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.

Implications of nocebo in anaesthesia care

“…in healthy humans and refers to increased pain sensitivity resulting from negative experiences [18] or communications delivered in a way that generates negative expectancy [7].…”

“…Nocebo appears to be an important but variable influence on the pain experience [18]. Placebo analgesia and nocebo hyperalgesia are thought to initiate from the dorsal lateral prefrontal cortex subsequently triggering the brain's descending pain modulatory system and other pain regulation pathways [25].…”

A randomized pharmacological fMRI trial investigating d-cycloserine and brain plasticity mechanisms in learned pain responses

“…This evidence suggests that by agonizing NMDA receptors, DCS enhances specific learning processes, and can be used to manipulate and investigate how particular learning mechanisms may be involved in pain effects. Previous studies on experimentally induced nocebo and placebo effects indicate an involvement of brain areas that integrate prior experiences and memory into the processing of pain, such as the insula and amygdala 36 – 40 . Yet, neuroimaging findings in the field of nocebo and learning are still limited and somewhat inconsistent 36 .…”

“…Previous studies on experimentally induced nocebo and placebo effects indicate an involvement of brain areas that integrate prior experiences and memory into the processing of pain, such as the insula and amygdala 36 – 40 . Yet, neuroimaging findings in the field of nocebo and learning are still limited and somewhat inconsistent 36 . By utilizing fMRI while pharmacologically agonizing NMDA-mediated learning during nocebo induction, precise neural processes involved in learned pain can be examined.…”

Unraveling Negative Expectations and Nocebo-Related Effects in Musculoskeletal Pain

“…As a result, patients often experience negative emotions and adopt unhelpful coping strategies (i.e., catastrophic thinking, avoidance of movement), which are, per se , capable of worsening their clinical conditions and foster symptoms persistence ( Bunzli et al, 2015 ; Darlow, 2016 ). Moreover, they may develop negative expectations about the course of their illness and the likely outcomes ( Kravvariti et al, 2018 , 2021 ; Thomaidou et al, 2021 ).…”