Intrinsic connectivity between the hippocampus and posteromedial cortex predicts memory performance in cognitively intact older individuals
Introduction
Functional magnetic resonance imaging (fMRI) studies have shown that spontaneous fluctuations of the blood-oxygen-level-dependent (BOLD) signal occur continuously in the resting state, in the absence of external stimuli, in the human brain (Biswal et al., 1995). When examining the inter-regional correlation properties, termed “functional connectivity” or “intrinsic connectivity”, these spontaneous fluctuations demonstrate temporally coherent activity within widely distributed functional-anatomic systems (Biswal et al., 1995, Greicius et al., 2003, Seeley et al., 2007), which are thought to reflect the intrinsic functional architecture of the human brain (Vincent et al., 2007). Spatially distinct functional-anatomic networks underlying sensorimotor function, language, dorsal and ventral attention, executive control, and long-term memory have been identified by observing the topographic distribution of intrinsic connectivity (Biswal et al., 1995, Fox et al., 2006, Hampson et al., 2002, Lowe et al., 1998, Seeley et al., 2007, Vincent et al., 2006).
Importantly, recent studies have suggested that these coherent spontaneous fluctuations in distinct brain systems may have functional implications, and may be relevant to individual variability in human behavior. For example, the strength of spontaneous correlation between the posterior cingulate cortex and medial prefrontal and ventral anterior cingulate cortices have been reported to predict individual difference in working memory performance (Hampson et al., 2006). Variance in prescan anxiety ratings and Trail-Making Test performance has been linked to the variability of intrinsic connectivity within a “salience” network and an executive control network (Seeley et al., 2007). However, the functional significance of coherent spontaneous fluctuations in other functional-anatomic systems, such as the network supporting episodic memory, remains to be studied.
It has long been acknowledged that the hippocampus and surrounding medial temporal lobe structures are essential for episodic memory function (Squire et al., 2004). Emerging evidence from functional imaging further suggests that memory function may be subserved by a distributed network that includes not only the hippocampal memory system, but also medial and lateral parietal regions involved in the default mode or “core” network (Buckner et al., 2008, Spreng et al., 2009). For example, event-related fMRI studies in young subjects have revealed that activity within medial and lateral parietal regions can be specifically modulated during memory processes, resulting in “activation” in episodic memory retrieval (Wagner et al., 2005, Wheeler and Buckner, 2003), or in “deactivation” during successful encoding (Daselaar et al., 2004, Otten and Rugg, 2001). Furthermore, recent evidence suggests that the ability to flexibly modulate activity from encoding deactivation to retrieval activation in the precuneus and posterior cingulate cortex (PPC) may be critical to memory success (Daselaar et al., 2009, Kim et al., 2010).
Recent studies in older adults across the spectrum of normal aging, mild cognitive impairment (MCI), and mild Alzheimer's disease (AD) have suggested that alterations in hippocampal activation are inversely correlated with changes in deactivation in posteromedial regions over the course of AD (Celone et al., 2006, Pihlajamaki et al., 2008, Pihlajamaki et al., 2009). In addition, age-related memory impairment has been shown to be associated with loss of deactivation in the posteromedial cortices (Miller et al., 2008). These findings suggest that successful memory formation requires the coordinated modulation of neural activity among regions in a distributed memory network, in particular the hippocampus and posteromedial cortices, which may be particularly vulnerable in the process of brain aging.
In parallel with these findings from a task-invoked activity response, the investigation of functional connectivity during the resting state has delineated a set of regions in parietal cortex, including the PPC and bilateral inferior parietal lobules, as well as regions in medial prefrontal and lateral temporal cortices, which constitute an intrinsically correlated network associated with the hippocampus (Greicius et al., 2004, Kahn et al., 2008, Vincent et al., 2006). Notably, the intrinsic hippocampal connectivity map shows considerable overlap with default network map (Buckner et al., 2008, Vincent et al., 2006), and these network regions also closely correspond to regions responsive to episodic memory processing (Miller et al., 2008, Wheeler and Buckner, 2004). Interestingly, these regions are selectively vulnerable to early AD pathology (Sperling et al., 2009). These observation that the key nodes in the network, identified by intrinsic connectivity, overlap the regions required for successful encoding and retrieval suggests the possibility that the coherence of the spontaneous fluctuations across the hippocampus and the posteromedial regions of the default network might be related to the engagement of these regions in memory processes.
In the present study, we investigated the behavioral significance of coherent fluctuations during the resting state in a group of cognitively intact older individuals. We first determined the regions engaged in successful encoding during a cross-modal associative memory paradigm, and then measured the correlation between spontaneous BOLD signal fluctuations across these regions, acquired during a period of rest prior to the memory task. We hypothesized that the strength of intrinsic connectivity at rest within the distributed memory network, in particular, between the hippocampus and posteromedial cortices, might be predictive of individual performance on memory tests.
Section snippets
Participants
Seventeen healthy old adults (ages 62 to 83) participated this study. The subjects were drawn from participants in an ongoing longitudinal study examining cognitive aging and preclinical predictors of AD. Written informed consent was obtained from each subject and the study procedures were approved by the Human Research Committee at the Massachusetts General Hospital and Brigham and Women's Hospital. All subjects were screened for neurologic and psychiatric illnesses, and underwent
Results
Demographic information and memory performance with All-hits and HC-hits on the post-scan recognition test are presented in Table 1.
Discussion
These data demonstrate that individual differences in performance on an associative episodic memory task can be predicted by individual differences in intrinsic hippocampal–posteromedial cortical connectivity during the resting state. Specifically, the intrinsic connectivity between regions that are maximally engaged during successful memory performance was examined during quiet wakefulness prior to performance of the memory task. Stronger correlations between the spontaneous fluctuations in
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