Subfield Volumes Research Articles

Hippocampal subfield associations with memory depend on stimulus modality and retrieval mode.

Hippocampal atrophy is a well-known feature of age-related memory decline, and hippocampal subfields may contribute differently to this decline. In this cross-sectional study, we investigated the associations between hippocampal subfield volumes and performance in free recall and recognition memory tasks in both verbal and visual modalities in older adults without dementia. We collected MRIs from 97 (41 males) right-handed participants aged over 60. We segmented the right and left hippocampi into (i) dentate gyrus and cornu ammonis 4 (DG/CA4); (ii) CA2 and CA3 (CA2/CA3); (iii) CA1; (iv) strata radiatum, lacunosum and moleculare; and (v) subiculum. Memory was assessed with verbal free recall and recognition tasks, as well as visual free recall and recognition tasks. Amyloid-β and hippocampal tau positivity were assessed using [18F]AZD4694 and [18F]MK6240 PET tracers, respectively. The verbal free recall and verbal recognition performances were positively associated with CA1 and strata radiatum, lacunosum and moleculare volumes. The verbal free recall and visual free recall were positively correlated with the right DG/CA4. The visual free recall, but not verbal free recall, was also associated with the right CA2/CA3. The visual recognition was not significantly associated with any subfield volume. Hippocampal tau positivity, but not amyloid-β positivity, was associated with reduced DG/CA4, CA2/CA3 and strata radiatum, lacunosum and moleculare volumes. Our results suggest that memory performances are linked to specific subfields. CA1 appears to contribute to the verbal modality, irrespective of the free recall or recognition mode of retrieval. In contrast, DG/CA4 seems to be involved in the free recall mode, irrespective of verbal or visual modalities. These results are concordant with the view that DG/CA4 plays a primary role in encoding a stimulus' distinctive attributes, and that CA2/CA3 could be instrumental in recollecting a visual memory from one of its fragments. Overall, we show that hippocampal subfield segmentation can be useful for detecting early volume changes and improve our understanding of the hippocampal subfields' roles in memory.

Piecing it together: atrophy profiles of hippocampal subfields relate to cognitive impairment along the Alzheimer's disease spectrum.

People with Alzheimer's disease (AD) experience more rapid declines in their ability to form hippocampal-dependent memories than cognitively normal healthy adults. Degeneration of the whole hippocampal formation has previously been found to covary with declines in learning and memory, but the associations between subfield-specific hippocampal neurodegeneration and cognitive impairments are not well characterized in AD. To improve prognostic procedures, it is critical to establish in which hippocampal subfields atrophy relates to domain-specific cognitive declines among people along the AD spectrum. In this study, we examine high-resolution structural magnetic resonance imaging (MRI) of the medial temporal lobe and extensive neuropsychological data from 29 amyloid-positive people on the AD spectrum and 17 demographically-matched amyloid-negative healthy controls. Participants completed a battery of neuropsychological exams including select tests of immediate recollection, delayed recollection, and general cognitive status (i.e., performance on the Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]). Hippocampal subfield volumes (CA1, CA2, CA3, dentate gyrus, and subiculum) were measured using a dedicated MRI slab sequence targeting the medial temporal lobe and used to compute distance metrics to quantify AD spectrum-specific atrophic patterns and their impact on cognitive outcomes. Our results replicate prior studies showing that CA1, dentate gyrus, and subiculum hippocampal subfield volumes were significantly reduced in AD spectrum participants compared to amyloid-negative controls, whereas CA2 and CA3 did not exhibit such patterns of atrophy. Moreover, degeneration of the subiculum along the AD spectrum was linked to a significant decline in general cognitive status measured by the MMSE, while degeneration scores of the CA1 and dentate gyrus were more widely associated with declines on the MMSE and tests of learning and memory. These findings provide evidence that subfield-specific patterns of hippocampal degeneration, in combination with cognitive assessments, may constitute a sensitive prognostic approach and could be used to better track disease trajectories among individuals on the AD spectrum.

Hippocampal subfield volumes contribute to working memory interference control in aging: Evidence from longitudinal associations over 5 years

In memory, familiar but no longer relevant information may disrupt encoding and retrieval of to-be-learned information. While it has been demonstrated that the ability to resolve proactive interference (PI) in working memory (WM) is reduced in aging, the neuroanatomical components of this decline have yet to be determined. Hippocampal (HC) involvement in age-related decline in control of PI is currently not known. In particular, the association between HC subfield volumes and control of PI in WM has not been examined previously. Here we investigate the associations between mean level and 5-year trajectories of gray matter subfield volumes and PI in WM across the adult life span (N = 157). Longitudinal analyses over 5-years across all participants revealed that reduced volume in the subiculum was related to impaired control of PI. Age-stratified analyses showed that this association was most pronounced in older adults. Furthermore, we found that in older adults the effect of age on PI was mediated by GM volume in the HC. The current results show that HC volume is associated with the ability to control PI in WM, and that these associations are modulated by age.

Volumetric alterations of the hippocampal subfields in major depressive disorder with and without suicidal ideation

Major depressive disorder (MDD) is often accompanied with suicidal ideation (SI). Previous studies suggested that MDD patients who experienced suicidal attempts (SA) exhibited smaller hippocampal volume than those without SA. The hippocampus consists of several subfields that are histologically and functionally unique respectively. However, few studies have been designed to investigate the relationship between suicide and volumetric changes of the hippocampal subfields in MDD. A total of 92 participants, including 24 MDD patients with SI (MDD-SI), 30 MDD patients without SI (MDD-nSI), and 38 healthy controls (HC) were recruited in this study. High-resolution structural magnetic resonance images (MRI) were obtained and analyzed by using the automated hippocampal substructure module in FreeSurfer 7.3.2 Analyses of variance (ANOVA) were performed to obtain hippocampal subfields with significant differences among three groups and then post hoc tests were calculated for inter-group comparisons. Finally, the relationships between volumes of the hippocampal subfields and clinical characteristics were assessed using correlation analyses. The ANOVA revealed significant volumetric differences of the hippocampal subfields among three groups in the bilateral cornu ammonis (CA) 1 head, CA4 body, granule cell layer of the dentate gyrus (GC-ML-DG), molecular layer (ML), the right hippocampus-amygdala transition area (HATA), the right subiculum (Sub) body, and the left CA4 head. Relative to HC, both groups of MDD showed decreased volumes in the CA1 head, CA4, GC-ML-DG head, ML head, and whole hippocampal head of the left hippocampus, the right HATA, and bilateral whole hippocampal body, and whole hippocampus. Meanwhile, the MDD-SI group further exhibited diminished volume in the CA1 head, GC-ML-DG head, ML head, CA4 body, Sub body, and whole hippocampal head of the right hippocampus, as well as bilateral GC-ML-DG body and ML body. Additionally, the MDD-SI group also showed decreased volumes in the right GC-ML-DG body, ML body, and Sub body when compared to MDD-nSI group. However, no significant association was observed between hippocampal subfield volumes and clinical features in MDD. The present findings suggested that SI in MDD might be attributed to subfield abnormalities in the subiculum and DG-dominant circuit of the right hippocampus.

Modelling the overlap and divergence of autistic and schizotypal traits on hippocampal subfield volumes and regional cerebral blood flow

Psychiatric disorders show high co-morbidity, including co-morbid expressions of subclinical psychopathology across multiple disease spectra. Given the limitations of classical case-control designs in elucidating this overlap, new approaches are needed to identify biological underpinnings of spectra and their interaction. We assessed autistic-like traits (using the Autism Quotient, AQ) and schizotypy - as models of subclinical expressions of disease phenotypes and examined their association with volumes and regional cerebral blood flow (rCBF) of anterior, mid- and posterior hippocampus segments from structural MRI scans in 318 and arterial spin labelling (ASL) in 346 nonclinical subjects, which overlapped with the structural imaging sample (N = 298). We demonstrate significant interactive effects of positive schizotypy and AQ social skills as well as of positive schizotypy and AQ imagination on hippocampal subfield volume variation. Moreover, we show that AQ attention switching modulated hippocampal head rCBF, while positive schizotypy by AQ attention to detail interactions modulated hippocampal tail rCBF. In addition, we show significant correlation of hippocampal volume and rCBF in both region-of-interest and voxel-wise analyses, which were robust after removal of variance related to schizotypy and autistic traits. These findings provide empirical evidence for both the modulation of hippocampal subfield structure and function through subclinical traits, and in particular how only the interaction of phenotype facets leads to significant reductions or variations in these parameters. This makes a case for considering the synergistic impact of different (subclinical) disease spectra on transdiagnostic biological parameters in psychiatry.

Age-related differences in hippocampal subfield volumes across the human lifespan: A meta-analysis.

The human hippocampus (Hc) is critical for memory function across the lifespan. It is comprised of cytoarchitectonically distinct subfields: dentate gyrus (DG), cornu ammonis sectors (CA) 1-4, and subiculum, each of which may be differentially susceptible to neurodevelopmental and neurodegenerative mechanisms. Identifying age-related differences in Hc subfield volumes can provide insights into neural mechanisms of memory function across the lifespan. Limited evidence suggests that DG and CA3 volumes differ across development while other regions remain relatively stable, and studies of adulthood implicate a downward trend in all subfield volumes with prominent age effects on CA1. Due to differences in methods and limited sampling for any single study, the magnitude of age effects on Hc subfield volumes and their probable lifespan trajectories remain unclear. Here, we conducted a meta-analysis on cross-sectional studies (n = 48,278 participants, ages = 4-94 years) to examine the association between age and Hc subfield volumes in development (n = 11 studies), adulthood (n = 30 studies), and a combined lifespan sample (n = 41 studies) while adjusting estimates for sample sizes. In development, age was positively associated with DG and CA3-4 volumes, whereas in adulthood a negative association was observed with all subfield volumes. Notably, the observed age effects were not different across subfield volumes within each age group. All subfield volumes showed a nonlinear age pattern across the lifespan with DG and CA3-4 volumes showing a more distinct age trajectory as compared to the other subfields. Lastly, among all the study-level variables, only female percentage of the study sample moderated the age effect on CA1 volume: a higher female-to-male ratio in the study sample was linked to thegreater negative association between age and CA1 volume. These results document that Hc subfield volumes differ as a function of age offering broader implications for constructing theoretical models of lifespan memory development.

Contributions of hippocampal subfields and subregions to episodic memory performance in healthy cognitive aging

In the present study we investigated whether hippocampal subfield (cornu ammonis 1–3, dentate gyrus, and subiculum) and anteroposterior hippocampal subregion (head,body, and tail) volumes can predict episodic memory function using high-field high resolution structural magnetic resonance imaging (MRI). We recruited 126 healthy participants (18–85 years). MRI datasets were collected on a 4.7 T system. Participants were administered the Wechsler Memory Scale (WMS–IV) to evaluate episodic memory function. Structural equation modeling was used to test the relationship between studied variables. We found that the volume of the dentate gyrus subfield and posterior hippocampus (body) showed a significant direct effect on visuospatial memory performance; additionally, an indirect effect of age on visuospatial memory mediated through these hippocampal subfield/subregion was significant. Logical and verbal memory were not significantly associated with hippocampal subfield or subregion volumes.

KIBRA single nucleotide polymorphism is associated with hippocampal subfield volumes and cognition across development.

The hippocampus (Hc) consists of cytoarchitectonically and functionally distinct subfields: dentate gyrus (DG), cornu ammonis (CA1-3), and subiculum. In adults, a single nucleotide polymorphism (rs17070145, C→ T) in KIBRA, a gene encoding the eponymous (KIdney-BRAin) protein, is associated with variability in Hc subfield volumes and episodic memory. T-allele carriers have larger DG and CA volumes and better episodic memory compared to C-homozygotes. Little is known, however, about KIBRA's role in the development of the brain and cognition. In a sample of children, adolescents, and young adults (N = 176, ages 5- 25years), we replicated the adult association between KIBRA T-allele and larger DG and CA volumes but observed no relationship between KIBRA rs17070145 polymorphism and episodic memory. We noted, however, that a general cognitive performance index (IQ) differed across the allelic groups, with the lowest scores among T-homozygotes and the highest among C-homozygotes. Thus, in this developmental sample, KIBRA appears to have opposing effects on regional brain volume and cognition. These influences of KIBRA SNP may stem from associations between developmental reduction in brain volume and gains in cognitive performance-a hypothesis to be tested in longitudinal studies.

Verbal memory depends on structural hippocampal subfield volume.

To investigate correlates in hippocampal subfield volume and verbal and visual memory function in patients with temporal lobe epilepsy (TLE), mild amnestic cognitive impairment (MCI) and heathy participants (HP). 50 right-handed participants were included in this study; 11 patients with temporal lobe epilepsy (TLE), 18 patients with mild amnestic cognitive impairment (MCI) and 21 healthy participants (HP). Verbal memory performance was evaluated via the verbal memory test (VLMT) and visual memory performance via the diagnosticum for cerebral damage (DCM). Hippocampal subfield volumes of T1-weighted Magnetic Resonance Imaging (MRI) scans were computed with FreeSurfer version 7.1. Stepwise correlation analyses were performed between the left hippocampal subfield volumes and learning, free recall, consolidation and recognition performance scores of the VLMT as well as between right hippocampal subfield volumes and visual memory performance. The volume of the left subicular complex was highly correlated to learning performance (β = 0.284; p = 0.042) and free recall performance in the VLMT (β = 0.434; p = 0.001). The volume of the left CA3 subfield showed a significant correlation to the consolidation performance in the VLMT (β = 0.378; p = 0.006) and recognition performance in the VLMT (β = 0.290; p = 0.037). There was no significant correlation identified between the right hippocampal subfields and the visual memory performance. The results of this study show verbal memory correlates with hippocampal subfields and support the role of left subiculum and left CA2/CA3 in verbal memory performance.

Hippocampal subfield volumes in treatment resistant depression and serial ketamine treatment.

Subanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance. Patients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction. Patients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007). These results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.

Hippocampal subfield volumes in mild cognitive impairment and alzheimer's disease: a systematic review and meta-analysis.

The hippocampus is a complex structure that consists of several subfields with distinct and specialized functions. Although numerous studies have been performed to explore hippocampal atrophy at the sub-regional level in mild cognitive impairment (MCI) and Alzheimer's disease (AD), the results have been inconsistent especially for whether and which subfields can be served as the most potential biomarkers in MCI and AD. Herein, we used a meta-analytic approach to synthesize the extant literatures on hippocampal subfields in MCI and AD through PubMed, Web of Science, and Embase (PROSPERO CRD42021257586). As a result, a total of twenty studies using Freesurfer 5 and Freesurfer 6 were included in this investigation. These studies revealed that at the sub-regional level, hippocampal subfield volume reductions in MCI and AD were not restricted to specific subfields, and subiculum and presubiculum had the largest z-scores across most comparisons. However, none of the subfield performed much better in discriminating MCI and HC, AD and MCI, AD and HC as compared to whole hippocampus volume. These results suggested that we should explore the changes in the hippocampal subfields in subtypes of MCI or even at an earlier stage, that is subjective cognitive impairment.

Glucose metabolism, hippocampal subfields and cognition in first-episode and never-treated schizophrenia

BackgroundPrevious studies have indicated that glucose metabolism and altered hippocampal structure and function play a pivotal role in cognitive deficits in schizophrenia (SZ). This study was designed to explore the inter-relationship between glucose metabolism, hippocampal subfield volume, and cognitive function in the antipsychotics-naive first episode (ANFE) SZ patients. MethodsWe chose the fasting insulin, glucose, and insulin resistance (HOMA-IR) index as biomarkers of glucose metabolism. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). The hippocampal subfield volume, glucose metabolism biomarkers, and cognitive function were evaluated in 43 ANFE SZ and 29 healthy controls (HCs). ResultsCompared with HCs, SZ patients had higher fasting blood glucose and insulin levels and HOMA-IR (all p < 0.05). Correlation analysis revealed that category fluency performance was positively associated with fasting glucose level. Fasting insulin or HOMA-IR was positively associated with the hippocampal subfield volume in patients (all p<0.05). Moreover, the spatial span index score was associated with the volume of the right presubiculum, subiculum, and right hippocampal tail. In addition, multiple regression analysis found that the interaction effects of insulin × right fimbria or insulin × left fimbria were independent predictors of the MCCB total score. ConclusionsOur findings suggest that abnormal glucose metabolism and cognitive decline occur in the early stage of SZ. The interaction between abnormal glucose metabolism and hippocampal subfields was associated with cognitive functions in SZ.

Effects of a brief HIIT intervention on cognitive performance in older women.

Cardiorespiratory fitness (CRF) mitigates age-related decline in cognition and brain volume. Little is known, however, about the effects of high-intensity interval training (HIIT) on cognitive aging and the relationship between HIIT, cognition, hippocampal subfield volumes, and cerebral oxygen extraction fraction (OEF). Older sedentary women participated in an 8-week HIIT intervention. We conducted cognitive assessments, fitness assessments (VO2max), MRI scans: asymmetric spin echo oxygen extraction fraction (ASE-OEF), high-resolution multiple image co-registration and averaging (HR-MICRA) imaging, and transcranial Doppler ultrasonography before and after the intervention. VO2max increased from baseline (M = 19.36, SD = 2.84) to follow-up (M = 23.25, SD = 3.61), Z = - 2.93, p < .001, r = 0.63. Composite cognitive (Z = - 2.05, p = 0.041), language (Z = - 2.19, p = 0.028), and visuospatial memory (Z = - 2.22, p = 0.026), z-scores increased significantly. Hippocampal subfield volumes CA1 and CA3 dentate gyrus and subiculum decreased non-significantly (all p > 0.05); whereas a significant decrease in CA2 (Z = - 2.045, p = 0.041, r = 0.436) from baseline (M = 29.51; SD = 24.50) to follow-up (M = 24.50; SD = 13.38) was observed. Right hemisphere gray matter was correlated with language z-scores (p = 0.025; r = 0.679). The subiculum was correlated with attention (p = 0.047; r = 0.618) and verbal memory (p = 0.020; r = 0.700). The OEF and CBF were unchanged at follow-up (all p > .05). Although we observed cognitive improvements following 8weeks of our HIIT intervention, they were not explained by hippocampal, OEF, or CBF changes.

Development of human hippocampal subfield microstructure and relation to associative inference.

The hippocampus is a complex brain structure composed of subfields that each have distinct cellular organizations. While the volume of hippocampal subfields displays age-related changes that have been associated with inference and memory functions, the degree to which the cellular organization within each subfield is related to these functions throughout development is not well understood. We employed an explicit model testing approach to characterize the development of tissue microstructure and its relationship to performance on 2 inference tasks, one that required memory (memory-based inference) and one that required only perceptually available information (perception-based inference). We found that each subfield had a unique relationship with age in terms of its cellular organization. While the subiculum (SUB) displayed a linear relationship with age, the dentate gyrus (DG), cornu ammonis field 1 (CA1), and cornu ammonis subfields 2 and 3 (combined; CA2/3) displayed nonlinear trajectories that interacted with sex in CA2/3. We found that the DG was related to memory-based inference performance and that the SUB was related to perception-based inference; neither relationship interacted with age. Results are consistent with the idea that cellular organization within hippocampal subfields might undergo distinct developmental trajectories that support inference and memory performance throughout development.

Age-related differences in associative memory recognition of Chinese characters and hippocampal subfield volumes

Associative memory is a type of hippocampal-dependent episodic memory that declines with age. Studies have examined the neural substrates underlying associative memory and considered the hippocampus holistically; however, the association between associative memory decline and volumetric change in hippocampal subfields in the context of normal aging remains uncharacterized. Leveraging the distinct linguistic features of Chinese characters to evaluate distinct types of false recognition, we investigated age-related differences in associative recognition and hippocampal subfield volumes, as well as the relationship between behavioral performance and hippocampal morphometry in 25 younger adults and 32 older adults. The results showed an age-related associative memory deficit, which was exacerbated after a 30-min delay. Older adults showed higher susceptibility to false alarm errors with recombined and orthographically related foils compared to phonologically or semantically related ones. Moreover, we detected a disproportionately age-related, time-dependent increase in orthographic errors. Older adults exhibited smaller volumes in all hippocampal subfields when compared to younger adults, with a less pronounced effect observed in the CA2/3 subfield. Group-collapsed correlational analyses revealed associations between specific hippocampal subfields and associative memory but not item memory. Additionally, multi-subfield regions had prominent associations with delayed recognition. These findings underscore the significance of multiple hippocampal subfields in various hippocampal-dependent processes including associative memory, recollection-based retrieval, and pattern separation ability. Moreover, our observations of age-related difficulty in differentiating perceptually similar foils from targets provide a unique opportunity for examining the essential contribution of individual hippocampal subfields to the pattern separation process in mnemonic recognition.

More extensive structural damage in temporal lobe epilepsy with hippocampal sclerosis type 1

ObjectiveTo explore clinical and structural differences between mesial temporal lobe epilepsy (mTLE) patients with different hippocampal sclerosis (HS) subtypes. MethodsHigh-resolution T1-weighted MRI and diffusion tensor imaging data were obtained in 41 refractory mTLE patients and 52 age- and sex-matched healthy controls. Postoperative histopathological examination confirmed HS type 1 in 30 patients and HS type 2 in eleven patients. Clinical features, postoperative seizure outcomes, hippocampal subfields volumes, fractional anisotropy (FA) values of white matter regions and graph theory parameters were explored and compared between the HS type 1 and HS type 2 groups. ResultsNo significant differences in clinical features and postsurgical seizure outcomes were found between the HS type 1 and type 2 groups. However, the HS type 1 group showed extra atrophy in ipsilateral parasubiculum than healthy controls and more severe atrophy in contralateral hippocampal fissure than the HS type 2 group. More extensive FA decrease were also observed in the HS type 1 group, involving ipsilateral optic radiation, superior fronto-occipital fasciculus, contralateral uncinate fasciculus, tapetum, bilateral hippocampal cingulum, corona radiata, etc. Furthermore, in spite of similar impairments in characteristic path length, global efficiency and local efficiency in two HS groups, the HS type 1 group showed additional decrease of clustering coefficient than healthy controls. ConclusionsHS type 1 and 2 groups had similar clinical characteristics and postoperative seizure outcomes. More widespread neuronal cell loss in the HS type 1 group contributed to more extensive structural damage and connectivity abnormality. These results shed new light on the imaging correlates of different HS pathology.

Hippocampal subfield abnormalities and biomarkers of pathologic brain changes: from SARS-CoV-2 acute infection to post-COVID syndrome.

Cognitive deficits are among the main disabling symptoms in COVID-19 patients and post-COVID syndrome (PCS). Within brain regions, the hippocampus, a key region for cognition, has shown vulnerability to SARS-CoV-2 infection. Therefore, invivo detailed evaluation of hippocampal changes in PCS patients, validated on post-mortem samples of COVID-19 patients at the acute phase, would shed light into the relationship between COVID-19 and cognition. Hippocampal subfields volume, microstructure, and perfusion were evaluated in 84 PCS patients and compared to 33 controls. Associations with blood biomarkers, including glial fibrillary acidic protein (GFAP), myelin oligodendrocyte glycoprotein (MOG), eotaxin-1 (CCL11) and neurofilament light chain (NfL) were evaluated. Besides, biomarker immunodetection in seven hippocampal necropsies of patients at the acute phase were contrasted against eight controls. Invivo analyses revealed that hippocampal grey matter atrophy is accompanied by altered microstructural integrity, hypoperfusion, and functional connectivity changes in PCS patients. Hippocampal structural and functional alterations were related to cognitive dysfunction, particularly attention and memory. GFAP, MOG, CCL11 and NfL biomarkers revealed alterations in PCS, and showed associations with hippocampal volume changes, in selective hippocampal subfields. Moreover, post mortem histology showed the presence of increased GFAP and CCL11 and reduced MOG concentrations in the hippocampus in post-mortem samples at the acute phase. The current results evidenced that PCS patients with cognitive sequalae present brain alterations related to cognitive dysfunction, accompanied by a cascade of pathological alterations in blood biomarkers, indicating axonal damage, astrocyte alterations, neuronal injury, and myelin changes that are already present from the acute phase. Nominative Grant FIBHCSC 2020 COVID-19. Department of Health, Community of Madrid. Instituto de Salud Carlos III through the project INT20/00079, co-funded by European Regional Development Fund "A way to make Europe" (JAMG). Instituto de Salud Carlos III (ISCIII) through Sara Borrell postdoctoral fellowship Grant No. CD22/00043) and co-funded by the European Union (MDC). Instituto de Salud Carlos III through a predoctoral contract (FI20/000145) (co-funded by European Regional Development Fund "A way to make Europe") (MVS). Fundación para el Conocimiento Madri+d through the project G63-HEALTHSTARPLUS-HSP4 (JAMG, SOM).

Altered hippocampal subfield volumes in major depressive disorder with and without anhedonia

BackgroundPrevious neuroimaging findings have demonstrated the association between anhedonia and the hippocampus. However, few studies have focused on the structural changes in the hippocampus in major depressive disorder (MDD) patients with anhedonia. Meanwhile, considering that multiple and functionally specialized subfields of the hippocampus have their own signatures, the present study aimed to investigate the volumetric alterations of the hippocampus as well as its subfields in MDD patients with and without anhedonia.MethodsA total of 113 subjects, including 30 MDD patients with anhedonia, 40 MDD patients without anhedonia, and 43 healthy controls (HCs), were recruited in the study. All participants underwent high-resolution brain magnetic resonance imaging (MRI) scans, and the automated hippocampal substructure module in FreeSurfer 6.0 was used to evaluate the volumes of hippocampal subfields. We compared the volumetric differences in hippocampal subfields among the three groups by analysis of variance (ANOVA, post hoc Bonferroni), and partial correlation was used to explore the association between hippocampal subregion volumes and clinical characteristics.ResultsANOVA showed significant volumetric differences in the hippocampal subfields among the three groups in the left hippocampus head, mainly in the cornu ammonis (CA) 1, granule cell layer of the dentate gyrus (GC-ML-DG), and molecular layer (ML). Compared with HCs, both groups of MDD patients showed significantly smaller volumes in the whole left hippocampus head. Interestingly, further exploration revealed that only MDD patients with anhedonia had significantly reduced volumes in the left CA1, GC-ML-DG and ML when compared with HCs. No significant difference was found in the volumes of the hippocampal subfields between MDD patients without anhedonia and HCs, either the two groups of MDD patients. However, no association between hippocampal subfield volumes and clinical characteristics was found in either the subset of patients with anhedonia or in the patient group as a whole.ConclusionsThese preliminary findings suggest that MDD patients with anhedonia exhibit unique atrophy of the hippocampus and that subfield abnormalities in the left CA1 and DG might be associated with anhedonia in MDD.

Volumes of hippocampal subfields suggest a continuum between schizophrenia, major depressive disorder and bipolar disorder.

There is considerable debate as to whether the continuum of major psychiatric disorders exists and to what extent the boundaries extend. Converging evidence suggests that alterations in hippocampal volume are a common sign in psychiatric disorders; however, there is still no consensus on the nature and extent of hippocampal atrophy in schizophrenia (SZ), major depressive disorder (MDD) and bipolar disorder (BD). The aim of this study was to verify the continuum of SZ - BD - MDD at the level of hippocampal subfield volume and to compare the volume differences in hippocampal subfields in the continuum. A total of 412 participants (204 SZ, 98 MDD, and 110 BD) underwent 3 T MRI scans, structured clinical interviews, and clinical scales. We segmented the hippocampal subfields with FreeSurfer 7.1.1 and compared subfields volumes across the three diagnostic groups by controlling for age, gender, education, and intracranial volumes. The results showed a gradual increase in hippocampal subfield volumes from SZ to MDD to BD. Significant volume differences in the total hippocampus and 13 of 26 hippocampal subfields, including CA1, CA3, CA4, GC-ML-DG, molecular layer and the whole hippocampus, bilaterally, and parasubiculum in the right hemisphere, were observed among diagnostic groups. Medication treatment had the most effect on subfields of MDD compared to SZ and BD. Subfield volumes were negatively correlated with illness duration of MDD. Positive correlations were found between subfield volumes and drug dose in SZ and MDD. There was no significant difference in laterality between diagnostic groups. The pattern of hippocampal volume reduction in SZ, MDD and BD suggests that there may be a continuum of the three disorders at the hippocampal level. The hippocampus represents a phenotype that is distinct from traditional diagnostic strategies. Combined with illness duration and drug intervention, it may better reflect shared pathophysiology and mechanisms across psychiatric disorders.

Brain but not serum BDNF levels are associated with structural alterations in the hippocampal regions in patients with drug-resistant mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy is the most common type of focal epilepsy, imposing a significant burden on the health care system worldwide. Approximately one-third of patients with this disease who do not adequately respond to pharmacotherapy are considered drug-resistant subjects. Despite having some clues of how such epileptic activity and resistance to therapy emerge, coming mainly from preclinical models, we still witness a scarcity of human data. To narrow this gap, in this study, we aimed to estimate the relationship between hippocampal and serum levels of brain-derived neurotrophic factor (BDNF), one of the main and most widely studied neurotrophins, and hippocampal subfield volumes in patients with drug-resistant mesial temporal epilepsy undergoing neurosurgical treatment. We found that hippocampal (but not serum) BDNF levels were negatively correlated with the contralateral volumes of the CA1 and CA4 subfields, presubiculum, subiculum, dentate gyrus, and molecular layer of the hippocampus. Taken together, these findings are generally in accordance with existing data, arguing for a proepileptic nature of BDNF effects in the hippocampus and related brain structures.