Utilization of a rodent model to examine the neurological effects of early life adversity on adolescent pain sensitivity.

All children experience pain, and although many recover quickly, some go on to develop chronic pain. Adolescent chronic pain is a growing epidemic. It is unknown why some adolescents recover without incident and others experience persistent pain. Although unexplored, early life adversity may contribute to the development and maintenance of chronic pain. This study investigated the effects and underlying neurobiological mechanisms of an early life stressor on nociceptive (pain) sensitivity and emotional function in male and female Sprague-Dawley rats. Using maternal separation (MS) as an established model of early life stress, we addressed two aims: investigation of the effects of MS on behavior (anxiety and pain sensitivity), and investigation of the effects of MS on mRNA and pathophysiological changes associated with an acutely painful stimulus. Our results indicate that MS increased anxiety-like behavior and altered nociceptive responsivity in adolescent rats, with decreased mechanical withdrawal thresholds indicative of heightened and prolonged pain-related behavior. The MS groups also demonstrated increased expression of genes involved in regulating the stress and fight-or-flight response, mood, and neuroplasticity; as well as increased levels of inflammatory markers. We conclude that nociception, both at the behavioral and molecular level, is altered in response to the MS stressor.

Socialization of Pain Memories: Parent-Child Reminiscing About Past Painful and Sad Events.

OBJECTIVE: Parent-child reminiscing about past negative events has been linked to a host of developmental outcomes. Previous research has identified two distinct between-parent reminiscing styles, wherein parents who are more elaborative (vs. repetitive) have children with more optimal outcomes. To date, however, research has not examined how parents and children talk about past painful experiences nor compared parent-child reminiscing about past painful versus other distressing events despite key developmental differences in how young children respond to pain versus sadness in others. This study aimed to fill that gap. METHODS: Seventy-eight children aged 4 to 7 years underwent a tonsillectomy. Two weeks postsurgery, children and one of their parents discussed past autobiographical events (i.e., the tonsillectomy, another painful event, a sad event). Parent-child conversations were coded using established coding schemes to capture parental reminiscing style, content, and autonomy support. RESULTS: Findings revealed robust differences in parent-child reminiscing about painful versus sad events. Parents were less elaborative, used less emotionally negative words and explanations, and were less supportive of their children's autonomy while reminiscing about past painful versus sad events. CONCLUSIONS: These findings demonstrate that through reminiscing, parents may socialize children about pain in a way that is different from other distressing events (e.g., sadness). Future research should examine the influence of differential reminiscing about pain versus sadness on developmental and health outcomes.

Role of anxiety in young children's pain memory development after surgery.

Pediatric pain is common, and memory for it may be distressing and have long-lasting effects. Children who develop more negatively biased memories for pain (ie, recalled pain is higher than initial pain report) are at risk of worse future pain outcomes. In adolescent samples, higher child and parent catastrophic thinking about pain was associated with negatively biased memories for postsurgical pain. This study examined the influence of child and parent anxiety on the development of younger children's postsurgical pain memories. Seventy-eight children undergoing a tonsillectomy and one of their parents participated. Parents reported on their anxiety (state and trait) before surgery, and trained researchers observationally coded children's anxiety at anaesthesia induction. Children reported on their postsurgical pain intensity and pain-related fear for 3 days after discharge. One month after surgery, children recalled their pain intensity and pain-related fear using the same scales previously administered. Results revealed that higher levels of postsurgical pain and higher parent trait anxiety predicted more negatively biased memories for pain-related fear. Parent state anxiety and child preoperative anxiety were not associated with children's recall. Children who developed negatively biased pain memories had worse postsurgical pain several days after surgery. These findings underscore the importance of reducing parental anxiety and effective postsurgical pain management to potentially buffer against the development of negatively biased pain memories in young children.

Memories of Infant Pain in the Neonatal Intensive Care Unit Influence Posttraumatic Stress Symptoms in Mothers of Infants Born Preterm.

OBJECTIVES: The birth of a preterm infant and witnessing ones' infant in pain is remembered by parents as being one of the most stressful aspects of the neonatal intensive care unit (NICU). Elevated posttraumatic stress symptoms (PTSS) are highly prevalent among mothers of preterm infants, however, little is known about mothers' memories of invasive procedures in the NICU and how these memories may contribute to the development of PTSS. We examined the relationships between number of invasive procedures, mothers' memories of these procedures, and their PTSS at discharge from the NICU. MATERIALS AND METHODS: Participants included 36 mothers of infants born below 37 weeks gestational age recruited from a tertiary-level NICU. Medical chart review was performed between birth and discharge from the NICU. At discharge, a research nurse conducted a structured memory interview with the mothers to assess their memories of their infants' invasive procedures. Mothers also completed a self-report measure of PTSS (Posttraumatic Stress Disorder Checklist for the DSM-5). RESULTS: Mothers of infants exposed to greater numbers of invasive procedures had more elevated PTSS at discharge (R=0.37). Moreover, mothers who recalled having greater anxiety about their infant's invasive procedures had greater symptoms of reexperiencing (R=0.34) and avoidance (R=0.28) at discharge from the NICU. DISCUSSION: Greater neonatal exposure to invasive procedures and mothers' recall of these procedures were related to mothers' posttraumatic stress symptomatology at discharge. Invasive procedures in the NICU represent an important target area for neonatal intervention to reduce maternal distress and improve outcomes.

Sleep Mediates the Association Between PTSD Symptoms and Chronic Pain in Youth.

Symptoms of post-traumatic stress disorder (PTSS) and chronic pain have been shown to co-occur at high rates in adolescents and this co-occurrence is linked to worse pain and quality of life. Sleep disturbance has been posited as a mechanism underlying this co-occurrence in conceptual models of mutual maintenance. This study examined the mediating role of sleep in the relationship between PTSS and pain in youth (aged 10-17 years) with chronic pain. Ninety-seven participants completed measures of PTSS, pain (intensity and interference), anxiety symptoms, and sleep quality, in addition to demographic characteristics. Mediation models were conducted. Findings revealed that, over and above the influence of associated demographic characteristics (age, race) and anxiety symptoms, sleep quality partially mediated the relationships between PTSS and pain intensity and interference for youth with chronic pain. Specifically, higher levels of PTSS was linked to higher levels of pain intensity and pain interference, and these relationships were partially explained by poor sleep quality. Findings highlight the potential mechanistic role of sleep in explaining the co-occurrence of chronic pain and PTSS and suggest sleep might be an important target in future interventions. PERSPECTIVE: Consistent with the pediatric model of mutual maintenance in PTSS and chronic pain, poor sleep quality was found to underlie this co-occurrence in youth.

Severe retinopathy of prematurity predicts delayed white matter maturation and poorer neurodevelopment.

OBJECTIVE: To determine whether severe retinopathy of prematurity (ROP) is associated with (1) abnormal white matter maturation and (2) neurodevelopmental outcomes at 18 months' corrected age (CA) compared with neonates without severe ROP. DESIGN: We conducted a prospective longitudinal cohort of extremely preterm neonates born 24-28 weeks' gestational age recruited between 2006 and 2013 with brain MRIs obtained both early in life and at term-equivalent age. Severe ROP was defined as ROP treated with retinal laser photocoagulation. Using diffusion tensor imaging and tract-based spatial statistics (TBSS), white matter maturation was assessed by mean fractional anisotropy (FA) in seven predefined regions of interest. Neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development-III (Bayley-III) composite scores at 18 months' CA. Subjects were compared using Fisher's exact, Kruskal-Wallis and generalised estimating equations. SETTING: Families were recruited from the neonatal intensive care unit at BC Women's Hospital. PATIENTS: Of 98 extremely preterm neonates (median: 26.0 weeks) assessed locally for ROP, 19 (19%) had severe ROP and 83 (85%) were assessed at 18 months' CA. RESULTS: Severe ROP was associated with lower FA in the posterior white matter, and with decreased measures of brain maturation in the optic radiations, posterior limb of the internal capsule (PLIC) and external capsule on TBSS. Bayley-III cognitive and motor scores were lower in infants with severe ROP. CONCLUSIONS: Severe ROP is associated with maturational delay in the optic radiations, PLIC, external capsule and posterior white matter, housing the primary visual and motor pathways, and is associated with poorer cognitive and motor outcomes at 18 months' CA.

Mental Health Comorbidities in Pediatric Chronic Pain: A Narrative Review of Epidemiology, Models, Neurobiological Mechanisms and Treatment.

Chronic pain during childhood and adolescence can lead to persistent pain problems and mental health disorders into adulthood. Posttraumatic stress disorders and depressive and anxiety disorders are mental health conditions that co-occur at high rates in both adolescent and adult samples, and are linked to heightened impairment and disability. Comorbid chronic pain and psychopathology has been explained by the presence of shared neurobiology and mutually maintaining cognitive-affective and behavioral factors that lead to the development and/or maintenance of both conditions. Particularly within the pediatric chronic pain population, these factors are embedded within the broader context of the parent-child relationship. In this review, we will explore the epidemiology of, and current working models explaining, these comorbidities. Particular emphasis will be made on shared neurobiological mechanisms, given that the majority of previous research to date has centered on cognitive, affective, and behavioral mechanisms. Parental contributions to co-occurring chronic pain and psychopathology in childhood and adolescence will be discussed. Moreover, we will review current treatment recommendations and future directions for both research and practice. We argue that the integration of biological and behavioral approaches will be critical to sufficiently address why these comorbidities exist and how they can best be targeted in treatment.

Invasive procedures in preterm children: brain and cognitive development at school age.

BACKGROUND: Very preterm infants (born 24-32 weeks' gestation) undergo numerous invasive procedures during neonatal care. Repeated skin-breaking procedures in rodents cause neuronal cell death, and in human preterm neonates higher numbers of invasive procedures from birth to term-equivalent age are associated with abnormal brain development, even after controlling for other clinical risk factors. It is unknown whether higher numbers of invasive procedures are associated with long-term alterations in brain microstructure and cognitive outcome at school age in children born very preterm. METHODS: Fifty children born very preterm underwent MRI and cognitive testing at median age 7.6 years (interquartile range, 7.5-7.7). T1- and T2-weighted images were assessed for the severity of brain injury. Magnetic resonance diffusion tensor sequences were used to measure fractional anisotropy (FA), an index of white matter (WM) maturation, from 7 anatomically defined WM regions. Child cognition was assessed using the Wechsler Intelligence Scale for Children-IV. Multivariate modeling was used to examine relationships between invasive procedures, brain microstructure, and cognition, adjusting for clinical confounders (eg, infection, ventilation, brain injury). RESULTS: Greater numbers of invasive procedures were associated with lower FA values of the WM at age 7 years (P = .01). The interaction between the number of procedures and FA was associated with IQ (P = .02), such that greater numbers of invasive procedures and lower FA of the superior WM were related to lower IQ. CONCLUSIONS: Invasive procedures during neonatal care contribute to long-term abnormalities in WM microstructure and lower IQ.

Impact of repeated procedural pain-related stress in infants born very preterm.

The majority of infants born very preterm (24-32 wk gestational age) now survive; however, long-term neurodevelopmental and behavioral problems remain a concern. As part of their neonatal care, very preterm infants undergo repeated painful procedures during a period of rapid brain development and programming of stress systems. Infants born this early have the nociceptive circuitry required to perceive pain, however, their sensory systems are functionally immature. An imbalance of excitatory vs. inhibitory processes leads to increased nociceptive signaling in the central nervous system. Specific cell populations in the central nervous system of preterm neonates are particularly vulnerable to excitoxicity, oxidative stress, and inflammation. Neonatal rat models have demonstrated that persistent or repeated pain increases apoptosis of neurons, and neonatal pain and stress lead to anxiety-like behaviors during adulthood. In humans, greater exposure to neonatal pain-related stress has been associated with altered brain microstructure and stress hormone levels, as well as with poorer cognitive, motor, and behavioral neurodevelopment in infants and children born very preterm. Therefore, it is important that pain-related stress in preterm neonates is accurately identified, appropriately managed, and that pain management strategies are evaluated for protective or adverse effects in the long term.

Parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months corrected age in children born very prematurely.

Children born very preterm (≤ 32 weeks gestation) exhibit greater internalizing (anxious/depressed) behaviors compared to term-born peers as early as 2 years corrected age (CA); however, the role of early stress in the etiology of internalizing problems in preterm children remains unknown. Therefore, we examined the relationship between neonatal pain and internalizing behavior at 18 months CA in children born very preterm and examined whether parent behavior and stress moderated this relationship. Participants were 145 children (96 very preterm, 49 full term) assessed at 18 months CA. Neonatal data were obtained from medical and nursing chart review. Neonatal pain was defined as the number of skin-breaking procedures. Cognitive ability was measured with the Bayley Scales of Infant Development II. Parents completed the Parenting Stress Index III, Child Behavior Checklist 1.5-5, and participated in a videotaped play session with their child, which was coded using the Emotional Availability Scale IV. Very preterm children displayed greater Internalizing behaviors compared to full-term control children (P=.02). Parent Sensitivity and Nonhostility moderated the relationship between neonatal pain and Internalizing behavior (all P<.05); higher parent education (P<.03), lower Parenting Stress (P=.001), and fewer children in the home (P<.01) were associated with lower Internalizing behavior in very preterm children, after adjusting for neonatal medical confounders, gender, and child cognitive ability (all P>.05). Parent Emotional Availability and stress were not associated with Internalizing behaviors in full-term control children. Positive parent interaction and lower stress appears to ameliorate negative effects of neonatal pain on stress-sensitive behaviors in this vulnerable population.

Slower postnatal growth is associated with delayed cerebral cortical maturation in preterm newborns.

Slower postnatal growth is an important predictor of adverse neurodevelopmental outcomes in infants born preterm. However, the relationship between postnatal growth and cortical development remains largely unknown. Therefore, we examined the association between neonatal growth and diffusion tensor imaging measures of microstructural cortical development in infants born very preterm. Participants were 95 neonates born between 24 and 32 weeks gestational age studied twice with diffusion tensor imaging: scan 1 at a median of 32.1 weeks (interquartile range, 30.4 to 33.6) and scan 2 at a median of 40.3 weeks (interquartile range, 38.7 to 42.7). Fractional anisotropy and eigenvalues were recorded from 15 anatomically defined cortical regions. Weight, head circumference, and length were recorded at birth and at the time of each scan. Growth between scans was examined in relation to diffusion tensor imaging measures at scans 1 and 2, accounting for gestational age, birth weight, sex, postmenstrual age, known brain injury (white matter injury, intraventricular hemorrhage, and cerebellar hemorrhage), and neonatal illness (patent ductus arteriosus, days intubated, infection, and necrotizing enterocolitis). Impaired weight, length, and head growth were associated with delayed microstructural development of the cortical gray matter (fractional anisotropy: P < 0.001), but not white matter (fractional anisotropy: P = 0.529), after accounting for prenatal growth, neonatal illness, and brain injury. Avoiding growth impairment during neonatal care may allow cortical development to proceed optimally and, ultimately, may provide an opportunity to reduce neurological disabilities related to preterm birth.

Neonatal pain in relation to postnatal growth in infants born very preterm.

Procedural pain is associated with poorer neurodevelopment in infants born very preterm (≤ 32 weeks gestational age), however, the etiology is unclear. Animal studies have demonstrated that early environmental stress leads to slower postnatal growth; however, it is unknown whether neonatal pain-related stress affects postnatal growth in infants born very preterm. The aim of this study was to examine whether greater neonatal pain (number of skin-breaking procedures adjusted for medical confounders) is related to decreased postnatal growth (weight and head circumference [HC] percentiles) early in life and at term-equivalent age in infants born very preterm. Participants were n=78 preterm infants born ≤ 32 weeks gestational age, followed prospectively since birth. Infants were weighed and HC measured at birth, early in life (median: 32 weeks [interquartile range 30.7-33.6]) and at term-equivalent age (40 weeks [interquartile range 38.6-42.6]). Weight and HC percentiles were computed from sex-specific British Columbia population-based data. Greater neonatal pain predicted lower body weight (Wald χ(2)=7.36, P=0.01) and HC (Wald χ(2)=4.36, P=0.04) percentiles at 32 weeks postconceptional age, after adjusting for birth weight percentile and postnatal risk factors of illness severity, duration of mechanical ventilation, infection, and morphine and corticosteroid exposure. However, later neonatal infection predicted lower weight percentile at term (Wald χ(2)=5.09, P=0.02). Infants born very preterm undergo repetitive procedural pain during a period of physiological immaturity that appears to impact postnatal growth, and may activate a downstream cascade of stress signaling that affects later growth in the neonatal intensive care unit.

Procedural pain and brain development in premature newborns.

OBJECTIVE: Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants. METHODS: Infants born very preterm (N=86; 24-32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery. RESULTS: After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (ß=-0.0002, p=0.028) and reduced subcortical gray matter NAA/choline (ß=-0.0006, p=0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes. INTERPRETATION: Early procedural pain in very preterm infants may contribute to impaired brain development.

The influence of culture on maternal soothing behaviours and infant pain expression in the immunization context.

OBJECTIVE: To investigate how maternal culture (ie, individualist versus collectivist) influences soothing techniques and infant distress. METHODS: Archival data were analyzed using a subsample of 80 motherinfant dyads selected from a larger database of infant pain expression. RESULTS: Mothers belonging to the individualist group used more affection behaviours when attempting to regulate their infants' distress. No differences were observed in mothers' touching, holding, rocking, vocalizing, caregiving or distracting their infants. Mothers' culture did not appear to be related to the level of distress expressed by their infants. CONCLUSIONS: These results suggest that the similarities in soothing and infant pain expression between individualist and collectivist cultures are more prominent than their differences.