INTRODUCTION:The amygdala is critical for social cognition and undergoes profound damage in frontotemporal dementia (FTD). While its atrophy is well documented, changes in its structural connectivity and their behavioral relevance remain unclear. METHODS:Using fixel-based analysis and tractography, we examined amygdala connectivity in patients with behavioral variant FTD (bvFTD; n = 21), semantic dementia (SD; n = 19), progressive non-fluent aphasia (PNFA; n = 18), and 28 controls. Associations with empathy and emotion recognition were explored using partial correlations. RESULTS:BvFTD and SD showed marked degeneration of amygdala-associated tracts, while PNFA exhibited subtle left temporal changes. Tractography revealed reduced amygdala connectivity with regions supporting memory, visual, language, semantic, and motor functions, to varying degrees across subtypes. Social cognitive deficits were correlated with amygdala-cerebellum connectivity in bvFTD and with amygdala-hippocampus connectivity in SD. DISCUSSION:These findings were the first to demonstrate subtype-specific patterns of amygdala white matter alteration and their relevance to social cognitive symptoms in FTD.

Grey matter loss in the hippocampus is a hallmark of neurobiological aging, yet understanding the corresponding changes in its functional connectivity remains limited. Seed-based functional connectivity (FC) analysis enables voxel-wise mapping of the hippocampus's synchronous activity with cortical regions, offering a window into functional reorganization during aging. In this study, we develop an interpretable deep learning framework to predict brain age from hippocampal FC using a three-dimensional convolutional neural network (3D CNN) combined with LayerCAM saliency mapping. This approach maps key hippocampal-cortical connections, particularly with the precuneus, cuneus, posterior cingulate cortex, parahippocampal cortex, left superior parietal lobule, and right superior temporal sulcus, that are highly sensitive to age. Critically, disaggregating anterior and posterior hippocampal FC reveals distinct mapping aligned with their known functional specializations. These findings provide new insights into the functional mechanisms of hippocampal aging and demonstrate the power of explainable deep learning to uncover biologically meaningful patterns in neuroimaging data.

While research suggests that playing musical instruments promotes neuroplasticity in professional musicians, it remains unclear whether lifelong music experience benefits brain health in non-professional musicians. This study examined whether playing a musical instrument across the lifespan is associated with (a) altered grey matter (GM) density and (b) neuropsychological functioning in older adults at risk for dementia. Sixty-one individuals aged ≥ 50 years were recruited from a memory clinic. Participants underwent magnetic resonance imaging and neuropsychological assessment from which composite scores for learning, memory, and executive functioning were derived. Based on musical history, participants were classified as: active players (n = 15), former players (n = 20), and naïve (n = 26). Voxel-based morphometry analyses, correcting for age and total intracranial volume, assessed GM density differences. General linear models, controlling for age, tested associations between music experience and cognition. Active players showed increased GM density in the left planum temporale (p < 0.0001), left planum polare (p < 0.0001), right posterior insula (p < 0.0001), and left cerebellum exterior (p < 0.0001) compared to the naïve group. They also showed increased GM in the left cerebellum exterior (p < 0.0001) relative to former players. No GM differences were observed between former players and naïve individuals. Music experience was not significantly associated with neuropsychological performance. In older adults at risk for dementia, currently playing a musical instrument was associated with increased GM density in regions linked with musical training. Further research is needed to explore music’s role in brain health and dementia prevention.

The hippocampus is a heterogeneous structure with cytoarchitectonically distinct subfields that exhibit heterogeneous lifespan trajectories and are differentially susceptible to diseases. Advances in high-resolution imaging have accelerated research on these structures, yet variability in segmentation protocols limits cross-study comparability. The Hippocampal Subfields Group (HSG) is an international consortium addressing this challenge by developing a reliable, accessible, and freely available segmentation protocol for high-resolution T2-weighted 3 tesla MRI scans (http://www.hippocampalsubfields.com). Here, we present the harmonized protocol for the posterior portion of the hippocampus (the "tail"), complementing the previously established "body" protocol, and with an anterior "head" protocol under development. The tail protocol provides standardized definitions of the external boundaries for the posterior-most extent of the hippocampus, facilitating consistent segmentation from surrounding tissues. The research community was extensively involved through an online survey that incorporated comprehensive protocol details, feasibility assessments, tutorial videos, and illustrative segmentations. Through this collaborative process, consensus emerged to exclude subfield labeling in the hippocampal tail due to limited visibility of internal landmarks and substantial anatomical variability in this region. All proposed boundary guidelines were deemed clear and agreed upon via a Delphi procedure. The harmonized tail protocol has high intra- (Averaged ICC(2,1) > 0.98; Averaged Dice Similarity Coefficient = 0.92) and inter-rater reliability (Averaged ICC(2,k) > 0.98; Averaged Dice Similarity Coefficient = 0.86) and offers a practical framework for replicable segmentation. By establishing standardized guidelines, this protocol enhances comparability of findings across developmental, aging, and clinical research and is compatible with ongoing technological advances.

The hippocampus plays a central role in episodic memory and has been the focus of extensive research over past decades. A substantial body of work has demonstrated that age-related memory decline is linked to changes in how the hippocampus functionally interacts with distributed brain networks. While functional connectivity changes in ageing are well documented, relatively little is known about alterations in the structural connectivity (SC) of the hippocampus, despite its foundational role in supporting communication across neural systems. In this study, we combined high-quality data from the Human Connectome Project and advanced diffusion-weighted imaging (DWI) methods to investigate age-related changes in hippocampal SC. Using a recently developed tractography pipeline that allows greater anatomical specificity than conventional approaches, we systematically compared connectivity patterns between younger (26–30 years) and older (56–60 years) adults. Results revealed reduced hippocampal SC with the entorhinal cortex and medial parietal cortices in older participants, alongside increased SC with anterior temporal areas. This paradoxical pattern suggests that ageing is associated with both vulnerability and reorganisation of hippocampal networks, with increased hippocampal-temporal connectivity potentially reflecting compensatory plasticity in response to reduced posterior medial connection. These findings provide in vivo evidence of cortico-hippocampal structural reorganisation in late middle age, a critical period when pathological processes such as tau deposition are already detectable in cognitively healthy individuals. More broadly, they demonstrate the power of our anatomically refined tractography pipeline as a ‘proof of concept’ for detecting subtle, regionally specific changes in hippocampal pathway density. This approach holds promise for charting normative ageing trajectories and identifying early biomarkers of vulnerability and compensation in memory-related networks.

Understanding how structural and functional connectivity shape hippocampal interactions with the rest of the brain is critical for elucidating its role in cognition. Here, we combine high-resolution diffusion MRI, a novel fibre-tracking pipeline designed to specifically probe anatomical connectivity of the in vivo human hippocampus, and track-weighted dynamic functional connectivity (TW-dFC) to investigate how direct anatomical connections between the hippocampus and the rest of the brain relate to time-varying functional interactions. In Study 1, TW-dFC maps were computed for 10 participants from the Human Connectome Project and subjected to ICA and k-means clustering to derive a data-driven parcellation of the hippocampus based on its structure-function relationships. This revealed circumscribed clusters distributed along anterior-posterior and medial-lateral axes, which broadly aligned with hippocampal subfields. In Study 2, we examined the resting-state functional connectivity profiles of each TW-dFC derived cluster in an independent sample of 100 participants. Each hippocampal cluster displayed distinct patterns of functional connectivity with specific substructures within medial temporal, parietal, frontal and occipital cortices as well as subcortical and cerebellar regions. Our findings demonstrate that TW-dFC provides a powerful framework for anatomically informed functional parcellation of the hippocampus and offers new insights into the structural-functional organisation underlying hippocampal-(sub)cortical interactions. Our approach opens new avenues for probing memory systems in health and their disruption in aging and disease.

Mounting evidence indicates marked hippocampal degeneration in semantic dementia (SD) however, the spatial distribution of hippocampal atrophy profiles in this syndrome remains unclear. Using a recently developed parcellation approach, we extracted hippocampal volumes from four distinct subregions running from anterior to posterior along the longitudinal axis (anterior, intermediate rostral, intermediate caudal, and posterior). Volumetric differences in hippocampal subregions were compared between 21 SD, 24 matched Alzheimer's disease (AD), and 27 healthy older Control participants. Despite comparable overall hippocampal volume loss, SD and AD groups diverged in terms of the magnitude of atrophy along the anterior -posterior axis of the hippocampus. Global hippocampal atrophy was observed in AD, with no discernible gradation or lateralisation. In contrast, SD patients displayed graded bilateral hippocampal atrophy, most pronounced on the left-hand side, and concentrated in anterior relative to posterior subregions. Finally, we found preliminary evidence that disease -specific vulnerability along the anterior -posterior axis of the hippocampus was associated with canonical clinical features of these syndromes.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer’s disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized (20X resolution) slices with 5 mm spacing. Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists’ agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed more gradually. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed human neuroimaging research on the MTL cortex.

Advances in ultra-high field 7 Tesla functional magnetic resonance imaging (7 T fMRI) have provided unprecedented opportunities to gain insights into the neural underpinnings supporting human memory. The hippocampus, a heterogeneous brain structure comprising several subfields, plays a central role during vivid re-experiencing of autobiographical memories (AM). However, due to technical limitations, how hippocampal subfields differentially support AM, whether this contribution is specific to one portion along the hippocampal long-axis, and how subfields are functionally connected with other brain regions typically associated with AM retrieval remains elusive. Here, we leveraged technical advances of parallel imaging and employed a submillimeter Echo Planar Imaging sequence over the whole brain while participants re-experienced vivid, detail-rich AM. We found that all hippocampal subfields along the long-axis were engaged during AM retrieval. Nonetheless, only the pre/parasubiculum within the anterior body of the hippocampus contributed over and above to AM retrieval. Moreover, whole-brain functional connectivity analyses of the same data revealed that this part of the hippocampus was the only one that was strongly connected to other brain regions typically associated with AM, such as the ventromedial prefrontal cortex (vmPFC) and medial/lateral parietal regions. In the context of the broader literature, our results support recent proposals that the anterior body of the pre/parasubiculum may play an important role in scene-based cognition, such as its engagement during the re-experiencing of personal past events.

Amygdala atrophy has been found in frontotemporal dementia (FTD), yet the specific changes of its subregions across different FTD phenotypes remain unclear. The aim of this study was to investigate the volumetric alterations of the amygdala subregions in FTD phenotypes and how they evolve with disease progression. Patients clinically diagnosed with behavioral variant FTD (bvFTD) ( n = 20), semantic dementia (SD) ( n = 20), primary nonfluent aphasia (PNFA) ( n = 20), Alzheimer’s disease (AD) ( n = 20), and 20 matched healthy controls underwent whole brain structural MRI. The patient groups were followed up annually for up to 3.5 years. Amygdala nuclei were segmented using FreeSurfer, corrected by total intracranial volumes, and grouped into the basolateral, superficial, and centromedial subregions. Linear mixed effects models were applied to identify changes in amygdala subregional volumes over time. At baseline, bvFTD, SD, and AD displayed global amygdala volume reduction, whereas amygdala volume appeared to be preserved in PNFA. Asymmetrical amygdala atrophy (left > right) was most pronounced in SD. Longitudinally, SD and PNFA showed greater rates of annual decline in the right basolateral and superficial subregions compared to bvFTD and AD. The findings provide comprehensive insights into the differential impact of FTD pathology on amygdala subregions, revealing distinct atrophy patterns that evolve over disease progression. The characterization of amygdala subregional involvement in FTD and their potential role as biomarkers carry substantial clinical implications.

BACKGROUND AND PURPOSE:Obstructive sleep apnea is associated with increased dementia risk. Nocturnal hypoxemia, which can be more severe during rapid eye movement (REM) sleep, may be a key mechanism. This study examines how REM hypoxemia affects memory and explores whether hippocampal vulnerability to hypoxemia mediates this effect in older adults at risk for dementia. METHODS:Older adults aged ≥50 years (N = 338) with subjective or mild cognitive impairment (i.e., objective impairment) underwent neuropsychological, mood, and medical assessment, magnetic resonance imaging scanning (n = 135), and overnight polysomnography. Verbal learning and memory were assessed with the Rey Auditory Verbal Learning Test. REM sleep hypoxemia was measured using the Oxygen Desaturation Index-3% (REM-ODI). Hippocampal subfield (CA1, CA3, subiculum, and dentate gyrus) volumes were derived from T1 and high-resolution hippocampus T2 scans. We determined whether the relationship between REM-ODI and learning and memory was mediated by hippocampal subfield volume. Analyses were repeated in non-REM sleep to determine whether the effects were REM-specific. RESULTS:Although there was not a direct effect of REM-ODI on verbal learning (p > 0.05) or memory (p > 0.05), mediation analyses showed a significant indirect effect of high REM-ODI on poorer verbal learning (β = -0.09, 95% confidence interval [CI] = -0.238 to -0.005) and memory (β = -0.100, 95% CI = -0.255 to -0.005), which was mediated by CA1 volume. These associations were absent in non-REM sleep (p > 0.05). CONCLUSIONS:Hypoxemia during REM sleep may impair memory in people at risk for dementia by reducing CA1 hippocampal volume. Research is needed to explore whether interventions targeting REM sleep hypoxemia are protective against memory decline.

Human subcortical grey matter (SGM) structures are crucial hubs for processing, transmitting and modulating brain-wide signals. However, in-vivo characterisation of subnuclei within the SGM structures remains limited, restricting our knowledge of their roles in brain function and in disorders. To address this gap, we introduce the Sydney Subcortical Gray Matter (SydSGM) parcellation— based on a novel data-driven approach using multiple MRI contrasts to assess myelination, directionality of white matter fibres, and diffusion micro-environment. Fifty-four distinct parcels were identified across caudate, putamen, globus pallidus, nucleus accumbens, and thalamus based on the coherent representation of these attributes, which demonstrated remarkable concordance with histology-based delineations. The SydSGM parcellation now facilitates detailed structural connectivity analysis at the subnuclei scale. It can be adopted as a standalone atlas or incorporated into existing brain atlases. We demonstrate SydSGM parcellation’s advantage by revealing declined structural connectivity of highly resolved SGM subnuclei in patients with early Parkinson’s disease.

People vary substantially in their capacity to recall past experiences, known as autobiographical memories. Here we investigated whether the volumes of specific hippocampal subfields were associated with autobiographical memory retrieval ability. We manually segmented the full length of the two hippocampi in 201 healthy young adults into DG/CA4, CA2/3, CA1, subiculum, pre/parasubiculum and uncus, in the largest such manually segmented subfield sample yet reported. Across the group we found no evidence for an association between any subfield volume and autobiographical memory recall ability. However, when participants were assigned to lower and higher performing groups based on their memory recall scores, we found that bilateral CA2/3 volume was significantly and positively associated with autobiographical memory recall performance specifically in the lower performing group. We further observed that this effect was attributable to posterior CA2/3. By contrast, semantic details from autobiographical memories, and performance on a range of laboratory-based memory tests, did not correlate with CA2/3 volume. Overall, our findings highlight that posterior CA2/3 may be particularly pertinent for autobiographical memory recall. They also reveal that there may not be direct one-to-one mapping of posterior CA2/3 volume with autobiographical memory ability, with size mattering perhaps only in those with poorer memory recall.

The hippocampus is a brain structure central to a broad range of cognitive functions including episodic memory. In recent years, we have developed a greater understanding of the structural and functional connectivity of the human hippocampus. Despite these advances, we lack a detailed understanding of structure-function relationships of cortico-hippocampal connectivity. We addressed this gap by combining high-quality data from the Human Connectome Project with cutting-edge fibre-tracking and track-weighted dynamic functional connectivity methods to quantitatively characterise the relationship between anatomical and functional connectivity of the human hippocampus. Our results contribute to ongoing efforts to characterise structure-function relationships of the hippocampus.

Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo , the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter-dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health.

Background Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis. Methods A Phase 1/2A veterinary trial was conducted in N = 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippocampus using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses; these were compared to a brain bank (N = 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model (N = 16) was used to more closely evaluate intrahippocampal engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippocampal slice preparation. Results Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippocampus specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings: hippocampally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippocampus, neuronal differentiation in situ, and physiologically-correct integration into pyramidal layer circuits. Conclusions With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippocampus.

The hippocampus supports multiple cognitive functions including episodic memory. Recent work has highlighted functional differences along the anterior–posterior axis of the human hippocampus, but the neuroanatomical underpinnings of these differences remain unclear. We leveraged track-density imaging to systematically examine anatomical connectivity between the cortical mantle and the anterior–posterior axis of the in vivo human hippocampus. We first identified the most highly connected cortical areas and detailed the degree to which they preferentially connect along the anterior–posterior axis of the hippocampus. Then, using a tractography pipeline specifically tailored to measure the location and density of streamline endpoints within the hippocampus, we characterised where these cortical areas preferentially connect within the hippocampus. Our results provide new and detailed insights into how specific regions along the anterior–posterior axis of the hippocampus are associated with different cortical inputs/outputs and provide evidence that both gradients and circumscribed areas of dense extrinsic anatomical connectivity exist within the human hippocampus. These findings inform conceptual debates in the field and emphasise the importance of considering the hippocampus as a heterogeneous structure. Overall, our results represent a major advance in our ability to map the anatomical connectivity of the human hippocampus in vivo and inform our understanding of the neural architecture of hippocampal-dependent memory systems in the human brain.

The precise role played by the hippocampus in supporting cognitive functions such as episodic memory and future thinking is debated, but there is general agreement that it involves constructing representations comprised of numerous elements. Visual scenes have been deployed extensively in cognitive neuroscience because they are paradigmatic multi-element stimuli. However, questions remain about the specificity and nature of the hippocampal response to scenes. Here, we devised a paradigm in which we had participants search pairs of images for either colour or layout differences, thought to be associated with perceptual or spatial constructive processes respectively. Importantly, images depicted either naturalistic scenes or phase-scrambled versions of the same scenes, and were either simple or complex. Using this paradigm during functional MRI scanning, we addressed three questions: 1. Is the hippocampus recruited specifically during scene processing? 2. If the hippocampus is more active in response to scenes, does searching for colour or layout differences influence its activation? 3. Does the complexity of the scenes affect its response? We found that, compared to phase-scrambled versions of the scenes, the hippocampus was more responsive to scene stimuli. Moreover, a clear anatomical distinction was evident, with colour detection in scenes engaging the posterior hippocampus whereas layout detection in scenes recruited the anterior hippocampus. The complexity of the scenes did not influence hippocampal activity. These findings seem to align with perspectives that propose the hippocampus is especially attuned to scenes, and its involvement occurs irrespective of the cognitive process or the complexity of the scenes.

The hippocampus and ventromedial prefrontal cortex (vmPFC) play key roles in numerous cognitive domains including mind-wandering, episodic memory, and imagining the future. Perspectives differ on precisely how they support these diverse functions, but there is general agreement that it involves constructing representations composed of numerous elements. Visual scenes have been deployed extensively in cognitive neuroscience because they are paradigmatic multielement stimuli. However, it remains unclear whether scenes, rather than other types of multifeature stimuli, preferentially engage hippocampus and vmPFC. Here, we leveraged the high temporal resolution of magnetoencephalography to test participants as they gradually built scene imagery from three successive auditorily presented object descriptions and an imagined 3-D space. This was contrasted with constructing mental images of nonscene arrays that were composed of three objects and an imagined 2-D space. The scene and array stimuli were, therefore, highly matched, and this paradigm permitted a closer examination of step-by-step mental construction than has been undertaken previously. We observed modulation of theta power in our two regions of interest—anterior hippocampus during the initial stage and vmPFC during the first two stages, of scene relative to array construction. Moreover, the scene-specific anterior hippocampal activity during the first construction stage was driven by the vmPFC, with mutual entrainment between the two brain regions thereafter. These findings suggest that hippocampal and vmPFC neural activity is especially tuned to scene representations during the earliest stage of their formation, with implications for theories of how these brain areas enable cognitive functions such as episodic memory.