Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 µm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.

A (sub)field guide to quality control in hippocampal subfield segmentation on high-resolution T2-weighted MRI.

Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo, the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter-dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health.

Age-related differences in hippocampal subfield volumes across the human lifespan: A meta-analysis.

The human hippocampus (Hc) is critical for memory function across the lifespan. It is comprised of cytoarchitectonically distinct subfields: dentate gyrus (DG), cornu ammonis sectors (CA) 1-4, and subiculum, each of which may be differentially susceptible to neurodevelopmental and neurodegenerative mechanisms. Identifying age-related differences in Hc subfield volumes can provide insights into neural mechanisms of memory function across the lifespan. Limited evidence suggests that DG and CA3 volumes differ across development while other regions remain relatively stable, and studies of adulthood implicate a downward trend in all subfield volumes with prominent age effects on CA1. Due to differences in methods and limited sampling for any single study, the magnitude of age effects on Hc subfield volumes and their probable lifespan trajectories remain unclear. Here, we conducted a meta-analysis on cross-sectional studies (n = 48,278 participants, ages = 4-94 years) to examine the association between age and Hc subfield volumes in development (n = 11 studies), adulthood (n = 30 studies), and a combined lifespan sample (n = 41 studies) while adjusting estimates for sample sizes. In development, age was positively associated with DG and CA3-4 volumes, whereas in adulthood a negative association was observed with all subfield volumes. Notably, the observed age effects were not different across subfield volumes within each age group. All subfield volumes showed a nonlinear age pattern across the lifespan with DG and CA3-4 volumes showing a more distinct age trajectory as compared to the other subfields. Lastly, among all the study-level variables, only female percentage of the study sample moderated the age effect on CA1 volume: a higher female-to-male ratio in the study sample was linked to the greater negative association between age and CA1 volume. These results document that Hc subfield volumes differ as a function of age offering broader implications for constructing theoretical models of lifespan memory development.

Development and validation of a quality control procedure for automatic segmentation of hippocampal subfields.

Automatic segmentation methods for in vivo magnetic resonance imaging are increasing in popularity because of their high efficiency and reproducibility. However, automatic methods can be perfectly reliable and consistently wrong, and the validity of automatic segmentation methods cannot be taken for granted. Quality control (QC) by trained and reliable human raters is necessary to ensure the validity of automatic measurements. Yet QC practices for applied neuroimaging research are underdeveloped. We report a detailed QC and correction procedure to accompany our validated atlas for hippocampal subfield segmentation. We document a two-step QC procedure for identifying segmentation errors, along with a taxonomy of errors and an error severity rating scale. This detailed procedure has high between-rater reliability for error identification and manual correction. The latter introduces at maximum 3% error variance in volume measurement. All procedures were cross-validated on an independent sample collected at a second site with different imaging parameters. The analysis of error frequency revealed no evidence of bias. An independent rater with a third sample replicated procedures with high within-rater reliability for error identification and correction. We provide recommendations for implementing the described method along with hypothesis testing strategies. In sum, we present a detailed QC procedure that is optimized for efficiency while prioritizing measurement validity and suits any automatic atlas.

Household socioeconomic status relates to specific hippocampal subfield volumes across development.

The hippocampus is composed of cytoarchitecturally distinct subfields that support specific memory functions. Variations in total hippocampal volume across development have been linked to socioeconomic status (SES), a proxy for access to material resources, medical care, and quality education. High childhood household SES is associated with greater cognitive abilities in adulthood. Currently, it is not known whether household SES differentially impacts specific hippocampal subfield volumes. We assessed susceptibility of subfields to variations in household SES across development in a sample of 167 typically developing 5- to 25-year-old. Bilateral cornu ammonis (CA) 1-2, combined CA3-dentate gyrus (DG), and subiculum (Sub) volumes were measured by highly reliable manual segmentation of high-resolution T2-weighted images and adjusted for intracranial volume. A summary component score of SES measures (paternal education, maternal education, and income-to-needs ratio) was used to examine variability in volumes across ages. We did not identify age-related differences in any of the regional volumes, nor did age modify SES-related effects. Controlling for age, larger volumes of CA3-DG and CA1-2 were associated with lower SES, while Sub volume was not. Overall, these findings support the specific impact of SES on CA3-DG and CA1-2 and highlight the importance of considering environmental influences on hippocampal subfield development.

The fornix supports episodic memory during childhood.

Episodic memory relies on the coordination of widespread brain regions that reconstruct spatiotemporal details of an episode. These topologically dispersed brain regions can rapidly communicate through structural pathways. Research in animal and human lesion studies implicate the fornix-the major output pathway of the hippocampus-in supporting various aspects of episodic memory. Because episodic memory undergoes marked changes in early childhood, we tested the link between the fornix and episodic memory in an age window of robust memory development (ages 4-8 years). Children were tested on the stories subtest from the Children's Memory Scale, a temporal order memory task, and a source memory task. Fornix streamlines were reconstructed using probabilistic tractography to estimate fornix microstructure. In addition, we measured fornix macrostructure and computed free water. To assess selectivity of our findings, we also reconstructed the uncinate fasciculus. Findings show that children's memory increases from ages 4 to 8 and that fornix micro- and macrostructure increases between ages 4 and 8. Children's memory performance across nearly every memory task correlated with individual differences in fornix, but not uncinate fasciculus, white matter. These findings suggest that the fornix plays an important role in supporting the development of episodic memory, and potentially semantic memory, in early childhood.

A meta-analysis of the relation between hippocampal volume and memory ability in typically developing children and adolescents.

Memory is supported by a network of brain regions, with the hippocampus serving a critical role in this cognitive process. Previous meta-analyses on the association between hippocampal structure and memory have largely focused on adults. Multiple studies have since suggested that hippocampal volume is related to memory performance in children and adolescents; however, the strength and direction of this relation varies across reports, and thus, remains unclear. To further understand this brain-behavior relation, we conducted a meta-analysis to investigate the association between hippocampal volume (assessed as total volume) and memory during typical development. Across 25 studies and 61 memory outcomes with 1357 participants, results showed a small, but significant, positive association between total hippocampal volume and memory performance. Estimates of the variability across studies in the relation between total volume and memory were not explained by differences in memory task type (delayed vs. immediate; relational vs. nonrelational), participant age range, or the method of normalization of hippocampal volumes. Overall, findings suggest that larger total hippocampal volume relates to better memory performance in children and adolescents and that this relation is similar across the memory types and age ranges assessed. To facilitate enhanced generalization across studies in the future, we discuss considerations for the field moving forward.

Developmental changes in episodic memory across early- to mid-childhood: insights from a latent longitudinal approach.

Episodic memory is a cornerstone ability that allows one to recall past events and the spatiotemporal context in which they occur. In an effort to characterise the development of this critical ability, many different tasks have been used independently to assess age-related variations in episodic memory. However, performance on memory tasks is multiply determined, and the extent to which different tasks with varying features relate to each other and represent episodic memory as a latent cognitive construct across childhood is unclear. The present study sought to address this question by exploring the feasibility of using four different laboratory-based tasks to characterise changes in episodic memory ability during early- to mid-childhood in 200 typically developing children (4-8 years). Using longitudinal data and a structural equation modeling framework, results suggest that multiple tests of episodic memory can be utilised to indicate a comparable latent construct of episodic memory ability over this period of development, and that this ability improves consistently between 4 to 8 years. Overall, results highlight that episodic memory measured as a construct increases at a similar rate over early- to mid-childhood and demonstrate the benefits of using multiple laboratory tasks to characterise developmental changes in episodic memory.

Longitudinal development of hippocampal subregions from early- to mid-childhood.

Early childhood is characterized by vast changes in behaviors supported by the hippocampus and an increased susceptibility of the hippocampus to environmental influences. Thus, it is an important time to investigate the development of the hippocampus. Existing research suggests subregions of the hippocampus (i.e., head, body, tail) have dissociable functions and that the relations between subregions and cognitive abilities vary across development. However, longitudinal research examining age-related changes in subregions in humans, particularly during early childhood (i.e., 4-6 years), is limited. Using a large sample of 184 healthy 4- to 8-year-old children, the present study is the first to characterize developmental changes in hippocampal subregion volume from early- to mid-childhood. Results reveal differential developmental trajectories in hippocampal head, body, and tail during this period. Specifically, head volume showed a quadratic pattern of change, and both body and tail showed linear increases, resulting in a pattern of cubic change for total hippocampal volume. Further, main effects of sex on hippocampal volume (males > females) and hemispheric differences in developmental trajectories were observed. These findings provide an improved understanding of the development of the hippocampus and have important implications for research investigating a range of cognitive abilities and behaviors.

It's All in the Details: Relations Between Young Children's Developing Pattern Separation Abilities and Hippocampal Subfield Volumes.

The ability to keep similar experiences separate in memory is critical for forming unique and lasting memories, as many events share overlapping features (e.g., birthday parties, holidays). Research on memory in young children suggests their memories often lack high-resolution details, i.e., show impoverished pattern separation (PS). Recently developed assessments of PS suitable for children allow us to relate the formation of distinct, detailed memories for the development of the hippocampus, a neural structure critical for this ability in adults. The hippocampus displays a protracted developmental profile and underlies the ability to form detailed memories. This study examined age-related differences in hippocampal subfield volumes in 4- to 8-year-old children and relations with performance on a mnemonic similarity task (MST) designed to index memory specificity. Results revealed age-moderated associations between MST performance and cornu ammonis 2-4/dentate gyrus subfields. Specifically, age-related differences in the ability to form detailed memories tracked with normative patterns of volume increases followed by reductions over this age range. That is, greater volume correlated with better performance in younger children, whereas smaller volume correlated with better performance in older children. These findings support the hypothesis that developmental differences in hippocampal circuitry contribute to age-related improvements in detailed memory formation during this period.

Age- and performance-related differences in source memory retrieval during early childhood: Insights from event-related potentials.

Across early childhood, children's ability to remember individual items and the details that accompany these items (i.e., episodic memory) improves greatly. Given that these behavioral improvements coincide with increases in age, effects of age and performance are often confounded. This study used event-related potentials (ERPs) to investigate age- and performance-related differences in the neural processes underlying the development of memory for details during early childhood. Using a source memory paradigm, ERP components related to episodic memory, the negative component (Nc), and late slow wave (LSW) were examined in 4- to 8-year-old children. Analyses focused on trials for which children correctly remembered the source related to an item versus trials where the item was remembered but the source was forgotten. Results revealed LSW, but not Nc, differed as a function of age and performance. Specifically, LSW effects were similar across source correct and source incorrect trials in all high-performing children and in low-performing older children; however, LSW effects differed across conditions in low-performing younger children. Results show developmental differences in retrieval processes across early childhood and highlight the importance of considering age and performance when examining electrophysiological correlates of episodic memory during development.

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized (20X resolution) slices with 5 mm spacing. Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed more gradually. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed human neuroimaging research on the MTL cortex.

Longitudinal Exploration of Binding Ability across Early Childhood: The Differential Contribution of Hits and False Alarms.

Childhood is a period of pronounced improvements in children's ability to remember connections between details of an event (i.e. binding ability). However, the mechanisms supporting these changes remain unclear. Prior evidence is mixed, with some proposing that improvements in the ability to identify previous connections (i.e. increases in hits) account for memory changes, whereas other evidence suggests changes are additionally supported by the ability to identify inaccurate connections (i.e. decreases in false alarms). To disentangle the role of each process, we investigated changes in hits and false alarms within the same paradigm. The present study of 200 4-to-8-year-old children (100 female) used a cohort sequential design to assess longitudinal change in binding ability. Developmental trajectories of d', hit, and false alarm rates were examined using latent growth analysis. Findings demonstrated non-linear improvements in children's binding ability from age 4-to-8-years. Improvements were differentially supported by hits and false alarms. Hit rates improved non-linearly from 4-to-8-years, with greater growth from 4-to-6-years. False alarm rates did not significantly change from 4-to-6-years, but significantly decreased from 6-to-8-years. Overall, findings show improvements in binding ability are predominantly supported by increased hit rates between 4-to-6-years and by both increasing hit rates and decreasing false alarms rates between 6-to-8-years. Together, these results suggest that binding development is non-linear and that mechanisms underlying improvements differ across childhood.

Modeling longitudinal changes in hippocampal subfields and relations with memory from early- to mid-childhood.

The hippocampus has been suggested to show protracted postnatal developmental growth across childhood. Most previous studies during this developmental period have been cross-sectional in nature and have focused on age-related differences in either hippocampal subregions or subfields, but not both, potentially missing localized changes. This study capitalized on a latent structural equation modeling approach to examine the longitudinal development of hippocampal subfields (cornu ammonis (CA) 2-4/dentate gyrus (DG), CA1, subiculum) in both the head and the body of the hippocampus, separately, in 165 typically developing 4- to 8-year-old children. Our findings document differential development of subfields within hippocampal head and body. Specifically, within hippocampal head, CA1 volume increased between 4-5 years and within hippocampal body, CA2-4/DG and subiculum volume increased between 5-6 years. Additionally, changes in CA1 volume in the head and changes in subiculum in the body between 4-5 years related to improvements in memory between 4-5 years. These findings demonstrate the protracted development of subfields in vivo during early- to mid-childhood, illustrate the importance of considering subfields separately in the head and body of the hippocampus, document co-occurring development of brain and behavior, and highlight the strength of longitudinal data and latent modeling when examining brain development.

Reliability of subsequent memory effects in children and adults: The good, the bad, and the hopeful.

Functional MRI (fMRI) is a key tool for investigating neural underpinnings of cognitive development. Yet, in recent years, the reliability of fMRI effects has come into question and with it, the feasibility of using task-based fMRI to identify developmental changes related to cognition. Here, we investigated the reliability of task-based fMRI activations with a widely used subsequent memory paradigm using two developmental samples: a cross-sectional sample (n = 85, age 8-25 years) and a test-retest sample (n = 24, one-month follow up, age 8-20 years). In the large cross-sectional sample, we found good to excellent group-level reliability when assessing activation patterns related to the encoding task and subsequent memory effects. In the test-retest sample, while group-level reliability was excellent, the consistency of activation patterns within individuals was low, particularly for subsequent memory effects. We observed consistent activation patterns in frontal, parietal, and occipital cortices, but comparatively lower test-retest reliability in subcortical regions and the hippocampus. Together, these findings highlight the limitations of interpreting task-based fMRI effects and the importance of incorporating reliability analyses in developmental studies. Leveraging larger and densely collected longitudinal data may help contribute to increased reproducibility and the accumulation of knowledge in developmental sciences.

Empirical Evidence Supporting Neural Contributions to Episodic Memory Development in Early Childhood: Implications for Childhood Amnesia.

Memories for events that happen early in life are fragile-they are forgotten more quickly than expected based on typical adult rates of forgetting. Although numerous factors contribute to this phenomenon, data show one major source of change is the protracted development of neural structures related to memory. Recent empirical studies in early childhood reveal that the development of specific subdivisions of the hippocampus (i.e., the dentate gyrus) are related directly to variations in memory. Yet the hippocampus is only one region within a larger network supporting memory. Data from young children have also shown that activation of cortical regions during memory tasks and the functional connectivity between the hippocampus and cortex relate to memory during this period. Taken together, these results suggest that protracted neural development of the hippocampus, cortex, and connections between these regions contribute to the fragility of memories early in life and may ultimately contribute to childhood amnesia.

Microstructural Integrity of the Hippocampus During Childhood: Relations With Age and Source Memory.

The hippocampus is a brain structure known to be important for memory. However, studies examining relations between hippocampal volume and memory across development yield mixed results. This may be due in part to the fact that volume is a coarser measure of hippocampal composition. Studies have begun to examine measures of diffusion, which capture characteristics of the microstructure of the hippocampus, and thus may provide additional information about the integrity of the underlying neural circuits. The present study applied this approach to a developmental period characterized by dramatic changes in both hippocampal microstructure and memory behavior - early childhood. Specifically, measures of hippocampal microstructural integrity were related to age and source memory performance in 93 children aged 4-8 years. Results revealed significant negative associations between hippocampal mean diffusivity and both age and memory, even after controlling for differences in hippocampal volume. These results suggest that hippocampal diffusion may provide additional, independent information about hippocampal integrity compared to volume, particularly during early childhood when important developmental changes have been proposed.

Longitudinal Development of Memory for Temporal Order in Early to Middle Childhood.

Existing studies examining the development of temporal order memory show that although young children perform above chance on some tasks assessing temporal order memory, there are significant age-related differences across childhood. Yet, the trajectory of children's ability to retrieve temporal order remains unclear as existing conclusions are drawn from cross-sectional studies. The present study utilized an accelerated longitudinal design in order to characterize the developmental trajectory of temporal order memory in a sample of 200 healthy 4- to 8-year-old children. Specifically, two tasks commonly used in the literature were tested longitudinally: a primacy judgment task and an ordering task. Results revealed that, even after controlling for differences in IQ, linearly increasing trajectories characterized age-related change in performance for both tasks; however, change appeared greater for the temporal ordering task. Further, performance on the two tasks was positively related, suggesting shared underlying mechanisms. These findings provide a more thorough understanding of temporal order memory in early to middle childhood by characterizing the developmental trajectories of two commonly used tasks and have important implications for our understanding of children's developing memory more broadly.