Emotional modulation of memorability in mnemonic discrimination.

Although elements such as emotion may serve to enhance or impair memory for images, some images are consistently remembered or forgotten by most people, an intrinsic characteristic of images known as memorability. Memorability explains some of the variability in memory performance, however, the underlying mechanisms of memorability remain unclear. It is known that emotional valence can increase the memorability of an experience, but how these two elements interact is still unknown. Hippocampal pattern separation, a computation that orthogonalizes overlapping experiences as distinct from one another, may be a candidate mechanism underlying memorability. However, these two literatures have remained largely separate. To explore the interaction between image memorability and emotion on pattern separation, we examined performance on an emotional mnemonic discrimination task, a putative behavioral correlate of hippocampal pattern separation, by splitting stimuli into memorable and forgettable categories as determined by a convolutional neural network as well as by emotion, lure similarity, and time of testing (immediately and 24-hour delay). We measured target recognition, which is typically used to determine memorability scores, as well as lure discrimination, which taxes hippocampal pattern separation and has not yet been examined within a memorability framework. Here, we show that more memorable images were better remembered across both target recognition and lure discrimination measures. However, for target recognition, this was only true upon immediate testing, not after a 24-hour delay. For lure discrimination, we found that memorability interacts with lure similarity, but depends on the time of testing, where memorability primarily impacts high similarity lure discrimination when tested immediately but impacts low similarity lure discrimination after a 24-hour delay. Furthermore, only lure discrimination showed an interaction between emotion and memorability, in which forgettable neutral images showed better lure discrimination compared to more memorable images. These results suggest that careful consideration is required of what makes an image memorable and may depend on what aspects of the image are more memorable (e.g., gist vs. detail, emotional vs. neutral).

A novel face-name mnemonic discrimination task with naturalistic stimuli.

Difficulty remembering faces and names is a common struggle for many people and gets more difficult as we age. Subtle changes in appearance from day to day, common facial characteristics across individuals, and overlap of names may contribute to the difficulty of learning face-name associations. Computational models suggest the hippocampus plays a key role in reducing interference across experiences with overlapping information by performing pattern separation, which enables us to encode similar experiences as distinct from one another. Thus, given the nature of overlapping features within face-name associative memory, hippocampal pattern separation may be an important underlying mechanism supporting this type of memory. Furthermore, cross-species approaches find that aging is associated with deficits in hippocampal pattern separation. Mnemonic discrimination tasks have been designed to tax hippocampal pattern separation and provide a more sensitive measure of age-related cognitive decline compared to traditional memory tasks. However, traditional face-name associative memory tasks do not parametrically vary overlapping features of faces and names to tax hippocampal pattern separation and often lack naturalistic facial features (e.g., hair, accessories, similarity of features, emotional expressions). Here, we developed a face-name mnemonic discrimination task where we varied face stimuli by similarity, race, sex, and emotional expression as well as the similarity of name stimuli. We tested a sample of healthy young and older adults on this task and found that both age groups showed worsening performance as face-name interference increased. Overall, older adults struggled to remember faces and face-name pairs more than young adults. However, while young adults remembered emotional faces better than neutral faces, older adults selectively remembered positive faces. Thus, the use of a face-name association memory task designed with varying levels of face-name interference as well as the inclusion of naturalistic face stimuli across race, sex, and emotional expressions provides a more nuanced approach relative to traditional face-name association tasks toward understanding age-related changes in memory.

Emotion regulation during encoding reduces negative and enhances neutral mnemonic discrimination in individuals with depressive symptoms.

Individuals with depression exhibit dysfunctional emotion regulation, general episodic memory deficits, and a negativity bias, where negative experiences are better remembered. Recent work suggests that the negativity bias in depression may be driven by enhanced mnemonic discrimination, a memory measure that relies on hippocampal pattern separation - a computation that processes experiences with overlapping features as unique. Previously, we found that individuals with depressive symptoms show enhanced negative and impaired neutral mnemonic discrimination. The current study aimed to investigate emotion regulation as an approach toward modifying memory encoding of negative and neutral events in individuals with depressive symptoms. Here we show that applying psychological distancing (a cognitive reappraisal strategy characterized by taking a third-person perspective toward negative events) during encoding was associated with reduced negative and enhanced neutral mnemonic discrimination during retrieval in individuals with depressive symptoms. These results suggest that applying emotion regulation techniques during encoding may provide an effective approach toward altering dysfunctional memory in those with depressive symptoms. Given that pharmacological treatments often fail to treat depression, emotion regulation provides a powerful and practical approach toward modifying cognitive and emotional processes. Future neuroimaging studies will be important to determine how emotion regulation impacts the neural mechanisms underlying these findings.

Perceived antidepressant efficacy associated with reduced negative and enhanced neutral mnemonic discrimination.

Introduction: While antidepressants are one of the first-line treatments for depression, the mechanisms underlying antidepressant action are unclear. Furthermore, the extent to which antidepressants impact emotional and cognitive dysfunction in depression requires more fine-grained approaches toward measuring these impacts in humans. Depression is associated with emotion and mood dysregulation in addition to cognitive deficits. Depressed individuals experience general memory impairment as well as a negativity bias in episodic memory, where negative events are better remembered than positive or neutral events. One potential mechanism hypothesized to underlie the negativity bias in memory is dysfunctional hippocampal pattern separation, in which depressed individuals tend to show impaired general pattern separation but enhanced negative pattern separation. Mnemonic discrimination tasks have been designed to tax hippocampal pattern separation in humans and provide a powerful approach to develop a mechanistic account for cognitive dysfunction in depression. While antidepressants have been examined primarily in rodent models in the context of hippocampal pattern separation, this has yet to be examined in humans. Methods: Here, we investigated how antidepressant usage and their perceived efficacy was associated with emotional mnemonic discrimination, given our prior work indicating a negativity bias for mnemonic discrimination in individuals with greater depressive symptoms. Results: We found that individuals who reported a greater improvement in their depressive symptoms after taking antidepressants (responders) showed reduced negative and enhanced neutral mnemonic discrimination compared to those with little to no improvement (non-responders). Perceived antidepressant efficacy was the strongest predictor of a reduction in the negativity bias for mnemonic discrimination, even when controlling for current depressive symptoms, antidepressant type, and other relevant factors. Discussion: These results suggest that antidepressants, when effective, can shift memory dynamics toward healthy function.

Toward user-centered assistive technologies for aging in place with cognitive impairment: a survey.

PURPOSE: To reduce the burden of Alzheimer's disease, the use of assistive technologies for patients and their informal caregivers is considered essential. However, these technologies are made as "one size fits all" instead of being tailored to accommodate people with varying degrees of cognitive impairment and those with diverse races/ethnicities. Thus, the aim of this survey was to determine whether the types of assistance needed most, and the technology used by those with cognitive impairment differed by race (White/non-Hispanics, Black or African Americans, and Hispanic/Latinos or Puerto Ricans) and severity of dementia (mild, moderate, severe). RESEARCH DESIGN AND METHODS: One hundred and eighty informal caregivers of people with different levels of severity of cognitive impairment and several different races/ethnicities filled out an online survey regarding assistance needed and technologies used. RESULTS: The results show that racial minorities considered the needs for assistance with Basic Activities of Daily Living as more important compared to White/non-Hispanics with mild dementia. Furthermore, Hispanic/Latinos or Puerto Ricans and White/non-Hispanics with severe dementia were shown to use technology that is designed to help with Instrumental Activities of Daily Living more than those with moderate dementia. Lastly, during COVID-19, devices to assist with walking, preparing meals and personal hygiene have been used significantly more by White/non-Hispanics with severe dementia compared to Hispanic/Latinos or Puerto Ricans. CONCLUSION: The results point to the need to design for those with severe dementia, regardless of race, and should focus on addressing needs related to both Instrumental and Basic Activities of Daily Living.

Developers of assistive technology should consider designing technology that can accommodate all severity levels of cognitive impairment.More research is needed to determine the usability of assistive technology that is designed for those with cognitive impairments.

Iron-regulated assembly of the cytosolic iron-sulfur cluster biogenesis machinery.

The cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway delivers Fe-S clusters to nuclear and cytosolic Fe-S proteins involved in essential cellular functions. Although the delivery process is regulated by the availability of iron and oxygen, it remains unclear how CIA components orchestrate the cluster transfer under varying cellular environments. Here, we utilized a targeted proteomics assay for monitoring CIA factors and substrates to characterize the CIA machinery. We find that nucleotide-binding protein 1 (NUBP1/NBP35), cytosolic iron-sulfur assembly component 3 (CIAO3/NARFL), and CIA substrates associate with nucleotide-binding protein 2 (NUBP2/CFD1), a component of the CIA scaffold complex. NUBP2 also weakly associates with the CIA targeting complex (MMS19, CIAO1, and CIAO2B) indicating the possible existence of a higher order complex. Interactions between CIAO3 and the CIA scaffold complex are strengthened upon iron supplementation or low oxygen tension, while iron chelation and reactive oxygen species weaken CIAO3 interactions with CIA components. We further demonstrate that CIAO3 mutants defective in Fe-S cluster binding fail to integrate into the higher order complexes. However, these mutants exhibit stronger associations with CIA substrates under conditions in which the association with the CIA targeting complex is reduced suggesting that CIAO3 and CIA substrates may associate in complexes independently of the CIA targeting complex. Together, our data suggest that CIA components potentially form a metabolon whose assembly is regulated by environmental cues and requires Fe-S cluster incorporation in CIAO3. These findings provide additional evidence that the CIA pathway adapts to changes in cellular environment through complex reorganization.

Spousal caregiving, widowhood, and cognition: A systematic review and a biopsychosocial framework for understanding the relationship between interpersonal losses and dementia risk in older adulthood.

Accumulating research suggests that stressful life events, especially those that threaten close intimate bonds, are associated with an increased risk of dementia. Grieving the loss of a spouse, whether in the form of caregiving or after the death, ranks among 'life's most significant stressors', evoking intense psychological and physiological distress. Despite numerous studies reporting elevated dementia risk or poorer cognition among spousal caregivers and widow(er)s compared to controls, no review has summarized findings across cognitive outcomes (i.e., dementia incidence, cognitive impairment rates, cognitive performance) or proposed a theoretical model for understanding the links between partner loss and abnormal cognitive decline. The current systematic review summarizes findings across 64 empirical studies. Overall, both cross-sectional and longitudinal studies revealed an adverse association between partner loss and cognitive outcomes. In turn, we propose a biopsychosocial model of cognitive decline that explains how caregiving and bereavement may position some to develop cognitive impairment or Alzheimer's disease and related dementias. More longitudinal studies that focus on the biopsychosocial context of caregivers and widow(er)s are needed.

Integrity of the uncinate fasciculus is associated with emotional pattern separation-related fMRI signals in the hippocampal dentate and CA3.

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders involving emotional disruptions. One such pathway - the uncinate fasciculus - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity with the orbitofrontal cortex remains unknown. Here we asked if the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution fMRI, we found that reduced integrity of the UF is related to elevated BOLD fMRI activation of the DG/CA3 subregions of the hippocampus during emotional lure discrimination. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that greater activation in this network (possibly driven by CA3 recurrent collaterals) is associated with memory errors. Based on this work we suggest that the UF is one pathway that may allow the OFC to exert control on this network and improve discrimination of emotional experiences, although further work is necessary to fully evaluate this possibility. This work provides novel insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.

The Gα-interacting vesicle-associated protein interacts with and promotes cell surface localization of GRP78 during endoplasmic reticulum stress.

Cell surface translocation of the chaperone glucose-regulated protein 78 kDa (GRP78) is a key event that promotes cancer cell survival during endoplasmic reticulum (ER) stress. Here, we identify Gα-interacting vesicle-associated protein (GIV) - an enhancer of prosurvival signaling during ER stress - as a binding partner of GRP78. We show that GIV and GRP78 interact in an ER stress-dependent manner through their respective carboxyl terminal domains and that GIV aids in the localization of GRP78 to the plasma membrane. Kaplan-Meier analysis of disease-free survival in cancer patients shows poor prognosis for patients with high expression of both GIV and GRP78, further suggesting a vital role for these two proteins in enhancing cancer cell viability.

Development of a mnemonic discrimination task using naturalistic stimuli with applications to aging and preclinical Alzheimer's disease.

Most tasks test memory within the same day, however, most forgetting occurs after 24 h. Further, testing memory for simple words or objects does not mimic real-world memory experiences. We designed a memory task showing participants video clips of everyday kinds of experiences, including positive, negative, and neutral stimuli, and tested memory immediately and 24 h later. During the memory test, we included repeated and similar stimuli to tax both target recognition and lure discrimination ability. Participants' memory was worse after 24 h, especially the ability to discriminate similar stimuli. Emotional videos were better remembered when tested immediately, however, after 24 h we find gist versus detail trade-offs in emotional forgetting. We also applied this paradigm to a sample of cognitively normal older adults that also underwent amyloid and tau PET imaging. We found that older adults performed worse on the task compared to young adults. While both young and older adults showed similar patterns of forgetting of repeated emotional and neutral clips, older adults showed preserved neutral compared to emotional discrimination after 24 h. Further, lure discrimination performance correlated with medial temporal lobe tau in older adults with preclinical Alzheimer's disease. These results suggest factors such as time between encoding and retrieval, emotion, and similarity influence memory performance and should be considered when examining memory performance for an accurate picture of memory function and dysfunction.

Post-encoding stress enhances mnemonic discrimination of negative stimuli.

Stress influences how we remember emotional events and how these events shape future behaviors. However, the impact of stress on memory specificity for emotional events has yet to be examined. To this end, the present study utilized a mnemonic discrimination task that taxes hippocampal pattern separation, the process of distinguishing between overlapping experiences, thereby allowing us to better understand the mechanisms by which stress affects gist versus detail memory of emotional events. Participants encoded scenes composed of negative or neutral objects placed on neutral backgrounds and then underwent a psychosocial stressor or matched control task. Twenty-four hours later during testing, objects were presented separately, with some identical old objects (targets), some new objects (foils), and some similar but not identical objects (lures). Target recognition was enhanced for negative compared to neutral objects in both the stress and control groups. Interestingly, post-encoding stress selectively enhanced mnemonic discrimination of negative versus neutral objects, which was not the case in the control group. Measures of salivary cortisol revealed a quadratic inverted U relationship between negative mnemonic discrimination and cortisol increase. These findings suggest that moderate cortisol release following stress is associated with enhanced memory precision for negative information.

Subthreshold Amyloid Predicts Tau Deposition in Aging.

Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of ß-amyloid (Aß). However, the accumulation of Aß begins slowly, years before biomarkers become abnormal. We used longitudinal [11C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans (N = 71; mean age 75 years; 35% male). We used [18F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample (N = 37). We found evidence for an inverted-U relationship between baseline Aß levels and Aß slope in asymptomatic older adults, suggesting a slowing of Aß accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of Aß predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of Aß increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative.SIGNIFICANCE STATEMENT The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.

Integrating new findings and examining clinical applications of pattern separation.

Pattern separation, the ability to independently represent and store similar experiences, is a crucial facet of episodic memory. Growing evidence suggests that the hippocampus possesses unique circuitry that is computationally capable of resolving mnemonic interference by using pattern separation. In this Review, we discuss recent advances in the understanding of this process and evaluate the caveats and limitations of linking across animal and human studies. We summarize clinical and translational studies using methods that are sensitive to pattern separation impairments, an approach that stems from the fact that the hippocampus is a major site of disruption in many brain disorders. We critically evaluate the assumptions that guide fundamental and translational studies in this area. Finally, we suggest guidelines for future research and offer ways to overcome potential interpretational challenges to increase the utility of pattern separation as a construct that can further understanding of both memory processes and brain disease.

On the distinction between value-driven attention and selection history: Evidence from individuals with depressive symptoms.

When predictive of extrinsic reward as targets, stimuli rapidly acquire the ability to automatically capture attention. Attentional biases for former targets of visual search also can develop without reward feedback but typically require much longer training. These learned biases towards former targets often are conceptualized within a single framework and might differ merely in degree. That is, both are the result of the reinforcement of selection history, with extrinsic reward for correct report of the target providing greater reinforcement than correct report alone. A direct test of this shared mechanisms hypothesis is lacking, however. Recent evidence demonstrates that depressed individuals present with blunted value-driven attentional biases. Based on the shared mechanisms hypothesis, we predicted that depressed individuals would similarly show blunted attentional biases for former targets following unrewarded training. To the contrary, however, we found that the effects of selection history on attention were robust and equivalent between individuals experiencing depressive symptoms and control participants, whereas attentional capture by previously reward-associated stimuli was blunted in depressed individuals. Our results suggest a qualitative distinction between the effects of reward history and the effects of selection history on attention, with depressive symptoms impairing the former while leaving the latter unaffected.

Amygdala-hippocampal dynamics during salient information processing.

Recognizing motivationally salient information is critical to guiding behaviour. The amygdala and hippocampus are thought to support this operation, but the circuit-level mechanism of this interaction is unclear. We used direct recordings in the amygdala and hippocampus from human epilepsy patients to examine oscillatory activity during processing of fearful faces compared with neutral landscapes. We report high gamma (70-180 Hz) activation for fearful faces with earlier stimulus evoked onset in the amygdala compared with the hippocampus. Attending to fearful faces compared with neutral landscape stimuli enhances low-frequency coupling between the amygdala and the hippocampus. The interaction between the amygdala and hippocampus is largely unidirectional, with theta/alpha oscillations in the amygdala modulating hippocampal gamma activity. Granger prediction, phase slope index and phase lag analysis corroborate this directional coupling. These results demonstrate that processing emotionally salient events in humans engages an amygdala-hippocampal network, with the amygdala influencing hippocampal dynamics during fear processing.

Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline.

The amyloid hypothesis suggests that beta-amyloid (Aß) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer's disease. However, factors that underlie Aß deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased Aß deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives Aß deposition. To test this model, we examined the relationship between hippocampal activity during a memory task using fMRI and subsequent longitudinal change in Aß using PIB-PET imaging in cognitively normal older adults. We found that greater hippocampal activation at baseline was associated with increased Aß accumulation. Furthermore, increasing Aß accumulation mediated the influence of hippocampal activation on declining memory performance, demonstrating a crucial role of Aß in linking hippocampal activation and memory. These findings support a model linking increased hippocampal activation to subsequent Aß deposition and cognitive decline.

Disruption of amygdala-entorhinal-hippocampal network in late-life depression.

Episodic memory deficits are evident in late-life depression (LLD) and are associated with subtle synaptic and neurochemical changes in the medial temporal lobes (MTL). However, the particular mechanisms by which memory impairment occurs in LLD are currently unknown. We tested older adults with (DS+) and without (DS-) depressive symptoms using high-resolution fMRI that is capable of discerning signals in hippocampal subfields and amygdala nuclei. Scanning was conducted during performance of an emotional discrimination task used previously to examine the relationship between depressive symptoms and amygdala-mediated emotional modulation of hippocampal pattern separation in young adults. We found that hippocampal dentate gyrus (DG)/CA3 activity was reduced during correct discrimination of negative stimuli and increased during correct discrimination of neutral items in DS+ compared to DS- adults. The extent of the latter increase was correlated with symptom severity. Furthermore, DG/CA3 and basolateral amygdala (BLA) activity predicted discrimination performance on negative trials, a relationship that depended on symptom severity. The impact of the BLA on depressive symptom severity was mediated by the DG/CA3 during discrimination of neutral items, and by the lateral entorhinal cortex (LEC) during false recognition of positive items. These results shed light on a novel mechanistic account for amygdala-hippocampal network changes and concurrent alterations in emotional episodic memory in LLD. The BLA-LEC-DG/CA3 network, which comprises a key pathway by which emotion modulates memory, is specifically implicated in LLD. © 2017 Wiley Periodicals, Inc.

Age-related individual variability in memory performance is associated with amygdala-hippocampal circuit function and emotional pattern separation.

While aging is generally associated with episodic memory decline, not all older adults exhibit memory loss. Furthermore, emotional memories are not subject to the same extent of forgetting and appear preserved in aging. We conducted high-resolution fMRI during a task involving pattern separation of emotional information in older adults with and without age-related memory impairment (characterized by performance on a word-list learning task: low performers: LP vs. high performers: HP). We found signals consistent with emotional pattern separation in hippocampal dentate (DG)/CA3 in HP but not in LP individuals, suggesting a deficit in emotional pattern separation. During false recognition, we found increased DG/CA3 activity in LP individuals, suggesting that hyperactivity may be associated with overgeneralization. We additionally observed a selective deficit in basolateral amygdala-lateral entorhinal cortex-DG/CA3 functional connectivity in LP individuals during pattern separation of negative information. During negative false recognition, LP individuals showed increased medial temporal lobe functional connectivity, consistent with overgeneralization. Overall, these results suggest a novel mechanistic account of individual differences in emotional memory alterations exhibited in aging.

True self-alienation positively predicts reports of mindwandering.

Two studies assessed the relationship between feelings of uncertainty about who one truly is (i.e., true self-alienation) and self-reported task-unrelated thoughts (i.e., mindwandering) during performance tasks. Because true self-alienation is conceptualized as the subjective disconnect between conscious awareness and actual experience, we hypothesized that greater feelings of true self-alienation would positively relate to subjective reports of mindwandering. Two convergent studies supported this hypothesis. Moreover, this relationship could not consistently be accounted for by the independent influence of other aspects of authenticity, negative mood, mindfulness, or broad personality dimensions. These findings suggest that individual differences in true self-alienation are reliably associated with subjective reports of mindwandering. The implications of these findings for the true self-alienation construct, the ways that personality relates to mindwandering, and future research directions focused on curtailing mindwandering and improving performance and achievement are discussed.