The hippocampal formation represents a key region in the pathophysiology of schizophrenia. Aerobic exercise poses a promising add-on treatment to potentially counteract structural impairments of the hippocampal formation and associated symptomatic burden. However, current evidence regarding exercise effects on the hippocampal formation in schizophrenia is largely heterogeneous. Therefore, we conducted a systematic review and meta-analysis to assess the impact of aerobic exercise on total hippocampal formation volume. Additionally, we used data from a recent multicenter randomized-controlled trial to examine the effects of aerobic exercise on hippocampal formation subfield volumes and their respective clinical implications.

The meta-analysis comprised six studies that investigated the influence of aerobic exercise on total hippocampal formation volume compared to a control condition with a total of 186 people with schizophrenia (100 male, 86 female), while original data from 29 patients (20 male, 9 female) was considered to explore effects of six months of aerobic exercise on hippocampal formation subfield volumes.

Our meta-analysis did not demonstrate a significant effect of aerobic exercise on total hippocampal formation volume in people with schizophrenia (g = 0.33 [−0.12 to 0.77]), p = 0.15), but our original data suggested significant volume increases in certain hippocampal subfields, namely the cornu ammonis and dentate gyrus.

Driven by the necessity of better understanding the pathophysiology of schizophrenia, the present work underlines the importance to focus on hippocampal formation subfields and to characterize subgroups of patients that show neuroplastic responses to aerobic exercise accompanied by corresponding clinical improvements.

Attitudes toward risk and ambiguity significantly influence how individuals assess and value rewards. This fMRI study examines the reward valuation process under conditions of uncertainty and investigates the associated neural mechanisms in individuals who engage in nonsuicidal self-injury (NSSI) as a coping mechanism for psychological pain.

The study involved 44 unmedicated individuals who reported five or more NSSI episodes in the past year, along with 42 age-, sex-, handedness-, IQ-, and socioeconomic status-matched controls. During the fMRI scans, all participants were presented with decision-making scenarios involving uncertainty, both in terms of risk (known probabilities) and ambiguity (unknown probabilities).

In the NSSI group, aversive attitudes toward ambiguity were correlated with increased emotion reactivity and greater method versatility. Whole-brain analysis revealed notable group-by-condition interactions in the right middle cingulate cortex and left hippocampus. Specifically, the NSSI group showed decreased neural activation under ambiguity v. risk compared to the control group. Moreover, reduced hippocampal activation under ambiguity in the NSSI group was associated with increased emotion regulation problems.

This study presents the first evidence of reduced brain activity in specific regions during value-based decision-making under conditions of ambiguity in individuals with NSSI. These findings have important clinical implications, particularly concerning emotion dysregulation in this population. This study indicates the need for interventions that support and guide individuals with NSSI to promote adaptive decision-making in the face of ambiguous uncertainty.

Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity.

Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable.

Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI).

These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.

The aim of this study was to examine the structural change in the hippocampal subfields in early-onset (EO) mild cognitive impairment (MCI) patients associated with the APOE ε4 carrier state.

This study had 50 subjects aged 55-63 years, all of whom were diagnosed with amnestic MCI at baseline via the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K). The EO-MCI patients were divided into the MCI continued (MCIcont) and Alzheimer’s disease (AD) converted (ADconv) groups 2 years later. The volumes of hippocampal subfields were measured for all the subjects. The calculations were based on the change of the volumes between the 2-year-interval brain Magnetic resonance image (MRI) scans between MCIcont and ADconv groups according to the Apolipoprotein ε4 (APOE ε4) carrier state.

There was a significant correlation between APOE ε4 allele and structural changes in several hippocampal subfields. The volume reduction in cornus ammonis 1 (CA1) field and subiculum, especially in the APOE ε4 carriers. The significance was more prominent in ADconv group.

These results suggest that the possession of APOE ε4 allele may lead to significantly greater predilection for the structural changes in hippocampal subfields, showing significant changes, especially in the ADconv patients compared with MCIcont patients.

Executive function is known to decline in later life, largely attributed to structural and functional changes in the prefrontal cortex. However, other regions of the brain are integral to executive functioning, including the hippocampus. The hippocampus plays a large role in memory but its intricate connections to limbic regions including the prefrontal cortex likely underlies associations between the hippocampus and executive functions. Due to the hippocampus’ complex structure, hippocampal subregions may be differentially associated with executive function, but this possibility remains largely unexplored. Therefore, we examined the association between volume of the hippocampus and its subregions with executive function to understand these relationships across the adult lifespan.

The study included 32 healthy, community-dwelling participants (age range = 18-81, mean age = 51.06 ± 20.98, 91% white, 72% female) who received a 3-Tesla magnetic resonance imaging (MRI) scan and completed a cognitive battery. We calculated an executive composite based on Trail Making Test Part B and the interference score from the Stroop Color and Word Test. Freesurfer (version 5.3) as used to quantify total hippocampal volume and subfield volumes for CA1, CA2-3, CA4-dentate gyrus, subiculum, and presubiculum. We conducted mixed-effects regression analyses with total hippocampal and subfield volume, age group (young, middle-aged, and older), and their interaction predicting the executive function composite, controlling for total intracranial volume.

Larger hippocampal subregion volumes in CA1 (p = 0.03), the subiculum (p = 0.01), and the CA4-dentate gyrus (p = 0.04) predicted better executive function. Total hippocampal volume and the presubiculum were not significantly associated with the executive function composite. The age group interaction was not significant for any of the models. Follow-up analyses by hemisphere showed that the effects were right lateralized in CA1and CA4-dentate gyrus, and bilateral in the subiculum.

These data support the literature demonstrating the involvement of the hippocampus in executive function and demonstrates variation across hippocampal subfields. The lack of significant age interactions suggests these relationships may not differ across the lifespan, although this finding would need to be replicated in larger samples. These findings support previous literature showing CA4-dentate gyrus’ association with neurogenesis may facilitate better executive function by increasing connection strength among CA1, CA2-3, and the frontal cortex. This study contributes to our understanding of how specific hippocampal subregions relate to executive function, which has both clinical and research implications.

One of the greatest challenges of the Alzheimer’s disease (AD) epidemic is identifying the disease prior to substantial neurological compromise. The established biomarkers of AD, such as measures of cognitive impairment, hippocampal atrophy, and CSF measures of beta amyloid and tau, used in research and drug trials are less indicative of AD pathology in preclinical, non-demented, populations. Olfactory dysfunction, a well-established sensory impairment of AD found to correlate strongly with tau burden and hippocampal volume measures, has shown to be a promising preclinical biomarker for AD progression. Several studies have found either impaired odor identification or odor memory at baseline to predict 5-year follow-up cognitive decline and conversion from MCI to AD, but less is known about how olfactory performance reflects the integrity of associated brain regions such as the hippocampus. The present analysis aims to explore the value of psychophysical olfactory assessment as biomarker measure in preclinical AD studies and drug trials by investigating its relationships with structural measures of the hippocampus.

A sample consisted of non-demented older adults (age >75), recruited from the UCSD Alzheimer’s Disease Research Center as part of a ongoing olfactory biomarker study. Participants completed the AD Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13), San Diego Odor Identification Test (SDOIT), tests of odor recognition memory (ORMem) and odor associative memory (OAM), and MRI derived hippocampal volumes and average hippocampal occupancy (Avg HOC). Left and right hippocampal volumes were adjusted for each participant’s estimated intracranial volume. Bivariate correlations were calculated for ADAS-Cog-13 and SDOIT total scores, performance scores for odor recognition and odor associative memory tests, and the three hippocampal measures (bilateral volumes and average occupancy).

ADAS-Cog-13 score did not show significant correlations with either hippocampal measure at the .05 level. SDOIT scores were significantly correlated with the measure of Avg HOC (p<.05). ORMem false positive responses were significantly correlated with Avg HOC (p<.01) and right hippocampal volume (p<.05). ORMem miss responses and OAM errors were both correlated with left (p<.05) and right (p<.01) hippocampal volumes.

These results demonstrate that psychophysical assessments of odor identification and odor memory can better reflect the integrity of the hippocampus in nondemented older adults, compared to the neuropsychological ADAS-Cog-13. This is congruent with olfactory dysfunction preceding cognitive-memory decline in AD cases and provides support for the utility of psychophysical olfactory assessment along with other established AD biomarkers in research and drug trials in preclinical populations.

Supported by NIH grant # R01AG062006-04 from the National Institute on Aging to CM. Special thank you to the staff and participants of the UCSD ADRC, especially Christina Gigliotti, and Aaron Jacobson at the UCSD Center for fMRI.

Multiple Sclerosis (MS) affects up to 500,000 adults in the United States, with cognitive impairment present in 45%-65% of people. Studies showed hippocampal atrophy in MS, but the underlying mechanisms remain unknown. Inflammation has been proposed to play a significant role, and associations between systemic inflammatory biomarkers and hippocampal atrophy have been shown in other neurological conditions. However, research exploring serum biomarker and volumetric associations in MS are lacking. Given that conventional imaging methods lack resolution for hippocampal internal architecture (HIA), new protocols were developed. We used the High-Resolution Multiple Image Co-Registration and Averaging (HR-MICRA) method to visualize the HIA subfields. We investigated the relationship between subfield volumes generated from HR-MICRA scans and systemic serum biomarkers in MS.

Patients with MS were recruited (N= 34, mean age= 54.6, 35.3% Black) underwent Magnetic Resonance Imaging (MRI), and serum biomarkers were obtained, specifically chosen for their potential role in MS. Inflammatory biomarkers included; granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor- a (TNF- a), and growth factors; vascular endothelial growth factor (VEGF); insulin-like growth factor-1 (IGF-1), and brain derived growth factor (BDNF). Imaging was performed in a Siemens Prisma 3T scanner with a 64-channel head coil using the HR-MICRA method. Hippocampal subfields were calculated using the Automated Segmentation of Hippocampal Subfields (ASHS) package. We used the Magdeburg Young Adult 7T Atlas for sub-hippocampal structures and Penn Temporal Lobe Epilepsy T1-MRI Whole Hippocampus ASHS Atlas for general hippocampal structure and segmentation. Pearson's product-moment analyses provided correlations between biomarkers and hippocampal subfield volumes for each cerebral hemisphere. A statistical significance level of p < 0.05 was used for all analyses.

Correlations emerged between left hemisphere Cornu Ammonis (CA) 2 and G-CSF (r = -.384; p = .025); IL-10 (r = -.342; p = .048); VEGF (r = -.371; p= .031); and CA3 with IL-10 (r = -.488, p = .003); G-CSF (r = -.386; p= .024); VEGF (r = -.352; p= .041). Dentate gyrus correlated with MMP-9 (r =.416; p=.014); IL-10 (r = -.365; p =.034). BDNF was correlated with right hemisphere CA1 (r = -.417, p = .014), CA2 (r = -.497; p= .003) and CA3 (r = -.451; p=.007).

In our sample of persons with MS, left hemisphere hippocampal subfield volumes were negatively correlated with inflammatory biomarkers, supporting previous reports linking inflammation to reduced brain volumes in other neurological conditions. In the right hemisphere, we found negative correlations between HIA and BDNF, suggesting a neuroprotective function for BDNF in this neurodegenerative disease. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between HIA and systemic serum biomarkers in MS.

Hippocampal pathology is a consistent feature in persons with temporal lobe epilepsy (TLE) and a strong biomarker of memory impairment. Histopathological studies have identified selective patterns of cell loss across hippocampal subfields in TLE, the most common being cellular loss in the cornu ammonis 1 (CA1) and dentage gyrus (DG). Structural neuroimaging provides a non-invasive method to understand hippocampal pathology, but traditionally only at a whole-hippocampal level. However, recent methodological advances have enabled the non-invasive quantification of subfield pathology in patients, enabling potential integration into clinical workflow. In this study, we characterize patterns of hippocampal subfield atrophy in patients with TLE and examine the associations between subfield atrophy and clinical characteristics.

High-resolution T2 and T1-weighted MRI were collected from 31 participants (14 left TLE; 6 right TLE; 11 healthy controls [HC], aged 18-61 years). Reconstructions of hippocampal subfields and estimates of their volumes were derived using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Total hippocampal volume was calculated by combining estimates of the subfields CA1-3, DG, and subiculum. To control for variations in head size, all volume estimates were divided by estimates of total brain volume. To assess disease effects on hippocampal atrophy, hippocampi were recoded as either ipsilateral or contralateral to the side of seizure focus. Two sample t-tests at a whole-hippocampus level were used to test for ipsilateral and contralateral volume loss in patients relative to HC. To assess whether we replicated the selective histopathological patterns of subfield atrophy, we carried out mixed-effects ANOVA, coding for an interaction between diagnostic group and hippocampal subfield. Finally, to assess effects of disease load, non-parametric correlations were performed between subfield volume and age of first seizure and duration of illness.

Patients had significantly smaller total ipsilateral hippocampal volume compared with HC (d=1.23, p<.005). Contralateral hippocampus did not significantly differ between TLE and HC. Examining individual subfields for the ipsilateral hemisphere revealed significant main-effects for group (F(1, 29)=8.2, p<0.01), subfields (F(4, 115)=550.5, p<0.005), and their interaction (F(4, 115)=8.1, p<0.001). Post-hoc tests revealed that TLE had significantly smaller volume in the ipsilateral CA1 (d=-2.0, p<0.001) and DG (d = -1.4, p<0.005). Longer duration of illness was associated with smaller volume of ipsilateral CA2 (p=-0.492, p<0.05) and larger volume of contralateral whole-hippocampus (p=0.689, p<0.001), CA1 (p=0.614, p < 0.005), and DG (p=0.450, p<0.05).

Histopathological characterization after surgery has revealed important associations between hippocampal subfield cell loss and memory impairments in patients with TLE. Here we demonstrate that non-invasive neuroimaging can detect a pattern of subfield atrophy in TLE (i.e., CA1/DG) that matches the most common form of histopathologically-observed hippocampal sclerosis in TLE (HS Type 1) and has been linked directly to both verbal and visuospatial memory impairment. Finally, we found evidence that longer disease duration is associated with larger contralateral hippocampal volume, driven by increases in CA1 and DG. This may reflect subfield-specific functional reorganization to the unaffected brain tissue, a compensatory effect which may have important implications for patient function and successful treatment outcomes.

Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown.

Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses.

Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo.

These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

The ability to extinguish a maladaptive conditioned fear response is crucial for healthy emotional processing and resiliency to aversive experiences. Therefore, enhancing fear extinction learning has immense potential emotional and health benefits. Mindfulness training enhances both fear conditioning and recall of extinguished fear; however, its effects on fear extinction learning are unknown. Here we investigated the impact of mindfulness training on brain mechanisms associated with fear-extinction learning, compared to an exercise-based program.

We investigated BOLD activations in response to a previously learned fear-inducing cue during an extinction paradigm, before and after an 8-week mindfulness-based stress reduction program (MBSR, n = 49) or exercise-based stress management education program (n = 27).

The groups exhibited similar reductions in stress, but the MBSR group was uniquely associated with enhanced activation of salience network nodes and increased hippocampal engagement.

Our results suggest that mindfulness training increases attention to anticipatory aversive stimuli, which in turn facilitates decreased aversive subjective responses and enhanced reappraisal of the memory.

Higher cardiorespiratory fitness (CRF) induces neuroprotective effects in the hippocampus, a key brain region for memory and learning. We investigated the association between CRF and functional connectivity (FC) of the hippocampus in healthy young adults. We also examined the association between hippocampal FC and neurocognitive function. Lastly, we tested whether hippocampal FC mediates the association between 2-Min Walk Test (2MWT) and neurocognitive function.

913 young adults (28.7 ± 3.7 years) from the Human Connectome Project were included in the analyses. The 2MWT performance result was used as a proxy for cardiovascular endurance. Fluid and crystalized composite neurocognitive scores were used to assess cognition. Resting-state functional MRI data were processed to measure hippocampal FC. Linear regression was used to examine the association between 2MWT, hippocampal FC, and neurocognitive outcomes after controlling for age, sex, years of education, body mass index, systolic blood pressure, and gait speed.

Better 2MWT performance was associated with greater FC between the anterior hippocampus and right posterior cingulate and left middle temporal gyrus. No associations between 2MWT and posterior hippocampal FC, whole hippocampal FC, and caudate FC (control region) were observed. Greater anterior hippocampal FC was associated with better crystalized cognition scores. Lastly, greater FC between the anterior hippocampus and right posterior cingulate mediated the association between better 2MWT scores and higher crystalized cognition scores.

Anterior hippocampal FC may be one underlying neurophysiological mechanism that promotes the association between 2MWT performance and crystalized composite cognitive function in healthy young adults.