Assessment of Neighborhood Poverty, Cognitive Function, and Prefrontal and Hippocampal Volumes in Children.

Importance: The association between poverty and unfavorable cognitive outcomes is robust, but most research has focused on individual household socioeconomic status (SES). There is increasing evidence that neighborhood context explains unique variance not accounted for by household SES. Objective: To evaluate whether neighborhood poverty (NP) is associated with cognitive function and prefrontal and hippocampal brain structure in ways that are dissociable from household SES. Design, Setting, and Participants: This cross-sectional study used a baseline sample of the ongoing longitudinal Adolescent Brain Cognitive Development (ABCD) Study. The ABCD Study will follow participants for assessments each year for 10 years. Data were collected at 21 US sites, mostly within urban and suburban areas, between September 2019 and October 2018. School-based recruitment was used to create a participant sample reflecting the US population. Data analysis was conducted from March to June 2019. Main Outcomes and Measures: NP and household SES were included as factors potentially associated with National Institutes of Health Toolbox Cognitive Battery subtests and hippocampal and prefrontal (dorsolateral prefrontal cortex [DLPFC], dorsomedial PFC [DMPFC], superior frontal gyrus [SFG]) volumes. Independent variables were first considered individually and then together in mixed-effects models with age, sex, and intracranial volume as covariates. Structural equation modeling (SEM) was used to assess shared variance in NP to brain structure and cognitive task associations. The tested hypotheses were formulated after data collection. Results: A total of 11 875 children aged 9 and 10 years (5678 [47.8%] girls) were analyzed. Greater NP was associated with lower scores across all cognitive domains (eg, total composite: ß = -0.18; 95% CI, -0.21 to -0.15; P < .001) and with decreased brain volume in the DLPFC (eg, right DLPFC: ß = -0.09; 95% CI, -0.12 to -0.07; P < .001), DMPFC (eg, right DMPC: ß = -0.07; 95% CI, -0.09 to -0.05; P < .001), SFG (eg, right SFG: ß = -0.05; 95% CI, -0.08 to -0.03; P < .001), and right hippocampus (ß = -0.04; 95% CI, -0.06 to -0.01; P = .01), even when accounting for household income. Greater household income was associated with higher scores across all cognitive domains (eg, total composite: ß = 0.30; 95% CI, 0.28 to 0.33; P < .001) and larger volume in all prefrontal and hippocampal brain regions (eg, right hippocampus: ß = 0.04; 95% CI, 0.02 to 0.07; P < .001) even when accounting for NP. The SEM model was a good fit across all cognitive domains, with prefrontal regions being associated with NP relations to language (picture vocabulary: estimate [SE], -0.03 [0.01]; P < .001; oral reading: estimate [SE], -0.02 [0.01]; P < .001), episodic memory (picture sequence: estimate [SE], -0.02 [0.01]; P = .008), and working memory (dimensional card sort: estimate [SE], -0.02 [0.01]; P = .001; flanker inhibitory control: estimate [SE], -0.01 [0.01]; P = .01; list sorting: estimate [SE], -0.03 [0.01]; P < .001) and hippocampal regions being associated with NP associations with language (picture vocabulary: estimate [SE], -0.01 [0.004]; P < .001) and episodic memory (picture sequence: estimate [SE], -0.01 [0.004]; P < 0.001). Conclusions and Relevance: In this study, NP accounted for unique variance in cognitive function and prefrontal and right hippocampal brain volume. These findings demonstrate the importance of including broader environmental influences when conceptualizing early life adversity.

Engagement in Enriching Early-Life Activities Is Associated With Larger Hippocampal and Amygdala Volumes in Community-Dwelling Older Adults.

OBJECTIVES: Numerous studies show benefits of mid- and late-life activity on neurocognitive health. Yet, few studies have examined how engagement in enriching activities during childhood, when the brain is most plastic, may confer long-term neurocognitive benefits that may be especially important to individuals raised in low-income settings. We examined associations between enriching early-life activities (EELAs) and hippocampal and amygdala volumes in a sample of predominantly African-American, community-dwelling older adults. We further assessed whether these associations were independent of current activity engagement. METHODS: Ninety participants from the baseline Brain Health Substudy of the Baltimore Experience Corps Trial (mean age: 67.4) completed retrospective activity inventories and an magnetic resonance imaging scan. Volumes were segmented using FreeSurfer. RESULTS: Each additional EELA was associated with a 2.3% (66.6 mm3) greater amygdala volume after adjusting for covariates. For men, each additional EELA was associated with a 4.1% (278.9 mm3) greater hippocampal volume. Associations were specific to these regions when compared with the thalamus, used as a control region. DISCUSSION: Enriching lifestyle activities during an important window of childhood brain development may be a modifiable factor that impacts lifelong brain reserve, and results highlight the importance of providing access to such activities in historically underserved populations.

Subcortical structural variations associated with low socioeconomic status in adolescents.

Low socioeconomic status (SES) is associated with a higher probability of multiple exposures (e.g., neighborhood violence, poor nutrition, housing instability, air pollution, and insensitive caregiving) known to affect structural development of subcortical brain regions that subserve threat and reward processing, however, few studies have examined the relationship between SES and such subcortical structures in adolescents. We examined SES variations in volume and surface morphometry of subcortical regions. The sample comprised 256 youth in eighth grade (mean age = 13.9 years), in whom high dimensional deformation mapping of structural 3T magnetic resonance imaging scans was performed. Vertex-wise linear regression analyses examined associations between income to poverty ratio and surfaces of the hippocampus, amygdala, thalamus, caudate, putamen, nucleus accumbens and pallidum, with the covariates age, pubertal status, and intracranial volume. Given sex differences in pubertal development and subcortical maturation at this age, the analyses were stratified by sex. Among males, who at this age average an earlier pubertal stage than females, the relationship between SES and local shape variation in subcortical regions was almost entirely positive. For females, the relationship between SES and local shape variation was negative. Racial identity was associated with SES in our sample, however supplementary analyses indicated that most of the associations between SES and subcortical structure were independent of it. Although these cross-sectional results are not definitive, they are consistent with a scenario where low SES delays structural maturation of subcortical regions involved with threat and reward processing. Future longitudinal studies are needed to test this hypothesis.

Socioeconomic disadvantage, brain morphometry, and attentional bias to threat in middle childhood.

Socioeconomic disadvantage is associated with higher rates of psychopathology as well as hippocampus, amygdala and prefrontal cortex structure. However, little is known about how variations in brain morphometry are associated with socio-emotional risks for mood disorders in children growing up in families experiencing low income. In the current study, using structural magnetic resonance imaging, we examined the relationship between socioeconomic disadvantage and gray matter volume in the hippocampus, amygdala, and ventrolateral prefrontal cortex in a sample of children (n = 34) in middle childhood. Using an affective dot probe paradigm, we examined the association between gray matter volume in these regions and attentional bias to threat, a risk marker for mood disorders including anxiety disorders. We found that lower income-to-needs ratio was associated with lower bilateral hippocampal and right amygdala volume, but not prefrontal cortex volumes. Moreover, lower attentional bias to threat was associated with greater left hippocampal volume. We provide evidence of a relationship between income-related variations in brain structure and attentional bias to threat, a risk for mood disorders. Therefore, these findings support an environment-morphometry-behavior relationship that contributes to the understanding of income-related mental health disparities in childhood.

The hippocampus: detailed assessment of normative two-dimensional measurements, signal intensity, and subfield conspicuity on routine 3T T2-weighted sequences.

PURPOSE: The hippocampus has a critical role in many common disease processes. Currently, routine 3 Tesla structural MRI is a mainstay of clinical diagnosis. The goal of our study is to evaluate the normal variability in size and/or conspicuity of the hippocampal subcomponents in routine clinical 3 Tesla high-resolution T2-weighted images to provide a basis for better defining pathological derangements. Additionally, we utilize diffusion data acquired from a 17.6 Tesla MRI of the hippocampus as a benchmark to better illustrate these subcomponents. METHODS: The hippocampus was retrospectively assessed on 104 clinically normal patients undergoing coronal T2-weighted imaging. The conspicuity of the majority of hippocampal subcomponents was assessed in each portion of the hippocampus. Additionally, easily applicable cross-sectional measurements and signal intensities were obtained to evaluate the range of normal, as well as inter- and intra-subject variability. RESULTS: The normal range of cross-sectional measurements of the hippocampal subcomponents was calculated. There was minimal side-to-side variability in cross-sectional measurements of hippocampal subcomponents (< 5%) with the exception of the subiculum (R>L by 8.3%) and the CA4/DG (R>L by 5.8%). The internal architecture showed high variability in visibility of subcomponents between different segments of the hippocampus. CONCLUSIONS: Confident clinical assessment of the hippocampus requires a thorough knowledge of hippocampal size and signal, but also the internal architecture expected to be seen. The data provided in this study will provide the reader with vital information necessary for distinguishing a normal from abnormal exam.

APOE ε4 Genotype and Cognitive Reserve Effects on the Cognitive Functioning of Healthy Elders.

AIM: To test the association between cognitive performance and APOE genotype, and to assess potential modifications of this association by sociodemographic and neuroanatomical factors in a sample of 74 healthy elders. METHODS: Firstly, we explored the isolated role of the APOE ɛ4 genotype (i.e., APOE4) in different neuropsychological tests, and then the effects of its interaction with sociodemographic (i.e., age, gender, and educational level) and neuroanatomical (i.e., hippocampal volumes) variables. Subsequently, we performed the same analyses after dividing the sample into two subgroups according to their Mini-Mental State Examination scores (control-high group ≥29 and control-low group < 29). RESULTS: In the whole group, APOE4 carriers exhibited a significantly poorer execution in several cognitive domains including global cognitive functioning, episodic memory, verbal fluency, and naming. This effect was more noticeable in older and less educated subjects. The separated analyses revealed that APOE4 carriers in the control-low group exhibited lower scores in global cognitive functioning and episodic memory, while no effects were observed in the control-high group. Neither gender nor hippocampal volumes showed a significant interaction effect with APOE genotype. CONCLUSIONS: Current results point out that APOE4 genotype influences healthy aged cognition, although factors such age or educational attainment seem to modulate its effects.

Age-Related Differences in Cortical Thickness Vary by Socioeconomic Status.

Recent findings indicate robust associations between socioeconomic status (SES) and brain structure in children, raising questions about the ways in which SES may modify structural brain development. In general, cortical thickness and surface area develop in nonlinear patterns across childhood and adolescence, with developmental patterns varying to some degree by cortical region. Here, we examined whether age-related nonlinear changes in cortical thickness and surface area varied by SES, as indexed by family income and parental education. We hypothesized that SES disparities in age-related change may be particularly evident for language- and literacy-supporting cortical regions. Participants were 1148 typically-developing individuals between 3 and 20 years of age. Results indicated that SES factors moderate patterns of age-associated change in cortical thickness but not surface area. Specifically, at lower levels of SES, associations between age and cortical thickness were curvilinear, with relatively steep age-related decreases in cortical thickness earlier in childhood, and subsequent leveling off during adolescence. In contrast, at high levels of SES, associations between age and cortical thickness were linear, with consistent reductions across the age range studied. Notably, this interaction was prominent in the left fusiform gyrus, a region that is critical for reading development. In a similar pattern, SES factors significantly moderated linear age-related change in left superior temporal gyrus, such that higher SES was linked with steeper age-related decreases in cortical thickness in this region. These findings suggest that SES may moderate patterns of age-related cortical thinning, especially in language- and literacy-supporting cortical regions.

Family income, parental education and brain structure in children and adolescents.

Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. We investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1,099 typically developing individuals between 3 and 20 years of age. Income was logarithmically associated with brain surface area. Among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data imply that income relates most strongly to brain structure among the most disadvantaged children.

Genetic, psychosocial and clinical factors associated with hippocampal volume in the general population.

The hippocampus--crucial for memory formation, recall and mood regulation--is involved in the pathophysiology of dementia and depressive disorders. Recent genome-wide association studies (GWAS) have identified five genetic loci associated with hippocampal volume (HV). Previous studies have described psychosocial and clinical factors (for example, smoking, type 2 diabetes and hypertension) to have an impact on HV. However, the interplay between genetic, psychosocial and clinical factors on the HV remains unclear. Still, it is likely that genetic variants and clinical or psychosocial factors jointly act in modifying HV; it might be possible they even interact. Knowledge of these factors might help to quantify ones individual risk of or rather resilience against HV loss. We investigated subjects (N=2463; 55.7% women; mean age 53 years) from the Study of Health in Pomerania (SHIP-2; SHIP-TREND-0) who underwent whole-body magnetic resonance imaging (MRI) and genotyping. HVs were estimated with FreeSurfer. For optimal nonlinear model fitting, we used regression analyses with restricted cubic splines. Genetic variants and associated psychosocial or clinical factors were jointly assessed for potential two-way interactions. We observed associations between HV and gender (P<0.0001), age (P<0.0001), body height (P<0.0001), education (P=0.0053), smoking (P=0.0058), diastolic blood pressure (P=0.0211), rs7294919 (P=0.0065), rs17178006 (P=0.0002), rs6581612 (P=0.0036), rs6741949 (P=0.0112) and rs7852872 (P=0.0451). In addition, we found three significant interactions: between rs7294919 and smoking (P=0.0473), rs7294919 and diastolic blood pressure (P=0.0447) and between rs7852872 and rs6581612 (P=0.0114). We suggest that these factors might have a role in the individual susceptibility to hippocampus-associated disorders.

Multi-atlas segmentation of the whole hippocampus and subfields using multiple automatically generated templates.

INTRODUCTION: Advances in image segmentation of magnetic resonance images (MRI) have demonstrated that multi-atlas approaches improve segmentation over regular atlas-based approaches. These approaches often rely on a large number of manually segmented atlases (e.g. 30-80) that take significant time and expertise to produce. We present an algorithm, MAGeT-Brain (Multiple Automatically Generated Templates), for the automatic segmentation of the hippocampus that minimises the number of atlases needed whilst still achieving similar agreement to multi-atlas approaches. Thus, our method acts as a reliable multi-atlas approach when using special or hard-to-define atlases that are laborious to construct. METHOD: MAGeT-Brain works by propagating atlas segmentations to a template library, formed from a subset of target images, via transformations estimated by nonlinear image registration. The resulting segmentations are then propagated to each target image and fused using a label fusion method. We conduct two separate Monte Carlo cross-validation experiments comparing MAGeT-Brain and basic multi-atlas whole hippocampal segmentation using differing atlas and template library sizes, and registration and label fusion methods. The first experiment is a 10-fold validation (per parameter setting) over 60 subjects taken from the Alzheimer's Disease Neuroimaging Database (ADNI), and the second is a five-fold validation over 81 subjects having had a first episode of psychosis. In both cases, automated segmentations are compared with manual segmentations following the Pruessner-protocol. Using the best settings found from these experiments, we segment 246 images of the ADNI1:Complete 1Yr 1.5 T dataset and compare these with segmentations from existing automated and semi-automated methods: FSL FIRST, FreeSurfer, MAPER, and SNT. Finally, we conduct a leave-one-out cross-validation of hippocampal subfield segmentation in standard 3T T1-weighted images, using five high-resolution manually segmented atlases (Winterburn et al., 2013). RESULTS: In the ADNI cross-validation, using 9 atlases MAGeT-Brain achieves a mean Dice's Similarity Coefficient (DSC) score of 0.869 with respect to manual whole hippocampus segmentations, and also exhibits significantly lower variability in DSC scores than multi-atlas segmentation. In the younger, psychosis dataset, MAGeT-Brain achieves a mean DSC score of 0.892 and produces volumes which agree with manual segmentation volumes better than those produced by the FreeSurfer and FSL FIRST methods (mean difference in volume: 80 mm(3), 1600 mm(3), and 800 mm(3), respectively). Similarly, in the ADNI1:Complete 1Yr 1.5 T dataset, MAGeT-Brain produces hippocampal segmentations well correlated (r>0.85) with SNT semi-automated reference volumes within disease categories, and shows a conservative bias and a mean difference in volume of 250 mm(3) across the entire dataset, compared with FreeSurfer and FSL FIRST which both overestimate volume differences by 2600 mm(3) and 2800 mm(3) on average, respectively. Finally, MAGeT-Brain segments the CA1, CA4/DG and subiculum subfields on standard 3T T1-weighted resolution images with DSC overlap scores of 0.56, 0.65, and 0.58, respectively, relative to manual segmentations. CONCLUSION: We demonstrate that MAGeT-Brain produces consistent whole hippocampal segmentations using only 9 atlases, or fewer, with various hippocampal definitions, disease populations, and image acquisition types. Additionally, we show that MAGeT-Brain identifies hippocampal subfields in standard 3T T1-weighted images with overlap scores comparable to competing methods.

Assessment of human hippocampal developmental neuroanatomy by means of ex-vivo 7 T magnetic resonance imaging.

During development, the hippocampus undergoes numerous changes in its cell morphology and cyto- and myelo-architecture that begin during the fetal period and continue after birth. We investigated the developmental changes occurring in healthy fetal (20-32 gestational weeks) and post-natal human hippocampi (from 1 day to adulthood) by combining high-resolution 7 T magnetic resonance imaging (MRI) and histological and immunohistochemical analyses in order to compare variations in signal intensity with cyto- and myeloarchitectural organization. During fetal period the intensity of the T2-weighted images was related to the cell density and the subregions of Ammon's horn and dentate gyrus, characterized by densely packed neurons, were recognizable as hypointense areas. The inverse correlation between MRI signal intensity and cell density was visualized by line profile results. At the age of two post-natal weeks, the low MRI signal was still related to cell density, although thin myelinated fibers were observed in hypointense regions such as the alveus and stratum lacunosum-moleculare. The myelin content subsequently increases until the complete hippocampal myeloarchitecture is reached in adulthood. Comparison of the MRI findings and corresponding histological sections indicated that the differences in the T2-weighted images between the age of seven years and adulthood reflect the increasing density of myelinated fibers. These results provide useful information concerning the interpretation of MRI signals and the developmental changes visualized by in vivo MRI at lower field strengths, and may be used as a reference for the future use of high spatial resolution MRI in clinical practice.

What are the links between maternal social status, hippocampal function, and HPA axis function in children?

The association of parental social status with multiple health and achievement indicators in adulthood has driven researchers to attempt to identify mechanisms by which social experience in childhood could shift developmental trajectories. Some accounts for observed linkages between parental social status in childhood and health have hypothesized that early stress exposure could result in chronic disruptions in hypothalamic-pituitary-adrenal (HPA) axis activation, and that this activation could lead to long-term changes. A robust literature in adult animals has demonstrated that chronic HPA axis activation leads to changes in hippocampal structure and function. In the current study, consistent with studies in animals, we observe an association between both maternal self-rated social status and hippocampal activation in children and between maternal self-rated social status and salivary cortisol in children.

Seasonal and sex differences in the hippocampus of a wild rodent.

Studies across and within species suggest that hippocampus size is sexually dimorphic in polygamous species, but not in monogamous species. Although hippocampal volume varies with sex, season and mating system, few studies have simultaneously tested for sex and seasonal differences. Here, we test for sex and seasonal differences in the hippocampal volume of wild Richardson's ground squirrels (Urocitellus richardsonii), a polygamous species that lives in matrilineal, kin-based social groups and has profound sex differences in behavior. Based on the behavior and ecology of this species, we predicted that males would have a significantly larger hippocampus than females and that the hippocampus would be largest in males during the breeding season. Analyses of both absolute and relative volumes of the hippocampus yielded a significant difference between the sexes and seasons as well as an interaction between the two such that non-breeding males have significantly larger hippocampal volumes than breeding males or females from either season. Dentate gyrus, CA1 and CA3 subfield volumes were generally larger in the non-breeding season and in males, but no significant interaction effects were detected. This sex and seasonal variation in hippocampal volume is likely the result of their social organization and male-only food caching behavior during the non-breeding season. The demonstration of a sex and seasonal variation in hippocampal volume suggests that Richardson's ground squirrel may be a useful model for understanding hippocampal plasticity within a natural context.

Neural correlates of socioeconomic status in the developing human brain.

Socioeconomic disparities in childhood are associated with remarkable differences in cognitive and socio-emotional development during a time when dramatic changes are occurring in the brain. Yet, the neurobiological pathways through which socioeconomic status (SES) shapes development remain poorly understood. Behavioral evidence suggests that language, memory, social-emotional processing, and cognitive control exhibit relatively large differences across SES. Here we investigated whether volumetric differences could be observed across SES in several neural regions that support these skills. In a sample of 60 socioeconomically diverse children, highly significant SES differences in regional brain volume were observed in the hippocampus and the amygdala. In addition, SES × age interactions were observed in the left superior temporal gyrus and left inferior frontal gyrus, suggesting increasing SES differences with age in these regions. These results were not explained by differences in gender, race or IQ. Likely mechanisms include differences in the home linguistic environment and exposure to stress, which may serve as targets for intervention at a time of high neural plasticity.

Childhood socioeconomic status and adult brain size: childhood socioeconomic status influences adult hippocampal size.

OBJECTIVE: To investigate in older adults without dementia the relationships between socioeconomic status (SES) in childhood and magnetic resonance imaging (MRI)-derived brain volume measures typical of brain aging and Alzheimer's disease (AD). METHODS: Using a cross-sectional and longitudinal observation approach, we invited volunteers without dementia, all born in 1936, and who were participants in the 1947 Scottish Mental Survey, for MR brain imaging; 249 of 320 (77%) agreed. We measured whole brain and hippocampal volumes and recorded childhood SES history, the number of years of education undertaken, and adult SES history. Mental ability at age 11 years was recorded in 1947 and was also available. RESULTS: Analysis shows a significant association between childhood SES and hippocampal volume after adjusting for mental ability at age 11 years, adult SES, gender, and education. INTERPRETATION: A significant association between childhood SES and hippocampal volumes in late life is consistent with the established neurodevelopmental findings that early life conditions have an effect on structural brain development. This remains detectable more than 50 years later.

Subfields of the hippocampal formation at 7 T MRI: in vivo volumetric assessment.

Animal and human autopsy studies suggest that subfields of the hippocampal formation are differentially affected by neuropsychiatric diseases. Therefore, subfield volumes may be more sensitive to effects of disease processes. The few human studies that segmented subfields of the hippocampal formation in vivo either assessed the subfields only in the body of the hippocampus, assessed only three subfields, or did not take the differential angulation of the head of the hippocampus into account. We developed a protocol using 7 Tesla MRI with isotropic voxels to reliably delineate the entorhinal cortex (ERC), subiculum (SUB), CA1, CA2, CA3, dentate gyrus (DG)&CA4 along the full-length of the hippocampus. Fourteen subjects (aged 54-74 years, 2 men and 12 women) were scanned with a 3D turbo spin echo (TSE) sequence with isotropic voxels of 0.7 × 0.7 × 0.7 mm(3) on a 7 T MRI whole body scanner. Based on previous protocols and extensive anatomic atlases, a new protocol for segmentation of subfields of the hippocampal formation was formulated. ERC, SUB, CA1, CA2, CA3 and DG&CA4 were manually segmented twice by one rater from coronal MR images. Good-to-excellent consistency was found for all subfields (Intraclass Correlation Coefficient's (ICC) varying from 0.74 to 0.98). Accuracy as measured with the Dice Similarity Index (DSI) was above 0.82 for all subfields, with the exception of the smaller subfield CA3 (0.68-0.70). In conclusion, this study shows that it is possible to delineate the main subfields of the hippocampal formation along its full-length in vivo at 7 T MRI. Our data give evidence that this can be done in a reliable manner. Segmentation of subfields in the full-length of the hippocampus may bolster the study of the etiology neuropsychiatric diseases.

Association between income and the hippocampus.

Facets of the post-natal environment including the type and complexity of environmental stimuli, the quality of parenting behaviors, and the amount and type of stress experienced by a child affects brain and behavioral functioning. Poverty is a type of pervasive experience that is likely to influence biobehavioral processes because children developing in such environments often encounter high levels of stress and reduced environmental stimulation. This study explores the association between socioeconomic status and the hippocampus, a brain region involved in learning and memory that is known to be affected by stress. We employ a voxel-based morphometry analytic framework with region of interest drawing for structural brain images acquired from participants across the socioeconomic spectrum (n = 317). Children from lower income backgrounds had lower hippocampal gray matter density, a measure of volume. This finding is discussed in terms of disparities in education and health that are observed across the socioeconomic spectrum.

In vivo hippocampal measurement and memory: a comparison of manual tracing and automated segmentation in a large community-based sample.

While manual tracing is the method of choice in measuring hippocampal volume, its time intensive nature and proneness to human error make automated methods attractive, especially when applied to large samples. Few studies have systematically compared the performance of the two techniques. In this study, we measured hippocampal volumes in a large (N = 403) population-based sample of individuals aged 44-48 years using manual tracing by a trained researcher and automated procedure using Freesurfer (http://surfer.nmr.mgh.harvard.edu) imaging suite. Results showed that absolute hippocampal volumes assessed with these methods were significantly different, with automated measures using the Freesurfer software suite being significantly larger, by 23% for the left and 29% for the right hippocampus. The correlation between the two methods varied from 0.61 to 0.80, with lower correlations for hippocampi with visible abnormalities. Inspection of 2D and 3D models suggested that this difference was largely due to greater inclusion of boundary voxels by the automated method and variations in subiculum/entorhinal segmentation. The correlation between left and right hippocampal volumes was very similar by the two methods. The relationship of hippocampal volumes to selected sociodemographic and cognitive variables was not affected by the measurement method, with each measure showing an association with memory performance and suggesting that both were equally valid for this purpose. This study supports the use of automated measures, based on Freesurfer in this instance, as being sufficiently reliable and valid particularly in the context of larger sample sizes when the research question does not rely on 'true' hippocampal volumes.

Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: evidence that the duration of hormone deprivation after ovariectomy compromises 17beta-estradiol effectiveness in altering CA1 spines.

Two pulses of 17beta-estradiol (10 microg) are commonly used to increase hippocampal CA1 apical dendritic spine density and alter spatial performance in ovariectomized (OVX) female rats, but rarely are the measures combined. The goal of this study was to use this two-pulse injection protocol repeatedly with intervening wash-out periods in the same rats to: 1) measure spatial ability using different tasks that require hippocampal function and 2) determine whether ovarian hormone depletion for an extended 10-week period reduces 17beta-estradiol's effectiveness in elevating CA1 apical dendritic spine density. Results showed that two injections of 10 microg 17beta-estradiol (72 and 48 h prior to testing and timed to maximize CA1 apical spine density at behavioral assessment) corresponded to improved spatial memory performance on object placement. In contrast, two injections of 5 microg 17beta-estradiol facilitated spatial learning on the water maze compared to rats given two injections of 10 microg 17beta-estradiol or the sesame oil vehicle. Neither 17beta-estradiol dose altered Y-maze performance. As expected, the intermittent two-pulse injection protocol increased CA1 apical spine density, but 10 weeks of OVX without estradiol treatment decreased the effectiveness of 10 microg 17beta-estradiol to increase CA1 apical spine density. Moreover, two pulses of 5 microg 17beta-estradiol injected intermittently failed to alter CA1 apical spine density and decreased basal spine density. These results demonstrate that extended time without ovarian hormones reduces 17beta-estradiol's effectiveness to increase CA1 apical spine density. Collectively, these findings highlight the complex interactions among estradiol, CA1 spine density/morphology, and task requirements, all of which contribute to behavioral outcomes.

A role for dorsal and ventral hippocampus in inter-temporal choice cost-benefit decision making.

Previous studies suggest a preferential role for dorsal hippocampus (dHPC) in spatial memory tasks, whereas ventral hippocampus (vHPC) has been implicated in aspects of fear and/or anxiety. In this study, we tested the hypothesis that vHPC may be a critical subregion for performance on a delay-based, cost-benefit decision making task. Rats chose between the two goal arms of a T maze, one containing an immediately available small reward, the other containing a larger reward that was only accessible after a delay. dHPC, vHPC, and complete hippocampal (cHPC) lesions all reduced choice of the delayed high reward (HR) in favor of the immediately available low reward (LR). The deficits were not due to a complete inability to remember which reward size was associated with which arm of the maze. When an equivalent 10-s delay was introduced in both goal arms, all rats chose the HR arm on nearly all trials. The deficit was, however, reinstated when the inequality was reintroduced. Our results suggest an important role for both dHPC and vHPC in the extended neural circuitry that underlies intertemporal choice.