Maternal cortisol is associated with neonatal amygdala microstructure and connectivity in a sexually dimorphic manner

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1. 

   eLife

   Sep 7, 2020

   ###This manuscript is in revision at eLife

   The decision letter after peer review, sent to the authors on August 26 2020, follows.

   Summary

   This study investigates the relationship between maternal cortisol levels (measured from hair) and infant amygdala microstructure in a cohort of 78 mother-infant dyads. The neonates were a mix of those born at term (n=42) and those born prematurely (n=36) but all were scanned at term equivalent age. The authors demonstrate sex-stratified relationships, with a strong relationship between cortisol and amygdala microstructure in males and a relationship between amygdala and other temporal/subcortical regions in females.

   The reviewers agreed that the manuscript is both interesting and timely. The imaging methods are well performed. However, we shared a series of concerns that should be addressed before we …

   ###This manuscript is in revision at eLife

   The decision letter after peer review, sent to the authors on August 26 2020, follows.

   Summary

   This study investigates the relationship between maternal cortisol levels (measured from hair) and infant amygdala microstructure in a cohort of 78 mother-infant dyads. The neonates were a mix of those born at term (n=42) and those born prematurely (n=36) but all were scanned at term equivalent age. The authors demonstrate sex-stratified relationships, with a strong relationship between cortisol and amygdala microstructure in males and a relationship between amygdala and other temporal/subcortical regions in females.

   The reviewers agreed that the manuscript is both interesting and timely. The imaging methods are well performed. However, we shared a series of concerns that should be addressed before we can consider publication.

   Essential Revisions

   Sample:

   -- The incidence of preterm birth is ~10%, while in this cohort the incidence is much higher. Were the women recruited from a high-risk pregnancy clinic (which may be a high stress population) or do the gestational ages largely reflect twins included in the sample?

   -- All infants were imaged at term for this protocol. However, NICU-related procedures occurring between birth and scan (primarily days of mechanical ventilation and infection) are associated with alterations subcortical development in preterms. Was the preterm cohort a critically-ill cohort? Were these clinical variables available?

   -- Maternal education is an important predictor of brain development and outcome. Had the authors considered to adjust for this variable in their analyses, particularly for the volumetric analyses?

   Stress and cortisol:

   -- The last line of the abstract implicates that the amygdala cortisol relationship gives an insight into the relationship between maternal stress and child outcome. Cortisol levels are shown here to covary with microstructure but do they reflect actual maternal stress in pregnancy in this sample? Are there any maternal stress (anxiety or depression) questionnaires that could be reported to address this?

   Sex Divergence:

   -- It's not just one sex that is affected but rather sex-specific effects dependent on the outcome examined (amygdala microstructure in male babies and microstructure of connecting white matter from the amygdala in female babies). The abstract doesn't describe this divergence, focusing on results only with respect to female neonates but actually the interaction effects both sexes in different ways / regions. It would also be very helpful to have plots to illustrates the relationships (residualised for covariates).

   Interpretation of measures:

   -- The major conclusions concerning HCC, the interaction with infant biological sex and the diffusion measures revealing evidence for alterations in "dendritic structure, axonal configuration, and the packing density of neurites..." aren't entirely supported by the findings based on the results from volumetric analyses. The alterations in ODI seen with HCC should be paralleled by changes in the volume data.

   Given that brain volume differences are also believed to underlie alterations in dendritic structure, the authors' conclusions wouldn't entirely be supported. Modifying the central claims would be recommended but more data aren't required to support the findings.

   -- The lack of a significant association between macrostructural changes in the amygdala and HCC was surprising. This is in consideration of previous work in the area in the GUSTO cohort, which focused primarily on amygdalar volumes. The discussion of the results related to the volume data should be expanded upon.

   -- How inter-related were the measures - e.g. is there a negative association between amygdala microstructure and amygdala connections that could explain the split in sex associations and directionality.

   Discussion:

   -- What potential biological mechanism do the authors propose underlies these sex specific results. There are only really two vague sentences on this but the complex results need more.

   -- The authors present an extremely comprehensive overview of the connectivity of the amygdala. Given the authors' conclusions regarding future social cognition assessments, it's surprising to see that the subcortical gaze pathway was not examined (amygdala, thalamus, superior colliculus) as this pathway rapidly processing eye/face processing. Examining connectivity with midbrain structures might be infeasible in the neonatal brain; however, including a discussion of this pathway would be useful for future research in the area.

   -- For the HCC relationships with microstructure, maternal HCC values for the preterm infants reflects exposure during (coarsely) a different trimester to the term-born infants. The subgroup analyses (term/preterm) indicate that the results are largely independent of this so does this implicate that the influences on amygdala development are from early gestation?

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2. 

   Version published to 10.1101/2020.06.16.154922 on bioRxiv

   Jun 17, 2020