Optimizing the mnemonic similarity task for efficient, widespread use.

Introduction: The Mnemonic Similarity Task (MST) has become a popular test of memory and, in particular, of hippocampal function. It has been heavily used in research settings and is currently included as an alternate outcome measure on a number of clinical trials. However, as it typically requires ~15 min to administer and benefits substantially from an experienced test administrator to ensure the instructions are well-understood, its use in trials and in other settings is somewhat restricted. Several different variants of the MST are in common use that alter the task format (study-test vs. continuous) and the response prompt given to participants (old/similar/new vs. old/new). Methods: In eight online experiments, we sought to address three main goals: (1) To determine whether a robust version of the task could be created that could be conducted in half the traditional time; (2) To determine whether the test format or response prompt choice significantly impacted the MST's results; and (3) To determine how robust the MST is to repeat testing. In Experiments 1-7, participants received both the traditional and alternate forms of the MST to determine how well the alternate version captured the traditional task's performance. In Experiment 8, participants were given the MST four times over approximately 4 weeks. Results: In Experiments 1-7, we found that test format had no effect on the reliability of the MST, but that shifting to the two-choice response format significantly reduced its ability to reflect the traditional MST's score. We also found that the full running time could be cut it half or less without appreciable reduction in reliability. We confirmed the efficacy of this reduced task in older adults as well. Here, and in Experiment 8, we found that while there often are no effects of repeat-testing, small effects are possible, but appear limited to the initial testing session. Discussion: The optimized version of the task developed here (oMST) is freely available for web-based experiment delivery and provides an accurate estimate of the same memory ability as the classic MST in less than half the time.

Impact of spaceflight stressors on behavior and cognition: A molecular, neurochemical, and neurobiological perspective.

The response of the human body to multiple spaceflight stressors is complex, but mounting evidence implicate risks to CNS functionality as significant, able to threaten metrics of mission success and longer-term behavioral and neurocognitive health. Prolonged exposure to microgravity, sleep disruption, social isolation, fluid shifts, and ionizing radiation have been shown to disrupt mechanisms of homeostasis and neurobiological well-being. The overarching goal of this review is to document the existing evidence of how the major spaceflight stressors, including radiation, microgravity, isolation/confinement, and sleep deprivation, alone or in combination alter molecular, neurochemical, neurobiological, and plasma metabolite/lipid signatures that may be linked to operationally-relevant behavioral and cognitive performance. While certain brain region-specific and/or systemic alterations titrated in part with neurobiological outcome, variations across model systems, study design, and the conspicuous absence of targeted studies implementing combinations of spaceflight stressors, confounded the identification of specific signatures having direct relevance to human activities in space. Summaries are provided for formulating new research directives and more predictive readouts of portending change in neurobiological function.

Impaired Behavioral Pattern Separation in Refractory Temporal Lobe Epilepsy and Mild Cognitive Impairment.

OBJECTIVE: Episodic memory impairment and hippocampal pathology are hallmark features of both temporal lobe epilepsy (TLE) and amnestic mild cognitive impairment (aMCI). Pattern separation (PS), which enables the distinction between similar but unique experiences, is thought to contribute to successful encoding and retrieval of episodic memories. Impaired PS has been proposed as a potential mechanism underling episodic memory impairment in aMCI, but this association is less established in TLE. In this study, we examined behavioral PS in patients with TLE and explored whether profiles of performance in TLE are similar to aMCI. METHOD: Patients with TLE, aMCI, and age-matched, healthy controls (HCs) completed a modified recognition task that relies on PS for the discrimination of highly similar lure items, the Mnemonic Similarity Task (MST). Group differences were evaluated and relationships between clinical characteristics, California Verbal Learning Test-Second Edition scores, and MST performance were tested in the TLE group. RESULTS: Patients with TLE and aMCI demonstrated poorer PS performance relative to the HCs, but performance did not differ between the two patient groups. Neither the side of seizure focus nor having hippocampal sclerosis affected performance in TLE. However, TLE patients with clinically defined memory impairment showed the poorest performance. CONCLUSION: Memory performance on a task that relies on PS was disrupted to a similar extent in TLE and aMCI. The MST could provide a clinically useful tool for measuring hippocampus-dependent memory impairments in TLE and other neurological disorders associated with hippocampal damage.

Regional Cortical Thickness Predicts Top Cognitive Performance in the Elderly.

While aging is typically associated with cognitive decline, some individuals are able to diverge from the characteristic downward slope and maintain very high levels of cognitive performance. Prior studies have found that cortical thickness in the cingulate cortex, a region involved in information processing, memory, and attention, distinguish those with exceptional cognitive abilities when compared to their cognitively more typical elderly peers. Others major areas outside of the cingulate, such as the prefrontal cortex and insula, are also key in successful aging well into late age, suggesting that structural properties across a wide range of areas may better explain differences in cognitive abilities. Here, we aim to assess the role of regional cortical thickness, both in the cingulate and the whole brain, in modeling Top Cognitive Performance (TCP), measured by performance in the top 50th percentile of memory and executive function. Using data from National Alzheimer's Coordinating Center and The 90 + Study, we examined healthy subjects aged 70-100 years old. We found that, while thickness in cingulate regions can model TCP status with some degree of accuracy, a whole-brain, network-level approach out-performed the localist, cingulate models. These findings suggests a need for more network-style approaches and furthers our understanding of neurobiological factors contributing to preserved cognition.

Playing Minecraft Improves Hippocampal-Associated Memory for Details in Middle Aged Adults.

Concerns are often raised about the impact that playing video games may have on cognition and behavior, whether gameplay is intense and protracted as with competitive Esports or whether it is more casual gameplay. Work in our lab and others, however, has shown that at least some classes of games can improve memory function. In particular, playing immersive 3D games that provide rich experiences and novelty improve memory on tasks that rely upon the hippocampus in effects that mirror the effects of "environmental enrichment" in numerous rodent studies. Our goal in the present study was to determine whether even modest amounts of gameplay (~30 min/day for 4 weeks) would result in improved memory performance in middle-aged adults. Not only is this demographic potentially highly receptive to gaming (they make up a significant portion of Esports viewers and of game players), but interventions in middle age may be a prime time for reducing later age-related cognitive decline. Here, we found that the benefits in middle age paralleled effects previously observed in young adults as playing Minecraft, showing improved memory performance on a hippocampal dependent memory task.

Remembering facts versus feelings in the wake of political events.

Amid rising political polarisation, inaccurate memory for facts and exaggerated memories of grievances can drive individuals and groups further apart. We assessed whether people with more accurate memories of the facts concerning political events were less susceptible to bias when remembering how events made them feel. Study 1 assessed participants' memories concerning the 2016 U.S. presidential election (N = 571), and included 33 individuals with Highly Superior Autobiographical Memory (HSAM). Study 2 assessed participants' memories concerning the 2018 referendum on abortion in Ireland (N = 733). Participants rated how happy, angry, and scared they felt days after these events. Six months later, they recalled their feelings and factual information. In both studies, participants overestimated how angry they had felt but underestimated happiness and fear. Adjusting for importance, no association was found between the accuracy of memory for facts and feelings. Accuracy in remembering facts was predicted by media exposure. Accuracy in remembering feelings was predicted by consistency over time in feelings and appraisals about past events. HSAM participants in Study 1 remembered election-related facts better than others, but not their feelings. Thus, having a good grasp of the facts did not protect against bias in remembering feelings about political events.

Age-related alterations in functional connectivity along the longitudinal axis of the hippocampus and its subfields.

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.

Age- and memory- related differences in hippocampal gray matter integrity are better captured by NODDI compared to single-tensor diffusion imaging.

Single-tensor diffusion imaging (DTI) has traditionally been used to assess integrity of white matter. For example, we previously showed that integrity of limbic white matter tracts declines in healthy aging and relates to episodic memory performance. However, multi-compartment diffusion models may be more informative about microstructural properties of gray matter. The current study examined hippocampal gray matter integrity using both single-tensor and multi-compartment (neurite orientation dispersion and density imaging, NODDI) diffusion imaging. Younger (20-38 years) and older (59-84 years) adults also completed the Mnemonic Similarity Task to measure mnemonic discrimination performance. Results revealed age-related declines in both single-tensor (lower fractional anisotropy, higher mean diffusivity) and multi-compartment (higher restricted, hindered and free diffusion) measures of hippocampal gray matter integrity. As expected, NODDI measures (hindered and free diffusion) captured more age-related variance than DTI measures. Moreover, mnemonic discrimination of highly similar lure items in memory was related to hippocampal gray matter integrity in younger but not older adults. These findings support the notion that age-related differences in gray matter integrity are better captured by multi-compartment versus single-tensor diffusion models and show that the relationship between mnemonic discrimination and hippocampal gray matter integrity is moderated by age.

Enriching Hippocampal Memory Function in Older Adults Through Real-World Exploration.

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.

Enriching hippocampal memory function in older adults through video games.

Healthy aging is accompanied by a steady cognitive decline with clear losses in memory. Animal studies have consistently demonstrated that simply modifying an animal's 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.

Microstructural Alterations in Hippocampal Subfields Mediate Age-Related Memory Decline in Humans.

Aging, even in the absence of clear pathology of dementia, is associated with cognitive decline. Neuroimaging, especially diffusion-weighted imaging, has been highly valuable in understanding some of these changes in live humans, non-invasively. Traditional tensor techniques have revealed that the integrity of the fornix and other white matter tracts significantly deteriorates with age, and that this deterioration is highly correlated with worsening cognitive performance. However, traditional tensor techniques are still not specific enough to indict explicit microstructural features that may be responsible for age-related cognitive decline and cannot be used to effectively study gray matter properties. Here, we sought to determine whether recent advances in diffusion-weighted imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI) and Constrained Spherical Deconvolution, would provide more sensitive measures of age-related changes in the microstructure of the medial temporal lobe. We evaluated these measures in a group of young (ages 20-38 years old) and older (ages 59-84 years old) adults and assessed their relationships with performance on tests of cognition. We found that the fiber density (FD) of the fornix and the neurite density index (NDI) of the fornix, hippocampal subfields (DG/CA3, CA1, and subiculum), and parahippocampal cortex, varied as a function of age in a cross-sectional cohort. Moreover, in the fornix, DG/CA3, and CA1, these changes correlated with memory performance on the Rey Auditory Verbal Learning Test (RAVLT), even after regressing out the effect of age, suggesting that they were capturing neurobiological properties directly related to performance in this task. These measures provide more details regarding age-related neurobiological properties. For example, a change in fiber density could mean a reduction in axonal packing density or myelination, and the increase in NDI observed might be explained by changes in dendritic complexity or even sprouting. These results provide a far more comprehensive view than previously determined on the possible system-wide processes that may be occurring because of healthy aging and demonstrate that advanced diffusion-weighted imaging is evolving into a powerful tool to study more than just white matter properties.

Neural substrates of mnemonic discrimination: A whole-brain fMRI investigation.

INTRODUCTION: A fundamental component of episodic memory is the ability to differentiate new and highly similar events from previously encountered events. Numerous functional magnetic resonance imaging (fMRI) studies have identified hippocampal involvement in this type of mnemonic discrimination (MD), but few studies have assessed MD-related activity in regions beyond the hippocampus. Therefore, the current fMRI study examined whole-brain activity in healthy young adults during successful discrimination of the test phase of the Mnemonic Similarity Task. METHOD: In the study phase, participants made "indoor"/"outdoor" judgments to a series of objects. In the test phase, they made "old"/"new" judgments to a series of probe objects that were either repetitions from the memory set (targets), similar to objects in the memory set (lures), or novel. We assessed hippocampal and whole-brain activity consistent with MD using a step function to identify where activity to targets differed from activity to lures with varying degrees of similarity to targets (high, low), responding to them as if they were novel. RESULTS: Results revealed that the hippocampus and occipital cortex exhibited differential activity to repeated stimuli relative to even highly similar stimuli, but only hippocampal activity predicted discrimination performance. CONCLUSIONS: These findings are consistent with the notion that successful MD is supported by the hippocampus, with auxiliary processes supported by cortex (e.g., perceptual discrimination).

Exploring the Spatial Relationships Between Real and Virtual Experiences: What Transfers and What Doesn't.

Virtual environments are commonly used to assess spatial cognition in humans. For the past few decades, researchers have used virtual environments to investigate how people navigate, learn, and remember their surrounding environment. In combination with tools such as electroencephalogram, neuroimaging, and electrophysiology, these virtual environments have proven invaluable in their ability to help elucidate the underlying neural mechanisms of spatial learning and memory in humans. However, a critical assumption that is made whenever using virtual experiences is that the spatial abilities used in the navigation of these virtual environments accurately represents the spatial abilities used in the real-world. The aim of the current study is to investigate the spatial relationships between real and virtual environments to better understand how well the virtual experiences parallel the same experiences in the real-world. Here, we performed three independent experiments to examine whether spatial information about object location, environment layout, and navigation strategy transfers between parallel real-world and virtual-world experiences. We show that while general spatial information does transfer between real and virtual environments, there are several limitations of the virtual experience. Compared to the real-world, the use of information in the virtual-world is less flexible, especially when testing spatial memory from a novel location, and the way in which we navigate these experiences are different as the perceptual and proprioceptive feedback gained from the real-world experience can influence navigation strategy.

Predicted and remembered emotion: tomorrow's vividness trumps yesterday's accuracy.

People rely on predicted and remembered emotion to guide important decisions. But how much can they trust their mental representations of emotion to be accurate, and how much do they trust them? In this investigation, participants (N = 957) reported their predicted, experienced, and remembered emotional response to the outcome of the 2016 U.S. presidential election. They also reported how accurate and vivid they perceived their predictions and memories to be, and the importance of the election. Participants remembered their emotional responses more accurately than they predicted them. But, strikingly, they perceived their predictions to be more accurate than their memories. This perception was explained by the greater importance and vividness of anticipated versus remembered experience. We also assessed whether individuals with Highly Superior Autobiographical Memory for personal and public events (N = 33) showed superior ability to predict or remember their emotional responses to events. They did not and, even for this group, predicting emotion was a more intense experience than remembering emotion. These findings reveal asymmetries in the phenomenological experience of predicting and remembering emotion. The vividness of predicted emotion serves as a powerful subjective signal of accuracy even when predictions turn out to be wrong.

Mnemonic Similarity Task: A Tool for Assessing Hippocampal Integrity.

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.

Excitatory/Inhibitory Imbalance in Anterior Lateral Occipital Complex Can Impair Hippocampal Mnemonic Discrimination.

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.

Response bias, recollection, and familiarity in individuals with Highly Superior Autobiographical Memory (HSAM).

The current study focused on individuals with Highly Superior Autobiographical Memory (HSAM) and had two main objectives: 1) investigate whether HSAMs have increased recollection performance compared to controls, and 2) investigate whether HSAMs have a reliably different response bias than controls. While previous lab-based recognition tests have shown that HSAMs have normal memory performance, these tests were based on a mixture of both recollection and familiarity. Here, we employed recognition tests specifically designed to separate recollected responses from those based on familiarity. Additionally, we were interested in how HSAMs make their memory decisions. Several studies have shown a great deal of variability between individuals in their response bias. Here, individuals with HSAM and age- matched controls completed a remember/know and a source memory test. HSAMs behaved like controls in both overall and recollection-based memory discrimination. However, HSAMs showed a significantly more liberal response bias, endorsing more items as "old" than controls. These findings contribute to our understanding of how memory processes - especially those related to decision-making - function in those with superior memory abilities and may help elucidate how other (non-HSAM) memory experts make decisions.

Recognition Memory Dysfunction Relates to Hippocampal Subfield Volume: A Study of Cognitively Normal and Mildly Impaired Older Adults.

OBJECTIVES: The current study examined recognition memory dysfunction and its neuroanatomical substrates in cognitively normal older adults and those diagnosed with mild cognitive impairment (MCI). METHODS: Participants completed the Mnemonic Similarity Task, which provides simultaneous measures of recognition memory and mnemonic discrimination. They also underwent structural neuroimaging to assess volume of medial temporal cortex and hippocampal subfields. RESULTS: As expected, individuals diagnosed with MCI had significantly worse recognition memory performance and reduced volume across medial temporal cortex and hippocampal subfields relative to cognitively normal older adults. After controlling for diagnostic group differences, however, recognition memory was significantly related to whole hippocampus volume, and to volume of the dentate gyrus/CA3 subfield in particular. Recognition memory was also related to mnemonic discrimination, a fundamental component of episodic memory that has previously been linked to dentate gyrus/CA3 structure and function. DISCUSSION: Results reveal that hippocampal subfield volume is sensitive to individual differences in recognition memory in older adults independent of clinical diagnosis. This supports the notion that episodic memory declines along a continuum within this age group, not just between diagnostic groups.

Modulation of associative learning in the hippocampal-striatal circuit based on item-set similarity.

Mounting evidence suggests that the medial temporal lobe (MTL) and striatal learning systems support different forms of learning, which can be competitive or cooperative depending on task demands. We have previously shown how activity in these regions can be modulated in a conditional visuomotor associative learning task based on the consistency of response mappings or reward feedback (Mattfeld & Stark, 2015). Here, we examined the shift in learning towards the MTL and away from the striatum by placing strong demands on pattern separation, a process of orthogonalizing similar inputs into distinct representations. Mnemonically, pattern separation processes have been shown to rely heavily on processing in the hippocampus. Therefore, we predicted modulation of hippocampal activity by pattern separation demands, but no such modulation of striatal activity. Using a variant of the conditional visuomotor associative learning task that we have used previously, we presented participants with two blocked conditions: items with high and low perceptual overlap during functional magnetic resonance imaging (fMRI). As predicted, we observed learning-related activity in the hippocampus, which was greater in the high than the low overlap condition, particularly in the dentate gyrus. In contrast, the associative striatum also showed learning related activity, but it was not modulated by overlap condition. Using functional connectivity analyses, we showed that the correlation between the hippocampus and dentate gyrus with the associative striatum was differentially modulated by high vs. low overlap, suggesting that the coordination between these regions was affected when pattern separation demands were high. These findings contribute to a growing literature that suggests that the hippocampus and striatal network both contribute to the learning of arbitrary associations that are computationally distinct and can be altered by task demands.

What's in a context? Cautions, limitations, and potential paths forward.

The purpose of memory is to guide current and future behavior based on previous experiences. Part of this process involves either discriminating between or generalizing across similar experiences that contain overlapping conditions (such as space, time, or internal state), which we often conceptualize as "contexts". In this review, we highlight major challenges facing the field as we attempt a neuroscience-based approach to the study of context and its impact on learning and memory. Here, we review some of the methodologies and approaches used to investigate context in both animals and humans, including the neurobiological mechanisms involved. Finally, we propose three tenets for operationalizing context in the experimental setting: 1) contexts must be stable over time along an experiential dimension; 2) contexts must be at least moderately complex in nature and their representations must be modifiable or adaptable, and 3) contexts must have some behavioral relevance (be it overt or incidental) so that its role can be measured.