Ruth V Grunau

Professor

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Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Impact of repeated invasive procedures during neonatal intensive care on brain microstructure, growth, neurodevelopment and behavior in children born very preterm (2015)

As part of their lifesaving care in the neonatal intensive care unit (NICU), infants born very preterm (between 24 and 32 weeks gestation), undergo frequent invasive procedures that induce pain and stress, during a period of rapid brain development. We examined whether repeated exposure to invasive procedures was associated with altered brain development, and thereby poorer neurodevelopmental and behavioral outcome in children born very preterm. We also explored whether parent interaction moderates long-term effects of invasive procedures on child behavior. Data were collected from two prospective cohorts of infants born ≤32 weeks gestation between February 2001–July 2004 and March 2006–January 2009. Neonatal data were recorded from birth to term-equivalent age. Infants in the 2006–2009 cohort were scanned sequentially, once near birth and again at term-equivalent age. Infants in the 2001–2004 cohort were followed-up at 18 months corrected age (CA), and again at 7.5 years of age, when they underwent an MRI. At 18 months CA, parents of the 2001–2004 cohort completed questionnaires and participated in a recorded play session with their child, from which the parent-child interaction was later coded. All statistical analyses were adjusted for known neonatal and clinical confounders. In a series of 4 studies, greater exposure to invasive procedures in the NICU was associated with slower postnatal body and head growth, and slower growth was associated with delayed cerebral cortical maturation. Among the preterm children exposed to a higher number of invasive procedures, more positive parental interaction was associated with fewer anxious/depressive behaviors reported at 18 months CA. Furthermore, greater exposure to invasive procedures was related to poorer white matter maturation at 7.5 years, and together these factors predicted lower IQ. Greater exposure to invasive procedures was associated with slower body and head growth, altered brain maturation and poorer outcomes, after adjustment for clinical confounders. It is necessary that pain management strategies be evaluated for the extent that they are brain protective, in order to minimize the long-term impact of ongoing pain/stress in the NICU. Furthermore, interventions should address the parent-child relationship in order to improve later outcomes.

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Focused attention and heart rate during exploratory play in healthy preterm and term-born infants (2008)

Infant attention is central to early development. Previous research has linked focused attentionduring infant exploratory play to preschool cognition. Importantly, focused attention andinformation processing have been related to sustained decreases in heart rate (HR), which showdevelopmental changes in infancy. Few studies have examined the relationship between focusedattention, heart rate and development in very preterm infants, who are vulnerable to cognitive andattention problems. Participants were 35 extremely low gestational age (ELGA; ≤28 weeks), 48very low gestational age (VLGA; 29-32 weeks) and 46 healthy term-born infants seen at 8-months corrected age. Focused attention was timed and global focused attention was rated using atoy exploration paradigm. Heart rate was recorded continuously during attention testing. MeanHR and heart rate variability (HRV) were assessed during infant exploration. Additionally,change in mean HR for all focused episodes, and the mean and greatest HR change for the peakfocus were calculated. Bayley Scales of Infant Development (BSID-II, Mental DevelopmentIndex [MDI]) were administered.Term-born infants were rated higher on global focused attention than VLGA, andmarginally higher than ELGA infants. For all infants, greater HRV suppression duringexploration and magnitude ofHR deceleration during the peak focus were related to greaterattentiveness. No group differences were seen in HRV suppression. However, ELGA infantsshowed greater HR deceleration during focused attention compared to VLGA and Term-borninfants. Furthermore, after controlling for perinatal risk, infant peak focus and degree of HRdeceleration predicted 8-month MDI for the ELGA (49% of the total variance), but not VLGAinfants. This may reflect enhanced attentional effort to compensate for information processingdeficits among the highest risk infants. These findings extend research on attention and heart rateduring exploratory play to understanding the links between attention regulation, heart rate andcognitive development in very preterm infants. Further knowledge in this area will facilitate thedevelopment of effective methods to identify infants very early in life who are at-risk for attentionand cognitive problems, and may lead to interventions that can improve developmental outcomesfor vulnerable infants.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Regional cerebral metabolic rate of oxygen and levels of respiratory support in preterm neonates (2023)

Background: Preterm birth is associated with a higher rate of brain injury and neurodevelopmental delays in children. The brain is dependent on oxidative metabolism of glucose to meet its significant energy requirements. Understanding the cerebral metabolic rate of oxygen (CMRO₂) and how it is affected by ventilation in the neonatal population is crucial to the advancement of neonatal medicine. This study aims to assess the feasibility of quantifying CMRO₂ and cerebral blood flow (CBF) using magnetic resonance imaging (MRI) in preterm infants at term equivalent age (TEA) and to determine how various ventilatory support may affect CMRO₂. We hypothesized that increased time on mechanical ventilation would be negatively associated with CMRO2 and CBF levels in preterm neonates at TEA.Methods: Very preterm neonates (n=19) born
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Early pain/stress and math skills in relation to fMRI during visuospatial processing at age 8 years in children born very preterm (2022)

Children born very preterm exhibit neurodevelopmental problems, compared to term-born peers. Math underperformance is particularly evident and is associated with poorer visuospatial skills. Neonatal exposure to repeated invasive procedures during neonatal intensive care unit (NICU) stay that induce pain and stress has been identified as one contributing factor to poorer cognitive performance, but relationships with mathematics achievement have not been studied.Partial least squares correlation (PLSC) analyses were performed to investigate whether:1. Neonatal pain-related stress and clinical factors are related to math skills at age 8 years, and whether: a) maternal education, b) white matter injury, and c) child sex, contribute to the relationship.2. Neonatal pain-related stress and clinical factors are related to functional network activation during visuospatial processing.3. Functional network activation during visuospatial processing is related to math skills.In an ongoing prospective longitudinal cohort study, N=118 (63 male) children born very preterm at 8 years underwent neuropsychological and math skills assessment, and N=75 children also completed a visuospatial mental rotation of hands task. Prospective daily clinical chart review conducted across the NICU stay recorded pain/stress (number of invasive procedures) and clinical factors. No child with major brain injury and/or severe motor, sensory, or cognitive impairments was included. I found that:1. Greater pain/stress exposure was related to poorer math skills, along with morphine, gestational age, ventilation, and infection (τ=80%, p<.001 none="" of="" maternal="" education="" white="" matter="" injury="" or="" child="" sex="" contributed="" to="" the="" relationship.2.="" greater="" neonatal="" pain="" morphine="" ventilation="" snap-ii="" infection="" and="" lower="" gestational="" age="" were="" then="" related="" increased="" brain="" network="" activation="" that="" included="" right="" superior="" parietal="" lateral="" occipital="" left="" inferior="" temporal="" cortices="" p="" poorer="" scores="" in="" all="" math="" domains="" including="" bilaterally="" with="" concomitant="" decreased="" cortex="" this="" study="" suggests="" a="" link="" via="" visuospatial="" processing="" between="" supports="" importance="" abilities="" relation="" performance="" for="" children="" born="" very="" preterm.="">
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Hippocampus, amygdala, and thalamus volumes in very preterm children at 8 years: neonatal pain and genetic variation (2022)

Altered hippocampal morphology and reduced volumes have been found in children born preterm compared to full-term. Stress inhibits neurogenesis in the hippocampus, and neonatal stress/noxious stimulation in rodent pups are associated with long-term alterations in hippocampal volumes. We have previously shown reduced cortical thickness and cerebellar volumes in relation to more exposure to pain-related stress of neonatal invasive procedures in children born very preterm. We have reported targeted gene-by-pain environment interactions that contribute to long-term brain development and outcomes in this population. We now aim to determine whether exposure to neonatal pain-related stress (adjusted for clinical factors) deferentially impacts regional structures within the limbic system and thalamus and investigate relationships with outcomes in very preterm children. Our study included 57 children born very preterm (
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Neonatal Pain and COMT Val158Met Genotype in Relation to Serotonin Transporter (SLC6A4) Promoter Methylation in Very Preterm Children at School Age (2015)

Children born very preterm are exposed to repeated neonatal procedures that induce pain and stress during hospitalization in the neonatal intensive care unit (NICU). The COMT Val158Met genotype is involved with pain sensitivity, and early life stress is implicated in altered expression of methylation of the serotonin transporter. We examined: (1) whether methylation of the serotonin transporter gene (SLC6A4) promoter differs between very preterm children and full-term controls at school age, (2) relationships with child behavior problems, and (3) whether the extent of neonatal pain exposure interacts with the COMT Val158Met genotype to predict SLC6A4 methylation at 7 years in the very preterm children. We examined the associations between the COMT genotypes, neonatal pain exposure (adjusted for neonatal clinical confounders), SLC6A4 methylation and behavior problems. Very preterm children had significantly higher methylation at 7/10 CpG sites in the SLC6A4 promoter compared to full-term controls at 7 years. Neonatal pain (adjusted for clinical confounders) was significantly associated with total child behaviour problems on the Child Behavior Checklist (CBCL) questionnaire (adjusted for concurrent stressors and 5HTTLPR genotype, p = 0.035). CBCL Total Problems was significantly associated with greater SLC6A4 methylation in very preterm children (p = 0.01). Neonatal pain (adjusted for clinical confounders) and COMT Met/Met genotype were associated with SLC6A4 promoter methylation in very preterm children (p = 0.001). These findings provide evidence that both genetic predisposition and early environment need to be considered in understanding susceptibility for developing behavioral problems in this vulnerable population.

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