Orthodontic pain induced by orthodontic treatment is a complex afflictive experience that accompanies most orthodontic procedures. This pain starts 2 to 3 hours later after orthodontic treatment and reaches its peak 24 hours later. It is considered to be the major cause of discontinuing orthodontic treatment. A placebo is an agent that has no direct effect on the treatment of a patient, but may help relieve the symptoms. However, the neural mechanism of placebo effects in orthodontic pain remains largely unknown. In the present study, we investigated the placebo modulation of brain activity associated with orthodontic pain using task-based fMRI.Twenty-three female college students were recruited (aged from 18 to 23, with mean age =20.22±1.38 years). For each subject, orthodontic separators were placed between two nearby teeth 24 hours before a task-based fMRI scan. At baseline, the subjects were scanned without placebo. After a wash-out period of at least one month, all subjects were scanned for the 2nd time after taking placebos. The short-form McGill pain questionnaire (SF-MPQ) was used to measure sensory, affective, and evaluative dimensions of pain for all subjects. The MRI examinations were performed with a 3-Telsa Siemens MRI system using an 8-channel phase array head coil. The fMRI scan parameters were: TR/TE=2000/30ms, flip angle=90°, FOV= 240 × 240, matrix = 64 × 64, slice thickness=3.8mm without gap, 33 axial slices, 100 volumes in total. During the scan, participants were instructed to perform a bite (with maximum strength)/no-bite block design fMRI task with their eyes closed. The task had six blocks and each block started from a 20s no-bite period, and was followed by a 10s bite period. A standard GLM analysis was then performed using FSL.Orthodontic pain induced by separators demonstrated similar patterns of brain activities without or with placebo. For both conditions, significant activations were shown in pain-related brain regions, including bilateral insular cortex, central opercular cortex, and planum polare. However, compared with the non-placebo condition, the participants demonstrated significant reduced activities in multiple brain regions, i.e., pre-central gyrus, superior frontal gyrus, superior parietal lobule and supramarginal gyrus (Figure.1), after taking placebos. Additionally, the anterior cingulate cortex was shown to be significant activated without placebo, but was not activated with placebo.The present study using task-based fMRI demonstrated similar brain activation patterns for subjects under orthodontic pain with or without placebos. These pain related regions, including bilateral insular cortex, central opercular cortex, and planum polare, are basically consistent with previous studies^1-6. With placebo, reduced activation in the pre-central gyrus, superior frontal gyrus, superior parietal lobule and supramarginal gyrus indicates that placebo may play its role by inhibiting primary sensory, sensory association cortex and pain regulation regions. Yet, how this inhabitation is applied remains to be further investigated. Overall, this study may provide new insights into the neural mechanism of analgesia by placebo.