Psychological Medicine, 2001, 31, 1437–1446.  2001 Cambridge University Press DOI : 10.1017S0033291701004561 Printed in the United Kingdom Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis K.RIDLER,  E.T.BULLMORE, P. J. DE VRIES, J. SUCKLING, G.J. BARKER, S. J. P. MEARA, S. C. R. WILLIAMS  P. F. BOLTON From the Brain Mapping Unit and Developmental Psychiatry Section, Department of Psychiatry, University of Cambridge ; and Clinical Age Research Unit, Department of Health Care of the Elderly, Brain Image Analysis Unit, Department of Biostatistics & Computing and Department of Neurology, Institute of Psychiatry, King’s College London and University Department of Clinical Neurology, Institute of Neurology, Queen Square, London ABSTRACT Background. Neuroimaging studies of tuberous sclerosis complex (TSC) have previously focused mainly on tubers or subependymal nodules. Subtle pathological changes in the structure of the brain have not been studied in detail. Computationally intensive techniques for reliable morphometry of brain structure are useful in disorders like TSC, where there is little prior data to guide selection of regions of interest. Methods. Dual-echo, fast spin-echo MRI data were acquired from 10 TSC patients of normal intelligence and eight age-matched controls. Between-group differences in grey matter, white matter and cerebrospinal fluid were estimated at each intracerebral voxel after registration of these images in standard space ; a permutation test based on spatial statistics was used for inference. CSF-attenuated FLAIR images were acquired for neuroradiological rating of tuber number. Results. Significant deficits were found in patients, relative to comparison subjects, of grey matter volume bilaterally in the medial temporal lobes, posterior cingulate gyrus, thalamus and basal ganglia, and unilaterally in right fronto-parietal cortex (patients 20 %). We also found significant and approximately symmetrical deficits of central white matter involving the longitudinal fasciculi and other major intrahemispheric tracts (patients 21 %) ; and a bilateral cerebellar region of relative white matter excess (patients 28 %). Within the patient group, grey matter volume in limbic and subcortical regions of deficit was negatively correlated with tuber count. Conclusions. Neuropathological changes associated with TSC may be more extensive than hitherto suspected, involving radiologically normal parenchymal structures as well as tubers, although these two aspects of the disorder may be correlated. INTRODUCTION Tuberous sclerosis complex (TSC) is a multi- system genetic disorder associated with a range of physical, behavioural and cognitive mani- festations. The prevalence of TSC is approxi- mately one in 10 000 live births (Osborne et al. 1991) ; it has an autosomal dominant pattern of  Address for correspondence : Ms Khanum Ridler, Brain Map- ping Unit, Department of Psychiatry, University of Cambridge, Box 189, Addenbrooke’s Hospital, Cambridge CB2 2QQ. inheritance with a spontaneous mutation rate up to 70% and a penetrance of almost 100%. Two genes associated with TSC have been cloned : TSC1 on chromosome 9q34 (van Slegtenhorst et al. 1997) encodes the protein hamartin ; and TSC2 on chromosome 16p13.3 (Nellist et al. 1993) encodes the protein tuberin. Both tuberin and hamartin have been shown to act as tumour suppressors, most likely through GTPase acti- vating protein (GAP) domains (Soucek et al. 1997). Although the genetic basis for tuberous 1437