ARTICLE IN PRESS Abnormal deep grey matter development following preterm birth detected using deformation-based morphometry i James P. Boardman, a,b Serena J. Counsell, a Daniel Rueckert, c Olga Kapellou, b Kanwal K. Bhatia, c Paul Aljabar, c Jo Hajnal, a Joanna M. Allsop, a Mary A. Rutherford, a and A. David Edwards a,b, * a Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK b Department of Paediatrics, Imperial College London, Hammersmith Hospital, London W12 0NN, UK c Department of Computing, Imperial College London, 180 Queen’s Gate, London SW7 2AZ, UK Received 20 December 2005; revised 13 March 2006; accepted 14 March 2006 Preterm birth is a leading risk factor for neurodevelopmental and cognitive impairment in childhood and adolescence. The most common known cerebral abnormality among preterm infants at term equivalent age is a diffuse white matter abnormality seen on magnetic resonance (MR) images. It occurs with a similar prevalence to subsequent impairment, but its effect on developing neural systems is unknown. MR images were obtained at term equivalent age from 62 infants born at 24 – 33 completed weeks gestation and 12 term born controls. Tissue damage was quantified using diffusion-weighted imaging, and defor- mation-based morphometry was used to make a non-subjective survey of the whole brain to identify significant cerebral morphological alterations associated with preterm birth and with diffuse white matter injury. Preterm infants at term equivalent age had reduced thalamic and lentiform volumes without evidence of acute injury in these regions (t = 5.81, P < 0.05), and these alterations were more marked with increasing prematurity (t = 7.13, P < 0.05 for infants born at less than 28 weeks) and in infants with diffuse white matter injury (t = 6.43, P < 0.05). The identification of deep grey matter growth failure in association with diffuse white matter injury suggests that white matter injury is not an isolated phenomenon, but rather, it is associated with the maldevelopment of remote structures. This could be mediated by a disturbance to corticothalamic connectivity during a critical period in cerebral development. Deformation-based morphometry is a powerful tool for modelling the developing brain in health and disease, and can be used to test putative aetiological factors for injury. D 2006 Elsevier Inc. All rights reserved. Keywords: Magnetic resonance imaging; Deformation-based morphometry; Preterm birth; Basal ganglia; Thalamus Introduction Preterm birth is associated with long-term neurodevelopmental impairment including cognitive and behavioral problems (Marlow et al., 1993; McCormick et al., 1996), which are more severe with prolonged exposure to the extra uterine environment (Bhutta et al., 2002; Marlow et al., 2005). The most common known cerebral abnormality in surviving preterm infants at term equivalent age is diffuse white matter injury (Figs. 1a and b), which is seen on conventional imaging in one half to two thirds of survivors and is quantifiable as increased apparent diffusion coefficient (ADC) values on diffusion-weighted imaging (DWI) (Maalouf et al., 1999; Counsell et al., 2003). However, it is not known how diffuse white matter injury affects neural development or function, and this significantly hinders the development of strategies to reduce the problems suffered by preterm infants. Cystic periventricular leucomalacia (PVL) is associated with loss of thalamic volume in late infancy (Lin et al., 2001), which draws attention to the role of white matter injury in thalamic development. An important role for the deep grey matter in preterm brain injury is suggested by its volume reduction in a dose- dependent manner with degree of prematurity at birth (Inder et al., 2005), which mirrors the prevalence of subsequent neurocognitive impairment among survivors (Bhutta et al., 2002; Marlow et al., 2005). Cystic PVL is uncommon and cannot account for the high prevalence of neural dysfunction seen in preterm infants. There have been no reports of the effect of the common but poorly understood diffuse white matter lesion on other brain regions, at least in part because of the technological difficulties of making such observations. To investigate the effect of prematurity and diffuse white matter injury on brain development in the neonatal period, we have combined conventional imaging with DWI and deformation-based morphometry (DBM), which uses image registration and statistical analysis to quantify structural differences between groups. We have 1053-8119/$ - see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.03.029 i Structural brain changes following preterm birth. * Corresponding author. Department of Paediatrics, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. Fax: +44 208 740 8281. E-mail address: david.edwards@imperial.ac.uk (A.D. Edwards). Available online on ScienceDirect (www.sciencedirect.com). www.elsevier.com/locate/ynimg YNIMG-03845; No. of pages: 9; 4C: 3, 5, 7 DTD 5 NeuroImage xx (2006) xxx – xxx