Developmental refinements to neural attentional state during semantic memory retrieval through adolescence.

Despite the fact that attention undergoes protracted development, little is known about how it may support memory refinements in childhood and adolescence. Here, we asked whether people differentially focus their attention on semantic or perceptual information over development during memory retrieval. First, we trained a multivoxel classifier to characterize whole-brain neural patterns reflecting semantic versus perceptual attention in a cued attention task. We then used this classifier to quantify how attention varied in a separate dataset in which children, adolescents, and adults retrieved autobiographical, semantic, and episodic memories. All age groups demonstrated a semantic attentional bias during memory retrieval, with significant age differences in this bias during the semantic task. Trials began with a preparatory picture cue followed by a retrieval question, which allowed us to ask whether attentional biases varied by trial period. Adults showed a semantic bias earlier during the picture cues, whereas adolescents showed this bias during the question. Adults and adolescents also engaged different brain regions-superior parietal cortex and ventral visual regions, respectively-during preparatory picture cues. Our results demonstrate that retrieval-related attention undergoes refinement beyond childhood. These findings suggest that alongside expanding semantic knowledge, attention-related changes may support the maturation of factual knowledge retrieval.

Anterior Hippocampal Engagement during Memory Formation Predicts Subsequent False Recognition of Similar Experiences.

People better remember experiences when they orient to meaning over surface-level perceptual features. Such an orientation-related memory boost has been associated with engagement of both hippocampus (HPC) and neocortex during encoding. However, less is known about the neural mechanisms by which a cognitive orientation toward meaning might also promote memory errors, with one open question being whether the HPC-a region traditionally implicated in precise memory formation-also contributes to behavioral imprecision. We used fMRI to characterize encoding-phase signatures as people oriented toward the meaning (story) versus perceptual style (artist) of storybook-style illustrations and then linked them to subsequent true and false memories. We found that story and artist orientation tasks were each associated with both unique univariate profiles and consistent neural states defined using multivoxel patterns. Linking these neural signatures to behavior, we found that greater medial pFC activation and alignment of neural patterns to the story (but not artist) state was related to subsequent memory success on a trial-by-trial basis. Moreover, among successfully remembered experiences, greater anterior HPC engagement at encoding was associated with a higher likelihood of related false recognitions, consistent with the encoding of broad traces in this region. Interestingly, these effects did not reliably vary by cued orientation. These results suggest that, irrespective of the cued encoding orientation, neocortical and hippocampal mechanisms associated with orienting to meaning (story) over perceptual (artist) features may support memory, with the formation of generalizable memories being a specialty of anterior HPC.

Development of human hippocampal subfield microstructure and relation to associative inference.

The hippocampus is a complex brain structure composed of subfields that each have distinct cellular organizations. While the volume of hippocampal subfields displays age-related changes that have been associated with inference and memory functions, the degree to which the cellular organization within each subfield is related to these functions throughout development is not well understood. We employed an explicit model testing approach to characterize the development of tissue microstructure and its relationship to performance on 2 inference tasks, one that required memory (memory-based inference) and one that required only perceptually available information (perception-based inference). We found that each subfield had a unique relationship with age in terms of its cellular organization. While the subiculum (SUB) displayed a linear relationship with age, the dentate gyrus (DG), cornu ammonis field 1 (CA1), and cornu ammonis subfields 2 and 3 (combined; CA2/3) displayed nonlinear trajectories that interacted with sex in CA2/3. We found that the DG was related to memory-based inference performance and that the SUB was related to perception-based inference; neither relationship interacted with age. Results are consistent with the idea that cellular organization within hippocampal subfields might undergo distinct developmental trajectories that support inference and memory performance throughout development.

Time separating spatial memories does not influence their integration in humans.

Humans can navigate through similar environments-like grocery stores-by integrating across their memories to extract commonalities or by differentiating between each to find idiosyncratic locations. Here, we investigate one factor that might impact whether two related spatial memories are integrated or differentiated: Namely, the temporal delay between experiences. Rodents have been shown to integrate memories more often when they are formed within 6 hours of each other. To test if this effect influences how humans spontaneously integrate spatial memories, we had 131 participants search for rewards in two similar virtual environments. We separated these learning experiences by either 30 minutes, 3 hours, or 27 hours. Memory integration was assessed three days later. Participants were able to integrate and simultaneously differentiate related memories across experiences. However, neither memory integration nor differentiation was modulated by temporal delay, in contrast to previous work. We further showed that both the levels of initial memory reactivation during the second experience and memory generalization to novel environments were comparable across conditions. Moreover, perseveration toward the initial reward locations during the second experience was related positively to integration and negatively to differentiation-but again, these associations did not vary by delay. Our findings identify important boundary conditions on the translation of rodent memory mechanisms to humans, motivating more research to characterize how even fundamental memory mechanisms are conserved and diverge across species.

Memories of structured input become increasingly distorted across development.

Trajectories of cognitive and neural development suggest that, despite early emergence, the ability to extract environmental patterns changes across childhood. Here, 5- to 9-year-olds and adults (N = 211, 110 females, in a large Canadian city) completed a memory test assessing what they remembered after watching a stream of shape triplets: the particular sequence in which the shapes occurred and/or their group-level structure. After accounting for developmental improvements in overall memory, all ages remembered specific transitions, while memory for group membership was only observed in older children and adults (age by test-type interaction η2 = .05). Thus, while young children form memories for specifics of structured experience, memory for derived associations is refined later-underscoring that adults and young children form different memories despite identical experience.

Learning strategy differentially impacts memory connections in children and adults.

Even once children can accurately remember their experiences, they nevertheless struggle to use those memories in flexible new ways-as in when drawing inferences. However, it remains an open question as to whether the developmental differences observed during both memory formation and inference itself represent a fundamental limitation on children's learning mechanisms, or rather their deployment of suboptimal strategy. Here, 7-9-year-old children (N = 154) and young adults (N = 130) first formed strong memories for initial (AB) associations and then engaged in one of three learning strategies as they viewed overlapping (BC) pairs. We found that being told to integrate-combine ABC during learning-both significantly improved children's ability to explicitly relate the indirectly associated A and C items during inference and protected the underlying pair memories from forgetting. However, this finding contrasted with implicit evidence for memory-to-memory connections: Adults and children both formed A-C links prior to any knowledge of an inference test-yet for children, such links were most apparent when they were told to simply encode BC, not integrate. Moreover, the accessibility of such implicit links differed between children and adults, with adults using them to make explicit inferences but children only doing so for well-established direct AB pairs. These results suggest that while a lack of integration strategy may explain a large share of the developmental differences in explicit inference, children and adults nevertheless differ in both the circumstances under which they connect interrelated memories and their ability to later leverage those links to inform flexible behaviours. RESEARCH HIGHLIGHTS: Children and adults view AB and BC pairs related through a shared item, B. This provides an opportunity for learners to connect A-C in memory. Being encouraged to integrate ABC during learning boosted performance on an explicit test of A-C connections (children and adults) and protected from forgetting (children). Children and adults differed in when implicit A-C connections were formed-occurring primarily when told to separately encode BC (children) versus integrate (adults), respectively. Adults used implicit A-C connections to facilitate explicit judgments, while children did not. Our results suggest developmental differences in the learning conditions promoting memory-to-memory connections.

Encoding-phase orientation toward thematic content over perceptual style benefits picture memory.

Orienting toward the meaning versus perceptual features of an experience benefits subsequent memory. Yet given that past work encouraged these orientations with different tasks, it is not clear if this memory benefit is solely due to internal processing factors versus external task-related ones. Moreover, it remains unclear how this benefit generalises from verbal to detailed picture memory. Here, we developed a novel paradigm that cued participants' attention to thematic (story) or stylistic (artist style) dimensions of storybook-style illustrations during a repeat-detection task. Afterwards, participants completed a recognition memory test with studied illustrations and lures along thematic and stylistic dimensions. In contrast to past work, both orienting tasks were identical except for the dimension participants were cued to attend to. Furthermore, our thematic and stylistic dimensions enabled us to separately examine memory quality along each dimension. We found that thematic attention yielded superior memory for studied illustrations over stylistic orientations. False alarms to lures varied by dimension and attention: errors were greater to thematic than stylistic lures overall and stylistic attention elevated false alarms to stylistic lures. Our results show that semantic encoding orientations enhance detailed picture memory, without a cost to memory quality along semantic or perceptual dimensions of experience.

OpenMaze: An open-source toolbox for creating virtual navigation experiments.

Incorporating 3D virtual environments into psychological experiments offers an innovative solution for balancing experimental control and ecological validity. Their flexible application to virtual navigation experiments, however, has been limited because accessible development tools best support only a subset of desirable task design features. We created OpenMaze, an open-source toolbox for the Unity game engine, to overcome this barrier. OpenMaze offers researchers the ability to conduct a wide range of first-person spatial navigation experiment paradigms in fully customized 3D environments. Crucially, because all experiments are defined using human-readable configuration files, our toolbox allows even those with no prior coding experience to build bespoke tasks. OpenMaze is also compatible with a variety of input devices and operating systems, broadening its possible applications. To demonstrate its advantages and limitations, we review and contrast other available software options before providing an overview of our design objectives and walking the reader through the process of building an experiment in OpenMaze.

Developmental differences in memory reactivation relate to encoding and inference in the human brain.

Despite the fact that children can draw on their memories to make novel inferences, it is unknown whether they do so through the same neural mechanisms as adults. We measured memory reinstatement as participants aged 7-30 years learned new, related information. While adults brought memories to mind throughout learning, adolescents did so only transiently, and children not at all. Analysis of trial-wise variability in reactivation showed that discrepant neural mechanisms-and in particular, what we interpret as suppression of interfering memories during learning in early adolescence-are nevertheless beneficial for later inference at each developmental stage. These results suggest that while adults build integrated memories well-suited to informing inference directly, children and adolescents instead must rely on separate memories to be individually referenced at the time of inference decisions.

General precedes specific in memory representations for structured experience.

Decades of work has shown that learners rapidly extract structure from their environment, later leveraging their knowledge of what is more versus less consistent with prior experience to guide behavior. However, open questions remain about exactly what is remembered after exposure to structure. Memory for specific associations-transitions that unfold over time-is considered a prime candidate for guiding behavior. However, other factors could influence behavior, such as memory for general features like reliable groupings or within-group positions. We also do not yet know whether memory depends upon the amount of experience with the input structure, leaving us with an incomplete understanding of how statistical learning supports behavior. In 4 experiments, we tracked the emergence of memory for item-item transitions, order-independent groups, and positions by having 400 adults watch a stream of shape triplets followed by a recognition memory test. We manipulated how closely test sequences corresponded to the input along each dimension of interest, allowing us to isolate the contribution of each factor. Both item-item transitions and order-independent group information influenced behavior, highlighting statistical learning as a mechanism through which we form both specific and generalized representations. Moreover, these factors drove behavior after different amounts of experience: With limited exposure, only group information impacted old-new judgments specific transitions gained importance later. Our findings suggest statistical learning proceeds by first forming a general representation of structure, with memory being later refined to include specifics after more experience. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Learning exceptions to the rule in human and model via hippocampal encoding.

Category learning helps us process the influx of information we experience daily. A common category structure is "rule-plus-exceptions," in which most items follow a general rule, but exceptions violate this rule. People are worse at learning to categorize exceptions than rule-following items, but improved exception categorization has been positively associated with hippocampal function. In light of model-based predictions that the nature of existing memories of related experiences impacts memory formation, here we use behavioural and computational modelling data to explore how learning sequence impacts performance in rule-plus-exception categorization. Our behavioural results indicate that exception categorization accuracy improves when exceptions are introduced later in learning, after exposure to rule-followers. To explore whether hippocampal learning systems also benefit from this manipulation, we simulate our task using a computational model of hippocampus. The model successful replicates our behavioural findings related to exception learning, and representational similarity analysis of the model's hidden layers suggests that model representations are impacted by trial sequence: delaying the introduction of an exception shifts its representation closer to its own category members. Our results provide novel computational evidence of how hippocampal learning systems can be targeted by learning sequence and bolster extant evidence of hippocampus's role in category learning.

The structure of hippocampal circuitry relates to rapid category learning in humans.

Prior work suggests that complementary white matter pathways within the hippocampus (HPC) differentially support the learning of specific versus general information. In particular, while the trisynaptic pathway (TSP) rapidly forms memories for specific experiences, the monosynaptic pathway (MSP) slowly learns generalities. However, despite the theorized significance of such circuitry, characterizing how information flows within the HPC to support learning in humans remains a challenge. We leveraged diffusion-weighted imaging as a proxy for individual differences in white matter structure linking key regions along with TSP (HPC subfields CA3 and CA1 ) and MSP (entorhinal cortex and CA1 ) and related these differences in hippocampal structure to category learning ability. We hypothesized that learning to categorize the "exception" items that deviated from category rules would benefit from TSP-supported mnemonic specificity. Participant-level estimates of TSP- and MSP-related integrity were constructed from HPC subfield connectomes of white matter streamline density. Consistent with theories of TSP-supported learning mechanisms, we found a specific association between the integrity of CA3 -CA1 white matter connections and exception learning. These results highlight the significant role of HPC circuitry in complex human learning.

Representations of common event structure in medial temporal lobe and frontoparietal cortex support efficient inference.

Prior work has shown that the brain represents memories within a cognitive map that supports inference about connections between individual related events. Real-world adaptive behavior is also supported by recognizing common structure among numerous distinct contexts; for example, based on prior experience with restaurants, when visiting a new restaurant one can expect to first get a table, then order, eat, and finally pay the bill. We used a neurocomputational approach to examine how the brain extracts and uses abstract representations of common structure to support novel decisions. Participants learned image pairs (AB, BC) drawn from distinct triads (ABC) that shared the same internal structure and were then tested on their ability to infer indirect (AC) associations. We found that hippocampal and frontoparietal regions formed abstract representations that coded cross-triad relationships with a common geometric structure. Critically, such common representational geometries were formed despite the lack of explicit reinforcement to do so. Furthermore, we found that representations in parahippocampal cortex are hierarchical, reflecting both cross-triad relationships and distinctions between triads. We propose that representations with common geometric structure provide a vector space that codes inferred item relationships with a direction vector that is consistent across triads, thus supporting faster inference. Using computational modeling of response time data, we found evidence for dissociable vector-based retrieval and pattern-completion processes that contribute to successful inference. Moreover, we found evidence that these processes are mediated by distinct regions, with pattern completion supported by hippocampus and vector-based retrieval supported by parahippocampal cortex and lateral parietal cortex.

Predictability Changes What We Remember in Familiar Temporal Contexts.

The human brain constantly anticipates the future based on memories of the past. Encountering a familiar situation reactivates memory of previous encounters, which can trigger a prediction of what comes next to facilitate responsiveness. However, a prediction error can lead to pruning of the offending memory, a process that weakens its representation in the brain and leads to forgetting. Our goal in this study was to evaluate whether memories are spared from such pruning in situations that allow for accurate predictions at the categorical level, despite prediction errors at the item level. Participants viewed a sequence of objects, some of which reappeared multiple times ("cues"), followed always by novel items. Half of the cues were followed by new items from different (unpredictable) categories, while others were followed by new items from a single (predictable) category. Pattern classification of fMRI data was used to identify category-specific predictions after each cue. Pruning was observed only in unpredictable contexts, while encoding of new items was less robust in predictable contexts. These findings demonstrate that how associative memories are updated is influenced by the reliability of abstract-level predictions in familiar contexts.

Progress update from the hippocampal subfields group.

INTRODUCTION: Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence. METHODS: Our international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption. RESULTS: This progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures. DISCUSSION: A harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

Performance of semi-automated hippocampal subfield segmentation methods across ages in a pediatric sample.

Episodic memory function has been shown to depend critically on the hippocampus. This region is made up of a number of subfields, which differ in both cytoarchitectural features and functional roles in the mature brain. Recent neuroimaging work in children and adolescents has suggested that these regions may undergo different developmental trajectories-a fact that has important implications for how we think about learning and memory processes in these populations. Despite the growing research interest in hippocampal structure and function at the subfield level in healthy young adults, comparatively fewer studies have been carried out looking at subfield development. One barrier to studying these questions has been that manual segmentation of hippocampal subfields-considered by many to be the best available approach for defining these regions-is laborious and can be infeasible for large cross-sectional or longitudinal studies of cognitive development. Moreover, manual segmentation requires some subjectivity and is not impervious to bias or error. In a developmental sample of individuals spanning 6-30 years, we assessed the degree to which two semi-automated segmentation approaches-one approach based on Automated Segmentation of Hippocampal Subfields (ASHS) and another utilizing Advanced Normalization Tools (ANTs)-approximated manual subfield delineation on each individual by a single expert rater. Our main question was whether performance varied as a function of age group. Across several quantitative metrics, we found negligible differences in subfield validity across the child, adolescent, and adult age groups, suggesting that these methods can be reliably applied to developmental studies. We conclude that ASHS outperforms ANTs overall and is thus preferable for analyses carried out in individual subject space. However, we underscore that ANTs is also acceptable and may be well-suited for analyses requiring normalization to a single group template (e.g., voxelwise analyses across a wide age range). Previous work has supported the use of such methods in healthy young adults, as well as several special populations such as older adults and those suffering from mild cognitive impairment. Our results extend these previous findings to show that ASHS and ANTs can also be used in pediatric populations as young as six.

The ontogeny of memory persistence and specificity.

Interest in the ontogeny of memory blossomed in the twentieth century following the initial observations that memories from infancy and early childhood are rapidly forgotten. The intense exploration of infantile amnesia in subsequent years has led to a thorough characterization of its psychological determinants, although the neurobiology of memory persistence has long remained elusive. By contrast, other phenomena in the ontogeny of memory like infantile generalization have received relatively less attention. Despite strong evidence for reduced memory specificity during ontogeny, infantile generalization is poorly understood from psychological and neurobiological perspectives. In this review, we examine the ontogeny of memory persistence and specificity in humans and nonhuman animals at the levels of behavior and the brain. To this end, we first describe the behavioral phenotypes associated with each phenomenon. Looking into the brain, we then discuss neurobiological mechanisms in the hippocampus that contribute to the ontogeny of memory. Hippocampal neurogenesis and critical period mechanisms have recently been discovered to underlie amnesia during early development, and at the same time, we speculate that similar processes may contribute to the early bias towards memory generalization.

Hippocampal representations as a function of time, subregion, and brain state.

How does the hippocampus represent interrelated experiences in memory? We review prominent yet seemingly contradictory theoretical perspectives, which propose that the hippocampus distorts experiential representations to either emphasize their distinctiveness or highlight common elements. These fundamentally different kinds of memory representations may be instantiated in the brain via conjunctive separated codes and adaptively differentiated codes on the one hand, or integrated relational codes on the other. After reviewing empirical support for these different coding schemes within the hippocampus, we outline two organizing principles which may explain the conflicting findings in the literature. First focusing on where the memories are formed and stored, we argue that distinct hippocampal regions represent experiences at multiple levels of abstraction and may transmit them to distinct cortical networks. Then focusing on when memories are formed, we identify several factors that can open and maintain specialized time windows, during which the very same hippocampal network is biased toward one coding scheme over the others. Specifically, we discuss evidence for (1) excitability-mediated integration windows, maintained by persistently elevated CREB levels following encoding of a specific memory, (2) fleeting cholinergically-mediated windows favoring memory separation, and (3) sustained dopaminergically-mediated windows favoring memory integration. By presenting a broad overview of different hippocampal coding schemes across species, we hope to inspire future empirical and modeling research to consider how factors surrounding memory formation shape the representations in which they are stored.

Ventromedial Prefrontal Cortex Is Necessary for Normal Associative Inference and Memory Integration.

The ability to flexibly combine existing knowledge in response to novel circumstances is highly adaptive. However, the neural correlates of flexible associative inference are not well characterized. Laboratory tests of associative inference have measured memory for overlapping pairs of studied items (e.g., AB, BC) and for nonstudied pairs with common associates (i.e., AC). Findings from functional neuroimaging and neuropsychology suggest the ventromedial prefrontal cortex (vmPFC) may be necessary for associative inference. Here, we used a neuropsychological approach to test the necessity of vmPFC for successful memory-guided associative inference in humans using an overlapping pairs associative memory task. We predicted that individuals with focal vmPFC damage (n = 5; 3F, 2M) would show impaired inferential memory but intact non-inferential memory. Performance was compared with normal comparison participants (n = 10; 6F, 4M). Participants studied pairs of visually presented objects including overlapping pairs (AB, BC) and nonoverlapping pairs (XY). Participants later completed a three-alternative forced-choice recognition task for studied pairs (AB, BC, XY) and inference pairs (AC). As predicted, the vmPFC group had intact memory for studied pairs but significantly impaired memory for inferential pairs. These results are consistent with the perspective that the vmPFC is necessary for memory-guided associative inference, indicating that the vmPFC is critical for adaptive abilities that require application of existing knowledge to novel circumstances. Additionally, vmPFC damage was associated with unexpectedly reduced memory for AB pairs post-inference, which could potentially reflect retroactive interference. Together, these results reinforce an emerging understanding of a role for the vmPFC in brain networks supporting associative memory processes.SIGNIFICANCE STATEMENT We live in a constantly changing environment, so the ability to adapt our knowledge to support understanding of new circumstances is essential. One important adaptive ability is associative inference which allows us to extract shared features from distinct experiences and relate them. For example, if we see a woman holding a baby, and later see a man holding the same baby, then we might infer that the two adults are a couple. Despite the importance of associative inference, the brain systems necessary for this ability are not known. Here, we report that damage to human ventromedial prefrontal cortex (vmPFC) disproportionately impairs associative inference. Our findings show the necessity of the vmPFC for normal associative inference and memory integration.

Hippocampal Structure Predicts Statistical Learning and Associative Inference Abilities during Development.

Despite the importance of learning and remembering across the lifespan, little is known about how the episodic memory system develops to support the extraction of associative structure from the environment. Here, we relate individual differences in volumes along the hippocampal long axis to performance on statistical learning and associative inference tasks-both of which require encoding associations that span multiple episodes-in a developmental sample ranging from ages 6 to 30 years. Relating age to volume, we found dissociable patterns across the hippocampal long axis, with opposite nonlinear volume changes in the head and body. These structural differences were paralleled by performance gains across the age range on both tasks, suggesting improvements in the cross-episode binding ability from childhood to adulthood. Controlling for age, we also found that smaller hippocampal heads were associated with superior behavioral performance on both tasks, consistent with this region's hypothesized role in forming generalized codes spanning events. Collectively, these results highlight the importance of examining hippocampal development as a function of position along the hippocampal axis and suggest that the hippocampal head is particularly important in encoding associative structure across development.