14 clinical implications of negative pain effects that are resistant to extinction or other forms of nocebo attenuation remain unclear 1. Cognitive-emotional factors Experimental nocebo models that include conditioning and negative suggestions also enable the study of diverse cognitive and emotional factors that may be involved in nocebo hyperalgesia. Cognitive manipulations, such as varying the type of learning, can shed a light on the intricate processes that give rise to the experience of pain. Factors that contribute to the formation or the persistence of nocebo effects can be studied using manipulations within experimental models. For instance, studies have shown that consistent and repetitive learning methods, such as classical conditioning with continuous reinforcement of an association, induces the strongest nocebo responses 42. However, interrupted or inconsistent learning is still able to induce nocebo hyperalgesia to some extent 42,45, which may be important from a clinical perspective, where pain and learning may be less consistent than in experimental settings. Partially reinforced learning has been shown to slow down the extinction or minimization of learned effects 45, including nocebo effects 46. Learning as an underlying cognitive factor contributing to the formation of nocebo effects may also be investigated at a neurobiological level. Brain plasticity has long been shown to be non-unitary 47–50, with multiple mechanisms and processes being involved in different types of memorization, learning, as well as recall 48,51,52. Given this multifaceted nature of learning, precise manipulations, targeting associative aspects of learning, hold the potential of enriching our understanding of hyperalgesic pain responses. For example, structures such as the NMethyl-D-aspartate (NMDA) receptor and neurochemicals such as glutamate have been consistently implicated in a broad array of brain
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