Task-related fronto-striatal functional connectivity during working memory performance in schizophrenia Yann Quidé a,b , Richard W. Morris c , Alana M. Shepherd a,b , Jesseca E. Rowland b , Melissa J. Green a,b,d,e, ⁎ a Schizophrenia Research Institute, Darlinghurst, NSW, Australia b School of Psychiatry, University of New South Wales, Randwick, NSW, Australia c Brain & Mind Research Institute, University of Sydney, Camperdown, NSW, Australia d Neuroscience Research Australia, Randwick, NSW, Australia e Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia abstract article info Article history: Received 28 March 2013 Received in revised form 21 July 2013 Accepted 10 August 2013 Available online 7 September 2013 Keywords: Schizophrenia Working memory Striatum Performance Functional connectivity fMRI Working memory (WM) deficits and associated brain dysfunction are among the most well replicated candidate endophenotypic processes in schizophrenia. However, previous studies demonstrate inconsistent over- and under-activation of dorsolateral and ventrolateral prefrontal cortices (DLPFC; VLPFC), inferior parietal lobule (IPL) during WM performance, as well as subcortical structures including the striatum, and dysfunctional connec- tivity among fronto-striatal regions in schizophrenia. However, no previous study has investigated task-related functional connectivity (FC) of DLPFC and striatal regions using a seed-based method; here we employed this method to assess patterns of cortical and subcortical functional connectivity among WM structures during a stan- dard 2-back WM task performed by 28 schizophrenia (SZ) and 28 healthy controls (HC). Initial group compari- sons of blood oxygenation level dependent (BOLD) responses during the WM task revealed significantly greater bilateral activity in the striatum in SZ relative to HC, but there was no significant group difference in WM cortical activity (right DLPFC, VLPFC or IPL). Analyses of FC within the cortico-subcortical WM network in the HC group revealed positive performance-related FC between the right DLPFC and the right caudate, and between the right VLPFC and the right IPL; this pattern was absent in SZ. In contrast, SZ patients showed negative performance- related functional connectivity between the left putamen and the right VLPFC. Direct group comparisons in functional connectivity showed significantly greater performance-related FC between the VLPFC and bilateral putamen, as well as unilaterally between the VLPFC and the right IPL, in HC. Results suggest a critical dysfunction of cortico-striatal connectivity underpinning information retrieval for SZ patients during WM performance. Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved. 1. Introduction Aberrant functional and structural connectivity between cortico- striatal structures are increasingly implicated in psychiatric phe- nomena (Quan et al., 2013; Shepherd, 2013), and have recently been associated with executive dysfunctions in working memory (WM; Fornito et al., 2012). Impaired WM is a promising endophenotypic candidate for schizophrenia, having filled a number of requirements for endophenotypic status (Gottesman and Gould, 2003): that is, the WM deficit is associated with illness, evident in unaffected relatives (Snitz et al., 2006; Gur et al., 2007), associated with an identifiable brain network (Bertolino et al., 2006; Ceaser et al., 2012), and there have been many replications of genetic asso- ciation of the catechol-O-methyltransferase (COMT) Val158Met polymorphism with WM performance (Alfimova et al., 2007; Lopez-Garcia et al., 2012). However, there remains ambiguity with respect to the precise neurophysiological substrate of WM dysfunc- tion, partly owing to mixed findings of hypo- and hyper-activation of frontal brain networks during WM performance in schizophrenia that have now accumulated in the literature (Eisenberg and Berman, 2010), and partly owing to the emergence of recent studies highlighting the importance of cortico-striatal connectivity for WM dysfunction (Meda et al., 2009; Satterthwaite et al., 2012). Accurate characterisation of the neurophysiological substrate of WM dysfunc- tion is important for future imaging genetic investigations that may be relevant to disorders beyond schizophrenia, in accord with the Research Domain Criteria (RDoC) endorsed by the NIMH (Cuthbert and Insel, 2010; Insel et al., 2010). In this context, the present study sought to determine task-related patterns of functional con- nectivity among the cortical and sub-cortical structures of the WM network, in relation to individual WM performance in schizophrenia. Substantial neuroimaging literature has accumulated to implicate inefficient activity of the DLPFC in association with WM deficits in schizophrenia, but the neurophysiological response of this structure does not appear to be linearly related to behavioural task performance: instead mixed findings from the many studies of brain activity during Schizophrenia Research 150 (2013) 468–475 ⁎ Corresponding author at: School of Psychiatry, University of New South Wales, NSW 2052, Australia. Tel.: +61 2 8382 1584; fax: +61 2 8382 1402. E-mail address: melissa.green@unsw.edu.au (M.J. Green). 0920-9964/$ – see front matter. Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.08.009 Contents lists available at ScienceDirect Schizophrenia Research journal homepage: www.elsevier.com/locate/schres