Structural Brain Abnormalities in Adolescent Anorexia Nervosa Before and After Weight Recovery and Associated Hormonal Changes VERENA MAINZ,PHD, MARTIN SCHULTE-RU ¨ THER,PHD, GEREON R. FINK, MD, BEATE HERPERTZ-DAHLMANN, MD, AND KERSTIN KONRAD,PHD Objective: The neurobiological mechanisms of structural brain abnormalities in patients with anorexia nervosa (AN) remain poorly understood. In particular, little is known about the changes in and the recovery of gray matter (GM) volumes after weight gain and the relation to hormonal normalization in adolescent patients with AN. Methods: Nineteen female patients aged 12 to 17 years were assessed using magnetic resonance imaging at the time of admission to the hospital (T1) and after weight recovery (T2). Patients were compared with typically developing girls matched for age and intelligence quotient. Structural brain images were analyzed using a voxel-based morphometric approach. Circulating levels of cortisol and gonadotropins were assessed in blood samples. Results: Compared with controls, patients with AN showed reduced GM in several brain regions along the cortical midline, reaching from the occipital cortex to the medial frontal areas. These GM reductions were mostly reversible at T1. Patients showed a GM increase from T1 to T2 along the cortical midline and in the occipital, temporal, parietal, and frontal lobes. GM increases at T2 correlated inversely with cortisol levels at T1 and positively with weight gain at T2. The strongest associations between regional GM increase and weight gain were found in the cerebellum. In addition, increases in GM volumes at T2 in the thalamus, hippocampus, and amygdala were associated with increases in follicle-stimulating hormone. Conclusions: Our data suggest that brain alterations in adolescents with acute AN are mostly reversible at T1 and that GM recovery in specific brain regions is associated with weight and hormonal normalization. Key words: anorexia nervosa, adolescence, brain volume, cortisol, gonadotropins. AN = anorexia nervosa; MRI = magnetic resonance imaging; WM = white matter; GM = gray matter; VBM = voxel-based morphometry; CSF = cerebrospinal fluid; BMI = body mass index; FSH = follicle- stimulating hormone; SPM = statistical parametric mapping; ROI = region of interest. INTRODUCTION A norexia nervosa (AN) is the third most common chronic illness of adolescents, with a typical age of onset between 15 and 19 years. It involves marked somatic complications afflicting almost every organ system, including the central nervous system (1). A great deal of evidence suggests that individuals with acute AN have reduced brain mass, particularly reductions in gray matter (GM) volumes. Considering the complex and often con- tradictory structural findings within the volumetric literature, voxel-based morphometry (VBM), which enables the voxel- wise comparisons of GM probabilities between groups of sub- jects across the whole brain (2), offers the promise of clarifying the structural deficits in AN. During the last year, approximately seven VBM studies have been conducted with patients with AN. These data suggest quite widespread reductions of GM volumes in areas including the cingulate cortex (3), the pre- cuneus, the inferior and superior parietal lobules (4), and the temporal (5) and temporoparietal regions (6) in the acute phase of illness. However, it is currently not clear whether structural brain abnormalities persist after recovery from AN, whether they are partially or fully reversible (7,8) to what degree the associations between weight and brain recovery are linear, what time interval is needed for plasticity processes in the brain to be completed, and what mechanisms lie behind structural brain changes and recovery in patients with AN. No abnormalities were found in the sample with the longest recovery time (average, 28 months). This study investigated young adult patients (average age, 24 years) (9), suggesting that brain tissue normalization might lag behind clinical improvement. Because AN mostly has its onset around puberty, one might also speculate that changes in the adolescent brain, which has not fully established struc- tural maturity, might differ from starvation effects in the adult brain. Previous longitudinal studies investigating the reversibility of brain abnormalities after weight gain in patients with AN provided evidence for small, persistent changes in GM vol- umes. For example, Mu¨ hlau et al. (10) reported global GM (not white) volume decreases of approximately 1%. However, in this study, adult patients with AN with an upper age range of 48 years and a short recovery time of 6 months were included. So far, one longitudinal study included a small sample of only adolescent patients with AN (12 subjects with AN and 9 con- trols) (5). The authors reported that, although global GM vol- ume was restored regionally, some regions in the right temporal and both supplementary motor areas (SMAs) were still smaller after 7 months of weight recovery. A possible explanation for the conflicting findings in patients who have recovered from AN might be the age of the patient sample and the duration of weight rehabilitation. Persis- tent GM alterations after short-term weight rehabilitation may be related to several factors, including persistent subclinical SPECIAL SERIES ON NEUROSCIENCE IN HEALTH AND DISEASE 574 Psychosomatic Medicine 74:574Y582 (2012) 0033-3174/12/7406Y0574 Copyright * 2012 by the American Psychosomatic Society From the Department of Child and Adolescent Psychiatry and Psychotherapy (V.M., M.S.-R., B.H.-D., K.K.), University Hospital of the RWTH Aachen, Aachen; Cognitive Development Group (V.M., M.S.-R., G.R.F., K.K.), Cog- nitive Neurology, Institute of Neuroscience and Medicine (INM-3), For- schungszentrum Ju¨lich, Ju¨lich; Department of Neurology (G.R.F.), University Hospital Cologne, Cologne; Ju¨lich-Aachen Research Alliance (JARA-BRAIN) (B.H.-D., K.K.), RWTH Aachen University, Aachen; Forschungszentrum Ju¨lich, Germany. Address correspondence and reprint requests to Verena Mainz, PhD, Child Neuropsychology Section, Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of the RWTH Aachen, Neuenhofer Weg 21, 52074 Aachen, Germany. E-mail: vmainz@ukaachen.de This study was supported by a grant of the German Ministry for Education and Research (01GV0602) to Drs. Herpertz-Dahlmann and Konrad. Received for publication June 20, 2011; revision received November 21, 2011. DOI: 10.1097/PSY.0b013e31824ef10e Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.