Aging and large-scale functional networks: White matter integrity, gray matter volume, and functional connectivity in the resting state
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 further 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 functional 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-positive network (FPN), which is associated with attention and cognitive control, and the salience network (SN) in anterior 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 networks 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 disease (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). However, it is an open question as to why and how aging affects the dynamic coordination of large-scale neural networks (Grady, 2012).
One possible reason for altered large-scale network activation with increasing age is that aging leads to widespread neurobiological changes, which impact the structural organization and integrity on which large-scale networks critically depend (van den Heuvel et al., 2008, Greicius et al., 2009, Teipel et al., 2010, Horn et al., 2013). Thus, structural changes related to aging would, in part, account for the functional changes associated with cognitive decline. This view is supported by studies that found correlations between functional integration of anterior and posterior medial regions and fractional anisotropy (FA) of connecting white matter tracts (Andrews-Hanna et al., 2007), between activity in the DMN during fixation and age-related decreases in FA across the whole white matter skeleton (Burzynska et al., 2013), and between functional connectivity in bilateral prefrontal cortex and FA of corpus callosum (Davis et al., 2012). In addition, there is evidence that the white matter networks of older adults are organized less efficiently and with less functional connectivity within the DMN, FPN, and SN than those of younger adults (Achard and Bullmore, 2007, Zhu et al., 2012, Geerligs et al., 2014; for a recent review of this body of evidence, see Ferreira and Busatto, 2013). These studies show correlations between functional activity in the DMN and indicators of white matter integrity for specific brain regions. However, no study has comprehensively addressed the relationship between whole-brain structural changes related to healthy aging and changes in functional connectivity across the three central large-scale neural networks. Therefore, the aim of this study was to investigate age-related differences in global white and gray matter properties and their relationship to functional activity in three large-scale neural networks (DMN, FPN, and SN) in the resting state.
We hypothesized that age-related neurobiological changes related to the processing and transmission of information would affect functional connectivity, and that indicators of white and gray matter integrity, such as FA, mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), cortical thickness, volume, and surface area, would significantly correlate with neural activity as measured by fMRI in each of the three networks. Specifically, we predicted that global age-related decline in microstructural integrity of white matter tracts as measured by decreasing FA and increasing MD, RD, and AD, would be indicative of reduced global efficiency of long-distance connections and lead to less functional connectivity in all three networks of older adults. Similarly, we expected to find that age-related reduction in gray matter thickness, surface area, and volume would affect efficiency of neural information processing in nodes of each network and further contribute to altered large-scale network activity in older adults.
Section snippets
Experimental procedures
16 older participants (mean age = 66 years; range = 59–81 years; 9 males) and 16 young participants (mean age = 30 years; range = 23–37 years; 7 males) took part in the experiment. All participants were right-handed, with normal or corrected to normal vision, native English speakers, and received a comparable number of years of formal education (mean older adults = 17 years, mean younger adults = 18 years). All older participants were considered cognitively intact, scoring in the high range of the Mini-Mental
Results
The comparison of white and gray matter between young and older adults resulted in significant group differences that are consistent with previous investigations of age-related structural changes. We found reduced cortical volume and thickness, as well as reduced FA and increased MD and RD values for older adults compared with the younger group (Fjell et al., 2009, Westlye et al., 2010; see Appendices B and C for detailed results).
Discussion
The aim of this study was to assess the impact of global age-related differences in the cerebral white and gray matter on functional activity in three large-scale neural networks central to cognition: the default mode network (DMN), the fronto-parietal network (FPN), and the salience network (SN). We first replicated typical findings of age-related structural changes, with a loss in global cortical gray matter (reduced thickness and volume) and an overall degeneration of white matter integrity
Acknowledgements
This work was funded by the National Health and Medical Research Council (NHMRC). HB is supported by the Australian Research Council’s Discovery Early Career Researcher Award (ARC DECRA; DE130101290). The authors acknowledge the invaluable practical support provided by Jeff McIntosh and staff at Macquarie Medical Imaging.
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