Mutation Carriers with Reduced C-Afferent Density Reveal Cortical Dynamics of Pain–Action Relationship during Acute Pain

Abstract

The evidence that action shapes perception has become widely accepted, for example, in the domain of vision. However, the manner in which action-relevant factors might influence the neural dynamics of acute pain processing has remained underexplored, particularly the functional roles of anterior insula (AI) and midanterior cingulate cortex (mid-ACC), which are frequently implicated in acute pain. To address this, we examined a unique group of heterozygous carriers of the rare R221W mutation on the nerve growth factor (NGF) gene. R221W carriers show a congenitally reduced density of C-nociceptor afferent nerves in the periphery, but can nonetheless distinguish between painful and nonpainful stimulations. Despite this, carriers display a tendency to underreact to acute pain behaviorally, thus exposing a potential functional gap in the pain–action relationship and allowing closer investigation of how the brain integrates pain and action information. Heterozygous R221W carriers and matched controls performed a functional magnetic resonance imaging (fMRI) task designed to dissociate stimulus type (painful or innocuous) from current behavioral relevance (relevant or irrelevant), by instructing participants to either press or refrain from pressing a button during thermal stimulation. Carriers’ subjective pain thresholds did not differ from controls’, but the carrier group showed decreased task accuracy. Hemodynamic activation in AI covaried with task performance, revealing a functional role in pain–action integration with increased responses for task-relevant painful stimulation (“signal,” requiring button-press execution) over task-irrelevant stimulation (“noise,” requiring button-press suppression). As predicted, mid-ACC activation was associated with action execution regardless of pain. Functional connectivity between AI and mid-ACC increased as a function of reported urge to withdraw from the stimulus, suggesting a joint role for these regions in motivated action during pain. The carrier group showed greater activation of primary sensorimotor cortices—but not the AI and mid-ACC regions—during pain and action, suggesting compensatory processing. These findings indicate a critical role for the AI–mid-ACC axis in supporting a flexible, adaptive action selection during pain, alongside the accompanying subjective experience of an urge to escape the pain.

Pain, Touch, and Decision Making : Behavioral and Brain Responses to Affective Somatosensory Stimulation

“…Somewhat more surprisingly, we also found an interaction between upcoming pain and controllability in AI. Nevertheless, this finding is in line with research showing that AI is sensitive to the behavioral relevance of pain and that functional connectivity between AI and MCC correlates with a self-reported urge to move during pain (Perini et al, 2020). In sum, our findings suggest that cortical processing of pain is influenced by the noxious nature of upcoming events as well as the ability to affect those events.…”

“…Although whole-brain analyses did not reveal any significant effects or interactions in any of the predicted brain regions, ROI analyses found interactions between upcoming pain and controllability in both AI and MCC. This interaction was expected in MCC, which is involved in producing motor responses during both pain and nonpain (e.g., Perini et al, 2013Perini et al, , 2020. BOLD responses in MCC also correlated with response times, suggesting that the MCC has a particular role in producing motor responses to pain, even when the pain has not yet occurred.…”

“…This motivation to act is arguably part of the painful experience itself (Morrison et al, 2013). Indeed, some of the brain activation that is observed during painful stimulation represents an action component that is unspecific to pain (Perini et al, , 2020. Specifically, the midcingulate cortex (MCC) is activated during action execution (a button press) regardless of whether ongoing stimulation is painful or nonpainful (Perini et al, 2013(Perini et al, , 2020, suggesting that the MCC plays an important role in producing voluntary action to avoid harm.…”

“…Indeed, some of the brain activation that is observed during painful stimulation represents an action component that is unspecific to pain (Perini et al, , 2020. Specifically, the midcingulate cortex (MCC) is activated during action execution (a button press) regardless of whether ongoing stimulation is painful or nonpainful (Perini et al, 2013(Perini et al, , 2020, suggesting that the MCC plays an important role in producing voluntary action to avoid harm. The MCC also works closely with the anterior insula (AI) in producing action during pain: functional connectivity between AI and MCC increases with self-reported urge to move during pain (Perini et al, 2020).…”

“…Pain motivates action to avoid harm. Previous research has shown that the MCC plays an important role in this action component during pain (Perini et al, 2013(Perini et al, , 2020, whereas AI responds to pain regardless of action and also predicts whether an upcoming stimulation is perceived as painful (Ploner et al, 2010;Wiech et al, 2010). In Paper III, we investigated how the ability to affect an upcoming painful event with a voluntary action (a button press) influences the brain's processing of ongoing stimulation.…”