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A 3D model of hippocampal subregion masks. Presented in their entirety (a) and with anterior slices progressively removed in an anteriorto-posterior direction to reveal internal subregion structure (b)?(f).
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Background: The hippocampus plays a central role in cognition, and understanding the specific contributions of its subregions will likely be key to explaining its wide-ranging functions. However, delineating substructures within the human hippocampus in vivo from magnetic resonance image scans is fraught with difficulties. To our knowledge, the ext...
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... are six parts to the protocol (Figure 1), corresponding to DG/CA4, CA3/2, CA1, prosubiculum/subiculum, pre/parasubic- ulum and the uncus. To help orient the experimenter, a 3D ren- dered example of the final product of this segmentation protocol is shown in Figure 2, where the characteristic elongated structure of the hippocampus extending in an anterior-posterior direction can be observed. Within each part of the protocol, there are three (DG/CA4, CA3/2, CA1) or two (subiculum, pre/parasubiculum, uncus) sub-sections describing salient divisions. ...
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... DG mask has been cre- ated in a previous step and can be used to adjust the ventromedial border of the CA1 mask. When moving into the hippocampal tail, as described in the previous section, the expansion of the ventral portion of the hippocampus can be seen (Figure 13(d)) as can the point from which the dorsal and ventral portions are both clear (see Figure 23(g)). ...
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... fill in the space enclosed within the boundary, being careful not to include the space within the VHS. Continue this method until the final slice in which grey matter can be seen within the shrinking ovoid hippocampus (see pro- gression in Figure 24(b)-(d)). ...
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... in the length or shape of subregions are common. For example, in some individuals, the subiculum lengthens in posterior regions, appearing to fan out in a medial direction, while in others it remains a consistent length down the long axis of the hippocampus (see Figure 25). A thorough discussion of individual variability in hippocampal morphology is beyond the scope of this article and, to the best of our knowledge, morpho- logical variability of hippocampal subregions has not been sys- tematically investigated in the human brain. ...
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... while it may be necessary to make amendments to elements of this protocol for 'unusual' hippocampi, we believe its core remains sound and its principles can be extended to less common hippocampal mor- phologies on a case-by-case basis. Figures 26-29 show some examples of commonly observed morphological characteristics which differ from elements described in this protocol. We have overlaid these images with examples of how we do the delinea- tions in these cases. ...
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... is important to note that in our protocol, there are two regions of tissue that are not included in any mask. The first is in the anterior hippocampus between the uncus, DG, CA3/2 and CA1 masks (see these unmasked areas in 'e', 'f' and 'g' of Figure 27. Individual variability in the anterior hippocampus 2. Example of a common morphological characteristic in the anterior hippocampus whereby after initial bending of the lateral external digitation ('*' in (b)), another digitation emerges laterally when moving in a posterior direction ('^' in 27(c)). ...
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... can make delineation of the CA1 region confusing. In these cases, we recommend considering both digitations to contain 'typical' CA1 as, when moving posteriorly, they generally merge to create a single digitation which becomes the dorsal wall of the body of the hippocampus (see Figure 27(h)). 'a' represents the anterior-most slice, with each subsequent panel ('b'-'h') representing a contiguous slice in the posterior direction. ...
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... can occur in the presence or absence of cavities and, on histology, the ventral extension of the VHS coincides with a thinning of the adjacent cortical areas (see Figure 17(c)). On MRI, the spontaneous ven- tral extension of the VHS can be confusing and make delineation Figure 28. Individual variability in the posterior hippocampus 1. ...
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... represents the anterior-most slice, with each subsequent panel ('b'-'p') representing a contiguous slice in the posterior direction. Figure 29. Individual variability in the posterior hippocampus 2. In this common variant of posterior hippocampal morphology, the 'ovoid' portion of the posterior hippocampus separates to become an island in a comparatively anterior portion of the hippocampus when compared with that noted in our protocol. ...
Citations
... The hippocampus is a heterogeneous structure consisting of several subfields, including the dentate gyrus (DG), the cornu ammonis (CA1-CA4), and the subiculum (SUB) (Dalton et al. 2017;Fogwe, Reddy, and Mesfin 2023), which have been suggested to play dissociable roles in the pattern separation and pattern completion processes. The canonical tri-synaptic circuit, extensively studied, describes the feedforward information flow in the hippocampus: the entorhinal This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. ...
Pattern separation and pattern completion in the hippocampus play a critical role in episodic learning and memory. However, there is limited empirical evidence supporting the role of the hippocampal circuit in these processes during complex continuous experiences. In this study, we analyzed high‐resolution fMRI data from the “Forrest Gump” open‐access dataset (16 participants) using a sliding‐window temporal autocorrelation approach to investigate whether the canonical hippocampal circuit (DG‐CA3‐CA1‐SUB) shows evidence consistent with the occurrence of pattern separation or pattern completion during a naturalistic audio movie task. Our results revealed that when processing continuous naturalistic stimuli, the DG‐CA3 pair exhibited evidence consistent with the occurrence of the pattern separation process, whereas both the CA3‐CA1 and CA1‐SUB pairs showed evidence consistent with pattern completion. Moreover, during the latter half of the audio movie, we observed evidence consistent with a reduction in pattern completion in the CA3‐CA1 pair and an increase in pattern completion in the CA1‐SUB pair. Overall, these findings improve our understanding of the evidence related to the occurrence of pattern separation and pattern completion processes during natural experiences.
... There are also a growing number of studies on the differential role of specific (para-)hippocampal subfields in episodic memory using tasks involving spatial (and temporal) information. Although one study in healthy young adults showed comparable levels of activation across multiple subfields of the hippocampus proper during retrieval 35 , other studies having looked at the whole hippocampal formation point to a specific involvement of anterior medial portions of the hippocampus, and of the anterior presubiculum and of the parasubiculum of the parahippocampus, in particular when scene-based information is involved 36,37 . The latter aligns with work having implicated the parasubiculum in episodic memory retrieval from autobiographical memory 38 , and in the mental construction of internal scenes during episodic memory recall 39 . ...
We assessed simultaneous bilinguals and monolinguals on inhibitory control and episodic memory, and assessed their grey matter volumes in brain regions known to be involved in language processing, executive control and memory. Bilinguals outperformed monolinguals on episodic memory, and performance on the memory and inhibition tasks were correlated, only in the bilingual group. This suggests that the bilingualism-related benefits on memory are related to individual differences in executive control. We found larger grey matter volumes in bilinguals in left pars opercularis and in bilateral SFG, caudate nuclei, and parasubiculum. Episodic memory performance was correlated with volumes of bilateral posterior hippocampi, again only in the bilinguals, again suggesting that bilingualism may be driving this effect. Finally, we found positive structural covariance between the volumes of the bilateral parasubiculum and that of important components of the executive control network. We provide a novel, mechanistic explanation accounting for observed behavioural advantage and brain structural differences: bilingualism may boost the prefrontal cortex-hippocampal neural circuitry commonly underlying both executive control and memory, via cascade and reverberant effects, leading to synergistic benefits in both cognitive domains. This new framework has important implications for protective effects on cognition and brain health in relation to second language learning.
... Resected hippocampal tissue was sliced to 300 m, incubated, and then plated onto an HD-MEA ( Fig. 1b ). We analyze six slices from three different subregions of the hippocampus: the inner apex of the dentate gyrus, the outer blade of the dentate gyrus, and CA1 ( Supplementary Table 1 ) 14 . Two slices with electrodes covering the outer blade exhibited seizure-like behavior after the administration of kainic acid. ...
... Signals are downsampled from 20 kHz to 1 kHz. A second bandpass filter is then applied to extract the subband frequencies of delta (0.5 -4 Hz), theta (4 -8 Hz), alpha (8)(9)(10)(11)(12)(13), beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and gamma (30 -50 Hz) waves. To plot the spectrogram, we run a continuous wavelet transform on the local field potential data. ...
How seizures begin at the level of microscopic neural circuits remains unknown. High-density CMOS microelectrode arrays provide a new avenue for investigating neuronal network activity, with unprecedented spatial and temporal resolution. We use high-density CMOS-based microelectrode arrays to probe the network activity of human hippocampal brain slices from six patients with mesial temporal lobe epilepsy in the presence of hyperactivity promoting media. Two slices from the dentate gyrus exhibited epileptiform activity in the presence of low magnesium media with kainic acid. Both slices displayed an electrophysiological phenotype consistent with a reciprocally connected circuit, suggesting a recurrent feedback loop is a key driver of epileptiform onset. Larger prospective studies are needed, but these findings have the potential to elucidate the network signals underlying the initiation of seizure behavior.
... Minor manual edits were made on the ITK-SNAP program (Yushkevich et al., 2006) to clean up the boundaries of the ASHS output using the Dalton et al. (2017) and Berron et al. (2017) protocols for the hippocampal subfields and the Insausti et al. (1998) and Pruessner et al. (2000Pruessner et al. ( , 2002 protocols for the adjacent MTL regions. For all 26 participants with highresolution T2 images, one experimenter manually edited the hippocampal subfields (CA1, CA2/3, DG, SUB), and another experimenter edited the MTL regions (ERC, PRC, PHC). ...
Despite the need for successful navigation, humans vary greatly in their ability to navigate, and these individual differences may relate to variation in brain structure. While prior research provides support for a correlation between hippocampal volume and navigation ability in both navigation experts and in older individuals, this relationship is under scrutiny for healthy, young adults. We assessed 99 healthy young adults' ability to navigate in a virtual, desktop maze and correlated their performance with total hippocampal gray matter volume. For a subset of these individuals, we further segmented the medial temporal lobe—including regions of the hippocampus—into anatomically-distinct subregions to uniquely examine the association between volumes of hippocampal subfields and navigation. Given the need to distinguish between similar-looking maze hallways and partially overlapping routes, young adults with stronger pattern separation ability may perform better in this task. Thus, we theorized that successful navigation would positively correlate with hippocampal CA3 and dentate gyrus (DG) subfield volumes due to these regions' role in pattern separation. CA1 and entorhinal cortex (ERC) are both associated with rodent spatial memory, too, suggesting a possible relationship between their volumes and navigation performance. Consistent with our hypotheses, we observed a positive relationship between volumes of hippocampal subfields and wayfinding accuracy, while ERC and parahippocampal cortex volumes correlated with navigation efficiency. However, when analyzing total hippocampal volume, a nuanced interpretation is warranted. We found evidence of Simpson's Paradox, where total hippocampal volume and navigation accuracy displayed no correlation in males, a negative correlation in females, yet a positive correlation when considering the full sample of males and females combined. Furthermore, no significant relationship was observed between total hippocampal volume and path efficiency. Given these findings, we urge caution in interpreting the results because these associations differ by analysis techniques (including voxel-based morphometry), after sex stratification, and with anterior and posterior hippocampal subdivisions. Overall, this study enhances our understanding of the relationship between brain volume and navigation ability for young adults but also emphasizes the need for methodological consistency across studies with respect to boundary definitions, neuroimaging techniques, statistical methods, and factors that give rise to individual differences.
... The human uncus [also termed the "uncal portion of the hippocampal formation"] (Amaral et al., 1984) is situated antero-medially and consists of slightly modified DG, CA3, CA2, CA1, and subiculum (Ding & Van Hoesen, 2015). For the segmentation of the hippocampus and its subregions, we followed the guide provided by Dalton et al. (2017). Given the difficulty to distinguish hippocampal CA fields on 1.5T and 3T-MRI acquisitions, we restricted our volumetric analyses to three ROIs: uncus (defined according to Ding and Van Hoesen) (Ding & Van Hoesen, 2015), CA-DG (CA fields and DG), and subicular complex (subiculum, presubiculum, and parasubiculum). ...
... Then we manually delineated 12 structures with 34 subdivisions associated with cognition following published guidelines [84,138,[148][149][150][151][152] (Figs. 2, 3, 4). Left and right units were delineated separately. ...
While treatments for primary brain tumors increase survival, they have cognitive sequelae. Neurocognition’s anatomical distribution makes it susceptible to brain damage. This study aims to evaluate the contribution of radiotherapy on short-term cognitive impairment.
Using a prospective database of cognitive rehabilitation in adults operated on for primary brain tumors, a retrospective sub-analysis of the contribution of radiotherapy was performed. Thirty-four subdivisions of 12 neurocognitive regions were delineated in 48 irradiated patients and 30 non-irradiated patients. In the first group, the correlation between radiation dose and deterioration was evaluated. In all patients, the impact of tumor and surgical changes on dysfunction was calculated and compared with dose-dependent response.
The correlation between cognitive status and radiation dose is especially strong and significant in the left hemisphere and in specific subdivisions such as the posterior hippocampus or the dorsolateral prefrontal cortex, with the left prevailing over posterior dominance. Memory is the most affected domain 1 month after radiotherapy, as attention is three months later. The hippocampus is involved in various cognitive domains in addition to memory. The prefrontal subregions and the genu of the corpus callosum are more affected by the relationship with disease and surgical changes than by radiation exposure. Patients ongoing a course of radiotherapy do not benefit from concurrent cognitive rehabilitation.
There is a correlation between the dose of radiation received by several encephalic regions and degree of short-term domain-specific cognition decline, considering other factors of risk and cognitive rehabilitation.
... The human uncus [also termed the "uncal portion of the hippocampal formation"] (Amaral et al., 1984) is situated antero-medially and consists of slightly modified DG, CA3, CA2, CA1, and subiculum (Ding & Van Hoesen, 2015). For the segmentation of the hippocampus and its subregions, we followed the guide provided by Dalton et al. (2017). Given the difficulty to distinguish hippocampal CA fields on 1.5T and 3T-MRI acquisitions, we restricted our volumetric analyses to three ROIs: uncus (defined according to Ding and Van Hoesen) (Ding & Van Hoesen, 2015), CA-DG (CA fields and DG), and subicular complex (subiculum, presubiculum, and parasubiculum). ...
Despite bilateral hippocampal damage dating to the perinatal or early childhood period and severely impaired episodic memory, patients with developmental amnesia continue to exhibit well‐developed semantic memory across the developmental trajectory. Detailed information on the extent and focality of brain damage in these patients is needed to hypothesize about the neural substrate that supports their remarkable capacity for encoding and retrieval of semantic memory. In particular, we need to assess whether the residual hippocampal tissue is involved in this preservation, or whether the surrounding cortical areas reorganize to rescue aspects of these critical cognitive memory processes after early injury. We used voxel‐based morphometry (VBM) analysis, automatic (FreeSurfer) and manual segmentation to characterize structural changes in the brain of an exceptionally large cohort of 23 patients with developmental amnesia in comparison with 32 control subjects. Both the VBM and the FreeSurfer analyses revealed severe structural alterations in the hippocampus and thalamus of patients with developmental amnesia. Milder damage was found in the amygdala, caudate, and parahippocampal gyrus. Manual segmentation demonstrated differences in the degree of atrophy of the hippocampal subregions in patients. The level of atrophy in CA‐DG subregions and subicular complex was more than 40%, while the atrophy of the uncus was moderate (−24%). Anatomo‐functional correlations were observed between the volumes of residual hippocampal subregions in patients and selective aspects of their cognitive performance, viz, intelligence, working memory, and verbal and visuospatial recall. Our findings suggest that in patients with developmental amnesia, cognitive processing is compromised as a function of the extent of atrophy in hippocampal subregions. More severe hippocampal damage may be more likely to promote structural and/or functional reorganization in areas connected to the hippocampus. In this hypothesis, different levels of hippocampal function may be rescued following this variable reorganization. Our findings document not only the extent, but also the limits of circuit reorganization occurring in the young brain after early bilateral hippocampal damage.
... To discern disease-sensitive and insensitive subregions more distinctly, we also present a second set of figures (Fig. 3(b), (d), and (f)), highlighting differences across AD-NC, AD-MCI, and NC-MCI groups. Notably, the changing voxels are primarily located in CA1 and Subiculum subregions, as in Dalton et al. (2017). These areas are recognized as the sensitive subregions exhibiting neurodegeneration in AD and as pivotal in the spread of neurodegeneration to other ROIs, as discussed in Kwak et al. (2022). ...
... The accurate segmentation of the hippocampus is a vital image-processing step to assist the study of the hippocampus and related neurological disorders caused by the impairment of the hippocampus. The early techniques of hippocampus segmentation primarily involved manual delineation, which is time consuming and prone to inter-rater variability [38][39][40]. The complexity of the shape of hippocampus and its variable appear-ance across individuals posed additional challenges. ...
The hippocampus is a crucial brain structure involved in memory formation, spatial navigation, emotional regulation, and learning. An accurate MRI image segmentation of the human hippocampus plays an important role in multiple neuro-imaging research and clinical practice, such as diagnosing neurological diseases and guiding surgical interventions. While most hippocampus segmentation studies focus on using T1-weighted or T2-weighted MRI scans, we explore the use of diffusion-weighted MRI (dMRI), which offers unique insights into the microstructural properties of the hippocampus. Particularly, we utilize various anisotropy measures derived from diffusion MRI (dMRI), including fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, for a multi-contrast deep learning approach to hippocampus segmentation. To exploit the unique benefits offered by various contrasts in dMRI images for accurate hippocampus segmentation, we introduce an innovative multimodal deep learning architecture integrating cross-attention mechanisms. Our proposed framework comprises a multi-head encoder designed to transform each contrast of dMRI images into distinct latent spaces, generating separate image feature maps. Subsequently, we employ a gated cross-attention unit following the encoder, which facilitates the creation of attention maps between every pair of image contrasts. These attention maps serve to enrich the feature maps, thereby enhancing their effectiveness for the segmentation task. In the final stage, a decoder is employed to produce segmentation predictions utilizing the attention-enhanced feature maps. The experimental outcomes demonstrate the efficacy of our framework in hippocampus segmentation and highlight the benefits of using multi-contrast images over single-contrast images in diffusion MRI image segmentation.
... The uncal apex, defined as the most posterior coronal slice in which the uncus is visible (Dalton et al., 2017;Malykhin et al., 2007;Poppenk, 2020), was for each participant manually identified in left and right hemispheres using anatomical T1-weighted images. To ensure reliability of manual ratings, two independent raters underwent training on how to recognize the landmark and established a common protocol. ...
... The uncal apex is the anatomical landmark most commonly used to demarcate the border between the anterior and the posterior hippocampus (Dalton et al., 2017;Duvernoy, 2013;Malykhin et al., 2007;Olsen et al., 2013), but the discovery that it retracts anteriorly with increasing age suggests that it might be unsuitable for this purpose in contexts where the hippocampus undergoes anatomical alterations (Poppenk, 2020). Critically, this anterior displacement may lead to the misclassification of anterior hippocampal tissue as posterior tissue, in turn, over-and underestimating the effects of age on these subregions, respectively (Poppenk, 2020). ...
Structural decline of the hippocampus occurs in heterogeneous patterns across its spatial extent, and is an important determinant of episodic memory dysfunction in aging. However, evidence indicate that the anatomical landmark uncal apex, used to demarcate anterior and posterior hippocampal subregions, changes position as the hippocampus atrophies. This emphasizes a risk of misclassifying gray matter into the incorrect subregion when using standard demarcation methods, contributing to over- and underestimation of age effects on anterior and posterior hippocampal volume. Yet, it remains unexplored whether inter-individual differences in uncal apex position predict episodic memory performance in itself. Here, we manually identified the uncal apex in anatomical MRI data from a healthy adult-lifespan sample (n=180; 20-79 years), assessed age differences in its position, and associations with word recollection performance. Increasing age was linked to a more anteriorly located uncal apex (retracting ~0.041 mm/year). Importantly, a more anterior uncal apex position was linked to lower memory performance. Whereas anterior hippocampal volume remained stable with increasing age, posterior volume displayed non-linear decline with an infliction point at approximately 45 years. Neither anterior nor posterior hippocampal volumes predicted memory performance, but the ratio of posterior to anterior volume showed a significant association with memory when taking the position of the uncal apex into account. These results indicate that uncal apex position may provide an estimate of hippocampal integrity sensitive to inter-individual differences in memory, independent of limitations associated with different segmentation methods.
