Probing white matter microstructure in youth with chronic pain and its relation to catastrophizing using neurite orientation dispersion and density imaging.

ABSTRACT: Chronic pain is common in young people and can have a major life impact. Despite the burden of chronic pain, mechanisms underlying chronic pain development and persistence are still poorly understood. Specifically, white matter (WM) connectivity has remained largely unexplored in pediatric chronic pain. Using diffusion-weighted imaging, this study examined WM microstructure in adolescents (age M = 15.8 years, SD = 2.8 years) with chronic pain (n = 44) compared with healthy controls (n = 24). Neurite orientation dispersion and density imaging modeling was applied, and voxel-based whole-white-matter analyses were used to obtain an overview of potential alterations in youth with chronic pain and tract-specific profile analyses to evaluate microstructural profiles of tracts of interest more closely. Our main findings are that (1) youth with chronic pain showed widespread elevated orientation dispersion compared with controls in several tracts, indicative of less coherence; (2) signs of neurite density tract-profile alterations were observed in several tracts of interest, with mainly higher density levels in patients; and (3) several WM microstructural alterations were associated with pain catastrophizing in the patient group. Implicated tracts include both those connecting cortical and limbic structures (uncinate fasciculus, cingulum, anterior thalamic radiation), which were associated with pain catastrophizing, as well as sensorimotor tracts (corticospinal tract). By identifying alterations in the biologically informative WM microstructural metrics orientation dispersion and neurite density, our findings provide important and novel mechanistic insights for understanding the pathophysiology underlying chronic pain. Taken together, the data support alterations in fiber organization as a meaningful characteristic, contributing process to the chronic pain state.

Altered neural oscillations in classical galactosaemia during sentence production.

Classical galactosaemia (CG) is a hereditary disease in galactose metabolism that despite dietary treatment is characterized by a wide range of cognitive deficits, among which is language production. CG brain functioning has been studied with several neuroimaging techniques, which revealed both structural and functional atypicalities. In the present study, for the first time, we compared the oscillatory dynamics, especially the power spectrum and time-frequency representations (TFR), in the electroencephalography (EEG) of CG patients and healthy controls while they were performing a language production task. Twenty-one CG patients and 19 healthy controls described animated scenes, either in full sentences or in words, indicating two levels of complexity in syntactic planning. Based on previous work on the P300 event related potential (ERP) and its relation with theta frequency, we hypothesized that the oscillatory activity of patients and controls would differ in theta power and TFR. With regard to behavior, reaction times showed that patients are slower, reflecting the language deficit. In the power spectrum, we observed significant higher power in patients in delta (1-3 Hz), theta (4-7 Hz), beta (15-30 Hz) and gamma (30-70 Hz) frequencies, but not in alpha (8-12 Hz), suggesting an atypical oscillatory profile. The time-frequency analysis revealed significantly weaker event-related theta synchronization (ERS) and alpha desynchronization (ERD) in patients in the sentence condition. The data support the hypothesis that CG language difficulties relate to theta-alpha brain oscillations.

Sleep disturbances, altered brain microstructure and chronic headache in youth.

Chronic headache (persistent or recurrent headache for 3-months or longer) is highly prevalent among youth. While sleep disturbances have been associated with headache, their inter-relationship with brain connectivity remains unknown. This observational study examined whether self-report and actigraphy measures of sleep were associated with alterations to white matter tracts (i.e., uncinate fasciculus and cingulum) in youth with chronic headache versus healthy controls. Thirty youth aged 10-18 years with chronic headache and thirty controls underwent an MRI. Diffusion tensor images were obtained and mean fractional anisotropy values of the cingulum and uncinate were extracted. One-week prior to their MRI, youth wore an actigraph to obtain sleep duration, wake after sleep onset and sleep efficiency measures. Moreover, they completed questionnaires regarding their sleep quality and pain symptomatology. Linear regression was applied to examine the relationships between sleep (self-report and actigraphy), fractional anisotropy, and number of headache days per month. Self-report and actigraphy measures of sleep did not differ between patients and controls. However, poorer self-reported sleep quality was associated with lower fractional anisotropy values in the left uncinate (P = 0.05). Lower left uncinate fractional anisotropy was related to increased headache frequency (P = 0.002) in youth with chronic headache. Therefore, alterations to connectivity may be associated with the relationship between altered perceptions of sleep and headache chronicity.

Gray Matter Adaptations to Chronic Pain in People with Whiplash-Associated Disorders are Partially Reversed After Treatment: A Voxel-based Morphometry Study.

Gray matter (GM) changes are often observed in people with chronic spinal pain, including those with chronic whiplash-associated disorders (CWAD). These GM adaptations may be reversed with treatment, at least partially. Pain neuroscience education combined with exercise (PNE+Exercise) is an effective treatment, but its neural underlying mechanisms still remain unexplored in CWAD. Here, we performed both cross-sectional and longitudinal voxel-based morphometry to 1) identify potential GM alterations in people with CWAD (n = 63) compared to age- and sex-matched pain-free controls (n = 32), and 2) determine whether these GM alterations might be reversed following PNE+Exercise (compared to conventional physiotherapy). The cross-sectional whole-brain analysis revealed that individuals with CWAD had less GM volume in the right and left dorsolateral prefrontal cortex and left inferior temporal gyrus which was, in turn, associated with higher pain vigilance. Fifty individuals with CWAD and 29 pain-free controls were retained in the longitudinal analysis. GM in the right dorsolateral prefrontal cortex increased after treatment in people with CWAD. Moreover, the longitudinal whole-brain analysis revealed that individuals with CWAD had decreases in GM volumes of the left and right central operculum and supramarginal after treatment. These changes were not specific to treatment modality and some were not observed in pain-free controls over time. Herewith, we provide the first evidence on how GM adaptations to CWAD respond to treatment. PERSPECTIVE: This article presents which gray matter adaptations are present in people with chronic pain after whiplash injuries. Then, we examine the treatment effect on these alterations as well as whether other neuroplastic effects on GM following treatment occur.

Use of Virtual Reality in Interdisciplinary Multimodal Pain Treatment With Insights From Health Care Professionals and Patients: Action Research Study.

BACKGROUND: Chronic pain is a widespread global health problem. Interdisciplinary multimodal pain treatment (IMPT) is a treatment option for people with chronic pain. Virtual reality (VR) could be used to broaden IMPT programs. However, despite the advantages of VR, it is rarely used in daily clinical practice. OBJECTIVE: This research aimed to explore how, when, and with whom VR can be used meaningfully during IMPT, either as an addition or substitution as a component of IMPT. METHODS: This research used an action research design to help health care professionals and patients learn how, when, and with whom they can use VR. Data were collected through reflection sessions with health care professionals and semistructured interviews with patients in 2 specialized centers that provide IMPT for chronic pain. Two researchers performed direct content analyses. RESULTS: In total, 4 physiotherapists, 1 occupational therapist, 3 psychologists, and 22 patients participated in this research. Three iteration cycles, including 9 reflection sessions and 8 semistructured interviews, were performed. Both health care professionals and patients considered VR to be useful in therapy as an addition but not a substitution. VR was used as a diagnostic and intervention tool with all patients at the rehabilitation center or home. VR was used to gain insight into patients' pain beliefs, cognitions, and irrational cognitions about additional damage and physical abilities. Considering VR as an intervention tool, the health care professionals had 3 goals: balancing relaxation and competition, grading activities, and exposure in vivo. CONCLUSIONS: VR could be a valuable addition to IMPT for both patients with chronic pain and health care professionals. More research should be performed to assess the additional effects of VR on patients' participation in daily life.

Neural processing of pain-related distress to neck-specific movements in people with chronic whiplash-associated disorders.

ABSTRACT: Pain-related distress contributes to long-term disability in chronic whiplash-associated disorders. Recently, neuroimaging studies have revealed altered neural responses to viewing pictures of movements associated with back pain in key regions for threat and affective processing. In this study, we examined neural correlates of imagining neck-specific movements designed to elicit pain-related distress in individuals with whiplash-associated disorders (n = 63) when compared with that in sex-matched pain-free controls (n = 32). In the scanner, participants were presented with neck-specific movement-related pictures divided into 3 categories (high fear, moderate-fear, and neutral control pictures) and asked to imagine how they would feel if they were performing the movement. Whole-brain analyses revealed greater differential activation (high-fear vs neutral) in individuals with whiplash-associated disorders when compared with that in pain-free controls in 6 clusters including right and left postcentral gyri, left parietal operculum, dorsal precuneus, left superior frontal gyrus/anterior cingulate cortex, and posterior cingulate cortex/ventral precuneus. For the contrast moderate-fear vs neutral, patients showed greater differential activation than controls in the right and left posterolateral cerebellum. Activation patterns in the precuneus and posterior cingulate cortex were negatively associated with pain-related fear, but no other correlations were observed. Together, the findings suggest that when conceptualizing neck-specific movements associated with pain, people with chronic whiplash-associated disorders may predict-and potentially amplify-their sensory and affective consequences and therewith trigger dysfunctional affective and/or behavioral responses. Herewith, we provide new insights into the neural mechanisms underlying chronic pain in people with whiplash-associated disorders, pointing towards a complex interplay between cognitive/affective and sensorimotor circuitry.

Neural mechanisms underlying the conditioned pain modulation response: a narrative review of neuroimaging studies.

ABSTRACT: Processing spatially distributed nociceptive information is critical for survival. The conditioned pain modulation (CPM) response has become a common psychophysical test to examine pain modulation capabilities related to spatial filtering of nociceptive information. Neuroimaging studies have been conducted to elucidate the neural mechanisms underlying the CPM response in health and chronic pain states, yet their findings have not been critically reviewed and synthesized before. This narrative review presents a simplified overview of MRI methodology in relation to CPM assessments and summarizes the findings of neuroimaging studies on the CPM response. The summary includes functional MRI studies assessing CPM responses during scanning as well as functional and structural MRI studies correlating indices with CPM responses assessed outside of the scanner. The findings are discussed in relation to the suggested mechanisms for the CPM response. A better understanding of neural mechanisms underlying spatial processing of nociceptive information could advance both pain research and clinical use of the CPM response as a marker or a treatment target.

Altered anterior insula functional connectivity in adolescent and young women with endometriosis-associated pain: Pilot resting-state fMRI study.

BACKGROUND: Endometriosis is the leading cause of chronic pelvic pain. Alterations in brain functional connectivity have been reported in adult women with endometriosis-associated pain (EAP), however, it is still unknown if similar patterns of changes exist in adolescents. METHODS: In this pilot study, resting-state fMRI scans were obtained from 11 adolescent and young women with EAP and 14 healthy female controls. Using a seed-to-voxel approach, we investigated functional connectivity between the anterior insula, medial prefrontal cortex, and the rest of the brain. Furthermore, we explored whether potential functional connectivity differences were correlated with clinical characteristics including disease duration, pain intensity, and different psychosocial factors (pain catastrophizing, fear of pain, functional disability, anxiety, and depression). RESULTS: Our findings revealed that patients with EAP demonstrated significantly decreased connectivity between the right anterior insula and two clusters: one in the right cerebellum, and one in the left middle frontal gyrus compared to controls. Additionally, functional connectivity between the right anterior insula and the right cerebellum was positively associated with pain intensity levels. In patients with EAP, brain changes were also correlated with state anxiety and fear of pain. CONCLUSIONS: Our results are relevant not only for understanding the brain characteristics underlying EAP at a younger age, but also in enhancing future pain treatment efforts by supporting the involvement of the central nervous system in endometriosis.

How do psychologically based interventions for chronic musculoskeletal pain work? A systematic review and meta-analysis of specific moderators and mediators of treatment.

Psychologically based interventions aim to improve pain-related functioning by targeting pain-related fears, cognitions and behaviors. Mediation and moderation analyses permit further examination of the effect of treatment on an outcome. This systematic review and meta-analysis aims to synthetize the evidence of specific mediators and moderators (i.e., treatment targets) of psychologically based treatment effects on pain and disability. A total of 28 mediation and 11 moderation analyses were included. Thirteen mediation studies were included in a meta-analysis, and the rest was narratively synthetized. Reductions in pain-related fear (indirect effect [IE]: -0.07; 95% confidence interval [CI]: -0.11, -0.04) and catastrophizing (IE: -0.07; 95%CI: -0.14, -0.00), as well as increases in self-efficacy (IE: -0.07; 95%CI: -0.11, -0.04), mediated effects of cognitive behavioral therapy on disability but not on pain intensity, when compared to control treatments. Enhancing pain acceptance (IE: -0.17; 95%CI: -0.31, -0.03) and psychological flexibility (IE: -0.30; 95%CI: -0.41, -0.18) mediated acceptance and commitment therapy effects on disability. The narrative synthesis showed conflicting evidence, which did not support a robust moderated effect for any of the examined constructs. Overall, the methodological quality regarding mediation was low, and some key pitfalls are highlighted alongside recommendations to provide a platform for future research.

Individual Patterns and Temporal Trajectories of Changes in Fear and Pain during Exposure In Vivo: A Multiple Single-Case Experimental Design in Patients with Chronic Pain.

Exposure in vivo (EXP) is an effective treatment to reduce pain-related fear and disability in chronic pain populations. Yet, it remains unclear how reductions in fear and pain relate to each other. This single-case experimental design study attempted to identify patterns in the individual responses to EXP and to unravel temporal trajectories of fear and pain. Daily diaries were completed before, during and after EXP. Multilevel modelling analyses were performed to evaluate the overall effect. Temporal effects were scrutinized by individual regression analyses and determination of the time to reach a minimal clinically important difference. Furthermore, individual graphs were visually inspected for potential patterns. Twenty patients with chronic low back pain and complex regional pain syndrome type I were included. On a group level, both fear and pain were reduced following EXP. Individually, fear was significantly reduced in 65% of the patients, while pain in only 20%. A decrease in fear was seen mostly in the first weeks, while pain levels reduced later or remained unchanged. Daily measurements provided rich data on temporal trajectories of reductions in fear and pain. Overall, reductions in fear preceded pain relief and seemed to be essential to achieve pain reductions.

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

ABSTRACT: 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 = 15.8, SD = 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 (CS+>CS-; rp = 0.49, P = 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.

Exposure in Vivo as a Treatment Approach to Target Pain-Related Fear: Theory and New Insights From Research and Clinical Practice.

Pain-related fear (PRF) can be a significant factor contributing to the development and maintenance of pain-related disability in individuals with persistent pain. One treatment approach to target PRF and related avoidance behavior is exposure in vivo (EXP). EXP has a long history in the field of anxiety, a field that is constantly evolving. This Perspective outlines recent theoretical advancements and how they apply to EXP for PRF, including suggestions for how to optimize inhibitory learning during EXP; reviews mechanistic work from neuroimaging supporting the targeting of PRF in people with chronic pain; and focuses on clinical applications of EXP for PRF, as EXP is moving into new directions regarding who is receiving EXP (eg, EXP in chronic secondary pain) and how treatment is provided (EXP in primary care with a crucial role for physical therapists). Considerations are provided regarding challenges, remaining questions, and promising future perspectives. IMPACT: For patients with chronic pain who have elevated pain-related fear (PRF), exposure is the treatment of choice. This Perspective highlights the inhibitory learning approach, summarizes mechanistic work from experimental psychology and neuroimaging regarding PRF in chronic pain, and describes possible clinical applications of EXP in chronic secondary pain as well as in primary care.

Temporal changes in pain processing after whiplash injury, based on Quantitative Sensory Testing: A systematic review.

BACKGROUND AND OBJECTIVE: After whiplash injury, some patients develop chronic whiplash-associated disorders. The exact pathophysiology of this chronification is still unclear and more knowledge is needed regarding the different post-injury phases. Therefore, studies were searched that examined temporal changes in pain processing, measured by Quantitative Sensory Testing (QST). DATABASES AND DATA TREATMENT: This systematic review searched three electronic databases (Medline, Web of Science and Embase) for articles meeting the eligibility requirements. Risk of bias was assessed according to a modified Newcastle-Ottawa Scale. RESULTS: The 12 included studies presented moderate to good methodological quality. These studies showed altered pain processing within the first month after injury and normalization within 3 months in 59%-78% of the patients. After 3 months, recovery stagnates during the following years. Thermal and widespread mechanical hyperalgesia occur already in the acute phase, but only in eventually non-recovered patients. CONCLUSIONS: Differences in pain processing between recovering and non-recovering patients can be observed already in the acute phase. Early screening for signs of altered pain processing can identify patients with high risk for chronification. These insights in temporal changes show the importance of rehabilitation in the acute phase. Future research should target to develop a standardized (bed-site) QST protocol and collect normative data which could, in relation with self-reported pain parameters, allow clinicians to identify the risk for chronification. SIGNIFICANCE: Altered pain processing is present soon after whiplash injury, but usually recovers within 3 months. Non-recovering patients show little to no improvements in the following years. Differences between recovering and non-recovering patients can be observed by Quantitative Sensory Testing already in the acute phase. Therefore, it is considered a feasible and effective tool that can contribute to the identification of high-risk patients and the prevention of chronification.

Subclinical post-traumatic stress symptomology and brain structure in youth with chronic headaches.

BACKGROUND/AIMS: Post-traumatic stress symptoms (PTSS) and chronic pain often co-occur at high rates in youth. PTSS may alter brain structure thereby contributing to headache chronicity. This study examined whether PTSS and altered limbic circuitry were associated with headache frequency in youth. METHODS: Thirty youth aged 10-18 years with chronic headaches and 30 age- and sex-matched controls underwent a 3T MRI scan. Volumes of the hippocampus and amygdala were obtained from T1-weighted images. Mean fractional anisotropy (FA, an index of white matter structure) axial and radial diffusivity values of the cingulum and uncinate fasciculus were extracted from diffusion-weighted images. Youth reported on their headaches daily, for one-month, and self-reported pubertal status, emotion regulation, adverse childhood experiences (ACEs) and PTSS using validated measures. Volumes of the hippocampus and amygdala and diffusivity values of the cingulum and uncinate were compared between patients and controls. Hierarchical linear regressions were used to examine the association between PTSS, subcortical volumes and/or diffusivity values and headache frequency. RESULTS: Mean FA values of the cingulum were higher in patients compared to controls (P = 0.02, Cohen's d = 0.69). Greater PTSS (P = 0.04), smaller amygdala volumes (P = 0.01) and lower FA of the cingulum (P = 0.04) were associated with greater headache frequency, after accounting for age, puberty, pain duration, emotion regulation, and ACEs (Adjusted R2 ≥ 0.15). Headache frequency was associated with increases in radial diffusivity (P = 0.002, Adjusted R2 = 0.59), as opposed to axial diffusivity (n.s.). CONCLUSIONS: PTSS, smaller amygdalar volume, and poorer cingulum structural connectivity were associated with headache frequency in youth, and may underlie headache chronicity.

Enhanced amygdala-frontal operculum functional connectivity during rest in women with chronic neck pain: Associations with impaired conditioned pain modulation.

BACKGROUND: Chronic neck pain is a leading cause of disability worldwide, affecting the lives of millions of people. Research investigating functional brain alterations in relation to somatosensory function is necessary to better understand mechanisms underlying pain development and maintenance in individuals with chronic neck pain, yet remains scarce. This case-control study aimed to examine resting-state functional connectivity alterations and associations with pain outcomes, self-reported central sensitization-related symptoms and quantitative sensory testing (QST) measures in patients with chronic non-traumatic (idiopathic/CINP) neck pain and chronic traumatic (whiplash associated/CWAD) neck pain compared to pain-free controls. METHODS: Resting-state functional magnetic resonance images were acquired in 107 female participants (38 CINP, 37 CWAD, 32 healthy controls). After data pre-processing, seed-to-seed analyses were conducted focusing on resting-state functional connectivity involving pre-defined regions of interest that have previously been observed to be structurally or functionally altered and/or associated with pain-related measures in this patient population. RESULTS: Findings demonstrate enhanced left amygdala functional coupling during rest with the left frontal operculum in women with CINP and CWAD compared to controls. This increased resting-state functional connectivity was associated with more self-reported symptoms related to central sensitization and decreased efficacy of conditioned pain modulation. Furthermore, enhanced connectivity between the left amygdala and left frontal orbital cortex, and between the left pallidum and the left frontal operculum was observed only in patients with CWAD compared to healthy controls. In patients, additional associations between local hyperalgesia and enhanced connectivity between the left superior parietal cortex and the left and right precentral gyrus were found. CONCLUSIONS: In line with our hypotheses, patients with CWAD showed the most pronounced alterations in resting-state functional connectivity, encompassing subcortical limbic (amygdala) and basal ganglia (pallidum), and ventral frontal regions (frontal operculum, orbitofrontal cortex) when compared to CINP and controls. Findings are generally in line with the idea of a continuum, in absence of significant group differences across CINP and CWAD. Enhanced amygdala-frontal operculum functional connectivity was the most robust and only connectivity pair in the cluster that was associated with QST (i.e., dynamic QST; endogenous pain inhibition), and that was observed in both patient groups. In addition, independent of group differences, enhanced resting-state functional connectivity between superior parietal cortex (involved in attention) and primary motor cortex was associated with static QST (i.e., greater local hyperalgesia). Taken together, our findings show a key role for enhanced amygdala-ventral frontal circuitry in chronic neck pain, and its association with diminished endogenous pain inhibition further emphasizes the link between cognitive-affective and sensory modulations of pain in women with chronic non-traumatic and traumatic neck pain.

Corticolimbic Circuitry in Chronic Pain Tracks Pain Intensity Relief Following Exposure In Vivo.

Background: A subset of patients with chronic pain who receive exposure in vivo (EXP) treatment experience clinically relevant relief of pain intensity. Although pain relief is not an explicit therapeutic target, it is important to understand how and why this concomitant effect occurs in some patients but not others. This longitudinal study therefore aimed to characterize brain plasticity as well as to explore pretreatment factors related to pain relief. Methods: Resting-state functional magnetic resonance imaging data were acquired in 30 patients with chronic pain. Twenty-three patients completed EXP, and 6-month follow-up data were available in 20 patients (magnetic resonance imaging data in 17 patients). Pain-free control data were acquired at two time points (n = 29, n = 21). Seed-based resting-state functional connectivity (rsFC) analyses were performed, with seeds in the amygdala, hippocampus, and nucleus accumbens. Results: Pain relief after EXP was highly variable, with 60% of patients reporting a clinically relevant improvement. Amygdala rsFC with the middle frontal gyrus decreased significantly over time in patients but was not associated with pain relief. In contrast, greater pain relief was associated with greater decreases over time in hippocampus rsFC with the precuneus, which was related to reductions in catastrophizing (EXP therapeutic target) as well. Greater pain relief was also associated with lower pretreatment rsFC between nucleus accumbens and postcentral gyrus. Conclusions: While changes in hippocampus rsFC were associated with pain relief after EXP, pretreatment nucleus accumbens rsFC showed potential prognostic value. Our findings further support the importance of corticolimbic circuitry in chronic pain, emphasizing its relation to pain relief and identifying potential underlying mechanisms and prognostic factors, warranting further testing in independent samples.

The neural correlates of pain-related fear: A meta-analysis comparing fear conditioning studies using painful and non-painful stimuli.

Compared to the field of anxiety research, the use of fear conditioning paradigms for studying chronic pain is relatively novel. Developments in identifying the neural correlates of pain-related fear are important for understanding the mechanisms underlying chronic pain and warrant synthesis to establish the state-of-the-art. Using effect-size signed differential mapping, this meta-analysis combined nine MRI studies and compared the overlap in these correlates of pain-related fear to those of other non-pain-related conditioned fears (55 studies). Pain-related fear was characterized by neural activation of the supramarginal gyrus, middle temporal gyrus, inferior/middle frontal gyri, frontal operculum and insula, pre-/post-central gyri, medial frontal and (para-)cingulate cortex, hippocampus, thalamus, and putamen. There were differences with other non-pain-related conditioned fears, specifically in the inferior frontal gyrus, medial superior frontal gyrus, post-central gyrus, middle temporal gyrus, parieto-occipital sulcus, and striatum. We conclude that pain-related and non-pain-related conditioned fears recruit overlapping but distinguishable networks, with potential implications for understanding the mechanisms underlying different psychopathologies.

Parent Responses to Their Child's Pain: Systematic Review and Meta-Analysis of Measures.

OBJECTIVE: Parent responses can have a major impact on their child's pain. The purpose of this systematic review is to (a) identify and describe measures assessing pain-related cognitive, affective, and behavioral responses in parents of children with chronic pain and (b) meta-analyze reported correlations between parent constructs and child outcomes (i.e., pain intensity, functional disability, and school functioning). Prospero protocol registration ID: CRD42019125496. METHODS: We conducted a systematic search of studies including a measure of parent/caregiver responses to their child's chronic pain. Study characteristics and correlations between parent measures and child outcomes were extracted. Data were summarized and meta-analyzed. RESULTS: Seventy-nine met inclusion criteria using 18 different measures of cognitive/affective (n = 3), behavioral (n = 5), and multidimensional responses (n = 10). Measures were used a median of three times (range 1-48), predominantly completed by mothers (88%), and primarily in mixed pain samples. Psychometrics of measures were generally adequate. Meta-analyses were based on 42 papers across five measures. Results showed that each of the cognitive, affective, and behavioral parent constructs we examined was significantly associated with pain-related functional disability. A small number of measures assessing parent cognitions and affective functioning were associated with higher child pain intensity; however, the majority were not. CONCLUSION: Findings demonstrate that there is a wealth of measures available, with adequate reliability overall but a lack of psychometrics on temporal stability. Synthesizing data across studies revealed small effects between parent responses and child functioning, and even smaller and/or absent effects on child pain intensity.