Studies have linked maternal childhood maltreatment to altered infant brain volumes, but none have examined infant hypothalamic-pituitary-adrenal (HPA) axis function as a mechanism linking the two domains. Further, studies among older children suggest that childhood abuse and neglect may be associated with different developmental outcomes and thus should be studied separately. Study participants were N = 57 mother-infant dyads, stratified for maternal childhood maltreatment. At 4 months, infant cortisol total output (AUCg) and change (AUCi) were assessed across the Still-Face Paradigm. Under natural sleep, infants completed T1-weighted MRI scans (M age = 12.28 months). Whole brain, amygdala, and hippocampal volumes were extracted via automated segmentation. Maternal childhood neglect, but not abuse, was directly associated with higher infant AUCg and AUCi, and was indirectly associated with larger amygdala and hippocampal volumes through infant AUCg. Results suggest that infant cortisol may be particularly influenced by maternal childhood neglect and may be one mechanism further influencing brain development.
AfacanO.EremB.RobyD.RothN.RothA.PrabhuS.WarfieldS. (2016). Evaluation of motion and its effect on brain magnetic resonance image quality in children. Pediatric Radiology, 46(12), 1728–1735. https://doi.org/10.1007/s00247-016-3677-9
2.
AlexA. M.The ENIGMA ORIGINs Group. (2023). A global multicohort study to map subcortical brain development and cognition in infancy and early childhood. Nature neuroscience, 27(1), 176–186. https://doi.org/10.1038/s41593-023-01501-6
BernierA.DégeilhF.LeblancÉ.DaneaultV.BaileyH. N.BeauchampM. H. (2019). Mother-infant interaction and child brain morphology: A multidimensional approach to maternal sensitivity. Infancy: The Official Journal of the International Society on Infant Studies, 24(2), 120–138. https://doi.org/10.1111/infa.12270
5.
BrandS. R.BrennanP. A.NewportD. J.SmithA. K.WeissT.StoweZ. N. (2010). The impact of maternal childhood abuse on maternal and infant HPA axis function in the postpartum period. Psychoneuroendocrinology, 35(5), 686–693. https://doi.org/10.1016/j.psyneuen.2009.10.009
6.
BussC.DavisE. P.ShahbabaB.PruessnerJ. C.HeadK.SandmanC. A. (2012). Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proceedings of the National Academy of Sciences of the United States of America, 109(20), E1312–E1319. https://doi.org/10.1073/pnas.1201295109
7.
BussC.EntringerS.MoogN. K.ToepferP.FairD. A.SimhanH. N.WadhwaP. D. (2017). Intergenerational transmission of maternal childhood maltreatment exposure: Implications for fetal brain development. Journal of the American Academy of Child & Adolescent Psychiatry, 56(5), 373–382. https://doi.org/10.1016/j.jaac.2017.03.001
8.
ChampagneD.BagotR.van HasseltF.RamakersG.MeaneyM.KrugersH.JoëlsM. (2008). Maternal care and hippocampal plasticity: Evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 28(23), 6037–6045. https://doi.org/10.1523/JNEUROSCI.0526-08.2008
9.
ChassonM.KhouryJ.Bosquet EnlowM.Lyons‐RuthK. (2025). Maternal caregiving moderates relations between maternal childhood maltreatment and infant cortisol regulation. The Journal of Child Psychology and Psychiatry and Allied Disciplines. https://doi.org/10.1111/jcpp.14171
10.
ChenY.AndresA. L.FrotscherM.BaramT. Z. (2012). Tuning synaptic transmission in the hippocampus by stress: The CRH system. Frontiers in Cellular Neuroscience, 6(13), 1–7. https://doi.org/10.3389/fncel.2012.00013
11.
DemersC. H.HankinB. L.HennesseyE. P.HaaseM. H.BagonisM. M.KimS. H.DavisE. P.HoffmanM. C.StynerM. A. (2022). Maternal adverse childhood experiences and infant subcortical brain volume. Neurobiology of Stress, 21, 100487. https://doi.org/10.1016/j.ynstr.2022.100487
DoshiJ.ErusG.OuY.ResnickS.GurR. C.SatterthwaiteT. D.FurthS.DavatzikosC.Alzheimer’s Neuroimaging Initiative. (2016). MUSE: Multi-atlas region segmentation utilizing ensembles of registration algorithms and parameters and locally optimal atlas selection. NeuroImage, 127, 186–195. https://doi.org/10.1016/j.neuroimage.2015.11.073
14.
DruryS. S.SánchezM. M.GonzalezA. (2016). When mothering goes awry: Challenges and opportunities for utilizing evidence across rodent, nonhuman primate and human studies to better define the biological consequences of negative early caregiving. Hormones and Behavior, 77, 182–192. https://doi.org/10.1016/j.yhbeh.2015.10.007
15.
DuffyK. A.SammelM. D.JohnsonR. L.MorrisonK. E.BaleT. L.EppersonC. N. (2024). Sex differences in stress-induced cortisol response among infants of mothers exposed to childhood adversity. Biological Psychiatry, 96(11), 876–885. https://doi.org/10.1016/j.biopsych.2024.05.015
16.
FelittiV.AndaR.NordenbergD.WilliamsonD.SpitzA.MarksJ.KossM. P. (1998). Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. American Journal of Preventive Medicine, 14(4), 245–258. https://doi.org/10.1016/s0749-3797(98)00017-8
17.
FoxJ. (2015). Applied regression analysis and generalized linear models. Sage Publications.
18.
GilmoreJ. H.ShiF.WoolsonS. L.KnickmeyerR. C.ShortS. J.LinW.ZhuH.HamerR. M.StynerM.ShenD. (2012). Longitudinal development of cortical and subcortical gray matter from birth to 2 years. Cerebral Cortex, 22(11), 2478–2485. https://doi.org/10.1093/cercor/bhr327
19.
GrantK. A.McMahonC.AustinM. P.ReillyN.LeaderL.AliS. (2009). Maternal prenatal anxiety, postnatal caregiving and infants’ cortisol responses to the still-face procedure. Developmental Psychobiology, 51(8), 625–637. https://doi.org/10.1002/dev.20397
20.
GunnarM. R. (2020). Early adversity, stress, and neurobehavioral development. Development and Psychopathology, 32(5), 1555–1562. https://doi.org/10.1017/S0954579420001649
21.
Guyon-HarrisK. L.MadiganS.BronfmanE.RomeroG.Huth-BocksA. C. (2021). Prenatal identification of risk for later disrupted parenting behavior using latent profiles of childhood maltreatment. Journal of Interpersonal Violence, 36(23-24), NP13517–NP13540. https://doi.org/10.1177/0886260520906175
22.
HanrahanK.McCarthyA. M.KleiberC.LutgendorfS.TsalikianE. (2006). Strategies for salivary cortisol collection and analysis in research with children. Applied Nursing Research: ANR, 19(2), 95–101. https://doi.org/10.1016/j.apnr.2006.02.001
23.
HendrixC. L.DilksD. D.McKennaB. G.DunlopA. L.CorwinE. J.BrennanP. A. (2021). Maternal childhood adversity associates with frontoamygdala connectivity in neonates. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 6(4), 470–478. https://doi.org/10.1016/j.bpsc.2020.11.003
24.
IlykaD.JohnsonM.Lloyd-FoxS. (2021). Infant social interaction and brain development: A systematic review. Neuroscience & Biobehavioral Reviews, 130, 448–469. https://doi.org/10.1016/j.neubiorev.2021.09.001
25.
JohnsonP. O.NeymanJ. (1936). Tests of certain linear hypotheses and their application to some educational problems. Statistical Research Memoirs, 1, 57–93.
26.
KhouryJ. E.AhtamB.OuY.JenkinsE.KlengelT.EnlowM. B.Lyons-RuthK. (2023). Linking maternal disrupted interaction and infant limbic volumes: The role of infant cortisol output. Psychoneuroendocrinology, 158, 106379. https://doi.org/10.1016/j.psyneuen.2023.106379
27.
KhouryJ. E.AhtamB.SisitskyM.OuY.GagoskiB.EnlowM. B.Lyons-RuthK.GrantP. E. (2021a). Maternal childhood maltreatment is associated with lower infant gray matter volume and amygdala volume during the first two years of life. Biological Psychiatry Global Open Science, 2(4), 440–449. https://doi.org/10.1016/j.bpsgos.2021.09.005
28.
KhouryJ. E.BeeneyJ.ShiffI.Bosquet EnlowM.Lyons-RuthK. (2021b). Maternal experiences of childhood maltreatment moderate patterns of mother-infant cortisol regulation under stress. Developmental Psychobiology, 63(5), 1309–1321. https://doi.org/10.1002/dev.22109
29.
KhouryJ.DimitrovL.Bosquet EnlowM.HaltiganJ. D.BronfmanE.Lyons-RuthK. (2022). (In this issue). Patterns of Maternal Childhood Maltreatment and Disrupted Interaction Between Mothers and Their 4-Month-Old Infants. Child Maltreatment, 27(3). DOI:10.1177/10775595211007567
30.
KnickmeyerR. C.XiaK.LuZ.AhnM.JhaS. C.ZouF.GilmoreJ. H.StynerM. (2017). Impact of demographic and obstetric factors on infant brain volumes: A population neuroscience study. Cerebral Cortex, 27(12), 5616–5625. https://doi.org/10.1093/cercor/bhw331
31.
LeeA.PohJ. S.WenD. J.TanH. M.ChongY. S.TanK. H.QiuA.FortierM. V.Rifkin-GraboiA. (2019). Maternal care in infancy and the course of limbic development. Developmental Cognitive Neuroscience, 40, 100714. https://doi.org/10.1016/j.dcn.2019.100714
32.
Lyons-RuthK.LiF. H.KhouryJ. E.AhtamB.SisitskyM.GrantE.EnlowM. B. (2023). Maternal childhood abuse versus neglect associated with differential patterns of infant brain development. Research on Child and Adolescent Psychopathology, 51(12), 1919–1932. https://doi.org/10.1007/s10802-023-01041-4
33.
Martinez-TorteyaC.DaytonC.BeeghlyM.SengJ.McGinnisE.MuzikM.RosenblumK. (2014). Maternal parenting predicts infant biobehavioral regulation among women with a history of childhood maltreatment. Development and Psychopathology, 26(2), 379–392. https://doi.org/10.1017/S0954579414000017
34.
McEwenB. S. (2001). Plasticity of the hippocampus: Adaptation to chronic stress and allostatic load. Annals of the New York Academy of Sciences, 933(1), 265–277. https://doi.org/10.1111/j.1749-6632.2001.tb05830.x
35.
McLaughlinK.WeissmanD.BitránD. (2019). Childhood adversity and neural development: A systematic review. Annual Review of Developmental Psychology, 1(1), 277–312. https://doi.org/10.1146/annurev-devpsych-121318-084950
36.
MehtaM. A.GolemboN. I.NosartiC.ColvertE.MotaA.WilliamsS. C.Sonuga-BarkeE. J. (2009). Amygdala, hippocampal and corpus callosum size following severe early institutional deprivation: The English and Romanian adoptees study pilot. The Journal of Child Psychology and Psychiatry and Allied Disciplines, 50(8), 943–951. https://doi.org/10.1111/j.1469-7610.2009.02084.x
37.
MesmanJ.Van IjzendoornM. H.Bakermans-KranenburgM. J. (2009). The many faces of the still-face Paradigm: A review and meta-analysis. Developmental Review, 29(2), 120–162. https://doi.org/10.1016/j.dr.2009.02.001
38.
MoogN. K.EntringerS.RasmussenJ. M.StynerM.GilmoreJ. H.KathmannN.BussC.WadhwaP. D. (2018). Intergenerational effect of maternal exposure to childhood maltreatment on newborn brain anatomy. Biological Psychiatry, 83(2), 120–127. https://doi.org/10.1016/j.biopsych.2017.07.009
39.
NazzariS.FearonP.RiceF.MolteniM.FrigerioA. (2022). Maternal caregiving moderates the impact of antenatal maternal cortisol on infant stress regulation. The Journal of Child Psychology and Psychiatry and Allied Disciplines, 63(8), 871–880. https://doi.org/10.1111/jcpp.13532
40.
OuY.AkbariH.BilelloM.DaX.DavatzikosC. (2014). Comparative evaluation of registration algorithms in different brain databases with varying difficulty: Results and insights. IEEE Transactions on Medical Imaging, 33(10), 2039–2065. https://doi.org/10.1109/TMI.2014.2330355
41.
OuY.SotirasA.ParagiosN.DavatzikosC. (2011). DRAMMS: Deformable registration via attribute matching and mutual-saliency weighting. Medical Image Analysis, 15(4), 622–639. https://doi.org/10.1016/j.media.2010.07.002
42.
OuY.ZölleiL.DaX.RetzepiK.MurphyS. N.GerstnerE. R.GollubR. L.GrantP. E.Kalpathy-CramerJ. (2018). Field of view normalization in multi-site brain MRI. Neuroinformatics, 16(3-4), 431–444. https://doi.org/10.1007/s12021-018-9359-z
43.
OuY.ZölleiL.RetzepiK.CastroV.BatesS. V.GrantP. E.AndrioleK. P.MurphyS. N.GollubR. L. (2017). Using clinically acquired MRI to construct age-specific ADC atlases: Quantifying spatiotemporal ADC changes from birth to 6-year-old. Human Brain Mapping, 38(6), 3052–3068. https://doi.org/10.1002/hbm.23573
44.
PlantD. T.PawlbyS.ParianteC. M.JonesF. W. (2018). When one childhood meets another - maternal childhood trauma and offspring child psychopathology: A systematic review. Clinical Child Psychology and Psychiatry, 23(3), 483–500. https://doi.org/10.1177/1359104517742186
45.
PruessnerJ.KirschbaumC.MeinlschmidG.HellhammerD. (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology, 28(7), 916–931. https://doi.org/10.1016/s0306-4530(02)00108-7
46.
RaoU.ChenL.BidesiA.ShadM.ThomasM.HammenC. (2010). Hippocampal changes associated with early-life adversity and vulnerability to depression. Biological Psychiatry, 67(4), 357–364. https://doi.org/10.1016/j.biopsych.2009.10.017
47.
Rifkin-GraboiA.MeaneyM.ChenH.BaiJ.HameedW.TintM.QiuA.ChongY. S.GluckmanP. D.FortierM. V. (2015). Antenatal maternal anxiety predicts variations in neural structures implicated in anxiety disorders in newborns. Journal of the American Academy of Child & Adolescent Psychiatry, 54(4), 313.e2–321.e2. https://doi.org/10.1016/j.jaac.2015.01.013
48.
RosseelY. (2012). lavaan: An R package for structural equation modeling. Journal of Statistical Software, 48(2), 1–36. https://doi.org/10.18637/jss.v048.i02
49.
ShangG.ZhouT.YanX.HeK.LieB.FengZ.ZhangY. (2025). Multi-scale analysis reveals hippocampal subfield vulnerabilities to chronic cortisol overexposure: Evidence from Cushing’s disease. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 10(8), 865–876.
50.
Sta CruzS.DinovI.HertingM.González-ZacaríasC.KimH.TogaA.SepehrbandF. (2020). Imputation strategy for reliable regional MRI morphological measurements. Neuroinformatics, 18(1), 59–70. https://doi.org/10.1007/s12021-019-09426-x
51.
SullivanR. M.OpendakM. (2021). Neurobiology of infant fear and anxiety: Impacts of delayed amygdala development and attachment figure quality. Biological Psychiatry, 89(7), 641–650. https://doi.org/10.1016/j.biopsych.2020.08.020
52.
TeicherM. H.PariggerA. (2015). The ‘Maltreatment and Abuse Chronology of Exposure’ (MACE) scale for the retrospective assessment of abuse and neglect during development. PLoS One, 10(2), Article e0117423. https://doi.org/10.1371/journal.pone.0117423
53.
TisdallM. D.HessA. T.ReuterM.MeintjesE. M.FischlB.van der KouweA. J. (2012). Volumetric navigators for prospective motion correction and selective reacquisition in neuroanatomical MRI. Magnetic Resonance in Medicine, 68(2), 389–399. https://doi.org/10.1002/mrm.23228
54.
TottenhamN.HareT. A.QuinnB. T.McCarryT. W.NurseM.GilhoolyT.CaseyB.GalvanA.DavidsonM. C.EigstiI. M.ThomasK. M.FreedP. J.BoomaE. S.GunnarM. R.AltemusM.AronsonJ. (2010). Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation. Developmental Science, 13(1), 46–61. https://doi.org/10.1111/j.1467-7687.2009.00852.x
55.
TronickE.AlsH.AdamsonL.WiseS.BrazeltonT. B. (1978). The infant’s response to entrapment between contradictory messages in face-to-face interaction. Journal of the American Academy of Child Psychiatry, 17(1), 1–13. https://doi.org/10.1016/s0002-7138(09)62273-1
56.
TureckiG.MeaneyM. J. (2016). Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review. Biological Psychiatry, 79(2), 87–96. https://doi.org/10.1016/j.biopsych.2014.11.022
57.
TustisonN. J.AvantsB. B.CookP. A.ZhengY.EganA.GeeJ. C. (2010). N4ITK: Improved N3 bias correction. IEEE Transactions on Medical Imaging, 29(6), 1310–1320. https://doi.org/10.1109/TMI.2010.2046908
58.
UyJ. P.ParksK. C.TanA. P.FortierM. V.GotlibI. H. (2025). Maternal childhood maltreatment, development of amygdala volume, and anxiety symptoms in offspring. Journal of the American Academy of Child & Adolescent Psychiatry.
59.
van den HeuvelM. I.MonkC.HendrixC. L.HectJ.LeeS.FengT.ThomasonM. E. (2023). Intergenerational transmission of maternal childhood maltreatment prior to birth: Effects on human fetal amygdala functional connectivity. Journal of the American Academy of Child & Adolescent Psychiatry, 62(10), 1134–1146. https://doi.org/10.1016/j.jaac.2023.03.020
60.
Van TieghemM.KoromM.FlanneryJ.ChoyT.CalderaC.HumphreysK.TottenhamN. (2021). Longitudinal changes in amygdala, hippocampus and cortisol development following early caregiving adversity. Developmental Cognitive Neuroscience, 48, 100916.
61.
VyasA.PillaiA. G.ChattarjiS. (2004). Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior. Neuroscience, 128(4), 667–673. https://doi.org/10.1016/j.neuroscience.2004.07.013
62.
WadeM.SheridanM. A.DruryS. S.TibuF.ZeanahC. H.FoxN. A.McLaughlinK. A. (2024). Blunted stress reactivity as a mechanism linking early psychosocial deprivation to psychopathology during adolescence. Nature Mental Health, 2(6), 703–711. https://doi.org/10.1038/s44220-024-00249-7
63.
WesargC.Van Den AkkerA. L.OeiN. Y.HoeveM.WiersR. W. (2020). Identifying pathways from early adversity to psychopathology: A review on dysregulated HPA axis functioning and impaired self-regulation in early childhood. European Journal of Developmental Psychology, 17(6), 808–827. https://doi.org/10.1080/17405629.2020.1748594
64.
YargerH.BronfmanE.CarlsonE.DozierM. (2020). Intervening with attachment and biobehavioral catch-up to decrease disrupted parenting behavior and attachment disorganization. Development and Psychopathology, 32(3), 1139–1148. https://doi.org/10.1017/S0954579419000786
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