Neural and psychological mechanisms of pain perception

National Center For Complementary & Integrative Health

Investigators

Linked publications & trials

Abstract

This was the eighth year of the Section on Affective Neuroscience and Pain, and despite continued impacts of the COVID-19 pandemic, the lab continued to progress, recruit new trainees, and resume data collection with new paradigms. Two new fellows (one postdoc, one postbac) joined the lab between October 2021 and September 2022. This progress report describes progress on our 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 were required to halt healthy volunteer research due to the COVID19 pandemic between March 2020 and April 2021, which had a serious impact on both data collection and our ability to train new personnel, as shadowing opportunities were lacking without research participants. Nonetheless, we spent the time focusing on data analysis and additional projects that used remote participants. Subject recruitment and personnel training resumed slowly in June of 2021, and by the fall most trainees were comfortable with the equipment and procedures and able to resume active data collection with healthy volunteers. We have completed behavioral piloting for one new paradigm for which we will soon begin fMRI scanning, and have begun behavioral piloting on a second paradigm. Both of these are described in more detail below. We published several papers from this protocol during the review period and made progress toward submission on several others. 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 the past fiscal year (Amir et al., Journal of Pain, 2022), in which we measured the reliability of pain sensitivity. We found that pain thresholds and tolerance were moderately reliable, but that the correlation between temperature and pain has low reliability across visits. Critically, we also examined sex differences in reliability, since hormonal fluctuations are often cited as a reason to exclude female participants from pain research. Strikingly, we found that female participants were more reliable than male participants for all three pain measures. We are now following up these findings by measuring how hormonal factors influence pain sensitivity in female participants. We completed data collection for three fMRI sub-studies in previous years and manuscripts are in various stages of submission. These have been described in detail in prior annual reports. We have submitted one paper that evaluates the effects of instructions and learning on pain and brain-responses to noxious stimulation during reversal learning, and our manuscript is under revision at the journal eLife. A second study 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 are now measuring whether the brain mechanisms that mediate these links differ as a function of modality (Zhao*, Lee*, et al., In prep). Finally, we are also analyzing data from an fMRI study that compared placebo analgesia with cue-based pain modulation (Akintola*, Necka*, et al., In prep). These two latter projects were led by fellows who completed their fellowships in the summer of 2019 and we are continuing to collaborate to complete analyses and draft the manuscripts, with the help of new trainees and our data analyst. Beginning in the fall two new postdocs completed training and designed the final two sub-studies on this protocol. We modified our planned experiment on taste vs pain in light of the pandemic and are now comparing appetitive and aversive learning for substudy II.ii. (Does learning transfer across domains?). Participants undergo associative learning in an aversive context or an appetitive context. In the aversive context, moderate pain represents the better-of-two options (i.e., participants receive high heat and moderate heat), whereas in the appetitive context, moderate heat represents the worse-of-two options (i.e., participants receive low heat and moderate heat). This fiscal year, 6 participants completed behavioral piloting and we observed that ratings in response to moderate heat were lower when in the context of high heat vs. when in the context of low heat (B = -1.4083, p = 0.03). With n=6, this effect of context (aversive vs. appetitive) was large (Cohen's d = 0.90). Results from a prospective power analysis given these data suggest that we would obtain 99% power with n=13 and 100% power with n > 13. As such, we will recruit 20 participants - and have sufficient power - to the associated fMRI sub-study, which will involve using high-field (7T) functional MRI to detect brain responses to contextual effects (aversive vs. appetitive) on pain perceptions. We are currently performing technical scanning and plan to begin scanning healthy volunteers using this paradigm at the end of the fiscal year or the start of FY23. A second new paradigm is examining the Affective Expectancy Model (Wilson, 1985) in Pain and specifically testing for Contrast effects which are yet to be demonstrated in pain. Previous literature shows that expectations can shape the perception of pain. Furthermore, 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. in Placebo & Nocebo effects, contrast effects have not been empirically demonstrated. Our experimental approach tests for contrast effects by manipulating both Prediction Error and uncertainty. We will also test the influence of verbal instructions on the development of contrast effects. We recently began piloting this task behaviorally with healthy volunteers in three groups (instructed assimilation, instructed contrast, no instruction). 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 and Uncertainty. We hypothesize that a combination of High Prediction Error and High Uncertainty will produce a contrast effect. Following power analyses, we plan to use fMRI to measure how expectancy, uncertainty, and error-based learning 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 (Atlas et al., Psychophysiology, 2021; Abend et al., 2022, Neurobiology of Stress; Atlas, 2021, Trends in Cognitive Sciences; Petre et al., PLOS Biology; Kohoutova et al, 2022, Nature Neuroscience).