Introduction

Children born preterm are at a significant risk of neurodevelopmental impairment.^1-3 However, the relationship between preterm birth and cognitive development remains unclear, particularly in children born preterm, without apparent brain injury. Resting-state fMRI (rs-fMRI) is a powerful, non-invasive tool with high sensitivity for delineating alterations in the developing brain.^4-5 Previous studies suggested that preterm birth leads to changes in resting state network development.^6-8 However, long-term effects of prematurity on resting state network architecture and their role in impaired neurodevelopmental outcomes remain incompletely investigated. Present study sought to identify differences in cognitive function in children born preterm compared to term-born controls, and to investigate the alteration of functional connectivity based resting-state functional MRI.

Method

Participants : Sixty-five children were recruited. At 6 years of age, 38 children born preterm (< 32 week’s gestation) and 27 term-born controls had undergone an MRI scan and neurodevelopmental assessment. Demographic and clinical characteristics are presented in Table 1.
Neurodevelopmental assessment : Evaluation involved use of the Wechsler Intelligence Scale for Children, 4th edition (WISC-IV). The WISC-IV provides not only the full-scale intelligence quotients (FSIQ), which indicates the overall cognitive abilities, but also four factor index scores based on specific cognitive profiles: the verbal comprehension index (VCI), perceptual reasoning index (PRI), working memory index (WMI), and processing speed index (PSI).
MRI data acquisition : rs-fMRI, and T1-magnetization-prepared rapid gradient-echo (MPRAGE) images of all subjects were obtained using a 3.0-Tesla MR scanner (Verio, Siemens with a Siemens matrix coil). The rs-fMRI imaging parameters used were as follows: TR = 3000 ms, TE = 30 ms, in-plane voxel resolution = 3.4 × 3.4 mm² , field-of-view = 220 mm × 220 mm, total acquisition time = 5 min 36 s, and slice thickness = 3.4 mm. T1-MPRAGE imaging parameters used were as follows: TR, 1900 ms; TE, 2.93 ms; flip angle, 8°; pixel bandwidth, 170 Hz/pixel; matrix size, 256 × 208; field-of-view, 256 mm; NEX, 1; slice thickness, 1 mm; total acquisition time, 4 min 9 s.
Functional network connectivity analysis : rs-fMRI was performed using the CONN toolbox (www.nitrc.org/projects/conn), version 18b.⁹ Briefly, it involves realignment to the first volume for head motion correction, outlier scrubbing, functional and structural segmentation, normalization to the EPI template with a resampling voxel size of 2 × 2 × 2 mm³ and smoothing kernel of 6-mm full-width half-maximum. The BOLD data were bandpass-filtered (0.008–0.09 Hz) to reduce low-frequency drift and noise effects. Between-group differences in functional connectivity were assessed at the network level. The ROI-to-ROI analysis was run using CONN resting state network nodes (CONN default), which included 32 seeds/targets. A second-level analysis was performed using ROI-to-ROI functional connectivity to investigate group differences between subjects [Preterm (1) Term (-1)]. Regression analyses were also performed to investigate the association between intelligence scores and functional connectivity. Results are reported at a height-threshold false discovery rate of P < 0.05, with two sided seed-level correction and permutation.

Results

The preterm group had significantly lower intelligence scores (83.94 ± 15.89, 98.65 ± 10.85, P < 0.001) and lower scores on all included subscales of the WISC-IV than the term-born controls. The results of the neurodevelopmental assessment are shown in Table 2. Fig. 1 illustrates functional connectivity differences in ROI-to-ROI functional connectivity between the two groups. The preterm infants showed increased functional connectivity between the left lateral prefrontal cortex (LPFC) and the right LPFC of the fronto-parietal network, the right inferior frontal gyrus (IFG) of the language network, and decreased functional connectivity between the right rostral prefrontal cortex (RPFC) and right supramarginal gyrus (SMG) of the salience network. The association between functional connectivity and cognitive ability is shown in Fig. 2. In the children born preterm, the association between FSIQ and inter-network connectivity was not significant, suggesting weakened synchronization between resting state networks. In contrast, in the term-born group, widespread networks were significantly related to FSIQ as well as all subscales of the WISC-IV, suggesting greater synchronization between the distributed resting state networks.

Discussion

In conclusion, we found that at school age, children born preterm had significantly lower intelligence scores and higher behavior problem scores. They exhibited significantly increased functional connectivity between the fronto-parietal network and the language network, and decreased functional connectivity between nodes of the right salience network compared to term-born controls. Alterations of functional connectivity in higher-order association cortices after preterm birth might reflect cognitive or behavior problems in school-aged children born preterm. Our results will help understanding the pathophysiology of cognitive and behavior development in children born preterm without apparent brain injury or major neurodevelopmental impairment.

Acknowledgements

This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (No. 2021R1C1C2003663)