| 其他摘要 | Pain sensitivity varies widely among individuals. Among the factors influencing individual differences in pain sensitivity, sex differences play an important role. Notably, sex differences in pain sensitivity have been consistently demonstrated in experimental and clinical investigations, that is, females usually report a higher pain sensitivity in response to noxious stimuli of different modalities than males. Previous studies reported that females typically experience more negative emotions during pain processing, especially fear, anxiety, and depression, and these differences could represent plausible contributors to sex differences in pain sensitivity. However, the specific role of negative emotions in sex differences in pain sensitivity remains unclear, the factors influencing sex differences in pain threshold and pain tolerance remains inconclusive, and the neural mechanism underlying sex differences in pain sensitivity needs to be explored. To address the above issues, 450 healthy individuals(160 men and 290 women) were recruited in the present study, pain sensitivity (i.e., pain threshold and tolerance)，negative emotions (i.e.，pain-related fear, pain-related anxiety, trait anxiety, and depression), and MRI data (i.e., high-resolution T1 structural images and resting一state functional images) were collected by using psychophysical methods and magnetic resonance brain imaging technology.
Firstly, to explore the sex differences in pain sensitivity and the role of negative emotion variables (i.e.，fear of pain, pain-related anxiety, trait anxiety, and depression) in different pain sensitivity indexes (pain threshold and pain tolerance), we quantified negative emotions using well一established questionnaires and pain sensitivity using the cold pressure test, and assessed the mediation relationship among sex, negative emotions and pain sensitivity using structural equation modeling in Study 1 .The results showed that, compared with males, females had a lower pain threshold and pain tolerance in response to cold pain, and reported higher scores in pain-related negative emotions (fear and anxiety). In addition, pain-related negative emotions were negatively correlated with pain threshold/tolerance for all subjects. While correlations between the pain-related fear and pain threshold/tolerance in males were significantly higher than that in females, and no significant differences in the correlation trend between pain-related anxiety and pain threshold/tolerance were found between males and females. At last, mediation analysis results showed that pain-related fear and anxiety were complementary mediators of the relationship between sex and pain threshold, and they were indirect-only mediators of the relationship between sex and pain tolerance. The results indicated that sex differences in pain sensitivity were mediated by pain-related fear and anxiety and the pain threshold and pain tolerance differ considerably in their loading on physiological and psychological components. Specifically, pain threshold could be influenced not only by physiological components (i.e.，sex) but also by psychological components，while pain tolerance may load more psychological components.
Secondly, to explore the brain structural underpinnings of sex difference in pain sensitivity, we collected high-resolution T1 structural images and performed cortical thickness and subcortical volume analyses in Study 2. The theoretical model was built to quantify the mediation relationship among sex, negative emotions, structural brain features, and pain sensitivity using path analyses and structural equation modeling. The results showed that the amygdala volume was significantly larger in males than that in females, and pain-related fear was negatively correlated with the volumes of the amygdala in the left hemisphere, especially the subnuclei of the lateral nucleus, basal nucleus, accessory basal nucleus, and cortico一amygdaloid transition area. Results of mediation analysis showed that the amygdala subnuclei (i.e., the lateral and basal nuclei in the left hemisphere) volumes were the complementary mediators on the relationship between sex and pain-related fear. The final structural equation model revealed the specific relationship among sex, pain-related negative emotions, amygdala volumes, and pain sensitivity, suggesting that the amygdala subnuclei volumes subserved the neural underpinnings of sex differences in pain sensitivity through the modulation of pain-related fear.
Lastly, to explore the resting-state brain functional features of sex differences in pain sensitivity, we collected resting-state functional data and performed amplitude of low-frequency fluctuations analysis and regions of interest (ROIs)-based and seed-based resting-state functional connectivity analyses in Study 3 and Study 4, respectively. Although significant sex differences in regional brain activities were detected in Study 3, no correlations were found between regional brain activities and pain sensitivity or negative emotions. In Study 4, results of the ROIs-based functional connectivity revealed that the strength of the functional connectivity between the cerebellum and frontal pole/occipital pole in males was significantly higher than that in females, and this circuit functional connectivity was significantly correlated with pain sensitivity. Moreover, the functional connectivity between the cerebellum and frontal pole/occipital pole mediated the relationship between sex and pain threshold and then influenced pain tolerance. Results of seed-based (i.e., the amygdala and subregions) functional connectivity showed that the correlations between amygdala functional connectivity and pain sensitivity/pain-related negative emotions were significantly different between males and females. These results demonstrated that the amygdala and its subregions might have sex-specific effects in the correlation with pain threshold and pain-related negative emotions.
In summary, this study systematically investigated the role of negative emotions in sex differences in pain sensitivity and its underlying neural mechanisms based on a large sample of behavioral, brain structural, and resting-state functional data. This study provides new insights into the neuropsychological underpinnings of sex differences in pain sensitivity and emphasizes the important role of pain-related negative emotions and the amygdala in this process. It should be noted that the sex and negative emotion levels should be considered in the evaluation, diagnosis, and treatment for clinical pain, which is important to tailor a personalized method for treating pain according to the sex and the level of pain-related negative emotions for patients with painful conditions. |
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