Brain Mechanisms of Fear Reduction Underlying Habituation to Pain in Humans

Habituation to painful stimuli reflects an endogenous pain alleviation mechanism, and reduced pain habituation has been demonstrated in many chronic pain conditions. In ethology, animals exhibit reduced fear responses while habituating to repeated threatening stimuli. It remains unclear whether pain habituation in humans involves a fear reduction mechanism. In an fMRI experiment, we investigated pain-related brain responses before and after the development of habituation to pain induced by repetitive painful stimulation in healthy adults. In another behavioral experiment, we examined emotional responses in another group of healthy adults to assess pain habituation-related emotional changes. Pain habituation at the repetitively stimulated forearm site entailed reduced fear and engaged the neural system implicated in fear reduction, which included the amygdala, anterior cingulate, and ventromedial prefrontal cortex (vmPFC). Individual pain-related fear, assessed via a questionnaire, predicted neural activity within the periaqueductal gray (a pain-modulating center), which covaried with vmPFC responsivity. Moreover, pain habituation also occurred at nonstimulated sites, and its extent was predicted by habituation at the repetitively stimulated site. This phenomenon again involved the vmPFC, which has also been implicated in safety generalization under threat. These results suggest a role of fear reduction in pain habituation that is related to individual pain fearfulness. The reduced fear acquired at the repetitively stimulated site can be generalized to other body parts to cope with similar aversive situations. The identified link between fear and pain habituation helps explain why impaired fear reduction and reduced pain habituation coexist in chronic pain conditions.