The Mechanisms Of Placebo/nocebo Effect In Pain: Modulation Effects Of Learning And Expectation

Placebo effect and nocebo effect,as two opposite phenomena,existing widely in clinical practice,are affected by complex psychosocial factors.So far,the research on these two effects is mainly concentrated in the field of pain: placebo effect in pain is the phenomenon of lower pain sensation after one accepting inert therapy,also called placebo analgesia;nocebo effect is the phenomenon of higher pain sensation after one accepting inert therapy,as known as nocebo hyperalgesia.Studies show that placebo analgesia and nocebo hyperalgesia share similar psychological mechanisms.Expectation,conditioning and other learning processes(social observation and prior experience)all play a key role.Conditioning(direct experience)and social observation are both important ways to gain experience.It is well known that the effectiveness of treatment experience can be affected by direct experience.In addition to first-person experience,observational experience can also induce placebo analgesia and nocebo hyperalgesia.However,it is still unclear whether social observation can still affect placebo/nocebo effects to subsequent treatments even if related experience gained several days ago.In addition,placebo/nocebo effect is not only manifested in the change of individual subjective pain report,but also in the change of brain activation patterns.At present,researchers have not reached a consensus on the brain mechanisms of placebo effect and nocebo effect.Studies have suggested that placebo effect and nocebo effect in pain may be regulated by the same brain regions(such as the thalamus,insula,anterior cingulate cortex and the somatosensory cortex),the difference is only the contrary of activation patterns.Some studies also show that the hippocampus,which is an unrelated brain area with the placebo effect,plays an important role in nocebo condition.Therefore,it is necessary to further explore the brain mechanism of placebo and nocebo effect,so as to provide a theoretical basis for optimizing the placebo effect and reducing the negative effect of the nocebo effect on clinical patients.Therefore,we first investigated the psychological mechanism of placebo and nocebo effects in pain from behavioral aspect(experiment 1).Then we discussed the brain mechanism of placebo and nocebo effects from the perspective of neuroimaging(experiment 2).In experiment 1,Eighty-two subjects were recruited and each of them was randomly assigned to one of the four experimental groups obtaining first-person or observational experience,which was either effective or ineffective.After Five or six days,all subjects underwent a conditioning phase,five minutes later,a test phase composed of two tests with a 5-minute interval were conducted.The results showed that 1)placebo and nocebo responses to subsequent treatments can be affected by prior experience obtained 5-6 days ago regardless of acquisition ways,the response magnitudes of the two experience acquisition ways were comparable,2)both placebo analgesia and nocebo hyperalgesia in effective condition were significantly larger than those in ineffective condition,regardless of the acquisition ways of prior experience,3)once placebo analgesia and nocebo hyperalgesia were elicited,nocebo effect was more significant and more persistent.The results indicated that observational experience acquired several days ago could also affect the following treatments,emphasize the negative prior experience could trigger a notorious response(nocebo hyperalgesia)to subsequent treatments and provide insights into clinical applications.In experiment 2,we used fMRI and an including expectancy/ conditioning manipulation model to investigate how expectations under placebo and nocebo conditions shape the ongoing brain state and thus influence the subsequent pain perception.The type and location of pain stimuli is the same as that in experiment 1,twenty-nine subjects were recruited.To induce analgesic and hyperalgesic expectations,we manipulated response expectancy(i.e.,positive and negative)by conditioning and verbal instructions.The conditioning phase was made 24 hours before MRI scanning(test phase).In this experiment,results showed that after administering experimental manipulation,significant placebo and nocebo effects were elicited.Brain imaging showed that,during anticipation of pain,compared with the control cues,low pain cues induced the bilateral superior frontal gyrus(SFG)and the supplementary motor area(SMA)activation significantly increased;high pain cues induced the medial prefrontal cortex(mPFC)and bilateral anterior cingulate cortex(ACC)activation significantly decreased.In perception stage of pain,compared with control condition,the placebo condition induced the activation of the bilateral thalamus,ACC,somatosensory cortex and the periaqueductal gray(PAG)decreased,while in nocebo conditions,the activation of bilateral posterior insula,secondary somatosensory cortex(S2)and the anterior and medial cingulate cortex(ACC/MCC)were significantly increased.These results showed that the psychological mechanism of placebo and nocebo are similar,such as expectation and conditioning.During anticipation of pain,high pain and low pain cues associated with activation patterns' changes in different brain regions.During perception of pain,although placebo and nocebo condition share same brain region with the contrary activation patterns,they are not entirely coincidence.It indicates that placebo effect and nocebo effect may have different brain mechanisms.This study deepened our understanding of the brain mechanisms of placebo effect and nocebo effect.