How Negative Experience Influences the Brain: A Comprehensive Review of the Neurobiological Underpinnings of Nocebo Hyperalgesia

Abstract

This comprehensive review summarizes and interprets the neurobiological correlates of nocebo hyperalgesia in healthy humans. Nocebo hyperalgesia refers to increased pain sensitivity resulting from negative experiences and is thought to be an important variable influencing the experience of pain in healthy and patient populations. The young nocebo field has employed various methods to unravel the complex neurobiology of this phenomenon and has yielded diverse results. To comprehend and utilize current knowledge, an up-to-date, complete review of this literature is necessary. PubMed and PsychInfo databases were searched to identify studies examining nocebo hyperalgesia while utilizing neurobiological measures. The final selection included 22 articles. Electrophysiological findings pointed toward the involvement of cognitive-affective processes, e.g., modulation of alpha and gamma oscillatory activity and P2 component. Findings were not consistent on whether anxiety-related biochemicals such as cortisol plays a role in nocebo hyperalgesia but showed an involvement of the cyclooxygenase-prostaglandin pathway, endogenous opioids, and dopamine. Structural and functional neuroimaging findings demonstrated that nocebo hyperalgesia amplified pain signals in the spinal cord and brain regions involved in sensory and cognitive-affective processing including the prefrontal cortex, insula, amygdala, and hippocampus. These findings are an important step toward identifying the neurobiological mechanisms through which nocebo effects may exacerbate pain. Results from the studies reviewed are discussed in relation to cognitive-affective and physiological processes involved in nocebo and pain. One major limitation arising from this review is the inconsistency in methods and results in the nocebo field. Yet, while current findings are diverse and lack replication, methodological differences are able to inform our understanding of the results. We provide insights into the complexities and involvement of neurobiological processes in nocebo hyperalgesia and call for more consistency and replication studies. By summarizing and interpreting the challenging and complex neurobiological nocebo studies this review contributes, not only to our understanding of the mechanisms through which nocebo effects exacerbate pain, but also to our understanding of current shortcomings in this field of neurobiological research.