Anticipatory brainstem activity predicts neural processing of pain in humans

Abstract

Previous neuroimaging studies have shown brain activity during not only the application of noxious stimuli, but also prior to stimulation. The functional significance of the anticipatory response, however, has yet to be explored. Two theoretical responses involve either a decrease or an increase in sensitivity of the nociceptive system. In a functional magnetic resonance imaging (fMRI) study, brainstem responses during anticipation and processing of thermal noxious stimuli were investigated. Twelve healthy subjects were warned prior to and then received noxious stimulation to their left hand. Behavioral data showed a positive correlation between the intensity of anticipation and pain. FMRI data revealed brainstem activation in the PAG during the anticipation period. When correlated with individual anticipation ratings, activation during anticipation included significant clusters within the entorhinal cortex and ventral tegmental area (VTA). During receipt, activation within the brainstem included the PAG, VTA, rostral ventromedial medulla (RVM), and the parabrachial nucleus (PB), all elements of descending pain pathways. Using a backward model approach, we explored the functional significance of the anticipatory neural response for subsequent pain processing. Results of this regression analysis revealed that insula activity during receipt was predicted by activity in both the entorhinal cortex and VTA during anticipation. We suggest that activation in both regions before and during pain may underlie anticipation and subsequent pain modulatory responses, possibly involving the appraisal and control of attention necessary for pain modulation. Together, the results suggest a possible role of brainstem areas in anticipatory mechanisms involved in the maintenance of chronic pain.

Cerebral and spinal modulation of pain by emotions

“…Among these regions, the PHG is of particular interest, because its activation was previously found during the anticipation of highly painful thermal stimuli (13). Also, in another study, the PHG was shown to be coactivated with the PAG and ventral tegmental area (VTA) and further predicted pain responses in the posterior insula (8). This is particularly interesting, because PAG activation was also observed here in response to unpleasant pictures, supporting the idea that the combined activation of the PHG and the PAG could be involved in the descending facilitation of pain.…”

“…Descending pain-modulatory pathways originate from various cerebral structures involved in emotions (6)(7)(8) and sensorimotor functions (9). These regions are thought to affect spinal nociception through their projections to several brainstem structures, including the periaqueductal gray matter (PAG), rostroventral medulla (RVM), dorsolateral pontine tegmentum (DLPT), and nucleus cuneiformis (NCF) (10).…”

Enhanced Medial Prefrontal-Default Mode Network Functional Connectivity in Chronic Pain and Its Association with Pain Rumination

“…However, it remains unknown how ongoing PAG activity in human chronic pain populations represents antinociceptive versus pronociceptive functions. Human imaging studies of acute pain in healthy individuals largely focus on an antinociceptive function of the PAG (Tracey and Mantyh, 2007), but activation of the PAG during pain anticipation may promote hyperalgesia (Fairhurst et al, 2007). To explore the functional significance of mPFC-PAG FC and its link with pain rumination in more detail, future studies could employ continuous online ratings of pain and perceptrelated fMRI Kwan et al, 2005) in patients with chronic pain.…”

Nociception and autonomic nervous system

“…In contrast, the ventrolateral column receives convergent input from both the superficial and deep dorsal horn relaying nociceptive afferent information from visceral, muscle, and C-fiber skin nociceptors as well as visceral inputs from the nucleus of the NTS and sacral spinal cord. Functional neuroimaging studies in humans indicate that PAG activation by nociceptive inputs is modulated by attention, emotion, expectation of pain and expectation-related placebo analgesia [54][55][56][57][58][59][60][61]. Experimental studies using chemical microstimulation indicate that the different columns of the PAG organize different coping strategies to pain and other stressors [62][63][64][65][66].…”