Gilmore Knickmeyer and Gao Nature Reviews Neuroscience 2018
The developmental origins of health and disease (DOHaD) or the fetal origins of adult disease (FOAD) models posit that environmental exposures early in evolution, and particularly during intrauterine life, accept lasting implications for health and disease beyond the life bridge (Barker, Reference Barker1990, Reference Barker1994, Reference Barker1994, Reference Barker1995; Gluckman & Hanson, Reference Gluckman and Hanson2004). At that place is compelling support for the DOHaD/FOAD hypotheses in terms of adult concrete health and mental health (Hanson & Gluckman, Reference Hanson and Gluckman2014). A large epidemiological literature provides support for the FOAD hypothesis by demonstrating that small size at birth is associated with increased risk for many pathologies throughout the life bridge, including eye disease, obesity, diabetes (Barker, Eriksson, Forsén, & Osmond, Reference Barker, Eriksson, Forsén and Osmond2002; Jornayvaz et al., Reference Jornayvaz, Vollenweider, Bochud, Mooser, Waeber and Marques-Vidal2016), and psychiatric illness (Class, Rickert, Larsson, Lichtenstein, & D'Onofrio, Reference Course, Rickert, Larsson, Lichtenstein and D'Onofrio2014; Sømhovd, Hansen, Brok, Esbjørn, & Greisen, Reference Sømhovd, Hansen, Brok, Esbjørn and Greisen2012; Thompson, Syddall, Rodin, Osmond, & Barker, Reference Thompson, Syddall, Rodin, Osmond and Barker2001). Small size at nascency is too linked to neurological evolution (DiPietro et al., Reference DiPietro, Kivlighan, Costigan, Rubin, Shiffler, Henderson and Pillion2010). Pocket-sized size at birth is not probable to be the cause of subsequent disease outcomes, but rather being born small reflects various prenatal perturbations. Prospective inquiry therefore is needed to characterize the prenatal environment and investigate how it shapes developmental trajectories (Howland, Sandman, Davis, & Glynn, Reference Howland, Sandman, Davis and Glynn2020). Building on the findings that intrauterine experiences shape mental health outcomes (O'Donnell & Meaney, Reference O'Donnell and Meaney2017), enquiry suggests that prenatal exposures tin can also have transformative neurobiological effects on fetal brain excursion maturation.
The prenatal flow is a time of rapid growth and the beginning of neurologic evolution for the fetal brain (Huttenlocher & Dabholkar, Reference Huttenlocher and Dabholkar1997; Stiles & Jernigan, Reference Stiles and Jernigan2010). The extraordinary rate of encephalon maturation in utero ways that both salutary and deleterious environmental signals have the potential to alter the trajectory of brain development. During the transformation from a zygote to a human newborn in the 9 months of full-term gestation, cell division and differentiation is both rapid and highly coordinated (Huttenlocher & Dabholkar, Reference Huttenlocher and Dabholkar1997; Stiles & Jernigan, Reference Stiles and Jernigan2010). White matter microstructure is fundamental to transmission of neural communication, and undergoes pronounced development during the prenatal period (Knickmeyer et al., Reference Knickmeyer, Gouttard, Kang, Evans, Wilber, Smith and Gilmore2008). White matter tracts begin emerging within the fetal brain between xiii and 19 gestational weeks, with evidence that major white matter tracts (eastward.g., the corpus callosum, superior and inferior fasciculi, and cingulum) are present by nascency (Gilmore, Knickmeyer, & Gao, Reference Gilmore, Knickmeyer and Gao2018).
Maternal psychological distress during the prenatal period is one important environmental signal that shapes developmental trajectories in the offspring. Rates of psychological distress including elevated symptoms of anxiety and depression are seen in up to 25% of meaning women (Muzik & Borovska, Reference Muzik and Borovska2010) with rates even college amid socioeconomically at-risk populations (Katz, Crean, Cerulli, & Poleshuck, Reference Katz, Crean, Cerulli and Poleshuck2018; Koleva, Stuart, O'Hara, & Bowman-Reif, Reference Koleva, Stuart, O'Hara and Bowman-Reif2011). The high prevalence of prenatal psychopathology is of critical public health importance, as it indicates impairment non only in maternal psychological wellbeing, but too has robust long-term consequences for child mental health (Capron et al., Reference Capron, Glover, Pearson, Evans, O'Connor, Stein and Ramchandani2015; Davis & Narayan, Reference Davis and Narayan2020; O'Donnell, Glover, Barker, & O'Connor, Reference O'Donnell, Glover, Barker and O'Connor2014; Plant, Pariante, Sharp, & Pawlby, Reference Plant, Pariante, Precipitous and Pawlby2015). Prenatal maternal distress is associated with a range of neurodevelopmental outcomes, including behavioral problems, difficult temperament, negative emotionality, and internalizing problems (Davis & Sandman, Reference Davis and Sandman2012; Park et al., Reference Park, Kim, Kim, Shin, Yoo, Lee and Cho2014; Van den Bergh, Calster, Smits, Huffel, & Lagae, Reference Van den Bergh, Calster, Smits, Huffel and Lagae2008). Chiefly, prenatal maternal symptoms of distress predict afterward infant and kid psychopathology and gamble mechanisms even when maternal symptoms of distress are subclinical and below diagnostic categorical thresholds (Glynn, Howland, & Pull a fast one on, Reference Glynn, Howland and Play a trick on2018; O'Connor, Monk, & Fitelson, Reference O'Connor, Monk and Fitelson2014; Sandman, Buss, Head, & Davis, Reference Sandman, Osculation, Head and Davis2015). These findings highlight the importance of investigating the intergenerational consequences of maternal distress from a transdiagnostic perspective as supported by the National Plant of Mental Health's inquiry domain criteria (RDoC) initiative (Gao et al., Reference Gao, Ostlund, Brown, Kaliush, Terrell, Vlisides-Henry and Conradt2021; Insel et al., Reference Insel, Cuthbert, Garvey, Heinssen, Pine, Quinn and Wang2010).
Accumulating testify across experimental studies in rodents and observational studies in humans have demonstrated that postnatal stress exposure, especially when experienced during early life, is associated with variability in the construction and function of frontolimbic and temporal circuitry (for review see Chen & Baram, Reference Chen and Baram2016; McLaughlin, Weissman, & Bitrán, Reference McLaughlin, Weissman and Bitrán2019). These neural circuits are important for affective processing, including the evaluation of social stimuli and emotion regulation (Dannlowski et al., Reference Dannlowski, Stuhrmann, Beutelmann, Zwanzger, Lenzen, Grotegerd and Kugel2012; Hartley & Phelps, Reference Hartley and Phelps2010). In experimental enquiry with rodents and nonhuman primates, prenatal stress exposure causes changes in the basic neuroarchitecture of the amygdala, with evidence of stress-related increases in dendritic arborization in rodents (Mitra, Jadhav, McEwen, Vyas, & Chattarji, Reference Mitra, Jadhav, McEwen, Vyas and Chattarji2005) and alterations in neuronal cytoskeleton and synapse formation post-obit glucocorticoid exposure in the fetal baboon (Antonow-Schlorke, Schwab, Li, & Nathanielsz, Reference Antonow-Schlorke, Schwab, Li and Nathanielsz2003). Human studies have focused primarily on prenatal influences on volume and thickness (Davis et al., Reference Davis, Hankin, Glynn, Head, Kim and Sandman2020; Moog et al., Reference Moog, Entringer, Rasmussen, Styner, Gilmore, Kathmann and Buss2018; Rifkin-Graboi et al., Reference Rifkin-Graboi, Bai, Chen, Hameed, Sim, Tint and Qiu2013; Sandman et al., Reference Sandman, Kiss, Head and Davis2015).
There are few studies in humans linking prenatal maternal distress to white matter integrity (for review see Demers, Aran, Glynn, & Davis, Reference Demers, Aran, Glynn, Davis, Wazana, Székely and Oberlander2021). Microstructural integrity of white matter tracts can be assessed noninvasively through DTI, providing an important methodology to study maturation of neural circuits and to probe white thing changes over the life span. Common DTI metrics include fractional anisotropy (the fraction of diffusion that is directionally dependent, i.eastward., anisotropic), mean diffusivity (the total water mobility), axial diffusivity (the diffusivity along the master fiber orientation), and radial diffusivity (the diffusivity perpendicular to the main fiber). Changes in diffusion can arise from a variety of biological events, including alterations in axonal fiber integrity, membrane proliferation, axon density, organization, and myelination. As fractional anisotropy is sensitive to this diversity of microstructural changes in the white matter, it can be difficult to interpret biologically. In contrast, studies have shown that changes in centric diffusivity largely reflect perturbation to axonal fiber organization and density, while decreases in radial diffusivity primarily indicate increases in axonal myelination (Winklewski et al., Reference Winklewski, Sabisz, Naumczyk, Jodzio, Szurowska and Szarmach2018) (see Table ane for DTI metric definitions). Higher fractional anisotropy is generally thought to indicate enhanced white matter integrity (Soares, Marques, Alves, & Sousa, Reference Soares, Marques, Alves and Sousa2013). A recent longitudinal study of normative early childhood encephalon circuit maturation has reported widespread increases in fractional anisotropy, as well as decreases in radial diffusivity and axial diffusivity, between birth and 1 year of age for the major white thing tracts (Stephens et al., Reference Stephens, Langworthy, Short, Girault, Styner and Gilmore2020).
Tabular array 1. Diffusion tensor imaging (DTI) metric definitions
A relatively small literature demonstrates links between prenatal maternal distress and persisting alterations in neural circuit development assessed with measures of white matter microstructure into babyhood (Hay et al., Reference Hay, Reynolds, Grohs, Paniukov, Giesbrecht, Letourneau and Lebel2020; Sarkar et al., Reference Sarkar, Craig, Dell'Acqua, O'Connor, Catani, Deeley and Irish potato2014) and immature adulthood (Marečková, Klasnja, Andrýsková, Brázdil, & Paus, Reference Marečková, Klasnja, Andrýsková, Brázdil and Paus2019). Although these studies advise that distress during pregnancy is associated with lasting influences on white matter integrity, the ability to achieve clear conclusions is limited by the fact that the imaging outcomes are nerveless later in childhood at a fourth dimension when the postnatal environment has had a significant impact. In an endeavor to isolate the unique effects of the distress during the prenatal period, several studies have investigated whether associations remain fifty-fifty when decision-making for postnatal distress (El Marroun et al., Reference El Marroun, Zou, Muetzel, Jaddoe, Verhulst, White and Tiemeier2018; Lebel et al., Reference Lebel, Walton, Letourneau, Giesbrecht, Kaplan and Dewey2016; Wen et al., Reference Wen, Poh, Ni, Chong, Chen, Kwek and Qiu2017). Assessments of white matter integrity shortly after birth let for a more than rigorous test of the hypothesis that prenatal maternal distress affects brain circuit evolution earlier postnatal factors, including parental intendance (Glynn & Baram, Reference Glynn and Baram2019), tin can exert an influence (see Figure 1 for conceptual model).
Effigy 1. Model of intergenerational transmission of risk. The prenatal period is a time when the fetal brain is highly susceptible to the effects of prenatal maternal depression and other signals of maternal psychological and physiological distress. Even so, the influence of prenatal low exposure on neonatal neural excursion maturation remains poorly understood. Alterations in the neurodevelopment of white matter microstructure is one potential etiological mechanism through which prenatal stress influences child outcomes.
Several longitudinal studies take considered associations betwixt prenatal distress exposure and evolution of white matter compages in neonates. Inside this pocket-size extant literature, at that place is emerging show that exposure to environmental signals in utero may influence the trajectory of white matter evolution as early every bit infancy. Notwithstanding, the literature to date is relatively limited, and existing studies have used inconsistent methodological approaches, both in terms of the assessment of prenatal distress and the brain regions investigated. Many of the studies assessing the role of prenatal distress on infant white thing integrity take focused specifically on amygdala–prefrontal circuits, given the importance of this circuitry in emotion regulation, and have found mixed results (Humphreys, Camacho, Roth, & Estes, Reference Humphreys, Camacho, Roth and Estes2020; Posner et al., Reference Posner, Cha, Roy, Peterson, Bansal, Gustafsson and Monk2016; Rifkin-Graboi et al., Reference Rifkin-Graboi, Bai, Chen, Hameed, Sim, Tint and Qiu2013). One study demonstrated associations betwixt categorically high and low symptoms of prenatal depression exposure and decreased structural connectivity of the amygdala–ventromedial prefrontal cortex circuit in newborns (Posner et al., Reference Posner, Cha, Roy, Peterson, Bansal, Gustafsson and Monk2016). Rifkin-Graboi et al. (Reference Rifkin-Graboi, Bai, Chen, Hameed, Sim, Tint and Qiu2013) institute evidence of decreased white matter integrity within the bilateral amygdala; this effect was just obtained when prenatal depressive symptoms were categorized into high versus low–normal groups; no significant associations were obtained when analyses were conducted with depressive symptoms assessed dimensionally. In that location is contempo evidence that prenatal distress besides may be associated with increases in white matter structural integrity of the amygdala–prefrontal tract. In a recent pilot study of 33 infants scanned approximately five weeks after birth, Humphreys et al. (Reference Humphreys, Camacho, Roth and Estes2020) found that prenatal stress was associated with increased structural connectivity between the amygdala and the medial prefrontal cortex. This finding held when covarying for preconception stress, highlighting the unique importance of the prenatal catamenia independent from the effects of cumulative life stress beyond the mother's life bridge.
One limitation of these studies is the focus on amygdala–prefrontal circuitry without consideration of other circuits within the neonatal encephalon. Emerging show from studies using a whole brain approach suggests that prenatal distress too may influence the development of circuits implicated in affective (temporolimbic tracts) and sensory (occipitotemporal tracts) processing. For instance, voxel-wise whole brain analyses comparing neonates of mothers reporting categorically high versus low prenatal feet identified decreases in fractional anisotropy in regions corresponding to the right insula and dorsolateral prefrontal cortex, inferior–frontal occipital fasciculus, uncinate fasciculus, posterior cingulate, and parahippocampus (Rifkin-Graboi et al., Reference Rifkin-Graboi, Meaney, Chen, Bai, Hameed, Tint and Qiu2015). Similarly, another study employing voxel-wise analyses found that elevations of a composite of prenatal anxiety and depressive symptoms was associated with increased radial and axial diffusivity within the corona radiata, external sheathing, and dorsolateral prefrontal cortex. Despite finding differences in white matter diffusivity, no significant differences were institute with partial anisotropy, suggesting that different metrics of white matter integrity have varying sensitivities to maternal distress (Dean et al., Reference Dean, Planalp, Wooten, Kecskemeti, Adluru, Schmidt and Davidson2018). In an opposing finding, a contempo written report in 6-calendar month-former infants demonstrated that prenatal maternal distress was associated with lower radial diffusivity and elevated fractional anisotropy within the corpus callosum, which in turn predicted later behavioral problems at 18 months (Borchers, Dennis, King, Humphreys, & Gotlib, Reference Borchers, Dennis, Male monarch, Humphreys and Gotlib2020).
The electric current study fills a significant gap in the literature past investigating the integrity of melancholia (i.e., temporolimbic) and sensory processing (i.e., occipitotemporal) circuits in addition to frontolimbic circuitry. Based on experimental and human studies of early life stress exposure, we aimed to investigate associations betwixt prenatal distress and structural integrity inside circuits involved in emotional regulation (i.eastward., uncinate fasciculus and cingulum), melancholia processing (i.e., fornix), and sensory processing (i.eastward., junior fronto-occipital fasciculus). This study used a prospective and longitudinal design with a racially and ethnically diverse sample of female parent–infant dyads recruited early on in pregnancy to investigate the association between prenatal maternal distress and infant white matter development. The state-trait anxiety inventory (STAI), a measure that is consistent with putative measures and constructs within the negative valence system of the RDoC framework (Cuthbert & Insel, Reference Cuthbert and Insel2013), was used to assess prenatal maternal stress. The RDoC initiative emphasizes evaluating and validating dimensional constructs, integrating psychosocial and biological factors, and may therefore be an important framework to apply in the investigation of intergenerational mechanisms of risk. Neonatal diffusion-weighted images were nerveless and analyzed using a robust atlas building arroyo (Verde et al., Reference Verde, Budin, Berger, Gupta, Farzinfar, Kaiser and Styner2014), which allows for the extraction of diffusion tensor metrics forth respective white matter tracts of interest. This method facilitates both subject outlier detection and the specification of localized regions along a given tract for targeted hypothesis testing.
Materials and Method
Study overview
Pregnant women were assessed at 17 and 29 gestational weeks to measure prenatal maternal distress. Neonatal white affair microstructure was assessed during natural slumber via DTI at 42–45 weeks' postconceptional age (~two–5 weeks after nascency).
Study participants
Participants included 85 female parent–baby dyads who were drawn from a longitudinal investigation of the impact of maternal mental health during pregnancy on offspring developmental outcomes (the Care Project) (Davis, Hankin, Swales, & Hoffman, Reference Davis, Hankin, Swales and Hoffman2018) and whose assessment was completed prior to the outset of the COVID-19 pandemic being declared a land of emergency (March 10, 2020). Recruitment was primarily from obstetrics clinics at 2 major medical centers in Denver, Colorado. All study procedures were canonical by the Institutional Board for the Protection of Human Subjects at the University of Denver and the University of Colorado Anschutz medical campus, and all mothers provided written informed consent for themselves and their infant.
Inclusion criteria for mothers' enrollment in the study were (a) maternal historic period between 18 and 45 years, (b) singleton pregnancy, (c) gestational age (GA) less than 25 weeks, and (d) proficiency in English. Exclusion criteria included (a) current illicit drug or methadone use, (b) major health conditions requiring invasive treatments (due east.m., dialysis, claret transfusions, chemotherapy), (c) electric current or by symptoms of psychosis or mania based on the structured clinical interview (SCID) for the Diagnostic and statistical manual of mental disorders, fifth edition, and (d) electric current participation in cognitive behavioral therapy or interpersonal therapy.
Additional exclusion criteria for the electric current written report included (a) preterm nascence <34 gestational weeks (n = 0), (b) major fetal or chromosomal anomalies (n = one) and neonatal complications requiring a neonatal intensive care unit of measurement stay (due east.m., mechanical ventilation; n = 0), and (c) any infant magnetic resonance imaging (MRI) contraindications (n = two) (e.one thousand., metal implant). Of the infants who attended the MRI scan, three were unable to be scanned (due east.g., infant did not fall asleep during the scanning window), 2 DTI scans were not acquired because the infant woke up in the scanner, and three scans failed initial quality control procedures. Post-obit additional quality command procedures for DTI image processing (see section on materials and methods for further details), thirteen of the 85 subjects were removed for the bed nucleus of the stria terminalis amygdala (BNST)–amygdala tract and three were excluded for the correct anterior cingulate tract.
Mothers in the written report were 21–41 years old (K = 31.37, SD = 5.fourteen) at delivery (encounter Tabular array 2 for sample characteristics). Median almanac household income was $lxx,000, and 31% of participants were living at or nearly federal classification of poverty (less than 200% income-to-needs ratio [INR]). Infants (51% female) were 39 weeks' gestation at birth on average and scanned at 43 weeks postconceptional age (range 41.6–49.iv). 50-nine percentage of participants were non-Hispanic white and 22% were Hispanic/Latina, with the residue of the sample identifying as Black, Asian, or Multi-ethnic.
Table 2. Demographic and medical characteristics of the sample
Maternal distress symptoms
Pregnant women'southward levels of distress were assessed via the 20-item land anxiety subscale of the STAI (Spielberger, Reference Spielberger1983) at 17 and 29 weeks' gestation. Factor analyses of the STAI indicate that items comprise a higher-club negative affectivity factor, and this cistron structure suggests that the STAI is best conceptualized equally a measure of general distress (Bados, Gómez-Benito, & Balaguer, Reference Bados, Gómez-Benito and Balaguer2010; Bieling, Antony, & Swinson, Reference Bieling, Antony and Swinson1998). Participants indicate how they have felt over the past calendar week, including today. Items include: "I am tense" and "I am worried". All items were rated on a 4-point Likert calibration, with higher scores indicating greater distress. The STAI has been extensively used to measure out distress during pregnancy (e.1000., Davis & Sandman, Reference Davis and Sandman2010; Fischbein et al., Reference Fischbein, Nicholas, Kingsbury, Falletta, Baughman and VanGeest2019). Within the current sample, internal consistency was excellent (α = .96 at 17 weeks and α = .96 at 29 weeks).
Sociodemographic characteristics
Maternal nascency date, socioeconomic status, cohabitation with child's father, marital status, educational attainment, and race and ethnicity were collected via maternal interview. A family INR was calculated past dividing the total reported household income by the poverty threshold corresponding to the number of persons living in the household at the fourth dimension of study entry, specified past the U.South. Census Bureau (2020).
Pregnancy and nascence outcomes
Prenatal obstetric complications, birth outcomes, infant biological sex at nascence, nascency weight, and 5-min Apgar score were abstracted from the medical record. In improver, birth weight percentile, which accounts for gestational age at nascence (GAB) and infant biological sexual activity, was determined. Estimated date of delivery was adamant by early ultrasound measures and date of terminal menstrual menses based on the American Higher of Obstetricians and Gynecologists guidelines and used to calculate GAB and postconceptional age at scan (Committee on Obstetric Practise, the American Plant of Ultrasound in Medicine, and the Order for Maternal-Fetal Medicine, 2017). An obstetric complications score was calculated, indicating the presence or absence of pregnancy-related complications, including prenatal infection, pregnancy-included hypertension, gestational diabetes, oligohydramnios, polyhydramnios, preterm labor, vaginal bleeding, placenta previa, or anemia (Hobel, Reference Hobel, Bolognese, Schwartz and Schneider1982). Seventy-one percent of the women had none or one of the obstetric complications on this index. Fetal exposures to illicit drugs, marijuana, cigarettes, and alcohol were assessed via maternal interview and presence of positive infant toxicology screens at nascence.
Magnetic resonance imaging acquisition
Infants were scanned unsedated during natural slumber. Noise from the scanner was reduced by the use of malleable ear plugs and neonatal ear covers. Headphones played white noise during prototype acquisition. A Siemens Skyra 3 T MRI system equipped with a 20-channel head coil at the Brain Imaging Center at the University of Colorado Anschutz medical campus was used.
Improvidence tensor images were obtained using a simultaneous multislice sequence (repetition time, TR = half-dozen,100 ms, echo time, TE = 60, field of view, FOV = 220, matrix size = 128 × 128; 50 axial slices with 2.0 mm thickness; stage-encoding [PE] direction = anterior–posterior, AP). Improvidence MRI information were acquired with 3 improvidence weightings (b-values) (b = 300, 800, 2,000 s/mmii), with 10, 30, and 64 unique gradient directions per respective shell (104 slope directions total). In addition, 18 interspersed b = 0 s/mm2 images were caused equally a baseline. The total acquisition time was 7 min (multiband dispatch iii, TE/TR 92/3,600 ms).
Paradigm processing
A study-specific quality command protocol was applied to all raw diffusion-weighted imaging (DWI) data using DTIPrep (www.nitrc.org/projects/dtiprep), which includes slice-wise and gradient-wise artifact detection, as well every bit eddy current and motion correction. For all analyses, the b = 300 and b = 800 shells (40 gradients total) were used to calculate the improvidence tensor images using the weighted least-squares algorithm (Salvador et al., Reference Salvador, Peña, Menon, Carpenter, Pickard and Bullmore2005). Lower b-values were employed for adding of the diffusion tensor given the decreased indicate-to-noise and the increased non-Gaussian contribution to the diffusion bespeak at college b-value acquisitions (Jones & Basser, Reference Jones and Basser2004). Every bit an additional quality control step, interactive tractography was performed in Slicer (http://www.slicer.org) and visually assessed for artifacts undetectable by voxel-wise inspection, such as any consistently observed directional biases. Skull and nonbrain tissue were masked using the encephalon extraction tool (BET) (Smith, Reference Smith2002) on the geometric mean of the DWI image, followed by manual correction, if necessary.
Two motion scores were calculated per subject: (a) The number of DWI gradients removed by the DTI Prep preprocessing pipeline, and (b) the number of DWI gradients with pregnant levels of corrected motion, defined equally whatever gradient with a corrected rotation exceeding 1 degree or a translation exceeding ane mm. These ii scores were summed to create the single motion antiquity covariate used in the clan analyses.
Using the UNC−Utah National Brotherhood for Medical Image Computing DTI framework (Verde et al., Reference Verde, Budin, Berger, Gupta, Farzinfar, Kaiser and Styner2014), a report-specific DTI atlas was created from the sample data. Nonlinear, diffeomorphic pair-wise registration was performed to map individual bailiwick DTIs into atlas infinite, and registration accuracy was visually inspected in DTI-AtlasBuilder to determine if the computed transforms were appropriate. Major fiber tracts were determined semi-automatically in this atlas space (Ngattai Lam et al., Reference Ngattai Lam, Belhomme, Ferrall, Patterson, Styner and Prieto2018). Resulting deformation fields were then used to map the atlas fibers into individual subject space, where improvidence tensor metrics were extracted at evenly spaced points (arc lengths) along each fiber tract. These metrics included, partial anisotropy (FA, a measure of the directional coherence for the fiber tracts), hateful diffusivity (MD, the average magnitude of molecular deportation by improvidence), axial diffusivity (Advertising, the length of the longest axis of diffusion tensor), and radial diffusivity (RD, the average length of two remaining axes of the diffusion tensor). Equally an boosted quality command pace, individuals were excluded from further association analyses for a given tract if their fractional anisotropy profile was weakly correlated with the population tract average profile (correlation <0.seventy). A depression correlation typically flags poor alignment of the subject area's DTI to the atlas beyond the respective fiber regions. For each subject, the profile of the respective diffusion tensor metric was then averaged forth the respective cobweb to yield robust tract metric averages for the clan analyses.
Of note, the bed nucleus of the stria terminalis amygdala (BNST) and the cingulate gyrus both have a lower signal-to-dissonance ratio within the developing neonate brain compared to the other fiber tracts examined in this report. Regions forth these two tracts exhibit fractional anisotropy values approaching the noise floor, leading to increased variability among subjects. To address this event, a tract region of interest along each tract was selected for the average computation based on fractional anisotropy point and tract anatomy (Supplementary Appendix Figure 1). Equally the signal-to-dissonance ratio of these ii tracts remains lower than for the other tracts of interest, fifty-fifty after tract region selection, a lower correlation threshold of <0.50 was used to exclude those subjects that exhibit poor alignment with the atlas. Three subjects with a correlation threshold lower than 0.l were removed for the BNST–amygdala tract and 13 were excluded for the right inductive cingulate tract.
Statistical analyses
Partial correlations were used to examine associations between cocky-reported distress at 17 and 29 weeks' GA and white matter integrity in 13 tracts correcting for motility artifact level, postconceptional historic period and biological sexual practice at birth. The following tracts were investigated: bilateral BNST–amygdala, cingulate anterior portion, cingulate–hippocampal, fornix, inferior occipital fasciculus, uncinate and corpus callosum (see Figure 2). For tracts associated with prenatal maternal distress, hierarchical linear regressions were then conducted to evaluate robustness of findings afterward including obstetric and sociodemographic covariates. Based on prior research demonstrating associations with either the predictor or outcome, we included the following covariates in these regression analyses: postconceptional age at browse, infant biological sex, INR, birth weight percentile, GAB, obstetric complications, and move artifact level (Davis et al., Reference Davis, Buss, Muftuler, Head, Hasso, Fly and Sandman2011; Jha et al., Reference Jha, Meltzer-Brody, Steiner, Cornea, Woolson, Ahn and Knickmeyer2016; Kim et al., Reference Kim, Davis, Sandman, Sporns, O'Donnell, Kiss and Hetrick2016a; Thompson et al., Reference Thompson, Kelly, Chen, Beare, Alexander, Seal and Cheong2019). Postconceptional age, biological sex, and motion antiquity level were analyzed within the showtime cake of the model; the remaining covariates were entered into the second block. Three subjects were missing self-report data for INR and STAI at 29 weeks' GA. Picayune's (Reference Little1988) missing completely at random (MCAR) test was nonsignificant, χ2 (76) = 88.63, p = .152, suggesting that information were missing completely at random. Missing data were imputed using expectation maximization procedures in SPSS version 26.
Figure 2. Improvidence tensor metrics are calculated along select white thing tracts. (a) White affair fiber tracts analyzed in the current study. Top: red = uncinate (UNC); yellowish = knee of corpus callosum (knee); light bluish = inferior fronto-occipital fasciculus (IFOF). Lesser: purple = bed nucleus of the stria terminalis amygdala (BNST); bluish = fornix (FNX); greenish = cingulum hippocampal part (CGH); orange = cingulum gyrus part (CGC) (i.e., inductive cingulum). (b) Sagittal (left) and axial (right) view of the partial anisotropy (FA) (top) and axial diffusivity (Advertising) (bottom) calculated for a single subject.
For tracts that showed significant associations with distress symptoms, follow-up analyses were then conducted with mean diffusivity, radial diffusivity, and centric diffusivity to farther investigate the nature of the white matter microstructure associations. Sensitivity analyses using identical statistical analyses were conducted excluding infants of mothers with regular substance (north = 4) or psychotropic medication (n = 8) utilise during pregnancy.
Results
The STAI scores at 17 and 29 weeks' GA were 36.0 (SD = 12.9) and 33.9 (SD = xi.6), respectively. The STAI scores at the two fourth dimension points were correlated (r = .675, p = <.001). Lower INR was associated with college STAI at both 17 (r = −0.266, p = .014) and 29 weeks' GA (r = −0.230, p = .034). Maternal STAI at 29 weeks' GA was positively associated with postconceptional age at scan (r = .217, p = .046); maternal STAI was not associated with any other birth result or demographic characteristic.
White matter microstructure
Higher prenatal maternal STAI scores at 29 weeks' GA were associated with increased fractional anisotropy within the correct inductive cingulate tract (r = .313, p = .009), correcting for biological sex, motion artifact level, and postconceptional historic period. No other pregnant associations were found with prenatal distress exposure and tract fractional anisotropy at 29 weeks' GA, or earlier in gestation (encounter Table 3). This association betwixt maternal distress at 29 weeks' GA and higher partial anisotropy in the correct anterior cingulate remained after considering GAB, BW percentile, and INR in the regression, b = .283, t (64) = 2.319, p = .024 (Effigy 3a).
Figure 3. STAI at 29 weeks' GA and right anterior cingulate tract. Maternal distress is associated with increased (a) fractional anisotropy (FA) and (b) increased axial diffusivity (AD). Residuals plotted after bookkeeping for biological sex at birth, postconceptional age, and motion.
Table iii. Partial correlations of prenatal distress and tract partial anisotropy (FA) controlling for biological sex at birth, postconceptional age, and motion
Iii follow-upwards regression analyses were and so conducted with metrics of mean, radial, and axial diffusivity to further investigate the nature of the white thing microstructure associations inside the right anterior cingulate tract. Higher prenatal maternal STAI at 29 weeks' GA was associated with increased centric diffusivity within the right anterior cingulate, b = .254, t (64) = two.067 p = .043 (Figure 3b). No other meaning associations were establish with mean diffusivity, b = .101, t (64) = .818, p = .417, or radial diffusivity, b = −.023, t (64) = −.184, p = .855, within the right anterior cingulate. Sensitivity analyses demonstrated that removal of the infants of mothers with prenatal substance use (north = 4) and medication exposure (n = 8) showed similar outcome sizes for both fractional anisotropy and centric diffusivity. Partial correlations with biological sex, motility artifact level, and postconceptional historic period demonstrated a like issue in the clan between distress at 29 weeks' GA and right cingulate fractional anisotropy (r = .290, p = .023) and axial diffusivity (r = .393, p = .002).
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The DOHaD/FOAD hypothesis highlights the importance of fetal experiences for shaping developmental trajectories with long-term consequences for health and well-existence. Few studies, notwithstanding, have prospectively examined the influence of prenatal exposures on neural circuit development. The current study evaluated the association between the STAI, an RDoC-informed indicator of prenatal maternal distress within the negative valence system and white matter integrity in neonates. Findings demonstrated that prenatal maternal distress during the 3rd trimester was associated with alterations in neonatal white matter microstructure such that higher prenatal maternal distress at 29 weeks' GA was associated with higher partial anisotropy and centric diffusivity within the right anterior cingulate tract. Associations remained after considering biological sex at birth, postconceptional age, GAB, birth weight percentile, INR, and move. Maternal distress was not associated with variability in the white affair microstructure of the other tracts under investigation, nor was maternal distress before in gestation. These findings provide evidence that variability in developing white matter microstructure may be an important ontogenetic vulnerability, although support for this hypothesis was express to the right anterior cingulate tract.
Experimental work with rodents provides compelling evidence that prenatal exposure to stress shapes neural circuit evolution, especially within circuits associated with threat–reactivity (for review see Bock, Rether, Gröger, Xie, & Braun, Reference Bock, Rether, Gröger, Xie and Braun2014; Chen & Baram, Reference Chen and Baram2016; van Bodegom, Homberg, & Henckens, Reference van Bodegom, Homberg and Henckens2017); however, the homo literature is modest and fairly inconsistent both in methods and findings. Within the emerging literature, three studies have focused specifically on amygdala–prefrontal circuitry and found evidence of both decreased (Posner et al., Reference Posner, Cha, Roy, Peterson, Bansal, Gustafsson and Monk2016; Rifkin-Graboi et al., Reference Rifkin-Graboi, Bai, Chen, Hameed, Sim, Tint and Qiu2013) and increased white thing integrity (Humphreys et al., Reference Humphreys, Camacho, Roth and Estes2020). Of notation, the studies finding a negative clan between prenatal stress and white matter integrity used a categorical approach in defining prenatal distress, whereas a more than recent study assessing distress dimensionally establish evidence of increased white matter structural integrity (Humphreys et al., Reference Humphreys, Camacho, Roth and Estes2020).
Building on emerging research from whole brain analyses (Dean et al., Reference Dean, Planalp, Wooten, Kecskemeti, Adluru, Schmidt and Davidson2018; Graham et al., Reference Graham, Jiang, McCorkle, Bellando, Sorensen, Glasier and Ou2020; Rifkin-Graboi et al., Reference Rifkin-Graboi, Meaney, Chen, Bai, Hameed, Tint and Qiu2015), our written report sought to examine the role of prenatal distress exposure on circuits more broadly involved in processes of emotion regulation (temporolimbic) and perception (occipitotemporo) beyond a limited focus on amygdala–prefrontal circuitry. We found that prenatal distress in the third trimester of gestation was associated with increased fractional anisotropy and axial diffusivity within the right anterior cingulate tract. The cingulate plays an of import role in appraisal, generation and regulation of emotion, with evidence that the inductive subregion is particularly involved in regulating emotional responses (Etkin, Egner, & Kalisch, Reference Etkin, Egner and Kalisch2011). This region may exist susceptible to prenatal influences, equally the development of the anterior cingulate has been linked to early on life stress (Ansell, Rando, Tuit, Guarnaccia, & Sinha, Reference Ansell, Rando, Tuit, Guarnaccia and Sinha2012; Cohen et al., Reference Cohen, Grieve, Hoth, Paul, Sweet, Tate and Williams2006). In neonates, one previous whole brain study (Rifkin-Graboi et al., Reference Rifkin-Graboi, Meaney, Chen, Bai, Hameed, Tint and Qiu2015) identified white matter changes associated with prenatal maternal anxiety within the posterior cingulate, although results showed the contrary relation whereby elevated anxiety was associated with decreased fractional anisotropy. Further, prenatal maternal distress is associated with lower fractional anisotropy and higher diffusivity within the cingulate tract in 8-year-olds suggesting neurodevelopmental alterations in white affair integrity may persist into childhood (El Marroun et al., Reference El Marroun, Zou, Muetzel, Jaddoe, Verhulst, White and Tiemeier2018).
The implications of increased fractional anisotropy and axial diffusivity post-obit prenatal distress are unclear. As fractional anisotropy typically increases beyond development, higher fractional anisotropy is thought to reflect improved anatomical connectivity and more advanced maturation (Dubois et al., Reference Dubois, Dehaene-Lambertz, Kulikova, Poupon, Hüppi and Hertz-Pannier2014; Soares et al., Reference Soares, Marques, Alves and Sousa2013). Prenatal stress is associated with acceleration of fetal maturation in training for survival outside the womb; for example, stressed fetuses tend to accept greater lung maturity when born preterm (Glynn, Schetter, Hobel, & Sandman, Reference Glynn, Schetter, Hobel and Sandman2008; Schetter, Reference Schetter2009) and at that place is evidence that elevated levels of the stress hormone tardily in gestation are associated with benefits to encephalon development and cognitive function (Davis & Sandman, Reference Davis and Sandman2010; Davis, Head, Buss, & Sandman, Reference Davis, Head, Buss and Sandman2017). Information technology is plausible that the observed association with higher fractional anisotropy reflects accelerated maturation of this brain region. However, the observed association of prenatal stress with higher centric diffusivity is contrary to the hypothesis of accelerated maturation given show that diffusivity normatively decreases over evolution (Geng et al., Reference Geng, Gouttard, Sharma, Gu, Styner, Lin and Gilmore2012). In that location is some support for the dispatch hypothesis from studies of postnatal adversity (Colich et al., Reference Colich, Williams, Ho, King, Humphreys, Toll and Gotlib2017; Gee et al., Reference Gee, Gabard-Durnam, Flannery, Goff, Humphreys, Telzer and Tottenham2013), although several others have plant evidence for delays or more immature pattern of connectivity following early arduousness (Cisler et al., Reference Cisler, James, Tripathi, Mletzko, Heim, Hu and Kilts2013; Silvers et al., Reference Silvers, Lumian, Gabard-Durnam, Gee, Goff, Fareri and Tottenham2016). Future inquiry with replication and longitudinal follow-upwards is needed to determine whether the observation that prenatal adversity is associated with increased fractional anisotropy reflects accelerated maturation of neural circuits.
The biological mechanisms underlying the association between prenatal maternal distress and neural excursion maturation remain unknown. Dysregulation of the hypothalamic–pituitary–adrenal axis and immune system signaling are two promising pathways through which exposure to prenatal distress may influence white affair integrity. Fetal neural circuits are sensitive to stress hormone exposure. Experimental research in rodents demonstrates that exposure of immature neurons to corticotropin releasing hormone has a dose–response relation on dendritic branching and neuronal growth (Curran, Sandman, Davis, Glynn, & Baram, Reference Curran, Sandman, Davis, Glynn and Baram2017). Similarly, prenatal constructed glucocorticoid treatment has been shown to accept an touch on on neuronal jail cell proliferation and neurogenesis within the fetal mouse brain (Noorlander et al., Reference Noorlander, Tijsseling, Hessel, de Vries, Derks, Visser and de Graan2014). Prefrontal and limbic regions (including the rostral anterior cingulate) are peculiarly afflicted by excess glucocorticoids because of the affluence of glucocorticoid receptors in these brain regions (Rodrigues, LeDoux, & Sapolsky, Reference Rodrigues, LeDoux and Sapolsky2009). Fetal exposure to glucocorticoids has been associated with neonatal white matter microstructure and structural connectivity (Stoye et al., Reference Stoye, Blesa, Sullivan, Galdi, Lamb, Black and Boardman2020), equally well as persisting alterations into preadolescence in functional connectivity (Graham et al., Reference Graham, Rasmussen, Entringer, Ben Ward, Rudolph, Gilmore and Buss2019; Kim et al., Reference Kim, Davis, Sandman, Sporns, O'Donnell, Buss and Hetrick2016b) and encephalon structure (Buss et al., Reference Buss, Davis, Shahbaba, Pruessner, Head and Sandman2012; Davis et al., Reference Davis, Caput, Kiss and Sandman2017), including inside the anterior cingulate (Davis, Sandman, Buss, Wing, & Head, Reference Davis, Sandman, Buss, Wing and Head2013). Further, pro-inflammatory cytokines are another promising mechanistic pathway. For example, elevated levels of cytokine IL-6, one of the most studied pro-inflammatory cytokines, is associated with reduced integrity of the uncinate fasciculus, a main frontolimbic fiber tract (Rasmussen et al., Reference Rasmussen, Graham, Entringer, Gilmore, Styner, Fair and Buss2019). In addition, prenatal maternal interleukin-half dozen concentration has also been linked with amygdala book and amygdala connectivity regions involved in sensory processing, salience detection, and learning and retentivity (Graham et al., Reference Graham, Rasmussen, Rudolph, Heim, Gilmore, Styner and Buss2018).
Strengths and Limitations
A significant strength of this written report is the investigation of neurodevelopmental differences in white matter microstructure within neonates prior to the intervening furnishings of the postnatal environment. Rigorous protocols were employed to acquire high-quality data in infants without sedation during natural sleep (Gilmore et al., Reference Gilmore, Lin, Corouge, Vetsa, Smith, Kang and Gerig2007; Howell et al., Reference Howell, Styner, Gao, Yap, Wang, Baluyot and Elison2019). These include alignment of the scan fourth dimension with the baby nap schedule, a quiet room to feed and put the infant to sleep, swaddling and securing of the infant's caput in a vacuum-fixation device to limit motion and allowing sufficient time between scan acquisitions to repeat scans if needed. Further, the majority of studies assess distress once during pregnancy and therefore cannot evaluate the importance of specific timing effects relative to the normative trajectory of white matter development. Consistent with evidence of the emergence of limbic and associative fiber tracks between 12 and 22 weeks' GA (Dubois et al., Reference Dubois, Dehaene-Lambertz, Kulikova, Poupon, Hüppi and Hertz-Pannier2014), nosotros found associations with prenatal maternal distress assessed at 29 weeks and non 17 weeks' GA. Supporting this timing effect, prior inquiry has found straight associations of prenatal maternal mood and fetal behavior from 27 to 28 weeks' GA onwards (Van den Bergh, Mulder, Mennes, & Glover, Reference Van den Bergh, Mulder, Mennes and Glover2005), and a contempo written report showed that maternal self-reported distress during the 3rd, but not second trimester, was associated with infant hippocampal connectivity (Scheinost, Spann, McDonough, Peterson, & Monk, Reference Scheinost, Spann, McDonough, Peterson and Monk2020). Even so, another study examining associations betwixt prenatal maternal depression and child brain structure found associations that were limited to second trimester maternal stress (Lebel et al., Reference Lebel, Walton, Letourneau, Giesbrecht, Kaplan and Dewey2016). Myelination continues quickly during infancy, with protracted microstructural maturation in childhood (for review meet Lebel, Treit, & Beaulieu, Reference Lebel, Treit and Beaulieu2019); therefore, additional longitudinal research should exist conducted to determine the role of prenatal maternal stress exposure on the developmental trajectory of white matter maturation.
In that location are several limitations to annotation. Offset, there is evidence that the function of prenatal distress exposure on neurodevelopment differs by sexual practice (Clifton, Reference Clifton2010; Dean et al., Reference Dean, Planalp, Wooten, Kecskemeti, Adluru, Schmidt and Davidson2018; Sandman, Glynn, & Davis, Reference Sandman, Glynn and Davis2013; Wen et al., Reference Wen, Poh, Ni, Chong, Chen, Kwek and Qiu2017). Because of the limited sample size, nosotros were underpowered to examine moderation past infants' biological sex. Second, given that this study investigated naturally occurring variations in maternal distress, rather than experimental manipulations, it is besides hard to disentangle the effects of prenatal maternal distress exposure from other potential contributing factors such as genetic influences (O'Donnell & Meaney, Reference O'Donnell and Meaney2017). In that location is prove that white matter microstructure such as partial anisotropy is heritable (Kochunov et al., Reference Kochunov, Jahanshad, Marcus, Winkler, Sprooten, Nichols and Van Essen2015), and that genetic risk may serve as an important moderator betwixt mothers' depression and the neurodevelopment of offspring (Qiu et al., Reference Qiu, Shen, Buss, Chong, Kwek, Saw and Meaney2017). Findings for children conceived via in vitro fertilization who are non genetically related to their mothers replicate cross-fostering studies in rodents (Rice et al., Reference Rice, Harold, Boivin, van den Bree, Hay and Thapar2010) and demonstrate contributions of the prenatal environment to child development independent of genetic effects (Lewis, Rice, Harold, Collishaw, & Thapar, Reference Lewis, Rice, Harold, Collishaw and Thapar2011; for review see Natsuaki et al., Reference Natsuaki, Shaw, Neiderhiser, Ganiban, Harold, Reiss and Leve2014). 3rd, we used the STAI as one self-report measure out intended to assess the RDoC-informed theoretical construct of potential threat ("anxiety"), as a narrow dimension assessment of a hypothesized construct located within the higher-gild negative valence system. At the higher-gild level, RDoC the negative valence organization captures and reflects higher-guild negative affectivity that cuts across traditional internalizing disorder categories (eastward.g., depression, social anxiety, panic disorder, generalized anxiety disorder) and may therefore be an important susceptibility cistron to employ in the investigation of intergenerational transmission of risk (Gao et al., Reference Gao, Ostlund, Brown, Kaliush, Terrell, Vlisides-Henry and Conradt2021). As with any measurement of a latent construct, our results are express by the extent to which the STAI provides a valid indication of the hypothesized narrow-based construct of anxiety (Cronbach & Meehl, Reference Cronbach and Meehl1955) equally conceptualized within the RDoC system. Future work would benefit from additional measures of this narrow-band construct of anxiety (e.g., Anxiety Sensitivity scale; Behavioral Inhibition scale) as well as expanded measurement of the higher-order negative valence organization (e.1000., loss, astute threat) as these other narrow-order dimensions inside the negative valence arrangement may prove different patterns of associations with infant white matter. Fourth and finally, it is hard to completely dominion out the possibility that alternative factors such every bit obstetric or neonatal complications, exposure to psychiatric medications (Jha et al., Reference Jha, Meltzer-Brody, Steiner, Cornea, Woolson, Ahn and Knickmeyer2016), and substance utilize contribute to study findings (Donald et al., Reference Donald, Roos, Fouche, Koen, Howells, Woods and Stein2015; Gao et al., Reference Gao, Grewen, Knickmeyer, Qiu, Salzwedel, Lin and Gilmore2019; Walhovd, Watts, Amlien, & Woodward, Reference Walhovd, Watts, Amlien and Woodward2012). Sensitivity analyses, however, showed similar furnishings with removal of participants with medication and substance utilize, and covarying obstetric complications and nascence outcomes did not impact report findings.
Implications
Findings from the present written report provide added back up for the DOHaD/FOAD hypothesis and the importance of the intrauterine environment past demonstrating that exposure to prenatal maternal distress is associated with some early on alterations in portions of neonatal neural circuit maturation. Highlighting their predictive utility as a potential biomarker of vulnerability, there is preliminary evidence that white matter microstructural changes associated with prenatal distress are in plow associated with later behavioral problems (Borchers et al., Reference Borchers, Dennis, King, Humphreys and Gotlib2020), and internalizing symptoms (Rifkin-Graboi et al., Reference Rifkin-Graboi, Meaney, Chen, Bai, Hameed, Tint and Qiu2015). Time to come work should keep to investigate variability in white affair microstructure every bit an early marker of ontogenetic risk. The majority of studies in humans examining the programming influences of prenatal distress on infant neurodevelopment accept been correlational in nature, limiting causal inferences. Experimental manipulation of prenatal depression is a promising avenue to resolve discrepancies in the literature to date examining child ontogenetic vulnerability to psychopathology. Therefore, our group is currently conducting a randomized controlled trial (Davis et al., Reference Davis, Hankin, Swales and Hoffman2018) to test whether treatment of maternal distress during pregnancy improves babe outcomes that are linked with subsequent evolution of psychopathology. Evaluation of the etiological mechanisms such as the development of white matter microstructure underlying intergenerational risk for psychopathology may help to inform targets for more effective intervention and prevention efforts.
Source: https://www.cambridge.org/core/journals/development-and-psychopathology/article/exposure-to-prenatal-maternal-distress-and-infant-white-matter-neurodevelopment/9CC388D177CC45C6256090FCCAA8E676
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