Neural and psychological mechanisms of pain perception

National Center For Complementary & Integrative Health

Investigators

Linked publications, trials & patents

Abstract

This was the ninth year of the Section on Affective Neuroscience and Pain, and the lab continued to progress, recruit new trainees, and continue piloting with new paradigms. Three new fellows (one postdoc, two postbacs) joined the lab between October 2022 and September 2023, and six fellows (two postdocs, 4 postbacs) matriculated and began new positions in graduate school, full time scientific employment, or other endeavors. This progress report describes progress on our main human subjects protocol "Neural and psychological mechanisms of pain perception." The protocol includes five sub-studies designed to a) isolate different aspects of pain modulation, b) compare acute pain modalities (e.g., thermal pain versus shock-induced pain), and c) compare and contrast pain with other hedonic and perceptual domains (e.g., taste). In all studies, we measure decisions about pain experience (self-report) as well as neural and physiological responses to noxious stimuli that cause pain. During analysis, we combine computational modeling with advanced neuroimaging analyses to isolate the neural and psychological mechanisms that mediate the effects of expectations, attention, and emotion on subjective pain. We published and submitted several papers from this protocol during the review period. Our protocol requires all participants to go through an initial calibration session, following screening. Participants complete questionnaires, and then undergo an adaptive staircase calibration (ASC) procedure that evaluates pain ratings in response to noxious heat stimuli and determines each participants pain threshold, tolerance, and reliability of the association between temperature and pain. Over 350 individuals have completed this procedure to date on this protocol or on our pre-screening protocol (16-AT-0077). We published one manuscript based on this ASC procedure in FY22 (Amir et al., Journal of Pain, 2022), in which we measured the reliability of pain sensitivity and found that pain thresholds and tolerance were moderately reliable. Critically, we also found that female participants were more reliable than male participants for all three pain measures. We recently completed a follow-up study to test whether thermode type and stimulus duration impact pain sensitivity as measured using the ASC task (Parsons et al., under review). Participants underwent the ASC task twice during a visit, and we compared pain sensitivity as a function of stimulus duration. Pain thresholds and tolerance did not differ as a function of thermode size or stimulus duration, which provides support for large scale analyses that collapse across studies which may vary in stimulus parameters. We again observed important sex differences in pain sensitivity, driven by higher consistency across thermodes in female participants, relative to males. We completed data collection for three fMRI sub-studies in previous years and have been focusing on analysis and manuscript submission. Last year, we published results from our fMRI experiment that evaluates the effects of instructions and learning on pain and brain-responses to noxious stimulation during reversal learning in eLife (Atlas et al., 2022). Our findings have been described in detail in prior annual reports. We are now preparing a manuscript for submission to report results from our second fMRI study, which compared thermal pain with unpleasant and pleasant tastes to evaluate whether effects of learned expectations on brain responses to pain are specific to pain or reflect domain-general value processing. We observe effects of cues on intensity processing in all domains, and find that the insula and orbitofrontal cortex mediate domain-general impacts of expectancy regardless of modality (Zhao*, Lee*, et al., In prep). Finally, we have recently completed data analyses from an fMRI study that compared placebo analgesia with cue-based pain modulation (Necka*, Akintola*, et al., In prep). We find that cues and placebos interact to shape pain, and observe related interactions in the dorsolateral prefrontal cortex. Both papers will be submitted in the first half of FY24. During FY23, we piloted one new paradigm, adapted based on a pilot study that was conducted in FY22. Studies from other sensory domains have shown that percepts can be biased either towards (assimilation effect) or away (contrast effect) from expectation. While a significant body of work in the pain field has shown assimilation effects (e.g. placebo & nocebo effects), contrast effects have not been empirically demonstrated. Our experimental approach tests for contrast effects by manipulating both prediction error and verbal instructions. Healthy volunteers are randomly assigned to three groups (instructed assimilation, instructed contrast, no instruction) and undergo conditioning and reversal with pain-predictive cues. During FY23, 13 participants completed piloting on the most recent version of the task. Following data collection from 6 participants per group, we will perform power analyses based on pain ratings when medium heat is crossed with Predictive Cues. We hypothesize that contrast effects will be observed in the Instructed Contrast group following large prediction errors. We anticipate that piloting will be complete by the start of FY24. Following power analyses, we plan to use fMRI to measure how expectancy, error-based learning, and verbal instructions impact brain responses in pain and learning-related regions of interest. In addition to the projects mentioned above, we published several collaborative papers and reviews that are relevant to this line of research. We published the first paper to measure the impact of human ventromedial prefrontal cortex lesions on pain and expectancy-based modulation (Motzkin et al., 2023, Cortex). We find that VMPFC lesions enhance expectancy-based pain modulation without altering pain sensitivity or brain-body relationships. This is consistent with the dissociations between verbal instructions and feedback-driven learning that we have observed in prior work (Atlas et al., 2016 eLife; Atlas et al., 2022 eLife, Atlas 2019). We also published an invited review of the impact of instructions, learning, and expectancy on pain in the journal Annual Review of Neuroscience (Atlas, 2023).