Repetitive neonatal pain and neurocognitive abilities in ex-preterm children

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PAIN 154 (2013) 1899–1901

www.elsevier.com/locate/pain

Commentary

Repetitive neonatal pain and neurocognitive abilities in ex-preterm children

Burgeoning research has focused on the neurocognitive outcomes of prematurity among school-aged children [5,6,8,38] and young adults [10,45], because of its impact on adult cognition, physical and mental health, and employment status. Most studies reported that those born before 28 weeks’ gestation were particularly vulnerable to poor neurocognitive and behavioral outcomes [14]. One prospective longitudinal study, for example, found that independent risk factors for school age impairments were gestational age 24–28 weeks, chronic lung disease, and abnormal electroencephalogram (EEG) before hospital discharge [8]. Various risk factors were postulated to explain the poor neurocognitive outcomes of preterm children compared with their term-born peers, including perinatal infections or inflammation, birth asphyxia, recurrent apnea/bradycardia, prolonged ventilation, hypothyroidism, hyperbilirubinemia, nutritional deficiencies, or the drugs used to treat preterm neonates, including glucocorticoids, theophylline, morphine, and others [11,34,37]. Among all NICU experiences, acute pain is arguably the most physiologically disruptive and developmentally unexpected of all stimuli, though some clinicians do not consider it a risk factor for neurocognitive outcomes [37]. In this issue of Pain, however, Doesburg et al. [15] provide evidence linking repetitive neonatal pain with changes in the ratio of gamma to alpha oscillatory activity (which they interpret as a deviation of the developmental trajectory of thalamocortical activity) and with cognitive outcomes in school-age children. These are potentially ground-breaking observations because they identify abnormal patterns of cortex-wide activity, critical windows for pain exposure and development of visual-perceptual abilities, but they also establish recurrent neonatal pain as a risk factor for impaired neurocognitive outcomes. The carefully designed study procedures, exclusion of children with sensory, motor, or cognitive impairments, psychoactive medications, or cranial ultrasound abnormalities, inclusion of pretermand term-born controls, and their well-designed multivariable analyses underscore the importance of these results. For the reasons listed below, their conclusions linking neonatal pain with visual-perceptual abilities and the development of thalamocortical connections in 7–8-year old extremely low gestational age (ELGA) children suggest a number of additional research questions to clarify these relationships. First, the authors show that cumulative neonatal pain, while controlling for various confounders, was associated with cortexwide oscillatory activity in ELGAs, as measured by gamma/alpha ratios on magnetoencephalography (MEG). They also found that gamma/alpha ratios in ELGAs were negatively correlated with q

visual-perceptual ability (simple Pearson correlation with WISCIV perceptual reasoning (P = 0.03), but not Beery’s perceptual subscale [P = 0.13]). However, direct relationships between cumulative neonatal skin-breaking procedures and visual-perceptual scores were not reported. It is logical to infer that neonatal pain exposures may lead to impaired visual-perceptual abilities in ELGA children, but further research will be needed to explore direct relationships between these outcomes. Second, the choice of the ratio of global gamma/alpha oscillatory activity among an extensive number of alternative measures though heuristically valuable should be interpreted in the light of the following considerations: although such ratios have been used (see, eg, their reference [22]) they are only interpretable as indices of regional but not global cortical activity contingent on regional cortical engagement in tasks [48,41]. MEG scans showing increased gamma/alpha ratios in the ELGA children were performed at rest rather than during cognitive tasks. Gamma oscillations typically represent recruitment of cortical areas during the active performance of cognitive tasks, with different patterns representing specific tasks, task complexity, and performance monitoring [35,49]. Since Doesburg et al. recorded spontaneous gamma activity occurring at rest, would it reflect the recruitment of cortical areas for active cognition? Despite well-known decreases in processing speed among ELGA children [1,33,40], could this explain why their gamma/alpha ratios were not correlated with the WISC-IV Processing Speed Index? A proposed link between global variation in gamma/alpha power ratios and thalamocortical connectivity is intriguing. However, given that the gamma/alpha ratios may be interpreted with but also without reference to thalamocortical connectivity, the suggested link should, at present, be viewed as a hypothesis inviting further exploration. Third, MEG recordings were filtered to measure gamma activity at 30–60 Hz [15], whereas others have measured gamma spectra at 30–150 Hz [19,20,23,49], thus identifying the functional significance of high vs. low gamma-band activity [20,49]. Given their unique patient population, however, these data provide important new insights into brain processing in ex-preterm children. They also pave the way for future studies to examine functional brain activity during specific cognitive tasks in preterm- and term-born children. Fourth, the anatomical localization of these changes needs to be explored. Global measures of cortical function may be fraught with the dangers of oversimplication or averaging across diverse functional areas. In preterm children without hemorrhagic or white matter damage, cognitive outcomes were associated with global

DOI of original article: http://dx.doi.org/10.1016/j.pain.2013.04.009

0304-3959/$36.00 Ó 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.pain.2013.06.027

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Commentary / PAIN 154 (2013) 1899–1901

cortical volume [21,39], or with the volumes of middle temporal/ postcentral gyri [43], cerebellum [3,27], caudate nucleus [2], or hippocampus [38,46]. Altered cortical oscillations in this study could plausibly also result from injury to subplate neurons. These are the first cortical neurons; they have the greatest vulnerability to perinatal injury and they play major roles in developing and refining thalamocortical connections via activity-dependent mechanisms [30,31]. Subplate neurons include glutamatergic projection neurons and GABAergic local interneurons, strategically located at the cortical/white matter interface to regulate the differential ‘‘gating’’ of all cortical inputs [25]. Thus, decreased numbers of surviving subplate neurons from perinatal injuries lead to poor cognition and impaired frontal lobe executive functions [25,26]. The peak period of subplate development does coincide with the pain exposures for ELGA children in this study, possibly leading to excitotoxic cell death of these neurons [4]. The spatial and temporal resolution of MEG studies during specific tasks will allow better definition of cortical areas and functions affected in ELGA children. Finally, the specific physiological mechanisms, including the possible thalamocortical ones underlying the changes discovered by Doesburg et al. should be investigated. One possibility is that higher numbers of subplate GABAergic neurons in cortical layer I may lead to increased inhibition of prefrontal cortical neurons. Even if they represent a minor fraction of total cortical neurons, their strategic location alters the ‘‘gating’’ of other cortical and subcortical inputs, creating a functional disconnectivity between the prefrontal brain and other areas [26]. Another possibility is the sparseness of intracortical, callosal, or thalamocortical connections in the brains of ELGA children. Among ex-preterm children born at 24–35 weeks’ gestation, increasing prematurity was associated with widespread reductions in connection strength in tracts involving all cortical lobes and subcortical structures [36]. Tracts like the superior longitudinal fasciculus may subserve different cognitive functions [17]; future MEG studies can evaluate the functional implications of these findings. Despite behavioral monitoring by research assistants, a third possibility is that preterm children had altered pre-attentional or attentional processes. Previous studies reported variable levels of arousal (hyperarousal, normal, hypoarousal) and poor performance in a psychomotor vigilance task (PVT) in ex-preterm children [18]. MEG studies during PVT will not only elucidate the underlying mechanisms for these findings, but could also examine the effects of therapeutic interventions. We urge a life course perspective to examine the consequences of neonatal pain [28]. Its central tenets are (a) time-specific effects of stimuli during ‘‘sensitive periods’’; (b) ‘‘cumulative effects’’ of these stimuli or insults; and (c) ‘‘developmental trajectories’’ influenced by these time-specific and cumulative influences over time. However, before we attribute the changes in visual-perceptual abilities and functional brain activity to neonatal pain-related stress, other factors with known impact on neurocognitive development should be excluded. Confounders with well-known effects on neurocognitive development include exposures to prenatal or postnatal infection/inflammation [24,44,47], early socioeconomic adversity [9,7], or the quality of maternal–infant interactions [32,50]. Their contributions to thalamocortical oscillations or visual-perceptual abilities in ELGA children must be included in the multivariable models examining the consequences of cumulative neonatal pain. Neonatal morphine exposures did not reduce the impact of recurrent neonatal pain on functional brain activity or visual-perceptual abilities, but did not increase it either [15]. Similarly, expreterm children who received morphine vs. placebo during their NICU course, showed no differences in their cognitive, neuromotor, or behavioral outcomes at 5–6 years age [29]. Other children exposed to neonatal morphine (vs. placebo) were rated lower on

overall intelligence quotient (IQ) at age 5 years, but this difference disappeared after correction for clinically relevant variables [12]. Another pilot study in 5–7-year-old ex-preterm children found less socialization and adaptive behaviors in the morphine-exposed group, with longer choice response latencies and 27% less task completion during a short-term memory task [16]. Conversely, morphine-exposed ex-preterm children at 8–9 years showed less externalizing problems and improved executive functions as compared to a placebo-control group [13]. These conflicting outcomes may result from subtle differences in cognitive processing between morphine-exposed or unexposed preterm children, depending on the dose, duration, and developmental period(s) exposed to morphine vs. repetitive pain. Although recent studies of ELGA children show improved neurodevelopmental outcomes, with diminishing burdens of moderate or severe disability [42], milder or subtle forms of cognitive impairment may affect large numbers of ex-preterm children. Doesburg et al. have laudably taken the first step towards identifying the functional basis for these cognitive deficits and the neonatal factors that may lead to these outcomes. To the extent that is clinically feasible, such factors need to be reduced or eliminated to realize the full benefit of billions of dollars spent on neonatal intensive care for ELGA neonates each year. Acknowledgements The authors would like to thank Dr. R. Whit Hall at University of Arkansas for Medical Sciences for reviewing this manuscript. The authors have no conflicts of interest to disclose. References [1] Aarnoudse-Moens CS, Duivenvoorden HJ, Weisglas-Kuperus N, Van Goudoever JB, Oosterlaan J. The profile of executive function in very preterm children at 4 to 12 years. Dev Med Child Neurol 2012;54:247–53. [2] Abernethy LJ, Cooke RW, Foulder-Hughes L. Caudate and hippocampal volumes, intelligence, and motor impairment in 7-year-old children who were born preterm. Pediatr Res 2004;55:884–93. [3] Allin M, Matsumoto H, Santhouse AM, Nosarti C, AlAsady MH, Stewart AL, Rifkin L, Murray RM. Cognitive and motor function and the size of the cerebellum in adolescents born very pre-term. Brain 2001;124:60–6. [4] Anand KJ, Garg S, Rovnaghi CR, Narsinghani U, Bhutta AT, Hall RW. Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res 2007;62:283–90. [5] Bhutta AT, Anand KJS. Abnormal cognition and behavior in preterm neonates linked to smaller brain volumes. Trends Neurosci 2001;24:129–30. [6] Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes of school-aged children who were born preterm: a metaanalysis. JAMA 2002;288:728–37. [7] Brent DA, Silverstein M. Shedding light on the long shadow of childhood adversity. JAMA 2013;309:1777–8. [8] Brevaut-Malaty V, Busuttil M, Einaudi MA, Monnier AS, D’Ercole C, Gire C. Longitudinal follow-up of a cohort of 350 singleton infants born at less than 32 weeks of amenorrhea: neurocognitive screening, academic outcome, and perinatal factors. Eur J Obstet Gynecol Reprod Biol 2010;150:13–8. [9] D’Angiulli A, Van Roon PM, Weinberg J, Oberlander TF, Grunau RE, Hertzman C, Maggi S. Frontal EEG/ERP correlates of attentional processes, cortisol and motivational states in adolescents from lower and higher socioeconomic status. Front Hum Neurosci 2012;6:306. [10] Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A, Harding JE. Psychological functioning and health-related quality of life in adulthood after preterm birth. Dev Med Child Neurol 2007;49:597–602. [11] Dammann O, Kuban KC, Leviton A. Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm. Ment Retard Dev Disabil Res Rev 2002;8:46–50. [12] de Graaf J, van Lingen RA, Simons SHP, Anand KJS, Duivenvoorden HJ, Weisglas-Kuperus N, Roofthooft DWE, Groot Jebbink LJM, Veenstra RR, Tibboel D, van Dijk M. Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: five-year follow-up of a randomized controlled trial. PAINÒ 2011;152:1391–7. [13] de Graaf J, van Lingen RA, Valkenburg AJ, Weisglas-Kuperus N. Groot Jebbink L, Wijnberg-Williams B, Anand KJS, Tibboel D, van Dijk M. Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? PAINÒ 2013;154:449–58. [14] Delobel-Ayoub M, Arnaud C, White-Koning M, Casper C, Pierrat V, Garel M, Burguet A, Roze JC, Matis J, Picaud JC, Kaminski M, Larroque B. Behavioral

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Kanwaljeet J.S. Anand St. Jude Endowed Chair for Critical Care Medicine, University of Tennessee Health Science Center, Memphis, TN, USA ⇑ Tel.: +1 901 287 6303; fax: +1 901 287 6336. E-mail address: [email protected] Frederick B. Palmer Boling Center for Developmental Disabilities, University of Tennessee Health Science Center, Memphis, TN, USA Andrew C. Papanicolaou Division of Clinical Neurosciences, University of Tennessee Health Science Center, Memphis, TN, USA