Understanding pediatric pain \200\224evidence from neurophysiological studies Evaluation in early life Neurophysiological methods have fundamentally contributed to unraveling the dev elopment of pain processing, especially dur- ing early infancy (e.g. Fabrizi et al., 2011 ; see also Chapter 40 40 Poorun and Slater, Chapter 39, this volume). In 2006, using NIRS, t wo studies were the fi rst to demonstrate that, as early as 25 weeks postmenstrual age, an invasive painful medical procedure (e.g. heel lance, venepuncture) as compared to non-painf ul touch elicits a distinct haemodynamic response in the contralateral somatosensory cortex , hence at this developmental stage thalam- ocortical pathways are suffi ciently mature for cortical processing of nociceptive input (Bartocci et al., 2006 ; Slater et al., 2006 ). A lso, diff erent intensive care procedures are accompanied by signifi cant cerebral haemodyn amic changes (Limperopoulos et al., 2008 ). Extending these fi ndings, time-locked EEG reco rdings in infants undergoing heel lance revealed a distinct component consisting of a negat ive and positive defl ection at about 500 ms (N420 \200\223P560) Indirect measures of neural activity: metabolism, oxygen consumption, and blood \202 ow A nother approach is to record changes in metabolism, oxygen consumption, and blood fl ow bas ed on the assumption that these are closely related to neural activity. FMRI is based on me asuring changes in the ratio of oxygenated to deoxygenated hemoglobin CHAPTER 40 sensory processing and neurophysiological evaluation in children 413 Chronic pain In chronic pediatric pain, EEG has been used to study cognitive aspects of pai n processing and specifi c pathophysiological mech- anisms. In children with migraine and c hildren with recurrent abdominal pain, we recorded somatosensory-evoked potentials in respo nse to painful and non-painful mechanical stimuli which had to be ignored while performing a primary task (Hermann et al., 2008 ; Zohsel et al., 2008a ). Painful stimuli elicited a s ignifi cantly larger vertex potential (N150 \200\223P260) compared to non-painful stimuli. In both pain groups, the P300 in response to both pain- ful and non-painful stimuli was sig nifi cantly greater than in the controls (see Figure 40.2 ). Th is suggests that chronic pa in in chil- dren is associated with automatic attention to painful and poten- tially painfu l stimuli. In migraine, heightened cortical excitability and altered cortical sensory proce ssing have been proposed as pathogenetic mechanisms. Consistent with such concepts, in chil - dren with migraine, both cross-sectional and longitudinal studies entailing the measureme nt of ERPs to sensory stimuli (e.g. visual) and slow cortical potentials suggest altered ma turation of cortical information processing (Oelkers-Ax et al., 2008 ; Siniatchkin et al., 2010 ). Th us far, only one study has used fRMI in chronic pediatric pain. Children with co mplex regional pain syndrome (CRPS) were exposed to non-noxious thermal and mechanical stim ulation during the acute pain phase and aft er recovery (Lebel et al., 2008 ; see also Clin ch, Chapter 24, this volume). In the acute pain phase, patients experienced allodynia in th e aff ected extremity and, consistently, at electrode sites above the somatosensory cortex that is specifi c for nociceptive input a nd is larger in preterm compared to full- term-born infants (Slater et al., 2010b , 2010c). Such direct meas- uring of cortical activity is especially promising for evaluating the ef fi cacy of (non-)pharmacological treatments for infants given that, at this age, pain measu rement usually relies exclusively on behavioral observations and physiological parameters ( e.g. heart rate, oxygen saturation). For example, in infants, oral sucrose as compared to w ater did not reduce the cortical response to a pain- ful heel stick despite resulting in an attenuated behavioral pain response (Slater et al., 2010a ). Using fMRI, we studied the lo ng- term impact of neonatal pain experiences on brain activation in response to heat pain i n school-aged preterm and full-term-born children having undergone treatment in a neonatal intensive care unit (NICU) and control children (Hohmeister et al., 2010 ). In all three gr oups, tonic heat pain led to signifi cant activations of brain regions typically involved i n pain processing (see Figure 40.1 ). Th e preterm, but not the full-term NICU children exh ibited signifi - cant activations in a number of brain regions (thalamus, anterior cingulat e cortex, cerebellum, basal ganglia, and periaqueductal gray) that were not signifi cantly activated in controls. Moreover, the preterms showed signifi cantly higher activations than con- trols in primary somatosensory cortex, anterior cingulate cortex, and insula. Hence, exposure to pain at a vulnerable stage of the developing pain circuitry, may aff ect both s ensory and aff ective processing of pain later in life. Figure 40.1 Signi \201 cant brain activations ( p <0.001, k \211 10) during painful toni c heat stimulation in NICU-preterms (red), NICU-full-terms (blue), and the controls (green) , superimposed on a normalized T 1 -weighted brain. X-coordinates of brain slices (in mm) r efer to the Montreal Neurological Institute standard brain. PFC = prefrontal cortex; PPC = posterior parietal cortex; PMC = premotor cortex; antIns = anterior insula; Cereb = cerebel lum; BG = basal ganglia; pre-SMA = pre-supplementary motor area; ACC = anterior cingulate c ortex; Th al = thalamus; PAG = periaqueductal gray. Reproduced from Johanna Hohmeister et a l., Cerebral processing of pain in school-aged children with neonatal nociceptive input: An exploratory MRI study, PAIN , Volume 150, pp. 257 \200\223267, Copyright 2010. Th is \201 gure has been reproduced with permission of the International Association for the St udy of Pain (IASP). Th e \201 gure may NOT be reproduced for any other purpose without permission. Th is \201 gure is reproduced in color on the back endpaper. SECTION 5 measurement of pain 414 this is most likely accounted for by ethical considerations given the relatively high deman d on children \200\231s compliance with instructions and measurement requirements. References Agostinho , C. M. 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Premature infants display increased noxious-evoked neuronal activity in the brain co mpared to healthy age-matched term-born infants . Neuroimage , 52 , 583 \200\223589. CHAPTER 41 Measurement of health- related quality of life and physical function See Wan Th am , Anna C. Wilson, and Tonya M. Palermo Summary Th is chapter reviews the measurement of health-related quality of life (HRQOL) and physical function in pediatric pain populations. We present available data on HRQOL and ph ysical function in chil- dren with pain, methods of assessment, details about specifi c que s- tionnaire and performance-based measures, and recommendations for the use of measures ba sed on available evidence. Because many children and adolescents with pain report impairmen t in partici- pation in physical activities such as walking, running, and sports, physical functioning is a core target and outcome for intervention, particularly for youth with chro nic pain. However, the domain of physical functioning encompasses a number of constructs su ch as physical fi tness, physical activity, and subjective disability, which are interrelat ed, but represent distinct aspects of functioning. Moreover, HRQOL is a broader concept tha t subsumes physical and psychosocial function. A wide variety of measurement tools are in u se, but no guidelines for measurement have been estab- lished. A better understanding of me asurement of HRQOL and physical function may enable researchers and clinicians to track chi ldren \200\231s functional impact and changes in function over time, and to improve the des ign and testing of potentially eff ective interven- tions for children with pain. functioning), and (3) an overall assessment of well-being (e.g. glo- bal health status). HR QOL scores are oft en summarized as broad- band scores for physical health and psychosocial health. Integral to the assessment of HRQOL is the domain of physical functioning. Physica l functioning refers to actual participation in physical activi- ties and ability to perfor m physical tasks, as well as the individual \200\231s perception of diffi culty or restrict ion in activity participation. Physical function should be a primary treatment outcome for youth with pain and represents a specifi c domain requiring detailed assessment. Th e Pediatric Initiative on Methods, Mea surement, and Pain Assessment in Clinical Trials (Ped-IMMPACT) recommended outcome measures for clinical trials investigating acute and chronic pain in children (McGrath et al., 2008 ) and identifi ed physical and role functioning as two of the eight core outcome domains. In this chapter, we review approaches for assessment of HRQOL as a mul- tidimensional const ruct that incorporates the domains of physical and role functioning, and we separately revi ew specifi c approaches to the assessment of physical functioning. We further describe meas ures of HRQOL and physical functioning in pediatric pain populations. Health-related quality of life and physical function in children with painful conditions Se veral examinations of HRQOL in children and adolescents with pain conditions (e.g. headache , sickle cell disease, mixed pain con- ditions) have found that they report signifi cantly poorer HRQOL in comparison to healthy children (Nodari et al., 2002 ; Palermo et al., 2002 ). Moreover, unexplained chronic pain in adolescents has been associated with poor quality of life for the adolescent and his or her family (Hunfeld et al., 2001 ). Predictors of poo r HRQOL within pain populations include the presence of sleep problems (Palermo and Kiska, 2005 ), fatigue (Berrin et al., 2007 ), pain-re- lated hospitalizations (Palermo et al., 20 02 ), low socioeconomic conditions (Palermo et al., 2008c ) and increasing child age. Littl e is known, however, about how HRQOL changes over time in youth with pain. Introduction It is well recognized that medical conditions and ill health may have signifi cant impact across diff erent areas of a child \200\231s life. Pain, particu- larly chronic pain, may impair school attendance, mobility, self-care, interpersonal interactions, life activities, and community activities (Palermo, 2000 ). Health-related quality of life (HRQO L) refers to an individual \200\231s perception of the impact of an illness, symptoms, and its consequent treatment on their physical, psychological, and social well-being, as well a s perception of overall well-being in relation to their health (Eiser et al. 2001 ). Measur ement of HRQOL incorpo- rates assessment of three levels: (1) components of specifi c domai ns of functioning (e.g. diffi culty walking up stairs), (2) individual domains of functioni ng (e.g. psychosocial, physical, school, and role SECTION 5 measurement of pain 418 Similarly, physical function has also been fairly extensively stud- ied in youth with vario us pain conditions primarily to identify how chronic pain can aff ect children \200\231s pa rticipation in developmentally appropriate physical and social activities. In one epidemiol ogical study of chronic pain in a community sample of youth (Roth-Isigkeit, et al., 2005 ), impairments most commonly reported were: sleep problems (53.6%), inability to pursue hobbi es (53.3%), eating prob- lems (51.1%), school absence (48.8%), and inability to meet friend s (46.7%). Huguet and Miro (2008) examined pain severity including impact from pain using v alidated measures in a population based sample. Th ey found that 36.8% of youth had some di sability, with 31.7% categorized as having a low level of disability and 5.1% having modera te to severe disability. Th ese studies highlight that pain and disability can vary conside rably among children with pain. interview to establish rapport, obtain a pain history, and to under- stand impact of pain o n aspects of the child \200\231s daily life. Interview probes about school, daily activitie s, sports participation, recrea- tional and peer activities, and self-care activities can u ncover areas of signifi cant limitation in physical function (see Table 41.1 ). See supplem entary online materials for additional interview probes in multiple domains of assessment. Functional goals are oft en developed with children and parents around specifi c areas of l imitation tailored to each child \200\231s needs. Re-assessment of these allows for monitor ing and tracking of patient outcomes. Th ere are limitations to the use of clinical inter- views to assess physical function, however, including that questions may be asked in diff e rent ways (i.e. lack of standardization), demand characteristics may infl uence responses, and there is a limited abil- ity to make comparisons across children. Empirical support is not yet available to recommend a standardized clinical interview for assessing physical fun ction in pediatric pain. Prior reviews of HRQOL and function measures Several recent reviews have provided summaries of measures that have been used to assess HRQOL and physical function in medical populatio ns experiencing chronic pain or chronic illness. Eccleston et al. ( 2006 ) identifi ed nine measures of the impact of pain on HRQOL and physical functioning in children with headache , arthri- tis, abdominal pain, and mixed pain conditions. Th ey concluded that for the majo rity of the measures, the psychometric evaluations were limited in scope, and had only been used in a few studies. HRQOL questionnaires HRQOL can be assessed on questionnaires that can be generic or conditi on-specifi c measures (Palermo et al., 2008b ). Generic measures are not intended for a spe cifi c population, and allow for comparisons across children with diff erent pain or medica l condi- tions. Condition-specifi c HRQOL measures, on the other hand, are developed for ex amination of specifi c impairments experienced by children with the same health conditions. Th is may increase sen- sitivity in capturing the nuances of living with specifi c conditi ons. However, condition-specifi c instruments do not allow for com- parative measurements a cross diff erent illness groups, or between children with and without pain. Palermo et al. ( 2008b ) reviewed 16 measures of HRQOL and func- tional impairment that hav e been used with pediatric populations including children with painful conditions. Th is re view classifi ed measures as being well established, approaching well established, or promi sing. Several well-established measures were found used in pain populations including the P ediatric Quality of Life Inventory (PedsQL; Varni et al., 1999 ), the Functional Disability Inventory (FDI; Walker and Greene, 1991 ), and the Child Activity Limitations Interview (C ALI; Palermo, et al., 2004 ). Specifi c measures are dis- cussed in more detail in later se ctions. Th is review called for further research, particularly regarding the validity of HR QOL and func- tional disability measures in response to interventions, and the clin- ical u tility of changes in these measures (Palermo et al., 2008b ). Two commonly used, well-established generic HRQOL meas- ures that have been applied to pain populations are the Child Health Questionnaire (CHQ) and PedsQL. Th e CHQ is a widely used instrument, initially developed for use in healthy children Table 41.1 Clinical interview questions to assess physical and role function