The role of reward system in the regulation of pain perception by subjective expectation

Pain has become a major public health issue According to statistics, chronic pain afflicts about one fifth of the world's adults (Breivik et al., 2006; Goldberg & McGee, 2011) In China alone, the annual economic loss caused by chronic pain is up to hundreds of billions of RMB (Yu et al., 2011; Zhang et al., 2016) As a subjective experience, pain is regulated by many psychological factors (wiech, ploner, & Tracey, 2008), one of which is focused on the subjective psychological expectation of pain (geeter, koban, & wager, 2017; wager & atlas, 2015; wager et al., 2004; wager, Scott, & zubieta, 2007) Regulating psychological expectation can relieve pain and has potential clinical value, so it is necessary to study the neural mechanism of psychological expectation regulating pain The classical conditioned reflex paradigm is usually used to establish a specific expectation of pain, so that a specific cue stimulus can form a connection with a certain pain experience It has been found that the formation and processing of psychological expectation are related to the activation of dopamine neurons in the midbrain cortex marginal circuit of reward system (de la fuente fern á ndez & stoessl, 2002; Lidstone et al., 2010) However, the role of functional connections and structural characteristics between different brain regions in the midbrain cortex limbic circuit in the regulation of anticipated pain remains unclear In order to solve these problems, Hu Li, a researcher at the Key Laboratory of mental health, Institute of psychology, Chinese Academy of Sciences, and Tu Yiheng, a doctor from Harvard Medical College, worked together to improve the classical conditioned reflex paradigm, combine multimodal MRI, structural equation modeling and machine learning algorithm to study the ventral tegmental area of the midbrain cortex marginal circuit The role of functional connections and structural characteristics between area (VTA), rostral anterior cingulate cortex (rACC) and nucleus accumbens (NAC) in pain regulation was studied The study recruited 30 healthy subjects The whole study consists of three stages: the first stage is to measure the sensitivity of different subjects to pain stimulus, and to determine the three stimulus intensities of low intensity pain, medium intensity pain and high intensity pain; the second stage is to match different visual cues with low intensity pain and high intensity pain stimulus respectively, so as to establish the relationship between different visual cues and pain expectation; the third stage After different visual cues were given moderate intensity pain stimulation, to test whether the associated expectation successfully affected the subjective pain perception, and functional magnetic resonance imaging (fMRI) scanning was performed at the same time Different from the previous experimental paradigm, this study set up a time interval of up to 15s between visual cues and pain stimuli, so as to better measure the brain activity and functional connection caused by the psychological expectation of pain after visual cues Finally, the brain structure images of each subject were collected The results show that the classic conditioned reflex paradigm can indeed form different psychological expectations of pain and affect pain perception At the level of both subjects and between subjects, the midbrain cortex limbic circuit plays an important role in the expected regulation of pain Compared with the neutral visual cues which were not matched with pain stimulation in the second stage, the low pain visual cues which were matched with low intensity pain enhanced the functional connection between VTA rACC and VTA NAC; the high pain visual cues which were matched with high intensity pain reduced the functional connection between VTA rACC and VTA NAC Weak (Figure 1) Further analysis showed that at the level of subjects, the functional connection between vta-racc and VTA NAC played an intermediary role in the process of adjusting pain perception by visual cues, and the functional connection based on VTA regulated pain perception by affecting the activities of thalamus and insula during the pain prediction stage (Fig 2) At the level of subjects, the gray matter volume of VTA, rACC and NAC can effectively predict the degree of positive expected pain relief, while the gray matter volume of rACC can also effectively predict the degree of negative expected increased pain The results show that the midbrain cortex limbic circuit plays an important role in the regulation of pain perception by psychological anticipation, and it can encode the pain anticipation effect This study not only deepens people's understanding of the role of reward system in pain regulation, but also enlightens the development of new methods of psychological analgesia.