Chapter 3 – Comprehensive review 65 Introduction Negative thinking, such as having negative outcome expectations, can blunt the effect of active treatments, enhance the experience of aversive side-effects, and even produce deleterious effects in relation to recovery from symptoms such as pain, all leading to a phenomenon known as nocebo hyperalgesia 1–3. Nocebo hyperalgesia refers to increased pain sensitivity and increased pain reports that mainly result from negative outcome expectations. Nocebo effects have been shown to be most relevant for alterations in pain tolerance or intensity and lead to higher pain reports when compared to baseline or control stimulations 4–6. The neurobiological correlates of nocebo hyperalgesia are gaining research attention, but in lack of a comprehensive summary of findings, the neurobiology of these effects remains poorly understood. Gaining a better understanding of nocebo hyperalgesia on pain and its neural signature is an important step in the detection and prevention of these effects in patients, as well as the development of methods that may potentially counteract nocebo hyperalgesia. Studies examining the neural correlates of nocebo hyperalgesia utilize (combinations of) different learning processes to induce nocebo hyperalgesia experimentally in order to explore the various mechanisms by which pain circuitry and experienced pain can be modulated (Figure 1) 7–9: classical conditioning, instructional learning (i.e. through verbal suggestions), and social observational learning 10,11. Classical conditioning forms and reinforces expectations through associative learning 12. In conditioning models of nocebo hyperalgesia, an association is formed by repeated pairing between a high pain stimulus and an initially neutral stimulus (e.g., an inert treatment), that later becomes the nocebo stimulus. After repeated trials, an association is formed between the nocebo stimulus and the worsening of pain. Due to
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