Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume

The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery samples, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target sample enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery sample were strongly associated in our trauma/PTSD enriched sample (n = 7580) with respective subcortical volumes of the hippocampus (p = 1.10 × 10−20), thalamus (p = 7.46 × 10−10), caudate (p = 1.97 × 10−18), putamen (p = 1.7 × 10−12), and nucleus accumbens (p = 1.99 × 10−7). We found a significant association between the hippocampal volume PGS and hippocampal volume in control subjects from our sample, but was absent in individuals with PTSD (GxE; (beta = −0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted (p < 1 × 10−19) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippocampal volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973; p = 2.16 × 10−7) or PTSD (rs10861272; p = 1.78 × 10−6) in the CHST11 gene. The hippocampus and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippocampal volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.

Heterogeneity of depression across the socioeconomic spectrum

Why is low socioeconomic status associated with high rates of depression? And, is the surplus of depression at lower SES just more of the same type as depression found at higher levels, or distinctive? We addressed these questions by examining the relations among SES, amygdala volume and symptoms of depression in healthy young adults. Amygdala volume, a risk factor for depression, does not synergize with SES in a diathesis-stress relation, nor does it mediate the relation of SES to depression. Rather, SES and amygdala volume are independent, additive risk factors. They are also associated with different depression symptoms and, whereas perceived stress fully mediates the relation of SES to depression, it has no relation to amygdala volume. These findings suggest heterogeneity of depression across the socioeconomic spectrum, with implications for treatment selection as well as for future genetic and imaging studies.

The Volume Alterations of the Amygdala in Autism Spectrum Disorder: A Meta-Analysis on MRI Study

Background:Due to the unclear etiology and pathogenesis of autism spectrum disorder (ASD), there is still a lack of effective drugs for prevention and treatment of ASD, which can improve the prognosis of autism through early intervention. However, the current diagnostic methods are mainly based on qualitative indicators such as behavioral standards, which cannot timely and accurately diagnose autism. A large number of studies have found abnormal amygdala volume in autism patients.This study aimed to evaluate amygdala volume in patients with ASD and elucidat the potential relationship between amygdala volume and ASD by using systematic review and meta-analysis, with a view to providing a new approach for early diagnosis of ASD. Methods: Comprehensive electronic search in Pubmed, Web of Science, EBSCOhost, Embase, the Cochrane Review Library, CNKI and WanFang data to find original articles about the relationship between amygdala volume and the ASD. Heterogeneity across studies were assessed using I2 and Q statistics. Random-effects model was used to estimate the odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analyses to assess the influence of individual studies on the pooled estimate. Publication bias was investigated using funnel plots and Egger's regression test. If the funnel plot is asymmetry, the reason is distinguished by using the contour-enhanced funnel plots and trim-and-fill method. Results: The results showed that the volume of the right amygdala significantly increased in patients with ASD (WMD: 0.137, 95% CI: [0.051, 0.222], Z = 3.132, P < 0.001). Subgroup analysis by age showed that the volume of the left amygdala significantly increased in young child patients with ASD (MD: 0.153, 95% CI: [0.025, 0.281], Z = 2.341, P < 0.05), but not change in child (MD: 0.153, 95% CI: [-0.026, 0.332], Z = 1.672, P > 0.05), adolescent (MD: 0.095, 95% CI: [-0.189, 0.379], Z = 0.654, P > 0.05) and adult (MD: 0.068, 95% CI: [-0.103, 0.240], Z = 0.781, P > 0.05) ASD patient. The volume of the right amygdala significantly increased in young child (MD: 0.174, 95% CI: [0.043, 0.304], Z = 2.60, P < 0.05) and child patients(MD: 0.192, 95% CI: [0.040, 0.343], Z = 2.480, P < 0.05) with ASD, but not change in adolescent (MD: 0.208, 95% CI: [-0.201, 0.618], Z = 0.998, P > 0.05) and adulthood patients (MD: 0.126, 95% CI: [-0.040, 0.291], Z = 1.488, P > 0.05). Subgroup analysis by gender showed that the volume of the left amygdala not change in male (MD: 0.101, 95% CI: [-0.031, 0.233], Z = 1.498, P > 0.05) and female group (MD: 0.067, 95% CI: [-0.023, 0.157], Z = 1.452, P > 0.05). The volume of the right amygdala significantly increased in female group (MD: 0.099, 95% CI: [0.019, 0.178], Z = 2.439, P < 0.05), but not change in male group (MD: 0.117, 95% CI: [-0.014, 0.248], Z = 1.755, P > 0.05).Conclusions: The volume of the amygdala significantly increased in young children with ASD. These findings suggest that the volume of the amygdala in young children might be a potential early auxiliary imaging diagnosis method of ASD.

Amygdala Abnormalities Are Related to Anxiety in Patients With Sporadic Amyotrophic Lateral Sclerosis

To explore selective atrophy patterns and resting-state functional connection (FC) alterations in the amygdala at different stages of amyotrophic lateral sclerosis (ALS), and to determine any correlations between amygdala abnormalities and neuropsychiatric symptoms. We used the King’s clinical staging system for ALS to divide 83 consecutive patients with ALS into comparable subgroups at different disease stages. We investigated the pattern of selective amygdala subnucleus atrophy and analysed amygdala-based whole-brain FC analysis in the patients and 94 healthy controls (HCs). Cognitive and emotional functions were also evaluated using a neuropsychological test battery. There were no significant differences between King’s stage 1 ALS patients and HCs for any amygdala subnucleus volumes. Compared with HCs, King’s stage 2 patients had significantly lower left accessory basal nucleus and cortico-amygdaloid transition volumes after Bonferroni correction. Furthermore, after Bonferroni correction, King’s stage 3 patients demonstrated significant reductions in most subnucleus volumes as well as global amygdala volume compared with HCs. Notably, amygdala-based resting-state FC was unaltered in ALS patients until King’s stage 3. Specific subnucleus volumes were significantly associated with Mini-Mental State Examination scores and Hamilton Anxiety Rating Scale scores in ALS patients. In conclusions, our study provides a comprehensive profile of amygdala abnormalities in ALS patients. The pattern of amygdala abnormalities in ALS patients differed across King’s clinical disease stages, and our findings suggest that amygdala abnormalities are an important feature of patients with ALS. Moreover, amygdala volume may play an important role in anxiety and cognitive dysfunction in ALS patients.

Developmental variation in testosterone:cortisol ratio alters cortical- and amygdala-based cognitive processes

Testosterone (T) and cortisol (C) are the end products of neuroendocrine axes that interact with the process of shaping brain structure and function. Relative levels of T:C (TC ratio) may alter prefrontal–amygdala functional connectivity in adulthood. What remains unclear is whether TC-related effects are rooted to childhood and adolescence. We used a healthy cohort of 4–22-year-olds to test for associations between TC ratios, brain structure (amygdala volume, cortical thickness (CTh), and their coordinated growth), as well as cognitive and behavioral development. We found greater TC ratios to be associated with the growth of specific brain structures: 1) parietal CTh; 2) covariance of the amygdala with CTh in visual and somatosensory areas. These brain parameters were in turn associated with lower verbal/executive function and higher spatial working memory. In sum, individual TC profiles may confer a particular brain phenotype and set of cognitive strengths and vulnerabilities, prior to adulthood.

Association Between Amygdala Volume and Trajectories of Neuropsychiatric Symptoms in Alzheimer's Disease and Dementia With Lewy Bodies

Introduction: The amygdala is implicated in psychiatric illness. Even as the amygdala undergoes significant atrophy in mild dementia, amygdala volume is underexplored as a risk factor for neuropsychiatric symptoms (NPS).Objective: To analyze the association between baseline amygdala volume and the longitudinal trajectories of NPS and cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) over 5 years.Methods: Eighty-nine patients with mild dementia were included (AD = 55; DLB = 34). Amygdala volume was segmented from structural magnetic resonance images (sMRI) using a semi-automatic method (Freesurfer 6.0) and normalized by intracranial volumes. The intracranial volume-normalized amygdala was used as a predictor of the Neuropsychiatric Inventory (NPI) total score, ordinal NPI item scores (0 = absence of symptoms, 1–3 = mild symptoms, ≥4 = clinically relevant symptoms), and Mini-Mental State Examination (MMSE) as measured annually over 5 years using gamma, ordinal, and linear mixed-effects models, respectively. The models were adjusted for demographic variables, diagnosis, center of sMRI acquisition, and cognitive performance. Multiple testing-corrected p-values (q-values) are reported.Results: Larger intracranial volume-normalized amygdala was associated with less agitation/aggression (odds ratio (OR) = 0.62 [0.43, 0.90], p = 0.011, q = 0.038) and less MMSE decline per year (fixed effect = 0.70, [0.29, 1.03], p = 0.001, q = 0.010) but more depression (OR = 1.49 [1.09, 2.04], p = 0.013, q = 0.040).Conclusions: Greater amygdala volume in mild dementia is associated with lower odds of developing agitation/aggression, but higher odds of developing depression symptoms during the 5-year study period.

The Genetic Architecture of Amygdala Nuclei

Background: Whereas a number of genetic variants influencing total amygdala volume have been identified in previous research, genetic architecture of its distinct nuclei have yet to be thoroughly explored. We aimed to investigate whether increased phenotypic specificity through segmentation of the nuclei aids genetic discoverability and sheds light on the extent of shared genetic architecture and biological pathways between the nuclei and disorders associated with the amygdala. Methods: T1-weighted brain MRI scans (n=36,352, mean age= 64.26 years, 52% female) of trans-ancestry individuals from the UK Biobank were segmented into nine amygdala nuclei with FreeSurfer v6.1, and genome-wide association analyses were performed on the full sample and a European-only subset (n=31,690). We estimated heritability using Genome-wide Complex Trait Analysis, derived estimates of polygenicity, discoverability and power using MiXer, and identified genetic correlations and shared loci with psychiatric disorders using Linkage Disequilibrium Score Regression and conjunctional FDR, followed by functional annotation using FUMA. Results: The SNP-based heritability of the nuclei ranged between 0.17-0.33, and the central nucleus had the greatest statistical power for discovery. Across the whole amygdala and the nuclei volumes, 38 novel significant (p < 5x10-9) loci were identified, with most loci mapped to the central nucleus. The mapped genes and associated pathways revealed both unique and shared effects across the nuclei, and immune-related pathways were particularly enriched across several nuclei. Conclusions: These findings indicate that the amygdala nuclei volumes have significant genetic heritability, increased power for discovery compared to whole amygdala volume, may have unique and shared genetic architectures, and a significant immune component to their aetiology.

Real-time individual benefit from social interactions before and during the lockdown: The crucial role of personality, neurobiology and genes.

Background: Social integration is a major resilience factor for staying healthy. However, the COVID-19-pandemic led to unprecedented restrictions in social life. The consequences of these social lockdowns on momentary well-being are yet not fully understood. Method: We investigated the individual affective benefit from social interactions in a longitudinal birth cohort study. We used two real-time, real-life ecological momentary assessments once before and once during the initial lockdown of the pandemic (N~6800 total observations) to determine the protective role of social interactions on well-being. Moreover, we used a multimethod approach combining the ecological assessment data with individual risk and resilience factors to analyze the moderating mechanisms of personality, neurobiology and genes. Results: Social contacts were linked to higher positive affect both during normal times and during the COVID-19 pandemic, highlighting the beneficial role of social embedding. Moreover, this relationship was moderated by amygdala volume, neuroticism and polygenic risk for schizophrenia. In detail, participants with a larger left amygdala volume and higher trait neuroticism exhibited an affective benefit from more social interactions prior to the pandemic. This pattern changed during the pandemic with participants with smaller amygdala volumes and lower neurotic traits showing a social affective gain during the pandemic. Moreover, participants with low genetic risk for schizophrenia showed an affective benefit from social interactions irrespective of the time point. Conclusion: Our results highlight the protective role of social integration on momentary well-being. Thereby, we offer new insights into how this relationship is differently affected by a person's neurobiology, personality, and genes under adverse circumstances.