102 Chapter 6 DISCUSSION In this study of white matter microstructure using DTI, we have focused on significant differences of ʎ1, ʎ2 and ʎ3 in the major white matter tracts of 0-2 years old non operated craniosynostosis patients and controls in the major white matter tracts. Consistent with previous studies of white matter asymmetry,22 our results show lateralization in lambdas. Syndromic craniosynostosis shows not to be a significant factor influencing the DTI parameters in the assessed major white matter tracts. Age and FOHR shows to be significant factors affecting the RD in the tracts corpus callosum genu and the hippocampal segment of the left cingulate bundle. Biological effect on increased RD The corpus callosum is an early myelinated region of the brain, undergoing development in weeks 12 to 16 of pregnancy.23 During normal brain development and white matter maturation, FA increases and diffusivity (MD, AD and RD) decreases.24, 25 Although differences in DTI can demonstrate differences in microstructure, the physics of the measurement is nonspecific and could reflect a variety of mechanisms.22 As water movement is more restricted perpendicular to myelin membranes than it is parallel to these membranes, it is presumed that RD reflects myelin integrity. Furthermore, RD is determined by axon density and/or diameter of the white matter tract.26, 27 Our previous study of 7 to 15 years olds with sCS, compared to aged matched controls, found increased RD values in the corpus callosum and cingulate bundle.14 Could this be an intrinsic cause? The fibroblast growth factor receptors have a role in myelination of the corpus callosum and cingulate gyrus. Wilke et al showed that in craniofacial development, FGFR2 and 3 are involved in telencephalon development from which the cingulate bundle and corpus callosum arises.28 FGFR genes are critical to cerebral cortex developmental processes including neuronal migration and stabilization of dendritic patterning.7, 29 Mutations in the FGFR gene could potentially result in abnormal dendritic arborisation patterns, measured as increased diffusivity values. TWIST1 is a transcription factor which is involved in mesodermal differentiation and development.30 In the current study, we did not find increased diffusivity values in the major white matter tracts in the groups: sCS patients vs controls. Although we did additional analyses comparing specific syndromes to controls (Supplemental Table 1 &2) , we were not able to find any statistically significant difference compared to controls. However, we do not have enough statistical power to assess this question. Mechanical effect on increased RD We also used the current study to examine for any potential association between brain white matter microarchitecture changes and ventriculomegaly.31, 32 We used FOHR as a measure of ventriculomegaly and found that in non-operated sCS patients, compared with controls, there was a significant interaction between RD and FOHR
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