Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm methods
Aim. Evidence-backed execution summary for Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm methods from Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm.
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rat
Subject model for the experiment.
- Use
- confirm full cohort details in the source paper
Clinical data collection
reagent used in the protocol.
- Use
- Medical and nursing chart review of neonatal data from birth to term equivalent was carried out by highly trained neonatal research nurses. Data collected included, but was not limited to, birth weight, gestational age (GA), number of days on mechanical ventilation and/or oscillation, illness severity on day 1 (Scor...
Cortical thickness measures
reagent used in the protocol.
- Use
- Regional cortical thickness was calculated using a topology aware technique originally proposed by Gibson et al. which modifies the normally accepted method of calculating the thickness as the length of the streamlines obtained from the well-established and validated Laplacian streamlines method,. This implementat...
3. Statistical Analysis
reagent used in the protocol.
- Use
- Principal component analysis (PCA) is a method of data reduction of large sets of related variables by reducing them to a few vectors of weightings that best explain the variance, while losing as little information as possible. Each extracted vector, referred to as a "component", accounts for a portion o...
3. Statistical Analysis
reagent used in the protocol.
- Use
- Then, to further examine the individual contribution of each neonatal predictor on the measured variations of cortical thickness, we conducted a generalized linear (GENLIN) modeling analysis, adjusting for neonatal clinical factors (GA, SNAP-II at day 1, culture proven infection, number of days on mechanical ventila...
Results
reagent used in the protocol.
- Use
- The variance in cortical thickness explained by the 7 neonatal clinical factors within each component is shown in. The external analysis in CPCA showed that pain-related stress was the strongest predictor from our set of 7 neonatal factors. The number of skin-breaking procedure loaded highly on the first two compon...
Results
reagent used in the protocol.
- Use
- C.I. = 95% confidence interval; Pain = number of skin-breaking procedures exposure; Morphine = cumulative daily dose in milligrams adjusted for daily body weight; Ventilation = number of days on mechanical ventilation; Surgery = number of surgeries; Infecti...
2. Generalized Linear Modeling (GENLIN)
reagent used in the protocol.
- Use
- Cortical thickness in two of the brain regions where most significant ( p ≤0.0001) thinning in relation to neonatal pain-related stress was found. A) Scatter plot of right hemisphere postcentral cortical thickness in relation to neonatal pain-related stress (number of skin-breaking procedures log transformed)...
2. Generalized Linear Modeling (GENLIN)
reagent used in the protocol.
- Use
- R, right hemisphere; L, left hemisphere; Infection = number of culture proven infection; Pain = number of skin-breaking procedures exposure; Ventilation = number of days on mechanical ventilation; Morphine = cumulative daily dose in milligrams adjusted for daily body w...
Methods
42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custo...
- Use
- 42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custo...
2. Procedures
MRI was performed using a standard 12 channel head coil on a Siemens 1.5 Tesla Avanto (Berlin, Germany) with VB 16 software. The following images were acquired: a 3D T1 weighted SPGR sequence 18/9.2/256/1 mm/0/256 × 256 (TR/TE/FOV/Thickness/Gap/Matrix), axial FSE T2 4030/90/220/3 mm/0.1 mm/512 × 354, axial FLA...
- Use
- MRI was performed using a standard 12 channel head coil on a Siemens 1.5 Tesla Avanto (Berlin, Germany) with VB 16 software. The following images were acquired: a 3D T1 weighted SPGR sequence 18/9.2/256/1 mm/0/256 × 256 (TR/TE/FOV/Thickness/Gap/Matrix), axial FSE T2 4030/90/220/3 mm/0.1 mm/512 × 354, axial FLA...
Cortical thickness measures
Cortical thickness was calculated for each individual brain using the segmentation output from the preprocessing step, where the output obtained is the pial surface for each subject where each vertex has a thickness value associated with it. The surfaces used to define the outer and inner boundaries in our methods w...
- Use
- Cortical thickness was calculated for each individual brain using the segmentation output from the preprocessing step, where the output obtained is the pial surface for each subject where each vertex has a thickness value associated with it. The surfaces used to define the outer and inner boundaries in our methods w...
Discussion
During their NICU care, preterm neonates are exposed to multiple factors that may alter the developing brain, and teasing out specific pain-related effects is challenging. Prenatal and post-natal clinical factors and treatments might interact or may lead to similar end points, which makes them difficult to isolate....
- Use
- During their NICU care, preterm neonates are exposed to multiple factors that may alter the developing brain, and teasing out specific pain-related effects is challenging. Prenatal and post-natal clinical factors and treatments might interact or may lead to similar end points, which makes them difficult to isolate....
3. Statistical Analysis
Software used for acquisition, scoring, statistics, or reporting.
- Use
- Principal component analysis (PCA) is a method of data reduction of large sets of related variables by reducing them to a few vectors of weightings that best explain the variance, while losing as little information as possible. Each extracted vector, referred to as a "component", accounts for a portion o...
3. Statistical Analysis
Software used for acquisition, scoring, statistics, or reporting.
- Use
- Then, to further examine the individual contribution of each neonatal predictor on the measured variations of cortical thickness, we conducted a generalized linear (GENLIN) modeling analysis, adjusting for neonatal clinical factors (GA, SNAP-II at day 1, culture proven infection, number of days on mechanical ventila...
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Clinical data collection
Medical and nursing chart review of neonatal data from birth to term equivalent was carried out by highly trained neonatal research nurses. Data collected included, but was not limited to, birth weight, gestational age (GA), number of days on mechanical ventilation and/or oscillation, illness severity on day 1 (Score for Neonatal Acute Physiology [SNAP]- II ), number of surgeries, presence of culture proven infection, and cumulative dose of morphine. The cumulative dose of morphine was calculated (intravenous dose plus converted oral dose) as the average daily dose adjusted for daily body weight, multiplied by the number of days the drug was given, as we have used previously,. We quantified neonatal pain-related stress as the number of skin-breaking procedures (e.g., heel lance, peripheral intravenous or central line insertion, chest-tube insertion, tape removal, and nasogastric tub...
Methods
42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling.
Materials and Methods
Participants were part of a larger longitudinal study of long-term effects of neonatal pain-related stress on neurodevelopment of children born very preterm (24-32 weeks gestation) e.g.,, who were admitted to the level III NICU at British Columbia's Women's Hospital between 2000 and 2004. Out of 106 children seen at age 7 years, 43 refused magnetic resonance imaging (MRI), leaving 63 school-age children, 2 were not scanned, 61 underwent MRI. From the 61 preterm children that underwent MRI scans at age 7 years, 13 were excluded due to poor quality MR images due to movement artifact and one for missing neonatal clinical data. In addition, two children with periventricular leukomalacia (PVL) and/or intraventricular hemorrhage (IVH) grade 3 or 4 on neonatal ultrasound and confirmed on MR at age 7 years (author KP) were excluded, and three left handed children were excl...
2. Procedures
MRI was performed using a standard 12 channel head coil on a Siemens 1.5 Tesla Avanto (Berlin, Germany) with VB 16 software. The following images were acquired: a 3D T1 weighted SPGR sequence 18/9.2/256/1 mm/0/256 × 256 (TR/TE/FOV/Thickness/Gap/Matrix), axial FSE T2 4030/90/220/3 mm/0.1 mm/512 × 354, axial FLAIR 8900/87/5 mm/1 mm/256 × 154 and a 12 direction DTI sequence 7800/82/256/2 mm/0/128 × 128 using B values of 700 and 1000. All imaging sessions were performed without sedation. On the study day, each child first had a session in a mock scanner to acclimatize to the noise and feeling of being in a MRI scanner, followed by the actual study scan. Children were instructed to remain still and watched a video during the sessions that lasted approximately 30 minutes.
3. Statistical Analysis
Principal component analysis (PCA) is a method of data reduction of large sets of related variables by reducing them to a few vectors of weightings that best explain the variance, while losing as little information as possible. Each extracted vector, referred to as a "component", accounts for a portion of the total variance in the data: the first component accounts for the largest amount of variance, with each successive component accounting for a smaller amount of the total variance. Constrained principal component analysis (CPCA) combines multivariate multiple regression and PCA, and allows examination of the component structure of the variance in a set of dependent variables that is specifically predicted by a set of predictor variables -. CPCA is two-step process, referred to as the external and internal analysis. The external analysis consists of a multivariate...
Results
The variance in cortical thickness explained by the 7 neonatal clinical factors within each component is shown in. The external analysis in CPCA showed that pain-related stress was the strongest predictor from our set of 7 neonatal factors. The number of skin-breaking procedure loaded highly on the first two components, infection loaded significantly only on component 1, while surgery significantly loaded uniquely and predominately on component 2. Morphine exposure and duration of mechanical ventilation significantly loaded on all three components but dominated the 3 rd component. Severity of illness on day 1 (SNAP-II) loaded significantly on all 3 components. Component 1 suggests that the number of skin-breaking procedures during NICU care, illness severity on day 1, culture-proven infection, gestational age, cumulative morphine exposure, and days on mechanical ventilation are relat...
Results
C.I. = 95% confidence interval; Pain = number of skin-breaking procedures exposure; Morphine = cumulative daily dose in milligrams adjusted for daily body weight; Ventilation = number of days on mechanical ventilation; Surgery = number of surgeries; Infection = number of culture proven infection; SNAP-II = score for neonatal acute physiology; GA = gestational age.
2. Generalized Linear Modeling (GENLIN)
Neonatal clinical factors were inspected for normality, then when necessary were log transformed (neonatal skin-breaking procedures and number of days on mechanical ventilation). Using the findings from the CPCA, a GENLIN model for each of the 66 brain regions was conducted, corrected for multiple comparisons (i.e. 5% FDR). After adjusting for neonatal clinical factors (i.e. gestational age, SNAP-II at day 1, infection, number of days on mechanical ventilation, number of surgery, cumulative morphine exposure), greater number of neonatal skin-breaking procedures was significantly associated with reduced cortical thickness in 21 out of the 66 brain regions assessed ( p -values ranged from 0.00001 to 0.014; ), p -value threshold for significance adjusted for multiple comparisons with a FDR correction set at 5%. Most significant ( p ≤0.001) thinning in relation to neonatal pain-rela...
Measurement outputs
What raw and processed outputs should exist?
Medical and nursing chart review of neonatal data from birth to term equivalent was carried out by highly trained neonatal research nurses. Data collected included, but was not...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children...
- Raw artifact
- Field or section images captured from matched samples
- Processed artifact
- Selected representative panels with quantified intensity, counts, or area measurements
- Reported as
- Per-group imaging summaries with representative figures and quantified endpoints
Early-life adversity in animal models, including maternal separation - and pain exposure -, induces long-term changes in brain and behavior (reviews, ). Infants bo...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
Participants were part of a larger longitudinal study of long-term effects of neonatal pain-related stress on neurodevelopment of children born very preterm (24-32 weeks g...
- Raw artifact
- Per-sample or per-animal endpoint measurements collected during the experiment
- Processed artifact
- Structured table with cleaned measurements ready for comparison
- Reported as
- Summary statistics and between-group or across-timepoint comparisons
Analysis plan
How should the outputs become interpretable results?
Acquisition
Collect raw experimental outputs with enough metadata to preserve sample identity, condition, and timing.
inferred from protocolPreprocessing / cleaning
Regional cortical thickness was calculated using a topology aware technique originally proposed by Gibson et al.
from paperScoring or quantification
Quantify the primary readouts for this experiment: Medical and nursing chart review of neonatal data from birth to term equivalent was carried out by highly trained neonatal research nurses. Data collected included, but was not...; 42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children...; Early-life adversity in animal models, including maternal separation - and pain exposure -, induces long-term changes in brain and behavior (reviews, ). Infants bo...; Participants were part of a larger longitudinal study of long-term effects of neonatal pain-related stress on neurodevelopment of children born very preterm (24-32 weeks g....
from paperStatistical comparison
Regional cortical thickness was calculated using a topology aware technique originally proposed by Gibson et al. which modifies the normally accepted method of calculating the t...; Principal component analysis (PCA) is a method of data reduction of large sets of related variables by reducing them to a few vectors of weightings that best explain the varianc...; Then, to further examine the individual contribution of each neonatal predictor on the measured variations of cortical thickness, we conducted a generalized linear (GENLIN) mode...; Neonatal clinical factors were inspected for normality, then when necessary were log transformed (neonatal skin-breaking procedures and number of days on mechanical ventilation)...
from paperReporting output
Report representative outputs alongside summary comparisons for Medical and nursing chart review of neonatal data from birth to term equivalent was carried out by highly trained neonatal research nurses. Data collected included, but was not..., 42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children..., Early-life adversity in animal models, including maternal separation - and pain exposure -, induces long-term changes in brain and behavior (reviews, ). Infants bo..., Participants were part of a larger longitudinal study of long-term effects of neonatal pain-related stress on neurodevelopment of children born very preterm (24-32 weeks g....
inferred from protocolStructured statistical methods
Regional cortical thickness was calculated using a topology aware technique originally proposed by Gibson et al. which modifies the normally accepted method of calculating the t...; Principal component analysis (PCA) is a method of data reduction of large sets of related variables by reducing them to a few vectors of weightings that best explain the varianc...; Then, to further examine the individual contribution of each neonatal predictor on the measured variations of cortical thickness, we conducted a generalized linear (GENLIN) mode...; Neonatal clinical factors were inspected for normality, then when necessary were log transformed (neonatal skin-breaking procedures and number of days on mechanical ventilation)...
source structuredSource and audit
What supports the facts on this page?
Evidence quotes (8)
Medical and nursing chart review of neonatal data from birth to term equivalent was carried out by highly trained neonatal research nurses. Data collected included, but was not limited to, birth weight, gestational age (GA), number of days on mechanical ventilation and/or oscillation, illness severity on day 1 (Score for Neonatal Acute Physiology [SNAP]- II ), number of surgeries, presence of culture proven infection, and cumulative dose of morphine. The cumulative dose of morphine was calculated (intravenous dose plus converted oral dose) as the average daily dose adjusted for daily body weight, multiplied by the number of days the drug was given, as we have used previously,. We quantified neonatal pain-related stress as the number of skin-breaking procedures (e.g., heel lance, peripheral intravenous or central line insertion, chest-tube insertion, tape removal, and nasogastric tube insertion) during the stay in the NICU, as previously used,,. Each attempt at a procedure was counted as one skin-break; all nursing staff in our NICU have been trained to precisely record each attempt.
42 right-handed children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling.
Participants were part of a larger longitudinal study of long-term effects of neonatal pain-related stress on neurodevelopment of children born very preterm (24-32 weeks gestation) e.g.,, who were admitted to the level III NICU at British Columbia's Women's Hospital between 2000 and 2004. Out of 106 children seen at age 7 years, 43 refused magnetic resonance imaging (MRI), leaving 63 school-age children, 2 were not scanned, 61 underwent MRI. From the 61 preterm children that underwent MRI scans at age 7 years, 13 were excluded due to poor quality MR images due to movement artifact and one for missing neonatal clinical data. In addition, two children with periventricular leukomalacia (PVL) and/or intraventricular hemorrhage (IVH) grade 3 or 4 on neonatal ultrasound and confirmed on MR at age 7 years (author KP) were excluded, and three left handed children were excluded to eliminate the effect of handedness on cortical thickness asymmetries,. We included in our study three very preterm infants diagnosed on neonatal ultrasound with IVH grade 1 or 2 (two infants with IVH grade 1) and six children that showed minimal to moderate white matter injury (≤3 le...
MRI was performed using a standard 12 channel head coil on a Siemens 1.5 Tesla Avanto (Berlin, Germany) with VB 16 software. The following images were acquired: a 3D T1 weighted SPGR sequence 18/9.2/256/1 mm/0/256 × 256 (TR/TE/FOV/Thickness/Gap/Matrix), axial FSE T2 4030/90/220/3 mm/0.1 mm/512 × 354, axial FLAIR 8900/87/5 mm/1 mm/256 × 154 and a 12 direction DTI sequence 7800/82/256/2 mm/0/128 × 128 using B values of 700 and 1000. All imaging sessions were performed without sedation. On the study day, each child first had a session in a mock scanner to acclimatize to the noise and feeling of being in a MRI scanner, followed by the actual study scan. Children were instructed to remain still and watched a video during the sessions that lasted approximately 30 minutes.
Principal component analysis (PCA) is a method of data reduction of large sets of related variables by reducing them to a few vectors of weightings that best explain the variance, while losing as little information as possible. Each extracted vector, referred to as a "component", accounts for a portion of the total variance in the data: the first component accounts for the largest amount of variance, with each successive component accounting for a smaller amount of the total variance. Constrained principal component analysis (CPCA) combines multivariate multiple regression and PCA, and allows examination of the component structure of the variance in a set of dependent variables that is specifically predicted by a set of predictor variables -. CPCA is two-step process, referred to as the external and internal analysis. The external analysis consists of a multivariate least squares multiple regression of the dependent measures on the independent measures, producing predicted and residual scores for each dependent measure. In the present study, the matrix of predicted scores reflects the variance in cortical thickness that can be accounted for by the neonatal cli...
The variance in cortical thickness explained by the 7 neonatal clinical factors within each component is shown in. The external analysis in CPCA showed that pain-related stress was the strongest predictor from our set of 7 neonatal factors. The number of skin-breaking procedure loaded highly on the first two components, infection loaded significantly only on component 1, while surgery significantly loaded uniquely and predominately on component 2. Morphine exposure and duration of mechanical ventilation significantly loaded on all three components but dominated the 3 rd component. Severity of illness on day 1 (SNAP-II) loaded significantly on all 3 components. Component 1 suggests that the number of skin-breaking procedures during NICU care, illness severity on day 1, culture-proven infection, gestational age, cumulative morphine exposure, and days on mechanical ventilation are related to reduced cortical thickness, primarily in frontal and parietal regions. Component 2 in addition, captured predominately surgery, but not infection, and is related to reduced cortical thickness, primarily in parietal, temporal and occipital regions. Component 3, contrary to the two other compone...
C.I. = 95% confidence interval; Pain = number of skin-breaking procedures exposure; Morphine = cumulative daily dose in milligrams adjusted for daily body weight; Ventilation = number of days on mechanical ventilation; Surgery = number of surgeries; Infection = number of culture proven infection; SNAP-II = score for neonatal acute physiology; GA = gestational age.
Neonatal clinical factors were inspected for normality, then when necessary were log transformed (neonatal skin-breaking procedures and number of days on mechanical ventilation). Using the findings from the CPCA, a GENLIN model for each of the 66 brain regions was conducted, corrected for multiple comparisons (i.e. 5% FDR). After adjusting for neonatal clinical factors (i.e. gestational age, SNAP-II at day 1, infection, number of days on mechanical ventilation, number of surgery, cumulative morphine exposure), greater number of neonatal skin-breaking procedures was significantly associated with reduced cortical thickness in 21 out of the 66 brain regions assessed ( p -values ranged from 0.00001 to 0.014; ), p -value threshold for significance adjusted for multiple comparisons with a FDR correction set at 5%. Most significant ( p ≤0.001) thinning in relation to neonatal pain-related stress was found in bilateral postcentral, superior frontal, rostral middle frontal, left hemisphere precentral and pars orbitalis, as well as the right hemisphere supramarginal region. Of all the neonatal clinical factors, pain-related stress (adjusted for neonatal clinical factors) was the mos...
Machine-readable layer
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"text": "The variance in cortical thickness explained by the 7 neonatal clinical factors within each component is shown in. The external analysis in CPCA showed that pain-related stress was the strongest predictor from our set of 7 neonatal factors. The number of skin-breaking procedure loaded highly on the first two components, infection loaded significantly only on component 1, while surgery significantly loaded uniquely and predominately on component 2. Morphine exposure and duration of mechanical ventilation significantly loaded on all three components but dominated the 3 rd component. Severity of illness on day 1 (SNAP-II) loaded significantly on all 3 components. Component 1 suggests that the number of skin-breaking procedures during NICU care, illness severity on day 1, culture-proven infection, gestational age, cumulative morphine exposure, and days on mechanical ventilation are relat..."
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