Mnemonic But Not Contextual Feedback Signals Defy Dedifferentiation in the Aging Early Visual Cortex.

Perception is an intricate interplay between feedforward visual input and internally generated feedback signals that comprise concurrent contextual and time-distant mnemonic (episodic and semantic) information. Yet, an unresolved question is how the composition of feedback signals changes across the lifespan and to what extent feedback signals undergo age-related dedifferentiation, that is, a decline in neural specificity. Previous research on this topic has focused on feedforward perceptual representation and episodic memory reinstatement, suggesting reduced fidelity of neural representations at the item and category levels. In this fMRI study, we combined an occlusion paradigm that filters feedforward input to the visual cortex and multivariate analysis techniques to investigate the information content in cortical feedback, focusing on age-related differences in its composition. We further asked to what extent differentiation in feedback signals (in the occluded region) is correlated to differentiation in feedforward signals. Comparing younger (18-30 years) and older female and male adults (65-75 years), we found that contextual but not mnemonic feedback was prone to age-related dedifferentiation. Semantic feedback signals were even better differentiated in older adults, highlighting the growing importance of generalized knowledge across ages. We also found that differentiation in feedforward signals was correlated with differentiation in episodic but not semantic feedback signals. Our results provide evidence for age-related adjustments in the composition of feedback signals and underscore the importance of examining dedifferentiation in aging for both feedforward and feedback processing.

Deficits in memory metacognitive efficiency in late adulthood are related to distinct brain profile.

The tendency of falsely remembering events that did not happen in the past increases with age. This is particularly evident in cases in which features presented at study are re-presented at test in a recombined constellation (termed rearranged pairs). Interestingly, older adults also express high confidence in such false memories, a tendency that may indicate reduced metacognitive efficiency. Within an existing cohort study, we aimed at investigating age-related differences in memory metacognitive efficiency (as measured by meta d' ratio) in a sample of 1522 older adults and 397 young adults. The analysis showed an age-related deficit in metacognition which was more pronounced for rearranged pairs than for new pairs. We then explored associations between cortical thickness and memory metacognitive efficiency for rearranged pairs in a subsample of 231 older adults. By using partial least square analysis, we found that a multivariate profile composed by ventromedial prefrontal cortex, insula, and parahippocampal cortex was uniquely associated with between-person differences in memory metacognitive efficiency. These results suggest that the impairment in memory metacognitive efficiency for false alarms is a distinct age-related deficit, above and beyond a general age-related decline in memory discrimination, and that it is associated with brain regions involved in metacognitive processes.

Concurrent contextual and time-distant mnemonic information co-exist as feedback in the human visual cortex.

Efficient processing of the visual environment necessitates the integration of incoming sensory evidence with concurrent contextual inputs and mnemonic content from our past experiences. To examine how this integration takes place in the brain, we isolated different types of feedback signals from the neural patterns of non-stimulated areas of the early visual cortex in humans (i.e., V1 and V2). Using multivariate pattern analysis, we showed that both contextual and time-distant information, coexist in V1 and V2 as feedback signals. In addition, we found that the extent to which mnemonic information is reinstated in V1 and V2 depends on whether the information is retrieved episodically or semantically. Critically, this reinstatement was independent on the retrieval route in the object-selective cortex. These results demonstrate that our early visual processing contains not just direct and indirect information from the visual surrounding, but also memory-based predictions.

Disentangling age and schooling effects on inhibitory control development: An fNIRS investigation.

Children show marked improvements in executive functioning (EF) between 4 and 7 years of age. In many societies, this time period coincides with the start of formal school education, in which children are required to follow rules in a structured environment, drawing heavily on EF processes such as inhibitory control. This study aimed to investigate the longitudinal development of two aspects of inhibitory control, namely response inhibition and response monitoring and their neural correlates. Specifically, we examined how their longitudinal development may differ by schooling experience, and their potential significance in predicting academic outcomes. Longitudinal data were collected in two groups of children at their homes. At T1, all children were roughly 4.5 years of age and neither group had attended formal schooling. One year later at T2, one group (P1, n = 40) had completed one full year of schooling while the other group (KG, n = 40) had stayed in kindergarten. Behavioural and brain activation data (measured with functional near-infrared spectroscopy, fNIRS) in response to a Go/No-Go task and measures of academic achievement were collected. We found that P1 children, compared to KG children, showed a greater change over time in activation related to response monitoring in the bilateral frontal cortex. The change in left frontal activation difference showed a small positive association with math performance. Overall, the school environment is important in shaping the development of the brain functions underlying the monitoring of one own's performance.

Neural Correlates of Successful Memory Encoding in Kindergarten and Early Elementary School Children: Longitudinal Trends and Effects of Schooling.

From age 5 to 7, there are remarkable improvements in children's cognitive abilities ("5-7 shift"). In many countries, including Germany, formal schooling begins in this age range. It is, thus, unclear to what extent exposure to formal schooling contributes to the "5-7 shift." In this longitudinal study, we investigated if schooling acts as a catalyst of maturation. We tested 5-year-old children who were born close to the official cutoff date for school entry and who were still attending a play-oriented kindergarten. One year later, the children were tested again. Some of the children had experienced their first year of schooling whereas the others had remained in kindergarten. Using 2 functional magnetic resonance imaging tasks that assessed episodic memory formation (i.e., subsequent memory effect), we found that children relied strongly on the medial temporal lobe (MTL) at both time points but not on the prefrontal cortex (PFC). In contrast, older children and adults typically show subsequent memory effects in both MTL and PFC. Both children groups improved in their memory performance, but there were no longitudinal changes nor group differences in neural activation. We conclude that successful memory formation in this age group relies more heavily on the MTL than in older age groups.

Home assessment of visual working memory in pre-schoolers reveals associations between behaviour, brain activation and parent reports of life stress.

Visual working memory (VWM) is reliably predictive of fluid intelligence and academic achievements. The objective of the current study was to investigate individual differences in pre-schoolers' VWM processing by examining the association between behaviour, brain function and parent-reported measures related to the child's environment. We used a portable functional near-infrared spectroscopy system to record from the frontal and parietal cortices of 4.5-year-old children (N = 74) as they completed a colour change-detection VWM task in their homes. Parents were asked to fill in questionnaires on temperament, academic aspirations, home environment and life stress. Children were median-split into a low-performing (LP) and a high-performing (HP) group based on the number of items they could successfully remember during the task. LPs increasingly activated channels in the left frontal and bilateral parietal cortices with increasing load, whereas HPs showed no difference in activation. Our findings suggest that LPs recruited more neural resources than HPs when their VWM capacity was challenged. We employed mediation analyses to examine the association between the difference in activation between the highest and lowest loads and variables from the questionnaires. The difference in activation between loads in the left parietal cortex partially mediated the association between parent-reported stressful life events and VWM performance. Critically, our findings show that the association between VWM capacity, left parietal activation and indicators of life stress is important to understand the nature of individual differences in VWM in pre-school children.

Oscillatory Mechanisms of Successful Memory Formation in Younger and Older Adults Are Related to Structural Integrity.

We studied oscillatory mechanisms of memory formation in 48 younger and 51 older adults in an intentional associative memory task with cued recall. While older adults showed lower memory performance than young adults, we found subsequent memory effects (SME) in alpha/beta and theta frequency bands in both age groups. Using logistic mixed effects models, we investigated whether interindividual differences in structural integrity of key memory regions could account for interindividual differences in the strength of the SME. Structural integrity of inferior frontal gyrus (IFG) and hippocampus was reduced in older adults. SME in the alpha/beta band were modulated by the cortical thickness of IFG, in line with its hypothesized role for deep semantic elaboration. Importantly, this structure-function relationship did not differ by age group. However, older adults were more frequently represented among the participants with low cortical thickness and consequently weaker SME in the alpha band. Thus, our results suggest that differences in the structural integrity of the IFG contribute not only to interindividual, but also to age differences in memory formation.

Neural Pattern Similarity Differentially Relates to Memory Performance in Younger and Older Adults.

Age-related memory decline is associated with changes in neural functioning, but little is known about how aging affects the quality of information representation in the brain. Whereas a long-standing hypothesis of the aging literature links cognitive impairments to less distinct neural representations in old age ("neural dedifferentiation"), memory studies have shown that overlapping neural representations of different studied items are beneficial for memory performance. In an electroencephalography (EEG) study, we addressed the question whether distinctiveness or similarity between patterns of neural activity supports memory differentially in younger and older adults. We analyzed between-item neural pattern similarity in 50 younger (19-27 years old) and 63 older (63-75 years old) male and female human adults who repeatedly studied and recalled scene-word associations using a mnemonic imagery strategy. We compared the similarity of spatiotemporal EEG frequency patterns during initial encoding in relation to subsequent recall performance. The within-person association between memory success and pattern similarity differed between age groups: For older adults, better memory performance was linked to higher similarity early in the encoding trials, whereas young adults benefited from lower similarity between earlier and later periods during encoding, which might reflect their better success in forming unique memorable mental images of the joint picture-word pairs. Our results advance the understanding of the representational properties that give rise to subsequent memory, as well as how these properties may change in the course of aging.SIGNIFICANCE STATEMENT Declining memory abilities are one of the most evident limitations for humans when growing older. Despite recent advances of our understanding of how the brain represents and stores information in distributed activation patterns, little is known about how the quality of information representation changes during aging and thus affects memory performance. We investigated how the similarity between neural representations relates to subsequent memory in younger and older adults. We present novel evidence that the interaction of pattern similarity and memory performance differs between age groups: Older adults benefited from higher similarity during early encoding, whereas young adults benefited from lower similarity between early and later encoding. These results provide insights into the nature of memory and age-related memory deficits.

Effects of stress on 6- and 7-year-old children's emotional memory differs by gender.

Understanding effects of emotional valence and stress on children's memory is important for educational and legal contexts. This study disentangled the effects of emotional content of to-be-remembered information (i.e., items differing in emotional valence and arousal), stress exposure, and associated cortisol secretion on children's memory. We also examined whether girls' memory is more affected by stress induction. A total of 143 6- and 7-year-old children were randomly allocated to the Trier Social Stress Test for Children (n = 103) or a control condition (n = 40). At 25 min after stressor onset, children incidentally encoded 75 objects varying in emotional valence (crossed with arousal) together with neutral scene backgrounds. We found that response bias corrected memory was worse for low-arousing negative items than for neutral and positive items, with the latter two categories not being different from each other. Whereas boys' memory was largely unaffected by stress, girls in the stress condition showed worse memory for negative items, especially the low-arousing ones, than girls in the control condition. Girls, compared with boys, reported higher subjective stress increases following stress exposure and had higher cortisol stress responses. Whereas a higher cortisol stress response was associated with better emotional memory in girls in the stress condition, boys' memory was not associated with their cortisol secretion. Taken together, our study suggests that 6- and 7-year-old children, more so girls, show memory suppression for negative information. Girls' memory for negative information, compared with that of boys, is also more strongly modulated by stress experience and the associated cortisol response.

Hippocampal maturity promotes memory distinctiveness in childhood and adolescence.

Adaptive learning systems need to meet two complementary and partially conflicting goals: detecting regularities in the world versus remembering specific events. The hippocampus (HC) keeps a fine balance between computations that extract commonalities of incoming information (i.e., pattern completion) and computations that enable encoding of highly similar events into unique representations (i.e., pattern separation). Histological evidence from young rhesus monkeys suggests that HC development is characterized by the differential development of intrahippocampal subfields and associated networks. However, due to challenges in the in vivo investigation of such developmental organization, the ontogenetic timing of HC subfield maturation remains controversial. Delineating its course is important, as it directly influences the fine balance between pattern separation and pattern completion operations and, thus, developmental changes in learning and memory. Here, we relate in vivo, high-resolution structural magnetic resonance imaging data of HC subfields to behavioral memory performance in children aged 6-14 y and in young adults. We identify a multivariate profile of age-related differences in intrahippocampal structures and show that HC maturity as captured by this pattern is associated with age differences in the differential encoding of unique memory representations.

Clinical Phenotype of LRRK2 R1441C in 2 Chinese Sisters.

Pathogenic and risk variants in the LRRK2 gene are among the main genetic contributors to Parkinson's disease (PD) worldwide, and LRRK2-targeted therapies for patients with PARK-LRRK2are now entering clinical trials. However, in contrast to the LRRK2 G2019S mutation commonly found in Caucasians, North-African Arabs, and Ashkenazi Jews, relatively little is known about other causative LRRK2 mutations, and data on genotype-phenotype correlations are largely lacking. This report is from an ongoing multicentre study in which next-generation sequencing-based PD gene panel testing has so far been conducted on 499 PD patients of various ethnicities from Malaysia. We describe 2 sisters of Chinese ancestry with PD who carry the R1441C mutation in LRRK2 (which in Asians has been reported in only 2 Chinese patients previously), and highlight interesting clinical observations made over a decade of close follow-up. We further explored the feasibility of using a brief, expert-administered rating scale (the Clinical Impression of Severity Index; CISI-PD) to capture data on global disease severity in a large (n = 820) unselected cohort of PD patients, including severely disabled individuals typically excluded from research studies. All patients in this study were managed and evaluated by the same PD neurologist, and these data were used to make broad comparisons between the monogenic PD cases versus the overall "real world" PD cohort. This report contributes to the scarce literature on R1441C PARK-LRRK2, offering insights into natural history and epidemiological aspects, and provides support for the application of a simple and reliable clinical tool that can improve the inclusion of under-represented patient groups in PD research.

Optimization and validation of automated hippocampal subfield segmentation across the lifespan.

Automated segmentation of hippocampal (HC) subfields from magnetic resonance imaging (MRI) is gaining popularity, but automated procedures that afford high speed and reproducibility have yet to be extensively validated against the standard, manual morphometry. We evaluated the concurrent validity of an automated method for hippocampal subfields segmentation (automated segmentation of hippocampal subfields, ASHS; Yushkevich et al., ) using a customized atlas of the HC body, with manual morphometry as a standard. We built a series of customized atlases comprising the entorhinal cortex (ERC) and subfields of the HC body from manually segmented images, and evaluated the correspondence of automated segmentations with manual morphometry. In samples with age ranges of 6-24 and 62-79 years, 20 participants each, we obtained validity coefficients (intraclass correlations, ICC) and spatial overlap measures (dice similarity coefficient) that varied substantially across subfields. Anterior and posterior HC body evidenced the greatest discrepancies between automated and manual segmentations. Adding anterior and posterior slices for atlas creation and truncating automated output to the ranges manually defined by multiple neuroanatomical landmarks substantially improved the validity of automated segmentation, yielding ICC above 0.90 for all subfields and alleviating systematic bias. We cross-validated the developed atlas on an independent sample of 30 healthy adults (age 31-84) and obtained good to excellent agreement: ICC (2) = 0.70-0.92. Thus, with described customization steps implemented by experts trained in MRI neuroanatomy, ASHS shows excellent concurrent validity, and can become a promising method for studying age-related changes in HC subfield volumes.

Knowledge Acquisition during Exam Preparation Improves Memory and Modulates Memory Formation.

UNLABELLED: According to the schema-relatedness hypothesis, new experiences that make contact with existing schematic knowledge are more easily encoded and remembered than new experiences that do not. Here we investigate how real-life gains in schematic knowledge affect the neural correlates of episodic encoding, assessing medical students 3 months before and immediately after their final exams. Human participants were scanned with functional magnetic resonance imaging while encoding associative information that varied in relatedness to medical knowledge (face-diagnosis vs face-name pairs). As predicted, improvements in memory performance over time were greater for face-diagnosis pairs (high knowledge-relevance) than for face-name pairs (low knowledge-relevance). Improved memory for face-diagnosis pairs was associated with smaller subsequent memory effects in the anterior hippocampus, along with increased functional connectivity between the anterior hippocampus and left middle temporal gyrus, a region important for the retrieval of stored conceptual knowledge. The decrease in the anterior hippocampus subsequent memory effect correlated with knowledge accumulation, as independently assessed by a web-based learning platform with which participants studied for their final exam. These findings suggest that knowledge accumulation sculpts the neural networks associated with successful memory formation, and highlight close links between knowledge acquired during studying and basic neurocognitive processes that establish durable memories. SIGNIFICANCE STATEMENT: In a sample of medical students, we tracked knowledge accumulation via a web-based learning platform and investigated its effects on memory formation before and after participants' final medical exam. Knowledge accumulation led to significant gains in memory for knowledge-related events and predicted a selective decrease in hippocampal activation for successful memory formation. Furthermore, enhanced functional connectivity was found between hippocampus and semantic processing regions. These findings (1) demonstrate that knowledge facilitates binding in the hippocampus by enhancing its communication with the association cortices, (2) highlight close links between knowledge induced in the real world and basic neurocognitive processes that establish durable memories, and (3) exemplify the utility of combining laboratory-based cognitive neuroscience research with real-world educational technology for the study of memory.

Memory integration in humans with hippocampal lesions.

Adaptive behavior frequently depends on inference from past experience. Recent studies suggest that the underlying process of integrating related memories may depend on interaction between hippocampus and prefrontal cortex. Here, we investigated how hippocampal damage affects memory integration. Subjects with mediotemporal lesions and healthy controls learned a set of overlapping AB- and BC-associations (object-face- and face-object pairs) and were then tested for memory of these associations ("direct" trials) and of inferential AC-associations ("indirect" trials). The experiment consisted of four encoding/retrieval cycles. In direct trials, performance of patients and controls was similar and stable across cycles. By contrast, in indirect trials, patients and controls showed distinct patterns of behavior. Whereas patients and controls initially showed only minor differences, controls increased performance across subsequent cycles, while patient performance decreased to chance level. Further analysis suggested that this deficit was not merely a consequence of impaired associative memory but rather resulted from an additional hippocampal contribution to memory integration. Our findings further suggest that contextual factors modulate this contribution. Patient deficits in more complex memory-guided behavior may depend on the flexible interaction of hippocampus-dependent and -independent mechanisms of memory integration.

Does One Year of Schooling Improve Children's Cognitive Control and Alter Associated Brain Activation?

The "5-to-7-year shift" refers to the remarkable improvements observed in children's cognitive abilities during this age range, particularly in their ability to exert control over their attention and behavior-that is, their executive functioning. As this shift coincides with school entry, the extent to which it is driven by brain maturation or by exposure to formal schooling is unclear. In this longitudinal study, we followed 5-year-olds born close to the official cutoff date for entry into first grade and compared those who subsequently entered first grade that year with those who remained in kindergarten, which is more play oriented. The first graders made larger improvements in accuracy on an executive-function test over the year than did the kindergartners. In an independent functional MRI task, we found that the first graders, compared with the kindergartners, exhibited a greater increase in activation of right posterior parietal cortex, a region previously implicated in sustained attention; increased activation in this region was correlated with the improvement in accuracy. These results reveal how the environmental context of formal schooling shapes brain mechanisms underlying improved focus on cognitively demanding tasks.

Neural activation patterns during retrieval of schema-related memories: differences and commonalities between children and adults.

Schemas represent stable properties of individuals' experiences, and allow them to classify new events as being congruent or incongruent with existing knowledge. Research with adults indicates that the prefrontal cortex (PFC) is involved in memory retrieval of schema-related information. However, developmental differences between children and adults in the neural correlates of schema-related memories are not well understood. One reason for this is the inherent confound between schema-relevant experience and maturation, as both are related to time. To overcome this limitation, we used a novel paradigm that experimentally induces, and then probes for, task-relevant knowledge during encoding of new information. Thirty-one children aged 8-12 years and 26 young adults participated in the experiment. While successfully retrieving schema-congruent events, children showed less medial PFC activity than adults. In addition, medial PFC activity during successful retrieval correlated positively with children's age. While successfully retrieving schema-incongruent events, children showed stronger hippocampus (HC) activation as well as weaker connectivity between the striatum and the dorsolateral PFC than adults. These findings were corroborated by an exploratory full-factorial analysis investigating age differences in the retrieval of schema-congruent versus schema-incongruent events, comparing the two conditions directly. Consistent with the findings of the separate analyses, two clusters, one in the medial PFC, one in the HC, were identified that exhibited a memory × congruency × age group interaction. In line with the two-component model of episodic memory development, the present findings point to an age-related shift from a more HC-bound processing to an increasing recruitment of prefrontal brain regions in the retrieval of schema-related events.

Training-induced changes in subsequent-memory effects: No major differences among children, younger adults, and older adults.

The neural correlates of encoding mode, or the state of forming new memory episodes, have been found to change with age and mnemonic training. However, it is unclear whether neural correlates of encoding success, termed subsequent-memory (SM) effects, also differ by age and mnemonic skill. In a multi-session training study, we investigated whether SM effects are altered by instruction and training in a mnemonic skill, and whether such alterations differ among children, younger adults, and older adults. Before and after strategy training, fMRI data were collected while participants were memorizing word pairs. In all age groups, participants receiving training showed greater performance gains than control group participants. Analysis of task-relevant regions showed training-induced reductions in SM effects in left frontal regions. Reductions in SM effects largely generalized across age and primarily reflected greater training-induced activation increases for omissions than for remembered items, indicating that training resulted in more consistent use of the mnemonic strategy. The present results reveal no major age differences in SM effects in children, younger adults, and older adults.

Behavioral correlates of changes in hippocampal gray matter structure during acquisition of foreign vocabulary.

Experience can affect human gray matter volume. The behavioral correlates of individual differences in such brain changes are not well understood. In a group of Swedish individuals studying Italian as a foreign language, we investigated associations among time spent studying, acquired vocabulary, baseline performance on memory tasks, and gray matter changes. As a way of studying episodic memory training, the language learning focused on acquiring foreign vocabulary and lasted for 10weeks. T1-weighted structural magnetic resonance imaging and cognitive testing were performed before and after the studies. Learning behavior was monitored via participants' use of a smartphone application dedicated to the study of vocabulary. A whole-brain analysis showed larger changes in gray matter structure of the right hippocampus in the experimental group (N=33) compared to an active control group (N=23). A first path analyses revealed that time spent studying rather than acquired knowledge significantly predicted change in gray matter structure. However, this association was not significant when adding performance on baseline memory measures into the model, instead only the participants' performance on a short-term memory task with highly similar distractors predicted the change. This measure may tap similar individual difference factors as those involved in gray matter plasticity of the hippocampus.

Differences in the neural signature of remembering schema-congruent and schema-incongruent events.

New experiences are remembered in relation to one's existing world knowledge or schema. Recent research suggests that the medial prefrontal cortex (mPFC) supports the retrieval of schema-congruent information. However, the neural mechanisms supporting memory for information violating a schema have remained elusive, presumably because incongruity is inherently ambiguous in tasks that rely on world knowledge. We present a novel paradigm that experimentally induces hierarchically structured knowledge to directly contrast neural correlates that contribute to the successful retrieval of schema-congruent versus schema-incongruent information. We hypothesize that remembering incongruent events engages source memory networks including the lateral PFC. In a sample of young adults, we observed enhanced activity in the dorsolateral PFC (DLPFC), in the posterior parietal cortex, and in the striatum when successfully retrieving incongruent events, along with enhanced connectivity between DLPFC and striatum. In addition, we found enhanced mPFC activity for successfully retrieved events that are congruent with the induced schema, presumably reflecting a role of the mPFC in biasing retrieval towards schema-congruent episodes. We conclude that medial and lateral PFC contributions to memory retrieval differ by schema congruency, and highlight the utility of the new experimental paradigm for addressing developmental research questions.

Deficits in process-specific prefrontal and hippocampal activations contribute to adult age differences in episodic memory interference.

The ability to distinguish currently relevant from familiar but irrelevant memories is important in everyday life. We used functional magnetic resonance imaging to examine the neural correlates of age differences in the ability to withstand interference from similar past events. Younger and older adults worked on a continuous recognition task consisting of 3 consecutive runs. Each run was composed of the same set of word pairs, and participants were instructed to recognize word pair repetitions within runs. The monitoring demands associated with rejecting familiar, but currently irrelevant information were assumed to increase over consecutive runs. Over runs, older, but not younger adults showed decline in memory performance, whereas younger, but not older adults showed increasing engagement of anterior prefrontal cortex. Individual differences in cortical thickness and task-related activation of anterior prefrontal areas predicted performance differences within and across age groups. Compared with younger adults, older adults also showed a reduced hippocampal response to novel associations of familiar stimuli. We conclude that monitoring deficits due to impaired involvement of prefrontal regions and reduced hippocampal responses to associative novelty contribute to aging-related deficits in disambiguating the contextual information of familiar events.