Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan

Abstract

Accurate memory for discrete events is thought to rely on pattern separation to orthogonalize the representations of similar events. Previously, we reported that a behavioral index of pattern separation was correlated with activity in the hippocampus (dentate gyrus, CA3) and with integrity of the perforant path, which provides input to the hippocampus. If the hippocampus operates as part of a broader neural network, however, pattern separation would likely also relate to integrity of limbic tracts (fornix, cingulum bundle, and uncinate fasciculus) that connect the hippocampus to distributed brain regions. In this study, healthy adults (20-89 years) underwent diffusion tensor imaging and completed the Behavioral Pattern Separation Task-Object Version (BPS-O) and Rey Auditory Verbal Learning Test (RAVLT). After controlling for global effects of brain aging, exploratory skeleton-wise and targeted tractography analyses revealed that fornix integrity (fractional anisotropy, mean diffusivity, and radial diffusivity; but not mode) was significantly related to pattern separation (measured using BPS-O and RAVLT tasks), but not to recognition memory. These data suggest that hippocampal disconnection, via individual- and age-related differences in limbic tract integrity, contributes to pattern separation performance. Extending our earlier work, these results also support the notion that pattern separation relies on broad neural networks interconnecting the hippocampus.

Age-related impairment on a forced-choice version of the Mnemonic Similarity Task.

“…Specifically, it appears that the discrimination between targets and similar lures in the old/new test format most closely resembles the A-A’ test format. Previous studies from our lab and others have revealed an age-related impairment in the discrimination between targets and similar lures across a variety of test formats, including old/similar/new (Toner et al, 2009; Yassa et al, 2011a, 2011b; Stark et al, 2013, 2015; Bennett et al, 2015), old/new (Stark et al, 2015), and old/new with confidence ratings (Stark et al, 2015). Moreover, these effects maintained across a variety of encoding conditions—e.g., incidental encoding, intentional encoding, continuous recognition (Stark et al, 2015).…”

“…Through extensive testing, we have previously demonstrated that the lures have a controlled range of false alarm rates when used during recognition tests (Yassa et al, 2011a; Stark et al 2013; 2015). In addition, performance on these similar lures is sensitive to hippocampal damage (Kirwan et al, 2012), aging (Stark et al, 2013; 2015; Toner et al, 2009) and to the age-related changes in both the activity of the dentate gyrus and CA3 subfields during aging (Yassa et al, 2011b), and to disruptions of hippocampal circuitry (Yassa et al, 2011b; Bennett et al, 2015). Together, these findings demonstrate the viability of this task as a sensitive and appropriate measure of age-related memory change and of hippocampal function.…”

“…Importantly, working memory versions of the task have failed to find age-related differences in the ability to discriminate between targets and similar lures (e.g., Yassa et al, 2011a), suggesting a mnemonic rather than a perceptual deficit driving the effect in healthy older adults in this task. Previous studies have typically used a test format in which participants are instructed to respond “old” to exact repetitions of items seen during the encoding phase, to respond “similar” to images which are similar to—but not exactly the same as—a previously viewed image, and to respond “new” to images that they have not seen in the context of the experiment (Kirwan & Stark, 2007; Toner et al, 2009; Yassa et al, 2011a, 2011b; Kirwan et al, 2012; Stark et al, 2013, 2015; Bennett et al, 2015). Stark et al (2015) also used a test format that instructed participants to respond “old” only to exact repetitions and to respond “new” to both similar lures and unrelated foils, including a version with confidence ratings.…”

Superficial white matter as a novel substrate of age-related cognitive decline

“…Moreover, many studies have shown that age-related differences in behavioral and motor task performance are mediated by age-related variations in DWM DTI metrics (Bucur et al, 2008;Hedden et al, 2014;Holtrop et al, 2014;Jacobs et al, 2013;Kerchner et al, 2012;Madden et al, 2009). Nevertheless, in several recent studies, the relationships between DWM diffusion metrics and cognitive ability is attenuated or completely lost after accounting for the effects of age (Bennett et al, 2014;Borghesani et al, 2013;Koch et al, 2013;Lockhart et al, 2012;Metzler-Baddeley et al, 2011;Salami et al, 2012). This heterogeneity of results may be attributed to a number of factors such as the DWM tracts studied, the metrics reported (e.g., FA, MD, or other metrics), the cognitive tests used, the sample size, or the population studied.…”

Discrimination performance in aging is vulnerable to interference and dissociable from spatial memory

“…Of note, human studies that have assessed spatial discrimination have also used screen-based presentation of stimuli, requiring subjects to gauge the position of shapes or pictures of objects on the screen (Stark et al 2010;Holden et al 2012;Reagh et al 2014Reagh et al , 2016, which is quite different from using real world spatial representations and/or path integration to guide discrimination. Nonetheless, studies using this type of stimulus presentation have found age-associated discrimination deficits to be correlated with altered CA3 and dentate gyrus activity (Yassa et al 2011a,b;Bakker et al 2012), and more specifically with loss of integrity of perforant path inputs from the entorhinal cortex to the hippocampus and dentate gyrus (Bennett et al 2015;Bennett and Stark 2016). The extent to which prefrontal cortical input is also necessary and engaged by these behaviors in humans will need to be explored.…”