An experimental investigation into the mediating role of pain-related fear in boosting nocebo hyperalgesia

Thomaidou, Mia A.; Veldhuijzen, Dieuwke S.; Meulders, Ann; Evers, Andrea

doi:10.1097/j.pain.0000000000002017

Cited by 29 publications

(21 citation statements)

References 73 publications

(51 reference statements)

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“…This links gamma oscillations, which were shown to be involved in nocebo in this study, to a role of the hippocampus in learning and nocebo hyperalgesia 42 , 43 . It is also noteworthy that emotional processes that may play a mediating role in nocebo hyperalgesia, such as fear 44 , may engage patterns of gamma coupling in the amygdala 45 , a structure that has also been implicated in nocebo hyperalgesia 43 , 46 , 47 . Our finding of increased complexity of gamma-band oscillations in those more susceptible to nocebo hyperalgesia may thus point towards potential electrophysiological indications of specific underlying cognitive-emotional processes, such as associative learning ability as well as fear processing.…”

Section: Discussionmentioning

confidence: 99%

Temporal structure of brain oscillations predicts learned nocebo responses to pain

Thomaidou

Blythe

Houtman

et al. 2021

Sci Rep

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This study aimed to identify electrophysiological correlates of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) has been found to impact how healthy and patient populations experience pain and is a phenomenon that could be better understood in terms of its neurophysiological underpinnings. In this study, nocebo hyperalgesia was induced in 36 healthy participants through classical conditioning and negative suggestions. Electroencephalography was recorded during rest (pre- and post-acquisition) and during pain stimulation (baseline, acquisition, evocation) First, participants received baseline high thermal pain stimulations. During nocebo acquisition, participants learned to associate an inert gel applied to their forearm with administered high pain stimuli, relative to moderate intensity control stimuli administered without gel. During evocation, all stimuli were accompanied by moderate pain, to measure nocebo responses to the inert gel. Pre- to post-acquisition beta-band alterations in long-range temporal correlations (LRTC) were negatively associated with nocebo magnitudes. Individuals with strong resting LRTC showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. These findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing.

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Section: Discussionmentioning

confidence: 99%

Temporal structure of brain oscillations predicts learned nocebo responses to pain

Thomaidou

Blythe

Houtman

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This links gamma oscillations, which were shown to be involved in nocebo in this study, to a role of the hippocampus in learning and nocebo hyperalgesia 46,47 . It is also noteworthy that emotional processes that may play a mediating role in nocebo hyperalgesia, such as fear 48 , may engage patterns of gamma coupling in the amygdala 49 , a structure that has also been implicated in nocebo hyperalgesia 47,50,51 . Our nding of increased complexity of gamma-band oscillations in those more susceptible to nocebo hyperalgesia may thus provide electrophysiological evidence of speci c underlying cognitive-emotional processes, such as associative learning ability as well as fear processing.…”

Section: Discussionmentioning

confidence: 99%

Temporal Structure of Brain Oscillations Is A Biomarker of Pain and Predicts Learned Nocebo Responses.

Thomaidou

Blythe

Houtman

et al. 2021

Preprint

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This study aimed to identify electrophysiological biomarkers of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) was induced in 36 healthy participants through classical conditioning and negative suggestions. In a baseline phase, participants received high thermal pain stimulations. During acquisition, participants learned to associate an inert gel applied to their forearm with high pain, relative to a moderate intensity control stimulus administered without gel. During evocation, nocebo and control stimuli were both accompanied by moderate pain to measure nocebo responses. Electroencephalography was recorded during rest (pre and post nocebo acquisition) and during pain stimulation (baseline, nocebo acquisition and evocation). Nocebo hyperalgesia led to pre- to post-acquisition increases in long-range temporal correlations (LRTC), with beta-band alterations being negatively associated with nocebo magnitudes. Moreover, individuals with strong LRTC at rest showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. By involving LRTC, these findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing. This study provides novel insights into neural underpinnings of nocebo hyperalgesia, a phenomenon that greatly impacts the experience of pain.

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“…All three studies used negative suggestions to induce nocebo hyperalgesia (Benedetti et al, 2006(Benedetti et al, , 2014Scott et al, 2008). Benedetti et al (2006) studied cortisol and the hypothalamicpituitary-adrenal (HPA) axis by using a neuropharmacological approach to examine neurochemical correlates of anxiety, a state that is related to fear and may thus, similarly to fear (Thomaidou et al, 2021b), also be linked to nocebo hyperalgesia (Colloca and Benedetti, 2007). Participants were subdivided into 4 groups and underwent ischemic pain inductions.…”

Section: Neurochemical and Biochemical Correlates Of Nocebo Hyperalgesiamentioning

confidence: 99%

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

et al. 2021

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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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An experimental investigation into the mediating role of pain-related fear in boosting nocebo hyperalgesia

Abstract: Supplemental Digital Content is Available in the Text. Pain-related fear is shown to mediate the amplification of nocebo hyperalgesia, only when high pain is experienced and not when it is merely anticipated.

Cited by 29 publications

References 73 publications

Temporal structure of brain oscillations predicts learned nocebo responses to pain

Temporal structure of brain oscillations predicts learned nocebo responses to pain

Temporal Structure of Brain Oscillations Is A Biomarker of Pain and Predicts Learned Nocebo Responses.

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

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