Temporally anticorrelated brain networks during working memory performance reveal aberrant prefrontal and hippocampal connectivity in patients with schizophrenia Robert Christian Wolf a, ⁎, Nenad Vasic a , Fabio Sambataro b , Annett Höse c , Karel Frasch c , Markus Schmid a , Henrik Walter d a Department of Psychiatry and Psychotherapy III, University of Ulm, Leimgrubenweg 12-14 89075 Ulm, Germany b Clinical Brain Disorders Branch, Genes Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, USA c Department of Psychiatry and Psychotherapy II, University of Ulm, Günzburg, Germany d Department of Psychiatry, Division for Medical Psychology, Friedrich Wilhelms University, Bonn, Germany abstract article info Article history: Received 3 July 2009 Received in revised form 22 July 2009 Accepted 26 July 2009 Available online 8 August 2009 Keywords: Functional connectivity Functional magnetic resonance imaging Hippocampus Independent component analysis Prefrontal cortex Schizophrenia Functional neuroimaging studies on cognitive dysfunction in schizophrenia have suggested regional brain activation changes in the dorsolateral prefrontal cortex and the medial temporal lobe. However, less is known about the functional coupling of these areas during cognitive performance. In this study, we used functional magnetic resonance imaging, a verbal working memory (WM) task and multivariate statistical techniques to investigate the functional coupling of temporally anticorrelated neural networks during cognitive processing in patients with schizophrenia (n = 16) compared to healthy controls (n = 16). Independent component analysis identified 18 independent components (ICs) among which two ICs were selected for further analyses. These ICs included temporally anticorrelated networks which were most highly associated with the delay period of the task in both healthy controls and patients with schizophrenia. Functional network abnormalities in patients with schizophrenia were detected within a “task-positive” lateral frontoparietal network, where increased functional connectivity was found in bilateral dorsolateral prefrontal regions. In addition, aberrant functional coupling of the hippocampal cortex in patients with schizophrenia was detected within a “task-negative” medial frontotemporal network. In patients with schizophrenia, functional connectivity indices in the left dorsolateral prefrontal cortex and the right hippocampal cortex were positively correlated with accuracy during the WM task, while the connectivity strength in the right dorsolateral prefrontal cortex was negatively correlated with measures of symptom severity. These data suggest that within two temporally anticorrelated network states, patients with schizophrenia exhibit increased and persistent dorsolateral prefrontal and hippocampal connectivity during WM performance. © 2009 Elsevier Inc. All rights reserved. 1. Introduction Since the pioneering studies of Ingvar and Franzén (1974) numerous functional neuroimaging studies have expanded the initial findings of “hypofrontality” in patients with schizophrenia by showing a dysfunction of the lateral prefrontal cortex during cognitive processing (Barch et al., 2001; Brahmbhatt et al., 2006; Callicott et al., 2003; Manoach et al., 2000; Perlstein et al., 2001; Stevens et al., 1998; Tan et al., 2006; Volz et al., 1999). Apart from prefrontal dysfunction, brain activation abnormalities have been repeatedly demonstrated in the parietal cortex (Barch and Csernansky, 2007; Hugdahl et al., 2004), the temporal lobe (Heckers et al., 1998; Hofer et al., 2003; Ragland et al., 2008) and in subcortical regions such as the basal ganglia and the thalamus (Andreasen et al., 1996; Manoach et al., 2000), suggesting widespread functional deficits within brain net- works associated with performance across a range of cognitive domains such as attention, episodic memory, executive function and working memory. Beyond task-related increases in brain activity (i.e. task-positive activation responses), several brain areas exhibiting task-induced deactivation (TID) during cognitive performance have been suggested to play a relevant role in the pathophysiology of schizophrenia (Harrison et al., 2007; Pomarol-Clotet et al., 2008), see also Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 1464–1473 Abbreviations: ANOVA, analysis of variance; BA, Brodmann area; BPRS, Brief Psychiatric Rating Scale; COI, component of interest; DLPFC, dorsolateral prefrontal cortex; FDR, false discovery rate; fMRI, functional magnetic resonance imaging; GIFT, group ICA for fMRI toolbox; GLM, General Linear Model; ICA, independent component analysis; MNI, Montreal Neurological Institute; PANSS, Positive and Negative Syndrome Scale; RT, reaction times; SPM, Statistical Parametric Mapping; TID, task-induced deactivation; VLPFC, ventrolateral prefrontal cortex; WM, working memory. ⁎ Corresponding author. Tel.: +49 731 50061571. E-mail address: christian.wolf@uni-ulm.de (R.C. Wolf). 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.07.032 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp