Abstract
Substantial controversy exists as to which part of brain activity is genuinely attributable to pain-related percepts and which activity is due to general aspects of sensory stimulation, such as its salience, or the accompanying arousal. The challenge posed by this question rests largely in the fact that pain per se exhibits highly intense but unspecific characteristics. These therefore should be matched by potential control conditions. Here, we used a unique combination of functional magnetic resonance imaging (fMRI) and behavioral and autonomic measures to address this longstanding debate in pain research. Subjects rated perceived intensity in a sequence alternating between heat and sound stimuli. Neuronal activity was monitored using fMRI. Either modality was presented in 6 different intensities, 3 of which lay above the pain threshold (for heat) or the unpleasantness threshold (for sound). We performed our analysis on 26 volunteers in which psychophysiological responses (as per skin conductance responses [SCRs]) did not differ between the 2 stimulus modalities. Having thus ascertained a comparable amount of stimulation-related but unspecific activation, we analyzed stimulus-response functions (SRFs) after painful stimulation and contrasted them with those of the matched acoustic control condition. Furthermore, analysis of fMRI data was performed on the brain surface to circumvent blurring issues stemming from the close proximity of several regions of interest located in heavily folded cortical areas. We focused our analyses on insular and peri-insular regions that are strongly involved in processing of painful stimuli. We employed an axiomatic approach to determine areas showing higher activation in painful compared to nonpainful heat and, at the same time, showing a steeper SRF for painful heat compared to unpleasant sound. Intriguingly, an area in the posterior parietal operculum emerged, whose response showed a pain preference after satisfying all axiomatic constraints. This result has important implications for the interpretation of functional imaging findings in pain research, because it clearly demonstrates that there are areas where activity following painful stimulation is not due to general attributes or results of sensory stimulation, such as salience or arousal. Conversely, several areas did not conform to the formulated axioms to rule out general factors as explanations.
Highlights
Pain is a multidimensional experience, including sensory-discriminative, affective-motivational, and cognitive-evaluative as well as motor components [1] and is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [2]
We performed an additional analysis, in which we investigated whether areas show BOLD responses that are correlated with subjects’ behavioral ratings
This study aimed to identify regions relevant for heat pain processing and to determine whether their activation can be explained by salience or other modality-independent characteristics
Summary
Pain is a multidimensional experience, including sensory-discriminative, affective-motivational, and cognitive-evaluative as well as motor components [1] and is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [2]. Following the advent of brain imaging, recurring patterns of brain activity following painful stimuli were identified, comprising primary and secondary somatosensory cortices, cingulate cortices, and the insular subregions, among other structures [3,4]. This activity has frequently been attributed to pain per se. General processes have long been posited as alternative explanations—for example, stimulus anticipation [7], magnitude estimation [8], or stimulus salience [5] These contributions have led to lively controversy [9,10,11,12], and a large number of studies continue to address related issues using multiple modalities and both univariate and multivariate approaches [13,14,15,16,17,18]. This review reemphasized that great care should be taken experimentally to match nonpainful control modalities, which has frequently been neglected in previous studies
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