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Context contributes to multiple aspects of human episodic memory including segmentation and retrieval. The present studies tested if, in adult male and female mice, context influences the encoding of odors encountered in a single unsupervised sampling session of the type used for the routine acquisition of episodic memories. The three paradigms used differed in complexity (single vs. multiple odor cues) and period from sampling to testing. Results show that males consistently encode odors in a context-dependent manner: the mice discriminated novel from previously sampled cues when tested in the chamber of initial cue sampling but not in a distinct yet familiar chamber. This was independent of the interval between cue encounters or the latency from initial sampling to testing. In contrast, female mice acquired both single cues and the elements of multi-cue episodes, but recall of that information was dependent upon the surrounding context only when the cues were presented serially. These results extend the list of episodic memory features expressed by rodents and also introduce a striking and unexpected sex difference in context effects.

IntroductionCardiovascular fat is a novel risk factor that may link to dementia. Fat volume and radiodensity are measurements of fat quantity and quality, respectively. Importantly, high fat radiodensity could indicate healthy or adverse metabolic processes.MethodsThe associations of cardiovascular fat (including epicardial, paracardial, and thoracic perivascular adipose tissue [PVAT]) quantity and quality assessed at mean age of 51 with subsequent cognitive performance measured repeatedly over 16 years of follow-up were examined using mixed models among 531 women.ResultsHigher thoracic PVAT volume was associated with a higher future episodic memory (β[standard error (SE)] = 0.08 [0.04], P = 0.033), while higher thoracic PVAT radiodensity with lower future episodic (β[SE] = -0.06 [0.03], P = 0.045) and working (β[SE] = -0.24 [0.08], P = 0.003) memories. The latter association is prominent at higher volume of thoracic PVAT.DiscussionMid-life thoracic PVAT may have a distinct contribution to future cognition possibly due to its distinct adipose tissue type (brown fat) and anatomical proximity to the brain circulation.HighlightsHigher mid-life thoracic perivascular adipose tissue (thoracic PVAT) volume is related to a better future episodic memory in women. Higher mid-life thoracic PVAT radiodensity is related to worse future working and episodic memories. Negative association of high thoracic PVAT radiodensity with working memory is prominent at higher thoracic PVAT volume. Mid-life thoracic PVAT is linked to future memory loss, an early sign of Alzheimer's disease. Mid-life women's epicardial and paracardial fat are not related to future cognition.

Context contributes to multiple aspects of human episodic memory including segmentation and retrieval. The present studies tested if, in adult male and female mice, context influences the encoding of odors encountered in a single unsupervised sampling session of the type used for the routine acquisition of episodic memories. The three paradigms used differed in complexity (single vs. multiple odor cues) and period from sampling to testing. Results show that males consistently encode odors in a context-dependent manner: the mice discriminated novel from previously sampled cues when tested in the chamber of initial cue sampling but not in a distinct yet familiar chamber. This was independent of the interval between cue encounters or the latency from initial sampling to testing. In contrast, female mice acquired both single cues and the elements of multi-cue episodes, but recall of that information was dependent upon the surrounding context only when the cues were presented serially. These results extend the list of episodic memory features expressed by rodents and also introduce a striking and unexpected sex difference in context effects. [ABSTRACT FROM AUTHOR]

BACKGROUND: Major Depressive Disorder, characterized by cognitive affective biases, is a considerable public health challenge. Past work has shown that higher depressive symptoms are associated with augmented memory of negative stimuli. In contrast, anxiety symptoms have been associated with overgeneralization of emotional memories. Given the high comorbidity of depression and anxiety, it is critical to understand how cognitive affective biases are differentially associated with clinical symptoms. METHOD: We used continuous measures of depression (Beck Depression Inventory [BDI-II]) and anxiety (Beck Anxiety Inventory [BAI]) to evaluate an adult sample (N = 79; 18-41 years old, 58 female). Emotional memory discrimination and recognition memory were tested using an emotional discrimination task. We applied exploratory factor analysis to questions from the BAI and BDI-II to uncover latent constructs consisting of negative affect, anhedonia, somatic anxiety, and cognitive anxiety. RESULTS: We report evidence that anxious symptoms were associated with impaired recognition of negative items after accounting for age and sex. Our exploratory factor analysis revealed that impaired negative item recognition is largely associated with somatic and cognitive anxiety factors. LIMITATIONS: Interpretations in a mixed pathology sample, especially given collinearity among factors, may be difficult. CONCLUSIONS: We provide evidence that somatic and cognitive anxiety are related to impaired recognition memory for negative stimuli. Future clinical investigations should uncover the neurobiological basis supporting the link between recognition of negative stimuli and somatic/cognitive symptoms of anxiety.

Chemotherapy may impair cognition and contribute to accelerated aging. The purpose of this study was to assess the effects of chemotherapy on the connectivity of the default mode network (DMN) in older women with breast cancer. This prospective longitudinal study enrolled women aged ≥ 60 years with stage I-III breast cancer (CTx group) and matched healthy controls (HC group). Study assessments, consisting of resting-state functional MRI (rs-fMRI) and the Picture Sequence Memory (psm) test for episodic memory from the NIH Toolbox for Cognition, were obtained at baseline and within one month after the completion of chemotherapy for the CTx group and at matched intervals for the HC group. Two-sample t-test and FDR multiple comparison were used for statistical inference. Our analysis of the CTx group (N = 19; 60-82 years of age, mean = 66.6, SD = 5.24) compared to the HC group (N = 14; 60-78 years of age, mean = 68.1, SD = 5.69) revealed weaker DMN subnetwork connectivity in the anterior brain but stronger connectivity in the posterior brain at baseline. After chemotherapy, this pattern was reversed, with stronger anterior connectivity and weaker posterior connectivity. In addition, the meta-level functional network connectivity (FNC) among the DMN subnetworks after chemotherapy was consistently weaker than the baseline FNC as seen in the couplings between anterior cingulate cortex (ACC) and retrosplenial (rSplenia) region, with ΔFNC(ACC,rSplenia)=-0.14, t value=-2.44, 95 %CI=[-0.27,-0.10], pFDR

The hippocampus, well known for its role in episodic memory, might also be an important brain region for extracting structure from our experiences in order to guide future decisions. Recent evidence in rodents suggests that the hippocampus supports decision making by representing task structure in cooperation with the orbitofrontal cortex (OFC). Here, we examine how the human hippocampus and OFC represent task structure during an associative learning task that required learning of both context-determined and context-invariant probabilistic associations. We find that after learning, hippocampal and lateral OFC representations differentiated between context-determined and context-invariant task structures. The degree of this differentiation within the hippocampus and lateral OFC is highly correlated. These results advance our understanding of the hippocampus and suggest that the hippocampus and OFC support goal-directed behavior by representing information that guides the selection of appropriate decision strategies.

The mechanisms underlying accumulation of Alzheimer's disease (AD)-related tau pathology outside of the medial temporal lobe (MTL) in older adults are unknown but crucial to understanding cognitive decline. A growing body of evidence from human and animal studies strongly implicates neural connectivity in the propagation of tau in humans, but the pathways of neocortical tau spread and its consequences for cognitive function are not well understood. Using resting state functional magnetic resonance imaging (fMRI) and tau PET imaging from a sample of 97 male and female cognitively normal older adults, we examined MTL structures involved in medial parietal tau accumulation and associations with memory function. Functional connectivity between hippocampus (HC) and retrosplenial cortex (RsC), a key region of the medial parietal lobe, was associated with tau in medial parietal lobe. By contrast, connectivity between entorhinal cortex (EC) and RsC did not correlate with medial parietal lobe tau. Further, greater hippocampal-retrosplenial (HC-RsC) connectivity was associated with a stronger correlation between MTL and medial parietal lobe tau. Finally, an interaction between connectivity strength and medial parietal tau was associated with episodic memory performance, particularly in the visuospatial domain. This pattern of tau accumulation thus appears to reflect pathways of neural connectivity, and propagation of tau from EC to medial parietal lobe via the HC may represent a critical process in the evolution of cognitive dysfunction in aging and AD.SIGNIFICANCE STATEMENT The accumulation of tau pathology in the neocortex is a fundamental process underlying Alzheimer's disease (AD). Here, we use functional connectivity in cognitively normal older adults to track the accumulation of tau in the medial parietal lobe, a key region for memory processing that is affected early in the progression of AD. We show that the strength of connectivity between the hippocampus (HC) and retrosplenial cortex (RsC) is related to medial parietal tau burden, and that these tau and connectivity measures interact to associate with episodic memory performance. These findings establish the HC as the origin of medial parietal tau and implicate tau pathology in this region as a crucial marker of the beginnings of AD.

Diffusion imaging studies have observed age-related degradation of white matter that contributes to cognitive deficits separately in younger-old (ages 65-89) and oldest-old (ages 90+) adults. But it remains unclear whether these age effects are magnified in advanced age groups, which may reflect disease-related pathology. Here, we tested whether age-related differences in white matter microstructure followed linear or nonlinear patterns across the entire older adult lifespan (65-98 years), these patterns were influenced by oldest-old adults at increased risk of dementia (cognitive impairment no dementia, CIND), and they explained age effects on episodic memory. Results revealed nonlinear microstructure declines across fiber classes (medial temporal, callosal, association, projection and/or thalamic) that were largest for medial temporal fibers. These patterns remained after excluding oldest-old participants with CIND, indicating that aging of white matter microstructure cannot solely be explained by pathology associated with early cognitive impairment. Moreover, finding that the effect of age on episodic memory was mediated by medial temporal fiber microstructure suggests it is essential for facilitating memory-related neural signals across the older adult lifespan.

OBJECTIVES: Participating in a variety of daily activities (i.e., activity diversity) requires people to adjust to a variety of situations and engage in a greater diversity of behaviors. These experiences may, in turn, enhance cognitive functioning. This study examined associations between activity diversity and cognitive functioning across adulthood. METHOD: Activity diversity was defined as the breadth and evenness of participation in seven common daily activity domains (e.g., paid work, time with children, leisure, physical activities, volunteering). Participants from the National Survey of Daily Experiences (NSDE: N = 732, Mage = 56) provided activity data during eight consecutive days at Wave 1 (W1) and Wave 2 (W2) 10 years apart. They also provided cognitive data at W2. RESULTS: Greater activity diversity at W2 was associated with higher overall cognitive functioning and higher executive functioning at W2. Individuals who increased activity diversity from W1 to W2 also exhibited higher scores in overall cognitive functioning and executive functioning at W2. Overall cognitive functioning, executive functioning, and episodic memory were better in those who had higher activity diversity at both waves, or increased activity diversity from W1 to W2, compared to those who had lower activity diversity or decreased activity diversity over time. DISCUSSION: Activity diversity is important for cognitive health in adulthood. Future work can study the directionality between activity diversity and cognitive functioning and underlying social and neurological mechanisms for these associations.

The brain signature concept aims to characterize brain regions most strongly associated with an outcome of interest. Brain signatures derive their power from data-driven searches that select features based solely on performance metrics of prediction or classification. This approach has important potential to delineate biologically relevant brain substrates for prediction or classification of future trajectories. Recent work has used exploratory voxel-wise or atlas-based searches, with some using machine learning techniques to define salient features. These have shown undoubted usefulness, but two issues remain. The preponderance of recent work has been aimed at categorical rather than continuous outcomes, and it is rare for non-atlas reliant voxel-based signatures to be reported that would be useful for modelling and hypothesis testing. We describe a cross-validated signature region model for structural brain components associated with baseline and longitudinal episodic memory across cognitively heterogeneous populations including normal, mild impairment and dementia. We used three non-overlapping cohorts of older participants: from the UC Davis Aging and Diversity cohort (n = 255; mean age 75.3 ± 7.1 years; 128 cognitively normal, 97 mild cognitive impairment, 30 demented and seven unclassified); from Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 (n = 379; mean age 75.1 ± 7.2; 82 cognitively normal, 176 mild cognitive impairment, 121 Alzheimer's dementia); and from ADNI2/GO (n = 680; mean age 72.5 ± 7.1; 220 cognitively normal, 381 mild cognitive impairment and 79 Alzheimer's dementia). We used voxel-wise regression analysis, correcting for multiple comparisons, to generate an array of regional masks corresponding to different association strength levels of cortical grey matter with baseline memory and brain atrophy with memory change. Cognitive measures were episodic memory using Spanish and English Neuropsychological Assessment Scales instruments for UC Davis and ADNI-Mem for ADNI 1 and ADNI2/GO. Performance metric was the adjusted R2 coefficient of determination of each model explaining outcomes in two cohorts other than where it was computed. We compared within-cohort performances of signature models against each other and against other recent signature models of episodic memory. Findings were: (i) two independently generated signature region of interest models performed similarly in a third separate cohort; (ii) a signature region of interest generated in one imaging cohort replicated its performance level when explaining cognitive outcomes in each of other, separate cohorts; and (iii) this approach better explained baseline and longitudinal memory than other recent theory-driven and data-driven models. This suggests our approach can generate signatures that may be easily and robustly applied for modelling and hypothesis testing in mixed cognition cohorts.

Background/objectivesExposure to air pollution may contribute to both increasing depressive symptoms and decreasing episodic memory in older adulthood, but few studies have examined this hypothesis in a longitudinal context. Accordingly, we examined the association between air pollution and changes in depressive symptoms (DS) and episodic memory (EM) and their interrelationship in oldest-old (aged 80 and older) women.DesignProspective cohort data from the Women's Health Initiative Memory Study-Epidemiology of Cognitive Health Outcomes.SettingGeographically diverse community-dwelling population.ParticipantsA total of 1,583 dementia-free women aged 80 and older.MeasurementsWomen completed up to six annual memory assessments (latent composite of East Boston Memory Test and Telephone Interview for Cognitive Status) and the 15-item Geriatric Depression Scale (GDS-15). We estimated 3-year average exposures to regional particulate matter with aerodynamic diameter below 2.5 μm (PM2.5 ) (interquartile range [IQR] = 3.35 μg/m3 ) and gaseous nitrogen dioxide (NO2 ) (IQR = 9.55 ppb) at baseline and during a remote period 10 years earlier, using regionalized national universal kriging.ResultsLatent change structural equation models examined whether residing in areas with higher pollutant levels was associated with annual changes in standardized EM and DS while adjusting for potential confounders. Remote NO2 (β = .287 per IQR; P = .002) and PM2.5 (β = .170 per IQR; P = .019) exposure was significantly associated with larger increases in standardized DS, although the magnitude of the difference, less than 1 point on the GDS-15, is of questionable clinical significance. Higher DS were associated with accelerated EM declines (β = -.372; P = .001), with a significant indirect effect of remote NO2 and PM2.5 exposure on EM declines mediated by DS. There were no other significant indirect exposure effects.ConclusionThese findings in oldest-old women point to potential adverse effects of late-life exposure to air pollution on subsequent interplay between DS and EM, highlighting air pollution as an environmental health risk factor for older women.

Nonhuman research has implicated developmental processes within the hippocampus in the emergence and early development of episodic memory, but research in humans has been constrained by the difficulty of examining hippocampal function during early development. In the present study, we assessed 48 2-year-olds with a novel paradigm in which participants completed two games on a tablet that required remembering associations between unique characters, the places they visited, and the temporal order with which they did so. At the completion of each game, a unique, novel song played. Toddlers remembered spatial locations better than temporal order during an immediate test, after a 20-minute delay, and after a week delay. After the last behavioral session, toddlers underwent an fMRI task during natural nocturnal sleep evaluating hippocampal activation in response to learned and novel songs. We found that the extent of hippocampal activation for learned songs compared to novel songs during sleep was correlated with memory for temproal order across all time delays, but not with memory for spatial locations. The results confirm that that the functional contribution of the hippocampus to early memory can be assessed during sleep and suggest that assessment of temporal aspects of memory in the current task best capture this contribution.

Goal-directed attention is usually studied by providing individuals with explicit instructions on what they should attend to. But in daily life, we often use past experiences to guide our attentional states. Given the importance of memory for predicting upcoming events, we hypothesized that memory-guided attention is supported by neural preparation for anticipated attentional states. We examined preparatory coding in the human hippocampus and mPFC, two regions that are important for memory-guided behaviors, in two tasks: one where attention was guided by memory and another in which attention was explicitly instructed. Hippocampus and mPFC exhibited higher activity for memory-guided vs. explicitly instructed attention. Furthermore, representations in both regions contained information about upcoming attentional states. In the hippocampus, this preparation was stronger for memory-guided attention, and occurred alongside stronger coupling with visual cortex during attentional guidance. These results highlight the mechanisms by which memories are used to prepare for upcoming attentional goals.

IntroductionA 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.MethodIn 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.ResultsResults 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.ConclusionsThese findings are consistent with the notion that successful MD is supported by the hippocampus, with auxiliary processes supported by cortex (e.g., perceptual discrimination).

Episodic memory, or the ability to remember past events with specific detail, is central to the human experience and is related to learning and adaptive functioning in a variety of domains. In typically developing children, episodic memory emerges during infancy and improves during early childhood and beyond. Developmental processes within the hippocampus are hypothesized to be primarily responsible for both the early emergence and persistence of episodic memory in late infancy and early childhood. However, these hypotheses are based on non-human models. In-vivo investigations in early human development of hippocampal processes have been significantly limited by methodological challenges in acquiring neuroimaging data, particularly task-related functional neuroimaging data, from infants and toddlers. Recent studies in adults have shown neural activity in the brain regions supporting episodic memory during slow-wave sleep using functional magnetic resonance imaging (fMRI), and fMRI has been increasingly utilized in infancy and early childhood to address other research questions. We review initial evidence and present preliminary data showing the promise of this approach for examining hippocampal contribution to how infants and toddlers remember individual events, and their association with information about the context in which the event occurred. Overall, our review, integrated with the presentation of some preliminary data provides insight on leveraging sleep to gain new perspectives on early memory functioning.

BackgroundEmerging data suggests PM2.5 (particulate matter with aerodynamic diameter

Episodic memory, or the ability to remember past events with specific detail, is central to the human experience and is related to learning and adaptive functioning in a variety of domains. In typically developing children, episodic memory emerges during infancy and improves during early childhood and beyond. Developmental processes within the hippocampus are hypothesized to be primarily responsible for both the early emergence and persistence of episodic memory in late infancy and early childhood. However, these hypotheses are based on non-human models. In-vivo investigations in early human development of hippocampal processes have been significantly limited by methodological challenges in acquiring neuroimaging data, particularly task-related functional neuroimaging data, from infants and toddlers. Recent studies in adults have shown neural activity in the brain regions supporting episodic memory during slow-wave sleep using functional magnetic resonance imaging (fMRI), and fMRI has been increasingly utilized in infancy and early childhood to address other research questions. We review initial evidence and present preliminary data showing the promise of this approach for examining hippocampal contribution to how infants and toddlers remember individual events, and their association with information about the context in which the event occurred. Overall, our review, integrated with the presentation of some preliminary data provides insight on leveraging sleep to gain new perspectives on early memory functioning.

BackgroundThe degree to which individuals with autism spectrum disorder (ASD) evidence impairments in episodic memory relative to their typically developing (TD) counterparts remains unclear. According to a prominent view, ASD is associated with deficits in encoding associations between items and recollecting precise context details. Here, we evaluated behavioral and neural evidence for this impaired relational binding hypothesis using a task involving relational encoding and recollection during functional magnetic resonance imaging.MethodsAdolescents and young adults (nASD = 47, nTD = 60) performed the Relational and Item-Specific Encoding task during functional magnetic resonance imaging, including item and associative recognition testing. We modeled functional recruitment within the medial temporal lobes (MTLs), and connectivity between MTL and the posterior medial (PM) network thought to underlie relational memory. The impaired relational binding model would predict a behavioral deficit driven by aberrant recruitment and connectivity of MTL and the PM network.ResultsThe ASD and TD groups showed indistinguishable item and associative recognition performance. During relational encoding, the ASD group demonstrated increased hippocampal recruitment, and decreased connectivity between MTL and PM regions relative to the TD group. Within ASD, hippocampal recruitment and MTL-PM connectivity were inversely correlated.ConclusionsThe lack of a behavioral deficit in ASD does not support the impaired relational binding hypothesis. Instead, the current data suggest that increased recruitment of the hippocampus compensates for decreased MTL-PM connectivity to support preserved episodic memory in ASD. These findings suggest a compensatory neurodevelopmental mechanism that may support preserved cognitive domains in ASD: local hyperrecruitment may offset connectivity aberrations in individuals with ASD relative to TD subjects.

Educational attainment is associated with cognition among older adults, but this association is complex and not well understood. While associated with better cognition among healthy adults, more education predicts faster decline in older adults with cognitive impairment. Education may influence cognitive functioning through mechanisms involving brain maintenance (BM: reduced age-related pathology) or cognitive reserve (CR: altered pathology-cognition association). We examined evidence for each mechanism by quantifying main and interaction effects of education within a well-studied pathway involving systolic blood pressure, white matter hyperintensities (WMH), and episodic memory in 2 samples without dementia at the baseline (total N = 1136). There were no effects of education on systolic blood pressure or WMH, suggesting a lack of evidence for BM. In the sample less likely to progress to dementia, education attenuated the effect of WMH on memory at the baseline. In the sample more likely to progress to dementia, education exacerbated this effect at the baseline. These moderations provide evidence for a CR mechanism and are consistent with previous findings of faster decline once CR is depleted.

Spaced learning has been shown consistently to benefit memory compared with massed learning, yet the neural representations and processes underlying the spacing effect are still poorly understood. In particular, two influential models (i.e., the encoding variability hypothesis and the study-phase retrieval hypothesis) could both model behavioral performance very well, but they make opposite hypotheses regarding the spacing effect's neural mechanisms. The present study attempted to provide empirical neural evidence to adjudicate these competing hypotheses. Using spatiotemporal pattern similarity (STPS) analysis of EEG data, this study investigated whether and how repetition lags (massed/short-spaced/long-spaced) modulated the STPS's contribution to episodic memory encoding in male and female human participants. The results revealed that greater item-specific STPS in the right frontal electrodes at 543-727 ms after stimulus onset was associated with better memory performance. More importantly, this STPS was larger under the spaced-learning condition than the massed-learning condition and partially mediated the spacing effect on memory performance. In addition, we found that massed learning was associated with stronger repetition suppression in the N400 component that reflected momentary retrieval strength, but reduced activity in the late positive component that was associated with memory retrieval. These results suggest that spaced learning improves long-term memory by increasing retrieval effort and enhancing the pattern reinstatement of prior neural representations, which may be achieved by reducing the momentary retrieval strength as the extended repetition lags might help to eliminate the residual representation in working memory.SIGNIFICANCE STATEMENT As one of the most ubiquitous and fundamental phenomena in the history of memory research, the spacing effect provides an important window into understanding how enduring memory is formed in the brain and how different practice strategies could modulate these mechanisms to affect memory performance. By leveraging the neural representational analysis on scalp EEG data, the current study provides the first empirical data to show that spaced learning enhances memory by improving the spatiotemporal similarity that occurs at a late time window. Our results support the study-phase retrieval hypothesis but not the encoding variability hypothesis and emphasize the role of neural pattern reinstatement in strengthening memory via repeated study.

Age-related cognitive decline is a public health problem but highly diverse and difficult to predict. We captured nonoverlapping cognitive phenotypes in high-functioning adults and identified baseline factors differentiating trajectories. Three hundred fourteen functionally normal adults (M = 69 y) completed 2+ visits. Participants with sample-based longitudinal slopes in memory or processing speed less than -1 SD were classified as "declining" on that measure; 29 and 50 individuals had slopes less than -1 SD on processing speed or memory, respectively; 2.5% met criteria for both, who were excluded. At baseline, speed decliners demonstrated greater age, inflammation, and cognitive complaints compared with speed-stable adults; memory decliners were more likely to be male and had lower depressive symptoms, gray matter volumes, and white matter hyperintensities compared with memory-stable adults. Baseline speed, TNFα, and cognitive complaints accurately classified 96.3% of future speed decliners; baseline memory, sex, precuneal volume, and white matter hyperintensities accurately classified 88.5% of future memory decliners. There are discrete cognitive aging phenotypes reflecting nonoverlapping vulnerabilities in high-functioning adults. Early markers can predict cognition even within the "normal" spectrum and underscore therapeutic targets.

OBJECTIVE:Prospective memory (the ability to remember to do things) has clear implications for everyday functioning, including employment, in people with severe mental illnesses (SMI). This study aimed to evaluate prospective memory performance and its relationship to real-world functional variables in an employment-seeking sample of people with SMI (Clinical Trial registration number NCT00895258). METHOD:153 individuals with DSM-IV diagnosis of depression (n = 58), bipolar disorder (n = 37), or schizophrenia (n = 58) who were receiving outpatient psychiatric care at a university clinic enrolled in a trial of supported employment and completed a baseline assessment. Prospective memory was measured with the Memory for Intentions Test (MIST); real-world functional status included work history variables, clinical history variables, baseline functional capacity (UCSD Performance-based Skills Assessment-Brief), and work outcomes (weeks worked and wages earned during two years of supported employment). RESULTS:Participants with schizophrenia performed worse on the MIST than did those with affective disorders. Independent of diagnosis, education, and estimated intellectual functioning, prospective memory significantly predicted variance in measures of disability and illness burden (disability benefits, hospitalization history, current functional capacity), and work outcomes over two years of supported employment (weeks worked). CONCLUSIONS:Worse prospective memory appears to be associated with greater illness burden and functional disability in SMI. Mental health clinicians and employment specialists may counsel clients to use compensatory prospective memory strategies to improve work performance and decrease functional disability associated with SMI.

A fundamental question in memory research is how different forms of memory interact. Previous research has shown that people rely on working memory (WM) in short-term recognition tasks; a common view is that episodic memory (EM) only influences performance on these tasks when WM maintenance is disrupted. However, retrieval of memories from EM has been widely observed during brief periods of quiescence, raising the possibility that EM retrievals during maintenance-critically, before a response can be prepared-might affect short-term recognition memory performance even in the absence of distraction. We hypothesized that this influence would be mediated by the lingering presence of reactivated EM content in WM. We obtained support for this hypothesis in three experiments, showing that delay-period EM reactivation introduces incidentally associated information (context) into WM, and that these retrieved associations negatively impact subsequent recognition, leading to substitution errors (Experiment 1) and slowing of accurate responses (Experiment 2). FMRI pattern analysis showed that slowing is mediated by the content of EM reinstatement (Experiment 3). These results expose a previously hidden influence of EM on WM, raising new questions about the adaptive nature of their interaction.

The current study investigated longitudinal change in hippocampal and prefrontal contribution to episodic retrieval. Functional neuroimaging data were collected during an item-context association memory task for children between the ages of 8 and 14 with individuals scanned 1-3 times over the course of 0.75-3.7 years (Timepoint 1 N = 90; Timepoint 2 N = 83, Timepoint 3 N = 75). We investigated developmental changes in functional activation associated with episodic retrieval (correct item-context > incorrect item-context contrast) and asked whether pubertal changes contributed to developmental changes in pattern of activation. Non-linear developmental trajectories were observed. In the hippocampus, activation decreased with age during childhood and then increased into early adolescence. In the dorsolateral prefrontal cortex, activation was largely absent initially, but quickly accelerated over time. Independent of age, changes in pubertal status additionally predicted increases in item-context activation in initially older children, and decreases in initially younger children across both regions and two indicators of puberty: the Pubertal Development Scale and salivary testosterone. These findings suggest that changes in both age and pubertal status uniquely contribute to memory-related activation, and the timing of pubertal onset may play an important role in the neural mechanisms supporting memory retrieval.

Two factors that influence HIV health behaviors and therefore may contribute to gaps in the HIV treatment continuum are poor health-related self-efficacy and HIV-associated neurocognitive disorders (HAND). However, the relationship between HAND and self-efficacy has not been assessed. In an HIV sample, 91 individuals with intact cognition (HAND-) and 40 individuals with HAND (HAND+) were administered a measure of self-efficacy for healthcare interactions with providers. Participants with HAND had significantly lower scores on this measure, which were correlated with poorer episodic and semantic memory performance, as well as self-reported memory symptoms in daily life. Findings suggest that neurocognitive impairment, and particularly memory dysfunction, may play an important role in self-efficacy for healthcare interactions in HIV. Further examination of the interplay between HAND and self-efficacy is warranted as these two factors may be important for the public health goal of identifying targets for improving access, delivery, and maintenance of HIV care.

Multiple Sclerosis (MS), a myelin- targeting autoimmune disease of CNS, targets cognitive abilities in patients. The degree of this dysfunction would be different from one patient to another regarding their disease duration, age, EDSS, and lesion location in brain networks. The cognitive impairment will impact patients’ life adversely. Therefore, the present cross-sectional study aimed to evaluate the verbal episodic memory performance in Iranian Relapsing- Remitting Multiple Sclerosis (RRMS) patients and their healthy counterparts. Due to the susceptibility of women to MS, 35 female patients and 35 age, gender, and education-matched healthy controls were selected based on convenient sampling. The MS patients with Expanded Disability Status Scale (EDSS) scores ≤ 6 were recruited. The Montreal Cognitive Assessment (MoCA) and the California Verbal Learning Test (CVLT-II) were used for screening participants’ cognitive and verbal episodic memory function respectively. MoCA test (Persian version) was used to screen the participants for their cognitive function due to the higher sensitivity of the MoCA to the Mini-Mental State Exam (MMSE) for measuring cognitive function in individuals with MS. CVLT-II assess attention, learning strategies, recall accuracy and consistency, proactive and retroactive interference, recall errors, and recognition. The results revealed that MS patients were significantly impaired in the short and long-term recall as well as recognition list compared to their healthy counterparts. The findings showed that Multiple sclerosis has an adverse impact on verbal episodic memory performance.

Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%[Formula: see text]) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3-neocortical functional connectivity.

ObjectivesChronic stress is associated with poorer age-related cognition, but the mechanisms of this relationship are not well understood. Aging increases expression of activated macrophages, leading to exacerbated immune responses to stressors. We examined the impact of stress and aging on macrophage-related inflammation and cognition in clinically normal adults.MethodsThree hundred eighty clinically normal adults were followed longitudinally (age M = 73 years; visit range: 1-8; M = 2.5 visits). Participants completed the Perceived Stress Scale, a neuropsychological battery, and blood draws. Plasma was analyzed for cytokines related to macrophage function (interleukin 6, tumor necrosis factor alpha, macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta). Linear mixed-effects examined the effects of age, baseline stress, and their interaction predicting macrophage cytokines, adjusting for sex, education, and depressive symptoms. Latent growth curve models assessed the mediating role of macrophage cytokines in the relationship between age and cognition in high or low stress.ResultsBaseline perceived stress interacted with age to predict macrophage cytokines longitudinally. Specifically, high-stress adults demonstrated accelerated age-related elevations in macrophage cytokines across time. Macrophage cytokines negatively tracked with executive functioning longitudinally. Macrophage cytokines mediated 19% of the relationship between age and executive function in high-stress, but not low-stress, adults.ConclusionsOur data provide evidence of accelerated immune aging among individuals with high stress. Elevated macrophage cytokine trajectories mediated the effect of age on executive function only in individuals with high stress, suggesting these constructs may be more tightly linked in elevated stress contexts. Stress interventions are warranted to optimize immune aging, with possible downstream cognitive benefits among even clinically normal adults.

Individuals with HIV disease often evidence deficits in prospective memory (PM), which interfere with daily functioning and increase the risk of suboptimal health behaviours. This study examined the benefits of simple encoding and cueing supports on naturalistic time-based PM in 47 HIV-positive young adults. All participants completed a naturalistic time-based PM task in which they were instructed to text the examiner once per day for seven days at a specified time. Participants were randomised into (1) a Calendaring condition in which they created a calendar event in their mobile telephone for the specified texting time; (2) an Alarm condition in which they programmed an alarm into their mobile telephone for the specified texting time; (3) a Combined calendaring and alarm condition; and (4) a Control condition. Participants in the Combined condition demonstrated significantly better naturalistic PM performance than participants in the Control and Calendaring conditions. Findings indicate that HIV-positive young people may benefit from a combined calendaring and alarm supportive strategy for successful execution of future intentions in daily life.

BackgroundWith the disappointing outcomes of clinical trials on patients with Alzheimer's disease or mild cognitive impairment (MCI), there is increasing attention to understanding cognitive decline in normal elderly individuals, with the goal of identifying subjects who are most susceptible to imminent cognitive impairment.Purpose/hypothesisTo evaluate the potential of cerebral blood flow (CBF) as a biomarker by investigating the relationship between CBF at baseline and cognition at follow-up.Study typeProspective longitudinal study with a 4-year time interval.Population309 healthy subjects aged 20-89 years old.Field strength/sequence3T pseudo-continuous-arterial-spin-labeling MRI.AssessmentCBF at baseline and cognitive assessment at both baseline and follow-up.Statistical testsLinear regression analyses with age, systolic blood pressure, physical activity, and baseline cognition as covariates.ResultsLinear regression analyses revealed that whole-brain CBF at baseline was predictive of general fluid cognition at follow-up. This effect was observed in the older group (age ≥54 years, β = 0.221, P = 0.004), but not in younger or entire sample (β = 0.018, P = 0.867 and β = 0.089, P = 0.098, respectively). Among major brain lobes, frontal CBF had the highest sensitivity in predicting future cognition, with a significant effect observed for fluid cognition (β = 0.244 P = 0.001), episodic memory (β = 0.294, P = 0.001), and reasoning (β = 0.186, P = 0.027). These associations remained significant after accounting for baseline cognition. Voxelwise analysis revealed that medial frontal cortex and anterior cingulate cortex, part of the default mode network (DMN), are among the most important regions in predicting fluid cognition.Data conclusionIn a healthy aging cohort, CBF can predict general cognitive ability as well as specific domains of cognitive function.Level of evidence1 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2018;48:449-458.

Nonhuman research has implicated developmental processes within the hippocampus in the emergence and early development of episodic memory, but methodological challenges have hindered assessments of this possibility in humans. Here, we delivered a previously learned song and a novel song to 2-year-old toddlers during natural nocturnal sleep and, using functional magnetic resonance imaging, found that hippocampal activation was stronger for the learned song compared with the novel song. This was true regardless of whether the song was presented intact or backwards. Toddlers who remembered where and in the presence of which toy character they heard the song exhibited stronger hippocampal activation for the song. The results establish that hippocampal activation in toddlers reflects past experiences, persists despite some alteration of the stimulus, and is associated with behavior. This research sheds light on early hippocampal and memory functioning and offers an approach to interrogate the neural substrates of early memory.

The default mode network (DMN) supports memory functioning and may be sensitive to preclinical Alzheimer's pathology. Little is known, however, about the longitudinal trajectory of this network's intrinsic functional connectivity (FC). In this study, we evaluated longitudinal FC in 111 cognitively normal older human adults (ages 49-87, 46 women/65 men), 92 of whom had at least three task-free fMRI scans (n = 353 total scans). Whole-brain FC and three DMN subnetworks were assessed: (1) within-DMN, (2) between anterior and posterior DMN, and (3) between medial temporal lobe network and posterior DMN. Linear mixed-effects models demonstrated significant baseline age × time interactions, indicating a nonlinear trajectory. There was a trend toward increasing FC between ages 50-66 and significantly accelerating declines after age 74. A similar interaction was observed for whole-brain FC. APOE status did not predict baseline connectivity or change in connectivity. After adjusting for network volume, changes in within-DMN connectivity were specifically associated with changes in episodic memory and processing speed but not working memory or executive functions. The relationship with processing speed was attenuated after covarying for white matter hyperintensities (WMH) and whole-brain FC, whereas within-DMN connectivity remained associated with memory above and beyond WMH and whole-brain FC. Whole-brain and DMN FC exhibit a nonlinear trajectory, with more rapid declines in older age and possibly increases in connectivity early in the aging process. Within-DMN connectivity is a marker of episodic memory performance even among cognitively healthy older adults.SIGNIFICANCE STATEMENT Default mode network and whole-brain connectivity, measured using task-free fMRI, changed nonlinearly as a function of age, with some suggestion of early increases in connectivity. For the first time, longitudinal changes in DMN connectivity were shown to correlate with changes in episodic memory, whereas volume changes in relevant brain regions did not. This relationship was not accounted for by white matter hyperintensities or mean whole-brain connectivity. Functional connectivity may be an early biomarker of changes in aging but should be used with caution given its nonmonotonic nature, which could complicate interpretation. Future studies investigating longitudinal network changes should consider whole-brain changes in connectivity.

The medial temporal lobe (MTL) is an early site of tau accumulation and MTL dysfunction may underlie episodic-memory decline in aging and dementia. Postmortem data indicate that tau pathology in the transentorhinal cortex is common by age 60, whereas spread to neocortical regions and worsening of cognition is associated with β-amyloid (Aβ). We used [18F]AV-1451 and [11C]PiB positron emission tomography, structural MRI, and neuropsychological assessment to investigate how in vivo tau accumulation in temporal lobe regions, Aβ, and MTL atrophy contribute to episodic memory in cognitively normal older adults (n = 83; age, 77 ± 6 years; 58% female). Stepwise regressions identified tau in MTL regions known to be affected in old age as the best predictor of episodic-memory performance independent of Aβ status. There was no interactive effect of MTL tau with Aβ on memory. Higher MTL tau was related to higher age in the subjects without evidence of Aβ. Among temporal lobe subregions, episodic memory was most strongly related to tau-tracer uptake in the parahippocampal gyrus, particularly the posterior entorhinal cortex, which in our parcellation includes the transentorhinal cortex. In subjects with longitudinal MRI and cognitive data (n = 57), entorhinal atrophy mirrored patterns of tau pathology and their relationship with memory decline. Our data are consistent with neuropathological studies and further suggest that entorhinal tau pathology underlies memory decline in old age even without Aβ.SIGNIFICANCE STATEMENT Tau tangles and β-amyloid (Aβ) plaques are key lesions in Alzheimer's disease (AD) but both pathologies also occur in cognitively normal older people. Neuropathological data indicate that tau tangles in the medial temporal lobe (MTL) underlie episodic-memory impairments in AD dementia. However, it remains unclear whether MTL tau pathology also accounts for memory impairments often seen in elderly people and how Aβ affects this relationship. Using tau-specific and Aβ-specific positron emission tomography tracers, we show that in vivo MTL tau pathology is associated with episodic-memory performance and MTL atrophy in cognitively normal adults, independent of Aβ. Our data point to MTL tau pathology, particularly in the entorhinal cortex, as a substrate of age-related episodic-memory loss.

Neurocomputational models have long posited that episodic memories in the human hippocampus are represented by sparse, stimulus-specific neural codes. A concomitant proposal is that when sparse-distributed neural assemblies become active, they suppress the activity of competing neurons (neural sharpening). We investigated episodic memory coding in the hippocampus and amygdala by measuring single-neuron responses from 20 epilepsy patients (12 female) undergoing intracranial monitoring while they completed a continuous recognition memory task. In the left hippocampus, the distribution of single-neuron activity indicated that only a small fraction of neurons exhibited strong responding to a given repeated word and that each repeated word elicited strong responding in a different small fraction of neurons. This finding reflects sparse distributed coding. The remaining large fraction of neurons exhibited a concurrent reduction in firing rates relative to novel words. The observed pattern accords with longstanding predictions that have previously received scant support from single-cell recordings from human hippocampus.

ObjectiveAging is often associated with declines in episodic memory. Reliable tracking of memory requires assessment instruments that are stable over time to better understand changes potentially attributable to neurodegenerative disease. While prior studies support the test-retest reliability of memory instruments over brief intervals, follow-up testing in clinical settings typically occurs at least one-year later. The present study evaluated the long-term test-retest reliability of the California Verbal Learning Test - second edition (CVLT-2), a widely used measure of episodic learning and memory.MethodOne hundred and fifty seven healthy older adults (mean age = 68.47 years; education = 17.28 years) underwent repeat assessment at an average of 1.30 years apart. Participants underwent repeat assessment using either parallel or alternate forms at follow-up. We utilized a standardized regression-based (SRB) approach to determine statistically significant changes in test scores over time.ResultsThis study revealed modest 1-year test-retest correlation coefficients for the primary CVLT-2 measures (range = .57-.69) Results of SRB formulae are provided to assist clinicians with defining clinically relevant cognitive change on the CVLT-2 while controlling for confounding factors.ConclusionsFindings from this study support repeat test administration of the CVLT-2 over longer periods, and may enhance its applicability in determining longitudinal change in memory performance.

ObjectiveIndividuals with schizophrenia have disproportionate memory impairments when encoding relational versus item-specific information, and when using recollection versus familiarity during retrieval. It is unclear whether this pattern is unique to people with chronic schizophrenia, or if it occurs in individuals after a first episode of psychosis (FE), or when at clinical high-risk for psychosis (CHR).MethodsWe administered the Relational and Item-Specific Memory task (RiSE) to 22 CHR, 101 FE, and 58 typically developing (TD) participants. We examined group differences in item and relational encoding, and familiarity-based and recollection-based retrieval using parametric analysis and structural equation modeling (SEM). Longitudinal data allowed us to examine relations between baseline RiSE performance and change in clinical symptoms at 1-year follow-up in the FE group.ResultsGroups did not differ on familiarity. FE and CHR groups were equally impaired on overall recognition accuracy. Although recollection was impaired in both FE and CHR groups following relational encoding, only the FE group had impaired recollection following item encoding. SEM showed atypical relationships between familiarity and recollection, as well as familiarity and item recognition for both the FE and CHR groups. For FE individuals, better baseline recognition accuracy predicted less severe negative symptoms at 1-year follow-up.ConclusionsImpaired relational and recollective memory may reflect neurodevelopmental abnormalities predating conversion to psychosis. These memory deficits appear related to negative symptom changes. In contrast, item specific recollection deficits appear to occur after the development of full psychosis. Familiarity appears to be a relatively preserved memory function across the psychosis spectrum.

Metamemory monitoring, or the ability to introspect on the accuracy of one's memories, improves considerably during childhood, but the underlying neural changes and implications for intellectual development are largely unknown. The present study examined whether cortical changes in key brain areas hypothesized to support metacognition contribute to the development of metamemory monitoring from late childhood into early adolescence. Metamemory monitoring was assessed among 7- to 12-y-old children (n = 145) and adults (n = 31). Children returned for up to two additional assessments at 8 to 14 y of age (n = 120) and at 9 to 15 y of age (n = 107) (n = 347 longitudinal scans). Results showed that metamemory monitoring continues to improve from childhood into adolescence. More pronounced cortical thinning in the anterior insula and a greater increase in the thickness of the ventromedial prefrontal cortex over the three assessment points predicted these improvements. Thus, performance benefits are linked to the unique patterns of regional cortical change during development. Metamemory monitoring at the first time point predicted intelligence at the third time point and vice versa, suggesting parallel development of these abilities and their reciprocal influence. Together, these results provide insights into the neuroanatomical correlates supporting the development of the capacity to self-reflect, and highlight the role of this capacity for general intellectual development.

The ability to exercise patience is important for human functioning. Although it is known that patience can be promoted by using top-down control, or willpower, to override impatient impulses, patience is also malleable-in particular, susceptible to framing effects-in ways that are difficult to explain using willpower alone. So far, the mechanisms underlying framing effects on patience have been elusive. We investigated the role of imagination in these effects. In a behavioral experiment (Experiment 1), a classic framing manipulation (sequence framing) increased self-reported and independently coded imagination during intertemporal choice. In an investigation of neural responses during decision making (Experiment 2), sequence framing increased the extent to which patience was related to activation in brain regions associated with imagination, relative to activation in regions associated with willpower, and increased functional connectivity of brain regions associated with imagination, but not willpower, relative to regions associated with valuation. Our results suggest that sequence framing can increase the role of imagination in decision making without increasing the exertion of willpower.

Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turn associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimer's disease-related protein aggregation as an underlying mechanism of age-related memory impairment.SIGNIFICANCE STATEMENT Alterations in episodic memory and the accumulation of Alzheimer's pathology are common in cognitively normal older adults. However, evidence of pathological effects on episodic memory has largely been limited to β-amyloid (Aβ). Because Aβ and tau often cooccur in older adults, previous research offers an incomplete understanding of the relationship between pathology and episodic memory. With the recent development of in vivo tau PET radiotracers, we show that Aβ and tau are associated with different aspects of memory encoding, leading to aberrant neural activity that is behaviorally detrimental. In addition, our results provide evidence linking Aβ- and tau-associated neural dysfunction to brain atrophy.

Highly Superior Autobiographical Memory (HSAM) is characterised as the ability to accurately recall an exceptional number of experiences and their associated dates from events occurring throughout much of one's lifetime. The source of this ability has only begun to be explored. The present study explores whether other enhanced cognitive processes may be critical influences underlying HSAM abilities. We investigated whether enhanced abilities in the domains of verbal fluency, attention/inhibition, executive functioning, mnemonic discrimination, perception, visual working memory, or the processing of and memory for emotional details might contribute critically to HSAM. The results suggest that superior cognitive functioning is an unlikely basis of HSAM, as only modest advantages were found in only a few tests. In addition, we examined HSAM subjects' memory of the testing episodes. Interestingly, HSAM participants recalled details of their own experiences far better than those experiences that the experimenter shared with them. These findings provide additional evidence that HSAM involves, relatively selectively, recollection of personal, autobiographical material.

The present prospective observational study aimed to identify the existence of successful cognitive agers among a group of well-defined cognitively healthy older adults (n = 354, mean age = 75 years), and to examine baseline individual-level predictors and associated health outcomes over time. Episodic memory (EM) and executive function (EF) composite scores and multiple health outcomes were obtained annually over 5 years. Potential individual-level predictors that were related to Alzheimer's disease pathology or genetic risk, neurodegeneration, and vascular risks were collected at baseline. Three latent classes with matched age and education were identified using growth mixture modeling: a group of participants who exhibited high, stable EM and EF (40.7% of the sample, "successful agers"); a group who had initial high cognitive performance that declined over time (21.2%, "declining agers"); and a group who had normal (EM) or poor (EF) but stable cognitive performance over time (38.1%, "low stable agers"). The group classification predicted significant differences in the incidence of global cognitive impairment, the development of at least one depressive symptom, and everyday functional impairment. Sex, apolipoprotein E allele 4, amyloid-β1-42, and t-tau significantly contributed to the difference in cognitive trajectories between the successful agers and the other two groups. Characterizing successful cognitive agers who are relatively resistant to both tau and amyloid pathology provides potential pathways for promoting successful cognitive aging and preventing cognitive decline.

ObjectivesHippocampal dysfunction has been proposed as a mechanism for memory deficits in schizophrenia. Available evidence suggests that the anterior and posterior hippocampus could be differentially affected. Accordingly, we used fMRI to test the hypothesis that activity in posterior hippocampus is disproportionately reduced in schizophrenia, particularly during spatial memory retrieval.Methods26 healthy participants and 24 patients with schizophrenia from the UC Davis Early Psychosis Program were studied while fMRI was acquired on a 3 Tesla Siemens scanner. During encoding, participants were oriented to critical items through questions about item features (e.g., "Does the lamp have a square shade?") or spatial location (e.g., "Is the lamp on the table next to the couch?"). At test, participants determined whether scenes were changed or unchanged. fMRI analyses contrasted activation in a priori regions of interest (ROI) in anterior and posterior hippocampus during correct recognition of item changes and spatial changes.ResultsAs predicted, patients with schizophrenia exhibited reduced activation in the posterior hippocampus during detection of spatial changes but not during detection of item changes. Unexpectedly, patients exhibited increased activation of anterior hippocampus during detection of item changes. Whole brain analyses revealed reduced fronto-parietal and striatal activation in patients for spatial but not for item change trials.ConclusionsResults suggest a gradient of hippocampal dysfunction in which posterior hippocampus - which is necessary for processing fine-grained spatial relationships - is underactive, and anterior hippocampus - which may process context more globally - is overactive.

UnlabelledCognitive neuroscience of aging studies traditionally target participants age 65 and older. However, epidemiological surveys show that many women report increased forgetfulness earlier in the aging process, as they transition to menopause. In this population-based fMRI study, we stepped back by over a decade to characterize the changes in memory circuitry that occur in early midlife, as a function of sex and women's reproductive stage. Participants (N = 200; age range, 45-55) performed a verbal encoding task during fMRI scanning. Reproductive histories and serologic evaluations were used to determine menopausal status. Results revealed a pronounced impact of reproductive stage on task-evoked hippocampal responses, despite minimal difference in chronological age. Next, we examined the impact of sex and reproductive stage on functional connectivity across task-related brain regions. Postmenopausal women showed enhanced bilateral hippocampal connectivity relative to premenopausal and perimenopausal women. Across women, lower 17β-estradiol concentrations were related to more pronounced alterations in hippocampal connectivity and poorer performance on a subsequent memory retrieval task, strongly implicating sex steroids in the regulation of this circuitry. Finally, subgroup analyses revealed that high-performing postmenopausal women (relative to low and middle performers) exhibited a pattern of brain activity akin to premenopausal women. Together, these findings underscore the importance of considering reproductive stage, not simply chronological age, to identify neuronal and cognitive changes that unfold in the middle decades of life. In keeping with preclinical studies, these human findings suggest that the decline in ovarian estradiol production during menopause plays a significant role in shaping memory circuitry.Significance statementMaintaining intact memory function with age is one of the greatest public health challenges of our time, and women have an increased risk for memory disorders relative to men later in life. We studied adults early in the aging process, as women transition into menopause, to identify neuronal and cognitive changes that unfold in the middle decades of life. Results demonstrate regional and network-level differences in memory encoding-related activity as a function of women's reproductive stage, independent of chronological age. Analyzing data without regard to sex or menopausal status obscured group differences in circuit-level neural strategies associated with successful memory retrieval. These findings suggest that early changes in memory circuitry are evident decades before the age range traditionally targeted by cognitive neuroscience of aging studies.

Associations between co-occurring stimuli are formed in the medial temporal lobe (MTL). Here, we recorded from 508 single and multi-units in the MTL while participants learned and retrieved associations between unfamiliar faces and unfamiliar scenes. Participant's memories for the face-scene pairs were later tested using cued recall and recognition tests. The results show that neurons in the parahippocampal cortex are most likely to respond with changes from baseline firing to these stimuli during both encoding and recognition, and this region showed the greatest proportion of cells showing differential responses depending on the phase of the task. Furthermore, we found that cells in the parahippocampal cortex that responded during both encoding and recognition were more likely to show decreases from baseline firing than cells that were only recruited during recognition, which were more likely to show increases in firing. Since all stimuli shown during recognition were familiar to the patients, these findings suggest that with familiarity, cell responses become more sharply tuned. No neurons in this region, however, were found to be affected by recombining face/scene pairs. Neurons in other MTL regions, particularly the hippocampus, were sensitive to stimulus configurations. Thus, the results support the idea that neurons in the parahippocampal cortex code for features of stimuli and neurons in the hippocampus are more likely to represent their specific configurations.

IntroductionTo further investigate manifestations of episodic memory impairments in adolescents, we examined the role of encoding on recognition of stimuli in conditions designed to emphasize their item-specific versus relational characteristics in a group of 12-18 year olds with autism spectrum disorders (ASD). We also examined how strategic learning and memory processes, verbal abilities, attention, and age were associated with recognition in this group.Materials and methodTwenty two high functioning adolescents with ASD (mean age=15 years; SD=1.8; range=12.2-17.9), and 26 age, gender, and IQ-matched adolescents with typical development (TYP) (mean age=14.7 years; SD=1.9; range=12.3-17.8) completed the Relational and Item-Specific Encoding task (RiSE), the California Verbal Learning Test-Children's Version (CVLT-C), the Wechsler Abbreviated Scales of Intelligence, and the Connors' Parent Rating Scale-Revised. Univariate statistical analyses were performed.ResultsThe ASD group showed poorer performance on strategic memory assessed by the CVLT-C. Surprisingly, on the RiSE, ASD showed poorer discriminability for objects encoded in item-specific versus relational encoding conditions and were more impaired in familiarity (after relational encoding) than in recollection. ASD also did not show the hypothesized association between item and associative recognition and CVLT-C performance found in TYP. Instead, in the ASD group recognition was associated with increased age.ConclusionsFindings from the RiSE task demonstrated that adolescents with ASD do not always exhibit impaired memory for relational information as commonly believed. Instead, memory was worse when cognitive control demands were high, when encoding focused on specific item features, and when familiarity was used to retrieve relational information. Recognition also was better in older participants. This suggests that learning and memory deficits in adolescents with ASD, may not be due primarily to failed relational binding processes in the hippocampus but, rather to disrupted strategic memory and familiarity processes associated with the prefrontal and perirhinal cortices. These findings demonstrate the importance and utility of using well-validated cognitive neuroscience tasks and of considering the ages of participants when comparing the neural underpinnings of different memory processes in both typical and atypical populations.

The goal of the present study was to investigate whether hippocampal contribution to episodic memory retrieval varies as a function of age (8-9 versus 10-11 versus adults), performance levels (high versus low) and hippocampal sub-region (head, body, tail). We examined fMRI data collected during episodic retrieval from a large sample (N=126). Participants judged whether a stimulus had been encoded previously, and, if so, which of three scenes it had been paired with (i.e., source judgment). For 8- to 9-years-olds as well as low-performing 10- to 11-year-olds, hippocampal activations did not reliably differentiate between trials on which item-scene associations were correctly recalled (correct source), incorrectly recalled (incorrect source), or trials on which the item was forgotten (miss trials). For high-performing 10-11-year olds and low-performing adults, selective hippocampal activation was observed for correct source relative to incorrect source and miss trials; this effect was observed across the entire hippocampus. For high-performing adults, hippocampal activation also distinguished between correct and incorrect source trialsl, but only in the hippocampal head, suggesting that good performance in adults is associated with more focal hippocampal recruitment. Thus, both age and performance are important factors for understanding the development of memory and hippocampal function.

Events are often remembered as having occurred in a specific order, but almost nothing is known about how the brain encodes this temporal information. It is commonly assumed that temporal information is encoded via a single mechanism, based either on the temporal context in which the event occurred or inferred from the strength of the memory trace itself. By analyzing time-dependent changes in activity patterns, we show that the distinctiveness of contextual representations in the hippocampus and anterior and medial prefrontal cortex was associated with accurate recency memory. In contrast, overall activation in the perirhinal and lateral prefrontal cortices predicted whether an object would be judged more recent, regardless of accuracy. These results demonstrate that temporal information was encoded through at least two complementary neural mechanisms.

Recollection reflects the retrieval of complex qualitative information about prior events. Recently, Harlow and Donaldson developed a method for separating the probability of recollection success from the precision of the mnemonic information retrieved. In the current study, we ask if these properties are separable on the basis of subjective reports-are participants aware of these two aspects of recollection and can they reliably report on them? Participants studied words paired with a location on a circle outline, and at test recalled the location for a given word as accurately as possible. Additionally, participants provided separate subjective ratings of recollection confidence and recollection precision. The results indicated that participants either recollected the target location with considerable (but variable) precision or retrieved no accurate location information at all. Importantly, recollection confidence reliably predicted whether locations were recollected, while precision ratings instead reflected the precision of the locations retrieved. The results demonstrate the experimental separability of recollection success and precision, and highlight the importance of disentangling these two different aspects of recollection when examining episodic memory.

Although it is generally accepted that ageing is associated with recollection impairments, there is considerable disagreement surrounding how healthy ageing influences familiarity-based recognition. One factor that might contribute to the mixed findings regarding age differences in familiarity is the estimation method used to quantify the two mnemonic processes. Here, this issue is examined by having a group of older adults (N = 39) between 40 and 81 years of age complete remember/know (RK), receiver-operating characteristic (ROC) and process dissociation (PD) recognition tests. Estimates of recollection, but not familiarity, showed a significant negative correlation with chronological age. Inconsistent with previous findings, the estimation method did not moderate the relationship between age and estimates of recollection and familiarity. In a final analysis, recollection and familiarity were estimated as latent factors in a confirmatory factor analysis that modelled the covariance between measures of free recall and recognition, and the results converged with the results from the RK, PD and ROC tasks. These results are consistent with the hypothesis that episodic memory declines in older adults are primary driven by recollection deficits, and also suggest that the estimation method plays little to no role in age-related decreases in familiarity.

Functional magnetic resonance imaging (fMRI) was employed to examine the effects of a study task manipulation on pre-stimulus activity in the hippocampus predictive of later successful recollection. Eighteen young participants were scanned while making either animacy or syllable judgments on visually presented study words. Cues presented before each word denoted which judgment should be made. Following the study phase, a surprise recognition memory test was administered in which each test item had to be endorsed as "Remembered," "Known," or "New." As expected, "deep" animacy judgments led to better memory for study items than did "shallow" syllable judgments. In both study tasks, pre-stimulus subsequent recollection effects were evident in the interval between the cue and the study item in bilateral anterior hippocampus. However, the direction of the effects differed according to the study task: whereas pre-stimulus hippocampal activity on animacy trials was greater for later recollected items than items judged old on the basis of familiarity (replicating prior findings), these effects reversed for syllable trials. We propose that the direction of pre-stimulus hippocampal subsequent memory effects depends on whether an optimal pre-stimulus task set facilitates study processing that is conducive or unconducive to the formation of contextually rich episodic memories.