Identifying the brain's most globally connected regions Michael W. Cole a,b,c, ⁎, Sudhir Pathak c , Walter Schneider c,d a Department of Psychology, Washington University in St. Louis, MO 63130, USA b Department of Neuroscience and Center for the Neural Basis of Cognition, University of Pittsburgh, PA 15260, USA c Learning Research and Development Center, University of Pittsburgh, PA 15260, USA d Department of Psychology, University of Pittsburgh, PA 15260, USA abstract article info Article history: Received 12 August 2009 Revised 7 October 2009 Accepted 1 November 2009 Available online 10 November 2009 Recent advances in brain connectivity methods have made it possible to identify hubs—the brain's most globally connected regions. Such regions are essential for coordinating brain functions due to their connectivity with numerous regions with a variety of specializations. Current structural and functional connectivity methods generally agree that default mode network (DMN) regions have among the highest global brain connectivity (GBC). We developed two novel statistical approaches using resting state functional connectivity MRI—weighted and unweighted GBC (wGBC and uGBC)—to test the hypothesis that the highest global connectivity also occurs in the cognitive control network (CCN), a network anti-correlated with the DMN across a variety of tasks. High global connectivity was found in both CCN and DMN. The newly developed wGBC approach improves upon existing methods by quantifying inter-subject consistency, quantifying the highest GBC values by percentage, and avoiding arbitrary connection strength thresholding. The uGBC approach is based on graph theory and includes many of these improvements, but still requires an arbitrary connection threshold. We found high GBC in several subcortical regions (e.g., hippocampus, basal ganglia) only with wGBC despite the regions' extensive anatomical connectivity. These results demonstrate the complementary utility of wGBC and uGBC analyses for the characterization of the most highly connected, and thus most functionally important, regions of the brain. Additionally, the high connectivity of both the CCN and the DMN demonstrates that brain regions outside primary sensory-motor networks are highly involved in coordinating information throughout the brain. © 2009 Elsevier Inc. All rights reserved. Introduction The brain is thought to have evolved from simple reflex circuits, bestowing flexibility on behavior by integrating specialized brain regions into coordinated networks. Perhaps reflecting our especially flexible behavioral repertoire, the human brain is estimated to have hundreds of specialized brain regions (Van Essen, 2004). However, it is unknown how these specialized regions are integrated so behavior can be coordinated. Recent research has found that some regions have much higher global brain connectivity (GBC) than others, perhaps reflecting their role in integrating brain activity in order to coordinate cognition and behavior (Achard et al., 2006; Buckner et al., 2009; Hagmann et al., 2008; Heuvel et al., 2008; Salvador et al., 2005a; Sporns et al., 2007). Existing GBC methods, using both anatomical (Hagmann et al., 2008) and functional (Buckner et al., 2009) connectivity, have identified regions in the default mode network (DMN) as having the highest GBC. This high connectivity may reflect connections necessary to implement the wide variety of cognitive functions the network is involved in. Consistent with this notion, we hypothesized that another large-scale network implementing a variety of cognitive function, the cognitive control network (CCN), also has among the highest GBC. The CCN has been reported in many studies of cognitive control processes, and is likely involved in coordinating networks of brain regions during novel and non-routine tasks (Cole and Schneider, 2007; Dosenbach et al., 2006). The DMN has been reported in studies of resting state activity, suggesting it is active “by default” (Raichle et al., 2001). However, the DMN is engaged by mind wandering (Mason et al., 2007), prospective and retrospective self-reflection (D'Argembeau et al., 2008), and memory retrieval (Buckner et al., 2005), suggesting that the ‘default mode’ involves ongoing processing of information for relevance to the self. The CCN is thought to consist of dorsolateral prefrontal cortex (DLPFC), rostrolateral prefrontal cortex (RLPFC), dorsal–caudal anterior cingulate cortex (ACC), pre-supplementary motor area (pre-SMA), inferior frontal junction (IFJ), posterior parietal cortex (PPC), pre-motor cortex (PMC), and anterior insula cortex (AIC). The DMN is thought to consist of posterior cingulate cortex (PCC), rostral anterior cingulate cortex (rACC), anterior temporal lobe (aTL), superior frontal cortex (SFC), and inferior parietal cortex (IPC). Importantly, the CCN and DMN are anti-correlated during task performance and uncorrelated at rest (Fox et al., 2005; Murphy et al., 2008)(Fig. 1A), suggesting they are relatively independent networks. We predicted, given their NeuroImage 49 (2010) 3132–3148 ⁎ Corresponding author. Department of Psychology, Washington University in St. Louis, MO 63130, USA. Fax: +1 314 935 8790. E-mail address: mwcole@mwcole.net (M.W. Cole). 1053-8119/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2009.11.001 Contents lists available at ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg