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.hippocampal subfields | episodic memory | specificity | pattern separation | child development M any years ago, the Swiss developmentalist Jean Piaget noted an imbalance between assimilation and accommodation during early and middle childhood in the sense that children tend to extract schematic knowledge at the expense of learning and recollecting specific events (1, 2). This imbalance has resurfaced in computational models of memory (3), and later as the imbalance between pattern completion and pattern separation, processes linked to computational properties of subfields within the hippocampus (HC) (4-6). Understanding the developmental organization of HC subfields is therefore crucial to understand how associated changes in HC-subfield computations drive concomitant changes in learning and memory.An important step toward unraveling controversies about human hippocampal maturation (7,8) is to acknowledge that the HC is not a homogeneous structure, but rather is composed of cytoarchitectonically and functionally distinct subfields (9). The availability of high-resolution, in vivo magnetic resonance imaging (MRI) of the HC permits the study of specific contributions of different HC subfields in humans (10-12). Computational and rodent models of HC function and high-resolution MRI studies in humans have sought to establish the contributions of individual HC subfields to specific mnemonic functions. For example, the dentate gyrus (DG) has been closely linked to pattern separation (6). Developmental findings from animal models (13) and initial evidence from human studies (14) suggest that the DG matures later than other HC subfields. Likewise, memory funct...

During early ontogeny, the rapid and cumulative acquisition of world knowledge contrasts with slower improvements in the ability to lay down detailed and long-lasting episodic memories. This emphasis on generalization at the expense of specificity persists well into middle childhood and possibly into adolescence. During this period, recognizing regularities, forming stable representations of recurring episodes, predicting the structure of future events, and building up semantic knowledge may be prioritized over remembering specific episodes. We highlight recent behavioral and neuroimaging evidence suggesting that maturational differences among subfields within the hippocampus contribute to the developmental lead-lag relation between generalization and specificity, and lay out future research directions.

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.

Lower socioeconomic status (SES) environments are marked by higher stress that is hypothesized to alter cortisol secretion in children, thereby damaging hippocampal volume and memory performance. However, empirical evidence demonstrating these putative links is lacking. We assessed the diurnal cortisol awakening response (CAR) on two mornings and cortisol stress reactivity (CSR) with the Trier Social Stress Test for Children in 102 healthy, socio-demographically diverse 6-to-7-year-old children (46% female). Children performed a hippocampal-dependent item-location associative memory task and 60 of these children underwent structural MRI scanning for hippocampal volume. Cortisol values were modeled with latent-change structural equation models to represent overall levels and change. We found lower income is associated with a flatter CAR, blunted reactivity and recovery to acute stress, and smaller hippocampal volume. Furthermore, hyporeactivity in CSR was related to lower memory among lower-income children, whereas there was no reliable association of CSR and memory among higher-income children (an income x cortisol interaction). We found no evidence that smaller hippocampal volume in lower income was associated with poorer memory performance. Notably, hyporeactivity in both CAR and CSR was specific to using income as the SES predictor. The income x cortisol interaction and smaller hippocampal effects, however, were replicated with education and an SES composite score. This suggests that hyporeactivity to acute stress may function as a mediator in SES-cognition associations at the lower end of the SES spectrum, but it does not imply environmental- or genetically-mediated causation.

The testing effect refers to the phenomenon that repeated retrieval of memories promotes better long-term retention than repeated study. To investigate the neural correlates of the testing effect, we used event-related functional magnetic resonance imaging methods while participants performed a cued recall task. Prior to the neuroimaging experiment, participants learned Swahili-German word pairs, then half of the word pairs were repeatedly studied, whereas the other half were repeatedly tested. For half of the participants, the neuroimaging experiment was performed immediately after the learning phase; a 1-week retention interval was inserted for the other half of the participants. We found that a large network of areas identified in a separate 2-back functional localizer scan were active during the final recall of the word pair associations. Importantly, the learning strategy (retest or restudy) of the word pairs determined the manner in which the retention interval affected the activations within this network. Recall of previously restudied memories was accompanied by reduced activation within this network at long retention intervals, but no reduction was observed for previously retested memories. We suggest that retrieval promotes learning via stabilizing cue-related activation patterns in a network of areas usually associated with cognitive and attentional control functions.

The distinctiveness of neural information representation is crucial for successful memory performance but declines with advancing age. Computational models implicate age-related neural dedifferentiation on the level of item representations, but previous studies mostly focused on age differences of categorical information representation in higher-order visual regions. In an age-comparative fMRI study, we combined univariate analyses and whole-brain searchlight pattern similarity analyses to elucidate age differences in neural distinctiveness at both category and item levels and their relation to memory. Age-related neural dedifferentiation was shown as reduced category-selective processing in ventral visual cortex and impoverished item specificity in occipital regions. Importantly, successful subsequent memory performance built upon high item stability which was greater in younger than older adults. Finally, we identified a multivariate profile of neural distinctiveness across representational levels that captured both age group and recognition performance differences, emphasizing that neural dedifferentiation is a generalized phenomenon in the aging brain.

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.

The human hippocampus, a brain structure crucial for memory across the lifespan, is highly sensitive to adverse life events. Stress exposures during childhood have been linked to altered hippocampal structure and memory performance in adulthood. Animal studies suggest that these differences are in part driven by aberrant glucocorticoid secretion during development, with strongest effects on the CA3 region and the dentate gyrus (CA3-DG) of the hippocampus, alongside associated memory impairments. However, only few pediatric studies have examined glucocorticoid associations with hippocampal subfield volumes and their functional relevance. In 84 children (age range: 6-7 years), we assessed whether volumes of hippocampal subregions were related to cumulative glucocorticoid levels (hair cortisol), parenting stress, and performance on memory tasks known to engage the hippocampus. We found that higher hair cortisol levels were specifically related to lower CA3-DG volume. Parenting stress did not significantly correlate with hair cortisol, and there was no evidence to suggest that individual differences in hippocampal subregional volumes manifest in memory performance. Our results suggest that the CA3-DG may be the hippocampal region most closely associated with hair cortisol levels in childhood. Establishing causal pathways underlying this association and its relation to environmental stress and memory development necessitates longitudinal studies.