White matter brain and trigeminal nerve abnormalities in temporomandibular disorder Massieh Moayedi a,b , Irit Weissman-Fogel b , Tim Vaughn Salomons b , Adrian Philip Crawley c,d , Michael Brian Goldberg e,f , Bruce Victor Freeman e,f , Howard Charles Tenenbaum a,e,f , Karen Deborah Davis a,b,g,⇑ a Institute of Medical Science, University of Toronto, Toronto, ON, Canada b Division of Brain, Imaging and Behaviour – Systems Neuroscience, Toronto Western Research Institute, Toronto, ON, Canada c Department of Medical Imaging, University of Toronto, Toronto, ON, Canada d Department of Medical Imaging, University Health Network, Toronto, ON, Canada e Faculty of Dentistry, University of Toronto, Toronto, ON, Canada f Mount Sinai Hospital Dental Clinic, Toronto, ON, Canada g Department of Surgery, University of Toronto, Toronto, ON, Canada Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. article info Article history: Received 25 November 2011 Received in revised form 22 February 2012 Accepted 5 April 2012 Keywords: MRI White matter DTI Chronic pain TMD Plasticity Trigeminal nerve abstract Temporomandibular disorder (TMD) is a prevalent chronic pain disorder that remains poorly understood. Recent imaging studies reported functional and gray matter abnormalities in brain areas implicated in sensorimotor, modulatory, and cognitive function in TMD, but it is not known whether there are white matter (WM) abnormalities along the trigeminal nerve (CNV) or in the brain. Here, we used diffusion ten- sor imaging, and found that, compared to healthy controls, TMD patients had 1) lower fractional anisot- ropy (FA) in both CNVs; 2) a negative correlation between FA of the right CNV and pain duration; and 3) diffuse abnormalities in the microstructure of WM tracts related to sensory, motor, cognitive, and pain functions, with a highly significant focal abnormality in the corpus callosum. Using probabilistic tractog- raphy, we found that the corpus callosum in patients had a higher connection probability to the frontal pole, and a lower connection probability to the dorsolateral prefrontal cortex, compared to controls. Finally, we found that 1) FA in tracts adjacent to the ventrolateral prefrontal cortex and tracts coursing through the thalamus negatively correlated with pain intensity; 2) FA in the internal capsule negatively correlated with pain intensity and unpleasantness; and 3) decreases in brain FA were associated with increases in mean diffusivity and radial diffusivity, markers of inflammation and oedema. These data pro- vide novel evidence for CNV microstructural abnormalities that may be caused by increased nociceptive activity, accompanied by abnormalities along central WM pathways in TMD. Ó 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. 1. Introduction Temporomandibular disorder (TMD) is a chronic pain disorder characterized by pain in the masticatory muscles and/or temporo- mandibular joint, and can be exacerbated by mandibular function. TMD is prevalent in 10%–20% of the population, mostly in women [27,33,57,70]. In idiopathic TMD there is no clear aetiology [26,28,29,67]. Abnormal central nervous system (CNS) function is thought to initiate or maintain TMD pain [74] based on TMD symp- tomatology such as persistent pain, allodynia, and hyperalgesia, sometimes extending to regions distant from the face [32,35,42, 62,73,94]; enhanced temporal summation of pain to repetitive noxious heat stimuli [60]; and dysfunctional diffuse noxious inhib- itory controls [49]. Abnormalities of these centrally mediated processes suggest that ascending nociceptive pathways and/or descending pain modulatory pathways [54] are affected. Addition- ally, TMD patients can exhibit cognitive [37–39] and motor dys- function [86] possibly related to abnormalities in brain regions associated with these functions [77,78,87,100]. Structural brain imaging provides an opportunity to delineate anatomical substrates of CNS abnormalities in TMD. We reported that patients with TMD have increased cortical thickness in the orofacial region of the primary somatosensory cortex (S1), the ventrolateral prefrontal cortex (vlPFC), and the frontal pole [63]. 0304-3959/$36.00 Ó 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.pain.2012.04.003 ⇑ Corresponding author. Address: Division of Brain, Imaging and Behaviour – Systems Neuroscience, Toronto Western Research Institute, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Room MP14-306, Toronto, ON, Canada M5T 2S8. Tel.: +1 416 603 5662; fax: +1 416 603 5745. E-mail address: kdavis@uhnres.utoronto.ca (K.D. Davis). PAIN Ò 153 (2012) 1467–1477 www.elsevier.com/locate/pain