1992) by dentists at the Mount Sinai Hospital Dental Clinic. Inclusion criteria included: 1) TMD
Patient demographics
The characteristics of individual patients are shown in Table 1. Patients and controls did not differ in age (patients: mean age ± SD: 33.1 ± 11.9 years; controls: 32.2 ± 10.1 years; p = 0.94) or in neuroticism scores (patients: mean age ± SD: 19.35 ± 6.84; controls: 18.35 ± 7.95; p = 0.70). Interestingly, TMD pain intensity and pain unpleasantness scores were not significantly correlated (r = 0.40, p = 0.12), unlike the tight correlation of these dimension in healthy subject in acute pain paradigms (Rainville et
Discussion
This structural imaging study identified striking abnormalities in patients with chronic idiopathic TMD pain and highlights the contribution of both TMD-related and neuroticism-related factors. Our key findings were that, compared to controls, patients with TMD had 1) cortical thickening of the S1, frontal pole and vlPFC, 2) pain intensity-dependent cortical thinning in the aMCC and M1 and pain unpleasantness-dependent cortical thinning in the OFC, 3) TMD duration-dependent GM increase in the
Conclusions
This study provides evidence for GM abnormalities in both the ascending pain and descending antinociceptive systems as well as motor and cognitive areas in TMD. Further, we have shown that the personality trait neuroticism and TMD characteristics can affect GM, suggesting the presence of both personality-based and chronic pain-related abnormalities.
Acknowledgments
We thank Mr. Geoff Pope, Dr. Mary-Pat McAndrews, Mr. Eugene Hlasny and Mr. Keith Ta for expert technical assistance and Dr. Yair Lenga for patient screening. We also thank Dr. Tim Salomons for technical assistance and for insightful feedback on earlier drafts of the manuscript.
This work was supported by the Canadian Institute of Health Research (Grant Number MOP 53304). MM is funded by a CIHR Banting and Best Canada Graduate Scholarship, an Ontario Graduate Scholarship, and the CIHR Pain: M2C
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