Altered Brainstem Pain Modulating Circuitry Functional Connectivity in Chronic Painful Temporomandibular Disorder

Abstract

There is evidence from preclinical models of chronic pain and human psychophysical investigations to suggest that alterations in endogenous brainstem pain-modulation circuit functioning are critical for the initiation and/or maintenance of pain. Whilst preclinical models have begun to explore the functioning of this circuitry in chronic pain, little is known about such functioning in humans with chronic pain. The aim of this investigation was to determine whether individuals with chronic non-neuropathic pain, painful temporomandibular disorders (TMD), display alterations in brainstem pain-modulating circuits. Using resting-state functional magnetic resonance imaging, we performed static and dynamic functional connectivity (FC) analyses to assess ongoing circuit function in 16 TMD and 45 control subjects. We calculated static FC as the correlation of functional magnetic resonance imaging signals between regions over the entire scan and dynamic FC as the correlation of signals in short (50s) windows. Compared with controls, TMD subjects showed significantly greater (static) FC between the rostral ventromedial medulla and both the subnucleus reticularis dorsalis and the region that receives orofacial nociceptive afferents, the spinal trigeminal nucleus. No differences were found in other brainstem pain-modulating regions such as the midbrain periaqueductal gray matter and locus coeruleus. We also identified that TMD subjects experience greater variability in the dynamic functional connections between the rostral ventromedial medulla and both the subnucleus reticularis dorsalis and spinal trigeminal nucleus. These changes may underlie enhanced descending pain-facilitating actions over the region that receives nociceptive afferents, ultimately leading to enhanced nociceptive transmission to higher brain regions and thus contributing to the ongoing perception of pain. PerspectivePsychophysical studies suggest that brainstem pain-modulation circuits contribute to the maintenance of chronic pain. We report that individuals with painful TMD display altered static and dynamic FC within the brainstem pain-modulation network. Modifying this circuitry may alter an individual's ongoing pain.