Lower effective connectivity between amygdala and parietal regions in response to fearful faces in schizophrenia Prerona Mukherjee ⁎, Heather C. Whalley, James W. McKirdy, Andrew M. McIntosh, Eve C. Johnstone, Stephen M. Lawrie, Jeremy Hall Division of Psychiatry, University of Edinburgh, UK abstract article info Article history: Received 27 October 2010 Received in revised form 19 September 2011 Accepted 26 September 2011 Available online 22 October 2011 Keywords: Fear processing Inferior parietal lobule Precuneus PPI Effective connectivity fMRI Functional connectivity Schizophrenia Behavioral abnormalities related to processing negative emotions such as fear have been demonstrated in schizophrenia. The amygdala is strongly associated with fear processing, and alterations in amygdala function and structure have been demonstrated in schizophrenia. Further, functional disconnectivity has been attributed as key to the etiology of schizophrenia, with a number of lines of evidence supporting this theory. In the present study, we examine the effective connectivity corresponding to fear processing, from the amygdala to the whole brain, and compare this between patients with schizophrenia and control participants. An implicit facial emotion processing task was performed by 19 patients with schizophrenia and 24 matched controls during fMRI scanning. During the task, participants made gender judgments from facial images with either neutral or fearful emotion. Neural response to fearful images versus neutral was used as contrast of interest to estimate effective connectivity between the amygdala and the whole brain using the psycho-physiological interactions approach. This connectivity was compared between patients with schizophrenia and healthy controls. We show that when looking at fearful compared to neutral faces patients with schizophrenia show significantly reduced effective connectivity from the amygdala to a large cluster of regions including parts of the precuneus and parietal lobe, compared to healthy controls. These regions have been associated with emotion processing and high level social cognition tasks involving self related processing and mental representations about other people. The reduced amygdala connectivity in schizophrenia shown here further illuminates the neural basis for the behavioral abnormalities in emotional and social function found in the disorder. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Schizophrenia is a severely debilitating disorder, with a complex clin- ical presentation of positive and negative symptoms (Crow, 1980). Posi- tive symptoms are characterized by delusional ideation, thought disorders, auditory and visual hallucinations, while negative symptoms include social withdrawal, lack of motivation, and flattened affect (Frith, 1992). Many of these symptoms relate to social behavior and cognition, which have been suggested to be of key importance in the manifestation of schizophrenia (Lee et al., 2004; Brunet-Gouet and Decety, 2006; Burns, 2006; Couture et al., 2006; Penn et al., 2006; Baas et al., 2008). One important component of social cognition is processing emotion based on socially salient stimuli such as facial expressions. Processing facial expressions has been found to be impaired in schizophrenia (Mandal et al., 1998; Earnst and Kring, 1999; Phillips et al., 2003; Trémeau, 2006; Marwick and Hall, 2008 and Ochsner, 2008). Processing facial emotion, particularly related to adverse emotions such as fear, has been extensively reported in schizophrenia (Edwards et al., 2002; Bigelow et al., 2006; Chambon et al., 2006; Schneider et al., 2006; Bediou et al., 2007; Hall et al., 2008; Michalopoulou et al., 2008; Derntl et al., 2009; Johnston et al., 2010) some of these findings have been discussed in Morris et al., 2009. Further, these effects have been related to positive and negative symptoms such as paranoia and flattened affect (Frith, 1992; Heimberg et al., 1992; Gur et al., 2007; Van't Wout et al., 2007). The amygdala plays a pivotal role in fear processing (Morris et al., 1996; Calder et al., 2001; LeDoux, 2003; Adolphs et al., 2005; Ohman, 2005; Phelps, 2006; Delgado et al., 2008). Studies have repeatedly demonstrated that patients with schizophrenia show abnormalities in the amygdala with respect to its structure (Wright et al., 1999; Wright et al., 2000; Shenton et al., 2001; Namiki et al., 2007) functional activation (Gur et al., 2002; Holt et al., 2006; Williams et al., 2007; Yamada et al., 2007; Baas et al., 2008; Hall et al., 2008; Li et al., 2009; Pinkham et al., 2011; Anticevic et al., 2010) and connectivity (Williams et al., 2004; Das et al., 2007; Benes, 2009), as reviewed in Aleman and Kahn (2005), Kucharska-Pietura et al. (2003) and Shayegan and Stahl (2005). Fear related positive symptoms such as paranoia have as well been associated with abnormal amygdala function (Taylor et al., 2002; Williams et al., 2004; Russell et al., 2007; Williams et al., 2007). Schizophrenia Research 134 (2012) 118–124 ⁎ Corresponding author at: Division of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK. Tel.: + 44 131 537 6687; fax: +44 131 537 6531. E-mail address: pmukherjee@sms.ed.ac.uk (P. Mukherjee). 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.09.033 Contents lists available at SciVerse ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres