Hippocampal gray matter reduction associates with memory deficits in adolescents with history of prematurity Mo ´ nica Gime ´nez, a Carme Junque ´, a, * Ana Narberhaus, a Xavier Caldu ´, a Pilar Salgado-Pineda, a Nu ´ ria Bargallo ´, b Dolors Segarra, a and Francesc Botet c a Department of Psychiatry and Clinical Psychobiology, Institut d’Investigacions Biome `diques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036, Barcelona, Spain b Neuroradiology Section, Radiology Department, Centre de Diagno `stic per la Imatge (CDI), Hospital Clı ´nic, Faculty of Medicine, University of Barcelona, 08036, Barcelona, Spain c Pediatrics Section, Department of Obstetrics and Gynecology, Pediatrics, Radiology and Physics Medicine, Hospital Clı ´nic, Casa Maternitat, 08028, Barcelona, Spain Received 15 December 2003; revised 30 June 2004; accepted 7 July 2004 Using optimized voxel-based morphometry (VBM), we compared the relationship between hippocampal and thalamic gray matter loss and memory impairment in 22 adolescents with history of prematurity (HP) and 22 normal controls. We observed significant differences between groups in verbal learning and verbal recognition, but not in visual memory. VBM analysis showed significant left hippocampal and bilateral thalamic reductions in HP subjects. Using stereological methods, we also observed a reduction in hippocampal volume, with left posterior predominance. We found correlations between left hippocampal gray matter reductions (assessed by VBM) and verbal memory (learning and percentage of memory loss) in the premature group. The stereological analysis showed a correlation between verbal learning and the left posterior hippocampus. Our results suggest that left hippocampal tissue loss may be responsible for memory impair- ment and is probably related to the learning disabilities that HP subjects present during schooling. D 2004 Elsevier Inc. All rights reserved. Keywords: Hippocampus; Memory deficits; Prematurity; Voxel-based morphometry Introduction Prematurity and very low birth weight are risk factors for brain abnormalities (Bhutta and Anand, 2001; Stewart et al., 1999; Ward and Beachy, 2003). The main MRI structural findings in prema- turity that can be identified by visual inspection are ventricular enlargement (Cooke and Abernethy, 1999; Felderhoff-Mueser et al., 1999; Isaacs et al., 2000; Stewart et al., 1999), periventricular lucencies (Cooke and Abernethy, 1999; Inder et al., 2003; Kr7geloh-Mann et al., 1999), and corpus callosum atrophy (Cooke and Abernethy, 1999; Santhouse et al., 2002; Stewart et al., 1999). Brain volumetric studies are able to identify subtle changes that cannot be evaluated by the standard clinical radiological approach. In subjects with history of prematurity, decreased volumes have been described in the whole brain (Nosarti et al., 2002), cortical gray matter (Nosarti et al., 2002; Peterson et al., 2000), cerebellum (Peterson et al., 2000), basal ganglia (Abernethy et al., 2002; Peterson et al., 2000), and hippocampus (Isaacs et al., 2000, 2003; Peterson et al., 2000). Neuropsychological studies of premature children have reported deficits in global intelligence, learning, attention, visuo- perceptual memory, and frontal lobe functions (Anderson et al., 2003; Bhutta and Anand, 2001; Rushe et al., 2001). The relation- ship between neuropsychological deficits and their cerebral substrate is not always clear (Rushe et al., 2001). Patients with substantial MRI lesions that can be identified by visual inspection have cerebral palsy, mental retardation, and also attention and hyperactivity symptoms (Kr7geloh-Mann et al., 1999). However, Rushe et al. (2001) were unable to relate MRI findings with cognitive status. They reported that premature children with and without MRI lesions did not differ in terms of long-term neuro- psychological outcome. Few studies have correlated volumetric MRI data and neuropsychological performance. Peterson et al. (2000) found strong correlations of regional gray matter with global intelligence quotient and several subtests of the Wechsler Intelligence Scale. Isaacs et al. (2000) found that decreased 1053-8119/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2004.07.029 * Corresponding author. Department of Psychiatry and Clinical Psychobiology, Institut d’Investigacions Biome `diques August Pi i Sunyer (IDIBAPS), University of Barcelona, C/Casanova 143, 08036 Barcelona, Spain. Fax: +34 93 403 52 94. E-mail address: cjunque@ub.edu (C. Junque ´). Available online on ScienceDirect (www.sciencedirect.com.) www.elsevier.com/locate/ynimg NeuroImage 23 (2004) 869 – 877