Altered cortico-brainstem connectivity during spontaneous fluctuations in pain intensity in painful trigeminal neuropathy.

Abstract

Chronic neuropathic pain can result from nervous system injury and can persist in the absence of external stimuli. Although ongoing pain characterizes the disorder, in many individuals, the intensity of this ongoing pain fluctuates dramatically. Previously, it was identified that functional magnetic resonance imaging (fMRI) signal covariations between the midbrain periaqueductal gray matter (PAG), rostral ventromedial medulla (RVM), and spinal trigeminal nucleus (SpV) are associated with moment-to-moment fluctuations in pain intensity in individuals with painful trigeminal neuropathy (PTN). Since this brainstem circuit is modulated by higher brain input, we sought to determine which cortical sites might be influencing this brainstem network during spontaneous fluctuations in pain intensity. Over 12 minutes, we recorded ongoing pain intensity in 24 PTN participants, and classified them as fluctuating (n=13) or stable (n=11). Using a PAG seed, we identified connections between the PAG and emotional-affective sites such as the hippocampal and posterior cingulate cortices, the sensory-discriminative posterior insula, and cognitive-affective sites such as the dorsolateral prefrontal (dlPFC) and subgenual anterior cingulate cortices that were altered dependent on spontaneous high and low pain intensity. Additionally, sliding-window functional connectivity analysis revealed that the dlPFC-PAG connection anticorrelated with perceived pain intensity over the entire 12-minute period. These findings reveal cortical systems underlying moment-to-moment changes in perceived pain in PTN, which likely cause dysregulation in the brainstem circuits previously identified, and consequently alter the appraisal of pain across time.

Significance statement Whilst the intensity of an individual's chronic pain is often measured at a specific point in time, it is known that in a large proportion of individuals, pain intensity fluctuates dramatically from moment-to-moment. In individuals with chronic neuropathic pain, we found that these spontaneous pain intensity fluctuations are associated with neural function fluctuations, specifically of function reflected as neural connectivity between brainstem pain modulatory circuits and cortical regions, including the dorsolateral prefrontal and cingulate cortices. These findings raise the possibility that modulating brain regions such as the dorsolateral prefrontal cortex in individuals with fluctuating chronic pain may provide an avenue for analgesic treatment.