The neural basis of theory of mind and its relationship to social functioning and social anhedonia in individuals with schizophrenia ☆ David Dodell-Feder ⁎, Laura M. Tully, Sarah Hope Lincoln, Christine I. Hooker Department of Psychology, Harvard University, Cambridge, MA 02138, USA abstract article info Article history: Received 18 September 2013 Received in revised form 16 November 2013 Accepted 18 November 2013 Available online 27 November 2013 Keywords: Schizophrenia Theory of mind Social functioning Social anhedonia fMRI Theory of mind (ToM), the ability to attribute and reason about the mental states of others, is a strong determi- nant of social functioning among individuals with schizophrenia. Identifying the neural bases of ToM and their relationship to social functioning may elucidate functionally relevant neurobiological targets for intervention. ToM ability may additionally account for other social phenomena that affect social functioning, such as social an- hedonia (SocAnh). Given recent research in schizophrenia demonstrating improved neural functioning in re- sponse to increased use of cognitive skills, it is possible that SocAnh, which decreases one's opportunity to engage in ToM, could compromise social functioning through its deleterious effect on ToM-related neural circuit- ry. Here, twenty individuals with schizophrenia and 18 healthy controls underwent fMRI while performing the False-Belief Task. Aspects of social functioning were assessed using multiple methods including self-report (Inter- personal Reactivity Index, Social Adjustment Scale), clinician-ratings (Global Functioning Social Scale), and performance-based tasks (MSCEIT—Managing Emotions). SocAnh was measured with the Revised Social Anhe- donia Scale. Region-of-interest and whole-brain analyses revealed reduced recruitment of medial prefrontal cor- tex (MPFC) for ToM in individuals with schizophrenia. Across all participants, activity in this region correlated with most social variables. Mediation analysis revealed that neural activity for ToM in MPFC accounted for the re- lationship between SocAnh and social functioning. These findings demonstrate that reduced recruitment of MPFC for ToM is an important neurobiological determinant of social functioning. Furthermore, SocAhn may affect social functioning through its impact on ToM-related neural circuitry. Together, these findings suggest ToM ability as an important locus for intervention. © 2013 The Authors. Published by Elsevier Inc. All rights reserved. 1. Introduction Social functioning impairment is a hallmark of schizophrenia that is not amenable to most common forms of treatment (Swartz et al., 2007). Elucidating determinants of social functioning are thus a critical step in the development of effective interventions. Research in this area how- ever, may be limited by a lack of information regarding the neural mechanisms that give rise to social impairment. Such information may elucidate the neurocognitive processes and neural substrates to be targeted for remediation that will most likely result in functional improvements. Theory of mind (ToM), or the ability to attribute and reason about the mental states of others, is markedly impaired in individuals with schizophrenia (Bora et al., 2009; Sprong et al., 2007). Critically, among individuals with schizophrenia, these deficits have been consistently linked to aspects of social functioning (Couture et al., 2006; Fett et al., 2011; Horan et al., 2012), are more proximal to daily functioning (Bora et al., 2006; Couture et al., 2011; McGlade et al., 2008), and ac- count for more of the variance in daily functioning than other aspects of the illness, including non-social aspects of cognition and symptoms (Brune et al., 2007; Fett et al., 2011; Kosmidis et al., 2011; Pinkham and Penn, 2006). Though the neural bases of ToM have been fairly well characterized in healthy adults, encompassing right and left temporo-parietal junctions (RTPJ, LTPJ) and medial prefrontal cortex (MPFC) (Mar, 2011; Van Overwalle, 2009), less is known about the ToM network in individuals with schizophrenia. The extant literature suggests functional and anatomical abnormalities in MPFC (Benedetti et al., 2009; Brune et al., 2011, 2003; Das et al., 2012; Hooker et al., 2011; Lee et al., 2006, 2011; Walter et al., 2009a; Yamada et al., 2007). However, findings are inconsistent, and, surprisingly, few such studies investigate the relationship between neural activity for ToM and social functioning. Such data could provide biomarkers of social dysfunction, which may prospectively predict schizophrenia outcomes, and neural targets for remediation. Thus, the first aim of the current study was to characterize the neural bases of ToM in schizophrenia and investigate their relationship to aspects of social behavior using multiple methods of assessment. NeuroImage: Clinical 4 (2014) 154–163 ☆ 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. ⁎ Corresponding author at: Harvard University, Department of Psychology, 1008 William James Hall, 33 Kirkland St., Cambridge, MA 02138, USA. Tel.: +1 516 304 0697. E-mail address: feder@fas.harvard.edu (D. Dodell-Feder). 2213-1582/$ – see front matter © 2013 The Authors. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nicl.2013.11.006 Contents lists available at ScienceDirect NeuroImage: Clinical journal homepage: www.elsevier.com/locate/ynicl