In adults with complex pain, detailed phenotyping with patient-reported outcome measures (PROMs), Quantitative Sensory Testing (QST), and neuroimaging improve patient stratification for clinical trials and treatment and provide mechanistic insight.6–8,36 In adolescents, neuropathic pain (NeuP) is associated with significant pain and pain-related disability,18 but causes can differ from adults, and evidence from paediatric trials is limited.10 Ongoing innovation in paediatric pain research with translation into clinical practice is needed.3
Although PROMs and QST have been used for a range of chronic pain conditions in highly symptomatic adolescents, relatively few studies have used MRI in adolescents with NeuP.2,12,13,19,20,30,31 Lack of evidence regarding feasibility and practical or ethical burden of MRI in such cohorts28 may represent barriers to research study planning, ethical approval, and/or recruitment.33 Within a larger clinical cohort of adolescents with moderate–severe NeuP, a pilot study assessed MRI consent rate, postscan acceptability, and data quality.
Adolescents aged 10 to 18 years with clinically diagnosed NeuP were recruited from the Great Ormond Street Hospital Chronic Pain Management Service. The MRI pilot forms part of an ongoing cohort study evaluating PROMs and QST (clinicaltrials.gov NCT03312881). Written informed parental consent and adolescent assent/consent were obtained, and families were given the option to additionally consent to an MRI scan, which required 1 additional hospital visit within 3 months of QST testing and recruitment (see Text, Supplemental Digital Content 3, which contains further recruitment details, available at http://links.lww.com/PR9/A60). Age-matched healthy participant data with the same MRI protocol and scanner were available for comparison.
2.2.1. Pain intensity
At recruitment, adolescents completed visual analogue scales (VASs; 0–10 cm) for pain intensity (now, average and worst pain in the last week) and activity interference due to pain.40 Twelve adolescents also reported pain intensity immediately before MRI.
2.2.2. Patient-reported outcome measures
Validated questionnaires completed during clinic appointments included: Pediatric Index of Emotional Distress21; Paediatric Quality of Life Inventory38; and Pain Catastrophizing Scale—Children.35
After the scan, adolescents and parent(s) rated discomfort, perceived risk, and acceptability of current and future MRI scans (0–10 numerical rating scale [NRS]) (see Figures, Supplemental Digital Content 1–2, which contain postscan questionnaires completed by participants, available at http://links.lww.com/PR9/A60).
2.2.3. MRI acquisition and analysis
Multimodal neuroimaging was performed using a 3T Siemens Prisma MRI scanner with a 64-channel coil at Great Ormond Street Hospital. Neuroimaging included T1- and diffusion-weighted images and resting-state functional MRI (rsfMRI; see Text, Supplemental Digital Content 3, which provides MRI acquisition parameters and analysis methods, available at http://links.lww.com/PR9/A60). For the rsfMRI scan, participants were asked to keep their eyes closed and let their minds wander. Given our paediatric cohort, the protocol was restricted to 30 minutes.
As head motion can impair quality of fMRI,15 framewise displacement (FD)24 was measured as the movement of any given frame relative to the previous frame. Scans underwent standard preprocessing (see Text, Supplemental Digital Content 3, which provides MRI acquisition parameters and analysis methods, available at http://links.lww.com/PR9/A60) in the CONN toolbox (v18a),42 run on MATLAB (R2018a v9.4; Mathworks, Nantick, MA).
Framewise displacement values were compared between adolescents with NeuP and controls. As thresholds of 0.2 and 0.5 mm have been suggested to indicate high levels of motion in adults,24,25 we calculated the proportion of frames per participant above these thresholds.
2.3. Data analyses
Statistical analysis was performed with SPSS (v24; IBM, Portsmouth, United Kingdom). When assumptions of normality were not met, nonparametric tests were used. All tests were 2-tailed and assessed at α = 0.05.
Fifty adolescents with NeuP (n = 42) or predominantly NeuP (n = 8) were recruited to the NeuP study between October 2017 and April 2019 (Fig. 1).
3.2. Pain ratings and patient-reported outcome measures
At recruitment, average pain intensity in the last week was moderate–severe in both males (mean ± SD: 6.2 ± 1.5; n = 19) and females (6.5 ± 2.2; n = 31). Participants indicated high pain catastrophizing and emotional distress and impaired quality of life (Table 1).
3.3. MRI recruitment
Thirty-four of 47 (72%) adolescents aged 11 years and older and their families agreed to MRI. To reduce heterogeneity, we further excluded patients without neuropathic QST profiles of sensory gain/loss1,29 and those with multiple types of pain that could limit attribution of MRI changes to current NeuP (Fig. 1; see also Text, Supplemental Digital Content 3, which contains further exclusion details, available at http://links.lww.com/PR9/A60). Demographics, pain, and questionnaire measures in scanned patients did not differ from those who were excluded or declined MRI (Table 1). A higher but statistically insignificant proportion of females than males (10/30 vs 3/19) declined MRI.
3.4. Postscan acceptability and discomfort
Eighteen adolescents (10 female and 8 male) and 17 parents (1 declined as limited English) completed post-MRI questionnaires. Three parents felt unable to report child discomfort as they were not in the scanner room. Ratings for current research scan acceptability were high for both adolescents (range [median]: 8-10 ; 67% rated 10/10; “Overall, do you think it is ok for a brain scan to be performed to help understand "nerve" pain in children?”; see Figure, Supplemental Digital Content 1, which contains the postscan questionnaire completed by adolescents, available at http://links.lww.com/PR9/A60) and parents (7–10 ; 81% 10/10) (Fig. 2A). Acceptability of a future research scan was high for parents (7–10 ; 88% 10/10) but lower for adolescents (5–10 ; 67% 10/10) and did not differ from acceptability for future clinical scans (Fig. 2A).
Three adolescents declined MRI due to noise or discomfort during previous clinically required scans. Of 21 adolescents scanned for this study, 18 were asked to complete postscan questionnaires. Eight reported no discomfort, 6 mild discomfort (1–3/10), and 2 moderate (5–7/10) positional discomfort in the head or neck during MRI. One adolescent with 9/10 discomfort due to noise also reported the highest worry (6/10) and lowest acceptability of future research scans (5/10) (Fig. 2B, C). Within this small cohort, there was no correlation between pain intensity immediately before scanning and discomfort (Spearman's ρ = 0.13, P = 0.7; n = 12) or between previously completed PI-ED scores and worry during MRI (ρ = 0.33, P = 0.18; n = 18). Fifteen adolescents felt scan instructions were easy to understand (7–10/10, 61% 10/10). Two adolescents reporting difficulty understanding instructions (0/10) also had lower ratings for future scan acceptability (5–7/10) (Fig. 2C).
3.5. MRI data quality
Head motion during rsfMRI in NeuP patients did not differ from age-matched healthy controls (Table 2). Mean FD and the percentage of frames per adolescent with FD greater than either 0.2 or 0.5 mm were similar (Table 2), and there was a similar negative relationship between age and mean FD across both groups (Fig. 3).
Many adolescents with moderate–severe NeuP and families agreed to research MRI and reported high acceptability of the current and future scans. Logistical issues and MRI contraindications accounted for some refusals. Previous poor scan experience influenced recruitment, and adolescents reporting discomfort or difficulty understanding instructions also had lower ratings for future scan acceptability. Providing families with information about other children's scan experience may facilitate decisions regarding recruitment.32
Neuroimaging pain research is well-established in adults,7,36 but additional pediatric data are required. Nociceptive processing is developmentally regulated and sensitive to early life experience,4,39,40 and correction for significant age and sex-dependent changes in brain structure throughout adolescence5 is needed when assessing disease effects.34 MRI has identified altered brain structure and function in adolescents with complex regional pain syndrome,2,12,13,19,20,30,31 but evaluations of acceptability and feasibility, and in other NeuP cohorts, are limited. Despite experiencing persistent moderate–severe NeuP with high levels of emotional distress and pain catastrophizing, recruitment and parental and adolescent acceptability of research MRI was high.
There is no gold standard for measuring research procedural discomfort in children.33 Although not formally validated, our numerical scales and questions regarding discomfort, anxiety, or concerns about the procedure, and willingness to undergo future scans, parallel those used for MRI acceptability in adults14,22 and child discomfort during research procedures.32,33 As suggested, both adolescent and parental self-report was obtained immediately after the procedure to minimize recall bias.33 Although overall satisfaction with clinically required scans despite discomfort may be heightened by perceived diagnostic value,22 adolescents and parents did not differentiate between acceptability of future scans for clinical or research purposes.
Data regarding the type and degree of discomfort during research procedures in adolescents can aid ethics committee evaluations of potential burden.33,41 Unsedated healthy participants aged 8 to 18 years undergoing research MRI for 30 to 60 minutes reported low overall discomfort (1.6 ± 0.45, mean ± SD; 1–5 Likert scale).32 Our data mirror these findings: Despite chronic NeuP, most adolescents tolerated MRI with minimal discomfort.
Feasibility of research MRI in adolescents also depends on obtaining high-quality data within a tolerable duration. Pediatric and clinical populations may be more susceptible to head motion and movement artefact,23 and removing affected data frames can result in loss of 50% or more of data9 and adversely affect interpretation.24,25,27,37 Others suggest that head motion is heritable and stable over time11,17 and also reflects individual variability in functional organization.26,43 Real-time visual feedback can reduce head movement in younger patients,16 and motion analytics can facilitate scanning until the desired amount of low-movement data has been collected.9 With our 30-minute scan protocol, head motion tended to be higher at younger ages as previously reported,11,27 but did not differ between clinical and healthy adolescents, and data were high-quality.
Behavioral strategies can improve acceptability and tolerability of MRI for unsedated adolescents,16 and adequate preparation can reduce anticipated pain or worry.33 Despite high pain and anxiety scores, worry during MRI was low, with experienced pediatric radiographers providing age-appropriate instructions throughout scanning and maximizing comfort during positioning. In accordance with adolescent preferences during research procedures,16,32 participants viewed a movie of his/her choice, apart from during rsfMRI. Advances in neuroimaging that reduce scan time will further improve tolerability for adolescents.
The number of adolescents scanned for this pilot study is small (n = 21), and the MRI acceptability questionnaire was introduced after the first 3 participants. Acceptability ratings do not account for potential lower scores in 3 participants who declined due to previous poor scan experience. Females were more likely to decline MRI, but the sample is too small to draw conclusions, as reasons varied across both sexes (Fig. 1). All adolescents with a clinical diagnosis of NeuP were recruited irrespective of underlying cause, but several with complex or multiple types of pain were excluded from the MRI phase of the study. Refining inclusion/exclusion criteria to reduce heterogeneity in larger cohorts of adolescents with NeuP remains challenging. Current results may not generalize to studies with longer scanning protocols or task-based fMRI studies. Use of standardized postscan scales will facilitate comparison across studies.33
Research MRI is feasible and acceptable for most adolescents with moderate–severe NeuP.
The authors have no conflicts of interest to declare.
This research was supported by funds from Great Ormond Street Hospital Children's Charity Research Awards W1071H, W1071I (S.M.W.), and a University College London—University of Toronto Joint Research Project and Exchange Activities Award (C.A.C., M.M., M.V., and S.M.W.).
Research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Sections of this manuscript were presented in poster form at the 7th International Congress on Neuropathic Pain (NeuPSIG 2019; May 9–11, 2019).
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PR9/A60.
The authors acknowledge additional members of the Developmental Imaging and Biophysics Section who collected healthy control MRI data (Jamie M. Kawadler; Manuela Martinez-Barona Soye), and who contributed to discussions on processing of fMRI data; members of the UCL GOS ICH Paediatric Pain Research Group and Great Ormond Street Hospital Pain Service who supported the research and made contributions to collection of clinical data and recruitment; Great Ormond Street Hospital radiographers who ensured collection of high-quality scan data; and most importantly, the patients and families who generously participated in this research.
. Baron R, Maier C, Attal N, Binder A, Bouhassira D, Cruccu G, Finnerup NB, Haanpaa M, Hansson P, Hullemann P, Jensen TS, Freynhagen R, Kennedy JD, Magerl W, Mainka T, Reimer M, Rice AS, Segerdahl M, Serra J, Sindrup S, Sommer C, Tolle T, Vollert J, Treede RD. Peripheral neuropathic pain
: a mechanism-related organizing principle based on sensory profiles. PAIN
. Becerra L, Sava S, Simons LE, Drosos AM, Sethna N, Berde C, Lebel AA, Borsook D. Intrinsic brain networks normalize with treatment in pediatric complex regional pain
syndrome. Neuroimage Clin 2014;6:347–69.
. Chambers CT. Introduction to special issue on innovations in pediatric pain
research and care. Pain
Rep 2018;3(suppl 1):e684.
. Chau CM, Ranger M, Bichin M, Park M, Amaral R, Chakravarty M, Poskitt K, Synnes A, Miller SP, Grunau RE. Hippocampus, amygdala, and thalamus volumes in very preterm children
at 8 years: neonatal pain
and genetic variation. Front Behav Neurosci 2019;13:51.
. Clayden JD, Jentschke S, Munoz M, Cooper JM, Chadwick MJ, Banks T, Clark CA, Vargha-Khadem F. Normative development of white matter tracts: similarities and differences in relation to age, gender, and intelligence. Cereb Cortex 2012;22:1738–47.
. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN. Neuropathic pain
. Nat Rev Dis Primers 2017;3:17002.
. Davis KD. Imaging vs quantitative sensory testing to predict chronic pain
treatment outcomes. PAIN
. Davis KD, Seminowicz DA. Insights for clinicians from brain imaging studies of pain
. Clin J Pain
. Dosenbach NUF, Koller JM, Earl EA, Miranda-Dominguez O, Klein RL, Van AN, Snyder AZ, Nagel BJ, Nigg JT, Nguyen AL, Wesevich V, Greene DJ, Fair DA. Real-time motion analytics during brain MRI improve data quality and reduce costs. Neuroimage 2017;161:80–93.
. Eccleston C, Fisher E, Cooper TE, Gregoire MC, Heathcote LC, Krane E, Lord SM, Sethna NF, Anderson AK, Anderson B, Clinch J, Gray AL, Gold JI, Howard RF, Ljungman G, Moore RA, Schechter N, Wiffen PJ, Wilkinson NMR, Williams DG, Wood C, van Tilburg MAL, Zernikow B. Pharmacological interventions for chronic pain
: an overview of systematic reviews. PAIN
. Engelhardt LE, Roe MA, Juranek J, DeMaster D, Harden KP, Tucker-Drob EM, Church JA. Children
's head motion during fMRI tasks is heritable and stable over time. Dev Cogn Neurosci 2017;25:58–68.
. Erpelding N, Sava S, Simons LE, Lebel A, Serrano P, Becerra L, Borsook D. Habenula functional resting-state connectivity in pediatric CRPS. J Neurophysiol 2014;111:239–47.
. Erpelding N, Simons L, Lebel A, Serrano P, Pielech M, Prabhu S, Becerra L, Borsook D. Rapid treatment-induced brain changes in pediatric CRPS. Brain Struct Funct 2016;221:1095–111.
. Evans RE, Taylor SA, Beare S, Halligan S, Morton A, Oliver A, Rockall A, Miles A. Perceived patient burden and acceptability of whole body MRI for staging lung and colorectal cancer; comparison with standard staging investigations. Br J Radiol 2018;91:20170731.
. Fassbender C, Mukherjee P, Schweitzer JB. Minimizing noise in pediatric task-based functional MRI; Adolescents
with developmental disabilities and typical development. Neuroimage 2017;149:338–47.
. Greene DJ, Koller JM, Hampton JM, Wesevich V, Van AN, Nguyen AL, Hoyt CR, McIntyre L, Earl EA, Klein RL, Shimony JS, Petersen SE, Schlaggar BL, Fair DA, Dosenbach NUF. Behavioral interventions for reducing head motion during MRI scans in children
. Neuroimage 2018;171:234–45.
. Hodgson K, Poldrack RA, Curran JE, Knowles EE, Mathias S, Goring HHH, Yao N, Olvera RL, Fox PT, Almasy L, Duggirala R, Barch DM, Blangero J, Glahn DC. Shared genetic factors influence head motion during MRI and body mass index. Cereb Cortex 2017;27:5539–46.
. Howard RF, Wiener S, Walker SM. Neuropathic pain
. Arch Dis Child 2014;99:84–9.
. Lebel A, Becerra L, Wallin D, Moulton EA, Morris S, Pendse G, Jasciewicz J, Stein M, Aiello-Lammens M, Grant E, Berde C, Borsook D. fMRI reveals distinct CNS processing during symptomatic and recovered complex regional pain
syndrome in children
. Brain 2008;131:1854–79.
. Linnman C, Becerra L, Lebel A, Berde C, Grant PE, Borsook D. Transient and persistent pain
induced connectivity alterations in pediatric complex regional pain
syndrome. PLoS One 2013;8:e57205.
. O'Connor S, Ferguson E, Carney T, House E, O'Connor RC. The development and evaluation of the paediatric index of emotional distress (PI-ED). Soc Psychiatry Psychiatr Epidemiol 2016;51:15–26.
. Oliveri S, Pricolo P, Pizzoli S, Faccio F, Lampis V, Summers P, Petralia G, Pravettoni G. Investigating cancer patient acceptance of Whole Body MRI. Clin Imaging 2018;52:246–51.
. Poldrack RA, Pare-Blagoev EJ, Grant PE. Pediatric functional magnetic resonance imaging
: progress and challenges. Top Magn Reson Imaging 2002;13:61–70.
. Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage 2012;59:2142–54.
. Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE. Steps toward optimizing motion artifact removal in functional connectivity MRI; a reply to Carp. Neuroimage 2013;76:439–41.
. Pujol J, Macia D, Blanco-Hinojo L, Martinez-Vilavella G, Sunyer J, de la Torre R, Caixas A, Martin-Santos R, Deus J, Harrison BJ. Does motion-related brain functional connectivity reflect both artifacts and genuine neural activity? Neuroimage 2014;101:87–95.
. Satterthwaite TD, Wolf DH, Loughead J, Ruparel K, Elliott MA, Hakonarson H, Gur RC, Gur RE. Impact of in-scanner head motion on multiple measures of functional connectivity: relevance for studies of neurodevelopment in youth. Neuroimage 2012;60:623–32.
. Sava S, Lebel AA, Leslie DS, Drosos A, Berde C, Becerra L, Borsook D. Challenges of functional imaging research of pain
. Mol Pain
. Sethna NF, Meier PM, Zurakowski D, Berde CB. Cutaneous sensory abnormalities in children
with complex regional pain
. Simons LE, Erpelding N, Hernandez JM, Serrano P, Zhang K, Lebel AA, Sethna NF, Berde CB, Prabhu SP, Becerra L, Borsook D. Fear and reward circuit alterations in pediatric CRPS. Front Hum Neurosci 2016;9:703.
. Simons LE, Pielech M, Erpelding N, Linnman C, Moulton E, Sava S, Lebel A, Serrano P, Sethna N, Berde C, Becerra L, Borsook D. The responsive amygdala: treatment-induced alterations in functional connectivity in pediatric complex regional pain
. Staphorst MS, Benninga MA, Bisschoff M, Bon I, Busschbach JJV, Diederen K, van Goudoever JB, Haarman EG, Hunfeld JAM, Jaddoe VVW, de Jong KJM, de Jongste JC, Kindermann A, Konigs M, Oosterlaan J, Passchier J, Pijnenburg MW, Reneman L, Ridder L, Tamminga HG, Tiemeier HW, Timman R, van de Vathorst S. The child's perspective on discomfort during medical research procedures: a descriptive study. BMJ Open 2017;7:e016077.
. Staphorst MS, Timman R, Passchier J, Busschbach JJV, van Goudoever JB, Hunfeld JAM. The development of the DISCO-RC for measuring children
's discomfort during research procedures. BMC Pediatr 2017;17:199.
. Stotesbury H, Kirkham FJ, Kolbel M, Balfour P, Clayden JD, Sahota S, Sakaria S, Saunders DE, Howard J, Kesse-Adu R, Inusa B, Pelidis M, Chakravorty S, Rees DC, Awogbade M, Wilkey O, Layton M, Clark CA, Kawadler JM. White matter integrity and processing speed in sickle cell anemia. Neurology 2018;90:e2042–50.
. Sullivan MJL, Bishop SR, Pivik J. The pain
catastrophizing scale: development and validation. Psychol Assess 1995;7:524–32.
. Tracey I, Woolf CJ, Andrews NA. Composite pain
biomarker signatures for objective assessment and effective treatment. Neuron 2019;101:783–800.
. Van Dijk KR, Sabuncu MR, Buckner RL. The influence of head motion on intrinsic functional connectivity MRI. Neuroimage 2012;59:431–8.
. Varni JW, Burwinkle TM, Seid M. The PedsQL as a pediatric patient-reported outcome: reliability and validity of the PedsQL Measurement Model in 25,000 children
. Expert Rev Pharmacoecon Outcomes Res 2005;5:705–19.
. Walker SM. Early life pain
—effects in the adult. Curr Opin Physiol 2019;11:16–24.
. Walker SM, Melbourne A, O'Reilly H, Beckmann J, Eaton-Rosen Z, Ourselin S, Marlow N. Somatosensory function and pain
in extremely preterm young adults from the UK EPICure cohort: sex-dependent differences and impact of neonatal surgery. Br J Anaesth 2018;121:623–35.
. Wendler D. Is it possible to protect pediatric research subjects without blocking appropriate research? J Pediatr 2008;152:467–70.
. Whitfield-Gabrieli S, Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2012;2:125–41.
. Zeng LL, Wang D, Fox MD, Sabuncu M, Hu D, Ge M, Buckner RL, Liu H. Neurobiological basis of head motion in brain imaging. Proc Natl Acad Sci U S A 2014;111:6058–62.