Deoni SCL, D’Sa V, Volpe A, Beauchemin J, Croff JM, Elliott AJ, Pini N, Lucchini M, Fifer WP. Remote and at-home data collection: Considerations for the NIH HEALthy Brain and Cognitive Development (HBCD) study. Dev Cogn Neurosci. 2022 Apr;54:101059. doi: 10.1016/j.dcn.2022.101059. Epub 2022 Jan 6. PMID: 35033972; PMCID: PMC8762360.
The NIH HEALthy Brain and Cognitive Development (HBCD) study aims to characterize the impact of in utero exposure to substances, and related environmental exposures on child neurodevelopment and health outcomes. A key focus of HBCD is opioid exposure, which has disproportionately affected rural areas. While most opioid use and neonatal abstinence syndrome has been reported outside of large cities, rural communities are often under-represented in large-scale clinical research studies that involve neuroimaging, in-person assessments, or bio-specimen collections. Thus, there exists a likely mismatch between the communities that are the focus of HBCD and those that can participate. Even geographically proximal participants, however, are likely to bias towards higher socioeconomic status given the anticipated study burden and visit frequency. Wearables, ‘nearables’, and other consumer biosensors, however, are increasingly capable of collecting continuous physiologic and environmental exposure data, facilitating remote assessment. We review the potential of these technologies for remote in situ data collection, and the ability to engage rural, affected communities. While not necessarily a replacement, these technologies offer a compelling complement to traditional ‘gold standard’ lab-based methods, with significant potential to expand the study’s reach and importance.
Werchan, D.M., Hendrix, C.L., Ablow, J.C. et al. Behavioral coping phenotypes and associated psychosocial outcomes of pregnant and postpartum women during the COVID-19 pandemic. Sci Rep 12, 1209 (2022). https://doi.org/10.1038/s41598-022-05299-4
The impact of COVID-19-related stress on perinatal women is of heightened public health concern given the established intergenerational impact of maternal stress-exposure on infants and fetuses. There is urgent need to characterize the coping styles associated with adverse psychosocial outcomes in perinatal women during the COVID-19 pandemic to help mitigate the potential for lasting sequelae on both mothers and infants. This study uses a data-driven approach to identify the patterns of behavioral coping strategies that associate with maternal psychosocial distress during the COVID-19 pandemic in a large multicenter sample of pregnant women (N = 2876) and postpartum women (N = 1536). Data was collected from 9 states across the United States from March to October 2020. Women reported behaviors they were engaging in to manage pandemic-related stress, symptoms of depression, anxiety and global psychological distress, as well as changes in energy levels, sleep quality and stress levels. Using latent profile analysis, we identified four behavioral phenotypes of coping strategies. Critically, phenotypes with high levels of passive coping strategies (increased screen time, social media, and intake of comfort foods) were associated with elevated symptoms of depression, anxiety, and global psychological distress, as well as worsening stress and energy levels, relative to other coping phenotypes. In contrast, phenotypes with high levels of active coping strategies (social support, and self-care) were associated with greater resiliency relative to other phenotypes. The identification of these widespread coping phenotypes reveals novel behavioral patterns associated with risk and resiliency to pandemic-related stress in perinatal women. These findings may contribute to early identification of women at risk for poor long-term outcomes and indicate malleable targets for interventions aimed at mitigating lasting sequelae on women and children during the COVID-19 pandemic.
Nketia J, Amso D, Brito NH. Towards a more inclusive and equitable developmental cognitive neuroscience. Dev Cogn Neurosci. 2021 Dec;52:101014. doi: 10.1016/j.dcn.2021.101014. Epub 2021 Sep 20. PMID: 34571453; PMCID: PMC8476647.
Brain and cognitive development is a burgeoning area of scientific inquiry, with tremendous potential to better the lives of children. Large scale longitudinal neuroimaging studies offer opportunities for significant scientific advances in our understanding of developing brain structure and function. The proposed manuscript will focus on the scientific potential of the HEALthy Brain and Cognitive Development (HBCD) Study, highlighting what questions these data can and what they cannot answer about child development. Specifically, we caution against the misuse of these data for advancing de-contextualized and scientifically questionable narratives about the development of children from marginalized communities. We will focus on building and organizing a framework for interpreting HBCD data through the lens of sampling, cultural context, measurement, and developmental science theory. Our goal is to thoughtfully offer the scientific community opportunities to use the large scale and collaborative nature of HBCD to collectively revise practices in developmental science that to-date have not carefully considered their own role in perpetuating narratives that support systemic injustice.
Gustafsson HC, Young AS, Stamos G, et al. Innovative methods for remote assessment of neurobehavioral development. Developmental Cognitive Neuroscience, Volume 52, December 2021, 101015
In response to the COVID-19 pandemic, research institutions across the globe have modified their operations in ways that have limited or eliminated the amount of permissible in-person research interaction. In order to prevent the loss of important developmentally-timed data during the pandemic, researchers have quickly pivoted and developed innovative methods for remote assessment of research participants. In this manuscript, we describe methods developed for remote assessment of a parent child cohort with a focus on examining the perinatal environment, behavioral and biological indicators of child neurobehavioral development, parent-child interaction, as well as parent and child mental and physical health. We include recommendations relevant to adapting in-laboratory assessments for remote data collection and conclude with a description of the successful dissemination of the methods to eight research sites across the United States, each of whom are involved in Phase 1 of the HEALthy Brain and Child Development (HBCD) Study. These remote methods were born out of pandemic-related necessity; however, they have much wider applicability and may offer advantages over in-laboratory neurodevelopmental assessments.
Massey SH, Allen NB, Pool LR, et al. Impact of prenatal exposure characterization on early risk detection: Methodologic insights for the HEALthy Brain and Child Development (HBCD) study. Neurotoxicology and Teratology, Volume 88, November–December 2021, 107035.
Background
A major challenge in prenatal drug exposure research concerns the balance of measurement quality with sample sizes necessary to address confounders. To inform the selection of optimal exposure measures for the HEALthy Brain and Child Development (HBCD) Study, we employed integrated analysis to determine how different methods used to characterize prenatal tobacco exposure influence the detection of exposure-related risk, as reflected in normal variations in birth weight.
Methods
Participants were N = 2323 mother-infant dyads derived from 7 independent developmental cohorts harmonized on measures of exposure, outcome (birthweight), and covariates. We compared estimates of PTE-related effects on birthweight derived from linear regression models when PTE was categorized dichotomously based on any fetal exposure (30% exposed; 69% not exposed); versus categorically, based on common patterns of maternal smoking during pregnancy (never smoked 69%; quit smoking 16%; smoked intermittently 2%; smoked persistently 13%). We secondarily explored sex differences in PTE-birthweight associations across these categorization methods.
Results
When PTE was categorized dichotomously, exposure was associated with a − 125-g difference in birthweight (95% C.I. -173.7 – −76.6, p < .0001). When PTE was characterized categorically based on maternal smoking patterns, however, exposure was associated with either no difference in birthweight if mothers quit smoking by the end of the first trimester (B = -30.6, 95% C.I. -88.7–27.4, p = .30); or a − 221.8 g difference in birthweight if mothers did not [95% C.I. (−161.7 to −282.0); p < .001]. Qualitative sex differences were also detected though PTE x sex interactions did not reach statistical significance. Maternal smoking cessation during pregnancy was associated with a 239.3 g increase in birthweight for male infants, and a 114.0 g increase in birthweight for females infants (p = .07).
Conclusions
Categorization of PTE based on patterns of maternal smoking rather than the presence or absence of exposure alone revealed striking nuances in estimates of exposure-related risk. The described method that captures both between-individual and within-individual variability in prenatal drug exposure is optimal and recommended for future developmental investigations such as the HBCD Study.
Stephen JM, Hill DE, Candelaria-Cook FT. Examining the effects of prenatal alcohol exposure on corticothalamic connectivity: A multimodal neuroimaging study in children. Dev Cogn Neurosci. 2021 Dec;52:101019. doi: 10.1016/j.dcn.2021.101019. Epub 2021 Oct 8. PMID: 34666262; PMCID: PMC8524752.
Children with a fetal alcohol spectrum disorder (FASD) experience a range of cognitive and behavioral effects. Prior studies have demonstrated white matter changes in children with FASD relative to typically developing controls (TDC) and these changes relate to behavior. Our prior MEG study (Candelaria-Cook et al. 2020) demonstrated reduced alpha oscillations during rest in FASD relative to TDC and alpha power is correlated with behavior. However, little is known about how brain structure influences brain function. We hypothesized that alpha power was related to corticothalamic connectivity. Children 8-13 years of age (TDC: N = 25, FASD: N = 24) underwent rest MEG with eyes open or closed and MRI to collect structural and diffusion tensor imaging data. MEG spectral analysis was performed for sensor and source data. We estimated mean fractional anisotropy in regions of interest (ROIs) that included the corticothalamic tracts. The FASD group had reduced mean FA in three of the corticothalamic ROIs. FA in these tracts was significantly correlated with alpha power at the sensor and source level. The results support the hypothesis that integrity of the corticothalamic tracts influences cortical alpha power. Further research is needed to understand how brain structure and function influence behavior.
Norton ES, MacNeill LA, Harriott EM, Allen N, Krogh-Jespersen S, Smyser CD, Rogers CE, Smyser TA, Luby J, Wakschlag L. EEG/ERP as a pragmatic method to expand the reach of infant-toddler neuroimaging in HBCD: Promises and challenges. Dev Cogn Neurosci. 2021 Oct;51:100988. doi: 10.1016/j.dcn.2021.100988. Epub 2021 Jul 14. PMID: 34280739; PMCID: PMC8318873.
Though electrophysiological measures (EEG and ERP) offer complementary information to MRI and a variety of advantages for studying infants and young children, these measures have not yet been included in large cohort studies of neurodevelopment. This review summarizes the types of EEG and ERP measures that could be used in the HEALthy Brain and Cognitive Development (HBCD) study, and the promises and challenges in doing so. First, we provide brief overview of the use of EEG/ERP for studying the developing brain and discuss exemplar findings, using resting or baseline EEG measures as well as the ERP mismatch negativity (MMN) as exemplars. We then discuss the promises of EEG/ERP such as feasibility, while balancing challenges such as ensuring good signal quality in diverse children with different hair types. We then describe an ongoing multi-site EEG data harmonization from our groups. We discuss the process of alignment and provide preliminary usability data for both resting state EEG data and auditory ERP MMN in diverse samples including over 300 infants and toddlers. Finally, we provide recommendations and considerations for the HBCD study and other studies of neurodevelopment.
Merhar SL, Jiang W, Parikh NA, Yin W, Zhou Z, Tkach JA, Wang L, Kline-Fath BM, He L, Braimah A, Vannest J, Lin W. Effects of prenatal opioid exposure on functional networks in infancy. Dev Cogn Neurosci. 2021 Oct;51:100996. doi: 10.1016/j.dcn.2021.100996. Epub 2021 Jul 31. PMID: 34388637; PMCID: PMC8363826.
Prenatal opioid exposure has been linked to altered neurodevelopment and visual problems such as strabismus and nystagmus. The neural substrate underlying these alterations is unclear. Resting-state functional connectivity MRI (rsfMRI) is an advanced and well-established technique to evaluate brain networks. Few studies have examined the effects of prenatal opioid exposure on resting-state network connectivity in infancy. In this pilot study, we characterized network connectivity in opioid-exposed infants (n = 19) and controls (n = 20) between 4–8 weeks of age using both a whole-brain connectomic approach and a seed-based approach. Prenatal opioid exposure was associated with differences in distribution of betweenness centrality and connection length, with positive connections unique to each group significantly longer than common connections. The unique connections in the opioid-exposed group were more often inter-network connections while unique connections in controls and connections common to both groups were more often intra-network. The opioid-exposed group had smaller network volumes particularly in the primary visual network, but similar network strength as controls. Network topologies as determined by dice similarity index were different between groups, particularly in visual and executive control networks. These results may provide insight into the neural basis for the developmental and visual problems associated with prenatal opioid exposure.
Rajagopalan V, Deoni S, Panigrahy A, Thomason ME. Is fetal MRI ready for neuroimaging prime time? An examination of progress and remaining areas for development. Developmental Cognitive Neuroscience, Volume 51, October 2021, 100999
A major challenge in designing large-scale, multi-site studies is developing a core, scalable protocol that retains the innovation of scientific advances while also lending itself to the variability in experience and resources across sites. In the development of a common Healthy Brain and Child Development (HBCD) protocol, one of the chief questions is “is fetal MRI ready for prime-time?” While there is agreement about the value of prenatal data obtained non-invasively through MRI, questions about practicality abound. There has been rapid progress over the past years in fetal and placental MRI methodology but there is uncertainty about whether the gains afforded outweigh the challenges in supporting fetal MRI protocols at scale. Here, we will define challenges inherent in building a common protocol across sites with variable expertise and will propose a tentative framework for evaluation of design decisions. We will compare and contrast various design considerations for both normative and high-risk populations, in the setting of the post-COVID era. We will conclude with articulation of the benefits of overcoming these challenges and would lend to the primary questions articulated in the HBCD initiative.
Thomason ME, Palopoli AC, Jariwala NN, et al. Miswiring the brain: Human prenatal Δ9-tetrahydrocannabinol use associated with altered fetal hippocampal brain network connectivity. Developmental Cognitive Neuroscience, Volume 51, October 2021, 101000
Increasing evidence supports a link between maternal prenatal cannabis use and altered neural and physiological development of the child. However, whether cannabis use relates to altered human brain development prior to birth, and specifically, whether maternal prenatal cannabis use relates to connectivity of fetal functional brain systems, remains an open question. The major objective of this study was to identify whether maternal prenatal cannabis exposure (PCE) is associated with variation in human brain hippocampal functional connectivity prior to birth. Prenatal drug toxicology and fetal fMRI data were available in a sample of 115 fetuses [43 % female; mean age 32.2 weeks (SD = 4.3)]. Voxelwise hippocampal connectivity analysis in a subset of age and sex-matched fetuses revealed that PCE was associated with alterations in fetal dorsolateral, medial and superior frontal, insula, anterior temporal, and posterior cingulate connectivity. Classification of group differences by age 5 outcomes suggest that compared to the non-PCE group, the PCE group is more likely to have increased connectivity to regions associated with less favorable outcomes and to have decreased connectivity to regions associated with more favorable outcomes. This is preliminary evidence that altered fetal neural connectome may contribute to neurobehavioral vulnerability observed in children exposed to cannabis in utero.
Zhou J, Havens KL, Starnes CP, Pickering TA, Brito NH, Hendrix CL, Thomason ME, Vatalaro TC, Smith BA. Changes in social support of pregnant and postnatal mothers during the COVID-19 pandemic. Midwifery. 2021 Dec;103:103162. doi: 10.1016/j.midw.2021.103162. Epub 2021 Oct 1. PMID: 34649034; PMCID: PMC8485715.
Objective
Our objectives were to assess in perinatal women: the most effective methods used to meet social support needs during COVID-19, the impact of COVID-19 on self-reported social support levels, and how perceived change in social support related to distress, depression, and mental health.
Design
One-time survey administered from April to August 2020
Setting
Online
Participants
Pregnant and postpartum women with infants less than 6 months of age
Measurement and Findings
Participants indicated the methods they used to meet social support needs during COVID-19. They self-rated their social support level pre- and during pandemic and their distress, depressive symptoms, and mental health changes on a Likert scale. Out of 1142 participants, the most effective methods for obtaining social support during the pandemic were virtual means (e.g. video call) and interaction with friends. There was a significant difference in distribution of self-reported levels of social support before and during the pandemic, with more respondents reporting a decrease in support. Decreases in social support were associated with higher distress levels, higher levels of depressive symptoms, and poorer mental health.
Key Conclusions
Perinatal women reported decreased social support during the COVID-19 pandemic which was associated with poorer mental health. Using virtual means of social support and support provided by friends had the largest positive effect on perceived social support levels.
Implications for Practice
Interventions using virtual support means from friends may be helpful to improve social support and mental health in this population.
Deoni SCL, Bruchhage MMK, Beauchemin J, Volpe A, D’Sa V, Huentelman M, Williams SCR. Accessible pediatric neuroimaging using a low field strength MRI scanner. NeuroImage, Volume 238, September 2021, 118273, https://doi.org/10.1016/j.neuroimage.2021.118273
Magnetic resonance imaging (MRI) has played an increasingly relevant role in understanding infant, child, and adolescent neurodevelopment, providing new insight into developmental patterns in neurotypical development, as well as those associated with potential psychopathology, learning disorders, and other neurological conditions. In addition, studies have shown the impact of a child’s physical and psychosocial environment on developing brain structure and function. A rate-limiting complication in these studies, however, is the high cost and infrastructural requirements of modern MRI systems. High costs mean many neuroimaging studies typically include fewer than 100 individuals and are performed predominately in high resource hospitals and university settings within high income countries (HICs). As a result, our knowledge of brain development, particularly in children who live in lower and middle income countries (LMICs) is relatively limited. Low field systems, with magnetic fields less than 100mT offer the promise of lower scanning costs and wide-spread global adoption, but routine low field pediatric neuroimaging has yet to be demonstrated. Here we present the first pediatric MRI data collected on a low cost and assessable 64mT scanner in children 6 weeks to 16 years of age and replicate brain volumes estimates and developmental trajectories derived from 3T MRI data. While preliminary, these results illustrate the potential of low field imaging as a viable complement to more conventional high field imaging systems, and one that may further enhance our knowledge of neurodevelopment in LMICs where malnutrition, psychosocial adversities, and other environmental exposures may profoundly affect brain maturation.
Schneider N, Greenstreet E, Deoni SCL. Connecting inside out: Development of the social brain in infants and toddlers with a focus on myelination as a marker of brain maturation. Child Development, https://doi.org/10.1111/cdev.13649
Early childhood is a sensitive period for learning and social skill development. The maturation of cerebral regions underlying social processing lays the foundation for later social-emotional competence. This study explored myelin changes in social brain regions and their association with changes in parent-rated social-emotional development in a cohort of 129 children (64 females, 0–36 months, 77 White). Results reveal a steep increase in myelination throughout the social brain in the first 3 years of life that is significantly associated with social-emotional development scores. These findings add knowledge to the emerging picture of social brain development by describing neural underpinnings of human social behavior. They can contribute to identifying age-/stage-appropriate early life factors in this developmental domain.
Chen H, Liu J, Chen Y, Salzwedel A, Cornea E, Gilmore JH, Gao W. Developmental heatmaps of brain functional connectivity from newborns to 6-year-olds. Dev Cogn Neurosci. 2021 Aug;50:100976. doi: 10.1016/j.dcn.2021.100976. Epub 2021 Jun 16. PMID: 34174513; PMCID: PMC8246150.
Different functional networks exhibit distinct longitudinal trajectories throughout development, but the timeline of the dynamics of functional connectivity across the whole brain remains to be elucidated. Here we used resting-state fMRI to investigate the development of voxel-level changes in functional connectivity across the first six years of life. Globally, we found that developmental changes in functional connectivity are nonlinear with more changes during the first postnatal year than the second, followed by most significant changes from ages 2-4 and from ages 4-6. However, the overall global difference observed between the first and second year appears to have been driven by girls. Limbic and subcortical areas consistently demonstrated the most substantial changes, whereas primary sensory areas were the most stable. These patterns were consistent in full-term and preterm subgroups. Validation on randomly divided subsamples as well as in an independent cross-sectional sample revealed global patterns consistent with the main results. Overall, the derived developmental heatmaps reveal novel dynamics underlying functional circuit development during the first 6 years of life.
Kohlasch KL, Cioffredi L-A, Lenninger C, et al. Factors associated with parent views about participation in infant MRI research provide guidance for the design of the Healthy Brain and Child Development (HBCD) study. Developmental Cognitive Neuroscience, Volume 50, August 2021, 100986
Purpose
The National Institutes of Health announced the Healthy Brain and Child Development (HBCD) study to further understanding of infant brain development. This study examined perceptions and knowledge about research among the demographic groups to be studied in HBCD.
Method
1164 participants (n = 548 pregnant people and 616 mothers of infants < 12 months) completed anonymous, on-line surveys. Domains included research literacy, MRI knowledge, and attitudes about research incentives and biospecimen collection. Logistic regression was used to examine factors related to outcome variables.
Results
Knowledge of MRI safety was low and research literacy was high across participants. Likelihood of participation given various incentives differed between participants. Those with lower education were less likely to rate any items as increasing likelihood of participation. Substance use during pregnancy improved the model fit only for items about alternate visit structures (home and telephone visits) and confidentiality.
Conclusion
Overall results support the feasibility of infant imaging studies, such as HBCD with respondents having high research literacy and interest in learning about their baby’s development. Educating potential participants about MRI safety and providing flexible incentives for participation will improve the success of infant MRI studies.
DiPietro JL, Mackiewicz Seghete KL, Krans EE, et al. Stakeholder Perspectives on Advancing Understanding of Prenatal Opioid Exposure and Brain Development From the iOPEN Consortium of the Healthy Brain and Child Development Study. Front. Psychol., 30 July 2021, Sec. Developmental Psychology, https://doi.org/10.3389/fpsyg.2021.698766
Introduction: There is a dire need for research regarding the implications of opioid use during pregnancy on fetal and childhood development to better inform both medical practice and policy. The Healthy Brain and Child Development Study will examine brain and behavioral development from birth through the first decade of life. Due to large scope and anticipated complexity of this initiative, an 18-month planning phase was implemented across 28 sites across the nation. A core element of the Phase I initiative involved the development of Stakeholder Advisory Committees to inform the next phase of the initiative.
Methods: Phase I stakeholder meetings were conducted at Oregon Health and Science University, New York University Langone Medical Center, the University of Pittsburgh, and the University of Vermont to better understand perspectives and inform upcoming research. Despite differences in the structure of the stakeholder meetings by site, the overarching goals for the meetings included establishing relationships, gathering input, and learning about research engagement. Documents from each meeting were reviewed for location, duration, attendees, common research themes, and pertinent suggestions for improving research approaches.
Results: All stakeholders had high levels of interest in research for pregnant people with substance use disorders and agreed on research priorities including collaboration, connection, communication, and support. Different stakeholders offered unique perspectives on various aspects of study design and themes that emerged through meetings.
Discussion: Overall, there was excitement about the research, especially the opportunity to include the voices of people with lived experience; collaboration between providers, peer support specialists, patients, and others; and excitement around contributing to research that could elucidate new and pertinent findings in the realm of addiction medicine and child development. Sites also found that there is mistrust between people with substance use disorder and the medical system, and this could be addressed by including people with lived experience on the research team, forming connections, communicating clearly, training the research team in implicit bias, and practicing trauma-informed care. In conclusion, these stakeholder meetings provided valuable information for structuring upcoming studies; however, researchers would have benefitted from more time and more opportunities for in-person connection.
Lewis CR, Bonham KS, McCann SH, Volpe AR, D’Sa V, Naymik M, De Both MD, Huentelman MJ, Lemery-Chalfant K, Highlander SK, Deoni SCL, Klepac-Ceraj V. Family SES Is Associated with the Gut Microbiome in Infants and Children. Microorganisms. 2021 Jul 28;9(8):1608. doi: 10.3390/microorganisms9081608. PMID: 34442687; PMCID: PMC8398307.
Background: While early life exposures such as mode of birth, breastfeeding, and antibiotic use are established regulators of microbiome composition in early childhood, recent research suggests that the social environment may also exert influence. Two recent studies in adults demonstrated associations between socioeconomic factors and microbiome composition. This study expands on this prior work by examining the association between family socioeconomic status (SES) and host genetics with microbiome composition in infants and children.
Methods: Family SES was used to predict a latent variable representing six genera abundances generated from whole-genome shotgun sequencing. A polygenic score derived from a microbiome genome-wide association study was included to control for potential genetic associations. Associations between family SES and microbiome diversity were assessed.
Results: Anaerostipes, Bacteroides, Eubacterium, Faecalibacterium, and Lachnospiraceae spp. significantly loaded onto a latent factor, which was significantly predicted by SES (p < 0.05) but not the polygenic score (p > 0.05). Our results indicate that SES did not predict alpha diversity but did predict beta diversity (p < 0.001).
Conclusions: Our results demonstrate that modifiable environmental factors influence gut microbiome composition at an early age. These results are important as our understanding of gut microbiome influences on health continue to expand.
Thomason, M.E., Hect, J.L., Waller, R., Curtin P. Interactive relations between maternal prenatal stress, fetal brain connectivity, and gestational age at delivery. Neuropsychopharmacol. 46, 1839–1847 (2021). https://doi.org/10.1038/s41386-021-01066-7
Studies reporting significant associations between maternal prenatal stress and child outcomes are frequently confounded by correlates of prenatal stress that influence the postnatal rearing environment. The major objective of this study is to identify whether maternal prenatal stress is associated with variation in human brain functional connectivity prior to birth. We utilized fetal fMRI in 118 fetuses [48 female; mean age 32.9 weeks (SD = 3.87)] to evaluate this association and further addressed whether fetal neural differences were related to maternal health behaviors, social support, or birth outcomes. Community detection was used to empirically define networks and enrichment was used to isolate differential within- or between-network connectivity effects. Significance for χ2 enrichment was determined by randomly permuting the subject pairing of fetal brain connectivity and maternal stress values 10,000 times. Mixtures modelling was used to test whether fetal neural differences were related to maternal health behaviors, social support, or birth outcomes. Increased maternal prenatal negative affect/stress was associated with alterations in fetal frontoparietal, striatal, and temporoparietal connectivity (β = 0.82, p < 0.001). Follow-up analysis demonstrated that these associations were stronger in women with better health behaviors, more positive interpersonal support, and lower overall stress (β = 0.16, p = 0.02). Additionally, magnitude of stress-related differences in neural connectivity was marginally correlated with younger gestational age at delivery (β = −0.18, p = 0.05). This is the first evidence that negative affect/stress during pregnancy is reflected in functional network differences in the human brain in utero, and also provides information about how positive interpersonal and health behaviors could mitigate prenatal brain programming.
Rutherford S, Sturmfels P, Angstadt M, Hect J, Wiens J, van den Heuvel MI, Scheinost D, Sripada C, Thomason M. Automated Brain Masking of Fetal Functional MRI with Open Data. Neuroinformatics. 2021 Jun 15. doi: 10.1007/s12021-021-09528-5. Epub ahead of print. PMID: 34129169.
Fetal resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as a critical new approach for characterizing brain development before birth. Despite the rapid and widespread growth of this approach, at present, we lack neuroimaging processing pipelines suited to address the unique challenges inherent in this data type. Here, we solve the most challenging processing step, rapid and accurate isolation of the fetal brain from surrounding tissue across thousands of non-stationary 3D brain volumes. Leveraging our library of 1,241 manually traced fetal fMRI images from 207 fetuses, we trained a Convolutional Neural Network (CNN) that achieved excellent performance across two held-out test sets from separate scanners and populations. Furthermore, we unite the auto-masking model with additional fMRI preprocessing steps from existing software and provide insight into our adaptation of each step. This work represents an initial advancement towards a fully comprehensive, open-source workflow, with openly shared code and data, for fetal functional MRI data preprocessing.
Goldstein E, Bakhireva LN, Nervik K, et al. Recruitment and retention of pregnant women in prospective birth cohort studies: A scoping review and content analysis of the literature. Neurotoxicology and Teratology, Volume 85, May–June 2021, 106974.
Longitudinal cohort studies present unique methodological challenges, especially when they focus on vulnerable populations, such as pregnant women. The purpose of this review is to synthesize the existing knowledge on recruitment and retention (RR) of pregnant women in birth cohort studies and to make recommendations for researchers to improve research engagement of this population. A scoping review and content analysis were conducted to identify facilitators and barriers to the RR of pregnant women in cohort studies. The search retrieved 574 articles, with 38 meeting eligibility criteria and focused on RR among English-speaking, adult women, who are pregnant or in early postpartum period, enrolled in birth cohort studies. Selected studies were birth cohort (including longitudinal) (n = 20), feasibility (n = 14), and other (n = 4) non-interventional study designs. The majority were from low-risk populations. Abstracted data were coded according to emergent theme clusters. The majority of abstracted data (79%) focused on recruitment practices, with only 21% addressing retention strategies. Overall, facilitators were reported more often (75%) than barriers (25%). Building trusting relationships and employing diverse recruitment methods emerged as major recruitment facilitators; major barriers included heterogeneous participant reasons for refusal and cultural factors. Key retention facilitators included flexibility with scheduling, frequent communication, and culturally sensitive practices, whereas participant factors such as loss of interest, pregnancy loss, relocation, multiple caregiver shifts, and substance use/psychiatric problems were cited as major barriers. Better understanding of facilitators and barriers of RR can help enhance the internal and external validity of future birth/pre-birth cohorts. Strategies presented in this review can help inform investigators and funding agencies of best practices for RR of pregnant women in longitudinal studies.
Norr ME, Hect JL, Lenniger CJ, Van den Heuvel M, Thomason ME. An examination of maternal prenatal BMI and human fetal brain development. J Child Psychol Psychiatry. 2021 April ; 62(4): 458–469. doi:10.1111/jcpp.13301
Background
Prenatal development is a time when the brain is acutely vulnerable to insult and alteration by environmental factors (e.g., toxins, maternal health). One important risk factor is maternal obesity (Body Mass Index > 30). Recent research indicates that high maternal BMI during pregnancy is associated with increased risk for numerous physical health, cognitive, and mental health problems in offspring across the lifespan. It is possible that heightened maternal prenatal BMI influences the developing brain even before birth.
Methods
The present study examines this possibility at the level of macrocircuitry in the human fetal brain. Using a data-driven strategy for parcellating the brain into subnetworks, we test whether MRI functional connectivity within or between fetal neural subnetworks varies with maternal prenatal BMI in 109 fetuses between the ages of 26 and 39weeks.
Results
We discovered that strength of connectivity between two subnetworks, left anterior insula/inferior frontal gyrus (aIN/IFG) and bilateral prefrontal cortex (PFC), varied with maternal BMI. At the level of individual aIN/IFG-PFC connections, we observed both increased and decreased between-network connectivity with a tendency for increased within-hemisphere connectivity and reduced cross-hemisphere connectivity in higher BMI pregnancies. Maternal BMI was not associated with global differences in network topography based on network-based statistical analyses.
Conclusions
Overall effects were localized in regions that will later support behavioral regulation and integrative processes, regions commonly associated with obesity-related deficits. By establishing onset in neural differences prior to birth, this study supports a model in which maternal BMI-related risk is associated with fetal connectome-level brain organization with implications for offspring long-term cognitive development and mental health.
Volkow ND, Gordon JA, Freund MP. The Healthy Brain and Child Development Study—Shedding Light on Opioid Exposure, COVID-19, and Health Disparities. JAMA Psychiatry. 2021;78(5):471-472. doi:10.1001/jamapsychiatry.2020.3803
Croff, J.M., Bogdan, R., Johnson, S.B. et al. Early Environmental Exposures and Contaminants: a Design Framework for Biospecimen Collection and Analysis for a Prospective National Birth Cohort. ADV RES SCI 1, 269–283 (2020). https://doi.org/10.1007/s42844-020-00024-4
Identifying factors associated with disruptions in early neurodevelopment is imperative for promoting the health and wellbeing of children. We describe a design framework for biospecimen collection for the forthcoming HEALthy Brain and Child Development (HBCD) study, which seeks to establish a large cohort of pregnant women throughout the USA and follow their children into middle childhood. Biospecimens and biological outcomes of interest, together with validated questionnaires and other measures, may help to disentangle the effect of prenatal exposures from social and environment factors that extend across the prenatal and postnatal periods, including early life adversity (ELA). Biospecimen selection is discussed across four domains of interest: (a) substance use exposure, (b) other environmental exposures, (c) genomics and epigenomics, and (d) other biological markers of neurodevelopment and putative moderators and mediators of developmental effects. HBCD biospecimen working group recommendations were based on nine guiding principles including utility as a biomarker to assess neurodevelopment; feasibility of collection during critical periods of exposure with a broad detection window; logistics and cost of specimen collection, storage, and transportation; cultural acceptability; minimal invasiveness; flexibility; high sensitivity and specificity; anticipated expertise and infrastructure at participating sites; and availability of informative alternative non-biological measures. The proposed essential and recommended biospecimens will need to be integrated with the recommendations from other HBCD working groups to ascertain overall burden for the research participants and families, feasibility of multi-modal collection at each study visit, cost, and implications for recruitment and retention, as well as any potential legal repercussions.
Morris AS, Wakschlag L, Krogh-Jespersen S, Fox N, Planalp B, Perlman SB, Shuffrey LC, Smith B, Lorenzo NE, Amso D, Coles CD, Johnson SP. Principles for Guiding the Selection of Early Childhood Neurodevelopmental Risk and Resilience Measures: HEALthy Brain and Child Development Study as an Exemplar. Advers Resil Sci. 2020;1(4):247-267. doi: 10.1007/s42844-020-00025-3. Epub 2020 Nov 9. PMID: 33196052; PMCID: PMC7649097.
The vast individual differences in the developmental origins of risk and resilience pathways combined with sophisticated capabilities of big data science increasingly point to the imperative of large, neurodevelopmental consortia to capture population heterogeneity and key variations in developmental trajectories. At the same time, such large-scale population-based designs involving multiple independent sites also must weigh competing demands. For example, the need for efficient, scalable assessment strategies must be balanced with the need for nuanced, developmentally sensitive phenotyping optimized for linkage to neural mechanisms and specification of common and distinct exposure pathways. Standardized epidemiologic batteries designed for this purpose such as PhenX (consensus measures for Phenotypes and eXposures) and the National Institutes of Health (NIH) Toolbox provide excellent “off the shelf” assessment tools that are well-validated and enable cross-study comparability. However, these standardized toolkits can also constrain ability to leverage advances in neurodevelopmental measurement over time, at times disproportionately advantaging established measures. In addition, individual consortia often expend exhaustive effort “reinventing the wheel,” which is inefficient and fails to fully maximize potential synergies with other like initiatives. To address these issues, this paper lays forth an early childhood neurodevelopmental assessment strategy, guided by a set of principles synthesizing developmental and pragmatic considerations generated by the Neurodevelopmental Workgroup of the HEALthy Brain and Child Development (HBCD) Planning Consortium. These principles emphasize characterization of both risk- and resilience-promoting processes. Specific measurement recommendations to HBCD are provided to illustrate application. However, principles are intended as a guiding framework to transcend any particular initiative as a broad neurodevelopmentally informed, early childhood assessment strategy for large-scale consortia science.
Beasley LO, Ciciolla L, Jespersen JE, Chiaf AL, Schmidt M, Shreffler KM, Breslin FJ, Bakhireva LN, Sanjuan PM, Stephen JM, Coles CD, Chambers CD, Kable JA, Leeman L, Singer LT, Zellner J, Morris AS, Croff JM. Best Practices for Engaging Pregnant and Postpartum Women at Risk of Substance Use in Longitudinal Research Studies: a Qualitative Examination of Participant Preferences. Advers Resil Sci. 2020;1(4):235-246. doi: 10.1007/s42844-020-00019-1. Epub 2020 Oct 28. PMID: 33134976; PMCID: PMC7592139.
There are significant barriers in engaging pregnant and postpartum women that are considered high-risk (e.g., those experiencing substance use and/or substance use disorders (SUD)) into longitudinal research studies. To improve recruitment and retention of this population in studies spanning from the prenatal period to middle childhood, it is imperative to determine ways to improve key research engagement factors. The current manuscript uses a qualitative approach to determine important factors related to recruiting, enrolling, and retaining high-risk pregnant and postpartum women. The current sample included 41 high-risk women who participated in focus groups or individual interviews. All interviews were analyzed to identify broad themes related to engaging high-risk pregnant and parenting women in a 10-year longitudinal research project. Themes were organized into key engagement factors related to the following: (1) recruitment strategies, (2) enrollment, and (3) retention of high-risk pregnant and parenting women in longitudinal research studies. Results indicated recruitment strategies related to ideal recruitment locations, material, and who should share research study information with high-risk participants. Related to enrollment, key areas disclosed focused on enrollment decision-making, factors that create interest in joining a research project, and barriers to joining a longitudinal research study. With regard to retention, themes focused on supports needed to stay in research, barriers to staying in research, and best ways to stay in contact with high-risk participants. Overall, the current qualitative data provide preliminary data that enhance the understanding of a continuum of factors that impact engagement of high-risk pregnant and postpartum women in longitudinal research with current results indicating the need to prioritize recruitment, enrollment, and retention strategies in order to effectively engage vulnerable populations in research.
Singer LT, Chambers C, Coles C, Kable J. Fifty Years of Research on Prenatal Substances: Lessons Learned for the Opioid Epidemic. Advers Resil Sci. 2020 Dec;1(4):223-234. doi: 10.1007/s42844-020-00021-7. Epub 2020 Oct 27. PMID: 34316723; PMCID: PMC8312986.
Current efforts to design research on developmental effects of prenatal opioid exposure can benefit from knowledge gained from 50 years of studies of fetal alcohol and prenatal drug exposures such as cocaine. Scientific advances in neurobiology, developmental psychopathology, infant assessments, genetics, and imaging support the principles of developmental neurotoxicology that guide research in prenatal exposures. Important to research design is accurate assessment of amount, frequency, and timing of exposure which benefits from accurate self-report and biomarkers of exposure. Identifying and control of pre- and postnatal factors that impact development are difficult and dependent on appropriate research design and selection of comparison groups and measurement of confounding, mediating, and moderating variables. Polysubstance exposure has increased due to the number of prescribed and nonprescribed substances used by pregnant women and varying combinations of drugs may have differential effects on the outcome. Multiple experimental and clinical assessments of infant behavior have been developed but predicting outcome before 18–24 months of age remains difficult. With some exceptions, prenatal substance exposure effect sizes have been small, and cognitive and behavioral effects tend to be specific rather than global. Studies require large sample sizes, adequate retention, and support for social services in at-risk samples. The ethical and legal contexts and stigma associated with drug/alcohol use disorder should be considered in order to prevent harm to families in research programs. Recognition of the pervasive use of addictive substances in this nation should lead to broad scientific efforts to understand how substances affect child outcomes and to initiate prevention and intervention where needed.
Bakhireva, L.N., Nebeker, C., Ossorio, P. et al. Inclusion of American Indians and Alaskan Natives in Large National Studies: Ethical Considerations and Implications for Biospecimen Collection in the HEALthy Brain and Child Development Study. ADV RES SCI 1, 285–294 (2020). https://doi.org/10.1007/s42844-020-00020-8
This manuscript is the result of an interdisciplinary team approach to examine the ethical and cultural considerations of biospecimen collection among American Indian and Alaskan Native (AIAN) communities for the planned Healthy Brain and Child Development (HBCD) study. We begin by reviewing a brief history of the treatment of AIAN communities by the US government and within research studies. Based in part on this history, we highlight the overlapping and intersecting vulnerabilities of AIAN communities, including historical trauma, poverty, lack of healthcare access, and environmental hazards. After consideration of ethical and legal implications, we introduce our recommendations for biospecimen collection/biobanking with AIAN communities in the context of population-representative, multi-site, national studies. We recommend the following key considerations: (1) authentic partnership development; (2) beneficence to the community; (3) culturally respectful research design; (4) meaningful consent to support enrollment and retention; (5) culturally appropriate data management. Adherence to a culturally aware approach for inclusion of underrepresented communities assures external validity in the national studies and increases likelihood of bidirectional value exchange.
Jordan CJ, Weiss SRB, Howlett KD, Freund MP. Introduction to the Special Issue on “Informing Longitudinal Studies on the Effects of Maternal Stress and Substance Use on Child Development: Planning for the HEALthy Brain and Child Development (HBCD) Study”. Advers Resil Sci. 2020;1(4):217-221. doi: 10.1007/s42844-020-00022-6. Epub 2020 Oct 22. PMID: 33106790; PMCID: PMC7578232.
The HEALthy Brain and Child Development (HBCD) study will establish a large cohort of pregnant women from regions of the country significantly affected by the opioid crisis and follow them and their children for at least 10 years. Findings from this cohort will help researchers understand normative childhood brain development as well as the long-term impact of prenatal and postnatal opioid and other drug and environmental exposures. The study will collect data on pregnancy and fetal development; infant and early childhood structural and functional brain imaging; anthropometrics; medical history; family history; biospecimens; and social, emotional, and cognitive development. Knowledge gained from this research will be critical to help predict and prevent some of the known effects of prenatal and postnatal exposure to certain drugs or environmental exposures, including risk for future substance use, mental disorders, and other behavioral and developmental problems. In this special issue, a subset of investigators that received funding for planning grants for the HBCD study provide careful guidelines and frameworks for study design, recruitment and retention of vulnerable populations, culturally sensitive practices, and biospecimen and neurodevelopmental assessment recommendations gathered in feasibility studies that will help inform the full HBCD study planned to begin recruitment in 2022.
van de Ven MCJ, van den Heuvel MI, Bhogal A, Lewis T, Thomason ME. Impact of maternal childhood trauma on child behavioral problems: The role of child frontal alpha asymmetry. Dev Psychobiol. 2020 Mar;62(2):154-169. doi: 10.1002/dev.21900. Epub 2019 Aug 1. PMID: 31372993; PMCID: PMC6994323.
Childhood trauma is associated with many long-term negative outcomes, and is not limited to the individual experiencing the trauma, but extends to subsequent generations. However, mechanisms underlying the association between maternal childhood trauma and child psychopathology are not well understood. Here, we targeted frontal alpha asymmetry (FAA) as a potential underlying factor of the relationship between maternal childhood trauma and child behavioral problems. Electroencephalography (EEG) was recorded from (N = 45) children (Mean age = 57.9 months, SD = 3.13) during an eyes-closed paradigm in order to evaluate FAA. Mothers reported on their childhood trauma experiences using the Childhood Trauma Questionnaire (CTQ), and on their child’s behavior using the child behavior checklist (CBCL). We found that maternal childhood trauma significantly predicted child total, internalizing, and externalizing behavior at age 5 years. We also observed a role for FAA such that it acted as a moderator, but not mediator, for behavioral problems. We found that children with relative more right/less left frontal activity were more at risk to develop behavioral problems when their mother had been exposed to trauma in her childhood. These results indicate that child frontal asymmetry may serve as a susceptibility marker for child behavioral problems.
Thomason ME. Development of Brain Networks In Utero: Relevance for Common Neural Disorders. Biol Psychiatry. 2020 Jul 1;88(1):40-50. doi: 10.1016/j.biopsych.2020.02.007. Epub 2020 Feb 19. PMID: 32305217; PMCID: PMC7808399.
Magnetic resonance imaging, histological, and gene analysis approaches in living and nonliving human fetuses and in prematurely born neonates have provided insight into the staged processes of prenatal brain development. Increased understanding of micro- and macroscale brain network development before birth has spurred interest in understanding the relevance of prenatal brain development to common neurological diseases. Questions abound as to the sensitivity of the intrauterine brain to environmental programming, to windows of plasticity, and to the prenatal origin of disorders of childhood that involve disruptions in large-scale network connectivity. Much of the available literature on human prenatal neural development comes from cross-sectional or case studies that are not able to resolve the longitudinal consequences of individual variation in brain development before birth. This review will 1) detail specific methodologies for studying the human prenatal brain, 2) summarize large-scale human prenatal neural network development, integrating findings from across a variety of experimental approaches, 3) explore the plasticity of the early developing brain as well as potential sex differences in prenatal susceptibility, and 4) evaluate opportunities to link specific prenatal brain developmental processes to the forms of aberrant neural connectivity that underlie common neurological disorders of childhood.
Turk E, van den Heuvel MI, Benders MJ, de Heus R, Franx A, Manning JH, Hect JL, Hernandez-Andrade E, Hassan SS, Romero R, Kahn RS, Thomason ME, van den Heuvel MP (2022). Functional Connectome of the Fetal Brain. Journal of Neuroscience 4 December 2019, 39 (49) 9716-9724; DOI: https://doi.org/10.1523/JNEUROSCI.2891-18.2019.
Large-scale functional connectome formation and reorganization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated before birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules, and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function.
Boeve JL, Beeghly M, Stacks AM, Manning JH, Thomason ME. Using the Actor-Partner Interdependence Model to assess maternal and infant contributions to mother-infant affective exchanges during the Still-Face Paradigm. Infant Behav Dev. 2019 Nov;57:101351. doi: 10.1016/j.infbeh.2019.101351. Epub 2019 Aug 21. PMID: 31445430; PMCID: PMC6875632.
This study describes maternal and infant contributions to dyadic affective exchanges during the Still-Face Paradigm (SFP) in an understudied mostly low-income sample. One hundred eleven mothers and their 7-month-old infants were videotaped during the SFP to analyze how a social stressor affects mother-infant positive and negative affective exchanges during interaction. The SFP includes 3 episodes: baseline, maternal still-face, and reunion. Maternal and infant positive and negative affect were scored by masked reliable coders. Data were analyzed using the Actor-Partner Interdependence Model to test the hypotheses that each partner’s affectivity during the baseline episode would predict their own affectivity during the reunion episode (actor effects). We also expected that each partner’s affectivity during the baseline episode would influence the other partner’s affectivity during the reunion episodes (partner effects). After controlling for infant sex and maternal education, results provided evidence for actor effects for maternal and infant positive affect, and for partner effects for maternal baseline positive affect to infant positive affect during the reunion. One significant partner effect was observed for negative affect: Infant negativity during baseline predicted greater maternal negativity during reunion. Findings confirm that both mothers and infants contribute to dyadic affective processes during the SFP but specific findings vary depending on the affective valence in question. Clinical implications and future research are discussed.