Amygdala Volume Research Articles

Occupational stress is associated with sex and subregion specific modifications of the amygdala volumes

Background: Despite the rapid increase in reports of exhaustion syndrome (ES) due to daily occupational stress, the mechanisms underlying ES are unknown. In the present study, we investigated whether occupational ES is associated with specific modifications of the subfields of the amygdala and hippocampus resembling those described in other chronic stress conditions. Special focus was paid to possible sex differences. Methods: As a follow up to our previous studies of occupational ES, we carried out MRI-based subfield segmentation of the hippocampus and amygdala volumes in 58 patients with occupational ES (22 males) and 65 age-matched controls (27 males) (age range 30–46 years). Results: There was a significant and bilateral enlargement of the lateral, basal and central nucleus of the amygdala in patients with ES (corrected for the total intracranial volume (ICV)). These differences were detected only in females. Higher values in the right central and right basal amygdala remained when the whole amygdala volume was used as reference, instead of the ICV. Notably, in female patients the volumes of these specific nuclei were positively correlated with the degree of perceived stress. No changes in the hippocampus subfields were detected in female or male patients. Conclusions: The findings underline that ES is a chronic stress condition, suggesting that not only extreme forms of stress, but also the everyday stress is associated with localized differences from controls in the amygdala. The absence of significant alterations among men with ES despite a similar degree of perceived stress supports the notion that women seem more susceptible to stress-related cerebral changes, and may explain the higher prevalence of ES among women.

The effects of sexual abuse on female adolescent brain structures.

Sexual abuse (SA) is known for its effects on brain structures in adolescents. We aimed to explore if SA has any effect on limbic and prefrontal cortex (PFC) structures. We hypothesized that children with SA would have a thinner PFC with larger amygdala and hippocampus that lead to aberrations in threat detection, orientation and response circuit; that would be highly adaptive in a dangerous environment in the short term. We included 57 SA and 33 healthy control (HC) female participants. In addition to psychiatric evaluation, we acquired 3 T MR images from all participants. We compared prefrontal cortical thicknesses, hippocampus and amygdala volumes between groups. The age and education levels of study groups were matched, however, IQ scores and socioeconomic status (SES) scores of the SA group were lower than the controls. Total CTQ scores of the SA group were higher than the HC. Nevertheless, the mean value of sexual abuse scores was above the cut-off scores only for the SA participants. SA participants had larger right and left hippocampus and right amygdala volumes than the controls. SA group had reduced inferior frontal gyrus cortical thickness (T=3.5, p<0.01, cluster size=694 mm2, x=51 y=-30 z=6) than HC group. None of the structural findings were correlated with total or sexual abuse CTQ scores. Children with SA history has structural abnormalities in threat detection, orientation and response circuit. SA victims with no psychiatric diagnosis have a high probability of psychiatric problems with a possible contribution of these aberrations. SA cases that do not have a diagnosis must not be overlooked as they may have structural changes in emotion related brain regions. Careful follow-up is needed for all of all SA cases.

Efficient viral expression of a chemogenetic receptor in the old-world monkey amygdala.

Genetically encoded synthetic receptors, such as the chemogenetic and optogenetic proteins, are powerful tools for functional brain studies in animals. In the primate brain, with its comparatively large, intricate anatomical structures, it can be challenging to express transgenes, such as the hM4Di chemogenetic receptor, in a defined anatomical structure with high penetrance. Here, we compare parameters for lentivirus vector injections in the rhesus monkey amygdala. We find that four injections of 20μl, infused at 0.5μl/min, can achieve neuronal hM4Di expression in 50-100% of neurons within a 60mm3 volume, without observable damage from overexpression. Increasing the number of hM4Di_CFP lentivirus injections to up to 12 sites per hemisphere, resulted in 30%-40% neuronal coverage of the overall amygdala volume, with coverage reaching 60% in some subnuclei. Manganese Chloride was mixed with lentivirus and used as an MRI marker to verify targeting accuracy and correct unsuccessful injections in these experiments. In a separate monkey we visualized, in vivo, viral expression of the hM4Di receptor protein in the amygdala, using Positron Emission Tomography. Together, these data show efficient and verifiable expression of a chemogenetic receptor in old-world monkey amygdala.

Cognitive and functional connectivity impairment in post-COVID-19 olfactory dysfunction

ObjectivesTo explore the neuropsychological profile and the integrity of the olfactory network in patients with COVID-19-related persistent olfactory dysfunction (OD). MethodsPatients with persistent COVID-19-related OD underwent olfactory assessment with Sniffin’ Sticks and neuropsychological evaluation. Additionally, both patients and a control group underwent brain MRI, including T1-weighted and resting-state functional MRI (rs-fMRI) sequences on a 3 T scanner. Morphometrical properties were evaluated in olfaction-associated regions; the rs-fMRI data were analysed using graph theory at the whole-brain level and within a standard parcellation of the olfactory functional network. All the MR-derived quantities were compared between the two groups and their correlation with clinical scores in patients were explored. ResultsWe included 23 patients (mean age 37 ± 14 years, 12 females) with persistent (mean duration 11 ± 5 months, range 2–19 months) COVID-19-related OD (mean score 23.63 ± 5.32/48, hyposmia cut-off: 30.75) and 26 sex- and age-matched healthy controls. Applying population-derived cut-off values, the two cognitive domains mainly impaired were visuospatial memory and executive functions (17 % and 13 % of patients). Brain MRI did not show gross morphological abnormalities. The lateral orbital cortex, hippocampus, and amygdala volumes exhibited a reduction trend in patients, not significant after the correction for multiple comparisons. The olfactory bulb volumes did not differ between patients and controls. Graph analysis of the functional olfactory network showed altered global and local properties in the patients’ group (n = 19, 4 excluded due to artifacts) compared to controls. Specifically, we detected a reduction in the global modularity coefficient, positively correlated with hyposmia severity, and an increase of the degree and strength of the right thalamus functional connections, negatively correlated with short-term verbal memory scores. DiscussionPatients with persistent COVID-19-related OD showed an altered olfactory network connectivity correlated with hyposmia severity and neuropsychological performance. No significant morphological alterations were found in patients compared with controls.

Involvement of limbic structures in patients with isolated rapid eye movement sleep behavior disorder.

This study aimed to investigate the alterations in limbic structure volumes and limbic covariance network in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and to compare them with healthy controls. We retrospectively enrolled 35 patients with iRBD and 35 healthy controls who underwent three-dimensional T1-weighted brain MRI. Volumetric analysis of subcortical limbic structures, including the hippocampus, amygdala, thalamus, mammillary body, hypothalamus, basal forebrain, septal nuclei, fornix, and nucleus accumbens, was performed. Furthermore, the limbic covariance network was examined using graph theory based on the limbic structure volumes. Some of the limbic structure volumes differed significantly. The right amygdala and hypothalamus volumes were lower in the patients with iRBD than in the healthy controls (0.101% vs. 0.114%, p = 0.016, and 0.027% vs. 0.030%, p = 0.045, respectively). However, there were no significant differences in the limbic covariance network between the groups. This study demonstrated that the volumes of the right amygdala and hypothalamus are lower in patients with iRBD, even without cognitive impairments, than in healthy controls. However, there were no significant differences in the limbic covariance network between the groups. The involvements of the limbic structures could be related to the conversion to neurodegenerative diseases in patients with iRBD.

Socioeconomic disparities in sleep duration are associated with cortical thickness in children.

Disrupted sleep has been consistently linked with lower academic achievement and worse mental health in children. Less is understood about sleep as a potential factor underlying socioeconomic differences in brain morphometry in children. The goals of this study were to investigate the associations among socioeconomic factors, sleep duration, and brain morphometry in children, and to examine the roles of the sleep environment and family routines in these associations. Participants were 5- to 9-year-old children from socioeconomically diverse families (N=94; 61% female). Parents reported on children's weekday and weekend sleep durations, sleep environment, and family routines. High-resolution, T1-weighted structural magnetic resonance imaging (MRI) data were acquired. Analyses focused on cortical thickness, cortical surface area, and amygdala and hippocampal volume. Results indicated that lower family income-to-needs ratio and parental education were significantly associated with shorter weekday sleep duration in children. Shorter weekday sleep duration was significantly associated with reduced thickness in the left middle temporal, right postcentral, and right superior frontal cortices and smaller basolateral but not centromedial amygdala volume. Family routines significantly mediated the associations of family income-to-needs ratio and parental education with weekday sleep duration in children. These results contribute to our understanding of sleep factors as proximal mechanisms through which socioeconomic context may alter neural development during childhood.

Longitudinal Structural and Diffusion-Weighted Neuroimaging of Young Children Born Preterm

BackgroundChildren born preterm are at risk for diffuse injury to subcortical gray and white matter. MethodsWe used a longitudinal cohort study to examine the development of subcortical gray matter and white matter volumes, and diffusivity measures of white matter tracts following preterm birth. Our participants were 47 children born preterm (24 to 32 weeks gestational age) and 28 children born at term. None of the children born preterm had significant neonatal brain injury. Children received structural and diffusion weighted magnetic resonance imaging scans at ages five, six, and seven years. We examined volumes of amygdala, hippocampus, caudate nucleus, putamen, thalamus, brainstem, cerebellar white matter, intracranial space, and ventricles, and volumes, fractional anisotropy, and mean diffusivity of anterior thalamic radiation, cingulum, corticospinal tract, corpus callosum, inferior frontal occipital fasciculus, inferior longitudinal fasciculus, temporal and parietal superior longitudinal fasciculus, and uncinate fasciculus. ResultsChildren born preterm had smaller volumes of thalamus, brainstem, cerebellar white matter, cingulum, corticospinal tract, inferior frontal occipital fasciculus, uncinate fasciculus, and temporal superior longitudinal fasciculus, whereas their ventricles were larger compared with term-born controls. We found no significant effect of preterm birth on diffusivity measures. Despite developmental changes and growth, group differences were present and similarly strong at all three ages. ConclusionEven in the absence of significant neonatal brain injury, preterm birth has a persistent impact on early brain development. The lack of a significant term status by age interaction suggests a delayed developmental trajectory.

Neurostructural associations with traumatic experiences during child- and adulthood

Adverse experiences can lead to severe mental health problems, such as posttraumatic stress disorder (PTSD), throughout the lifespan. In individuals with PTSD, both global and local brain volume reductions have been reported—especially in the amygdala and hippocampus—while the literature on childhood maltreatment suggests a strong dependency on the timing of adverse events. In the present study, we pooled data from two studies to contrast the effects of reported trauma exposure during neurodevelopmentally sensitive periods in early life with trauma exposure during adulthood. A total of 155 women were allocated into one of six age-matched groups according to the timing of traumatization (childhood vs adulthood) and psychopathology (PTSD vs trauma-exposed healthy vs trauma-naïve healthy). Volumes of the amygdala and hippocampus were compared between these groups. Six additional exploratory regions of interest (ROI) were included based on a recent meta-analysis. Amygdala volume was strongly dependent on the timing of traumatization: Smaller amygdala volumes were observed in participants with childhood trauma and PTSD compared to the healthy control groups. In contrast, larger amygdala volumes were observed in both groups with trauma exposure during adulthood compared to the trauma-naïve control group. Hippocampal volume comparisons revealed no statistically significant differences, although the descriptive pattern was similar to that found for the amygdala. The remaining exploratory ROIs showed significant group effects, but no timing effects. The timing might be an important moderator for adversity effects on amygdala volume, potentially reflecting neurodevelopmental factors. Albeit confounded by characteristics like trauma type and multiplicity, these findings pertain to typical childhood and adulthood trauma as often observed in clinical practice and speak against a simple association between traumatic stress and amygdala volume.

Aging of the brain in bipolar disorder: Illness- and onset-related effects in cortical thickness and subcortical gray matter volume

BackgroundOlder adults with bipolar disorder (BD) have received little study, although they often have severe symptoms, treatment resistance and high suicide risk. Furthermore, a subset develops cognitive dysfunction for unknown reasons. MethodsHere, cortical thickness and subcortical gray matter volume were compared across individuals ages 40-79y: 103 with BD (“later-onset” at ages ≥25y, n = 21; “early-onset” < 25y, n = 82) and healthy controls (HCs, n = 98). ResultsOverall, those with BD showed lower prefrontal, cingulate, sensorimotor, parahippocampal, insula, temporal, parietal, and occipital cortical thickness (Cohen's d: 0.4 to 0.8) and hippocampal, amygdalar, thalamic, and striatal gray matter volume (d: 0.6 to 0.8). Later-onset BD showed negative relationships between age and parahippocampal, insular, temporal, parietal, and occipital cortical thickness, and hippocampal, thalamic and striatal volume (r: −0.7 to −0.4). Suicide attempt history was associated with lower dorsolateral prefrontal cortical thickness (d = 0.5). LimitationsThe study used a cross-sectional design and the sample of those with a later-onset of BD was relatively modest. ConclusionsResults support widespread gray matter decreases in older adults with BD, and also suggest a separable later-onset phenotype characterized by age-related gray matter reductions in regions subserving cognitive, emotional and perceptual processes. Moreover, the results are the first to demonstrate structural brain differences associated with a history of suicide attempts in older adults with BD.

Emotional recognition across the adult lifespan: Effects of age, sex, cognitive empathy, alexithymia traits, and amygdala subnuclei volumes.

The ability to recognize others' emotions is vital to everyday life. The goal of this study was to assess which emotions show age-related decline in recognition accuracy of facial emotional expressions across the entire adult lifespan and how this process is related to cognitive empathy (Theory of Mind [ToM]), alexithymia traits, and amygdala subnuclei volumes in a large cohort of healthy individuals. We recruited 140 healthy participants 18-85 years old. Facial affect processing was assessed with the Penn Emotion Recognition task (ER40) that contains images of the five basic emotions: Neutral, Happy, Sad, Angry, and Fearful. Structural magnetic resonance imaging (MRI) datasets were acquired on a 4.7T MRI system. Structural equation modeling was used to test the relationship between studied variables. We found that while both sexes demonstrated age-related reduction in recognition of happy emotions and preserved recognition of sadness, male participants showed age-related reduction in recognition of fear, while in female participants, age-related decline was linked to recognition of neutral and angry facial expressions. In both sexes, accurate recognition of sadness negatively correlated with alexithymia traits. On the other hand, better ToM capabilities in male participants were associated with improvement in recognition of positive and neutral emotions. Finally, none of the observed age-related reductions in emotional recognition were related to amygdala and its subnuclei volumes. In contrast, both global volume of amygdala and its cortical and centromedial subnuclei had significant direct effects on recognition of sad images.

Differential alterations of amygdala nuclei volumes in acutely ill patients with anorexia nervosa and their associations with leptin levels.

The amygdala is a subcortical limbic structure consisting of histologically and functionally distinct subregions. New automated structural magnetic resonance imaging (MRI) segmentation tools facilitate the in vivo study of individual amygdala nuclei in clinical populations such as patients with anorexia nervosa (AN) who show symptoms indicative of limbic dysregulation. This study is the first to investigate amygdala nuclei volumes in AN, their relationships with leptin, a key indicator of AN-related neuroendocrine alterations, and further clinical measures. T1-weighted MRI scans were subsegmented and multi-stage quality controlled using FreeSurfer. Left/right hemispheric amygdala nuclei volumes were cross-sectionally compared between females with AN (n = 168, 12-29 years) and age-matched healthy females (n = 168) applying general linear models. Associations with plasma leptin, body mass index (BMI), illness duration, and psychiatric symptoms were analyzed via robust linear regression. Globally, most amygdala nuclei volumes in both hemispheres were reduced in AN v. healthy control participants. Importantly, four specific nuclei (accessory basal, cortical, medial nuclei, corticoamygdaloid transition in the rostral-medial amygdala) showed greater volumetric reduction even relative to reductions of whole amygdala and total subcortical gray matter volumes, whereas basal, lateral, and paralaminar nuclei were less reduced. All rostral-medially clustered nuclei were positively associated with leptin in AN independent of BMI. Amygdala nuclei volumes were not associated with illness duration or psychiatric symptom severity in AN. In AN, amygdala nuclei are altered to different degrees. Severe volume loss in rostral-medially clustered nuclei, collectively involved in olfactory/food-related reward processing, may represent a structural correlate of AN-related symptoms. Hypoleptinemia might be linked to rostral-medial amygdala alterations.

Subcortical brain structure and APOE genotype: An analysis of 43,000 participants from the UK Biobank

AbstractBackgroundCarriers of the ε4 allele of the apolipoprotein (APOE) gene are at higher risk for developing Alzheimer’s disease (AD). In individuals with mild cognitive impairment or AD, the ε4 allele is associated with lower hippocampal and amygdala volumes. How ε4 affects brain structure in healthy individuals before AD symptom onset is less clear. APOE ε2 allele carriers may show slower rates of hippocampal volume loss, suggesting protection against AD. In this large‐scale analysis, we plot normative regional brain volume trajectories in adults (45‐82 years) and map regional subcortical volume differences between APOE genotypes.MethodWe used FreeSurfer 7.1 to segment average left and right accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus and lateral ventricle volumes from T1‐weighted brain MRI (N=43,000). Comparisons between APOE genotypes (ε2ε2, n=257; ε2ε3, n=5,479; ε3ε3, n=26,016; ε3ε4, n=10,263; ε4ε4, n=985) were made using linear mixed effect models, correcting for population structure, age, sex, and intracranial volume (ICV) as fixed effects, and site as a random effect. Results were adjusted for multiple comparisons (FDR q&lt;0.05). Nomograms were derived by adjusting subcortical volumes for population structure, ICV, and site then fitting normative quantile regression models based on the standardized residuals for each region stratified by genotype.ResultNomograms showed similar age‐related trajectories for all APOE genotypes, with smaller gray matter volume and larger ventricle volumes with increasing age. Significantly smaller amygdala and hippocampal volumes were found in ε4ε4 compared to ε3ε4, ε3ε3, and ε2ε3 carriers, and smaller amygdala volumes in ε2ε2 versus ε3ε3 carriers. Smaller accumbens volumes were found in ε4ε4 carriers versus ε2ε3 and ε3ε3, and in ε3ε4 versus ε3ε3 and ε2ε3. Smaller thalamus volumes were found in ε3ε4 versus ε2ε3 and ε3ε3, ε4ε4 carriers had smaller volumes versus ε2ε3 and ε3ε3, and ε2ε2 carriers had smaller volumes versus ε2ε3 and ε3ε3.ConclusionIn this large sample of generally healthy individuals, APOE ε4 allele carriers exhibited lower subcortical volumes compared to those with more neutral AD genetic risk background (ε3ε3). Carriers of ε2ε2 had smaller thalamus and amygdala volumes compared to ε3ε3, suggesting differential effects of AD genetic risk across brain structures known to play a role in AD pathophysiology.

Hippocampal volume mediates the association between depression and cognitive function differently by sex

AbstractBackgroundSex differences are prominent features of both depression and Alzheimer’s disease, with women showing an increased lifetime risk relative to men. However, the neural mechanisms that explain sex differences in the relationship between depression and cognition are poorly understood. The goal of this study was to evaluate whether smaller brain volumes mediate the relationship between higher depression symptom severity and poorer cognition, and whether this association differed by sex.MethodUK Biobank participants were included in the sample based on availability of demographic variables, mental health assessments, structural MRI scans, and four cognitive measures (Fluid Intelligence, Numeric Function, Pairs Matching, and Symbol Digit Substitution). Depression symptom severity was evaluated using the Patient Health Questionnaire (PHQ‐9). The indirect effect of depression symptom severity on cognition via hippocampal volumes was evaluated using causal mediation analyses. Models were adjusted for age, sex, APOE‐e4 status, and Townsend Deprivation Index, a measure of material deprivation (Fig.1). A priori sex‐stratified models evaluated sex differences. Exploratory analyses assessed the indirect effect of depressive symptom severity on cognition with amygdalar and total brain volumes as separate mediators. The significance of indirect effects was evaluated using bootstrapping procedures.ResultThe study sample consisted of 39,692 middle‐aged and older adults (53% women, mean age±SD = 64.1±7.6 years, 28% APOE‐e4 carriers). Hippocampal and amygdalar volumes mediated the effect of depression symptom severity on cognition, for Fluid Intelligence, Numeric Function, and Symbol Digit Substitution, but not Pairs Matching. Total brain volume mediated the effect of depression symptom severity on Symbol Digit Substitution performance (Fig.1, Table1). In sex‐stratified analyses, the effect of depression symptom severity on Fluid Intelligence, Numeric Function, and Symbol Digit Substitution was mediated by hippocampal and amygdalar volumes in women. In men, the effect of depression symptom severity on Symbol Digit Substitution was mediated by total brain volume (Table2).ConclusionDepression symptom severity influences cognition via hippocampal and amygdalar volumes in women, while in men, total brain volume mediated the relationship with cognition. These data suggest sex‐specific neural pathways for the relationship between depression and cognition.

Increased Bridging Characteristics in Social Networks are Associated with Increasing Amygdala Volume and Grey Matter Density

AbstractBackgroundSocial connectedness has been linked to decreased rates of cognitive decline particularly among older adults (Fratiglioni et al., 2004). Several studies have demonstrated that access to an expansive network of diverse, and loosely connected individuals (i.e., social bridging) plays a particularly unique role in conferring resilience against cognitive decline (Perry et al., 2021). We explored the association of social bridging with cortical atrophy measured by gray matter density (GMD) in cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s Disease (AD) participants from the Social Networks and Alzheimer’s Disease (SNAD) at the Indiana Alzheimer Disease Research Center.MethodWe analyzed baseline data of 176 SNAD participants (63 CN, 54 SCD, 47 MCI, 12 AD). Social bridging metrics were collected via in‐person interviews of egocentric social network data. MCI and AD were combined into a cognitively impaired group, resulting in 3 diagnostic groups (CN, SCD, CI). Demographic and biomarker differences across groups were analyzed using ANOVA. Pooled linear regressions were run with ROIs as the dependent variables and diagnosis, age, sex, education, and social bridging as regressors. A voxel‐wise multiple linear regression of GMD images in SPM12 yielded statistical maps across the pooled sample.ResultTable 1 shows the demographic and biomarker comparisons of all groups. The linear regression showed greater social bridging was associated with larger left and right amygdala volume (both p=0.01), and trending larger left frontal thickness (p=0.055), and left and right insula thickness (both p=0.09). Figure 1 and Figure 2 show scatterplot distribution of significant and trending brain regions versus bridging by diagnostic group with regression p‐values and lines. Statistical maps show increasing social bridging is associated with increasing GMD lateralized to the left hemisphere with a frontotemporoparietal pattern (Figure 3).ConclusionWe found that the effects of particular social enrichment on GMD, such as social bridging, are localized to regions primarily involving motivation and emotion. The left lateralization suggests this hemisphere’s propensity for protection against cognitive decline via social mechanisms. Future work should investigate potential associations between social bridging and amyloid and tau deposition.

Increased Bridging Characteristics in Social Networks are Associated with Increasing Amygdala Volume and Grey Matter Density

AbstractBackgroundSocial connectedness has been linked to decreased rates of cognitive decline particularly among older adults (Fratiglioni et al., 2004). Several studies have demonstrated that access to an expansive network of diverse, and loosely connected individuals (i.e., social bridging) plays a particularly unique role in conferring resilience against cognitive decline (Perry et al., 2021). We explored the association of social bridging with cortical atrophy measured by gray matter density (GMD) in cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s Disease (AD) participants from the Social Networks and Alzheimer’s Disease (SNAD) at the Indiana Alzheimer Disease Research Center.Method:We analyzed baseline data of 176 SNAD participants (63 CN, 54 SCD, 47 MCI, 12 AD). Social bridging metrics were collected via in‐person interviews of egocentric social network data. MCI and AD were combined into a cognitively impaired group, resulting in 3 diagnostic groups (CN, SCD, CI). Demographic and biomarker differences across groups were analyzed using ANOVA. Pooled linear regressions were run with ROIs as the dependent variables and diagnosis, age, sex, education, and social bridging as regressors. A voxel‐wise multiple linear regression of GMD images in SPM12 yielded statistical maps across the pooled sample.ResultTable 1 shows the demographic and biomarker comparisons of all groups. The linear regression showed greater social bridging was associated with larger left and right amygdala volume (both p=0.01), and trending larger left frontal thickness (p=0.055), and left and right insula thickness (both p=0.09). Figure 1 and Figure 2 show scatterplot distribution of significant and trending brain regions versus bridging by diagnostic group with regression p‐values and lines. Statistical maps show increasing social bridging is associated with increasing GMD lateralized to the left hemisphere with a frontotemporoparietal pattern (Figure 3).ConclusionWe found that the effects of particular social enrichment on GMD, such as social bridging, are localized to regions primarily involving motivation and emotion. The left lateralization suggests this hemisphere’s propensity for protection against cognitive decline via social mechanisms. Future work should investigate potential associations between social bridging and amyloid and tau deposition.

Effects of the COVID-19 Pandemic on Mental Health and Brain Maturation in Adolescents: Implications for Analyzing Longitudinal Data

BackgroundThe COVID-19 pandemic has caused significant stress and disruption for young people, likely leading to alterations in their mental health and neurodevelopment. In this context, it is not clear whether youths who lived through the pandemic and its shutdowns are comparable psychobiologically to their age- and sex-matched peers assessed before the pandemic. This question is particularly important for researchers who are analyzing longitudinal data that span the pandemic. MethodsWe compared carefully matched youths assessed before the pandemic (n = 81) and after the pandemic-related shutdowns ended (n = 82). ResultsWe found that youths assessed after the pandemic shutdowns had more severe internalizing mental health problems, reduced cortical thickness, larger hippocampal and amygdala volume, and more advanced brain age. ConclusionsThe COVID-19 pandemic not only appears to have led to poorer mental health and accelerated brain aging in adolescents, but it also poses significant challenges to researchers analyzing data from longitudinal studies of normative development that were interrupted by the pandemic.

The Effects of Stressful Life Events on Alzheimer’s Disease Biomarkers, Neuroinflammation and Brain Integrity in Later Life: A Life Course Perspective

AbstractBackgroundStress is associated with adverse health outcomes, but the pathways through which stressful life events affect brain health, and the age periods most vulnerable to these effects, are unknown. We investigated these questions in relation to Alzheimer’s disease (AD) pathophysiology and brain integrity in cognitively unimpaired participants at risk for AD.MethodIn this cross‐sectional cohort study, 1168 participants completed the 18‐item Elder’s Life Stress Inventory measuring the occurrence (and age at occurrence) of stressful life events. Of these, 393 participants had data available on AD biomarkers (cerebrospinal fluid [CSF] phosphorylated‐tau and amyloid‐beta1−42/amyloid‐beta1−40 ratio measured with Elecsys® assays and NeuroToolKit panel of robust prototype assays [Roche Diagnostics International Ltd, Rotkreuz, Switzerland], respectively) and neuroinflammation markers (CSF interleukin 6 [IL‐6], soluble TREM‐2 and glial fibrillary acidic protein measured with NeuroToolKit). In total, 830 had structural magnetic resonance imaging data available for amygdala and hippocampal volume, and grey matter volume/thickness for areas of the prefrontal cortex. The association of stressful events with AD biomarkers, neuroinflammation and brain integrity (adjusting for total intracranial volume) was examined using multiple regression analyses adjusting for sex, age and education. Associations of stressful events during early life (ages 0−25), early adulthood (26−40), middle adulthood (41−55) and late adulthood (≥56) were also examined. Analyses were stratified by sex and Apolipoprotein ε4 (APOE ε4)‐status.ResultParticipants’ age ranged between 47−76 and 62.5% were women. A higher number of stressful events during life‐course was associated with an increase in IL‐6 levels among APOE ε4‐carriers; with a decreased amyloid‐beta ratio among APOE ε4‐noncarriers; and with a reduction in caudal anterior cingulate cortex volume among women. A higher number of events during early adulthood was associated with higher phosphorylated‐tau levels and prefrontal brain integrity, and during middle adulthood was associated with decreased prefrontal brain integrity (Table 1. &amp; 2.).ConclusionStress may affect later‐life brain health through multiple pathways, including neuroinflammation, amyloid‐beta and brain integrity, depending on APOE ε4‐carrier status and sex. Stressful events during early adulthood may promote phosphorylated‐tau in later‐life, while events during early/middle adulthood may have differential effects on brain integrity, suggesting potential windows for stress‐prevention strategies.

Associations between anxiety, centromedial amygdala volume, and complex verbal fluency in middle-aged to older adults

ABSTRACT Symptoms of anxiety are related to decreases in cognitive performance in middle-aged to older adults (i.e., ages 50 and older; MOA). Verbal fluency (VF), assessed with the Delis-Kaplan Executive Function System (D-KEFS) Category Switching (VF-CS) task, captures elements of executive function such as semantic memory, response initiation and inhibition, and cognitive flexibility. The present study examined the link between anxiety symptoms and VF-CS to better understand how this association affects such executive functions in MOA. We hypothesized that higher subclinical Beck Anxiety Inventory (BAI) scores would be associated with lower VF-CS. To further investigate the underlying neurobiological basis of an expected inverse relationship, total amygdala volume, centromedial amygdala (CMA) volume, and basolateral amygdala (BLA) volume were examined as they related to VF-CS scores on the D-KEFS. Based on extant research on connectivity and functioning between the CMA and BLA, we hypothesized that larger BLA volumes would be associated with lower anxiety scores and exhibit positive relationships with VF-CS. A sample of 63 MOA were recruited from the Providence, Rhode Island area as a part of a parent study on cardiovascular diseases. Participants completed self-report measures about physical and emotional health, a neuropsychological assessment, and a magnetic resonance imaging scan (MRI). Multiple hierarchical regressions were performed to examine relationships between variables of interest. Contrary to hypotheses, no significant relationship emerged between VF-CS and BAI scores, and BLA volume was not associated with either BAI scores or VF-CS. However, a significant positive relationship was observed between CMA volume and VF-CS. The significant relationship found between CMA and VF-CS may reflect the upward slope of the quadratic relationship between arousal and cognitive performance on the Yerkes-Dodson curve. These findings newly implicate CMA volume specifically as a possible neuromarker linking emotional arousal and cognitive performance in MOA.

Identification of biopsychological trait markers in functional neurological disorders.

Stress is a well-known risk factor to develop a functional neurological disorder, a frequent neuropsychiatric medical condition in which patients experience a variety of disabling neurological symptoms. Only little is known about biological stress regulation, and how it interacts with predisposing biological and psychosocial risk factors. Dysregulation of the hypothalamic-pituitary-adrenal axis in patients with functional neurological disorders has been postulated, but its relationship to preceding psychological trauma and brain anatomical changes remains to be elucidated. We set out to study the hypothalamic-pituitary-adrenal axis analysing the cortisol awakening response and diurnal baseline cortisol in 86 patients with mixed functional neurological symptoms compared to 76 healthy controls. We then examined the association between cortisol regulation and the severity and duration of traumatic life events. Finally, we analysed volumetric brain alterations in brain regions particularly sensitive to psychosocial stress, acting on the assumption of the neurotoxic effect of prolonged cortisol exposure. Overall, patients had a significantly flatter cortisol awakening response (P < 0.001) and reported longer (P = 0.01) and more severe (P < 0.001) emotional neglect as compared to healthy controls. Moreover, volumes of the bilateral amygdala and hippocampus were found to be reduced in patients. Using a partial least squares correlation, we found that in patients, emotional neglect plays a role in the multivariate pattern between trauma history and hypothalamic-pituitary-adrenal axis dysfunction, while cortisol did not relate to reduced brain volumes. This suggests that psychological stress acts as a precipitating psychosocial risk factor, whereas a reduced brain volume rather represents a biological predisposing trait marker for the disorder. Contrarily, an inverse relationship between brain volume and cortisol was found in healthy controls, representing a potential neurotoxic effect of cortisol. These findings support the theory of reduced subcortical volumes representing a predisposing trait factor in functional neurological disorders, rather than a state effect of the illness. In summary, this study supports a stress-diathesis model for functional neurological disorders and showed an association between different attributes of trauma history and abnormalities in hypothalamus-pituitary-adrenal axis function. Moreover, we suggest that reduced hippocampal and amygdalar volumes represent a biological 'trait marker' for functional neurological disorder patients, which might contribute to a reduced resilience to stress.

Childhood trauma and brain structure in children and adolescents

The dimensional model of adversity proposes that experiences of threat and deprivation have distinct neurodevelopmental consequences. We examined these dimensions, separately and jointly, with brain structure in a sample of 149 youth aged 8–17—half recruited based on exposure to threat-related experiences. We predicted that greater threat would be uniquely associated with reduced cortical thickness and surface area in brain regions associated with salience processing including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and insula, and that deprivation experiences would be uniquely associated with reductions in cortical thickness and surface area in frontoparietal areas associated with cognitive control. As predicted, greater threat was associated with thinner cortex in a network including areas involved in salience processing (anterior insula, vmPFC), and smaller amygdala volume (particularly in younger participants), after controlling for deprivation. Contrary to our hypotheses, threat was also associated with thinning in the frontoparietal control network. However, these associations were reduced following control for deprivation. No associations were found between deprivation and brain structure. This examination of deprivation and threat concurrently in the same sample provided further evidence that threat-related experiences influence the structure of the developing brain independent of deprivation.