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Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability.

ABSTRACT: Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain's descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investigated the modulatory effects of anodal and cathodal tDCS at the right DLPFC on placebo analgesia and nocebo hyperalgesia using a randomized, double-blind and sham-controlled design. We found that compared with sham tDCS, active tDCS could 1) boost placebo and blunt nocebo effects and 2) modulate brain activity and connectivity associated with placebo analgesia and nocebo hyperalgesia. These results provide a basis for mechanistic manipulation of placebo and nocebo effects and may lead to improved clinical outcomes in medical practice.

SUBMITTER: Tu Y

PROVIDER: S-EPMC8126770 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability.

Tu Yiheng Y Wilson Georgia G Camprodon Joan J Dougherty Darin D DD Vangel Mark M Benedetti Fabrizio F Kaptchuk Ted J TJ Gollub Randy L RL Kong Jian J

Proceedings of the National Academy of Sciences of the United States of America 20210501 19

Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain's descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investig ...[more]

PMID: 33941677

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Project description:It is generally believed that the placebo response can elicit an analgesic effect, whilst the nocebo response can elicit a hyperalgesia effect in pain. Placebo analgesia and nocebo hyperalgesia effects are increasing concerns for researchers. Growing evidence suggests personality differences have an impact on both placebo and nocebo effects. However, previous studies have not reached a unified conclusion. We designed this study to explore the personality differences of functional magnetic resonance imaging (fMRI) signals in placebo response and nocebo response by using psychophysiological interaction (PPI) analysis. 30 healthy subjects underwent conditioning induction training to establish expectations of placebo effect and nocebo effect, and then, all subjects completed the following experimental procedures: (1) baseline scanning, (2) acute pain model establishment, (3) pain status scanning, and (4) pseudorandom scanning of block design of placebo response or nocebo response. Behavioral data were collected after each scan. The results of this study showed that (1) there were significant differences of VAS placebo intervention between the extrovert group and the introvert group (p = 0.004); (2) there were significant differences of VAS nocebo intervention between the extrovert group and the introvert group (p = 0.011); (3) there were significant differences between the VAS placebo intervention and VAS pain status (baseline) in both the extrovert group (p < 0.001) and the introvert group (p = 0.001); (4) there were significant differences between the VAS nocebo intervention and VAS pain status (baseline) in both the extrovert group (p = 0.008) and the introvert group (p < 0.001). Moreover, there were significant differences in the brain network for placebo and nocebo responses between different personalities. We found that (1) deactivation differences of the pain-related network and limbic system play an important role in personality differences associated with placebo analgesia and (2) differences of control of anxiety and activation of dorsolateral prefrontal cortex may cause the personality differences observed in nocebo hyperalgesia.

Project description: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.

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Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability.

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Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability.

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