AGING AND LARGE-SCALE FUNCTIONAL NETWORKS: WHITE MATTER INTEGRITY, GRAY MATTER VOLUME, AND FUNCTIONAL CONNECTIVITY IN THE RESTING STATE L. MARSTALLER, a,b * M. WILLIAMS, c,d,e A. RICH, c,d,e G. SAVAGE e,f AND H. BURIANOVA ´ a,e a Centre for Advanced Imaging, University of Queensland, Brisbane, Australia b ARC Science of Learning Research Centre, University of Queensland, Brisbane, Australia c Perception in Action Research Centre, Macquarie University, Sydney, Australia d Department of Cognitive Science, Macquarie University, Sydney, Australia e ARC Centre of Excellence in Cognition and its Disorders, Macquarie University, Sydney, Australia f Department of Psychology, Macquarie University, Sydney, Australia Abstract—Healthy aging is accompanied by neurobiological changes that affect the brain’s functional organization and the individual’s cognitive abilities. The aim of this study was to investigate the effect of global age-related differ- ences in the cortical white and gray matter on neural activity in three key large-scale networks. We used functional–struc- tural covariance network analysis to assess resting state activity in the default mode network (DMN), the fronto-parie- tal network (FPN), and the salience network (SN) of young and older adults. We further related this functional activity to measures of cortical thickness and volume derived from structural MRI, as well as to measures of white matter integ- rity (fractional anisotropy [FA], mean diffusivity [MD], and radial diffusivity [RD]) derived from diffusion-weighted imaging. First, our results show that, in the direct compari- son of resting state activity, young but not older adults reli- ably engage the SN and FPN in addition to the DMN, suggesting that older adults recruit these networks less consistently. Second, our results demonstrate that age- related decline in white matter integrity and gray matter vol- ume is associated with activity in prefrontal nodes of the SN and FPN, possibly reflecting compensatory mechanisms. We suggest that age-related differences in gray and white matter properties differentially affect the ability of the brain to engage and coordinate large-scale functional networks that are central to efficient cognitive functioning. Crown Copyright Ó 2015 Published by Elsevier Ltd. on behalf of IBRO. All rights reserved. Key words: aging, resting state networks, white and gray matter, multimodal imaging, neural plasticity. INTRODUCTION The brain at rest consistently yields activity in the default mode network (DMN), which includes areas in the posterior cingulate cortex (PCC), precuneus, medial prefrontal areas, and the medial temporal lobes (Raichle et al., 2001; Greicius et al., 2003). The DMN was initially considered to represent neural baseline activity until fur- ther investigations showed that activity within the DMN is functionally related to internally driven mental states, such as self-referential processing, long-term memory, and mentalizing, and that its deactivation plays a func- tional role during externally directed tasks (Buckner et al., 2008; Kelly et al., 2008; Burianova et al., 2010; Mennes et al., 2010; Sambataro et al., 2010; Anticevic et al., 2012). In addition, an emerging view suggests that cognitive performance in general might rely on the dynamic interaction between the DMN and two other large-scale neural networks: the fronto-parietal task-posi- tive network (FPN), which is associated with attention and cognitive control, and the salience network (SN) in ante- rior cingulate and fronto-insular cortex, which is involved in the selection of emotionally and motivationally relevant stimuli (Fox et al., 2005; Seeley et al., 2007; Sridharan et al., 2008; Chen et al., 2013; Spreng et al., 2013; Andrews-Hanna et al., 2014). These three neural net- works are central to cognition, as they are engaged in a large number of functions, and their disruption has been associated with a variety of clinical syndromes, such as schizophrenia, traumatic brain injury, and Alzheimer’s dis- ease (Zhou et al., 2010; Manoliu et al., 2014; Sharp et al., 2014). In addition, evidence suggests that the disruption of the dynamic coordination of these large-scale networks constitutes one of the main causes of cognitive decline associated with aging (Andrews-Hanna et al., 2007; Sambataro et al., 2010), as shown by reduced neural activity in the DMN and SN at rest (Allen et al., 2011; Onoda et al., 2012) and increased activity in the FPN of older adults during visual tasks (Grady et al., 2010). How- ever, it is an open question as to why and how aging http://dx.doi.org/10.1016/j.neuroscience.2015.01.049 0306-4522/Crown Copyright Ó 2015 Published by Elsevier Ltd. on behalf of IBRO. All rights reserved. * Correspondence to: L. Marstaller, Centre for Advance Imaging, University of Queensland, QLD 4072, Australia. E-mail address: l.marstaller@uq.edu.au (L. Marstaller). Abbreviations: AD, axial diffusivity; BOLD, blood-oxygenation-level dependent; BSR, boot strap ratio; DMN, default mode network; EEG, electroencephalography; FA, fractional anisotropy; FPN, fronto-parietal network; FSL, FMRIB Software Library; LVs, latent variables; MD, mean diffusivity; MNI, Montreal Neurological Institute; PCC, posterior cingulate cortex; PLS, Partial Least Squares; RD, radial diffusivity; ROI, region of interest; SN, salience network; TE, echo time; TR, repetition time. Neuroscience 290 (2015) 369–378 369