Changes in Affective Pain Processing in Human Volunteers

The experience of pain is more than the conscious perception of nociceptive signals. Emotional and motivational aspects accompany pain, leading to its aversiveness and motivation for avoidance. In chronic pain, a negative hedonic shift has been proposed that is characterized by disproportionally increased emotional-motivational compared to sensory-discriminative pain responses. Such a negative hedonic shift is, for example, mirrored in very high comorbidity rates of chronic pain and affective disorders such as depression and anxiety. The aim of this study is to develop methods that allow the differentiation of sensory-discriminative and emotional-motivational pain response and to characterize mechanisms of the negative hedonic shift.

The experience of pain is more than the conscious perception of nociceptive signals. Emotional and motivational aspects accompany pain, leading to its aversiveness and motivation for avoidance. In chronic pain, a negative hedonic shift has been proposed that is characterized by disproportionally increased emotional-motivational compared to sensory-discriminative pain responses. Such a negative hedonic shift is, for example, mirrored in very high comorbidity rates of chronic pain and affective disorders such as depression and anxiety. However, appropriate psychophysical methods to differentiate sensory-discriminative and emotional-motivational pain processing in humans are lacking. Therefore, only indirect evidence on the assumed negative hedonic shift in chronic pain is available, albeit understanding the mechanisms of such a shift would increase our knowledge on the development and maintenance of chronic pain in important ways with impact beyond pain research. The aim of this study is to develop methods that allow the differentiation of sensory-discriminative and emotional-motivational pain response and to characterize mechanisms of the negative hedonic shift.

A potential benefit of the study will be an increase in the knowledge on mechanisms of the development and maintenance of chronic pain with a focus on emotional-motivational processes likely also relevant in other diseases such as affective disorders.

This study involves only minimal risks for participants. The methods that will be used in the experimental investigations are within the range of standard procedures in pain research and experimental psychology and are frequently used in healthy participants and patients. Experimental pain stimulation will be adjusted to individual pain sensitivity, rendering the applied stimulation tolerable.

Substudy 1 Each participant will perform one testing session of approximately 1.5h duration at the Balgrist Campus, Balgrist University Hospital, Zurich. Healthy volunteers (N=31) will be recruited. The testing session will comprise a discrimination task and an avoidance task to assess sensory-discriminative and emotional-motivational pain components independently of each other. The tasks will be performed in counterbalanced order. After obtaining written informed consent, participants' individual heat pain threshold and tolerance will be determined, based on which the stimulation intensity to be used in the discrimination and the avoidance task will be calculated. After this assessment, participants either perform the discrimination or the avoidance task. Within the discrimination task, participants have to indicate whether they perceived a small increase in temperature or not. In the avoidance task, participants can avoid a painful stimulation by reacting fast enough to a visual cue. Participants will be randomly (balanced randomization) assigned to one of two learning conditions, either reinforcing successful discrimination or avoidance, to increase sensory-discriminative or emotional-motivational pain responses. Reinforcement, implemented by small monetary wins, will start depending on the condition after half the trials of the discrimination or the avoidance task. Subjective ratings of perceived pain intensity and unpleasantness will be assessed within both tasks as control variables to test whether increases in sensory-discriminative or emotional-motivational pain processing generalize to the subjective response channel. At the end of the testing session, participants will complete several questionnaires to investigate whether certain personality traits are related to learning capacity as tested in these tasks.

Substudy 2 Each participant will perform one testing session of approximately 1.5h duration at the Balgrist Campus, Balgrist University Hospital, Zurich. The sample will consist of patients with unspecific musculoskeletal chronic pain (N=31) and age- and sex-matched healthy controls (N=31). As in Substudy 1, the testing session will comprise the discrimination task and the avoidance task to assess sensory-discriminative and emotional-motivational pain components independently of each other. The tasks will be performed in counterbalanced order. After obtaining written informed consent, participants' individual heat pain threshold and tolerance will be determined, based on which the stimulation intensity to be used in the discrimination and the avoidance task will be calculated. After this assessment, participants either perform the discrimination or the avoidance task as in Substudy 1. In contrast to Substudy 1, reinforcement in the avoidance task will be implemented to decrease emotional-motivational pain responses because it is assumed that patients show already increased emotional-motivational compared to sensory-discriminative pain processing. Subjective ratings of perceived pain intensity and unpleasantness will be assessed within both tasks as control variables to test whether increases in sensory-discriminative or emotional-motivational pain processing generalize to the subjective response channel. At the end of the testing session, participants will complete several questionnaires, to investigate whether certain personality traits are related to heightened emotional-motivational pain processing.

Sample sizes for Substudy 1 and 2 are based on a priori sample size calculations using G\*Power 3.1 with a desired medium effect size f=0.25, alpha=0.05, beta=0.80, repeated measures ANOVA between-within-subject designs, and an attrition rate of 10%. Outcome variables () will be analyzed in separate mixed model analyses for ANOVA designs with appropriate within- and between-subject factors. Associations of primary endpoints () with personality traits (secondary outcomes) will be analyzed using Person- or Spearman correlation coeffients, where appropriate. Significance levels will be set to 5%, adjusted with false discovery rate for multiple testing. Effect sizes will be calculated in terms of generalized η2 and Cohen's d.

Substudy 3 Each participant will perform one testing session of approximately 1.25h duration at the Balgrist Campus, Balgrist University Hospital, Zurich. Healthy volunteers (N=30) will be recruited. During testing session participants will perform a psychophysical task to assess metacognition in pain perception as an indicator of the cognitive-evaluative pain component. The objective is to assess whether metacognition on pain perception are involved and subjective ratings of perceived pain and how metacognition relates to pain intensity. After obtaining written informed consent, participants' individual heat pain threshold and tolerance will be determined, based on which the stimulation intensity to be used in the experiment will be calculated. After this assessment, participants perform the cognitive pain task. Within this task, participants have to indicate whether they perceived a first or second heat pain stimulus as higher in intensity, whether the higher one was perceived as painful or not, and their confidence in both these answers. In addition, participants will complete several questionnaires to investigate whether certain personality traits and personal states are related to metacognition in pain.

The sample size of Substudy 3 is determined according to Kreft and Leeuw (2007) after which a great enough power will be reached with a sample size of 30 participants and 30 observations to identify cross-level interactions. Substudy 3 follows a within subject design with repeated measures. The tasks that will be performed by each participant include the within-subject factor 'temperature difference' (differences in temperature between first and second stimulus) and the within-subject factor 'temperature level' (temperature relative to individual pain threshold of each stimulus). The order of the different conditions in each task will be applied using a balanced pseudo-randomized order. For testing hypothesis 1ai, 1bi and 1c t-test will be conducted. For Hypothesis 1aii and 1bii chi square tests are planned. To test hypothesis 2a, 2c and 3 logistic hierarchic liner models and for hypothesis 2b and 2d hierarchic linear models will be performed.

Within this study methods that allow the separation of different components of the perception of pain will be developed and validated and which are currently not available. In addition, based on theses methods, a human model on how such components of pain can dissociate will be developed, thereby allowing investigating a prominent assumption on factors that crucially contribute to the development and maintenance of chronic pain. The expected results will form the basis for the development of novel mechanism-based pain therapies.

Psychophysical methods based on experimental psychology and pain research will be used, which have been shown before to be successful in investigating different aspects of pain perception and the modulation of pain perception. The methods used are in the standard range of methods from human pain research and experimental psychology and hold only minimal risk for participants (see above "Risk / Benefit Assessment").

Eligibility Criteria:
For Healthy participants

Inclusion Criteria:

* good overall health status
* sufficient knowledge of German or English to follow instructions
* ability to give written informed consent

Exclusion Criteria:

* pain longer than \>3 consecutive days and on more than 30 days within the last 12 months
* major psychiatric or neurological disorders, and substance abuse
* consumption of alcohol, illegal drugs, and analgesic drug within 24 hours before testing

For chronic pain patients

Inclusion Criteria:

* unspecific musculoskeletal chronic pain
* sufficient knowledge of German or English to follow instructions
* ability to give written informed consent

Exclusion Criteria:

* major psychiatric or neurological disorders, excluding depression and anxiety, and substance abuse
* consumption of alcohol, illegal drugs, and analgesic drugs within 24 hours before testing