Human ventromedial prefrontal cortex lesions enhance expectation-related pain modulation

Abstract

Pain is strongly modulated by expectations and beliefs. Research across species indicates that subregions of the ventromedial prefrontal cortex (VMPFC) play a fundamental role in learning and generating predictions about valued outcomes. Consistent with this overarching framework, neuroimaging studies of experimental pain indicate that VMPFC activation tracks expectations of pain relief and statistically mediates expectation-related reductions in responses to painful stimuli across a distributed pain processing network. However, lesion studies in preclinical models and in humans with refractory chronic pain suggest that VMPFC may play a more general role in representing the affective and motivational qualities of pain that contribute to its strong aversive drive. To test whether VMPFC is necessary for pain processing in general, or instead plays a more specific role in the modulation of pain by expectations, we studied responses to experimental heat pain in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage.All participants underwent quantitative sensory testing (QST) to characterize pain sensitivity, followed by a pain expectancy task. Participants were instructed that auditory cues would be followed by heat calibrated to elicit low or high pain. Following a conditioning phase, each cue was intermittently paired with a single temperature calibrated to elicit moderate pain. We compared ratings of moderate heat stimuli and subjective expectancy ratings as a function of cue to evaluate whether VMPFC lesions impact cue-based expectancy and expectancy effects on pain intensity and unpleasantness. We also analyzed QST measures to evaluate whether VMPFC lesions were associated with overall shifts in pain sensitivity.Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expectations as a function of pain-predictive cues, and stronger cue-based modulation of pain ratings, particularly for ratings of pain unpleasantness. There were no group differences in pain sensitivity, nor in the relationship between pain and autonomic arousal, indicating that the impact of VMPFC lesions is specific to expectancy-based modulation of pain unpleasantness.Our findings suggest that the VMPFC is not essential for basic subjective and physiological responses to painful stimuli. Rather, our findings of significantly enhanced cue- related expectancy effects may suggest that VMPFC plays an important role in updating expectations or integrating sensory information with expectations to guide subjective judgements about pain. Taken together, these results expand our understanding VMPFC’s contribution to pain and highlight the role of VMPFC in integrating cognitive representations with sensory information to yield affective responses.

Instructions and experiential learning have similar impacts on pain and pain-related brain responses but produce dissociations in value-based reversal learning

“…suppression) we observed is consistent with this modulation or down-regulation: Individuals who showed greater activation of these regions in response to high pain cues showed stronger negative associations between brain activation and subjective pain, controlling for cue. Identifying factors that predict individual differences in brain mediators is an important direction for future research, as is testing the causal contributions of these modulatory regions to placebo analgesia and expectancy-based pain modulation through interventions such as transcranial magnetic stimulation ( Krummenacher et al, 2010 ) or in individuals with neurosurgical lesions ( Motzkin et al, 2021 ).…”

“…Lateral OFC is thought to evaluate value of independent options, whereas medial OFC and VMPFC have been linked to value-based choice for the purpose of comparison ( Rudebeck and Murray, 2014 ). We recently showed that surgical lesions of the bilateral VMPFC enhance instructed cue effects on pain in a stable environment ( Motzkin et al, 2021 ). Additional studies that use lesion symptom mapping in heterogeneous frontal samples or measure aversive learning in nonhuman primates can provide further insights on the contribution of different portions of the VMPFC/OFC to pain modulation and instructed learning.…”

Increased functional connectivity between limbic brain areas in healthy individuals with high versus low sensitivity to cold pain: A resting state fMRI study

“…The authors concluded that these connectivity differences may contribute to the NAc activity that distinguishes the two groups [ 64 ]. The vmPFC may play a role in representing the affective and motivational qualities of pain that contribute to its strong aversive drive and was found as a critical link between cognitive state and the affective-motivational features of pain [ 67 ]. Yet, no significant differences were found in the connectivity of this region between our groups.…”

How instructions, learning, and expectations shape pain and clinical outcomes

“…We recently evaluated the contribution of the VMPFC, a region implicated in flexible learning and value-based decision making (Murray et al 2007;Roy et al 2012;Schneider & Koenigs 2017;Schoenbaum et al 2007). We compared pain and its modulation by expectation in individuals bilateral VMPFC lesions following surgical resection to healthy controls with intact brains (Motzkin et al 2021). Groups did not differ in pain sensitivity or the correspondence between pain and autonomic activity, but individuals with VMPFC lesions reported stronger cue-based pain modulation and larger differences in expectations, providing evidence that VMPFC is not necessary for the development of expectations.…”