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. 2026 May 13;36:e70101. doi: 10.1002/hipo.70101

Quantitative and Morphometric Measures in the Human Hippocampal Tail Using Ex Vivo Imaging Validated With Histology

Anne M Alexander 1, Emma W Rosenblum 1, Nathaniel Mercaldo 1,2, Erin‐Marie C Smith 1, Chiara Mauri 1,2, Bruce Fischl 1,2, Ruopeng Wang 1, Matthew P Frosch 2,3, André J W van der Kouwe 1,2, Jean C Augustinack 1,2,✉
PMCID: PMC13168921  PMID: 42124511

ABSTRACT

The human hippocampal tail is the posterior‐most portion of the hippocampus and has been implicated in brain disorders, such as depression, panic disorder, and epilepsy. The tail's clinical relevance and volumetric variability exhibit a need for improved characterization with high‐resolution imaging and histology at baseline. MRI provides three‐dimensional context without missing slices and histology validates with architecture; combining these methods provides an optimal approach. Twenty control brain hemispheres were evaluated, including 10 males and 10 females. We scanned the hemispheres using ex vivo MRI at 120 μm isotropic resolution. The tissue was then processed and histologically stained. We manually labeled the hippocampal tail in high‐resolution MRI, using six distinct coronal levels of the tail as guideposts, validating histologically. The volume and length of the tails were calculated using 3D MRI reconstructions; the median tail volume (median ± interquartile range) of our sample set was 715.6 ± 227.5 mm3. These data contribute a validated hippocampal tail volume. We calculated and quantified the medial flexure of the tail and compared sex as a biological variable. Male tail samples exhibited significantly larger angles than female samples (Mann–Whitney U test, p = 0.01). Our findings enable precise hippocampal tail delineation and may facilitate future research on function and mental health disorders.

Keywords: angle, fasciola cinereum, fasciolar gyrus, gyrus of Anders Retzius, hippocampus, morphology, volume

1. Introduction

The human hippocampus is known for its role in learning and memory (Eichenbaum 2004; Scoville and Milner 1957; Squire 2004) and is divided into three morphological parts: the head, body, and tail. The hippocampus has been studied for vulnerability in diseases such as Alzheimer's Disease (Braak and Braak 1991; Braak et al. 2006) and epilepsy (Bernasconi et al. 2003; Du et al. 1993; Engel et al. 2012; Graebenitz et al. 2011; Zawar et al. 2025), as well as in aging (Adler et al. 2018; Avila et al. 2010; Iglesias et al. 2015; Malykhin et al. 2017). In vivo neuroimaging studies have shown that the tail, the most posterior portion of the hippocampus, may be involved in psychiatric disorders. More specifically, volumetric abnormalities have been identified in patients with depression (Chu et al. 2024; Maller et al. 2007, 2012; Malykhin et al. 2017; Nogovitsyn et al. 2020), bipolar disorder (Haukvik et al. 2022), and panic disorder (Bonne et al. 2008; Lee et al. 2020). One study reported that hippocampal atrophy was primarily limited to the tail in female patients with major depressive disorder. Males with major depressive disorder had significant atrophy in the head, body, and tail of the hippocampus (Maller et al. 2007). These reports suggest clinical relevance of the hippocampal tail, particularly in mental health, and could inform future treatments.

The hippocampal tail structure has been studied less than the head and body, and only one study has investigated its full extent histologically (Palomero‐Gallagher et al. 2020). While several in vivo neuroimaging studies have produced volumetric measures of the tail (Adler et al. 2018; Bernasconi et al. 2003; Dong et al. 2019; Iglesias et al. 2015; Maller et al. 2007, 2012; Malykhin et al. 2007, 2017), volumes in these studies vary substantially in cognitive controls. The field needs standardized anatomical landmarks to establish consistency when analyzing the hippocampal tail. Characterizing the baseline morphology in the hippocampal tail will provide context to further understand the multiscale organization of the brain (Amunts et al. 2013; Tzourio‐Mazoyer et al. 2007).

This work utilized high‐resolution ex vivo magnetic resonance imaging (MRI), validated by histology, to measure, reconstruct, and analyze the hippocampal tail in the human brain. To build specificity, we established standardized landmarks and manually labeled the tail, incorporating prior nomenclature and introducing relevant terminology for anterior–posterior levels. We report tail volume, length, and medial flexure measures based on histologically validated MRI, evaluating laterality, sex, and age. The high‐resolution MRI reconstructions show the unique variability of the hippocampal tail in the human brain.

2. Materials and Methods

2.1. Tissue Samples

Twenty brain hemispheres were collected by the Massachusetts General Hospital Neuropathology Autopsy service (Massachusetts General Hospital, Boston, MA), fixed with 10% formalin for a minimum of 2 months, and then transferred to 2% periodate‐lysine‐paraformaldehyde. Permission to autopsy was obtained prior to death, and all experiments complied with guidelines approved by the Institutional Review Board at Mass General Brigham. Table S1 outlines the demographics of the samples. The ages ranged from 40 to 84 years and included 11 left and 9 right hemispheres from 10 males and 10 females. Postmortem intervals were 24 h or less for all samples, except for sample 11 (159 h) due to a positive COVID‐19 diagnosis during the pandemic, and sample 14 (49 h). None of the collected brain hemispheres were from donors who died of neurological causes or exhibited symptoms of cognitive impairment before death.

2.2. High‐Resolution MRI Acquisition

Hemispheres were packed in heat‐sealed plastic bags filled with 2% periodate lysine paraformaldehyde (n = 17) or Fomblin (YL VAC 06/6, Syensqo, Brussels, Belgium, n = 3). We scanned the hemispheres in a whole‐body ultra‐high‐field Siemens 7 T Magnetom (n = 17) or Terra/Terra.X (n = 3, Siemens Healthineers, Erlangen, Germany). Hemispheres were scanned using a 7‐channel phased‐array receiver coil (n = 13) or 31‐channel phased‐array coil (n = 7) with a birdcage transmit coil. We used a fast low‐angle shot (FLASH) sequence with 3D encoding and a 20° ± 10° flip angle to yield optimal contrast in ex vivo tissue, allowing for the visualization and differentiation of microanatomy. The echo time was 20 ± 20 ms and the repetition time was 45 ± 15 ms. The resolution was 1203 μm3 for MRI datasets, and we averaged two to three runs. The total acquisition time per sample ranged from 22 to 24 h. MRIs were rotated into the optimal configuration for the hippocampal head and tail using the transform tool in Freeview, a visualization tool included with FreeSurfer v7.4.1 (https://surfer.nmr.mgh.harvard.edu) (Fischl 2012).

2.3. Manual Labeling in High‐Resolution MRI

Each 1203 μm3 scan was manually labeled for hippocampal tail (AMA) and quality‐checked (EWR, JCA). The manual labels were used to calculate the volume of the hippocampal tail. The MRI labeling was guided by hippocampal tail boundaries (Palomero‐Gallagher et al. 2020) and corresponding Nissl staining (n = 14). An additional 13 samples were stained for Nissl and provided partial validation of tail landmarks but lacked MRI and were not included in the sample set. Nissl staining was used to determine architectonic boundaries of the hippocampus and accurately inform the manual MRI labeling. The Nissl stained series was especially useful for discerning the boundaries between the subicular cortices, subsplenial gyrus, and tail terminus. The high‐resolution MRI enabled us to create manual labels with improved accuracy and overall detail.

We evaluated four features previously used to demarcate the anterior boundary of the hippocampal tail in high resolution MRI: (1) crus of the fornix, (2) medial elongation of hippocampal tissue, (3) anterior limit of wing of the ambient cistern, and (4) small dentes in the dentate gyrus. We applied the anterior limit as the medial extension of cornu ammonis and dentate gyrus (medial elongation), or the full crus of the fornix (Maller et al. 2007; Watson et al. 1992), whichever occurs more anteriorly (Figure S1). The tail is superiorly and anteriorly limited by the atrium of the lateral ventricle, and inferiorly by either the posterior parahippocampal or retrosplenial cortex. Posteriorly, the hippocampal tail ends once it converges with the indusium griseum and decreases in size until no tail tissue remains. Figure S2 shows the manual label outlined in pink and describes the anatomical landmarks used to discern each boundary of the hippocampal tail in MRI.

2.4. Tissue Blocking

The medial temporal lobes were dissected from the surrounding temporal lobes perpendicular to the long axis of the hippocampus. The coronal blocking cuts included: (1) at the temporal pole, (2) at the level of the anterior body or at the posterior hippocampal body at the level of the pulvinar, and (3) posterior to the splenium of the corpus callosum to encapsulate the entire hippocampus in two blocks. The medial temporal lobe blocks were approximately 5 cm in length; the posterior block included the hippocampal posterior body and tail. Blocked tissue was stored in cryoprotectant for at least 3 months to ensure its integrity for frozen sectioning.

2.5. Sectioning and Histology

The tissue was frozen on a sliding freezing microtome with a custom stage (Leica SM2000R, Leica Biosystems Inc., Buffalo Grove, IL, USA) and sectioned coronally at a thickness of 50 μm. Each section was collected and stored in cryoprotectant at −20°C. Every 10th section was hand‐mounted onto gelatin‐coated glass slides for histochemical staining. Tissue was briefly rinsed in 0.1 M phosphate buffer solution to remove the cryoprotectant before mounting. Slides were dried overnight and stained for Nissl substance with thionin (Augustinack et al. 2005; Zilles et al. 2002). The protocol is as follows: (1) defat with a 1:1 solution of 100% ethanol and chloroform, (2) rinse once with 50% ethanol and once with double distilled water, (3) pretreatment with a 1:1:1:1 solution (acetic acid, acetone, double distilled water, 100% ethanol), (4) staining with 5% aqueous thionin, 1.36% sodium acetate stock, and 0.6% acetic acid stock, and (5) differentiation with 70% ethanol and glacial acetic acid. Slides were dehydrated in three ethanol concentrations (70%, 95%, 100%), cleared in xylene, and coverslipped using Permount (Fisher Scientific, Waltham, MA, USA).

2.6. Diagnoses and Pathology Staining

Samples were immunohistochemically stained (Llamas‐Rodríguez et al. 2023) for phosphorylated tau (CP13, epitope serine 199) and staged (JCA) according to the Braak and Braak (1991) classification (Braak et al. 2006). We excluded samples with brain weights below 1060 g and tail samples with pathology above Braak and Braak stage II. The pathology diagnoses were as follows: Braak and Braak (BB) stage 0 (controls, n = 8), BB I (n = 7), and BB II (n = 5).

2.7. Slide Digitization and Microscopic Analysis

The Nissl stained slides were digitized with a Keyence BZX800 (Keyence, Osaka, Japan) at 4× magnification. The tissue was also examined using a Nikon Si microscope with a DS‐Fi3 microscope camera (Nikon, Tokyo, Japan) and a double‐headed Olympus BH‐2 microscope (Precise Instrument, Tokyo, Japan). The Olympus was used to discuss and evaluate the overall appearance, while the Nikon Si allowed for high‐resolution evaluation and image capture.

2.8. Background Terminology of the Hippocampal Tail

Two structures, the gyrus fasciolaris and fasciola cinerea, unique to the tail, sit at the most medial portion of the tail. The gyrus fasciolaris corresponds to the posterior pole of CA3. The fasciola cinerea corresponds to the posterior‐most point of the dentate gyrus under the corpus callosum (Andersen et al. 2006; Duvernoy 1998; Giacomini 1884; Gloor 1997; González‐Arnay et al. 2024; Insausti and Amaral 2004; Klinger 1948). Posteriorly and superiorly, the gyrus fasciolaris joins with the indusium griseum, a thin neuronal lamina situated on the superior surface of the corpus callosum. Other relevant structures include the gyri of Anders Retzius (GAR), named for bulges in the medial portion of the tail that Anders Retzius documented in 1856 (Retzius 1896; Ziogas and Triarhou 2016). These digitations appear on the inferior surface of the tail, sometimes visible in gross examination (Andersen et al. 2006; Duvernoy 2005; Gloor 1997; Lancisi 1718). Historic literature has called gyrus fasciolaris and gyri of Anders Retzius the same structure (Williams and Warwick 1980). However, our data and other current reports (H. Duvernoy 2005; Palomero‐Gallagher et al. 2020; Zachlod et al. 2022) have described them as two distinct regions of the tail.

The tail has previously been parcellated into three extraventricular segments: the initial, middle, and terminal. The initial segment was described to resemble the hippocampal body but with the addition of dentes in the dentate gyrus (Duvernoy 2005). The middle segment of the tail includes the margo denticulatus, the fimbria joining the crus of the fornix, and the GAR forming on the surface of the parahippocampal gyrus. The terminal segment of the tail covers the inferior splenial surface and is often referred to as the subsplenial gyrus (Duvernoy 2005; Gloor 1997; Palomero‐Gallagher et al. 2020; Riley 1960). The abovementioned terms were useful when discussing the relationship between the internal structure of the tail and the hippocampal surface (Duvernoy 1998).

2.9. Coronal Landmarks of the Hippocampal Tail

The hippocampal head has been segmented into subfields based on morphology, cytoarchitecture, and receptor architecture traits (Ding and Van Hoesen 2015; Gloor 1997; Insausti and Amaral 2004; Palomero‐Gallagher et al. 2020; Williams et al. 2023). To add specificity and context to the hippocampal tail in the human brain, we named six coronal anterior–posterior landmarks to aid our labeling. Figure 1 demonstrates a schemata of these levels traced from coronal Nissl sections: (1) anterior tail, (2) fasciolar initium, (3) tail junction, (4) posterior tail, (5) separated tail, and (6) tail terminus. Anterior tail begins at either the medial elongation of tail tissue (Figure S1A–C) or the full crus of the fornix (Figure 1B; Figure S1D–F), whichever occurs more anteriorly. Fasciolar initium indicates that the medial pyramidal layer is fully prominent but still separate from the lateral pyramidal layer. Gyrus fasciolaris and fasciola cinerea first appear at fasciolar initium (n = 19), and the granule layer of the dentate gyrus is often jagged (e.g., spike‐like, having a highly convoluted ribbon) (Figure 1C). High‐resolution MRI validated with histology enabled us to visualize the start of gyrus fasciolaris. Tail junction appears when the medial and lateral pyramidal layers become continuous, encapsulating the hippocampus superiorly (Figure 1D). GAR (Retzius 1896) frequently appear largest at tail junction, although the gyri are visible at other levels, even occasionally in the posterior body. The morphological distinguishability of the tail is especially evident in the fasciolar initium and tail junction landmarks. Posterior tail begins once the dentate gyrus is no longer visible (Figure 1E); the size of the tail also tapers caudally. Separated tail appears when the lateral tail tissue separates from the medial‐most tissue (the terminus) of the hippocampal tail and the GAR have formed one or more isolated ovals (Figure 1F). Tail terminus begins once the lateral hippocampal gray matter is no longer visible (Figure 1G). The terminus then curves superiorly (Figure 1H), converges onto the subsplenial gyrus, and with the indusium griseum (Figure 1I).

FIGURE 1.

FIGURE 1

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Hippocampal tail schemata at several anterior–posterior landmarks. (A) shows the hippocampus at body (posterior) while B–I depict the tail's typical morphology and internal architecture at multiple coronal levels. (B) represents the anterior tail, where the hippocampus widens medially, and the fornix typically appears superiorly. (C) depicts the fasciolar initium, where the gyrus fasciolaris and fasciola cinerea first appear medially. (D) shows the tail junction level where the medial portion of the hippocampus meet with the lateral portion and exhibits the gyri of Anders Retzius (GAR), often large here. (E) depicts the posterior tail where the dentate gyrus is typically absent. (F) shows separated tail; the medial tail terminus detaches from the lateral tail tissue and joins the subsplenial cortex. Panels G–I illustrate the tail terminus, where the posterior‐most levels of gyrus fasciolaris and subiculum meet the indusium griseum (dotted blue lines in H and I; hippocampal remnant). Pink lines indicate hippocampus and subiculum, and bold pink lines indicate dentate gyrus; dotted black lines demarcate isocortex.

2.10. Medial Flexure Procedure

We refer to the posterior and medial curvature of the tail as the medial flexure (similar to the term angulation used by Adler et al. 2018). We describe the medial flexure by the 3D shape, which requires MRI, rather than by the cut of tissue. To calculate the medial flexure of each tail, we outlined a spline on each 3D reconstruction using the point set tool in Freeview. A point was placed on the lateral‐most portion of the hippocampal tail label at multiple slices following the described landmarks (Figure 1). For accuracy across labels, we used the grid overlay tool (Freeview, FreeSurfer development version, set to 1 mm) to find the superior to inferior midpoint of the tail, along the lateral edge. A point was placed at the base of each GAR and throughout the terminus to visualize the full extent of the tail shape. Figure 2 illustrates an example of the spline that was used to calculate the medial flexure of the tail. The exact number of points varied for each case, depending on the individual geometry of the tail. One rater (AMA) selected points and completed 20 splines, which were then quality checked by a second rater (ECS). We calculated the vectors between the three points that optimally represent the medial flexure (Figure 2). θ defines the angle calculated between the vectors BA and BC notated on the spline. The angle was then calculated using Equation (1), where a · b represents the dot product of the vectors, and |a| |b| represents the product of the magnitudes of those vectors:

θ=cos−1a·b/ab (1)

FIGURE 2.

FIGURE 2

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Calculating the medial flexure of the hippocampal tail. This 3D reconstruction displays the spline points (green dots) and the measured angle (θ). A, B, and C highlight the points that were used to calculate the vectors between points B and A, and B and C.

The vectors and angles were calculated in Python (version 3.6.12, Python Software Foundation, https://www.python.org) (ECS) and quality checked for accuracy (CM).

2.11. Statistical Analysis

Mann–Whitney U tests were conducted to compare the distributions of tail volume and tail flexure by sex. Kruskal‐Wallis tests were used to investigate the relationships between preclinical Braak and Braak stages and the tail volume or flexure. Pairwise comparisons were performed using Dunn's test. Spearman correlation coefficients were computed to quantify the monotonic association between age and tail volume or flexure. A Fisher's exact test was used to compare the number of hippocampal head pes and tail GAR. The significance level was set at p < 0.05, and statistical tests were two‐sided. Descriptive statistics were done in Prism version 10.6.1 (GraphPad, http://graphpad.com) and reported as median ± interquartile range. All other analyses were performed in R version 4.5.1.

3. Results

3.1. Morphological Findings in Ex Vivo MRI

The anatomy of the human hippocampal tail was visualized through high‐resolution ex vivo MRI. Figure 3 shows an example (sample 5) in coronal MRI series; the high contrast and resolution enabled the visualization and subsequent validation of tail substructures in MRI. At 120 μm isotropic, GAR, dentate gyrus, gyrus fasciolaris, and fasciola cinerea were distinguishable from surrounding structures. Within the sample set, the anterior limit of the tail was the contiguous fornix (n = 10, Figure 3B; Figure S1E,F), the medial extension of tail (n = 9, Figure 3B; Figure S1A–C), or both landmarks occurring on the same MRI slice (n = 1). The posterior limit of the tail was marked by terminus converging onto the subsplenial gyrus with the indusium griseum (Figure 3O,P).

FIGURE 3.

FIGURE 3

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The human hippocampal tail in ultra‐high‐resolution ex vivo MRI. FLASH images acquired at 1203 μm3 show a coronal series of hippocampal tail (sample 5). Images represent prominent morphology and internal architecture that occur in the hippocampal tail. (A) shows the posterior body for context but note the adjacent fornix has not yet elongated superiorly. The beginning and end of the hippocampal tail are denoted with dotted‐line circles in (B) and (O). The coronal tail levels include: Anterior tail (B, C), fasciolar initium (D–F), tail junction (G), posterior tail (H), separated tail (I–K), tail terminus (L–O). The white arrows in (D, E) indicate prominent GAR (gyri of Anders Retzius), present until K. Curved arrows in (F) indicate gyrus fasciolaris and fasciolar cinerea; both structures present until (O). Green arrows indicates the junction of the medial and lateral hippocampal portions (F, G). White bracket in (I, J) demarcates the tail terminus (on left) and the lateral tail tissue (on right), which separate from one another at this level. Pink arrows in (J, K) indicate the end of lateral tail tissue, and white arrowheads (K–O) indicate the posterior tail terminus as it appears medially and superiorly. (P) shows the end of the tail, no hippocampal tissue remains. Fx = fornix. Scale bar = 2 mm.

3.2. Histological Validation

To further strengthen our MRI label accuracy and anatomical understanding, we validated the hippocampal tail with histology using Nissl staining (Figure 4, n = 14). Figure 4A shows a Nissl section of hippocampal posterior body for context; it was not included in the tail segmentation of the MRI. The beginning of the hippocampal tail is indicated by the crus of the fornix in full profile in this sample (Figures 4B and 3B). Histological validation allowed for cytoarchitectural analysis of tail substructures gyrus fasciolaris and fasciolar cinerea (Figure 4D–F) to inform manual MRI labels (Figure 3F–O). The GAR seen in MRI (Figure 3D–K) was histologically validated (Figure 4C–F).

FIGURE 4.

FIGURE 4

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Histological validation of hippocampal tail. Nissl staining in the human hippocampal tail (sample 5) shows the cytoarchitecture and validates the corresponding postmortem MRI in Figure 3. (A) indicates posterior hippocampal body; note the adjacent fornix, which has not yet extended superiorly. Straight white arrows (B, C) indicate GAR (gyri of Anders Retzius (corresponds to Figure 3E, MRI)). Green arrow in (D) indicates the junction of the medial and lateral pyramidal layers. White bracket demarcates where the medial tail terminus and lateral tail tissue disconnect (corresponds to Figure 3I, MRI). Pink arrows (F) show the posterior end of the lateral tail tissue (corresponds to Figure 3K, MRI). (D–F) show gyrus fasciolaris (GF, curved arrow) and fasciola cinerea (FC, curved arrow) with inset in (F) shows magnified gyrus fasciolaris (GF, curved arrow) and fasciola cinerea (FC, curved arrow). The white arrowhead in (F) indicates the tail terminus. CA, cornu ammonis; DG, dentate gyrus; fx, fornix. Scale bar = 4 mm in (A–F); scale bar = 200 μm (inset).

3.3. High‐Resolution MRI Reconstructions

Figure 5 illustrates twenty 3D reconstructions of the hippocampal tail based on 1203 μm3 resolution ex vivo MRI. The 3D reconstructions revealed varying shapes of the hippocampal tail. Some samples exhibited sharp medial flexure (Figure 5A–D,F,H,J–O,Q,S,T), while others had a shallow medial flexure (Figure 5E,G,R), and others were in between (Figure 5I,P). In our sample set, n = 19 exhibited tail termini (Figure 5A–D,F–T) that extended beyond the end of the lateral hippocampal gray matter (Figure 3L–O). One hippocampus sample (Figure 5E) demonstrated tail terminus and lateral tail tissue ending simultaneously.

FIGURE 5.

FIGURE 5

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3D reconstructions of the hippocampal tail from postmortem high‐resolution MRI, showing shape and size variability in human brain. Panels A–T show 3D reconstructions of hippocampal tails (n = 20) based on 1203 μm3 ex vivo MRI. The top reconstructions (A–K) represent left while (L–T) represent right hemispheres. The 2D dotted outline depicts a placeholder for the hippocampal head and body. Age/sex (e.g., 40F) for each sample denoted medially. Note the variability in number of gyri of Anders Retzius; note samples with large digitations, which were visible externally (E, H, K, M, R, S, T). F, female; M, male. Scale bar = 5 mm.

The individual hippocampal tail volumes and lengths were calculated for differences between males and females (Table 1). The median tail volume of our sample set was 715.6 ± 227.5 mm3 (n = 20). Median tail length was 13.14 ± 3.39 mm. The median volume of left tails was 715.7 ± 186.3 mm3 and right was 715.5 ± 342.7 mm3, which did not show a significant difference (p = 0.66). Male samples (n = 10) exhibited a volume of 742.4 ± 218.5 mm3 and females 715.6 ± 238.9 mm3, which were not significantly different (p = 0.91, Figure 6A). We did not detect differences between tail volume and Braak stages 0‐II (p = 0.72); stages were preclinical only. Finally, the volume of hippocampal tail did not correlate with age (Spearman: −0.097, 95% confidence interval: [−0.52 to 0.36], p = 0.68) (data not illustrated). We compared the number of pes in the hippocampal head to the number of GAR in the hippocampal tail (Figure 6B). The pes ranged from two to four digitations, with the median being 3.0 ± 0.75 pes. The number of GAR ranged from zero to seven, with the median being 4.0 ± 1.0 GAR. There was not sufficient evidence of a correlation (Fisher's Exact Test, p = 0.14, Table S1). Qualitatively, we observed that the size and number of GAR appeared to be related to the degree of convolutedness in the granule layer of the dentate gyrus.

TABLE 1.

Volume and length of each sample in the hippocampal tail, distributed by sex and hemisphere.

Sex Sample number Hemi Volume (mm3) Length (mm) Group size (n)
Female 1 Left 748.974 13.44 n = 7
3 Left 894.098 16.56
4 Left 810.461 14.16
6 Left 586.151 18.84
15 Left 748.974 7.92
17 Left 715.679 10.20
20 Left 548.059 11.76
2 Right 440.403 10.92 n = 3
7 Right 715.536 18.72
16 Right 830.655 11.40
Male 8 Left 715.062 7.80 n = 4
12 Left 836.392 14.40
18 Left 637.419 12.84
19 Left 823.739 13.68
5 Right 840.665 15.12 n = 6
9 Right 769.682 12.24
10 Right 381.506 7.80
11 Right 532.272 13.56
13 Right 827.354 11.04
14 Right 685.297 13.56
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Note: Each measurement was based on the manual labeling and 3D reconstructions.

Abbreviations: Hemi, hemisphere; mm, millimeters.

FIGURE 6.

FIGURE 6

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Volume, digitations, and flexure of the hippocampal tails compared to sex and structural features. (A) displays the volume of the tail compared to the sex for each sample (Mann–Whitney U, p = 0.91). (B) shows the variation of pes in the hippocampal head and the GAR (gyri of Anders Retzius) in the tail (Wilcoxon matched‐pairs signed rank test, p = 0.17). (C) compares the tail flexure in males and females; males showed a significantly larger flexure than females (Mann–Whitney U, p = 0.01). (D) displays a negative correlation between hippocampal tail volume and flexure (Spearman: −0.46, [−0.75, −0.02] p = 0.04). The box indicates the interquartile range, and the whiskers show the maximum and minimum values.

3.4. Medial Flexure

The medial flexures of the hippocampal tail ranged from 53.25° to 162.4° with a median of 118.7° ± 39.4° (n = 20, Table S1). Male hippocampal tail samples exhibited significantly larger medial flexures than female samples (95% CI, [4.45, 50.27], p = 0.01, Figure 6C). We were unable to detect flexure differences among Braak and Braak stage (p = 0.51). The tail flexure did not correlate with age (Spearman: 0.14, [−0.32, 0.55], p = 0.55). The medial flexure and the volume of the hippocampal tail showed a significant negative correlation (Spearman: −0.46, [−0.75, −0.02], p = 0.04) (Figure 6D). The medial flexure and length of the hippocampal tail indicated a negative correlation trend (Spearman: −0.44, [−0.74, 0.009], p = 0.055). We did not illustrate the differences between medial flexure and other characteristics such as Braak and Braak stage, length, or age.

4. Discussion

In this study we characterized the hippocampal tail; we reported volume, length, and medial flexure in high‐resolution MRI, produced 3D reconstructions, and validated MRI with histology. We built on existing tail nomenclature and named coronal landmarks based on morphological features and internal anatomical structures (Figure 1; Figure S1). We used these landmarks to create histologically validated MRI labels (Figures 3 and 4; Figure S2) and quantify the hippocampal tail length and volume (Table 1). We compared tail volume to BB staging, age, and sex (Figure 6A). We further characterized the variability of the tail by the size and number of GAR (Figure 6B) and illustrated the shape with 3D reconstructions (Figure 5). We investigated the medial flexure of the tail (Figures 2 and 6C,D) by quantifying and comparing the angle to sex, age, Braak and Braak stage, length, and volume; we reported a sex difference between male and female samples (Figure 6C).

Previous tail studies have reported a wide range of volumetric measures, in part due to varying anterior and posterior boundaries (Table 2). The most commonly used landmark is the appearance of the crus of the fornix in continuous profile (Frisoni et al. 2015; Maller et al. 2007; Malykhin et al. 2017; Mueller et al. 2007; Watson et al. 1992). The superior and inferior colliculi (Berron et al. 2017; Wisse et al. 2017), ambient cistern (Yushkevich et al. 2015), and presence of small dentes in the dentate gyrus (Duvernoy 2005; Palomero‐Gallagher et al. 2020) have also been used, although less frequently. These boundaries were not consistently visible in standard resolution isotropic MRI or were too large to be precise landmarks. In this study, the anterior limit of the hippocampal tail was the medial elongation of the hippocampal tissue, and/or the full crus of the fornix. In lower resolution scans (i.e., 13 mm3), the hippocampal elongation medially and crus of fornix often appear at the same time. The Watson et al. protocol (Watson et al. 1992) excluded a considerable portion of the posterior tail, noted by (Maller et al. 2006). Subsequent studies applied Maller's protocol (Maller et al. 2012; Malykhin et al. 2007, 2017) or generated their own based on manual segmentation or histology (Adler et al. 2018; Iglesias et al. 2015), resulting in variability in reported MRI volumes due to differing tail boundaries (Table 2). Additionally, the wide range of resolutions and field strengths could have impacted landmark visibility and thus volume accuracy. By integrating existing nomenclature to describe segments of the tail, we aim to provide clarity for future segmentation in clinical and postmortem research.

TABLE 2.

Previous studies compared with current study for tail volume, hemisphere, segmentation protocol, resolution, and field strength.

Study Labeling method Anterior & posterior tail boundaries Field strength (Tesla) Resolution (mm3) Mean tail volume (mm3 ± std dev) Mean LH tail volume (mm3 ± std dev) Mean RH tail volume (mm3 ± std dev)
Reference protocol
Watson, 1992 Manual A: not reported 1.5 0.97 × 0.97 × 3 Not reported n/a n/a
P: crus of fornix
Bernasconi, 2003 Manual A: crus of fornix 1.5 1.0 × 1.0 × 1.0 Not reported 311 ± 97 324 ± 100
Watson et al. 1992 P: posterior border of PPC
Maller, 2006 Manual A: posterior of fornix crus 1.5 1.0 × 1.0 × 3 Not reported 315 ± 92 314 ± 7
P: gyrus fasciolaris at SSpG
Malykhin, 2007 Manual A: fornix/fornix separates from ventricle 1.5 Native spatial, 1.5 × 1.0 × 1.0, interpolated to 1.5 × 0.5 × 0.5 Not reported 503 ± 145 464 ± 101
Maller et al. 2006 P: SSG
Maller, 2012 Manual A: posterior to fornix crus 1.5 0.86 × 0.86 × 0.86 Not reported 278 ± 100 316 ± 93
Maller et al. 2006 P: gyrus fasciolaris becomes SSpG
Iglesias, 2015 Manual and Automatic c A: first slice where fornix is fully connected to the hippocampus 7 0.13 × 0.13 × 0.13 (average) 465 ex vivo n/a n/a
P: not described 350 in vivo
Malykhin, 2017 Manual A: posterior to fornix crus 4.7 0.52 × 0.68 × 1.0 M = 587 ± 117 n/a n/a
Maller et al. 2006 P: gyrus fasciolaris at SSpG F = 599 ± 153 a
Adler, 2018 Manual and Automatic c

A: posterior 1/3 hippocampus; included some body

P: not described

 9.4 0.2 × 0.2 × 0.2, 3 blocks 1131 ± 259 n/a n/a
Dong, 2019 Automatic A: fornix 3 1.0 × 1.0 × 1.0 Not reported 561 ± 68 b 600 ± 85 b
Iglesias et al. 2015 P: not described
Alexander, 2026 (current study) Manual A: fornix crus or medial elongation P: terminus meets with IG and disappears 7 0.12 × 0.12 × 0.12 688 712 ± 135 664 ± 187
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Note: Note the variability among studies in definitions and results. Volume findings were rounded to the nearest whole digit.

Abbreviations: F, female; LH, left hemisphere; M, male; mm, millimeters; n/a, not available; PPC, posterior parahippocampal cortex; RH, right hemisphere; SSpG, subsplenial gyrus; std dev, standard deviation.

a

This study reported multiple age groups, here we report only the age group closest to our sample median.

b

Control group.

c

Automatic labeling based on manual labeling from same study.

Another variable in analyzing the hippocampal tail is its medial flexure posteriorly, due to its inconsistent shape and arc. By calculating the medial flexure of the tail, we quantified this variable arc (Figures 2, 6C,D, Table S1), characterizing the hippocampal tail for further study. Understanding the medial flexure with MRI may be helpful when blocking for histology. Previous work resliced the hippocampal tail using MRI and described its shape both coronally and obliquely to illustrate the tail curvature (Adler et al. 2018; de Flores et al. 2020). Both studies reported that the hippocampal tail showed a hippocampal “body‐like” appearance in some samples when viewed coronally. Our data suggest the appearance of the tail is a matter of both rotation and the degree of the medial flexure. By presenting novel quantification of the medial flexure, we aim to provide a deeper understanding of the tail's curvature in the brain.

The combination of high‐resolution ex vivo MRI and histology allowed for the analysis and validation of several previously reported tail substructures. This study characterized tail digitations (GAR) relative to the hippocampal head and its morphology (pes), which has been more widely studied. It is unclear if the lack of correlation between tail GAR and head pes digitation is meaningful or deserves future study. GAR have also been referred to broadly as gyrifications, hippocampal dentation, or dentes subiculi (Beattie et al. 2017; Retzius 1896; ten Donkelaar et al. 2018). Past studies have parcellated the GAR to include CA1 and the subiculum (Adler et al. 2018; DeKraker et al. 2020; Palomero‐Gallagher et al. 2020) or the presubiculum (Gloor 1997, via the Yakovlev Collection, Washington, DC). Gyrus fasciolaris and fasciola cinerea only reside in the tail, although the respective underlying subfields CA3 and dentate gyrus do reside in the head and body (Ding and Van Hoesen 2015; Duvernoy 1998; Insausti and Amaral 2004; Williams et al. 2023). Figure S3 shows hippocampal tail subfield parcellation based on boundaries delineated by Palomero‐Gallagher et al. (2020), Williams et al. (2023) as well as validating and corresponding histology from this study. We also validated the presence of the hippocampal tail terminus (Figures 3 and 4; Figures S2 and S3), which corroborates Palomero‐Gallagher et al. (2020). The parcellation of the hippocampal tail based on cytoarchitectural traits from the pentad protocol (Williams et al. 2023) and further implementation to MRI will be a topic of future work.

The hippocampal tail and head likely have different functions and even origins. The structural connectivity of the tail has more connectivity with visual cortices, while the head and body have more connectivity to posterior parahippocampal cortex (TF) and temporal pole (TG, dorsal and ventral) (Dalton et al. 2022). The functional connectivity during memory encoding has shown hippocampal body and tail to display connectivity to lingual, fusiform, visual association areas, and putamen that the hippocampal head does not (Beason‐Held et al. 2021). Functional connectivity of the hippocampal tail has also been addressed in depression; Sun et al. showed a significant reduction in connectivity between the left hippocampal tail and primary visual cortex in patients with major depressive disorder (Sun et al. 2024). These connectivity differences strengthen the case that the hippocampal tail performs a separate function from the hippocampal head.

Our study supplied quantitative and morphometric data in cognitive controls providing a baseline for clinical research. Numerous studies found significantly lower hippocampal tail volumes in patients with depression (Chu et al. 2024; Maller et al. 2007, 2012), schizophrenia (Liou et al. 2024; Maller et al. 2012; Sasabayashi et al. 2021), bipolar disorder (Cao et al. 2017), and epilepsy (Bernasconi et al. 2003; Jamiolkowski et al. 2024; Zawar et al. 2025). Chu et al. reported that patients with major depressive disorder (MDD) had reduced gray matter volumes in the right hippocampal tail (2024). Maller et al. found significantly smaller tail volumes in both the left and right hemispheres of patients with MDD (2012). Reduced tail volumes in patients with schizophrenia have also been reported (Liou et al. 2024; Maller et al. 2012). Future clinical studies may utilize our anatomical boundaries in conjunction with in vivo neuroimaging, offering improved standardized nomenclature to assess disease.

Our study had some limitations. Our data represent a hospital‐based sample set and are not applicable to the general community. Second, our study did not contain whole brain samples (hemispheres only), precluding inter‐individual comparison. We did not include laterality in the statistical analyses among samples to avoid overinterpretation of results. Additionally, not all our MRI data (n = 20) had corresponding Nissl stained tissue for the full extent of the hippocampal tail terminus; nonetheless, we had 14 cases with tail terminus, which provided a strong number for inference to inform the reconstructions that did not. Finally, one sample had a long PMI (159 h) that could have affected the staining quality and integrity of the tissue, but none was noted.

Combining high‐resolution MRI and histology allowed for 3D assessment with cytoarchitectural detail. This study built upon existing nomenclature and characterized and quantified anatomical features of the hippocampal tail. We document the 3D MRI volume with validating histology and report a significant difference between sex and medial flexure. Our findings enable precise hippocampal tail delineation and may facilitate future research on function and mental health disorders.

Author Contributions

A.M.A.: formal analysis, investigation, figure design, writing, editing; E.W.R.: investigation, editing, reviewing; N.M.: formal analysis, editing, reviewing; E.‐M.C.S.: investigation, reviewing; C.M.: resources, reviewing; B.F.: resources, analysis, reviewing; R.W.: resources, reviewing; M.P.F.: resources, reviewing; A.J.W.K.: investigation, resources, reviewing; J.C.A.: conceptualization, formal analysis, investigation, figure design, supervision, funding acquisition, project administration, writing, reviewing, and editing.

Funding

This work was supported by National Institutes of Health, R01AG057672, R01AG072056, RF1AG082223, U24NS135561, U01MH117023.

Ethics Statement

Autopsy consent was obtained, and tissue was collected with allowance for tissue to be used in research under a protocol approved by a Mass General Brigham Institutional Review Board.

Conflicts of Interest

B.F. is an advisor to DeepHealth, a company whose medical pursuits focus on medical imaging and measurement technologies. B.F. interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflicts of interest policies.

Supporting information

Figure S1: Two examples of the initial slice of the hippocampal tail in postmortem MRI. (A–C) illustrate the anterior most limit of the hippocampal tail, indicated by medial elongation of tail tissue (black arrow). (D–F) show the crus of the fornix, continuous in E and F (white arrow). Number in the lower left corner of each panel represents the distance in millimeters from B or E. Pink box outlines the first tail slice for each respective sample (equal distribution in our sample set). fx, fornix; hp, hippocampus; Pul, pulvinar of the thalamus. Scale bar = 1 cm.

HIPO-36-0-s002.png (4.4MB, png)

Figure S2: Ultra‐high‐resolution ex vivo MRI annotated for hippocampal tail boundaries. This figure corresponds to Figure 3 (MRI) but adds annotation of the hippocampal tail manual labeling. Panels A–P have been annotated with a pink outline (B–O) indicating the boundaries that were used to label the hippocampal tail in MRI. In anterior portions of the tail (anterior tail—separated tail; Panels A–K), the hippocampus is limited superiorly by the fornix and lateral ventricle. It is limited inferiorly by parahippocampal white matter, medially by cerebrospinal fluid, and laterally by the lateral ventricle. In the anterior tail terminus (L, M) portion, the tail is limited superiorly and laterally by parahippocampal white matter and inferiorly by the retrosplenial gyrus. Posterior tail terminus (N, O) is limited superiorly by the indusium griseum and medially by the cingulate gyrus. cc, corpus callosum; fx, fornix; ig, indusium griseum; lv, lateral ventricle; pphg, posterior parahippocampal gyrus. Scale bar 2 mm.

HIPO-36-0-s003.png (7.9MB, png)

Figure S3: Histologic validation of anatomical boundaries of the human hippocampal tail with subfield annotation. Panels (A–F) correspond to Figure 4 (Nissl) but adds subfield parcellation based on boundaries delineated by (Palomero‐Gallagher et al. 2020; Williams et al. 2023), as well as the corresponding histology in this study. Each subfield is outlined in a colored dotted line and labeled. Black arrows indicate GF and FC. CA, cornu ammonis; DG, dentate gyrus; FC, fasciola cinerea; fx, fornix; GF, gyrus fasciolaris; PreS, presubiculum; PPHG, posterior parahippocampal gyrus; ProS, prosubiculum; Sub, subiculum. Scale bar = 4 mm.

HIPO-36-0-s004.png (5.2MB, png)

Table S1: Sample demographics in this study and individual data. The data include the number of digitations in the hippocampal head (pes) and tail (GAR) per individual. The posterior medial flexure of the hippocampal tail was calculated according to Figure 2 and Equation (1). Medial flexure measurements show variability among samples. BB, Braak and Braak stage; F, female; GAR, gyri of Anders Retzius; Hemi, hemisphere; HP, hippocampus; M, male; PMI, postmortem interval.

HIPO-36-0-s001.pdf (122.7KB, pdf)

Acknowledgments

We are grateful to our brain donors who made this work possible. We appreciate the late Dr. Peter Davies's generosity to researchers for the CP13 tau antibody. Funding for this work was supported by the National Institute of Health, National Institute of Aging: NIA R01AG057672, R01AG072056, RF1AG082223, U24NS135561, U01MH117023.

Data Availability Statement

All supporting data are available in the figures and Supporting Information.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1: Two examples of the initial slice of the hippocampal tail in postmortem MRI. (A–C) illustrate the anterior most limit of the hippocampal tail, indicated by medial elongation of tail tissue (black arrow). (D–F) show the crus of the fornix, continuous in E and F (white arrow). Number in the lower left corner of each panel represents the distance in millimeters from B or E. Pink box outlines the first tail slice for each respective sample (equal distribution in our sample set). fx, fornix; hp, hippocampus; Pul, pulvinar of the thalamus. Scale bar = 1 cm.

HIPO-36-0-s002.png (4.4MB, png)

Figure S2: Ultra‐high‐resolution ex vivo MRI annotated for hippocampal tail boundaries. This figure corresponds to Figure 3 (MRI) but adds annotation of the hippocampal tail manual labeling. Panels A–P have been annotated with a pink outline (B–O) indicating the boundaries that were used to label the hippocampal tail in MRI. In anterior portions of the tail (anterior tail—separated tail; Panels A–K), the hippocampus is limited superiorly by the fornix and lateral ventricle. It is limited inferiorly by parahippocampal white matter, medially by cerebrospinal fluid, and laterally by the lateral ventricle. In the anterior tail terminus (L, M) portion, the tail is limited superiorly and laterally by parahippocampal white matter and inferiorly by the retrosplenial gyrus. Posterior tail terminus (N, O) is limited superiorly by the indusium griseum and medially by the cingulate gyrus. cc, corpus callosum; fx, fornix; ig, indusium griseum; lv, lateral ventricle; pphg, posterior parahippocampal gyrus. Scale bar 2 mm.

HIPO-36-0-s003.png (7.9MB, png)

Figure S3: Histologic validation of anatomical boundaries of the human hippocampal tail with subfield annotation. Panels (A–F) correspond to Figure 4 (Nissl) but adds subfield parcellation based on boundaries delineated by (Palomero‐Gallagher et al. 2020; Williams et al. 2023), as well as the corresponding histology in this study. Each subfield is outlined in a colored dotted line and labeled. Black arrows indicate GF and FC. CA, cornu ammonis; DG, dentate gyrus; FC, fasciola cinerea; fx, fornix; GF, gyrus fasciolaris; PreS, presubiculum; PPHG, posterior parahippocampal gyrus; ProS, prosubiculum; Sub, subiculum. Scale bar = 4 mm.

HIPO-36-0-s004.png (5.2MB, png)

Table S1: Sample demographics in this study and individual data. The data include the number of digitations in the hippocampal head (pes) and tail (GAR) per individual. The posterior medial flexure of the hippocampal tail was calculated according to Figure 2 and Equation (1). Medial flexure measurements show variability among samples. BB, Braak and Braak stage; F, female; GAR, gyri of Anders Retzius; Hemi, hemisphere; HP, hippocampus; M, male; PMI, postmortem interval.

HIPO-36-0-s001.pdf (122.7KB, pdf)

Data Availability Statement

All supporting data are available in the figures and Supporting Information.

Articles from Hippocampus are provided here courtesy of Wiley

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