Provocation of Symmetry/Ordering Symptoms in Anorexia nervosa: A Functional Neuroimaging Study Masashi Suda 1 * . , Samantha J. Brooks 2. , Vincent Giampietro 3 , Rudolf Uher 1 , David Mataix-Cols 4 , Michael J. Brammer 3 , Steven C. R. Williams 3 , Janet Treasure 1 , Iain C. Campbell 1 1 Section of Eating Disorders, Institute of Psychiatry, King’s College London, London, United Kingdom, 2 Department of Neuroscience, Uppsala University, Uppsala, Sweden, 3 Centre for Neuroimaging Studies, Institute of Psychiatry, King’s College London, London, United Kingdom, 4 Departments of Psychosis Studies and Psychology, Institute of Psychiatry, King’s College London, London, United Kingdom Abstract Anorexia nervosa (AN), obsessive–compulsive disorder (OCD), and obsessive–compulsive personality disorder (OCPD) are often co-morbid; however, the aetiology of such co-morbidity has not been well investigated. This study examined brain activation in women with AN and in healthy control (HC) women during the provocation of symmetry/ordering-related anxiety. During provocation, patients with AN showed more anxiety compared to HCs, which was correlated with the severity of symmetry/ordering symptoms. Activation in the right parietal lobe and right prefrontal cortex (rPFC) in response to provocation was reduced in the AN group compared with the HC group. The reduced right parietal activation observed in the AN group is consistent with parietal lobe involvement in visuospatial cognition and with studies of OCD reporting an association between structural abnormalities in this region and the severity of ‘ordering’ symptoms. Reduced rPFC activation in response to symmetry/ordering provocation has similarities with some, but not all, data collected from patients with AN who were exposed to images of food and bodies. Furthermore, the combination of data from the AN and HC groups showed that rPFC activation during symptom provocation was inversely correlated with the severity of symmetry/ ordering symptoms. These data suggest that individuals with AN have a diminished ability to cognitively deal with illness- associated symptoms of provocation. Furthermore, our data also suggest that symptom provocation can progressively overload attempts by the rPFC to exert cognitive control. These findings are discussed in the context of the current neurobiological models of AN. Citation: Suda M, Brooks SJ, Giampietro V, Uher R, Mataix-Cols D, et al. (2014) Provocation of Symmetry/Ordering Symptoms in Anorexia nervosa: A Functional Neuroimaging Study. PLoS ONE 9(5): e97998. doi:10.1371/journal.pone.0097998 Editor: Cosimo Urgesi, University of Udine, Italy Received October 22, 2013; Accepted April 24, 2014; Published May 20, 2014 Copyright: ß 2014 Suda et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Masashi Suda was financially supported by Canon Foundation in Europe Fellowship, and Samantha J. Brooks was financially supported by the Nina Jackson Fellowship (Research Into Eating Disorders). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: sudamasashi7@gmail.com . These authors contributed equally to this work. Introduction The aetiology of anorexia nervosa (AN) is unclear [1], and the treatment of this disorder requires vast improvement [2,3]. Hence, there is a need to increase our understanding of the neurobiology of this condition [3] and how it relates to other eating disorders (ED), as well as to conditions that are often co-morbid with AN as these may be both causal and maintenance factors in this disease [4]. Anxiety disorders, particularly social anxiety and obsessive– compulsive disorder (OCD), are commonly co-morbid with and often precede the onset of AN. AN has a co-morbidity rate of 20– 40% for OCD and a 20–30% co-morbidity rate for obsessive– compulsive personality disorder (OCPD) [5]. Moreover, girls with OCD have a higher risk of developing an ED later in life [6]. The type of OCD behaviours that often present in patients with AN have been described as a need for symmetry or exactness, rather than aggressive obsessions and checking compulsions [7]. More- over, this need for symmetry remains after long-term recovery from AN [8]. In addition, one family study reported that the risk of OCPD was elevated only among relatives of anorexic probands, indicating these two disorders may involve shared familial risk factors [9]. Therefore, these results suggest a shared familial transmission of AN and OCPD, which raises the possibility that it is necessary to have a risk for both OCPD and an ED in order to develop AN. Thus, OCPD traits, such as the need for symmetry and exactness, are not merely correlates of AN, but may also be intermediate phenotypes. Current neurobiological models propose that AN involves anomalies in the corticolimbic pathways (lateral amygdala, medial prefrontal cortex, and orbitofrontal cortex) associated with anxiety, hypervigilance, and affective instability [10], as well as differences in the functioning of the frontostriatal pathways (lateral striatum, medial prefrontal cortex, and orbitofrontal cortex) associated with compulsivity, motivation, and habits [11]. These brain regions provide targets for emerging neural-based treatments such as repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS) [12]. Functional magnetic resonance imaging (fMRI) studies of AN have generally focused on specific aspects underlying the psychopathology of the disorder. For example, many studies have focused on examining brain responses to salient visual cues, such PLOS ONE | www.plosone.org 1 May 2014 | Volume 9 | Issue 5 | e97998