Age-related alterations in default mode network: Impact on working memory performance

Abstract

The default mode network (DMN) is a set of functionally connected brain regions which shows deactivation (task-induced deactivation, TID) during a cognitive task. Evidence shows an age-related decline in task-load-related modulation of the activity within the DMN during cognitive tasks. However, the effect of age on the functional coupling within the DMN and their relation to cognitive performance has hitherto been unexplored. Using functional magnetic resonance imaging, we investigated functional connectivity within the DMN in older and younger subjects during a working memory task with increasing task load. Older adults showed decreased connectivity and ability to suppress low frequency oscillations of the DMN. Additionally, the strength of the functional coupling of posterior cingulate (pCC) with medial prefrontal cortex (PFC) correlated positively with performance and was lower in older adults. pCC was also negatively coupled with task-related regions, namely the dorsolateral PFC and cingulate regions. Our results show that in addition to changes in canonical task-related brain regions, normal aging is also associated with alterations in the activity and connectivity of brain regions within the DMN. These changes may be a reflection of a deficit in cognitive control associated with advancing age that results in deficient resource allocation to the task at hand.

Introduction

Functional neuroimaging studies have traditionally investigated brain functioning by studying task-dependent increases in neural activity, typically called “activation”. Recently, much interest has been focused on task-induced deactivation (TID). TID is a decrease in brain activity that occurs during the performance of an experimental task relative to rest (Raichle et al., 2001) or a low demanding baseline condition (Greicius and Menon, 2004). One set of regions showing TID are thought to reflect a task-negative network, the so-called “default mode of brain function network” (DMN) that is active during rest and suppressed during an active task (Mazoyer et al., 2001, Raichle et al., 2001). The strong anticorrelation of the task-positive and the task-negative networks (Fransson, 2006, Fransson, 2005), suggests antagonistic psychological functions on these two systems (Fox et al., 2005). Accumulating evidence indeed suggests a role of the DMN in “stimulus independent thoughts”, ranging from internal and external monitoring (Gusnard and Raichle, 2001), to mind wandering (Mason et al., 2007).

The brain regions that consistently show TID irrespective of the task being performed include midline areas such as the medial prefrontal cortex (mPFC), posterior cingulate cortex (pCC), precuneus, and bilateral inferior parietal cortex (IPC). This group of brain regions is consistent across the lifespan (Grady et al., 2006). Nevertheless, numerous studies have consistently shown an age-related modulation of the spatial extent and the magnitude of TID within this network. Lustig et al. (2003) found decreased deactivation in older adults relative to younger subjects in both mPFC and pCC and parieto-temporal regions during a semantic classification task compared with rest. Older adults also showed a flattened and slowed time course of blood oxygen level-dependent (BOLD) fMRI response when compared to younger subjects. These results were further confirmed by Grady et al. (2006) who investigated a population spanning from 20 to 87 years and found an age-related linear increase in BOLD activity during a fixation baseline relative to a task in medial DMN regions, namely medial frontal gyrus, pCC as well as in bilateral temporal regions. Indeed, older adults showed an increase in activity of brain regions not traditionally recruited during the performance of the task such as the mPFC and pCC, whereas they showed decreased activation in task-relevant areas when compared to younger subjects. Persson et al. (2007) using a verb generation task showed greater deactivation, but only at levels of the task that required a higher selection demand. More interestingly within the DMN, posterior midline regions including pCC/precuneus show significantly smaller and slower deactivations in older adults when compared to their younger counterparts (Grady et al., 2006, Lustig et al., 2003). Furthermore, there is evidence that deactivation in these brain regions is even more severely reduced in patients with mild cognitive impairment (Rombouts et al., 2005) and Alzheimer's disease (AD; Greicius et al., 2004, Lustig et al., 2003).

Recent evidence also suggests that cognitive load can also modulate the degree of TID. McKiernan et al. (2003) demonstrated a linear increase in deactivation of the midline DMN regions with increasing task difficulty during an auditory detection task. Consistent with this, Tomasi et al. (2006) and Esposito et al. (2006) found a load-related general increase of TID in the DMN, during working memory (WM) tasks. These findings suggest reallocation of attentional resources from DMN to the brain regions actively involved in the ongoing tasks. Although, attentional impairment is a commonly reported age-related cognitive change (Gazzaley et al., 2007, West, 1999), studies on the effects of aging on load-related changes in DMN are relatively few and inconclusive. Gould et al. (2006) using a visuospatial paired associate learning task did not find any difference in deactivations with increasing task load between older and young subjects. Conversely, Persson et al. (2007) found an interaction of age-by-task-load in mPFC, pCC as well as in lateral parietal cortex, showing relatively decreased load-related deactivation in the older adults when compared to younger subjects.

The brain regions in the DMN show strong functional coupling (Fransson, 2005, Greicius et al., 2003) as revealed by synchronous low frequency oscillations (LFOs, <0.1 Hz) of BOLD signal at rest (Biswal et al., 1995, Greicius et al., 2003, Xiong et al., 1999). Connectivity patterns tend to be consistent albeit attenuated during a cognitive task (Fransson, 2006). Of further note, the strength of the functional coupling within DMN regions during a WM task correlates positively with performance on the task (Gilbert et al., 2006, Hampson et al., 2006), thus suggesting a facilitating (Gilbert et al., 2006) or monitoring role of DMN regions. Thus far none of the studies that explored an age-by-task-load interaction looked at the functional coupling among the DMN brain regions or their relationship to cognitive performance.

In the current study, we explored age-related changes in the DMN focusing not only on changes in single brain regions but also on the functional coupling among these regions, and the impact of these changes on WM performance. In order to address both global and regional changes in functional connectivity we used a WM task with increasing difficulty and both univariate and multivariate statistical approaches. Independent component analysis (ICA) is a model-independent multivariate statistical analysis technique designed to extract spatially independent and temporally synchronous activity patterns in brain regions, thus yielding functional covariance in brain regions. On the other hand, the general linear model (GLM) analyses use univariate statistics based on a priori defined task design and hemodynamic response function (HRF) as predictors of modulations in the BOLD signal. The combination of these two statistical techniques has already proven to be effective to explore different aspects of brain activity (Esposito et al., 2006), for e.g. GLM analysis is more sensitive to detect functional specificity, whereas ICA is better suited to define functional connectivity. Based on evidence to date (vide supra), our hypotheses were that: first, older adults would show decreased extent of the deactivation network and an altered functional connectivity within the DMN regions when compared to young subjects. Second, an increase in task load would increase deactivation in DMN in both age groups, although to a smaller degree in older adults. Third, these differences in fMRI measures would predict differences in task performances.