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.

Keywords: EEG; fMRI; hyperalgesia; learning; neurobiology; neurophysiology; nocebo; pain.

FIGURE 1

Illustration of three typical experimental paradigms for the induction of nocebo hyperalgesia. The acquisition column refers to the learning phase, whether conditioning-mediated, verbal, or observational learning. The evocation column refers to the evocation of the learned effect. Typically, an acquisition phase serves to induce negative expectations via conditioning, negative suggestions, observational learning, or any combination of these methods. Negative expectations are induced by combining an inert treatment with a surreptitious increase in pain stimulation (conditioning), by being told that a treatment will lead to increased pain sensitivity (negative suggestion), and/or by observing this negative treatment effect on someone else (observational learning). Subsequently, lower pain stimulations are administered in combination with the nocebo treatment in order to test whether nocebo hyperalgesia has been induced. A control group or condition where no nocebo is administered typically serves as a comparison to measure the magnitude of responses to the nocebo treatment. In this illustration, neutral faces express that there is no high-pain experience whereas sad faces represent the experience of high pain.

FIGURE 2

The neurobiological correlates of nocebo hyperalgesia. When classical conditioning and/or negative suggestions are used to experimentally induce nocebo hyperalgesia, a complex interplay of electrophysiology, neurochemistry, and central nervous system functionality come into play. These neurobiological factors involve a wide array of functions ranging from basic nociceptive to cognitive-affective. Green upward arrows indicate increases/activations of particular regions, components, or chemicals, while red downward arrows indicate decreases/deactivations (*CCK’s role cannot be simplified by a red/green arrow). EEG, electroencephalography; MEG, magnetoencephalography; SPN, stimulus-preceding negativity; CNV, contingent negative variation; (dl)PFC, (dorsolateral) prefrontal cortex; OFC, orbitofrontal cortex; MTG, middle temporal gyrus; PAG, periaqueductal gray; CCK, cholecystokinin; COX-PG, cyclooxygenase-prostaglandin pathway; DA, dopamine. This figure was created using BioRender.com.