The functional oculomotor network and saccadic cognitive control in healthy elders
Introduction
Aging is commonly associated with changes in cognitive function, which may reflect “normal aging” or an underlying neuropathological process. One of the earliest cognitive domains to exhibit age-related changes is executive function, which comprises higher-level cognitive control, such as planning, switching and inhibiting lower-level automatic functions (Stuss, 2007). Although age-related changes in executive function do not necessarily predict future cognitive decline, they may reflect underlying neuropathology of Alzheimer's disease or other forms of dementia (Grady, 2012). Thus, understanding the mechanisms underlying executive dysfunction in aging is critical for improving assessment of individuals at risk for future cognitive decline.
The antisaccade (AS) task has emerged as a sensitive tool for evaluating executive function and was recently validated in a multicenter study of normal elders and individuals with neurological disease (Hellmuth et al., 2012). It is a simple oculomotor paradigm that is commonly used to study basic aspects of cognitive control and inhibition, as well as cognitive changes in aging and neurological disease (Hallet, 1978, Luna et al., 2008, Munoz and Everling, 2004). The task requires individuals to inhibit a prepotent, visually-guided saccade towards a peripheral target and to generate a voluntary saccade in the opposite direction. In healthy elders, impaired AS performance is strongly correlated with executive dysfunction and frontal oculomotor network brain volume (Mirsky et al., 2011). The AS task is also highly sensitive to changes in brain structure that occur with neurodegenerative diseases of aging (Boxer et al., 2006, Boxer et al., 2012, Garbutt et al., 2008), including the detection of presymptomatic neurodegeneration (Golding et al., 2006). Although a variety of studies have identified correlations between advancing age and declining AS performance (Klein et al., 2000, Luna et al., 2008, Olincy et al., 1997), there is considerable variability in AS performance in healthy elders. Elucidating the neural mechanisms responsible for this heterogeneous AS performance could lead to better stratification of healthy elders at risk of future cognitive decline or potentially new strategies for mitigating age-associated executive dysfunction.
Functional magnetic resonance imaging (fMRI) studies of the AS task in young adults have demonstrated greater activation of frontal and parietal lobe oculomotor control regions during AS conditions relative to reflexive, visually-guided prosaccade (PS) control conditions (Connolly et al., 2002, Curtis and D'Esposito, 2003). This is consistent with human lesion studies of AS task performance that implicated similar structures, particularly the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate gyrus (ACC), as critical for correct performance (Hodgson et al., 2007, Pierrot-Deseilligny et al., 2003). In neurological diseases, such as schizophrenia, AS fMRI has elucidated neural mechanisms associated with executive dysfunction, revealing connectivity changes within the oculomotor network that correlate with impaired inhibition and error monitoring (Polli et al., 2008, Tu et al., 2010).
To investigate the neural mechanisms of executive function in healthy elders, we conducted an fMRI study of AS task performance to measure neural integrity in the cortical oculomotor network. Based on a previous study that found a significant relationship between volume loss in the right lateral frontal eye field (rlatFEF) and impaired AS task performance in patients (Boxer et al., 2006), we hypothesized that the rlatFEF would be an early site of executive dysfunction and that other key frontal regions, such as the DLPFC, would demonstrate compensatory activity to maintain performance in healthy elders.
Section snippets
Participants
Forty-five healthy elders (age 70.4 ± 7.1 years; range 57–85 years; 22 females) gave written informed consent to participate in this study, which was approved by the University of California, San Francisco Committee for Human Research. Two participants were removed from the group analysis due to poor data quality from excessive head motion. Participants were recruited from the University of California, San Francisco Memory and Aging center. Each participant underwent an extensive clinical
Demographics and neuropsychological testing
On all neuropsychological tests of executive function, the subjects performed within 1 SD of age- and education-matched normative values (Table 1).
AS task performance
Participants first completed the AS task outside of the scanner to become familiar with the task and to ensure similar performance during the fMRI scan. Participants completed the AS task outside of the scanner with 78.9 ± 20.7% accuracy and the AS task inside of the scanner with 76.4 ± 11.5% accuracy. There was high reliability of task performance
Discussion
The goal of this study was to determine the neural correlates of executive function performance in healthy elders, using the AS task as a tool to link brain function and connectivity to behavior within a well-defined cortical network. The rlatFEF, which had previously been identified as a selectively vulnerable node in structural neuroimaging studies, emerged in our study with a hyperactive BOLD signal that was associated with worse AS task performance in healthy elders. Using graph theoretical
Acknowledgments
This work was supported by the National Institutes of Health (R01AG031278 to A.L.B., K01AG034175 to J.P., and P50AG023501 B.L.M.), John Douglas French Foundation, and Larry L. Hillblom Foundation. We thank our research participants for their invaluable contribution to this work.
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