Reduced Thickness of Medial Orbitofrontal Cortex in Smokers Simone Kühn, Florian Schubert, and Jürgen Gallinat Background: Structural deficiencies within the prefrontal cortex might be related to drug-taking behavior that prevails in smokers. Cortical thickness has been found to be a structural modulator of cerebral function and cognition and a subtle correlate of mental disorders. However, to date an analysis of cortical thickness in smokers compared with never-smokers has not been undertaken. Methods: We acquired high-resolution magnetic resonance imaging scans from 22 smokers and 21 never-smokers and used FreeSurfer to model the gray-white and pial surfaces for each individual cortex to compute the distance between these surfaces to obtain a measure of cortical thickness. The main cortical folds were aligned across individuals with FreeSurfer’s surface-based averaging technique to compare whole brain differences in cortical thickness between smokers and never-smokers. Results: Relative to never-smokers, smokers showed greater cortical thinning in the left medial orbitofrontal cortex (mOFC). Cortical thickness measures extracted from mOFC correlated negatively with the amount of cigarettes consumed/day and the magnitude of lifetime exposure to tobacco smoke. Conclusions: The brains of smokers are structurally different from those of never-smokers in a dose-dependent manner. The cortical thinning in mOFC in smokers relative to never-smokers might imply dysfunctions of the brain’s reward, impulse control, and decision- making circuits. Related behavioral correlates are suggested to be relevant for smoking initiation and maintenance. Key Words: Addiction, cortical thickness, orbitofrontal cortex, smoking, nicotine, substance dependence W orldwide cigarette smoking is a highly prevalent sub- stance-dependence and the leading cause of early pre- ventable deaths in developed countries (1). Magnetic res- onance imaging studies have associated tobacco smoking with large-scale structural brain abnormalities. In a study on elderly indi- viduals, smoking has been linked to sulcal as well as ventricular grade and general atrophy (2,3). Moreover, smoking history has been associated with periventricular white matter abnormalities (2,4). More recent studies explored structural differences between smokers and nonsmokers, focusing on regional gray matter (and white matter) volumes as well as densities with voxel based mor- phometry (VBM) (5–8). Overall they found smaller gray matter vol- umes and densities for smokers. Gazdzinski et al. (8) showed a reduction in parietal and temporal gray matter, which is in line with findings of Durazzo et al. (6), reporting smaller temporal, parietal, and neocortical gray matter volume among smokers who were heavy drinkers. By contrast, two studies reported by Gallinat et al. (7) and Brody et al. (5) found structural deficiencies in anterior cingu- late cortex and bilateral prefrontal cortex, next to a multitude of other brain areas. However, VBM has been shown to be sensitive to a combination of changes in gray matter thickness, intensity, cortical surface area, and cortical folding (9,10). Moreover, VBM is especially susceptible to the degree of smoothing, differences in registration, and choice of normalization template (11,12). Therefore, surface-based mor- phology analysis has been proposed to assess the contributions of gray matter thinning independently of regional surface area (10). Cortical thickness has previously been found to be associated with normal aging, intelligence, cognitive performance, and mental dis- orders and is suggested to be a more sensitive parameter with a higher signal-to-noise ratio compared with VBM (9,13–15). More- over, cortical thickness measures might be easier to interpret than the probabilistic gray matter volumes in VBM (16). In a study by Hutton et al. (9) cortical thickness has been shown to provide a more sensitive measure of age-associated decline, compared with the gray matter volume measure typically used in VBM studies. There- fore, cortical thickness might be a more appropriate measure when trying to assess drug-related changes. We are not aware of any previous studies focusing on regional cortical thickness in smokers compared to nonsmokers. The only related study assessing cortical thickness measures in smokers ex- plored prenatal exposure to maternal cigarette smoking (17). The authors demonstrate that in adolescents with prenatal exposure the likelihood of drug experimentation correlates with thinning of the orbitofrontal cortex (OFC), whereas in nonexposed adolescents OFC thickness is increased with the number of drugs tried. These results, seen in the light of previous studies on various drugs of abuse that have demonstrated structural abnormalities related to OFC (18 –20), lead us to suspect that the OFC might be affected by smoking-related structural changes. The current study focuses on pos- sible alterations in cortical thickness in a sample of subjects without mental or medical disorder. Methods and Materials Participants Forty-three subjects, 22 smokers and 21 never-smokers, were recruited by means of newspaper advertisements. Never-smokers were naive with respect to tobacco consumption. Demographic and smoking data of the participants are given in Table 1. All sub- jects were free of medical, neurological, and psychiatric disorders— according to personal interviews (Mini-International Neuropsychi- From the Faculty of Psychology and Educational Sciences (SK), Department of Experimental Psychology and Ghent Institute for Functional and Met- abolic Imaging, Ghent University, Ghent, Belgium; Institute of Cognitive Neuroscience (SK), Department of Psychology, University College Lon- don, London, United Kingdom; Physikalisch-Technische Bundesanstalt (FS); and St. Hedwig Krankenhaus (SK, JG), Clinic for Psychiatry and Psychotherapy, Charité University Medicine, Berlin, Germany. Address correspondence to Simone Kühn, Dr., Department of Experimental Psychology, Ghent University, Henri Dunantlaan 2, 9000 Ghent, Belgium; E-mail: simone.kuhn@ugent.be. Received May 5, 2010; revised Aug 5, 2010; accepted Aug 5, 2010. BIOL PSYCHIATRY 2010;68:1061–1065 0006-3223/$36.00 doi:10.1016/j.biopsych.2010.08.004 © 2010 Society of Biological Psychiatry