12 Further insights come from biobehavioral studies illustrating that the experience of pain arises from a combination of bottom-up processes (for example, the type and intensity of nociceptive stimulation) 22–27 and top-down processing (for example nocebo-related processes such as learning or emotional modulation of incoming pain signals) 23,26,28–31. As one potential product of this interplay between sensory perception, cognition, and emotion, nocebo hyperalgesia is a complex phenomenon, and sophisticated experimental methods are required to understand its influence on pain. Experimental learning mechanisms Research typically induces nocebo effects by use of experimental learning models. Experimental models refer to simulations of conditions or responses to treatment that resemble clinical conditions and are induced in healthy individuals, artificially, in a laboratory. In nocebo research, learning manipulations consistently induce nocebo hyperalgesic responses. Typically, conditions in which a sham treatment is associated with pain aggravation are created by use of well-established learning techniques such as classical conditioning or providing negative verbal or written information. Experimentally induced nocebo hyperalgesia in healthy subjects enables researchers to examine these effects, in order to disentangle the mechanisms by which learning can affect pain sensitivity. In the most robust experimental models of nocebo hyperalgesia, classical conditioning forms and reinforces pain expectations through associative learning 11,32–34. In conditioning models of nocebo hyperalgesia, an association between a high-intensity pain stimulus (unconditioned stimulus, UCS) and a nocebo (inert treatment) conditioned stimulus (CS) is formed by repeatedly pairing the two stimuli. After repeated trials, an association between the nocebo
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