Shauna M. Stark

Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults.

There is widespread evidence that memory deteriorates with aging, however the exact mechanisms that underlie these changes are not well understood. Given the growing size of the aging population, there is an imperative to study age‐related neurocognitive changes in order to better parse healthy from pathological aging. Using a behavioral paradigm that taxes pattern separation (the ability to differentiate novel yet similar information from previously learned information and thus avoid interference), we investigated age‐related neural changes in the human hippocampus using high‐resolution (1.5 mm isotropic) blood‐oxygenation level‐dependent fMRI. Recent evidence from animal studies suggests that hyperactivity in the CA3 region of the hippocampus may underlie behavioral deficits in pattern separation in aged rats. Here, we report evidence that is consistent with findings from the animal studies. We found a behavioral impairment in pattern separation in a sample of healthy older adults compared with young controls. We also found a related increase in CA3/dentate gyrus activity levels during an fMRI contrast that stresses pattern separation abilities. In a detailed analysis of behavior, we also found that the pattern of impairment was consistent with the predictions of the animal model, where larger changes in the input (greater dissimilarity) were required in order for elderly adults to successfully encode new information as distinct from previously learned information. These findings are also consistent with recent fMRI and behavioral reports in healthy aging, and further suggest that a specific functional deficit in the CA3/dentate network contributes to memory difficulties with aging.

High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic mild cognitive impairment

Functional magnetic resonance imaging (fMRI) studies have observed hyperactivity in the hippocampal region in individuals with Mild Cognitive Impairment (MCI). However, the actual source of such hyperactivity is not well understood. Studies of aged rats observed similar hyperactive signals in the CA3 region of the hippocampus that correlated with spatial memory deficits and, in particular, with their ability to represent novel environments as being distinct from familiar ones (pattern separation). In this study, we tested the hypothesis that patients with amnestic MCI (aMCI) have deficits in pattern separation, along with hyperactive fMRI BOLD activity in the CA3 region of the hippocampus. We used high-resolution fMRI during a continuous recognition task designed to emphasize pattern separation. We conducted hippocampal subfield-level region of interest analyses to test for dysfunctional activity in aMCI patients. We found that patients showed impaired performance on trials that taxed their pattern separation abilities. We also observed hyperactive BOLD signals in the CA3/dentate and hypoactive signals in the entorhinal cortex during the separation condition. In a high-resolution morphometric analysis of hippocampal subfields, aMCI patients also had smaller CA3/dentate and CA1 volumes (no difference in the subiculum). The CA3/dentate region bilaterally also exhibited the largest shape deformations in aMCI patients, suggesting that this locus is affected early in the course of the disease. These findings suggest that structural and functional changes in the CA3/dentate region of the hippocampus contribute to the deficits in episodic memory that are observed in patients with aMCI. The functional hyperactivity may be evidence for a dysfunctional encoding mechanism, consistent with the predictions of computational models of hippocampal learning.

Age-related memory deficits linked to circuit-specific disruptions in the hippocampus

Converging data from rodents and humans have demonstrated an age-related decline in pattern separation abilities (the ability to discriminate among similar experiences). Several studies have proposed the dentate and CA3 subfields of the hippocampus as the potential locus of this change. Specifically, these studies identified rigidity in place cell remapping in similar environments in the CA3. We used high-resolution fMRI to examine activity profiles in the dentate gyrus and CA3 in young and older adults as stimulus similarity was incrementally varied. We report evidence for “representational rigidity” in older adults’ dentate/CA3 that is linked to behavioral discrimination deficits. Using ultrahigh-resolution diffusion imaging, we quantified both the integrity of the perforant path as well as dentate/CA3 dendritic changes and found that both were correlated with dentate/CA3 functional rigidity. These results highlight structural and functional alterations in the hippocampal network that predict age-related changes in memory function and present potential targets for intervention.

Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity

Producing and maintaining distinct (orthogonal) neural representations for similar events is critical to avoiding interference in long-term memory. Recently, our laboratory provided the first evidence for separation-like signals in the human CA3/dentate. Here, we extended this by parametrically varying the change in input (similarity) while monitoring CA1 and CA3/dentate for separation and completion-like signals using high-resolution fMRI. In the CA1, activity varied in a graded fashion in response to increases in the change in input. In contrast, the CA3/dentate showed a stepwise transfer function that was highly sensitive to small changes in input.

A task to assess behavioral pattern separation (BPS) in humans: Data from healthy aging and mild cognitive impairment

Changes in memory performance are one of the hallmark symptoms of mild cognitive impairment and are affected by healthy aging as well. Pattern separation, which refers to the process of orthogonalizing overlapping inputs into distinct memory representations, may be a sensitive marker of these memory changes. Here, we describe a paradigm, the Behavioral Pattern Separation Task-Object Version (BPS-O task), which reveals age-related changes in pattern separation performance. Specifically, we report an age-related decline in pattern separation in healthy adults, ranging from ages 20 to 89. When we classify those individuals aged 60 and older into two groups, Aged Unimpaired (AU) and Aged Impaired (AI) based on their delayed word recall performance, we observe impairments in pattern separation performance in the Impaired group, but no overall impairment in recognition performance. In contrast, those individuals diagnosed with mild cognitive impairment demonstrate worse performance than age-matched controls in both pattern separation and recognition memory performance. Therefore, the BPS-O task provides a sensitive measure for observing changes in memory performance across the lifespan and may be useful for the early detection of memory impairments that may provide an early signal of later development to mild cognitive impairment.

Norepinephrine-mediated emotional arousal facilitates subsequent pattern separation

Pattern separation, the process by which similar experiences can be stored as distinct memories, has been ascribed to the dentate gyrus (DG) of the hippocampus. The DG is the target of noradrenergic modulation directly and indirectly via the basolateral amygdala. We tested the hypothesis that noradrenergic activation (tested using salivary alpha-amylase) potentiates DG function, enhancing pattern separation, by showing participants fearful stimuli in a pre-training task and then testing their capacity for pattern separation in a later test. Consistent with our hypothesis, we found that increased levels of salivary alpha-amylase were positively correlated with enhanced pattern separation performance even after accounting for general enhancements in recognition.

Contributions of human hippocampal subfields to spatial and temporal pattern separation

We sought to explore the roles of the hippocampal subregions and adjacent medial temporal lobe regions in pattern separation and any differential contributions based on sequential or spatial information. Young adults performed an incidental‐encoding task on a sequence of four objects presented on the screen in one of eight locations while we collected high‐resolution functional MRI brain scans. We employed five trials of interest: first presentations, exact repetitions, lures in which the same objects were repeated in different locations (spatial lures), lures in which the same objects were presented in a different sequential order (sequential lures), and lures in which both the spatial location and sequence were changed (both lures). We found no evidence for spatial or sequential specialization in the hippocampal subfields, consistent with the hypothesis that the dentate gyrus acts as a universal pattern separator. Likewise, we did not observe specialization for the perirhinal or parahippocampal cortices for spatial or sequential information, though both regions show evidence for associative processing in this task.

Human Hippocampal Structure: A Novel Biomarker Predicting Mnemonic Vulnerability to, and Recovery from, Sleep Deprivation.

Sleep deprivation impairs the formation of new memories. However, marked interindividual variability exists in the degree to which sleep loss compromises learning, the mechanistic reasons for which are unclear. Furthermore, which physiological sleep processes restore learning ability following sleep deprivation are similarly unknown. Here, we demonstrate that the structural morphology of human hippocampal subfields represents one factor determining vulnerability (and conversely, resilience) to the impact of sleep deprivation on memory formation. Moreover, this same measure of brain morphology was further associated with the quality of nonrapid eye movement slow wave oscillations during recovery sleep, and by way of such activity, determined the success of memory restoration. Such findings provide a novel human biomarker of cognitive susceptibility to, and recovery from, sleep deprivation. Moreover, this metric may be of special predictive utility for professions in which memory function is paramount yet insufficient sleep is pervasive (e.g., aviation, military, and medicine). SIGNIFICANCE STATEMENT Sleep deprivation does not impact all people equally. Some individuals show cognitive resilience to the effects of sleep loss, whereas others express striking vulnerability, the reasons for which remain largely unknown. Here, we demonstrate that structural features of the human brain, specifically those within the hippocampus, accurately predict which individuals are susceptible (or conversely, resilient) to memory impairments caused by sleep deprivation. Moreover, this same structural feature determines the success of memory restoration following subsequent recovery sleep. Therefore, structural properties of the human brain represent a novel biomarker predicting individual vulnerability to (and recovery from) the effects of sleep loss, one with occupational relevance in professions where insufficient sleep is pervasive yet memory function is paramount.

A case study of amnesia: Exploring a paradigm for new semantic learning and generalization

Primary objective: The purpose of this study was to explore and extend previous findings that training with variant items improves generalization performance on novel semantic sentences in an individual with amnesia. Research design: A case study of an individual with severe amnesia, Patient T.E., who participated in an extended training and multiple testing paradigm. Methods and procedures: Patient T.E. participated in 16 training sessions and eight test sessions on his recognition and recall performance for novel 3-word sentences. Three conditions were compared: No Variance (one version of each sentence studied), Early Variance (three versions of each sentence studied from the onset) and Late Variance (each of three versions of each sentence gradually introduced throughout training). Performance on studied items and semantically related items was evaluated. Main outcomes and results: Patient T.E. demonstrated better learning for Variance items than No Variance items and better generalization to semantically related items for the Late Variance condition. However, he showed an advantage for the No Variance condition on the recall task. Conclusions: Gradually introducing the variant items into training may be the optimal strategy for training an individual with severe amnesia to learn and generalize new semantic information.

Age-related deficits in the mnemonic similarity task for objects and scenes.

Abstract 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.