Cerebral maturation in the early preterm period—A magnetization transfer and diffusion tensor imaging study using voxel-based analysis Revital Nossin-Manor a,b, ⁎, Dallas Card a , Charles Raybaud a,d , Margot J. Taylor a,b,d , John G. Sled c,e a Diagnostic Imaging, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada b Neurosciences and Mental Health, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada c Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada d Medical Imaging, University of Toronto, Toronto, ON M5S 3E2, Canada e Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada abstract article info Article history: Accepted 22 February 2015 Available online 27 February 2015 Keywords: Quantitative MRI MTR DTI Preterm neonates Brain maturation Voxel based analysis The magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) correlates of early brain development were examined in cohort of 18 very preterm neonates (27–31 gestational weeks) presenting with normal radio- logical findings scanned within 2 weeks after birth (28–32 gestational weeks). A combination of non-linear image registration, tissue segmentation, and voxel-wise regression was used to map the age dependent changes in MTR and DTI-derived parameters in 3D across the brain based on the cross-sectional in vivo preterm data. The regression coefficient maps obtained differed between brain regions and between the different quantitative MRI indices. Significant linear increases as well as decreases in MTR and DTI-derived parameters were observed throughout the preterm brain. In particular, the lamination pattern in the cerebral wall was evident on paramet- ric and regression coefficient maps. The frontal white matter area (subplate and intermediate zone) demonstrat- ed a linear decrease in MTR. While the intermediate zone showed an unexpected decrease in fractional anisotropy (FA) with age, with this decrease (and the increase in mean diffusivity (MD)) driven primarily by an increase in radial diffusivity (RD) values, the subplate showed no change in FA (and an increase in MD). The latter was the result of a concomitant similar increase in axial diffusivity (AD) and RD values. Interpreting the in vivo results in terms of available histological data, we present a biophysical model that describes the rela- tion between various microstructural changes measured by complementary quantitative methods available on clinical scanners and a range of maturational processes in brain tissue. © 2015 Elsevier Inc. All rights reserved. Introduction During the second and third trimesters of pregnancy, a sequence of maturation events establish the foundations for normal brain structure and function including neuronal proliferation and migration, the forma- tion of axonal pathways, programmed cell death and, toward the end of gestation, myelination (Volpe, 2008). These events proceed within laminarly arranged cellular zones, not found in the adult brain, which set the stage for development through to adulthood (Haynes et al., 2005; Kostovic et al., 2002; Rados et al., 2006). This transient laminar or- ganization develops during the mid-fetal period (17–24 gestational weeks) and attains its developmental peak during the early preterm pe- riod (26–34 gestational weeks) between 29 and 32 weeks gestational weeks. It consists of (from pia to ventricle): (a) a marginal zone (MZ), (b) the cortical plate (CP) with high cell-packing density, (c) the subplate (SP) zone, the most prominent zone rich in hydrophilic extra- cellular matrix (ECM) and subplate neurons, and the location of accu- mulation of ‘waiting’ thalamic afferent axons, (d) the intermediate zone (IZ; future white matter (WM)), containing migratory neurons, immature glial cells, large bundles of growing axons and their periventricular crossroads, (e) the subventricular zone (SVZ), a (callosal) fiber-rich zone and (f) the ventricular zone. The developing connections of thalamocortical axons, with their synaptic engagement in the CP after the ‘waiting’ period in the transient SP zone, followed by the similarly developing connections of the long association axons are the main connectivity events in the brain in the late fetal (22–25 gestational weeks) and early preterm (26–34 gestational weeks) NeuroImage 112 (2015) 30–42 Abbreviations: ACR, Anterior corona radiata; AD, Axial diffusivity; ALIC, Anterior limb of the internal capsule; CP, Cortical plate; DTI, Diffusion tensor imaging; EC, External capsule; ECM, Extracellular matrix; FA, Fractional anisotropy; FDR, False discovery rate; gCC, Genu of the corpus callosum; GM, Gray matter; GP, Globus pallidus; ILF, Inferior longitudinal fas- ciculus; IZ, Intermediate zone; MD, Mean diffusivity; MTI, Magnetization transfer imaging; MTR, Magnetization transfer ratio; MZ, Marginal zone; OR, Optic radiation; PLIC, Posterior limb of the internal capsule; RD, Radial diffusivity; sCC, Splenium of the corpus callosum; SFO, Superior fronto-occipital fasciculus; SLF, Superior longitudinal fasciculus; SP, Subplate; SS, Sagittal stratum; SVZ, Subventricular zone; VLN, Ventolateral thalamic nucle- us; WM, White matter. ⁎ Corresponding author at: Diagnostic Imaging, Neuroscience and Mental Health pro- gram, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada. Fax: +1 416 813 7362. E-mail address: rmanor@mouseimaging.ca (R. Nossin-Manor). http://dx.doi.org/10.1016/j.neuroimage.2015.02.051 1053-8119/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg