The Brain and Early Experience Study: Protocol for a Prospective Observational Study

Background Children raised in conditions of poverty (or near poverty) are at risk for nonoptimal mental health, educational, and occupational outcomes, many of which may be precipitated by individual differences in executive function (EF) skills that first emerge in early childhood. Objective The Brain and Early Experience study considers prenatal and postnatal experiences that may mediate the association between poverty and EF skills, including neural substrates. This paper described the study rationale and aims; research design issues, including sample size determination, the recruitment strategy, and participant characteristics; and a summary of developmental assessment points, procedures, and measures used to test the study hypotheses. Methods This is a prospective longitudinal study examining multiple pathways by which poverty influences normative variations in EF skills in early childhood. It is funded by the National Institute of Child Health and Human Development and approved by the institutional review board. Results Recruitment is complete with a sample of 203 participants, and data collection is expected to continue from September 2018 to February 2024. Of those recruited as low socioeconomic status (SES), 71% (55/78) reported income-to-needs (ITN) ratios of <2.0, and 35% (27/78) reported ITN ratios of <1.0. Among participants recruited into the not-low SES stratum, only 8.8% (11/125) reported ITN ratios of <2.0, and no participant reported ITN ratios of <1.0. The average ITN ratio for participants recruited into the low-income stratum was significantly lower than the average for the high-income recruitment cell (P<.001). Comparable recruitment outcomes were observed for both Black and non-Black families. Overall, the sample has adequate diversity for testing proposed hypotheses, with 13.3% (27/203) of participants reporting ITN ratios of <1 and >32.5% (66/203) reporting ratios of <2.0. Conclusions Preliminary results indicate that the recruitment strategy for maximizing variation in family SES was successful, including variation within race. The findings of this study will help elucidate the complex interplay between prenatal and postnatal risk factors affecting critical neurocognitive developmental outcomes in early childhood. International Registered Report Identifier (IRRID) DERR1-10.2196/34854

1A-Both genders, scientifically acceptable 1A-Minorities and non-minorities, scientifically acceptable 1A-Both Children and Adults, scientifically acceptable Clinical Research -not NIH-defined Phase III Trial This application proposes to examine the link between poverty and executive functions that undergo developmental changes during the first years of life. The strong scientific premise to identify brain mediators through which poverty leads to poor executive functioning is based on the developmental health and disease model. This submission has been responsive to the previous review and the application has improved. The application innovation lies in the examination of poverty on executive functioning via the effects of neurological development during the early years of life. During the discussion, the reviewers noted that the rigorous comprehensive methods and measurement of executive functioning tasks, sleep language exposure, and parenting, the multimodal assessments of structural and functional neuroimaging, the strong power analyses, the impressive preliminary data and systematic recruitment procedures, and the planned missing design were strengths of the application. Overall, the committee agreed that the proposed research is highly significant and innovative and has the potential to have a high impact in enhancing understanding of the effects of prenatal and postnatal poverty on the development of the brain and executive functioning, as well as, identifying subsequent preventative and early intervention efforts.

DESCRIPTION (provided by applicant):
Chronic stress for children growing up in poverty may lead to lasting effects on social, behavioral, and cognitive development. The difficulties of living in economic hardship has, indeed, been associated with deficits in cognitive and academic performance. The current study examines the link between poverty and executive functions (cognitive processes that facilitate learning, self-monitoring, and decision making) which are known to undergo rapid developmental change during the first years of life. Early neurological development will be examined as a mediator of this association examined from pregnancy to age 3. In addition to distal risk associated with living in poverty, we will investigate critical experiences within the proximal context (i.e., language exposure, caregiver behavior, child sleep hygiene) that may mediate the effect of this risk on child structural and functional brain development. Participants (n= 230) will be seen during the 28th week of pregnancy, and at 5 visits across the first 3 years of their child's life. Neuroimaging will be conducted at 2 weeks, 15 and 24 months (with an accompanying lab visit at 15 months). We will focus on developing white matter tracts that support cognitive processes of emerging executive functions: anterior cingulum (error monitoring); uncinate (joint attention); arcuate fasciculus (language processing) and individual differences in functional brain development, including resting state networks of salience, attention, executive control, and default-mode. At 6 and 24 months of age, an intensive home visit will include observational and objective measures of caregiver behavior, language exposure (via speech recorders) and sleep hygiene (via actigraphy for 7 days). Child cognitive development will be assessed at each assessment and an executive functioning battery will be administered at 36 months of age. This study will be the first to investigate the influence of poverty on emerging executive functioning at age 3 via effects on child neurological development over the first two years of life. In addition, findings will contribute critical information regarding whether specific measures of proximal experience (language exposure, caregiver behavior, child sleep hygiene) may mediate this risk.
PUBLIC HEALTH RELEVANCE: Federal and State governments invest billions of dollars annually in programs that are intended to help "level the playing field" between children who grow up in poverty relative to their peers who do not. However, these investments typically target the 1-2 years prior to kindergarten, which may be too late according to accumulating evidence that (a) early life experience spanning the prenatal period through the first few years of life has a major and lasting impact on children's cognitive development, academic outcomes and eventual opportunities for success and (b) brain structure and major neural networks that support these abilities resemble adult forms by 2 years of age. The proposed study has the potential to inform early intervention and prevention efforts, which is critically important given the severity of the income achievement gap and the limited public health 1 R01 HD091148-01A1 3 PDRP PROPPER, C resources available to address this issue; investments targeting children's early experiences can be more cost effective and impactful for promoting children's learning ability and their eventual opportunity for success.

CRITIQUE 1
Significance: 1 Investigator(s): 1 Innovation: 1 Approach: 1 Environment: 1 Overall Impact: This revised application proposes to examine the effect of poverty on brain development related to executive function in early life and mediating roles of early experiences (sleep, parenting, and language exposure) in the poverty/executive function associations. This prospective longitudinal study will involve 230 women and their children who will complete five assessments across the first three years of the child's life. Poverty has been related to poor neurocognitive development and later academic problems. The scientific premise of this study is strong as it is based on the developmental origins of health and disease model and uses three well-established environmental factors shown to be related to poverty in early life, including parenting, sleep, and language exposure. Findings from this study will generate knowledge to enhance our understanding of early neurological development as an explanatory mechanism for the association between poverty and executive function. The study's direct test of brain development using structural and functional imaging is innovative. The investigator team is excellent covering expertise in parenting, child executive functioning, neuroimaging, and advanced statistical analyses. In the revision, scientific rigor has been strengthened by improving the recruitment approach to ensure a sample representing sufficient variation in poverty. Scientific rigor of this study is strong with comprehensive measures of the three aspects of early experience using multi-method approaches (e.g., questionnaires, behavioral tasks observation, Actigraphy, speech recording), well-thought-out longitudinal analytic plans including multivariate mediational growth curve modeling, and comprehensive power analyses. In addition, the revision offers preliminary findings that provide supporting evidence for all three aims. The potential overall impact is high because this application represents an exciting and innovative study to evaluate the effects of prenatal and postnatal poverty on the development of the brain and executive functioning during the first three years.

Significance: Strengths
Poverty has been related to poor neurocognitive development and academic problems. This study targets brain development which may be influenced by poverty and early experiences (sleep, parenting, and language exposure) and contribute to executive functioning development early in life (zero to three years). The findings would enhance our understanding of early neurological development as an explanatory mechanism for the association between poverty and executive function. The developmental origins of health and disease model guides the hypotheses as an overarching theoretical model, strengthening the scientific premise of the study.
The mediating roles of the three experiences (sleep, parenting, and language exposure) are supported by the literature and preliminary data. Weaknesses None noted.

Strengths
Multiple Principal Investigator Propper has a strong background in child executive functioning, and Multiple Principal Investigator Cox is a leading scientist in developmental psychology and has made invaluable contributions to the parenting and child development research field. Other co-investigators cover expertise in neuroimaging and statistical analyses.

Weaknesses
None noted.

Innovation:
Strengths This study will be the first to investigate the influence of poverty on executive functioning at age three via effects on neurological development over the first two years of life.
Direct test of brain development during early ages using structural and functional imaging is innovative.

Weaknesses
The associations among main study constructs (including poverty, brain, and EF) are well established in the literature.

Strengths
The use of Actiwatch and a speech recorder aids objective, comprehensive assessments of sleep patterns and language exposure, respectively.
Both structural and functional neuroimaging assessments will be performed. For connectivity analyses, both seed-based and independent component analysis approaches are used.
Power analyses are comprehensive.
Preliminary findings provide supporting evidence for all three aims.
Systematic recruitment strategies are presented to ensure that the recruited sample will represent enough families of poverty.

Weaknesses
In the proposed growth curve model, according to the time sequence, early experiences (caregiving, sleep, and language) measured at 6 months and 24 months predict brain growth rates measured at neonatal/2 weeks, 15 months, and 24 months. Predicting the growth trajectories spanning from neonatal/2 weeks to 24 months by variables measured at 6 and 24 months does not make sense.
Even in early age, sex differences in brain development may be present, thus need to be considered.

Environment:
Strengths

Resubmission:
Strengths remain and weaknesses raised in the previous reviews were well addressed.

Budget and Period of Support:
Recommend as Requested:

CRITIQUE 2
Significance: 2 Investigator(s): 1 Innovation: 1 Approach: 2 Environment: 1 Overall Impact: The premise of the study is to examine the influence of early life poverty on young children's executive functioning via effects on brain development in the first two years of life. Language exposure, caregiver behavior, and child sleep hygiene will be examined as mediators of the povertybrain development association. The methods are rigorous with multiple assessments of the same construct, using observational assessments and established tasks. Mothers will be seen during the 1 R01 HD091148-01A1 6 PDRP PROPPER, C 28th week of pregnancy and then infants and primary caregivers will be seen at 5 visits across the first 3 years of the child's life. Neuroimaging will be conducted at 2 weeks, 15 months, and 24 months, with a focus on developing white matter tracts involved with language processing, error monitoring, and joint attention. Functional brain development will also be measured, including resting state networks of default-mode, salience, attention, and executive control. Home visits at 6 and 24 months of age will include observational and objective measures of caregiver behavior, language exposure, and quality of sleep. An executive functioning battery will be administered at 36 months of age. The study has many strengths including the importance of the question, the strong team with complementary areas of expertise, the recruitment during pregnancy, the longitudinal design with gold standard assessments, and the planned missingness design to reduce participant burden. The likely impact of the work is high.

Significance: Strengths
The scientific premise is to identify brain mediators (reduced cortical volumes and surface area) through which poverty leads to poor executive functioning in 3 year olds.
The longitudinal design will provide 3 time points of brain scans, allowing the modeling of trajectories of infant brain development.
By considering the proximal experience that mediate the effects of early poverty on brain development, we may identify actionable targets for subsequent preventative and early intervention efforts.
Moreover, the most prolific changes in brain development that inform early EF take place from birth to 2 years.

Strengths
The team is strong with appropriate expertise. Multiple Principal Investigator Propper has a strong background in studying child poverty and emotion regulation, currently a Research Scientist, Center for Developmental Science, University of North Carolina at Chapel Hill. She is currently principal investigator on two federal grants (R21 from NICHD and a K01 from NIDA).
Multiple Principal Investigator Short, Assistant Professor at the University of North Carolina in Chapel Hill. Dr. Short's K01 focused on white matter and working memory development in children.
Other co-investigators cover expertise in neuroimaging and statistical analyses.

Strengths
The focus on how early life experiences and cognitive and neural development contribute to young children's executive functioning is unique and addresses a gap in knowledge about brain development from birth to age 2 years.

Approach: Strengths
The approach is vigorous in that recruitment occurs before the birth of the child (230 women are recruited from the hospital around 28 weeks of pregnancy), and objective measures are utilized.
The planned missing design is efficient and reduces participant burden (families participate in 2 of 3 imaging visits).
Objective measures of sleep (actiwatch), language exposure (LENA), and parenting are considered as mediators of the poverty-brain development link.
Structural and functional neuroimaging including diffusion tensor imaging and resting state fMRI is used at multiple time points across infancy and early childhood (2 weeks, 15 months and 24 months).
A computerized battery of EF tasks (EF Touch) is used to measure inhibitory control, attentional shifting and working memory.

Impressive results of preliminary studies
Weaknesses None noted 5. Environment:

Strengths
The Center for Developmental Science, The Neuro Image Research and Analysis Laboratory (NIRAL) at University of North Carolina at Chapel Hill are excellent environments for the proposed study.

None noted
Protections for Human Subjects:

Acceptable Risks and/or Adequate Protections
Adequate protections are in place. Ear protection is used during the MRI scans, participants are swaddled and scanned during sleep, and parents are allowed to stay with their child.

Resubmission:
Responsive to the original reviews

Resource Sharing Plans:
Acceptable De-identified data will be shared through NIH's DNAR database in the last quarter of year 5 of the grant

CRITIQUE 3
Significance: 2 Investigator(s): 3 Innovation: 1 Approach: 3 Environment: 1 Overall Impact: The proposed study aims to examine the effects of poverty on executive function (EF) from birth to preschool age with an examination of brain structure and function, as well as child sleep, parenting behaviors, and word exposure as mediators of pathways from poverty to EF. The work is highly significant as children from low SES background start preschool behind in academic and socioemotional skills, many of which are promoted by EF. Deficits in EF in preschool predict health, wealth, and violence into adulthood, making the issue highly significant. Though there is much desire to "level the playing field" for children early, little is known about how poverty may be affecting early brain development during both the pre-and postnatal period. Thus, the results of this work can inform policy and early prevention efforts. The proposed project is quite innovative in using MRI with very young children and combining this approach with a developmental science approach to measuring poverty, environmental mediators, and EF outcomes longitudinally. The investigative team has complimentary areas of expertise across the wide range of areas covered by this application. In particular, both principal investigators have very separate and complimentary experience and there is a good balance of early career and senior investigators. Moreover, the neuroimaging half of the team have been pioneers in the very difficult task of using MRI (and fMRI in particular) with babies. The application is responsive to previous reviews and the study is improved through a sampling plan likely to yield a locally representative sample that contains ethnic and socioeconomic diversity. Other strengths of the study include an innovative planned missingness design, the use of longitudinal imaging and constructing growth curves using MRI data, the ability to separate prenatal (and genetic) experiential effects on the brain from early-life contextual effects through the use of multiple imaging timepoints and modeling change over time, and cutting edge measurement of mediators (using observational 1 R01 HD091148-01A1 9 PDRP PROPPER, C measures of parenting, actigraphy for sleep, and LENA for word exposure). The overall innovation and significance of the proposed project is slightly diminished by some minor weaknesses and details that are under-described in the application including a very large Investigative team with seemingly overlapping areas of expertise (which may make coordination of the team difficult), lack of details about how high quality infant imaging data is achieved (i.e., the team clearly is expert at this task, but there is little detail about how the infants are kept still and happy -are they asleep? If so, how is this achieved and is it really a "resting state" scan?), and a lack of details about how the neuroimaging data will be reduced/focused on and put into SEMs (extracted from only a few regions of interest? Using what methods?). These weaknesses are relatively minor. The study has a strong scientific premise and is guided well by the literature reviewed. The study also appears to be adequately powered and potentially well-sampled, which assures high rigor and potential reproducibility. Sex as a biological variable is not featured prominently, but is addressed adequately by recruitment of boys and girls. Finally, the institutions support this research are strong with adequate resources.

Acceptable Risks and/or Adequate Protections
The protection of subjects plan is thoughtful and careful in protecting family information The sample will be diverse ethnically and socioeconomically and contain half boys and half girls as well as parents, which are all justified scientifically.

Not Applicable (No Vertebrate Animals)
Biohazards:

Resubmission:
The application was responsive to previous reviews and the proposed study is now improved, making the research stronger with higher rigor.

Budget and Period of Support:
Recommend as Requested Footnotes for 1 R01 HD091148-01A1; PI Name: Propper, Cathi Barbra NIH has modified its policy regarding the receipt of resubmissions (amended applications). See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-074.html. The impact/priority score is calculated after discussion of an application by averaging the overall scores (1-9) given by all voting reviewers on the committee and multiplying by 10. The criterion scores are submitted prior to the meeting by the individual reviewers assigned to an application, and are not discussed specifically at the review meeting or calculated into the overall impact score. Some applications also receive a percentile ranking. For details on the review process, see http://grants.nih.gov/grants/peer_review_process.htm#scoring.

MEETING ROSTER Psychosocial Development, Risk and Prevention Study Section Risk, Prevention and Health Behavior Integrated Review Group
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