Hippocampal functional connectivity mediates the association between cardiorespiratory fitness and cognitive function in healthy young adults.

OBJECTIVE: Higher cardiorespiratory fitness (CRF) induces neuroprotective effects in the hippocampus, a key brain region for memory and learning. We investigated the association between CRF and functional connectivity (FC) of the hippocampus in healthy young adults. We also examined the association between hippocampal FC and neurocognitive function. Lastly, we tested whether hippocampal FC mediates the association between 2-Min Walk Test (2MWT) and neurocognitive function. METHODS: 913 young adults (28.7 ± 3.7 years) from the Human Connectome Project were included in the analyses. The 2MWT performance result was used as a proxy for cardiovascular endurance. Fluid and crystalized composite neurocognitive scores were used to assess cognition. Resting-state functional MRI data were processed to measure hippocampal FC. Linear regression was used to examine the association between 2MWT, hippocampal FC, and neurocognitive outcomes after controlling for age, sex, years of education, body mass index, systolic blood pressure, and gait speed. RESULTS: Better 2MWT performance was associated with greater FC between the anterior hippocampus and right posterior cingulate and left middle temporal gyrus. No associations between 2MWT and posterior hippocampal FC, whole hippocampal FC, and caudate FC (control region) were observed. Greater anterior hippocampal FC was associated with better crystalized cognition scores. Lastly, greater FC between the anterior hippocampus and right posterior cingulate mediated the association between better 2MWT scores and higher crystalized cognition scores. CONCLUSIONS: Anterior hippocampal FC may be one underlying neurophysiological mechanism that promotes the association between 2MWT performance and crystalized composite cognitive function in healthy young adults.

Temporal pole volume is associated with episodic autobiographical memory in healthy older adults.

Recollection of personal past events differs across the lifespan. Older individuals recall fewer episodic details and convey more semantic information than young. Here we examine how gray matter volumes in temporal lobe regions integral to episodic and semantic memory (hippocampus and temporal poles, respectively) are related to age differences in autobiographical recollection. Gray matter volumes were obtained in healthy young (n = 158) and old (n = 105) adults. The temporal pole was demarcated and hippocampus segmented into anterior and posterior regions to test for volume differences between age groups. The Autobiographical Interview was administered to measure episodic and semantic autobiographical memory. Volume associations with episodic and semantic autobiographical memory were then assessed. Brain volumes were smaller for older adults in the posterior hippocampus. Autobiographical memory was less episodic and more semanticized for older versus younger adults. Older adults also showed positive associations between temporal pole volumes and episodic autobiographical recall; in the young, temporal pole volume was positively associated with performance on standard laboratory measures of semantic memory. Exploratory analyses revealed that age-related episodic autobiographical memory associations with anterior hippocampal volumes depended on sex. These findings suggest that age differences in brain structures implicated in episodic and semantic memory may portend reorganization of neural circuits to support autobiographical memory in later life.

Disrupted anterior and posterior hippocampal structural networks correlate impaired verbal memory and spatial memory in different subtypes of mild cognitive impairment.

BACKGROUND AND PURPOSE: The anterior and posterior hippocampal networks represent verbal and spatial memory, respectively, and may play different roles in the pathological mechanism of amnestic mild cognitive impairment (aMCI) and non-amnestic MCI (naMCI), which has not been explored. METHODS: A total of 990 older adults with 791 normal controls (NCs) (65 ± 6 years, 502 women), 140 aMCI (66 ± 7 years, 84 women) and 59 naMCI (66 ± 7 years, 38 women) were included. A multivariate method, partial least squares, was used to assess the structural covariance networks of the anterior hippocampus (aHC) and posterior hippocampus (pHC), and their relationships with verbal memory and spatial memory in the three groups. RESULTS: Three aHC and pHC structural covariance network patterns emerged: (1) the age pattern; (2) the specific aMCI pattern; and (3) the spatial memory pattern. Furthermore, aMCI patients had more extensive and severe damage in the three patterns, and correlated with greater decline in verbal memory, which was mainly characterized by the aHC network. CONCLUSIONS: The aMCI and naMCI showed different patterns and damage in the structural covariance networks, and functional segregation of the aHC and pHC networks still exists in the process of pathological aging. A potential neural explanation is provided for the conversion of aMCI and naMCI into different types of dementia in the future.

Interplay of the long axis of the hippocampus and ventromedial prefrontal cortex in schema-related memory retrieval.

When new information is relevant to prior knowledge or schema, it can be learned and remembered better. Rodent studies have suggested that the hippocampus and ventromedial prefrontal cortex (vmPFC) are important for processing schema-related information. However, there are inconsistent findings from human studies on the involvement of the hippocampus and its interaction with the vmPFC in schema-related memory retrieval. To address these issues, we used a human analog of the rodent spatial schema task to compare brain activity during immediate retrieval of paired associations (PAs) in schema-consistent and schema-inconsistent conditions. The results showed that the anterior hippocampus was more involved in retrieving PAs in the schema-consistent condition than in the schema-inconsistent condition. Connectivity analyses showed that the anterior hippocampus had stronger coupling with the vmPFC when the participants retrieved newly learned PAs successfully in the schema-consistent (vs. schema-inconsistent) condition, whereas the coupling of the posterior hippocampus with the vmPFC showed the opposite. Taken together, the results shed light on how the long axis of the hippocampus and vmPFC interact to serve memory retrieval via different networks that differ by schema condition.

Uncal apex position varies with normal aging.

The uncal apex is an anatomical landmark frequently used for segmenting the hippocampus into its anterior and posterior segments, a necessary step for computing many measurements of its long axis. It functions well, as it is both local to the hippocampus and easy to identify. However, in spite of widespread use and definition in the EADC-ADNI Harmonized Hippocampal Protocol (HarP), how the uncal apex is influenced by gross hippocampal changes during normal aging has not been established, nor has the possible impact on measures of anterior hippocampus (aHPC) and posterior hippocampus (pHPC) volume. Here I drew upon three large data sets to describe and confirm these relationships, investigating them in one large data set and replicating my findings in the two others, evaluating a total of 4,434 hippocampi. I found the uncal apex fell in an increasingly more anterior position with increasing age. This age-related retraction of the uncus began after age 36, with the sharpest effects arising after age 60. This phenomenon exaggerates age-related aHPC volume decreases while simultaneously underestimating age-related pHPC volume decreases, a pattern I confirmed by juxtaposing uncal apex and MNI space-based landmarking. A hippocampally based reference frame was also rendered unstable by age-related shifts in the posterior extent of the hippocampus. Both the uncal apex and hippocampal reference frame should therefore be used with caution in aging research, or in research involving other demographic or disease factors known to evoke gross changes in the hippocampus. Instead, MNI coordinate-based heuristics may be appropriate for segmenting the hippocampus in study designs involving such factors. Apex-based segmentation is still attractive, however, in study designs where advanced age and atrophy are not used as regressors, including investigations into long-axis effects in healthy young adults. Progress toward localizing functional divisions within the hippocampus is needed to identify best practices for the field.

The influence of age and performance on hippocampal function and the encoding of contextual information in early childhood.

Studies in school-aged children and adults consistently implicate hippocampus, cortical regions, and their interaction as being critical for memory. However, few studies have examined this neural network in younger children (<8 years), despite the fact that behavioral studies consistently report substantial improvements in memory earlier in life. This study aimed to fill this gap by integrating task-based (i.e., memory encoding task) and task-free fMRI scans in 4- to 8-year-old children. Results showed that during memory encoding the hippocampus and several cortical regions (e.g., inferior frontal gyrus, IFG) were activated, consistent with findings in older individuals. Novel findings during memory encoding showed: 1) additional regions (i.e., orbital frontal gyrus, OFG) were recruited, 2) hippocampal activation varied due to age and performance, and 3) differentiation of connectivity between hippocampal subregions and IFG was greater in older versus younger participants, implying increased speicalization with age. Novel findings from task-free fMRI data suggested the extent of functional differentiation along the longitudinal axis of the hippocampus, particularly between hippocampus and OFG, was moderated by both age and performance. Our findings support and extend previous research, suggesting that maturation of hippocampal activity, connectivity, and differentiation may all contribute to development of memory during early childhood.

Automated segmentation of medial temporal lobe subregions on in vivo T1-weighted MRI in early stages of Alzheimer's disease.

Medial temporal lobe (MTL) substructures are the earliest regions affected by neurofibrillary tangle pathology-and thus are promising biomarkers for Alzheimer's disease (AD). However, automatic segmentation of the MTL using only T1-weighted (T1w) magnetic resonance imaging (MRI) is challenging due to the large anatomical variability of the MTL cortex and the confound of the dura mater, which is commonly segmented as gray matter by state-of-the-art algorithms because they have similar intensity in T1w MRI. To address these challenges, we developed a novel atlas set, consisting of 15 cognitively normal older adults and 14 patients with mild cognitive impairment with a label explicitly assigned to the dura, that can be used by the multiatlas automated pipeline (Automatic Segmentation of Hippocampal Subfields [ASHS-T1]) for the segmentation of MTL subregions, including anterior/posterior hippocampus, entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36, and parahippocampal cortex on T1w MRI. Cross-validation experiments indicated good segmentation accuracy of ASHS-T1 and that the dura can be reliably separated from the cortex (6.5% mislabeled as gray matter). Conversely, FreeSurfer segmented majority of the dura mater (62.4%) as gray matter and the degree of dura mislabeling decreased with increasing disease severity. To evaluate its clinical utility, we applied the pipeline to T1w images of 663 ADNI subjects and significant volume/thickness loss is observed in BA35, ERC, and posterior hippocampus in early prodromal AD and all subregions at later stages. As such, the publicly available new atlas and ASHS-T1 could have important utility in the early diagnosis and monitoring of AD and enhancing brain-behavior studies of these regions.

Theta band power increases in the posterior hippocampus predict successful episodic memory encoding in humans.

Functional differences in the anterior and posterior hippocampus during episodic memory processing have not been examined in human electrophysiological data. This is in spite of strong evidence for such differences in rodent data, including greater place cell specificity in the dorsal hippocampus, greater sensitivity to the aversive or motivational content of memories in ventral regions, connectivity analyses identifying preferential ventral hippocampal connections with the amygdala, and gene expression analyses identifying a dorsal-ventral gradient. We asked if memory-related oscillatory patterns observed in human hippocampal recordings, including the gamma band and slow-theta (2.5-5 Hz) subsequent memory effects, would exhibit differences along the longitudinal axis and between hemispheres. We took advantage of a new dataset of stereo electroencephalography patients with simultaneous, robotically targeted anterior, and posterior hippocampal electrodes to directly compare oscillatory subsequent memory effects during item encoding. This same data set allowed us to examine left-right connectivity and hemispheric differences in hippocampal oscillatory patterns. Our data suggest that a power increase during successful item encoding in the 2.5-5 Hz slow-theta frequency range preferentially occurs in the posterior hippocampus during the first 1,000 ms after item presentation, while a gamma band power increase is stronger in the dominant hemisphere. This dominant-nondominant pattern in the gamma range appears to reverse during item retrieval, however. Intrahippocampal phase coherence was found to be stronger during successful item encoding. Our phase coherence data are also consistent with existing reports of a traveling wave for theta oscillations propagating along the septotemporal (longitudinal) axis of the human hippocampus. We examine how our findings fit with theories of functional specialization along the hippocampal axis.

Functional and effective hippocampal-neocortical connectivity during construction and elaboration of autobiographical memory retrieval.

Autobiographical memory (AM) provides the opportunity to study interactions among brain areas that support the search for a specific episodic memory (construction), and the later experience of mentally reliving it (elaboration). While the hippocampus supports both construction and elaboration, it is unclear how hippocampal-neocortical connectivity differs between these stages, and how this connectivity involves the anterior and posterior segments of the hippocampus, as these have been considered to support the retrieval of general concepts and recollection processes, respectively. We acquired fMRI data in 18 healthy participants during an AM retrieval task in which participants were asked to access a specific AM (construction) and then to recollect it by recovering as many episodic details as possible (elaboration). Using multivariate analytic techniques, we examined changes in functional and effective connectivity of hippocampal-neocortical interactions during these phases of AM retrieval. We found that the left anterior hippocampus interacted with frontal areas during construction and bilateral posterior hippocampi with visual perceptual areas during elaboration, indicating key roles for both hippocampi in coordinating transient neocortical networks at both AM stages. Our findings demonstrate the importance of direct interrogation of hippocampal-neocortical interactions to better illuminate the neural dynamics underlying complex cognitive tasks such as AM retrieval.

Immunohistochemical field parcellation of the human hippocampus along its antero-posterior axis.

The primate hippocampus includes the dentate gyrus, cornu ammonis (CA), and subiculum. CA is subdivided into four fields (CA1-CA3, plus CA3h/hilus of the dentate gyrus) with specific pyramidal cell morphology and connections. Work in non-human mammals has shown that hippocampal connectivity is precisely patterned both in the laminar and longitudinal axes. One of the main handicaps in the study of neuropathological semiology in the human hippocampus is the lack of clear laminar and longitudinal borders. The aim of this study was to explore a histochemical segmentation of the adult human hippocampus, integrating field (medio-lateral), laminar, and anteroposterior longitudinal patterning. We provide criteria for head-body-tail field and subfield parcellation of the human hippocampus based on immunodetection of Rabphilin3a (Rph3a), Purkinje-cell protein 4 (PCP4), Chromogranin A and Regulation of G protein signaling-14 (RGS-14). Notably, Rph3a and PCP4 allow to identify the border between CA3 and CA2, while Chromogranin A and RGS-14 give specific staining of CA2. We also provide novel histological data about the composition of human-specific regions of the anterior and posterior hippocampus. The data are given with stereotaxic coordinates along the longitudinal axis. This study provides novel insights for a detailed region-specific parcellation of the human hippocampus useful for human brain imaging and neuropathology.

Structural Covariance Changes of Anterior and Posterior Hippocampus During Musical Training in Young Adults.

Musical training can induce the functional and structural changes of the hippocampus. The hippocampus is not a homogeneous structure which can be divided into anterior and posterior parts along its longitudinal axis, and the whole-brain structural covariances of anterior (aHC) and posterior hippocampus (pHC) show distinct patterns in young adults. However, little is known about whether the anterior and posterior hippocampal structural covariances change after long-term musical training. Here, we investigated the musical training-induced changes of the whole-brain structural covariances of bilateral aHC and pHC in a longitudinal designed experiment with two groups (training group and control group) across three time points [the beginning (TP1) and the end (TP2) of 24 weeks of training, and 12 weeks after training (TP3)]. Using seed partial least square, we identified two significant patterns of structural covariance of the aHC and pHC. The first showed common structural covariance of the aHC and pHC. The second pattern revealed distinct structural covariance of the two regions and reflected the changes of structural covariance of the left pHC in the training group across three time points: the left pHC showed significant structural covariance with bilateral hippocampus and parahippocampal gyrus, left calcarine sulcus only at TP1 and TP3. Furthermore, the integrity of distinct structural networks of aHC and pHC in the second pattern significantly increased in the training group. Our findings suggest that musical training could change the organization of structural whole-brain covariance for left pHC and enhance the degree of the structural covariance network differentiation of the aHC and pHC in young adults.

Longitudinal Differences in Human Hippocampal Connectivity During Episodic Memory Processing.

The question of longitudinal hippocampal functional specialization is critical to human episodic memory because an accurate understanding of this phenomenon would impact theories of mnemonic function and entail practical consequences for the clinical management of patients undergoing temporal lobe surgery. The implementation of the robotically assisted stereo electroencephalography technique for seizure mapping has provided our group with the opportunity to obtain recordings simultaneously from the anterior and posterior human hippocampus, allowing us to create an unparalleled data set of human subjects with simultaneous anterior and posterior hippocampal recordings along with several cortical regions. Using these data, we address several key questions governing functional hippocampal connectivity in human memory. First, we ask whether functional networks during episodic memory encoding and retrieval are significantly different for the anterior versus posterior hippocampus (PH). We also examine how connections differ across the 2-5 Hz versus 4-9 Hz theta frequency ranges, directly addressing the relative contribution of each of these separate bands in hippocampal-cortical interactions. While we report some overlapping connections, we observe evidence of distinct anterior versus posterior hippocampal networks during memory encoding related to frontal and parietal connectivity as well as hemispheric differences in aggregate connectivity. We frame these findings in light of the proposed AT/PM memory systems. We also observe distinct encoding versus retrieval connectivity patterns between anterior and posterior hippocampal networks, we find that overall connectivity is greater for the PH in the right hemisphere, and further that these networks significantly differ in terms of frontal and parietal connectivity. We place these findings in the context of existing theoretical treatments of human memory systems, especially the proposed AT/PM system. During memory retrieval, we observe significant differences between slow-theta (2-5 Hz) and fast-theta (4-9 Hz) connectivity between the cortex and hippocampus. Finally, we test how these distinct theta frequency oscillations propagate within the hippocampus, using phase slope index to estimate the direction slow-theta and fast-theta oscillations travel during encoding and retrieval. We uncover evidence that 2-5 Hz oscillations travel in the posterior-to-anterior direction, while 5-9 Hz oscillations travel from anterior-to-posterior. Taken together, our findings describe mnemonically relevant functional connectivity differences along the longitudinal axis of the human hippocampus that will inform interpretation of models of hippocampal function that seek to integrate rodent and human data.

Maternal sensitivity predicts anterior hippocampal functional networks in early childhood.

Maternal care influences child hippocampal development. The hippocampus is functionally organized along an anterior-posterior axis. Little is known with regards to the extent maternal care shapes offspring anterior and posterior hippocampal (aHPC, pHPC) functional networks. This study examined maternal behavior, especially maternal sensitivity, at 6 months postpartum in relation to aHPC and pHPC functional networks of children at age 4 and 6 years. Maternal sensitivity was assessed at 6 months via the "Maternal Behavior Q Sort (MBQS) mini for video". Subsequently, 61 and 76 children underwent resting-state functional magnetic resonance imaging (rs-fMRI), respectively, at 4 and 6 years of age. We found that maternal sensitivity assessed at 6 months postpartum was associated with the right aHPC functional networks in children at both 4 and 6 years of age. At age 4 years, maternal sensitivity was associated positively with the right aHPC's functional connectivity with the sensorimotor network and negatively with the aHPC's functional connectivity with the top-down cognitive control network. At 6 years of age, maternal sensitivity was linked positively with the right aHPC's functional connectivity with the visual-processing network. Our findings suggested that maternal sensitivity in infancy has a long-term impact on the anterior hippocampal functional network in preschool children, implicating a potential role of maternal care in shaping child brain development in early life.

Real-world navigation in amnestic mild cognitive impairment: The relation to visuospatial memory and volume of hippocampal subregions.

Spatial disorientation is a frequent symptom in Alzheimer's disease and in mild cognitive impairment (MCI). In the clinical routine, spatial orientation is less often tested with real-world navigation but rather with 2D visuoconstructive tasks. However, reports about the association between the two types of tasks are sparse. Additionally, spatial disorientation has been linked to volume of the right hippocampus but it remains unclear whether right hippocampal subregions have differential involvement in real-world navigation. Yet, this would help uncover different functional roles of the subregions, which would have important implications for understanding the neuronal underpinnings of navigation skills. We compared patients with amnestic MCI (aMCI; n = 25) and healthy elderly controls (HC; n = 25) in a real-world navigation task that engaged different spatial processes. The association between real-world navigation and different visuoconstructive tasks was tested (i.e., figures from the Consortium to Establish a Registry for Alzheimer's Disease; CERAD, the Rey-Osterrieth Complex Figure task; and clock drawing). Furthermore, the relation between spatial navigation and volume of right hippocampal subregions was examined. Linear regression and relative weight analysis were applied for statistical analyses. Patients with aMCI were significantly less able to correctly navigate through a route compared to HC but had comparable map drawing and landmark recognition skills. The association between visuoconstructive tasks and real-world navigation was only significant when using the visuospatial memory component of the Rey figure. In aMCI, more volume of the right hippocampal tail was significantly associated with better navigation skills, while volume of the right CA2/3 region was a significant predictor in HC. Standard visuoconstructive tasks (e.g., the CERAD figures or clock drawing) are not sufficient to detect real-world spatial disabilities in aMCI. Consequently, more complex visuoconstructive tasks (i.e., the Rey figure) should be routinely included in the assessment of cognitive functions in the context of AD. Moreover, in those elderly individuals with impaired complex visuospatial memory, route finding behaviour should be evaluated in detail. Regarding the contribution of hippocampal subregions to spatial navigation, the right hippocampal tail seems to be particularly important for patients with aMCI, while the CA2/3 region appears to be more relevant in HC.

Hippocampal Network Modularity Is Associated With Relational Memory Dysfunction in Schizophrenia.

BACKGROUND: Functional dysconnectivity has been proposed as a major pathophysiological mechanism for cognitive dysfunction in schizophrenia. The hippocampus is a focal point of dysconnectivity in schizophrenia, with decreased hippocampal functional connectivity contributing to the marked memory deficits observed in patients. Normal memory function relies on the interaction of complex corticohippocampal networks. However, only recent technological advances have enabled the large-scale exploration of functional networks with accuracy and precision. METHODS: We investigated the modularity of hippocampal resting-state functional networks in a sample of 45 patients with schizophrenia spectrum disorders and 38 healthy control subjects. Modularity was calculated for two distinct functional networks: a core hippocampal-medial temporal lobe cortex network and an extended hippocampal-cortical network. As hippocampal function differs along its longitudinal axis, follow-up analyses examined anterior and posterior networks separately. To explore effects of resting network function on behavior, we tested associations between modularity and relational memory ability. Age, sex, handedness, and parental education were similar between groups. RESULTS: Network modularity was lower in schizophrenia patients, especially in the posterior hippocampal network. Schizophrenia patients also showed markedly lower relational memory ability compared with control subjects. We found a distinct brain-behavior relationship in schizophrenia that differed from control subjects by network and anterior/posterior division-while relational memory in control subjects was associated with anterior hippocampal-cortical modularity, schizophrenia patients showed an association with posterior hippocampal-medial temporal lobe cortex network modularity. CONCLUSIONS: Our findings support a model of abnormal resting-state corticohippocampal network coherence in schizophrenia, which may contribute to relational memory deficits.

Differential Age-Related Changes in Structural Covariance Networks of Human Anterior and Posterior Hippocampus.

The hippocampus plays an important role in memory function relying on information interaction between distributed brain areas. The hippocampus can be divided into the anterior and posterior sections with different structure and function along its long axis. The aim of this study is to investigate the effects of normal aging on the structural covariance of the anterior hippocampus (aHPC) and the posterior hippocampus (pHPC). In this study, 240 healthy subjects aged 18-89 years were selected and subdivided into young (18-23 years), middle-aged (30-58 years), and older (61-89 years) groups. The aHPC and pHPC was divided based on the location of uncal apex in the MNI space. Then, the structural covariance networks were constructed by examining their covariance in gray matter volumes with other brain regions. Finally, the influence of age on the structural covariance of these hippocampal sections was explored. We found that the aHPC and pHPC had different structural covariance patterns, but both of them were associated with the medial temporal lobe and insula. Moreover, both increased and decreased covariances were found with the aHPC but only increased covariance was found with the pHPC with age (p < 0.05, family-wise error corrected). These decreased connections occurred within the default mode network, while the increased connectivity mainly occurred in other memory systems that differ from the hippocampus. This study reveals different age-related influence on the structural networks of the aHPC and pHPC, providing an essential insight into the mechanisms of the hippocampus in normal aging.