Introduction

In the fetal brain, the timing of sulcal emergence has been considered a key marker for evaluating the normality of cortical development in numerous studies^1–5. Sulcal emergence shows regionally different patterns that may be related to dynamic spatiotemporal patterns of gene expression^6–9. Since gene expression patterns are different across typical individuals, sulcal emergence may also have inter-subject variability. The timing and inter-subject variability of sulcal emergence in typically developing (TD) fetuses can provide crucial information to define normal range of fetal brain development and can be used as a reference to detect potential abnormalities in early brain development.
We aimed to quantitatively measure the timing of sulcal emergence and its inter-subject variability. We also provided a statistical approach to compare difference in timing and its variability between groups. Here, we statistically investigated hemispheric asymmetry and sex difference in the timing and variability of sulcal emergence.

Methods

A total of 89 TD fetuses were included in this study (gestational weeks [GW]: 26.6 ± 3.6 [mean ± standard deviation (SD)], sex: 47/40/2 [male/female/unknown]). We used our automatic pipeline for fetal brain MRI processing and cortical surface reconstruction¹⁰. Fetal sulci in the cortical surfaces were anatomically assigned to 19 labels using spatial and temporal information of fetal gyrification from multiple fetal templates from 23 to 33GW¹⁰. The fetal sulcal labels and abbreviations are shown in Figure 1. To estimate the timing and variability of sulcal emergence, the presence or absence of sulcal labels in each fetus was counted as binary variables. In each sulcus, we modeled a binary logistic curve to quantify the relationship between GW and the binary variables that represents the probability of sulcal label presence by GW. We estimated sulcal emergence timing using GW at 0.5 of probability in the curve (t₅₀). We also calculated interquartile range (IQR) of GWs between probability at 0.25 (t₂₅) and 0.75 (t₇₅) as the inter-subject variability of sulcal emergence (Figure 2A). To analyze hemispheric asymmetry and sex difference in the timing of sulcal emergence, we statistically compared two logistic curves modeled in each hemisphere (Figure 2B). Standard error (SE) of t₅₀ in a group (hemisphere or sex) were calculated and the statistical difference in the timings were calculated by z transformation of t₅₀s and SEs. Comparison of inter-subject variability was also performed by substituting t₅₀ for IQR.

Results

Table 1 shows the timing and variability of sulcal emergence. Emergence of the STS and CS occurred first as early as 23.67 and 24.10 GWs, respectively. The bilateral SFS, IFS, PreCS, PostCS, IPS, and OrbS emerged between 24.9 and 27 GWs. The bilateral MFS and OTS emerged after 27 GW. The inter-subject variability of sulcal emergence were variant across sulci. IQRs of left CS and PreCS were less than 1 week. Extremely small IQR were also found in the left IPS and right SFS. In contrast, the bilateral OTS, left IFS, right Post CS, right IFS, right ITS, right SPS had large IQR over two weeks. Since the SF, ColS, CingS, CalS, and POS emerge before 22 GW in all fetal brains, their binary logistic curves were not modeled, and we exclude them in the analysis.
Statistically significant earlier sulcal emergence timing in the right hemisphere was found in the CS (p = 0.042) and OTS (p = 0.010) (Table 1). Significantly smaller variability in the left hemisphere was found in the PostCS (p = 0.045). For sex difference (Table 2), the sulcal emergence timing of males was significantly earlier than that of females in the left PreCS (p < 0.001), left MFS (p = 0.023), left IFS (p = 0.005), and right ITS (p = 0.040). Significantly larger variability of sulcal emergence timing in male fetuses was found in the bilateral IPS (p = 0.003 [left] and 0.013 [right]).

Discussion

This study is the first to quantify sulcal emergence in a large sample of TD fetuses. The sequence of emergence timing estimated by our quantitative approach indicates that the sulcal emergence occurred from central to peripheral regions. This finding concurs with the prior studies^1,2,11–13 and may be related the temporo-parieto-occipital pattern of brain maturation. The majority of sulci showed 1-2 weeks of inter-subject variability of sulcal emergence timing, which is supported by previous studies with visual inspection^1,2. While the visual inspection studies reported uniform variabilities across sulci, our quantitative approach found the regionally diverse variability that may be associated with different temporal variability of gene expression in each region.
Furthermore, we found left CS and OTS emerged earlier than right, which is supported by previous studies on hemispheric asymmetry of brain structures^14–17. Sex difference in emergence timing and its variability reported in this study may be associated with sex difference in regional volumes in the fetal brain¹⁷.
In conclusion, our approach provided a quantitative timetable of sulcal emergence that could be a reference to assess normality of fetal gyrification, and to allow further statistical analysis of fetal gyrification. Future studies will include enrichment for numerous factors that need to be explored including race, ethnicity, socioeconomic status and maternal education.

Acknowledgements

No acknowledgement found.

References

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