Koolschijn et al. (2019) explore the influence of the release of cortical inhibition on neural mnemonic representations in the hippocampus and subsequent memory performance by evaluating neural activity via functional MRI, both before and after the application of tDCS aimed at increasing GABA in the anterior lateral occipital cortex.

The hippocampus is critical for learning and memory, relying in part on pattern separation processes supported by the dentate gyrus (DG) to prevent interference from overlapping memory representations. In 2007, we designed the Mnemonic Similarity Task (MST), a modified object recognition memory task, to be highly sensitive to hippocampal function by placing strong demands on pattern separation. The MST is now a widely used behavioral task, repeatedly shown to be sensitive to age-related memory decline, hippocampal connectivity, and hippocampal function, with specificity to the DG. Here, we review the utility of the MST, its relationship to hippocampal function, its utility in detecting hippocampal-based memory alterations across the lifespan, and impairments associated with clinical pathology from a variety of disorders.

Using the Mnemonic Similarity Task (MST), we have demonstrated an age-related impairment in lure discrimination, or the ability to recognize an item as distinct from one that was similar, but not identical to one viewed earlier. A growing body of evidence links these behavioral changes to age-related alterations in the hippocampus. In this study, we sought to evaluate a novel version of this task, utilizing scenes that might emphasize the role of the hippocampus in contextual and spatial processing. In addition, we investigated whether, by utilizing two stimulus classes (scenes and objects), we could also interrogate the roles of the PRC and PHC in aging. Thus, we evaluated differential contributions to these tasks by relating performance on objects versus scenes to volumes of the hippocampus and surrounding medial temporal lobe structures. We found that while there was an age-related impairment on lure discrimination performance for both objects and scenes, relationships to brain volumes and other measure of memory performance were stronger when using objects. In particular, lure discrimination performance for objects showed a positive relationship with the volume of the hippocampus, specifically the combined dentate gyrus (DG) and CA3 subfields, and the subiculum. We conclude that though using scenes was effective in detecting age-related lure discrimination impairments, it does not provide as strong a brain-behavior relationship as using objects.

Age-related structural and functional changes in the hippocampus can have a severe impact on hippocampal-dependent memory performance. Here, we tested the hypothesis that a real-world spatial exploration and learning intervention would improve hippocampal-dependent memory performance in healthy older adults. We developed a scavenger hunt task that participants performed over the course of a 4-week behavioral intervention period. Following this intervention, participants' lure discrimination index (LDI) on the Mnemonic Similarity Task was significantly higher than it was at baseline and greater than that of a No-Contact Control Group, while traditional recognition scores remained relatively unchanged. These results point to the viability of a spatial exploration intervention for improving hippocampal-dependent memory in older adults.

The hippocampus is a critical site for alterations that are responsible for age-related changes in memory. Here, we present a relatively novel approach of examining the relationship between memory performance and glutamate-glutamine levels using short echo time magnetic resonance spectroscopy. Specifically, we investigated the relationship between Glx (a composite of glutamate and glutamine) levels in the hippocampus, performance on a word-recall task, and resting-state functional connectivity. While there was no overall difference in Glx intensity between young and aging adults, we identified a positive correlation between delayed word-list recall and Glx, bilaterally in older adults, but not in young adults. Collapsed across age, we also discovered a negative relationship between Glx intensity and resting-state functional connectivity between the anterior hippocampus and regions in the subcallosal gyrus. These findings demonstrate the possible utility of Glx in identifying age-related changes in the brain and behavior and provide encouragement that magnetic resonance spectroscopy can be useful in predicting age-related decline before any physical abnormalities are present.

Healthy aging is accompanied by a steady cognitive decline with clear losses in memory. Animal studies have consistently demonstrated that simply modifying an animals living environment (known as environmental enrichment) can have a positive influence on age-related cognitive decline in the hippocampus. Previously, we showed that playing immersive 3D video games can improve hippocampal-based memory in young healthy adults, suggesting that the exploration of the large open worlds of modern-day video games may act as proxy for environmental enrichment in humans. Here, we replicated our previous video game study in healthy older adults, showing that playing video games for four weeks can improve hippocampal-based memory in a population that is already experiencing age-related decline in memory. Furthermore, we showed that the improvements last for up to four weeks past the intervention, highlighting the potential of video games as intervention for age-related cognitive decline.

The hippocampus is critical for learning and memory, relying in part on pattern separation processes supported by the dentate gyrus (DG) to prevent interference from overlapping memory representations. In 2007, we designed the Mnemonic Similarity Task (MST), a modified object recognition memory task, to be highly sensitive to hippocampal function by placing strong demands on pattern separation. The MST is now a widely used behavioral task, repeatedly shown to be sensitive to age-related memory decline, hippocampal connectivity, and hippocampal function, with specificity to the DG. Here, we review the utility of the MST, its relationship to hippocampal function, its utility in detecting hippocampal-based memory alterations across the lifespan, and impairments associated with clinical pathology from a variety of disorders.

According to the facial feedback hypothesis, when we see an angry or happy face, we contract or flex the relevant muscles to recreate the expression to assist in identifying and experiencing the emotion reflected. We investigated the facial feedback hypothesis by using botulinum toxin type A (onabotulinumtoxinA; onabotA) injections to induce temporary paralysis in the glabellar muscles (responsible for frowning) and measured functional brain activity during the processing of emotional faces. Ten females viewed pictures of happy and angry faces during two functional magnetic resonance imaging (fMRI) scan sessions: one prior (Pre) to onabotA and one following (Active) onabotA injections. We found Pre vs. Active onabotA modulation of activity in the amygdala for both happy and angry faces, as well as modulation of activity in the fusiform gyrus for happy faces. Consistent with our predictions, preventing frowning through inhibition of glabellar muscle contraction altered amygdala processing for emotional faces. The modulation of amygdala and fusiform gyrus activity following onabotA may reflect compensatory processes in a neuroanatomical circuit involved in emotional processing that is engaged when facial feedback is impaired. These data contribute to a growing literature suggesting that inhibition of glabellar muscle contraction alters neural activity for emotional processing.Clinical Trials.gov registration number: NCT03373162.

Hippocampal circuit alterations that differentially affect hippocampal subfields are associated with age-related memory decline. Additionally, functional organization along the longitudinal axis of the hippocampus has revealed distinctions between anterior and posterior (A-P) connectivity. Here, we examined the functional connectivity (FC) differences between young and older adults at high-resolution within the medial temporal lobe network (entorhinal, perirhinal, and parahippocampal cortices), allowing us to explore how hippocampal subfield connectivity across the longitudinal axis of the hippocampus changes with age. Overall, we found reliably greater connectivity for younger adults than older adults between the hippocampus and parahippocampal cortex (PHC) and perirhinal cortex (PRC). This drop in functional connectivity was more pronounced in the anterior regions of the hippocampus than the posterior ones, consistent for each of the hippocampal subfields. Further, intra-hippocampal connectivity also reflected an age-related decrease in functional connectivity within the anterior hippocampus in older adults that was offset by an increase in posterior hippocampal functional connectivity. Interestingly, the anterior-posterior dysfunction in older adults between hippocampus and PHC was predictive of lure discrimination performance on the Mnemonic similarity task (MST), suggesting a role in memory performance. While age-related dysfunction within the hippocampal subfields has been well-documented, these results suggest that the age-related dysfunction in hippocampal connectivity across the longitudinal axis may also contribute significantly to memory decline in older adults.