OBJECTIVE An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1–3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol. METHOD MRI scans of a single healthy adult human subject were acquired both at 3 Tesla and 7 Tesla. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement. RESULTS The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail. CONCLUSIONS The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

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...

The hippocampus is composed of distinct subfields: the four cornu ammonis areas (CA1–CA4), dentate gyrus (DG), and subiculum. The few in vivo studies of human hippocampal subfields suggest that the extent of age differences in volume varies across subfields during healthy childhood development and aging. However, the associations between age and subfield volumes across the entire lifespan are unknown. Here, we used a high-resolution imaging technique and manually measured hippocampal subfield and entorhinal cortex volumes in a healthy lifespan sample (N = 202), ages 8–82 years. The magnitude of age differences in volume varied among the regions. Combined CA1–2 volume evidenced a negative linear association with age. In contrast, the associations between age and volumes of CA3-DG and the entorhinal cortex were negative in mid-childhood and attenuated in later adulthood. Volume of the subiculum was unrelated to age. The different magnitudes and patterns of age differences in subfield volumes may reflect dynamic microstructural factors and have implications for cognitive functions across the lifespan.

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Due to the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies.

Advanced age is associated with decrements in episodic memory, which are more pronounced in memory for associations than in memory for individual items. The Associative Deficit Hypothesis (ADH) states that age differences in recognition memory reflect difficulty in binding components of a memory episode and retrieving bound units. To date, ADH has received support only in studies of extreme age groups, and the influence of sex, education, and health on age-related associative deficit is unknown. We address those issues using a verbal paired-associate yes/no recognition paradigm on a lifespan sample of 278 healthy, well-educated adults. In accord with the ADH, greater age was associated with lower hit and greater false alarm rates and more liberal response bias on associative recognition tests. Women outperformed men on recognition of items and associations, but among normotensive participants, women outperformed men only on memory for associations and not on item recognition. Thus, while supporting ADH in a large lifespan sample of healthy adults, the findings indicate that the effect may be partially driven by age-related increase in liberal bias in recognition of associations. Sex differences and health factors may modify the associative deficit regardless of age. Keywordsaging; memory; cognition; hypertension; sex differences Many studies of cognitive aging have reported moderate age-related decrements in episodic memory (Verhaeghen, Marcoen, & Goossens, 1993). Declines in memory for complex information have been ascribed to reduced ability to bind target information and the accompanying context into a cohesive and retrievable memory episode (Chalfonte & Johnson, 1996;Light, 1991;Mitchell, Johnson, Raye, & D'Esposito, 2000). The associative deficit hypothesis (ADH) of age-related declines in episodic memory posits that the binding deficit at encoding and the additional deficit in the retrieval of bound units are responsible for age-related memory declines (Naveh-Benjamin, 2000). The ADH predicts greater ageCorrespondence concerning this article should be addressed to Naftali Raz, 87 E. Ferry Street, 226 Knapp Building, Detroit, MI 48202. nraz@wayne.edu. Publisher's Disclaimer: The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript version, any version derived from this manuscript by NIH, or other third parties. The published version is available at www.apa.org/pubs/journals/PAG NIH Public Access Craik, 2003;Light, Patterson, Chung, & Healy, 2004;Naveh-Benjamin, 2000), the ADH has been supported by studies that employed other stimuli (see a meta-analysis by Old & NavehBenjamin, 2008).The extant studies on ADH have several limitations in design, sample characteristics, and ana...

Diffusion tensor imaging (DTI) studies show age-related differences in cerebral white matter (WM). However, few have studied WM changes over time, and none evaluated individual differences in change across a wide age range. Here, we examined two-year WM change in 96 healthy adults (baseline age 19-78 years), individual differences in change, and the influence of vascular and metabolic risk thereon. Fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) represented microstructural properties of normal appearing WM within 13 regions. Cross-sectional analyses revealed age-related differences in all WM indices across the regions. In contrast, latent change score analyses showed longitudinal declines in AD in association and projection fibers, and increases in anterior commissural fibers. FA and RD evidenced a less consistent pattern of change. Metabolic risk mediated the effects of age on FA and RD change in corpus callosum body and dorsal cingulum. These findings underscore the importance of longitudinal studies in evaluating individual differences in change, and the role of metabolic factors in shaping trajectories of brain aging.

Advanced age and vascular risk negatively affect episodic memory. The hippocampus (HC) is a complex structure, and little is known about the roles of different HC regions in age-related memory declines. Using data from an ongoing longitudinal study, we investigated whether memory functions are related to volumes of specific HC subregions (CA1-2, CA3-4/dentate gyrus, and subiculum). Furthermore, we inquired if arterial hypertension, a common age-related vascular risk factor, modifies age-related differences in HC regional volumes, concurrent memory performance, and improvement in memory over multiple administrations. Healthy adults (n = 49, 52-82 years old) completed associative recognition and free recall tasks. In grouped path models, covariance structures differed between hypertensive and normotensive participants. Whereas larger CA3-4/dentate gyrus volumes predicted greater improvement in associative memory over repeated tests regardless of vascular risk, CA1-2 volumes were associated with improvement in noun recall only in hypertensive participants. Only among hypertensive participants, CA1-2 volumes negatively related to age and CA3-4/dentate gyrus and CA1-2 volumes were associated with performance at the last measurement occasion. These findings suggest that relatively small regions of the HC may play a role in age-related memory declines and that vascular risk factors associated with advanced age may modify that relationship.

The few extant reports of longitudinal white matter (WM) changes in healthy aging, using diffusion tensor imaging (DTI), reveal substantial differences in change across brain regions and DTI indices. According to the last-in-first-out hypothesis of brain aging late-developing WM tracts may be particularly vulnerable to advanced age. To test this hypothesis we compared age-related changes in association, commissural and projection WM fiber regions using a skeletonized, region of interest DTI approach. Using linear mixed effects models, we evaluated the influences of age and vascular risk at baseline on seven-year changes in three indices of WM integrity and organization (axial diffusivity, AD, radial diffusivity, RD, and fractional anisotropy, FA) in healthy middle-aged and older adults (mean age = 65.4, SD = 9.0 years). Association fibers showed the most pronounced declines over time. Advanced age was associated with greater longitudinal changes in RD and FA, independent of fiber type. Furthermore, older age was associated with longitudinal RD increases in late-developing, but not early-developing projection fibers. These findings demonstrate the increased vulnerability of later developing WM regions and support the last-in-first-out hypothesis of brain aging.