Bilateral Hippocampal Volume Research Articles

SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

Structural brain abnormalities in schizophrenia patients with a history and presence of auditory verbal hallucination

Although many studies have demonstrated structural brain abnormalities associated with auditory verbal hallucinations (AVH) in schizophrenia, the results remain inconsistent because of the small sample sizes and the reliability of clinical interviews. We compared brain morphometries in 204 participants, including 58 schizophrenia patients with a history of AVH (AVH + ), 29 without a history of AVH (AVH−), and 117 healthy controls (HCs) based on a detailed inspection of medical records. We further divided the AVH+ group into 37 patients with and 21 patients without hallucinations at the time of the MRI scans (AVH++ and AVH+−, respectively) via clinical interviews to explore the morphological differences according to the persistence of AVH. The AVH + group had a smaller surface area in the left caudal middle frontal gyrus (F = 7.28, FDR-corrected p = 0.0008) and precentral gyrus (F = 7.68, FDR-corrected p = 0.0006) compared to the AVH− group. The AVH+ patients had a smaller surface area in the left insula (F = 7.06, FDR-corrected p = 0.001) and a smaller subcortical volume in the bilateral hippocampus (right: F = 13.34, FDR-corrected p = 0.00003; left: F = 6.80, FDR-corrected p = 0.001) compared to the HC group. Of these significantly altered areas, the AVH++ group showed significantly smaller bilateral hippocampal volumes compared to the AVH+− group, and a smaller surface area in the left precentral gyrus and caudal middle frontal gyrus compared to the AVH- group. Our findings highlighted the distinct pattern of structural alteration between the history and presence of AVH in schizophrenia, and the importance of integrating multiple criteria to elucidate the neuroanatomical mechanisms.

APOE4 genotype associations with longitudinal change in hippocampal microstructure

AbstractBackgroundApolipoprotein E4 (APOE4) is a major risk factor for late‐onset Alzheimer’s disease (AD). Associations between APOE4 genotype and hippocampal atrophy have been reported, but few longitudinal studies have evaluated microstructural changes. There is evidence that risk conferred by APOE4 may be partially driven by factors such as cerebral iron burden, neuronal injury, and inflammation. Brain iron concentration and other microstructural properties may be detected in vivo using quantitative susceptibility mapping (QSM) and diffusion‐weighted MRI (dMRI). Here, we characterized the effects of APOE4 genotype on longitudinal changes in hippocampal QSM and dMRI microstructural measures in a population‐based sample of adults from the UK Biobank (UKB).Method598 UKB participants of European ancestry (baseline age: 48‐78 years) with baseline and ∼2 year follow‐up brain MRI data were analyzed (Figure 1A). Four dMRI measures were derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI; Figure 1B). Median dMRI and QSM hippocampal measures were extracted and averaged across hemispheres. For comparison with microstructure, bilateral hippocampal volume was also estimated. Linear regressions were used to test associations between change in six hippocampal measures (FollowUp‐Baseline) and number of E4 alleles (e3e3/e3e4/e4e4) adjusting for the time‐interval between scans, baseline MRI measure, age, sex, age‐by‐sex, age2, age2‐by‐sex, education, and the first 4 genetic ancestry principal components. Age‐dependent effects were explored in post‐hoc analyses including a sensitivity analysis stratifying associations by age (< 65 or ≥ 65 yrs) and evaluation of APOE4‐by‐age interactions.ResultCompared to e3e3 homozygotes, E4 carriers had significantly greater increases in MD and ISOVF and greater decreases in ND (p<critical FDR threshold; q=0.05; Table 1). E4 carriers ≥65 had nominally greater increases in MD and ISOVF and greater decrease in volume (p<0.05); APOE4‐by‐age interactions were found for changes in ISOVF and volume (p<0.05; Figure 2).ConclusionDisease risk conferred by the APOE4 genotype may be linked with greater inflammation (greater diffusivity) or neuronal loss. E4 associations with atrophy were only found in the subset of older participants, suggesting that detection of microstructural changes may precede volumetric changes in the hippocampus.

Longitudinal medial temporal lobe gray matter volume and cognitive changes in late middle‐aged and older adults with treated and non‐treated obstructive sleep apnea

AbstractBackgroundNeuroimaging studies in obstructive sleep apnea (OSA) have found both gray matter atrophy and hypertrophy in medial temporal lobe subregions, the latter probably reflecting edema. Whether and how these changes progress over time when OSA is treated or untreated remains unclear. Here, we investigated gray matter volume changes in medial temporal lobe subregions in treated OSA, untreated OSA and control participants aged > 55 years. We also explored whether the medial temporal lobe volume at baseline could predict cognitive decline.MethodTwenty‐three non‐treated OSA participants (65.8 ±5.4 years) and twenty controls (64.0 ±6.4 years) were evaluated with overnight polysomnography, MRI session and neuropsychological assessment. Twelve OSA participants then started continuous positive airway pressure (CPAP) therapy and used it at least 4 hours per night, 4 nights per week. Eleven participants refused treatment. Participants were evaluated again with MRI and neuropsychology after 18 months. We extracted the entorhinal, hippocampal and parahippocampal volumes using FreeSurfer 7.1. We performed repeated‐measure ANOVAs with Group (treated OSA, untreated OSA and controls) and Time (baseline and follow‐up) on bilateral volumes. We also performed partial correlations between bilateral medial temporal volumes at baseline and changes in cognition (Montreal Cognitive Assessment, score at follow‐up – baseline) in each group separately. Analyses were corrected for age, sex, and total intracranial volume.ResultWe found a significant Group X Time interaction for bilateral parahippocampal volumes (F = 7.2; p = 0.002) where treated OSA participants showed a decreased volume over time (p tukey<0.001), while no changes occurred in the two other groups. Regarding the predictive value of medial temporal lobe volume, in untreated participants, higher bilateral hippocampal volume at baseline was associated with more severe cognitive decline over time (r = ‐0.77; p = 0.01). In treated participants, higher bilateral entorhinal cortex volume at baseline was associated with more cognitive decline (r = ‐0.74; p = 0.035). No associations were found in controls.ConclusionThese preliminary results showed that presenting hypertrophy of the medial temporal lobe subregions at baseline is associated with worse cognitive outcome at 18‐month follow‐up in OSA participants. In the CPAP group, the decrease in parahippocampal volume might represent a reduction in hypertrophy, possibly by limiting edema.

NIMG-76. MORPHOLOGIC CHANGES TO THE HIPPOCAMPI FOLLOWING SURGICAL RESECTION AND ADJUVANT CHEMORADIATION IN PATIENTS WITH HIGH GRADE TEMPORAL GLIOMAS

Abstract BACKGROUND The hippocampus is known to remodel in pathologic conditions including epilepsy and Alzheimer’s disease. Literature investigating the effect of high-grade gliomas (HGGs) on the hippocampus following resection and adjuvant chemoradiation are limited; no study has evaluated these effects in tumors exclusively in the temporal lobe. METHODS A retrospective chart review was conducted on 30 patients with temporal HGGs who underwent craniotomy for resection with adjuvant RT and TMZ. Brainlab Elements was used to manually contour bilateral hippocampal gray matter volumes in the subgranular zone using T1-precontrast MRI sequences (1.5 mm thickness or less) pre-resection and at time of most recent follow up. These volumes were compared using a student’s t-test with significance set at p< 0.05. RESULTS Average follow up time was 23.5 months from initial resection. Average pre-treatment hippocampal volumes in this temporal glioma cohort compared to healthy controls from prior studies were 2.93 vs 2.83 cm3 (right, p=0.31) and 2.78 vs 2.76 cm3 (left, p=0.39) respectively. Pre vs post resection right hippocampal volumes in patients with right sided lesions were 2.59 vs 1.75 cm3 (p=.002). Left hippocampal volumes in patients with left sided tumors were 2.99 vs 1.64 cm3 pre and post resection respectively(p=0.0009). No significant differences in hippocampal volumes contralateral to the tumor side were found following treatment (p=0.31 and 0.07 for right and left hippocampi respectively). CONCLUSIONS Temporal gliomas are in close anatomic proximity to the hippocampi also may invade and/or disrupt local circuits which output to the hippocampi. Resection and chemoradiation are correlated with decreased hippocampal volumes ipsilateral to the primary locus of disease. Further characterization of hippocampal subregions, particularly the dentate gyrus, in addition to results of neuropsychiatric testing pre and post treatment are necessary to better elucidate the clinical implications of these morphologic changes and the putative functional networks which underlie them.

Increase in Cerebral Blood Flow After Catheter Ablation of Atrial Fibrillation.

Recent studies have found that atrial fibrillation (AF) is a risk factor for cognitive impairment. Brain hypoperfusion is hypothesized as an underlying mechanism of cognitive decline in AF patients. This study sought to assess changes in cerebral blood flow (CBF) and brain volume after catheter ablation of AF. Patients undergoing catheter ablation of AF were enrolled in this prospective study. AF patients being treated with pharmaceuticals alone served as a control group. Brain magnetic resonance imaging was performed before and 6months after catheter ablation. CBF was assessed by 2-dimensional phase-contrast magnetic resonance angiography. Brain volume and bilateral hippocampal volume were measured using FreeSurfer software. Of the 57 study patients (age 64 ± 11 years; 45 men; paroxysmal AF: n=22; nonparoxysmal AF: n=35), 48patients were freed from tachyarrhythmia recurrence beyond a 3-month blanking period. Changes in CBF and brain perfusion over 6months were significantly greater in the study patients than control (CBF: 39.26 vs -34.86mL; P = 0.01, ANCOVA; brain perfusion: 3.78 vs -3.02mL/100mL/min; P = 0.009, ANCOVA), while changes in total brain volume and bilateral hippocampal volume were similar between 2 groups (total brain volume: 2.57 vs -2.15mL; P = 0.32, ANCOVA; bilateral hippocampal volume: 0.03 vs 0.04mL; P = 0.8, ANCOVA). Nonparoxysmal AF at baseline was an independent predictor of an increase in CBF of >32.6mL/min. Catheter ablation of AF has favorable effects on CBF, particularly in nonparoxysmal AF. Our results maypartially explain the association between cognitive decline and AF.

Association of homocysteine-related subcortical brain atrophy with white matter lesion volume and cognition in healthy aging

Homocysteine (Hcy) is a vascular risk factor associated with cognitive impairment and cerebrovascular disease but has also been implicated in Alzheimer's disease (AD). Using multivariate Scaled Subprofile Model (SSM) analysis, we sought to identify a network pattern in structural neuroimaging reflecting the regionally distributed association of plasma Hcy with subcortical gray matter (SGM) volumes and its relation to other health risk factors and cognition in 160 healthy older adults, ages 50–89. We identified an SSM Hcy-SGM pattern that was characterized by bilateral hippocampal and nucleus accumbens volume reductions with relative volume increases in bilateral caudate, pallidum, and putamen. Greater Hcy-SGM pattern expression was associated with greater white matter hyperintensity (WMH) volume, older age, and male sex, but not with other vascular and AD-related risk factors. Mediation analyses revealed that age predicted WMH volume, which predicted Hcy-SGM pattern expression, which, in turn, predicted cognitive processing speed performance. These findings suggest that the multivariate SSM Hcy-SGM pattern may be indicative of cognitive aging, reflecting a potential link between vascular health and cognitive dysfunction in healthy older adults.

Maternal adverse childhood experiences and infant subcortical brain volume

BackgroundA large body of research supports the deleterious effects of adverse childhood experiences (ACEs) on disease susceptibility and health for both the exposed individual and the next generation. It is likely that there is an intergenerational transmission of risk from mother to child; however, the mechanisms through which such risk is conferred remain unknown. The current study evaluated the association between maternal ACEs, neonatal brain development of the amygdala and hippocampus, and later infant negative emotionality at six months of age. MethodsThe sample included 85 mother-infant dyads (44 female infants) from a longitudinal study. Maternal ACEs were assessed with the Adverse Childhood Experiences Questionnaire (ACE-Q) and neonatal hippocampal and amygdala volume was assessed using structural magnetic resonance imaging (MRI). Infant negative emotionality was assessed at 6 months using the Infant Behavior Questionnaire (IBQ). ResultsMultivariate analyses demonstrated that maternal ACEs were associated with bilateral amygdala volume (F(2,78) = 3.697,p = .029). Specifically, higher maternal ACEs were associated with smaller left (β = -0.220, t(79) = -2.661, p = .009, R2= 0.494, and right (β = −0.167, t(79) = -2.043, p = .044, R2= 0.501) amygdala volume. No significant association between maternal ACEs and bilateral hippocampal volume (F(2,78) = 0.215,p = .0807) was found. Follow-up regression analyses demonstrated that both high maternal ACEs and smaller left amygdala volume were associated with higher infant negative emotionality at six months of age (β = .232, p = .040, R2= 0.094, and β = −0.337, p = .022, R2= 0.16, respectively) although statistically significant mediation of this effect was not observed (Indirect effect = 0.0187, 95% CI [-0.0016-0.0557]). ConclusionsMaternal ACEs are associated with both newborn amygdala volume and subsequent infant negative emotionality. These findings linking maternal adverse childhood experiences and infant brain development and temperament provide evidence to support the intergenerational transmission of adversity from mother to child.

Sex-dependent risk factors for PTSD: a prospective structural MRI study.

Female individuals are more likely to be diagnosed with PTSD following trauma exposure than males, potentially due, in part, to underlying neurobiological factors. Several brain regions underlying fear learning and expression have previously been associated with PTSD, with the hippocampus, amygdala, dorsal anterior cingulate cortex (dACC), and rostral ACC (rACC) showing altered volume and function in those with PTSD. However, few studies have examined how sex impacts the predictive value of subcortical volumes and cortical thickness in longitudinal PTSD studies. As part of an emergency department study completed at the Grady Trauma Project in Atlanta, GA, N = 93 (40 Female) participants were enrolled within 24 h following a traumatic event. Multi-echo T1-weighted MRI images were collected one-month post-trauma exposure. Bilateral amygdala and hippocampal volumes and rACC and dACC cortical thickness were segmented. To assess the longitudinal course of PTSD, the PTSD Symptom Scale (PSS) was collected 6 months post-trauma. We investigated whether regional volume/thickness interacted with sex to predict later PTSD symptom severity, controlling for PSS score at time of scan, age, race, and trauma type, as well as intracranial volume (ICV) for subcortical volumes. There was a significant interaction between sex and rACC for 6-month PSS, such that right rACC thickness was positively correlated with 6-month PSS scores in females, but not in males. In examining PTSD symptom subtypes and depression symptoms, greater rACC thickness in females predicted greater avoidance symptoms, while smaller rACC thickness in males predicted greater depression symptoms. Amygdala and hippocampus volume and dACC thickness showed no main effect or interaction with sex. The current findings provide evidence for sex-based differences in how brain volume predicts future PTSD severity and symptoms and supports the rACC as being a vital region regarding PTSD. Gender differences should be assessed in future longitudinal PTSD MRI studies for more accurate identification of future PTSD risk following trauma.

The transdiagnostic relationship of cumulative lifetime stress with memory, the hippocampus, and personality psychopathology

Stress has a detrimental impact on memory, the hippocampus, and psychological health. Psychopathology research on stress has centered mainly on psychiatric diagnoses rather than symptom dimensions, and less attention has been given to the neurobiological factors through which stress might be translated into psychopathology. The present work investigates the transdiagnostic relationship of cumulative stress with episodic memory and the hippocampus (both structure and function) and explores the extent to which stress mediates the relationship between personality psychopathology and hippocampal size and activation. Cumulative lifetime stress was assessed in a sample of females recruited to vary in stress exposure and severity of personality psychopathology. Fifty-six participants completed subjective and objective tests of episodic memory, a T2-weighted high-resolution magnetic resonance imaging (MRI) scan of the medial-temporal lobe, and functional MRI (fMRI) scanning during a learning and recognition memory task. Higher cumulative stress was significantly related to memory complaints (but not episodic memory performance), lower bilateral hippocampal volume, and greater encoding-related hippocampal activation during the presentation of novel stimuli. Furthermore, cumulative stress significantly mediated the relationship between personality psychopathology and both hippocampal volume and activation, whereas alternative mediation models were not supported. The findings suggest that structural and functional activation differences in the hippocampus observed in case-control studies of psychiatric diagnoses may share cumulative stress as a common factor, which may mediate broadly reported relationships between psychopathology and hippocampal structure and function.

Hippocampal morphological atrophy and distinct patterns of structural covariance network in Alzheimer's disease and mild cognitive impairment.

Elucidating distinct morphological atrophy patterns of Alzheimer’s disease (AD) and its prodromal stage, namely, mild cognitive impairment (MCI) helps to improve early diagnosis and medical intervention of AD. On that account, we aimed to obtain distinct patterns of voxel-wise morphological atrophy and its further perturbation on structural covariance network in AD and MCI compared with healthy controls (HCs). T1-weighted anatomical images of matched AD, MCI, and HCs were included in this study. Gray matter volume was obtained using voxel-based morphometry and compared among three groups. In addition, structural covariance network of identified brain regions exhibiting morphological difference was constructed and compared between pairs of three groups. Thus, patients with AD have a reduced hippocampal volume and an increased rate of atrophy compared with MCI and HCs. MCI exhibited a decreased trend in bilateral hippocampal volume compared with HCs and the accelerated right hippocampal atrophy rate than HCs. In AD, the hippocampus further exhibited increased structural covariance connected to reward related brain regions, including the anterior cingulate cortex, the putamen, the caudate, and the insula compared with HCs. In addition, the patients with AD exhibited increased structural covariance of left hippocampus with the bilateral insula, the inferior frontal gyrus, the superior temporal gyrus, and the cerebellum than MCI. These results reveal distinct patterns of morphological atrophy in AD and MCI, providing new insights into pathology of AD.

The Association Between Neighborhood Poverty and Hippocampal Volume Among Individuals at Clinical High-Risk for Psychosis: The Moderating Role of Social Engagement.

Reductions in hippocampal volume (HV) have been associated with both prolonged exposure to stress and psychotic illness. This study sought to determine whether higher levels of neighborhood poverty would be associated with reduced HV among individuals at clinical high-risk for psychosis (CHR-P), and whether social engagement would moderate this association. This cross-sectional study included a sample of participants (N = 174, age-range = 12-33 years, 35.1% female) recruited for the second phase of the North American Prodrome Longitudinal Study. Generalized linear mixed models tested the association between neighborhood poverty and bilateral HV, as well as the moderating role of social engagement on this association. Higher levels of neighborhood poverty were associated with reduced left (β = -0.180, P = .016) and right HV (β = -0.185, P = .016). Social engagement significantly moderated the relation between neighborhood poverty and bilateral HV. In participants with lower levels of social engagement (n = 77), neighborhood poverty was associated with reduced left (β = -0.266, P = .006) and right HV (β = -0.316, P = .002). Among participants with higher levels of social engagement (n = 97), neighborhood poverty was not significantly associated with left (β = -0.010, P = .932) or right HV (β = 0.087, P = .473). In this study, social engagement moderated the inverse relation between neighborhood poverty and HV. These findings demonstrate the importance of including broader environmental influences and indices of social engagement when conceptualizing adversity and potential interventions for individuals at CHR-P.

Episodic memory in progressive supranuclear palsy: a neuropsychological and neuroimaging study.

Episodic memory impairment may occur in progressive supranuclear palsy (PSP). However, it remains uncertain whether this is due to executive dysfunction or to the involvement of brain areas responsible for memory. To investigate the specific brain regions underlying episodic memory impairment in PSP. Twenty-one patients with PSP and 20 healthy controls underwent the Figure Memory Test (FMT) from the Brief Cognitive Screening Battery and brain MRI. We explored correlations between gray matter volumes and memory scores in PSP patients, adjusting for age and performance on the Frontal Assessment Battery. PSP patients performed worse than controls (p < 0.001) on delayed recall in the FMT. Delayed recall scores correlated to bilateral hippocampal and parahippocampal volumes in PSP patients. Medial temporal structures may play a role in episodic memory impairment in PSP, suggesting that amnesia in PSP is not solely due to executive dysfunction.

0128 Maternal Sleep Quality Across Pregnancy Predicts Newborn Neurodevelopment

Abstract Introduction The prenatal period is characterized by immense fetal neuronal growth. Such rapid growth can increase fetal susceptibility to prenatal environmental insults (Barker, 1998). A promising prenatal process that may alter fetal development is maternal prenatal sleep quality. Poor prenatal sleep quality is a public health concern affecting approximately 78% of pregnant individuals (Lucena et al., 2018). In rodents, maternal sleep deprivation across gestation predicts offspring hippocampal neurogenesis, with pups exposed to sleep deprivation early and late in pregnancy exhibiting more anxiety and depression-like behaviors (Peng et al., 2015). In humans, poor sleep quality in other developmental stages predicts hippocampi and amygdalae changes (Marshall &amp; Born, 2007; Saghir et al., 2018). However, the relation between prenatal sleep quality and offspring brain development in humans remains poorly understood. The present study examined associations between maternal sleep quality in early, mid, and late pregnancy, and newborn hippocampal and amygdala volume, regions implicated in memory and emotion. Methods Pregnant individuals (N=94; Mage=30.5; SDage=5.3) reported on sleep quality three times during pregnancy. Newborn (Mageinweeks=5.1; SDageinweeks=2.7) hippocampi and amygdalae volumes were assessed during an unsedated sleep cycle using magnetic resonance imaging (MRI). Tissue segmentation was collected using a multiatlas iterative algorithm that individually segmented the regions of interest and subsequently combined T1- and T2-weighted high-resolution images (See neonate multiatlas at https://www.nitrc.org/projects/unc_brain_atlas/). Bivariate correlations examined the association between prenatal sleep quality and hippocampus and amygdala volume. Partial correlations examined these associations in the presence of significant cofounding variables including intracranial volume, body weight percentile, sex, and postconceptional age. Results Partial correlations revealed that poor maternal sleep quality early in pregnancy predicted larger newborn bilateral hippocampal volume (all rs&amp;lt;.25; ps&amp;lt;.038). Associations with sleep later in gestation persisted for the right hippocampus (all rs&amp;lt;.25; ps&amp;lt;.038). Prenatal maternal sleep quality did not significantly predict newborn amygdala volume (all rs&amp;lt;-.06; ps&amp;gt;.58). Conclusion This study provides novel evidence linking prenatal sleep quality and newborn hippocampal volume in humans, suggesting the presence of an intergenerational link between prenatal sleep health and offspring well-being. Support (If Any) Support (if any): NIMH R01MH109662, NHLBI R01HL155744, and diversity training supplement for 1st author; F32MH125572 for 2nd author.

Left amygdala structure mediates longitudinal associations between exposure to threat and long-term psychiatric symptomatology in youth.

Traumatic experiences during childhood can have profound effects on stress sensitive brain structures (e.g., amygdala and hippocampus) and the emergence of psychiatric symptoms. Recent theoretical and empirical work has delineated dimensions of trauma (i.e., threat and deprivation) as having distinct neural and behavioral effects, although there are few longitudinal examinations. A sample of 243 children and adolescents were followed for three time points, with each assessment approximately 1 year apart (ages 9–15 years at Time 1; 120 males). Participants or their caregiver reported on youths' threat exposure, perceived stress (Time 1), underwent a T1‐weighted structural high‐resolution MRI scan (Time 2), and documented their subsequent psychiatric symptoms later in development (Time 3). The primary findings indicate that left amygdala volume, in particular, mediated the longitudinal association between threat exposure and subsequent internalizing and externalizing symptomatology. Greater threat exposure related to reduced left amygdala volume, which in turn differentially predicted internalizing and externalizing symptoms. Decreased bilateral hippocampal volume was related to subsequently elevated internalizing symptoms. These findings suggest that the left amygdala is highly threat‐sensitive and that stress‐related alterations may partially explain elevated psychopathology in stress‐exposed adolescents. Uncovering potential subclinical and/or preclinical predictive biomarkers is essential to understanding the emergence, progression, and eventual targeted treatment of psychopathology following trauma exposure.

Influence of exclusive breastfeeding on hippocampal structure, satiety responsiveness, and weight status.

Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given hippocampus sensitivity to diet and potential role in the integration of satiety signals, hippocampus may play a role in these relationships. We conducted a secondary analysis of 149, 7–11‐year‐olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume was extracted from structural scans using CAT12, weight status was assessed using age‐ and sex‐adjusted body mass index (%BMIp85), and parents reported exclusive breastfeeding duration and satiety responsiveness (Children's Eating Behaviour Questionnaire). Separate path models for left and right hippocampus tested: (1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal grey matter volume; (2) the direct effect of hippocampal grey matter volume on %BMIp85 and its indirect effect through satiety responsiveness. %BMIp85 was adjusted for maternal education, yearly income, and premature birth while hippocampal grey matter volume was adjusted for total intercranial volume, age, and study from which data were extracted. Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal grey matter volumes. In addition, better satiety responsiveness and greater left hippocampal grey matter volume were both associated with lower %BMIp85. However, hippocampal grey matter volumes were not associated with satiety responsiveness. Although no relationship was found between breastfeeding and child weight status, these results highlight the potential impact of exclusive breastfeeding duration on the hippocampal structure.

The relationship between cardiovascular risk and lifestyle activities on hippocampal volumes in normative aging.

Despite the life-course perspective of popular aging models, few studies on healthy aging to date have examined both younger and older adulthood. The current study examined how cumulative vascular risk factors and self-reported levels of physical, social, and cognitive activity are associated with differences in hippocampal volumes in healthy younger and older adults. 34 neurologically healthy participants were separated into two age cohorts: a younger adult group (age 25-35, n = 17) and an older adult group (age 65-82, n = 17). Participants underwent a 3 T T1 MRI and completed a series of questionnaires. Voxel-based morphometry examined whole-brain grey matter density differences between groups. Hippocampal volumes were computed. Analyses examined the association between hippocampal volumes, cumulative vascular risk, and self-reported levels of physical, social, and cognitive activity, both within and across groups. Between-group comparisons revealed greater cortical atrophy in older relative to young adults in regions including the left and right hippocampus and temporal fusiform cortex. Across-group analyses revealed a significant negative association between cardiovascular risk scores and bilateral hippocampal volumes across age groups. A significant negative association was identified between frequency of social activities and bilateral hippocampal volumes in older adults only. No significant associations were found between left or right hippocampal volumes and total, cognitive, or physical activities in both within- and across-group analyses. Greater cumulative vascular risk is associated with smaller hippocampal volumes across age cohorts. Findings suggest that social activities with low cognitive load may not be beneficial to structural brain outcomes in older age.

Earlier Age of First Exposure to Competitive Fighting Has an Adverse Impact on Neuropsychiatric Symptoms and Brain Volume

The objective of this study was to determine whether individuals who began fighting competitively at a younger age experienced adverse brain health outcomes compared to fighters who began competing at an older age. Established literature has made clear that fighting sports such as boxing and mixed martial arts can lead to head injury. Prior work from this group on the Professional Fighters Brain Health Study (PFBHS) found that exposure to repetitive head impacts is associated with lower brain volumes and decreased processing speed in fighters. As part of the PFBHS, current and previously licensed professional fighters were recruited, divided into active and retired cohorts, and matched with a control group that had no prior experience in sports with likely head trauma. This present study examined the relationship between age of first exposure (AFE) to fighting sports and brain structure (MRI regional volume), cognitive performance (CNS Vital Signs, iComet C3), and clinical neuropsychiatric symptoms (PHQ-9, Barratt Impulsiveness Scale). Brain MRI data showed significant correlations between earlier AFE and smaller bilateral hippocampal and posterior corpus callosum volumes for both retired and active fighters. Earlier AFE in active fighters was correlated with decreased processing speed and decreased psychomotor speed. Retired fighters showed a correlation between earlier AFE and higher measures of depression and impulsivity. The findings of this study help to inform clinicians, governing bodies, parents, and athletes of the risks associated with beginning to compete in fighting sports at a young age.

Differential impact of obstructive sleep apnea on hippocampal structure in late middle‐aged and older women and men

AbstractBackgroundRecent studies have suggested that obstructive sleep apnea (OSA) could be a modifiable risk factor for dementia. Consequently, efforts have been made to better understand the role of OSA on brain structure integrity, but results between studies are inconsistent. Discrepancies could be partly due to moderating factors (e.g., sex) or complex physiological mechanisms (e.g., oedema) that blur the association between OSA and brain structure. Here, we investigated the association between OSA severity and hippocampal grey matter volume in women and men. We also performed free‐water fraction analyses to understand how oedema could impact hippocampal volumes.MethodSeventy‐three men (age: 65.47±7.22 years; apnea‐hypopnea index [AHI]: 15.52±16.14 events/h; 31 with mild cognitive impairments [MCI]) and 47 women (age: 71.11 ± 6.65; AHI: 11.56 ± 9.92; 22 with MCI) underwent an overnight polysomnography, a neuropsychological evaluation and a magnetic resonance imaging session. Using the hippocampal subfield module in Freesurfer 7.1, total bilateral hippocampal volumes were extracted and normalised to the total intracranial volume. Diffusion data was preprocessed using TractoFlow‐ABS, and Freewater‐Flow and the Sherbrooke Connectivity Imaging Lab scripts were used to extract bilateral hippocampal free‐water fraction. Controlling for age and cognitive status, sex‐stratified linear regressions were performed between (i) the bilateral hippocampal volume or (ii) Free‐water‐corrected bilateral hippocampal volume and log‐transformed AHI.ResultIn women, we observed a positive association between the AHI and bilateral hippocampal volumes (r=0.414; p=0.005), where more severe OSA was associated with higher volumes. This association was not observed in men (p=0.427). When using the free‐water corrected volumes, this association was no longer significant in women (p=0.481), suggesting that the increased hippocampal volume could be due to OSA‐related cytotoxic (intracellular) oedema.ConclusionIn this cohort, while men’s hippocampal volume was unaffected by OSA, women with OSA presented hippocampal hypertrophy likely due to intracellular oedema. Cytotoxic oedema is a known precursor to vasogenic (extracellular) oedema and cell death, suggesting that women might be more vulnerable to the cerebral consequences of OSA than men. Since women have a higher lifetime risk of developing Alzheimer's disease, future studies on OSA should pay a particular attention to women.

Differences in white matter integrity and hippocampal volumetrics across APOE genotype mice: A blinded preliminary study

AbstractBackgroundGenome‐wide association studies have identified Apolipoprotein (APOE) as one of the strongest risk factors associated with Late‐Onset Alzheimer’s disease (LOAD) with females exhibiting a two‐fold higher incidence as compared to males. MRI studies of patients with LOAD link APOE‐e4 gene load with increased hippocampal volume loss as well as reduction in white matter integrity (WMI) in the limbic and medial temporal regions (Bagepally, 2012). However, there are few translational LOAD mouse model studies utilizing imaging. We hypothesized that hippocampal volume and WMI would be reduced in females and APOE e4 carriers in our humanized APOE (hAPOE) LOAD mouse model.MethodSix cohorts of APOE e3 and e4 genotype (M/F; N=53; mean age = 17.95 month) skull‐extracted ex‐vivo mouse brains were imaged (7T Bruker Biospec MRI scanner). Imaging included structural and diffusion weighted imaging. Bilateral hippocampal volumes, as well as total brain volume (TBV), were extracted using a well‐validated mouse brain atlas (Dorr, 2008). Fractional anisotropy (FA) was used to quantify WMI and between‐group comparisons were made using a groupwise connectometry approach (Yeh, 2013; Yeh, 2016).ResultMRI image analysis indicated genotypic differences in white matter FA where APOE‐e4 carriers exhibited lower FA values (mean tractography FA = 0.263 ± 0.043) compared to APOE‐e3/3 (mean tractography FA = 0.311 ± 0.067) in a total of 10657 tracts (FDR corrected p &lt; 0.003; Figure 1). No statistically significant differences were identified across genotypes for left or right hippocampal volumes. However, right hippocampal volume was significantly greater in males as compared to females (p = 0.007) whereas no effect was observed between sexes for left hippocampus.ConclusionOutcomes of MRI analyses indicate a significant reduction in FA values and reduced white matter integrity across the brain in APOE e4 carriers, irrespective of sex. Contrary to human literature, no significant volumetric differences between genotypes were found in this mouse sample. Consistent with sex‐dependent literature, males exhibited greater total brain volume and additionally greater right hippocampal volume compared to females, irrespective of genotype. These findings may provide evidence of deficits in cholesterol or lipid transport manifest in decreased white matter integrity in this hAPOE mouse model.