Grantee Research Project Results
2016 Progress Report: An MRI Study of the Effects of Prenatal and Early Childhood PAH Exposure on Brain Maturation and Its Mediating Influences on Adverse Adolescent Outcomes
EPA Grant Number: R836154C003Subproject: this is subproject number 003 , established and managed by the Center Director under grant R836154
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: The Columbia Center for Children’s Environmental Health
Center Director: Perera, Frederica P.
Title: An MRI Study of the Effects of Prenatal and Early Childhood PAH Exposure on Brain Maturation and Its Mediating Influences on Adverse Adolescent Outcomes
Investigators: Peterson, Brad
Current Investigators: Peterson, Bradley S
Institution: Columbia University in the City of New York
Current Institution: University of Southern California
EPA Project Officer: Callan, Richard
Project Period: September 1, 2015 through August 31, 2019 (Extended to August 31, 2020)
Project Period Covered by this Report: September 1, 2015 through August 31,2016
RFA: Children's Environmental Health and Disease Prevention Research Centers (2014) RFA Text | Recipients Lists
Research Category: Children's Health , Endocrine Disruptors , Human Health
Objective:
Aim 1: We will assess the effects of prenatal and early childhood postnatal exposure to PAH (hereafter, “early PAH exposure”) on the structure, function, and metabolism of self-regulatory systems (frontal, parietal, and mesial temporal cortices, and subcortical nuclei) in the brains of 350 cohort children who have undergone MRI scanning at 9-12 years of age.
Hypothesis 1: Early PAH exposure adversely affects the structure, function, and metabolism of neural systems that support the capacity for self-regulation. Specifically, PAH exposure will associate with (1a) reduced white matter volumes, (1b) increased resting perfusion, (1c) increased task-based activation, (1d) reduced DTI (diffusion tensor imaging) measures of white matter organization, and (1e) reduced NAA (N-acetyl aspartate, a metabolic index of neuronal viability) – all affecting the left cerebral hemisphere in particular.
Aim 2: We will assess whether PAH-related brain disturbances at 9-12 years of age (identified in Aim 1) mediate the association between prenatal PAH exposure and adverse CEBA outcomes at 15-17 years.
Hypothesis 2: PAH-related disturbances in the structure, function, and metabolism of neural systems supporting self-regulatory control at 9-12 years will mediate: (2a) the emergence of conduct disturbance, substance use, and depression, (2b) the persistence of ADHD symptoms, and (2c) adiposity measures, at 15-17 years of age.
Aim 3: We will acquire anatomical MRI scans at 15-17 years in 350 children with previous imaging at 9-12 years to assess how prenatal and early childhood exposures to PAH alter the trajectory of brain development throughout adolescence, and whether such alterations predict CEBA problems.
Hypothesis 3: Early exposure to high levels of PAH (3a) will significantly disrupt the normal changes in brain structure within self regulatory systems from childhood through adolescence, and those children with the most disrupted anatomical changes will experience the greatest degree of (3b) conduct disturbances, substance use, and depression, (3c) persistent ADHD symptoms, and (3d) adiposity measures, at 15-17 years of age.
Progress Summary:
In these first 9 months of the grant, we have focused on four main objectives for Project 3: (1) processing all of the MRI data for age 9-12 in our cohort (i.e., for Aims 1 and 2); (2) integrating with the MRI dataset all of the demographic, behavioral, and cognitive data acquired at ages 9-12; (3) initiating statistical analyses for Aims 1 and 2; (4) testing and finalizing the MRI pulse sequences for both the abdominal fat imaging in Project 2 and the anatomical brain imaging to be conducted in Project 3 (i.e., for Aim 3).
Aims 1 and 2: Processing of MRI data for ages 9-12.
We have made great progress in processing all of the MRI data.
(a) Processing of anatomical data – the most time-consuming and labor-intensive of all our image processing procedures – is nearly complete. We anticipate finishing these procedures by July of this year, at which time we will be able to coregister all of those data to a common template and conduct statistical analyses.
(b) Processing of task-based fMRI and ASL perfusion data is complete, and statistical analyses are underway.
(c) Processing of DTI data is nearly complete, and we expect that it will be fully ready for statistical analysis by early July of this year.
(d) Processing of MRS data is nearly complete, with only manual checks on quality of the spectra, correction for partial volume effects, and registration to a common template brain remaining. We expect these data to be ready for statistical analysis by August of this year at the latest.
Aims 1 and 2: Integrating with the MRI dataset all of the demographic, behavioral, and cognitive data acquired at ages 9-12.
This integration was completed in April 2016.
Aims 1 and 2: beginning of statistical analyses.
This analysis has begun for both ASL perfusion and the DTI datasets.
(a) Preliminary DTI Findings. We correlated the log of Total Prenatal PAH levels with FA (fractional anisotropy) values across the brain in 167 of our participants at ages 9-12 (Figure 1). Data for an additional 125 participants will soon be added to these. Already we detect significant positive correlations (indicated in yellow and red colors) of prenatal PAH exposure with FA measures in childhood within white matter, which in Figure 1 is shown in darker gray (because findings are plotted on the B0 diffusion weighted images of the template brain), with axial slices on the left side of the figure representing tissue lower (more ventral) in the brain, and those to the right representing slices progressively higher (more dorsal) in the brain. As FA is an index of the degree of tissue organization in the brain, particularly within white matter tracts, the positive correlations indicate that higher prenatal exposures to PAH are associated with proportionally greater degrees of white matter tissue organization. These findings are particularly evident in deep white matter tracts within the brain bilaterally, including the anterior and posterior limbs of the internal capsule (ALIC and PLIC, respectively) and the anterior and posterior portions of the corpus callosum (CC). The internal capsule carries fibers connecting the cortex to brainstem, spinal cord, basal ganglia, and thalamus, whereas the corpus callosum carries fibers connecting homotopic cortical regions across the left and right hemispheres of the brain. We also detected other scattered foci of correlations in long white matter fiber tracts.
Figure 1. DTI Findings. Locations where Log Total PAH concentration measured in pregnancy correlates with FA (fractional anisotropy). ALIC: anterior limb internal capsule; PLIC: posterior limb internal capsule; CC: corpus callosum.
These findings, combined with our prior anatomical findings of reduced white matter volumes in the left cerebral hemisphere, suggest that smaller white matter volumes are associated with a greater density and organization of white matter tissue in those exposed to higher prenatal PAH levels. This greater density or organization of white matter could derive from several different cellular features of white matter, including smaller and more densely packed axons, more glial cells or myelin, or reduced extracellular space and its fluids. Additional analyses of our DTI data (such as measures of axial or radial diffusivity) combined with our MRS measures (such as NAA, an index of neural density) will provide evidence favoring one or more of these cellular features and disfavoring others. These findings will in turn help to guide cytoarchitectural studies of white matter in animal models of PAH neurotoxicity.
Aim 3: Testing and finalizing the MRI pulse sequences for both the abdominal fat imaging in Project 2 and the anatomical brain imaging to be conducted in Project 3.
The greatest challenge in designing and implementing the pulse sequences has been for the abdominal imaging in Project 2. Funding limitations have precluded scanning the brains of our cohort on the 3T scanner and the abdomens of our participants on a 1.5T scanner. Therefore, we must acquire both the abdominal and brain images on the 3T scanner, particularly because brain MRI data at ages 9-12 in our cohort were acquired at 3T. Acquiring the abdominal scans at 3T poses some challenges that pertain to the fundamental physics of MRI at high field strengths and that include changes in tissue contrast (how well one can distinguish the grays of soft abdominal tissues from the white of fat, for example) and magnetic field susceptibility (which causes shadows and alterations in signal-to-noise) when imaging at 3Tesla (as in our case now) compared with imaging at 1.5Tesla (as has been the case for almost all of MRI abdominal imaging until now). Our MRI experts in Project 3, in collaboration with researchers at the University of Southern California (USC), The Mailman School of Public Health, and the New York Obesity Research Center and with consultation from an MR physicist at the New York Psychiatric Institute, have led the effort in developing and testing these pulse sequences. This development and testing of the MRI pulse sequences, together with several important and time-consuming repair services to the 3 Tesla scanner, has required time and contributed to some delay in start-up of our full fledged new imaging initiative under the auspices of this P50. Fortunately, we have been able to identify the parameters of pulse sequences that provide image quality that is as good, if not better (in terms of signal-to-noise especially) when acquired at 3T compared with 1.5T. Those images are shown in the progress report for Project 2. We anticipate the fine-tuning of these pulse sequences to be complete within the next week, after which we will be able to begin scanning children of our cohort at full capacity. We will accordingly accelerate our planned recruitment and follow-up of participants to counter the effects of the delays we have experienced. The MRI pulse sequences for the brain are finalized and are providing superb image quality.
Future Activities:
New Data Acquisition. In the next reporting period we will continue follow-up of the cohort members as they reach ages 16-18 years and expect to complete 135 follow-up visits. The next reporting period will focus in part on intensive MRI and behavioral data collection from study participants. Recruitment and data collection will follow the approaches described in our grant application. We will process data from each participant as it is collected.
Our original proposal called for follow-up and data collection from 100 subjects in Years 1, 2, and 3 of the project and from 50 participants in Year 4. As a result of the challenges we experienced in developing a single MRI scan protocol that acquires both brain and abdominal images on our 3T MRI scanner, the launch of participant recruitment and data collection was delayed. We anticipate beginning data collection in June 2016, and thus expect to collect data from 30 participants in Year 1 of the project. In Years 2 and 3 we plan to complete recruitment at data collection for 135 participants to bring us back on schedule by Year 4 of the project.
In the next reporting period we will complete processing of data in each MRI modality, readying those datasets for statistical analysis. Statistical models will be specified and implemented in each modality, incorporating relevant covariates and addressing potential confounds as indicated. Findings will be interpreted and, based on those interpretations, manuscripts will be prepared and submitted for publication.
Relevant Websites:
Columbia Center for Children’s Environmental Health Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R836154 The Columbia Center for Children’s Environmental Health Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R836154C001 The Impact of PAH Exposure on Adolescent Neurodevelopment: Disruption of Self-Regulatory Processes
R836154C002 The Impact of PAH Exposure on Childhood Growth Trajectories and Visceral Adipose Tissue
R836154C003 An MRI Study of the Effects of Prenatal and Early Childhood PAH Exposure on Brain Maturation and Its Mediating Influences on Adverse Adolescent Outcomes
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.