Age differences in hippocampal subfield volumes from childhood to late adulthood

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 yrs. 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. © 2015 Wiley Periodicals, Inc.     

Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors

The developing hippocampus is highly sensitive to chemotherapy and cranial radiation treatments for pediatric cancers, yet little is known about the effects that cancer treatents have on specific hippocampal subfields. Here, we examined hippocampal subfield volumes in 29 pediatric brain tumor survivors treated with cranial radiation and chemotherapy, and 30 healthy developing children and adolescents. We also examined associations between hippocampal subfield volumes and short‐term verbal memory. Hippocampal subfields (Cornus Ammonis (CA) 1, CA2‐3, dentate gyrus (DG)‐CA4, stratum radiatum—lacunosum—moleculare, and subiculum) were segmented using the Multiple Automatically Generated Templates for Different Brains automated segmentation algorithm. Neuropsychological assessment of short‐term verbal associative memory was performed in a subset of brain tumor survivors (N = 11) and typically developing children (N = 16), using the Children's Memory Scale or Wechsler's Memory Scale—third edition. Repeated measures analysis of variance showed that pediatric brain tumor survivors had significantly smaller DG‐CA4, CA1, CA2‐3, and stratum radiatum‐lacunosum‐moleculare volumes compared with typically developing children. Verbal memory performance was positively related to DG‐CA4, CA1, and stratum radiatum‐lacunosum‐moleculare volumes in pediatric brain tumor survivors. Unlike the brain tumor survivors, there were no associations between subfield volumes and memory in typically developing children and adolescents. These data suggest that specific subfields of the hippocampus may be vulnerable to brain cancer treatments, and may contribute to impaired episodic memory following brain cancer treatment in childhood.     

BDNF Val66Met genotype interacts with childhood adversity and influences the formation of hippocampal subfields

Childhood stress and genetic factors like the Val66MET polymorphism of the brain derived neurotrophic factor (BDNF) gene are associated with a higher risk for developing major depressive disorder (MDD) and might also influence hippocampal changes. The aim of this study was to determine which hippocampal dentate gyrus and cornu ammonis subfields are altered in MDD compared to healthy controls and which subfields are affected by the BDNF Val66Met polymorphism and child adversity. Adult patients with MDD and healthy matched controls underwent high‐resolution magnetic resonance imaging. Automatic segmentation using the programme FreeSurfer was used to segment the hippocampal subfields dentate gyrus (DG/CA4), CA1 and CA2/3. The history of possible childhood adversity was assessed using the Childhood Trauma Questionnaire and the Val66Met BDNF SNP (rs6265) genotypes were obtained. Patients with MDD had significantly smaller CA4/DG and CA2/3 volumes compared to healthy controls. Furthermore, there was a significant interactive effect of BDNF allele and childhood adversity on CA2/3 and CA4/DG volumes. Met allele carriers without childhood adversity had larger and with childhood adversity smaller CA4/DG and CA2/3 volumes than Val‐allele homozygotes. Our results highlight stress by gene interactions as relevant for hippocampal volume reductions, in particular for the subfield CA2/3 and dentate gyrus. Hum Brain Mapp 35:5776–5783, 2014. © 2014 Wiley Periodicals, Inc .     

Hippocampal subfields alterations in adolescents with post‐traumatic stress disorder

Reexperiencing symptoms in adolescent Post‐Traumatic Stress Disorder (PTSD) are characterized by the apparition of vivid intrusive images of the traumatic event. The emergence of these intrusions is thought to be related to a deficiency in context processing and could then be related to hippocampal alterations. The hippocampus is a complex structure which can be divided into several subfields, namely, the Cornu Ammonis (CA1, CA2, and CA3), the subiculum, and the dentate gyrus (DG). As each subfield presents different histological characteristics and functions, it appears more relevant to consider hippocampal subfields, instead of only assessing the whole hippocampus, to understand the neurobiology of PTSD. Hence, this study presents the first investigation of structural alterations within hippocampal subfields and their links to reexperiencing symptoms in adolescent PTSD. Hippocampal subfields were manually delineated on high‐resolution MRI images in 15 adolescents (13–18 years old) with PTSD and 24 age‐matched healthy controls. The volume of the region CA2‐3/DG region was significantly smaller in the PTSD group compared to controls in both hemispheres. No other significant difference was found for other subfields. Moreover, the volume of the left CA2‐3/DG was negatively correlated with the intrusion score (as measured by the Impact of Events Scale‐Revised) in the PTSD group. To conclude, an alteration in the hippocampal subregion CA2‐3/DG, known to resolve interferences between new and similar stored memories, could participate in the apparition of intrusive trauma memories in adolescents with PTSD.     

The atrophy and laterality of the hippocampal subfields in parents with or without posttraumatic stress disorder who lost their only child in China

Investigating hippocampal subfields may provide new and important insights into the pathophysiology of posttraumatic stress disorder (PTSD). However, no study has examined the hippocampal subfield volume changes in parents with or without PTSD who had lost their only child and could no longer conceive in China. Fifty-seven parents with PTSD (PTSD+), 11 trauma-exposed parents without PTSD (PTSD?), and 39 non-traumatized controls were recruited to examine the hippocampal subfield volumes using magnetic resonance imaging. Correlations of the volumes with the time since trauma and Clinician-Administered PTSD Scale (CAPS) scores were investigated in the PTSD+ group. The volumes of the bilateral cornu ammonis (CA) 2–3, CA4–dentate gyrus (DG), and left subiculum were significantly smaller in the PTSD+ and PTSD? groups than in the controls, but there were no significant differences between the PTSD+ and PTSD? groups. Additionally, the left CA2–3 and CA4–DG volumes reduced more than those on the right side in the PTSD+ and PTSD? groups. The subfield volumes were not related to the time since trauma and the CAPS scores in the PTSD+ group. In conclusion, hippocampal subfield volumes decreased in parents who lost their only child with or without PTSD, and the volumetric reduction may be independent of PTSD and trauma-related. Moreover, the hippocampal volume deficits showed laterality that the left side was affected more than the right, and the hippocampal subfields may show differential vulnerabilities to trauma/PTSD, with the CA2–3 and CA4–DG subfields more sensitive than others.     

Contributions of the hippocampal subfields and entorhinal cortex to disambiguation during working memory

The hippocampus and medial temporal lobes (MTL) support the successful formation of new memories without succumbing to interference from related, older memories. Computational models and animal findings have implicated the dentate gyrus (DG), CA3, CA1, and entorhinal cortex (EC) in the disambiguation and encoding of well‐established, episodic events that share common elements. However, it is unknown if these hippocampal subfields and MTL (entorhinal, perirhinal, parahippocampal) cortices also contribute during working memory when overlapping stimuli that share related features are rapidly encoded and subsequently maintained over a brief temporal delay. We hypothesized that activity in CA3/DG hippocampal subfields would be greater for the rapid encoding of stimuli with overlapping features than for the rapid encoding of stimuli with distinct features. In addition, we predicted that CA1 and EC, regions that are associated with creating long‐term episodic representations, would show greater sustained activity across both encoding and delay periods for representations of stimuli with overlapping features than for those with distinct features. We used high‐resolution fMRI during a delayed matching‐to‐sample (DMS) task using face pairs that either shared (overlapping condition, OL) or did not share (non‐overlapping condition, NOL) common elements. We contrasted the OL condition with the NOL condition separately at sample (encoding) and during a brief delay (maintenance). At sample, we observed activity localized to CA3/DG, the subiculum, and CA1. At delay, we observed activity localized to the subiculum and CA1 and activity within the entorhinal, perirhinal, and parahippocampal cortices. Our findings are consistent with our hypotheses and suggest that CA3/DG, CA1 and the subiculum support the disambiguation and encoding of overlapping representations while CA1, subiculum and entorhinal cortex maintain these overlapping representations during working memory. © 2013 Wiley Periodicals, Inc.     

Development of hippocampal subfield volumes from 4 to 22 years

The hippocampus supports several important cognitive functions known to undergo substantial development during childhood and adolescence, for example, encoding and consolidation of vivid personal memories. However, diverging developmental effects on hippocampal volume have been observed across studies. It is possible that the inconsistent findings may attribute to varying developmental processes and functions related to different hippocampal subregions. Most studies to date have measured global hippocampal volume. We aimed to explore early hippocampal development both globally and regionally within subfields. Using cross‐sectional 1.5 T magnetic resonance imaging data from 244 healthy participants aged 4–22 years, we performed automated hippocampal segmentation of seven subfield volumes; cornu ammonis (CA) 1, CA2/3, CA4/dentate gyrus (DG), presubiculum, subiculum, fimbria, and hippocampal fissure. For validation purposes, seven subjects were scanned at both 1.5 and 3 T, and all subfields except fimbria showed strong correlations across field strengths. Effects of age, left and right hemisphere, sex and their interactions were explored. Nonparametric local smoothing models (smoothing spline) were used to depict age‐trajectories. Results suggested nonlinear age functions for most subfields where volume increases until 13–15 years, followed by little age‐related changes during adolescence. Further, the results showed greater right than left hippocampal volumes that seemed to be augmenting in older age. Sex differences were also found for subfields; CA2/3, CA4/DG, presubiculum, subiculum, and CA1, mainly driven by participants under 13 years. These results provide a detailed characterization of hippocampal subfield development from early childhood. Hum Brain Mapp 35:5646–5657, 2014. © 2014 Wiley Periodicals, Inc.     

Intrinsic connectivity of hippocampal subfields in normal elderly and mild cognitive impairment patients

Hippocampal connectivity has been widely described but connectivity specificities of hippocampal subfields and their changes in early AD are poorly known. The aim of this study was to highlight hippocampal subfield networks in healthy elderly (HE) and their changes in amnestic patients with mild cognitive impairment (aMCI). Thirty‐six HE and 27 aMCI patients underwent resting‐state functional MRI scans. Specific intrinsic connectivity of bilateral CA1, SUB (subiculum), and CA2/3/4/DG was identified in HE (using seeds derived from manually delineation on high‐resolution scans) and compared between HE and aMCI. Compared to the other subfields, CA1 was more strongly connected to the amygdala and occipital regions, CA2/3/4/DG to the left anterior cingulate cortex, temporal, and occipital regions, and SUB to the angular, precuneus, putamen, posterior cingulate, and frontal regions. aMCI patients showed reduced connectivity within the SUB network (with frontal and posterior cingulate regions). Our study highlighted for the first time three specific and distinct hippocampal subfield functional networks in HE, and their alterations in aMCI. These findings are important to understand AD specificities in both cognitive deficits and lesion topography, given the role of functional connectivity in these processes. Hum Brain Mapp 38:4922–4932, 2017. © 2017 Wiley Periodicals, Inc.     

In vivo mapping of hippocampal subfields in mesial temporal lobe epilepsy: Relation to histopathology

A particularly popular automated magnetic resonance imaging (MRI) hippocampal subfield mapping technique is the one described by Van Leemput et al. (2009: Hippocampus 19:549–557) that is currently distributed with FreeSurfer software. This method assesses the probabilistic locations of subfields based on a priori knowledge of subfield topology determined from high‐field MRI. Many studies have applied this technique to conventionally acquired T1‐weighted MRI data. In the present study, we investigated the relationship between this technique applied to conventional T1‐weighted MRI data acquired at 3 T and postsurgical hippocampal histology in patients with medically intractable mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Patients with mTLE (n = 82) exhibited significant volume loss of ipsilateral CA1, CA2‐3, CA4‐dentate gyrus (DG), subiculum, and fimbria relative to controls (n = 81). Histopathological analysis indicated that the most significant neuronal loss was observed in CA1, then CA4 and CA3, and more subtle neuronal loss in CA2, consistent with classical HS. Neuronal density of CA1 significantly correlated with MRI‐determined volume of CA1, and increasingly so with CA2‐3 and CA4–DG. Patients with increased HS based on histopathology had greater volume loss of the ipsilateral hippocampal regions on MRI. We conclude by suggesting that whilst time efficient and fully reproducible when applied to conventional single acquisition sequences, the use of the automated subfield technique described here may necessitate the application to multiacquisition high‐resolution MR sequences for accurate delineation of hippocampal subfields. Hum Brain Mapp 35:4718–4728, 2014. © 2014 Wiley Periodicals, Inc .     

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.     

In vivo analysis of hippocampal subfield atrophy in mild cognitive impairment via semi-automatic segmentation of T2-weighted MRI

The measurement of hippocampal volumes using MRI is a useful in-vivo biomarker for detection and monitoring of early Alzheimer's disease (AD), including during the amnestic mild cognitive impairment (a-MCI) stage. The pathology underlying AD has regionally selective effects within the hippocampus. As such, we predict that hippocampal subfields are more sensitive in discriminating prodromal AD (i.e., a-MCI) from cognitively normal controls than whole hippocampal volumes, and attempt to demonstrate this using a semi-automatic method that can accurately segment hippocampal subfields. High-resolution coronal-oblique T2-weighted images of the hippocampal formation were acquired in 45 subjects (28 controls and 17 a-MCI (mean age: 69.5 ± 9.2; 70.2 ± 7.6)). CA1, CA2, CA3, and CA4/DG subfields, along with head and tail regions, were segmented using an automatic algorithm. CA1 and CA4/DG segmentations were manually edited. Whole hippocampal volumes were obtained from the subjects' T1-weighted anatomical images. Automatic segmentation produced significant group differences in the following subfields: CA1 (left: p = 0.001, right: p = 0.038), CA4/DG (left: p = 0.002, right: p = 0.043), head (left: p = 0.018, right: p = 0.002), and tail (left: p = 0.019). After manual correction, differences were increased in CA1 (left: p < 0.001, right: p = 0.002), and reduced in CA4/DG (left: p = 0.029, right: p = 0.221). Whole hippocampal volumes significantly differed bilaterally (left: p = 0.028, right: p = 0.009). This pattern of atrophy in a-MCI is consistent with the topography of AD pathology observed in postmortem studies, and corrected left CA1 provided stronger discrimination than whole hippocampal volume (p = 0.03). These results suggest that semi-automatic segmentation of hippocampal subfields is efficient and may provide additional sensitivity beyond whole hippocampal volumes.     

Subfield atrophy pattern in temporal lobe epilepsy with and without mesial sclerosis detected by high-resolution MRI at 4 Tesla: Preliminary results

Purpose:   High-resolution magnetic resonance imaging (MRI) at 4 Tesla depicts details of the internal structure of the hippocampus not visible at 1.5 Tesla, and so allows for in vivo parcellation of different hippocampal subfields. The aim of this study was to test if distinct subfield atrophy patterns can be detected in temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) and without (TLE-no) hippocampal sclerosis.
Methods:   High-resolution T₂-weighted hippocampal images were acquired in 34 controls: 15 TLE-MTS and 18 TLE-no. Entorhinal cortex (ERC), subiculum (SUB), CA1, CA2, and CA3, and dentate (CA3&DG) volumes were determined using a manual parcellation scheme.
Results:   TLE-MTS had significantly smaller ipsilateral CA1, CA2, CA3&DG, and total hippocampal volume than controls or TLE-no. Mean ipsilateral CA1 and CA3&DG z-scores were significantly lower than ipsilateral CA2, ERC, and SUB z-scores. There were no significant differences between the various subfield or hippocampal z-scores on either the ipsi- or the contralateral side in TLE-no. Using a z-score ≤−2.0 to identify severe volume loss, the following atrophy patterns were found in TLE-MTS: CA1 atrophy, CA3&DG atrophy, CA1 and CA3&DG atrophy, and global hippocampal atrophy. Significant subfield atrophy was found in three TLE-no: contralateral SUB atrophy, bilateral CA3&DG atrophy, and ipsilateral ERC and SUB atrophy.
Discussion:   Using a manual parcellation scheme on 4 Tesla high-resolution MRI, we found the characteristic ipsilateral CA1 and CA3&DG atrophy described in TLE-MTS. Seventeen percent of the TLE-no had subfield atrophy despite normal total hippocampal volume. These findings indicate that high-resolution MRI and subfield volumetry provide superior information compared to standard hippocampal volumetry.     

Hippocampal shape analysis in Alzheimer's disease and frontotemporal lobar degeneration subtypes

Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD.     

Functional connectivity along the anterior–posterior axis of hippocampal subfields in the ageing human brain

While age‐related volumetric changes in human hippocampal subfields have been reported, little is known about patterns of subfield functional connectivity (FC) in the context of healthy ageing. Here we investigated age‐related changes in patterns of FC down the anterior–posterior axis of each subfield. Using high resolution structural MRI we delineated the dentate gyrus (DG), CA fields (including separating DG from CA3), the subiculum, pre/parasubiculum, and the uncus in healthy young and older adults. We then used high resolution resting state functional MRI to measure FC in each group and to directly compare them. We first examined the FC of each subfield in its entirety, in terms of FC with other subfields and with neighboring cortical regions, namely, entorhinal, perirhinal, posterior parahippocampal, and retrosplenial cortices. Next, we analyzed subfield to subfield FC within different portions along the hippocampal anterior–posterior axis, and FC of each subfield portion with the neighboring cortical regions of interest. In general, the FC of the older adults was similar to that observed in the younger adults. We found that, as in the young group, the older group displayed intrinsic FC between the subfields that aligned with the tri‐synaptic circuit but also extended beyond it, and that FC between the subfields and neighboring cortical areas differed markedly along the anterior–posterior axis of each subfield. We observed only one significant difference between the young and older groups. Compared to the young group, the older participants had significantly reduced FC between the anterior CA1‐subiculum transition region and the transentorhinal cortex, two brain regions known to be disproportionately affected during the early stages of age‐related tau accumulation. Overall, these results contribute to ongoing efforts to characterize human hippocampal subfield connectivity, with implications for understanding hippocampal function and its modulation in the ageing brain.     

Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease

Background:

Histopathological studies and animal models suggest that hippocampal subfields may be differently affected by aging, Alzheimer's disease (AD), and other diseases. High‐resolution images at 4 Tesla depict details of the internal structure of the hippocampus allowing for in vivo volumetry of different subfields. The aims of this study were as follows: (1) to determine patterns of volume loss in hippocampal subfields in normal aging, AD, and amnestic mild cognitive impairment (MCI). (2) To determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for differentiation between groups.

Methods:

Ninety‐one subjects (53 controls (mean age: 69.3 ± 7.3), 20 MCI (mean age: 73.6 ± 7.1), and 18 AD (mean age: 69.1 ± 9.5) were studied with a high‐resolution T2 weighted imaging sequence aimed at the hippocampus. Entorhinal cortex (ERC), subiculum, CA1, CA1‐CA2 transition zone (CA1‐2), CA3 & dentate gyrus (CA3&DG) were manually marked in the anterior third of the hippocampal body. Hippocampal volume was obtained from the Freesurfer and manually edited.

Results:

Compared to controls, AD had smaller volumes of ERC, subiculum, CA1, CA1‐2, and total hippocampal volumes. MCI had smaller CA1‐2 volumes. Discriminant analysis and power analysis showed that CA1‐2 was superior to total hippocampal volume for distinction between controls and MCI.

Conclusion:

The patterns of subfield atrophy in AD and MCI were consistent with patterns of neuronal cell loss/reduced synaptic density described by histopathology. These preliminary findings suggest that hippocampal subfield volumetry might be a better measure for diagnosis of early AD and for detection of other disease effects than measurement of total hippocampus. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.

     

Correlation of Hippocampal Neuronal Density and FDG-PET in Mesial Temporal Lobe Epilepsy

Summary: Purpose: Interictal [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) reveals regional hypometabolism in 60–80% of patients with mesial temporal lobe epilepsy (MTLE). The extent of hypometabolism generally extends beyond the epileptogenic zone. The pathophysiology underlying this widespread change is unknown. This study evaluated the relation between hippocampal neuronal loss and hypometabolism in patients with MTLE.
Methods: Forty-three patients with MTLE after anterior temporal lobectomy were included. Pathology demonstrated mesial temporal sclerosis (n = 41) or endfolium sclerosis (n = 2). Interictal FDG-PET scans were graded by visual analysis on a scale ranging from normal (grade 1) to severe (grade 5) hypometabolism. Neuronal counting was performed in the subiculum, hippocampal subfields, and dentate granular cell layer (DG). Neuronal density of patients was compared with that of seven autopsy controls. Data were compared by using Student's t tests and Kruskal-Wallis one-way analysis of variance (ANOVA).
Results: Significant neuronal loss in CA1 through CA4 and DG was found in patients compared with controls. Neuronal density in the subiculum, CA1, CA4, and DG did not correlate with severity of hypometabolism. However, patients with abnormal FDG-PET had higher neuronal density in CA2 and CA3 versus patients with normal studies.
Conclusions: This study supports a previous observation that degree of FDG-PET hypometabolism does not parallel severity of hippocampal neuronal loss in MTLE.     

Differential associations of age with volume and microstructure of hippocampal subfields in healthy older adults

Hippocampal atrophy in advanced healthy aging has frequently been reported. However, the vulnerability of different hippocampal subfields to age‐related atrophy is still a source of debate. Moreover, the association of age with the microstructural integrity of subfields is largely unknown. In this study, we investigated the associations between age and volume as well as microstructural integrity of hippocampal subfields using a three‐dimensional (3D) surface mapping approach. Forty‐three healthy older adults spanning the age range from 60 to 85 years underwent T1‐weighted and diffusion‐tensor imaging. Analyses demonstrated an association of age with hippocampal volume predominantly in the most anterior part of the hippocampal head, mainly corresponding to the subiculum. In contrast, the association of age with hippocampal microstructural integrity was mainly confined to regions located in the hippocampal body and tail, corresponding to the subiculum and CA1. Results indicate that age‐related volumetric and microstructural alterations within hippocampal subfields provide complementary information and reflect different age‐related processes. Potential mechanisms underlying the differential associations of age with volume and microstructure of hippocampal subfields are discussed. Hum Brain Mapp 36:3819–3831, 2015. © 2015 Wiley Periodicals, Inc.     

Anterior vs Posterior Hippocampal Subfields in an Extended Psychosis Phenotype of Multidimensional Schizotypy in a Nonclinical Sample

Numerous studies have implicated involvement of the hippocampus in the etiology and expression of schizophrenia-spectrum psychopathology, and reduced hippocampal volume is one of the most robust brain abnormalities reported in schizophrenia. Recent studies indicate that early stages of schizophrenia are specifically characterized by reductions in anterior hippocampal volume; however, studies have not examined hippocampal volume reductions in subclinical schizotypy. The present study was the first to examine the associations of positive, negative, and disorganized schizotypy dimensions with hippocampal subfield volumes in a large sample (n = 195) of nonclinically ascertained young adults, phenotyped using the Multidimensional Schizotypy Scale (MSS). Hippocampal subfields were analyzed from high-resolution 3 Tesla structural magnetic resonance imaging scans testing anatomical models, including anterior vs posterior regions and the cornu ammonis (CA), dentate gyrus (DG), and subiculum subfields separately for the left and right hemispheres. We demonstrate differential spatial effects across anterior vs posterior hippocampus segments across different dimensions of the schizotypy risk phenotype. The interaction of negative and disorganized schizotypy robustly predicted left hemisphere volumetric reductions for the anterior and total hippocampus, and anterior CA and DG, and the largest reductions were seen in participants high in negative and disorganized schizotypy. These findings extend previous early psychosis studies and together with behavioral studies of hippocampal-related memory impairments provide the basis for a dimensional neurobiological hippocampal model of schizophrenia risk. Subtle hippocampal subfield volume reductions may be prevalent prior to the onset of detectable prodromal clinical symptoms of psychosis and play a role in the etiology and development of such conditions.     

Organization and detailed parcellation of human hippocampal head and body regions based on a combined analysis of Cyto‐ and chemoarchitecture

The hippocampal formation (HF) is one of the hottest regions in neuroscience because it is critical to learning, memory, and cognition, while being vulnerable to many neurological and mental disorders. With increasing high‐resolution imaging techniques, many scientists have started to use distinct landmarks along the anterior–posterior axis of HF to allow segmentation into individual subfields in order to identify specific functions in both normal and diseased conditions. These studies urgently call for more reliable and accurate segmentation of the HF subfields DG, CA3, CA2, CA1, prosubiculum, subiculum, presubiculum, and parasubiculum. Unfortunately, very limited data are available on detailed parcellation of the HF subfields, especially in the complex, curved hippocampal head region. In this study we revealed detailed organization and parcellation of all subfields of the hippocampal head and body regions on the base of a combined analysis of multiple cyto‐ and chemoarchitectural stains and dense sequential section sampling. We also correlated these subfields to macro‐anatomical landmarks, which are visible on magnetic resonance imaging (MRI) scans. Furthermore, we created three versions of the detailed anatomic atlas for the hippocampal head region to account for brains with four, three, or two hippocampal digitations. These results will provide a fundamental basis for understanding the organization, parcellation, and anterior–posterior difference of human HF, facilitating accurate segmentation and measurement of HF subfields in the human brain on MRI scans. J. Comp. Neurol. 523:2233–2253, 2015. © 2015 Wiley Periodicals, Inc.     

Regional vulnerability of hippocampal subfields to aging measured by structural and diffusion MRI

In the past few years, there has been an increasing awareness of the regional vulnerability of the hippocampus to age‐related processes. However, to date, no studies have assessed the effects of age on different structural magnetic resonance parameters in the specific hippocampal subfields. In this study, we measured volume, mean diffusivity (MD) and fractional anisotropy (FA) in the presubiculum, subiculum, fimbria, cornu ammonis (CA) 1,2‐3,4‐DG and the whole hippocampus in fifty cognitively intact elder adults between 50 and 75 years of age (20 men, 30 women). Segmentation of hippocampal subfields was performed using FreeSurfer. Individual MD and FA images were coregistered to T1‐weighted volumes using FLIRT of FSL. Linear regression analyses were performed to assess the effects of age on the anatomical measures of each subfield. In addition, multiple regression analyses were also carried out to assess which of the anatomical measures that showed a correlation with age in the previous analyses, were the best age predictors in the hippocampus. In agreement with previous studies, our results showed a significant association between age and volume (P < 0.001) as well as MD (P < 0.001) in the whole hippocampus. Regarding the specific hippocampal subfields, we found that age had a significant negative effect on volume in CA2‐3 (P < 0.001) and CA4‐DG (P < 0.001). Importantly, we found a positive effect of age on MD in CA2‐3 (P < 0.001) and fimbria (P < 0.001) as well as a negative age effect on FA in the subiculum (P < 0.001). Multiple regression analyses revealed that the best overall predictors of age in the hippocampus were MD in the fimbria and volume of CA2‐3, which explained 73.8% of the age variance. These results indicate that age has an effect both on volume and diffusion tensor imaging measures in different subfields, suggesting they provide complementary information on age‐related processes in the hippocampus. © 2013 Wiley Periodicals, Inc.