Introduction

One of the strongest risk factors for psychopathology is a family history of psychopathology, which may involve genetics, epigenetic modification, and in utero environment. Although brain white matter (WM) has a prolonged period of maturation, the most rapid development of WM occurs in the first 2-3 years [1]. Advances in diffusion MRI, such as multi-shell dMRI, allow us to characterize developmental changes with greater resolution and precision. Here we aimed to examine associations between maternal depression during pregnancy and infant brain development to examine whether these factors might constitute a pathway through which maternal depression increases offspring’s risk for psychopathology.

Methods

Participants were recruited as part of BABIES (Brain and Behavior Infant Experiences Study). 24 infants (11M/13F, average 6.7 months, SD=0.4 months) completed a multi-modal imaging session at 6 months of age, and their mothers completed measures of psychological functioning, including the Edinburgh Postnatal Depression Scale (EPDS) [2]. At this 6-month assessment mothers responded to the EPDS to rate their experience of depressive symptoms during pregnancy. We used a multi-shell diffusion scheme with 30 b=700, 64 b=2000, and 11 b=0. TR/TE=3400/80ms, 2mm isotropic voxels, 16 slices x 3 acquisition bands (48 slices total), in-plane/through-plane acceleration factor=2/3. FSL Eddy/Topup was used to unwarp the diffusion volumes and correct for eddy current distortion. Tractography was completed in DSI studio. We reconstructed the diffusion data using generalized q-sampling imaging [3] and used a deterministic fiber tracking algorithm [4]. We used a large number of seeds (200000) and a high angular threshold (75°) to ensure adequate reconstruction of smaller tracts of interest, such as the UF. The anisotropy threshold (QA: quantitative anisotropy) was determined automatically using 0.6 * (Otsu's threshold). Because our focus was on the UF, we excluded from analysis tracts shorter than 20 mm or longer than 250 mm. Tract clustering and identification was completed using TractStat [5]. We used an age-appropriate template from the UNC Early Brain Development Study (https://www.nitrc.org/projects/uncebds_neodti/) that had been aligned using 12 DOF to the Type II JHU-Eve atlas [6]. Briefly, track files were clustered using region of interest (ROI) definitions from the JHU atlas. Tracks were mapped to the JHU atlas using ANTs. For this analysis, we extracted the left and right UF. We removed false-positive and spurious fibers through regions of avoidance and a neighborhood constraint, and visually quality checked each bundle for all participants. We used bundles meeting strict quality assurance criteria to create population bundle templates. For each participant, streamlines were mapped to the closest streamline for that participant. The workflow is presented in Figure 1. We calculated average FA within the left and right UF as our primary outcome variables. In our primary statistical model examining the association between EPDS and average FA across the UF, we included age and sex of the infant as covariates. As a post hoc analysis, we used TractStat to examine associations between EPDS and FA along the length of the UF.

Results

There was a negative association between EPDS and average FA across the right UF (r=0.54 [0.17,0.77], p=0.0092). At 6 months of age, infants whose mothers reported experiencing greater depressive symptoms during pregnancy had lower FA in the right UF. Along this tract, lower FA was associated with greater maternal depressive symptoms in the mid-body of the right UF and the prefrontal projections controlling for multiple comparisons using FDR (q<0.05, crit. p=0.0015), shown in Figure 2.

Discussion

We present preliminary analyses applying a novel tract clustering toolbox, TractStat, to multi-shell dMRI conducted with 6-month-old infants. TractStat yielded robust reconstruction of the UF and enabled group-level analyses along this tract. We found that at six months of age, infants whose mothers retrospectively reported higher levels of depressive symptoms during pregnancy had poorer WM organization in this key limbic structure. This is consistent with findings from a prior study indicating poorer UF organization in newborns whose mothers reported more severe depressive symptoms during pregnancy [7]. Our results suggest that this effect persists through the first 6 months of life. Similarly, a recent study using multi-shell dMRI reported lower neurite density in newborn infants of depressed mothers [8].

Conclusions

Through further analysis of the association of maternal psychological health and offspring neurodevelopment and functioning, we can gain a more comprehensive understanding of the intergenerational transmission of risk for psychopathology and identify novel targets for prevention and intervention efforts.

Acknowledgements

Data collection was supported by the NIH (R21MH111978; R21HD090493 to IHG); ELD is supported by a grant from the NINDS (PI: Koerte, R01NS100952). Additional support is provided by P41 EB015922. We gratefully acknowledge the efforts of Lucinda Sisk, Anna Cichocki, Amar Ojha, and Marissa Roth in collecting these data.

References

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