72 Chapter 5 be used to investigate the white matter microarchitecture by analyzing white matter tracts. Recent studies have shown that the microstructure of white matter tracts may be altered in some types of craniosynostosis.13-17 However, to date, there have been no studies on the microstructure of the white matter in patients with isolated metopic synostosis. Therefore, the aim of this study is to investigate the white matter properties of the frontal lobe in unoperated patients with metopic synostosis as compared to healthy controls using DTI measurements. Based on the early development of white matter structures and on the higher prevalence of neuro-developmental disorders in patients with trigonocephaly, we hypothesize that the white matter microstructure of the frontal lobe is altered early in life. 4, 5 MATERIAL AND METHODS We conducted a prospective cohort study, which was approved by the Institutional Research Ethics Board at the Erasmus University Medical Center, Rotterdam, the Netherlands (MEC-2018-124). This study is part of ongoing work at the Dutch Craniofacial Center involving protocolized care, brain imaging, and clinical assessment. Subjects Patients were included between 2018 and 2020. We included all unoperated patients with nonsyndromic trigonocephaly, for whom a surgical correction was considered and for whom three-dimensional diffusion-weighted MRI and T1 -weighted MRI scans of the brain were available. We considered patients with a genetic variant (n = 3) of unknown significance as patients with nonsyndromic trigonocephaly. Patients with known pathogenic mutations (e.g., 9p deletion syndrome, Down syndrome, Jacobsen syndrome) or patients born prematurely were excluded from this study. Controls were identified from a historic hospital MRI database of children who had undergone MRI brain studies for clinical reasons between 2010 and 2020. Patients were considered a control if any cerebral and/or skull pathology was absent. Scans of potential controls were reviewed by an expert pediatric radiologist and a neurosurgeon to ensure the absence of any cerebral pathology and/or skull pathology. MRI brain scans of insufficient quality due to motion artefacts were excluded (n = 4). MRI acquisition All brain MRI data were acquired with a 1.5-Tesla unit (General Electric Healthcare, Milwaukee, Wisconsin), including a three-dimensional T1 -weighted fast-spoiled gradient-recalled sequence and a DTI sequence. DTI was obtained using a multirepetition single-shot echo-planar sequence with a slice thickness of 3 mm without a gap. Images were obtained in 25 of 35 gradient directions with the following parameters: b-value: 1000s/mm2; repetition time: 15,000 ms; time to echo: 82.1 ms; field of view: 240 x 240 mm2; and matrix size: 128 x 128, resulting in a voxel size of 1.8
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