Intrinsic attention to pain is associated with a pronociceptive phenotype

Capacity for modulation of incoming nociceptive signals is a determinant of our tendency to attend to pain.


Introduction
Individuals differ in their capacity to endogenously modulate nociceptive input. Yarnitsky et al. 21 proposed a "pronociceptive phenotype" associated with nociceptive facilitation, consisting of enhanced temporal summation (TS), and/or less efficient conditioned pain modulation (CPM). Temporal summation is a measure of "wind-up" or enhancement of pain with prolonged nociceptive exposure, with accumulating intensity drawing increased attention to the stimulus, facilitating adaptive response. CPM is based on the concept of "pain inhibits pain" derived from diffuse noxious inhibitory control (DNIC) in animal studies. 10 Conditioned pain modulation is said to quantify the efficiency of endogenous inhibition of pain. 4,14 In Yarnitsky's conceptualisation, the 2 modulatory mechanisms contribute independently towards a pronociceptive phenotype, likely because of the ascending facilitatory component of TS 15,16 and the descending inhibitory component of CPM. 9 This suggests there are measurable individual differences in how people modulate an incoming nociceptive stimulus at the spinal and supraspinal level.
Pain is an alarming signal and naturally captures attention to facilitate adaptive avoidance of harm. 6 The degree to which this focus is captured by pain may be a function of the competing salience of current contextual factors other than the nociceptive stimulus. 6 However, attention to pain is not a simple function of pain intensity and the contextual factors external to the individual. Individuals differ in their trait-like ability to mentally disengage from pain when it occurs. A previous study found "intrinsic attention to pain" (IAP-the likelihood that people focus on pain or "something else" during nociceptive stimulation) was stable within individuals across time, with a high intraclass correlation across sessions, suggesting IAP can be considered trait-like. Furthermore, IAP was associated with their performance on a cognitive task during the presence of pain, 8 suggesting this measure also taps individual differences in the likelihood that pain will distract from cognitive functioning. Neurally, IAP is associated with functional and structural connectivity between the medial prefrontal cortex and periaqueductal gray, suggesting an individual's propensity to attend to pain might be a function of the interplay between cortical evaluative processes and endogenous modulation of incoming sensory signals.
To date, however, little research has explored the role of the endogenous modulatory processes in how likely an individual is to be distracted by pain. This study, therefore, investigated whether Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
(and how) a pronociceptive phenotype is associated with trait-like attention to pain.

Participants
Forty-four healthy participants (23 female; M age 5 23.57, SD 5 5.50) were recruited and received payment for their participation. The study was approved by the University of Reading Ethics Committee. Informed consent was provided by each participant. This study was part of an ongoing study involving 13 experimental sessions (1 sensory/cognitive assessment, 1 imaging session, and 11 examining prolonged pain exposure) per participant. All data for this study were collected during the initial sensory assessment.

Materials
Evaluation of IAP, TS, and CPM involved thermal stimuli being administered by a 30 3 30 mm thermode (PATHWAY, Medoc, Israel) to the centre of the right calf. The baseline temperature for stimuli used in all testing was 32˚C, and the ramp up rate was 8˚C/s. For CPM and TS, participants verbally rated pain intensity on a Numerical Rating Scale (NRS) ranging from 0 ("no pain") to 10 ("extremely painful"). For IAP, participants provided verbal ratings indicating "to what degree were your thoughts/feelings about pain or something else," using a 4-point Likert scale provided on paper (2 5 "only pain," 1 5 "mostly pain," 21 5 "mostly something else," and 22 5 "only something else").

Intrinsic attention to pain
Participants received 10 thermal stimuli (5/10 NRS-calibrated as a 20-second stimulus rated between 4 and 6-if a rating was given outside these values, the stimulus was adjusted by 0.5˚C and the test was repeated) of 20 seconds(s) duration each and each with a 30-second interstimulus interval. After each stimulus, participants provided IAP ratings. IAP scores were calculated by averaging all 10 scores.

Temporal summation
Based on previous paradigms, 18 a calibrated (5/10 NRS) thermal stimulus was applied for 120 seconds. Every 10 seconds, participants were verbally prompted to state pain intensity using the NRS. TS scores were calculated by subtracting the first score from the last score in the series. A high TS score indicated greater sensitization.

Conditioned pain modulation
Based on previous paradigms, 22 the test stimulus was a calibrated 6/10 thermal stimulus applied to the right calf. The conditioning stimulus was submersion of the left hand in a 46.5˚C water bath (Julabo, TW20). The test stimulus was first applied in isolation, with pain ratings from the leg recorded 3 times, at 10 seconds intervals over a 30 seconds stimulus. After this, the hand was submerged in the water bath, with 3 pain ratings from the hand recorded at 10 seconds intervals over a 30 seconds stimulus, checking everyone rated the conditioning stimulus as nonzero (ie, painful). Finally, the test and conditioning stimuli were presented simultaneously with pain ratings from the leg recorded 3 times, at 10 seconds intervals over a 30 seconds stimulus. The CPM score was calculated by subtracting the average pain rating from the test (leg) stimulus during simultaneous presentation, from the average rating from the test stimulus only condition. A high CPM score indicated more efficient inhibition of pain. Four participants were unable to keep their hand in the bath for the entire task, so final analysis includes the data of 40 participants.

Analysis
Regression models were used to explore whether IAP was associated with CPM and TS both individually and modelled together. For visualisation purposes, we calculated a composite "pronociception" score by adding TS scores (high facilitation) to reverse coded CPM scores (low inhibition), following z-transformation of both scales (the IAP scale was not z-transformed). A Pearson's correlation analysis was performed to explore the association between IAP and pronociception score. All statistical analyses were performed using SPSS 25 (IBM Corp, Armonk) with the significance level set to P , 0.05.

Discussion
This study examined the degree to which attention to pain is associated with endogenous mechanisms that modulate incoming sensory signals. We found an individual's IAP was associated with both TS and CPM. Both mechanisms seem to contribute to pain engagement relatively independently of each other, together accounting for 39 percent of the variance of attention to pain. This suggests modulation of spinal/supraspinal pain signals does significantly influence how we attend to pain, but other factors (eg, higher order cognitive processes) may also contribute strongly, as 61 percent of the variance in IAP is left unaccounted for.
Temporal summation occurs when a high frequency of action potentials in the presynaptic neuron elicits postsynaptic potentials that summate with each other, 5 increasing pain perception. A previous study found that this windup was associated with activation of the ipsilateral and contralateral thalamus, medial thalamus, S1, bilateral S2, mid insula and posterior insula, rostral, and midanterior cingulate cortex, 17 regions that have been previously implicated in attention studies. 11,12,19 Less efficient CPM was also associated with IAP. CPM is strongly influenced by descending inhibitory signals from brainstem regions such as the periaqueductal gray. 1,4,7,20 Periaqueductal gray activity has also been linked with IAP. 8 This suggests the observed correlation may be related to overlapping mechanisms in the brainstem. Given that CPM explained only part of the variance in IAP, however, our findings are consistent with previous research indicating that distraction explained variance above and beyond CPM in explaining pain inhibition. 13 This indicates that multiple factors influence attention. These may include evaluative cognitions involved in decision-making, assessment of risk/reward vs pain, or punishment avoidance. 2 Yarnitksy acknowledges a "pronociceptive phenotype" consisting of 2 QST measures may not present a complete image of an individual's vulnerability to pain and could be supplemented with additional measures to achieve more precise characterization. 21 These results support this suggestion by demonstrating that propensity to attend to pain is a function of processes such as windup and DNIC included in the "pronociceptive phenotype", but these factors do not fully explain individual differences in IAP. Given that an individual's propensity to attend to pain is directly  related to their ability to maintain cognitive function while experiencing pain, further investigation of the factors that contribute to IAP will provide clinically relevant clues as to why some individuals are able to maintain adaptive function despite living with pain.

Disclosures
The authors have no conflicts of interest to declare.