Brain signatures of threat–safety discrimination in adolescent chronic pain

Heathcote, Lauren C.; Timmers, Inge; Kronman, Corey A.; Mahmud, Farah; Hernandez, J. Maya; Bentley, Jason; Youssef, Andrew M.; Pine, Daniel S.; Borsook, David; Simons, Laura E.

doi:10.1097/j.pain.0000000000001753

Cited by 19 publications

(17 citation statements)

References 56 publications

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“…That we nonetheless found group differences in predictive learning, despite less disability and psychological dysfunction compared to previously studied patient groups, is remarkable and raises the possibility that learning deficits may exist independent of psychological factors and may be present even in less severe cases of persistent pain. Finally, as we have disproportionately pioneered this line of research, replication from independent labs is needed, and indeed beginning to emerge (Both et al, 2017;Heathcote et al, 2020).…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Learning to predict pain: differences in people with persistent neck pain and pain-free controls

Harvie

Weermeijer

Olthof

et al. 2020

PeerJ

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Background Learning to predict threatening events enables an organism to engage in protective behavior and prevent harm. Failure to differentiate between cues that truly predict danger and those that do not, however, may lead to indiscriminate fear and avoidance behaviors, which in turn may contribute to disability in people with persistent pain. We aimed to test whether people with persistent neck pain exhibit contingency learning deficits in predicting pain relative to pain-free, gender-and age-matched controls. Method We developed a differential predictive learning task with a neck pain-relevant scenario. During the acquisition phase, images displaying two distinct neck positions were presented and participants were asked to predict whether these neck positions would lead to pain in a fictive patient with persistent neck pain (see fictive patient scenario details in Appendix A). After participants gave their pain-expectancy judgment in the hypothetical scenario, the verbal outcome (PAIN or NO PAIN) was shown on the screen. One image (CS+) was followed by the outcome “PAIN”, while another image (CS−) was followed by the outcome “NO PAIN”. During the generalization phase, novel but related images depicting neck positions along a continuum between the CS+ and CS− images (generalization stimuli; GSs) were introduced to assess the generalization of acquired predictive learning to the novel images; the GSs were always followed by the verbal outcome “NOTES UNREADABLE” to prevent extinction learning. Finally, an extinction phase was included in which all images were followed by “NO PAIN” assessing the persistence of pain-expectancy judgments following disconfirming information. Results Differential pain-expectancy learning was reduced in people with neck pain relative to controls, resulting from patients giving significantly lower pain-expectancy judgments for the CS+, and significantly higher pain-expectancy judgments for the CS−. People with neck pain also demonstrated flatter generalization gradients relative to controls. No differences in extinction were noted. Discussion The results support the hypothesis that people with persistent neck pain exhibit reduced differential pain-expectancy learning and flatter generalization gradients, reflecting deficits in predictive learning. Contrary to our hypothesis, no differences in extinction were found. These findings may be relevant to understanding behavioral aspects of chronic pain.

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Section: Limitations and Future Directionsmentioning

confidence: 99%

Learning to predict pain: differences in people with persistent neck pain and pain-free controls

Harvie

Weermeijer

Olthof

et al. 2020

PeerJ

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“…One article has been published before describing the fear acquisition and extinction paradigm findings. 34 Resting-state data have not been described before.…”

Section: Study Proceduresmentioning

confidence: 99%

“…8,43 In the subsequent fear extinction phase, both stimuli (CS1 and CS2) are presented in the absence of the US. At several time points, we assessed how anxious the participants were of each of the faces on a Numerical Rating Scale ranging from 1 (not anxious) to 10 (extremely anxious), as well as how unpleasant the faces were ranging from 1 (not unpleasant) to 10 (extremely unpleasant), and combined these into 1 "fear" composite rating (in line with 34 ). Note that the restingstate functional magnetic resonance imaging (fMRI) was acquired after acquisition, before extinction.…”

Section: Fear Conditioning Paradigm and Fear Assessmentmentioning

confidence: 99%

Amygdala functional connectivity mediates the association between catastrophizing and threat-safety learning in youth with chronic pain

Timmers

López‐Solà

Heathcote

et al. 2021

Pain

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There is a need to identify brain connectivity alterations predictive of transdiagnostic processes that may confer vulnerability for affective symptomology. Here, we tested whether amygdala resting-state functional connectivity (rsFC) mediated the relationship between catastrophizing (negative threat appraisals and predicting poorer functioning) and altered threat-safety discrimination learning (critical to flexibly adapt to new and changing environments) in adolescents with persistent pain. We examined amygdala rsFC in 46 youth with chronic pain and 29 healthy peers (age M 5 15.8, SD 5 2.9; 64 females) and its relationship with catastrophizing and threat-safety learning. We used a developmentally appropriate threat-safety learning paradigm and performed amygdala seed-based rsFC and whole-brain mediation analyses. Patients exhibited enhanced connectivity between the left amygdala and right supramarginal gyrus (SMG) (cluster-level P-FDR , 0.05), whereas right amygdala rsFC showed no group differences. Only in patients, elevated catastrophizing was associated with facilitated threat-safety learning (CS1.CS2; r p 5 0.49, P 5 0.001). Furthermore, in patients, elevated catastrophizing was associated with reduced left amygdala connectivity with SMG / parietal operculum, and increased left amygdala connectivity with hippocampus, dorsal striatum, paracingulate, and motor regions (P , 0.001). In addition, blunted left amygdala rsFC with right SMG/parietal operculum mediated the association between catastrophizing and threat-safety learning (P , 0.001). To conclude, rsFC between the left amygdala (a core emotion hub) and inferior parietal lobe (involved in appraisal and integration of bodily signals and attentional reorienting) explains associations between daily-life relevant catastrophizing and threat-safety learning. Findings provide a putative model for understanding pathophysiology involved in core psychological processes that cut across diagnoses, including disabling pain, and are relevant for their etiology.

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“…In adolescents with chronic pain, alterations in brain circuitry and/or activation have identified: brain regions associated with altered somatosensory function and pain modulation; interactions with psychological factors (eg. amygdala and pain-related fear [56] , frontolimbic circuitry and pain-related distress [57] ); and changes following treatment [ 13 , 58 ]. Ongoing studies in adolescents with neuropathic pain will provide further insights [ 59 , 60 ].…”

Section: Assessmentmentioning

confidence: 99%

Neuropathic pain in children: Steps towards improved recognition and management

Walker

2020

eBioMedicine

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Neuropathic pain in children can be severe and persistent, difficult to recognise and manage, and associated with significant pain-related disability. Recognition based on clinical history and sensory descriptors is challenging in young children, and screening tools require further validation at older ages. Confirmatory tests can identify the disease or lesion of the somatosensory nervous system resulting in neuropathic pain, but feasibility and interpretation may be influenced by age-and sex-dependent changes throughout development. Quantitative sensory testing identifies specific mechanism-related sensory profiles; brain imaging is a potential biomarker of alterations in central processing and modulation of both sensory and affective components of pain; and genetic analysis can reveal known and new causes of neuropathic pain. Alongside existing patient-and parent-reported outcome measures, somatosensory system research methodologies and validation of mechanism-based standardised end-points may inform individualised therapy and stratification for clinical trials that will improve evidence-based management of neuropathic pain in children.

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Brain signatures of threat–safety discrimination in adolescent chronic pain

Cited by 19 publications

References 56 publications

Learning to predict pain: differences in people with persistent neck pain and pain-free controls

Learning to predict pain: differences in people with persistent neck pain and pain-free controls

Amygdala functional connectivity mediates the association between catastrophizing and threat-safety learning in youth with chronic pain

Neuropathic pain in children: Steps towards improved recognition and management

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