Pain and the immature developing brain Brain reactivity to procedures Th e brain undergoes very rapid developmental changes in mac- rostructure, microstructure, and connectivity duri ng the time that infants born extremely preterm are undergoing neonatal intensive care. An example of the progression of structural brain matura- tion from 28 weeks of gestation to t erm-equivalent age is shown in Figure 4.1 . Magnetic resonance imaging (MRI) studies have r evealed atypical brain development in neonates born very preterm, e.g. smaller volume of th e brain and specifi c regions, abnormalities in white matter microstructure, reduced cortic al thickness, distur- bances of the thalamocortical system, and altered development of the cerebellum and other structures (e.g. see Ball et al., 2011; Volpe 2009; see also Poorun an d Slater, Chapter 39, this volume). Th ere has been long-standing concern that procedures conducted as part of life-saving care of preterm neonates may adversely aff ect brain development. Th irty years ago, Perlman an d Volpe (1983) reported that endotracheal suctioning aff ected neonatal cerebral blood fl o w. In recent years there have been a number of impor- tant studies of cortical activity dur ing procedural intervention in the NICU, utilizing near infrared spectroscopy to examine ce rebral blood fl ow and electroencephalography (EEG) to measure electrical CHAPTER 4 long-term effects of pain in children 33 A B Figure 4.1 Structural maturation of the developing brain in one preterm infant from 28 week s (A) to term equivalent age (B) MRI images courtesy of Dr Steven Miller. activity, demonstrating that blood collection evokes responses in the cortex (Bartocci et a l., 2006; Fabrizi et al., 2011; Slater et al., 2006, 2010; Tombini et al., 2009; Vanhatalo et al., 2009). Fabrizi et al. (2011) reported increased incidence of widely dispersed non- specifi c neuronal bursts of EEG activity in response to touch and pain in preterm infants, rather than the typical focused-evoked somatosensory potentials, maximal at the central el ectrodes that were evident in full-term neonates. Th is study is very important for underst anding the vulnerability of preterm neonates, as it under- scores the sensitivity of the pr eterm neonate to both mechanical and nociceptive stimulation. Th is phenomenon of responses wide- spread across the brain contributes to understanding why diaper change can evoke as much behavioral and autonomic reactivity as blood collection in preterm neonates while in t he NICU (Holsti et al., 2005). It is challenging to record specifi c brain activity in resp onse to painful procedures in young infants, since even aft er excluding overt movement art ifacts, tensing of muscles in the face and limbs may aff ect the signal, given the proximit y of the motor and somatosensory regions of the cortex (Maimon et al., 2013). carried out shortly aft er birth and again at term equivalent age in neonates born at 24 to 32 weeks of gestation. Aft er adjusting for multiple clinical confounding factors, such as gestational age at birth, infections, brain injury, and surgery, higher exposure to pro- c edural pain was associated with reduced development of white matter (indexed by fractional anisotropy (FA)) and subcortical gray matter (measured by N-acetylaspartate to choline rati o (NAA/ choline) \200\224a marker of cerebral metabolism and density). Reduced FA was predi cted by early pain prior to the fi rst brain scan, whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early eff ect on subcor- tical structures with secondary white matter changes. Th is study appears to be the fi rst in human infants to show that neonatal pain is associated with adverse brain develo pment. Until now, relation- ships between pain and brain development in preterm infants wer e speculative. In the fi rst study to examine whether neonatal pain is associ- ated with brain activity la ter in childhood, in a diff erent longi- tudinal cohort of preterm infants followed from bi rth to school age, Grunau and colleagues found an association between greater cumulative ne onatal pain and spontaneous oscillatory brain activ- ity under resting conditions using mag netoencephalography at age 7 years (Doesburg et al., 2013). In turn, the cortical activity was associated with cognitive function. Importantly, in this study the link between neonata l pain and brain function was evident in infants born extremely preterm at 24 to 28 weeks, but not in more mature preterm infant born 29 to 32 weeks. It is well established that ther e are progressive changes in the maturation of oscillatory brain activity throughout the pr eterm period, as shown in the spec- tral composition of EEG recordings (Okumura et al., 200 3). Th e fi nding that neonatal pain was associated with brain activity in infants born at 24 to 28 weeks, but not later, may refl ect the distinct phases of development occurring wi thin thalamocortical systems within the 24- to 28- and 29- to 32-week gestational periods, and the implications for how pain is processed within the developing CNS (Kostovic and Juda s, 2010). In the only fMRI study of the brain during pain stimulation, at age 9 to 14 years children born preterm showed greater activa- tion in the somatosensory cortex and several other brai n regions compared to children born full-term with or without early hospi- talization (Hohm eister et al., 2010; see also Hermann, Chapter 40, this volume). More research is needed to explicate relationships between brain, behavior, and autonomic reactivity in the preterm n eonate under various conditions across post-conceptional age in the NICU. Neonatal pain and brain development Utilizing state-of-the-art brain imaging techniques to study micro- structure development from early in life to term equivalent age, Grunau and co lleagues found an association between greater exposure to pain-related stress in preterm in fants in the NICU and poorer neonatal brain development (Brummelte et al., 2012). In a long itudinal design, serial MRI and diff usion tensor imaging was SECTION 1 introduction 34 Sleep Sleep \200\223waking states develop during the third trimester of fetal life, and thu s are emerging during the period that preterm infants are exposed to repeated procedural pa in in the NICU. Th ere is long- standing interest in eff ects of sleep disruption on the de veloping CNS (e.g. Anders and Roff warg, 1973; Scher et al., 2005). Sleep plays an essentia l role in brain development (Blumberg and Seelke, 2010). Shift s in sleep state occur in re sponse to pain in the NICU, thus have become a key part of pain assessment (e.g. Holsti et al., 2008; Stevens et al., 2010), however little is known about eff ects of pain and pain m anagement on sleep in preterm neonates. Importantly, opioids for pain management aff ect sl eep structure, for example, decreasing rapid eye movement sleep (Axelin et al., 2010). Fabr izi et al. (2011) reported that the occurrence of noxious- specifi c EEG potentials was not state dependent, since the propor- tion of awake infants was the same for those who did an d did not exhibit the noxious-specifi c EEG response. However, very preterm infants typical ly spend little time awake in the NICU. Further EEG and behavioral studies of eff ects of p ain on sleep are needed, to elucidate the role of pain in preterm infants on brain developm ent via disruption of sleep. Furthermore, the fi ndings described are consistent with reports that adverse early stress beyond pain exposure, such as maternal separation, is implicated in altered brain structure and function (Als et al., 2004; Milgrom et al., 2010; Smith et al., 2011). In one study (A ls et al., 2004), preterm neonates were randomized to receive the Neonatal Individualized D evelopmental Care and Assessment Program (NIDCAP; Als, 1982) or standard care during their NICU stay. Th e NIDCAP program involves recognition of infant stress cues and provision of supportive care. At 2 weeks CA, the infants that received the intervention program displaye d signifi cantly better motor system functions and self-regulatory behaviors, as well as in creased coherence between frontal and a broad spectrum of primarily occipital brain regions on electrophysiological testing (Als et al., 2004). Furthermore improved behavioral functi on was still apparent at 9 months CA. In another randomized controlled trial, eff ectivenes s of training parents to reduce stressful experiences for their very preterm infants in the NICU was evaluated (Milgrom et al., 2010). At term equivalent, the stress sensitivity trai ning was associated with fewer atypicalities in cerebral white matter micro- structure and connectivity on advanced MRI, compared to infants that received standard care. Taken together, these studies on brain reactivity to procedures, as well as associations be tween pain and brain development, begin to address the role that pain might play in contrib uting to altered spontaneous cortical oscillatory activity (within function- ally distinct frequency ranges, theta (46 \200\2237 Hz), alpha (8 \200\22314 Hz), beta (15 \200\22329 Hz) , and gamma (30 \200\22360 Hz) neuromagnetic activity (Doesburg et al., 2011a)) and atypica l long-range neuromagnetic synchronization during visual short-term and working memory main tenance associated with alteration and reorganization of func- tional connectivity in child ren born very preterm (Doesburg et al., 2011b), as well as a host of atypicalities in struc tural and functional brain development revealed by MRI in children born very preterm (see M ent et al., 2009 for review). Th ere is now converging evidence that the developing brain i s exquisitely sensitive to ongoing pro- cedural perturbations during a \200\230critical wi ndow \200\231 in early life, sug- gesting that the long-term eff ects of pain are potential ly greatest in extremely preterm infants during hospitalization in the NICU. Sex and gender Sex refers to biological and physiological characteristics, whereas gender i s defi ned as the socially constructed roles, behaviors, activities, and attributes that a given society considers appropriate for men and women (World Health Organization, 2012). Se x diff er- ences in long-term eff ects of early pain and stress are widely reported in the animal literature (Laprairie and Murphy, 2007), and gender diff erences in adult pain exper ience are well-established (Unruh, 1996). However, in human clinical studies of long-term e ff ects of early pain, sex and gender diff erences have rarely been examined. In a longitud inal cohort no diff erences were found between boys and girls in cortisol levels during inf ancy and toddlerhood (Grunau et al., 2004b, 2007). Contradictory fi ndings have been report ed, for example, in one study girls displayed greater pain sensitivity than boys among both preterm and full-term adolescents (Buskila et al., 2003). In a cohort of micropremies (S. M. Walker et al., 2009) term control boys were more sensitive than girls to cold and heat s timu- lation, but no gender diff erences were found in the preterm group. More research wit h larger sample sizes is needed to explicate the role of gender, and possible interactions with environmental caregiver factors. Programming of stress systems Altered programming of stress systems, including the HPA axis , due to both fetal and neonatal stress is well established in the animal literature (e.g. Matthews, 2002), and in humans in studies of post- traumatic stress disorder (G. E. Miller et al., 2007) or early adver- sity such as institutional care in orphanages (Loman and Gunn ar, 2010). Unexpectedly, in animal studies of long-term eff ects of early pain, no changes were found in HPA responses later in adult rats (Anand et al., 1999; C. D. Walker et al., 2 003). Importantly, C. D. Walker et al. (2003) showed that following pain, maternal licking and grooming increased, thus preventing changes to the stress hor- mone system. In preterm infants, exposure to repeated neonatal pain in the NICU is typically combined with the stre ss of maternal separation. Th e developmental trajectory of the expression of corti- sol (t he endpoint of HPA axis activity) appears to be altered across the fi rst 2 years of life i n infants born at extremely low gestational age (24 \200\22328 weeks), with downregulation extending from the NICU period (Grunau et al., 2005) switching to upregulation at 8 and 18 months CA (Grunau et al., 2004b, 2007), associated with greater exposure to procedural pain . Caregiver behavior and long-term e \200 ects of neonatal pain Setting the foundation for o ptimal infant support to minimize pain- related stress begins in the NICU. Nursing interven tions during pro- cedures, and teaching parents how to read their infant \200\231s cues and how to provide environmental support such as skin-to-skin contact, swaddling, and facilita ted tucking is likely to be fundamental in help- ing the infant to gradually self-regulate stress (Feldman et al., 2002; Maroney, 2003; Symington and Pinelli, 2006). Importantly, par ent involvement to reduce infant stress in the NICU led to improved behavior and EEG cohere nce (Milgrom et al., 2010). Social modeling, family factors, child temperament, culture, and gender aff ect pain expres sion and thereby pain threshold later in CHAPTER 4 long-term effects of pain in children 35 childhood and beyond. Th is body of work has been conducted pri- marily on full-terms (e.g. Braarud and Stormak 2006; Moon et al., 2008; Piira et al., 2007; Pillai Riddell and Chambe rs, 2007). Parent soothing is associated with greater reactivity, not less, whereas ver- ba lizations that promoted coping reduce pain responses in infants undergoing immunization. Li ttle research aft er NICU discharge has addressed whether parent behaviors across infancy a nd childhood may ameliorate or exacerbate eff ects of early pain on later pain sen- sitivit y or on neurodevelopment in children born preterm exposed to prolonged pain early in life. Greater parenting stress appears to compound the association between higher neonatal pain e xpo- sure and poorer cognitive development at 18 months in children born very preterm (Grun au et al., 2009). However, since poorer neurodevelopment in preterm children is in turn ass ociated with persisting parenting stress (Brummelte et al., 2011), it is diffi cult to dise ntangle these eff ects. Among infants with extensive history of exposure to neonatal pain i n the NICU due to extremely preterm birth, child and family factors predicted somatization at age 4 years (Grunau et al., 1994b). In another study, at age 9 to 14 years, mater- nal f actors in relation to responses to quantitative sensory testing of pain thresholds were com pared in three groups of children: those born preterm who had been in the NICU, full terms who had been in the NICU, and full-term healthy controls (Hohmeister et al., 2009). Th resh old testing was conducted with and without the infant \200\231s mother present. Only former preterms displayed more catastrophizing and elicited greater maternal solicitous responses to pain. Importantly, mother presence led to higher pain thresholds (reduced sensitivity) in all groups. systems likely occur irrespective of conscious awareness. Th us, con- sideration of the dis tinction between nociception and pain may be helpful in elucidating long-term impacts on di ff erent systems. It has been proposed that conscious perception of pain is required for pain to impact the i ndividual (e.g. Lee et al., 2005). Th is has led to a focus on the topic of when consciousn ess emerges in during fetal life, which has implications for intrauterine interventions as well as treatment of infants born very preterm. However, biological processes initiated by nociception stimuli can impact the organ- ism regardless of conscious awareness. Even extre mely preterm neonates born at 24 weeks of gestation display sensitization to skin-breaking stimulation, which is a basic physiological phenom- enon of the immature organism \200\231s hypersensitivity to tactile inputs, together with limited capacity to regulate excitatory and inhibitory systems (Andrews and Fitzgerald, 1994; Fitzgerald, 2005). Th us, nociceptive reactivity can be altered due to changes at the spinal cord level. Similarly, altered stre ss hormone levels associated with repetitive exposure to neonatal procedures do not have to involve higher order consciousness to induce short- and long-term eff ects. Th ese altered systems are signs of implicit biological memory, and the processes engaged can alter the C NS and stress physiol- ogy without any conscious perception of pain. Pain, on the other han d, is defi ned as a complex response engaging both emotional and nociceptive responses. Th is distinction between nociception and pain is important in considering long-term eff ects of proce- dural events in neonates and young infants. Th is distinction does not rule out t he possibility that higher-order cortical regions of the brain may be engaged in relation t o procedures early in infancy, but rather removes the idea that conscious perception of pai n is a requirement for a long-term impact to take place. Specifi cally, nociceptive respons e can initiate a physiological cascade of events that directly or indirectly impacts the br ain and stress development of very preterm neonates, regardless of whether they perceive pa in consciously . Major gaps in knowledge include whether parent involvement in NICU care can prevent eff ect s of neonatal pain on brain devel- opment, and whether in the long term, parent stress, anx iety, and other factors across childhood may exacerbate eff ects of pain expo- sure early i n life in vulnerable infants. Th e extent to which sensi- tive parenting may ameliorate eff ects of neonatal pain, and whether gender has diff erential eff ects, is also unknown. Conclusion Long-term eff ects of early pain on later pain and tactile sensitiv- ity are com plex, and depend on multiple factors such as age at pain stimulation, extent of tissue dama ge, type of noxious insult, intensity, duration, and age. Recent studies show that neonatal pain evokes changes in brain activity, providing important clini- cal evidence that the be havioral, autonomic, and hormonal responses to procedures in infants go beyond defensive re fl exes. Advanced imaging techniques have revealed that neonatal pain in preterm infants is associated with altered brain development during the neonatal period in very preterm infan ts, for the fi rst time providing clinical evidence of mechanisms that may under- lie the e merging association between cumulative procedural pain exposure and neurodevelopment and be havior in children born very preterm. Conscious awareness and adverse e \200 ects of pain Accepted defi nitions of pain as a phe nomenon involving a com- plex interplay of sensation and cognition are adult focused, and m ay not capture fundamental characteristics of the developing organism. Based on this adult orientation, attempts to under- stand when the fetus and neonate might become consciously a ware have been used to determine when pain might be perceived. Conditioned learning is evid ent early in life even during sleep (Fifer et al., 2010) \200\224 implying memory presumabl y without con- scious recall. Moreover, behavioral evidence of conditioning, as well as evo ked EEG and physiological responses aft er pain under- lie \200\230biological memory \200 \231. Th us, although infants cannot recall early experiences, the CNS appear to retain \200\230memory \200\231 that is manifested later in altered responses to pain in new situat ions (Grunau, 2003; Taddio et al., 1997). Probably the most unexpected fi nding in recent years has been convergent evidence from sev eral countries showing that, despite the impact of early pain on somatosensory processing a nd pain sen- sitivity, self-reported everyday pain problems do not appear to be more pronou nced in late adolescence or early adulthood following exposure to extensive pain in the neo natal period. However, long- term studies are needed to evaluate whether under life stresse s over time, diff erentially by gender, pain syndromes may develop later. Recent evidence suggests that the long-term impact of pain on later brain function diff ers depending on the biological maturity of the infant and the stage of underlying brain devel opment at the time of hospitalization (Doesburg et al., 2013). In the case of extremely pre mature birth (see case example), eff ects of repetitive procedural pain-related stress on t he vulnerable developing brain and stress SECTION 1 introduction 36 Anand, K. J. S, Coskun, V., Th rivikraman, K. V., Nemeroff , C. B., and Plotsky, P. M. (199 9). Long-term behavioral eff ects of repetitive pain in neonatal rat pups. Physiol Behav , 66 , 627 \200\223637 . Case example: long-term impact of pain in preterm twin girls As part of a longitudinal program of research in long-term eff ects of neonatal pain in pre term infants born at 24 to 32 weeks of gestation, non-identical twin girls (here referred t o as Iris and Betty \200\224not their real names) participated in studies in the NICU, and at ages 3 months, 8 months, 18 months, and 7 years. Th e twins were born at 29 weeks of ges tation with birthweight appropriate for their gestational age, and similar size at birth, b ut had diff er- ent neonatal experiences that illustrate divergent trajectories of early pa in and outcomes. Betty had 75 skin-breaking procedures from birth to term equivalent while Iris had 111; neither girl underwent surgery. Th e most striking discrepancy in outcome bet ween the sisters was that at age 7 years, when Betty \200\231s cogni- tive functioning was above average with verbal comprehension and perceptual reasoning at the 95th and 97th perce ntiles respec- tively, whereas Iris had scores signifi cantly lower than her sister, with v erbal comprehension at the 45th percentile and a defi cit in perceptual reasoning at the 4t h percentile. In addition, Iris was below age expectation in planning and problem solving a spects of executive functioning. Despite these low scores, in second grade Iris copes with early reading and arithmetic, displaying compen- sation for her diffi culties with aspects of cognitive abstraction. Th is capacity to compensate is consistent with the fi nding that very preterm children engage diff erent brain networks refl ect- ing brain plasticity over time (Doesburg et al., 2012), despite the association between neonatal pain and early brai n development while in the NICU from birth to term (Brummelte et al., 2012). Th ere are num erous confounding factors that obscure potential eff ects of neonatal pain per se in hospit alized infants, therefore it is important that neither of the children had any infections i n the neonatal period, received no postnatal steroids, and that Betty underwent no mechanic al ventilation and Iris only needed it for 4 days. Given that the twins grew up in the same family and broader social environment, the diff erence in skin-breaking neo- natal events appears to be a salient factor that may have contrib- uted to their diff erences in cogniti ve outcomes; however, clinical research alone can only establish associations, not causalit y. 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