Plasma IL-6 levels and their association with brain health and dementia risk: A population-based cohort study.

BACKGROUND: Recent studies have associated immune abnormalities with dementia. IL-6 is a crucial cytokine in inflammatory responses, and recent evidence has linked elevated IL-6 levels to changes in brain structure and cognitive decline. However, the connection between IL-6 levels, cognition, brain volumes, and dementia risk requires exploration in large prospective cohorts. METHODS: This study utilized a longitudinal cohort from the UK Biobank to analyze the correlation between IL-6 expression levels, cognitive performance, and cortical and subcortical brain volumes through linear regression. Additionally, we assessed the association between IL-6 levels and long-term dementia risk using Cox regression analysis. We also used one-sample Mendelian randomization to analyze the impact of genetic predisposition of dementia on elevated IL-6 levels. RESULTS: A total of 50,864 participants were included in this study, with 1,391 new cases of all-cause dementia identified. Higher plasma IL-6 levels are associated with cortical and subcortical atrophy in regions such as the fusiform, thalamus proper, hippocampus, and larger ventricle volumes. IL-6 levels are negatively associated with cognitive performance in pair matching, numeric memory, prospective memory, and reaction time tests. Furthermore, elevated IL-6 levels are linked to a 23-35 % increased risk of all-cause dementia over an average follow-up period of 13.2 years. The one-sample Mendelian randomization analysis did not show associations between the genetic predisposition of dementia and elevated IL-6 levels. CONCLUSIONS: Increased IL-6 levels are associated with worse cognition, brain atrophy, and a heightened risk of all-cause dementia. Our study highlights the need to focus on the role of peripheral IL-6 levels in managing brain health and dementia risk.

Heritability of cognitive abilities and regional brain structures in middle-aged to elderly East Asians.

This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer's and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.

Childhood trauma moderates morphometric associations between orbitofrontal cortex and amygdala: implications for pathological personality traits.

BACKGROUND: Research has demonstrated that chronic stress exposure early in development can lead to detrimental alterations in the orbitofrontal cortex (OFC)-amygdala circuit. However, the majority of this research uses functional neuroimaging methods, and thus the extent to which childhood trauma corresponds to morphometric alterations in this limbic-cortical network has not yet been investigated. This study had two primary objectives: (i) to test whether anatomical associations between OFC-amygdala differed between adults as a function of exposure to chronic childhood assaultive trauma and (ii) to test how these environment-by-neurobiological effects relate to pathological personality traits. METHODS: Participants were 137 ethnically diverse adults (48.1% female) recruited from the community who completed a clinical diagnostic interview, a self-report measure of pathological personality traits, and anatomical MRI scans. RESULTS: Findings revealed that childhood trauma moderated bilateral OFC-amygdala volumetric associations. Specifically, adults with childhood trauma exposure showed a positive association between medial OFC volume and amygdalar volume, whereas adults with no childhood exposure showed the negative OFC-amygdala structural association observed in prior research with healthy samples. Examination of the translational relevance of trauma-related alterations in OFC-amygdala volumetric associations for disordered personality traits revealed that trauma exposure moderated the association of OFC volume with antagonistic and disinhibited phenotypes, traits characteristic of Cluster B personality disorders. CONCLUSIONS: The OFC-amygdala circuit is a potential anatomical pathway through which early traumatic experiences perpetuate emotional dysregulation into adulthood and confer risk for personality pathology. Results provide novel evidence of divergent neuroanatomical pathways to similar personality phenotypes depending on early trauma exposure.

Reduced brain subcortical volumes in patients with glaucoma: a pilot neuroimaging study using the region-of-interest-based approach.

BACKGROUND: While numerous neuroimaging studies have demonstrated that glaucoma is associated with smaller volumes of the visual cortices in the brain, only a few studies have linked glaucoma with brain structures beyond the visual cortices. Therefore, the objective of this study was to compare brain imaging markers and neuropsychological performance between individuals with and without glaucoma. METHODS: We identified 64 individuals with glaucoma and randomly selected 128 age-, sex-, and education level-matched individuals without glaucoma from a community-based cohort. The study participants underwent 3 T brain magnetic resonance imaging and neuropsychological assessment battery. Regional cortical thickness and subcortical volume were estimated from the brain images of the participants. We used a linear mixed model after adjusting for potential confounding variables. RESULTS: Cortical thickness in the occipital lobe was significantly smaller in individuals with glaucoma than in the matched individuals (ß = - 0.04 mm, P = 0.014). This did not remain significant after adjusting for cardiovascular risk factors (ß = - 0.02 mm, P = 0.67). Individuals with glaucoma had smaller volumes of the thalamus (ß = - 212.8 mm3, P = 0.028), caudate (ß = - 170.0 mm3, P = 0.029), putamen (ß = - 151.4 mm3, P = 0.051), pallidum (ß = - 103.6 mm3, P = 0.007), hippocampus (ß = - 141.4 mm3, P = 0.026), and amygdala (ß = - 87.9 mm3, P = 0.018) compared with those without glaucoma. Among neuropsychological battery tests, only the Stroop color reading test  score was significantly lower in individuals with glaucoma compared with those without glaucoma (ß = - 0.44, P = 0.038). CONCLUSIONS: We found that glaucoma was associated with smaller volumes of the thalamus, caudate, putamen, pallidum, amygdala, and hippocampus.

Genetic scores for adult subcortical volumes associate with subcortical volumes during infancy and childhood.

Individual differences in subcortical brain volumes are highly heritable. Previous studies have identified genetic variants that underlie variation in subcortical volumes in adults. We tested whether those previously identified variants also affect subcortical regions during infancy and early childhood. The study was performed within the Generation R study, a prospective birth cohort. We calculated polygenic scores based on reported GWAS for volumes of the accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus. Participants underwent cranial ultrasound around 7 weeks of age (range: 3-20), and we obtained metrics for the gangliothalamic ovoid, a predecessor of the basal ganglia. Furthermore, the children participated in a magnetic resonance imaging (MRI) study around the age of 10 years (range: 9-12). A total of 340 children had complete data at both examinations. Polygenic scores primarily associated with their corresponding volumes at 10 years of age. The scores also moderately related to the diameter of the gangliothalamic ovoid on cranial ultrasound. Mediation analysis showed that the genetic influence on subcortical volumes at 10 years was only mediated for 16.5-17.6% of the total effect through the gangliothalamic ovoid diameter at 7 weeks of age. Combined, these findings suggest that previously identified genetic variants in adults are relevant for subcortical volumes during early life, and that they affect both prenatal and postnatal development of the subcortical regions.

Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD's etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes. METHODS: Using the large ENIGMA-ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks. RESULTS: Exploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case-control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men. CONCLUSIONS: Our results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case-control differences appear more pronounced at least in some of the subgroups.

Altered Gray Matter Structure and White Matter Microstructure in Patients with Congenital Adrenal Hyperplasia: Relevance for Working Memory Performance.

Congenital adrenal hyperplasia (CAH) has been associated with brain structure alterations, but systematic studies are lacking. We explore brain morphology in 37 (21 female) CAH patients and 43 (26 female) healthy controls, aged 16-33 years, using structural magnetic resonance imaging to estimate cortical thickness, surface area, volume, subcortical volumes, and white matter (WM) microstructure. We also report data on a small cohort of patients (n = 8) with CAH, who received prenatal dexamethasone (DEX). Patients with CAH had reduced whole brain volume (4.23%) and altered structure of the prefrontal, parietal, and superior occipital cortex. Patients had reduced mean FA, and reduced RD and MD, but not after correcting for brain volume. The observed regions are hubs of the visuospatial working memory and default mode (DMN) networks. Thickness of the left superior parietal and middle frontal gyri was associated with visuospatial working memory performance, and patients with CAH performed worse on this task. Prenatal treatment with DEX affected brain structures in the parietal and occipital cortex, but studies in larger cohorts are needed. In conclusion, our study suggests that CAH is associated with brain structure alterations, especially in the working memory network, which might underlie the cognitive outcome observed in patients.

Genetic correlations between subcortical brain volumes and psychiatric disorders.

Psychiatric disorders as well as subcortical brain volumes are highly heritable. Large-scale genome-wide association studies (GWASs) for these traits have been performed. We investigated the genetic correlations between five psychiatric disorders and the seven subcortical brain volumes and the intracranial volume from large-scale GWASs by linkage disequilibrium score regression. We revealed weak overlaps between the genetic variants associated with psychiatric disorders and subcortical brain and intracranial volumes, such as in schizophrenia and the hippocampus and bipolar disorder and the accumbens. We confirmed shared aetiology and polygenic architecture across the psychiatric disorders and the specific subcortical brain and intracranial volume.

Volume changes of subcortical structures in patients with post-hepatitis B cirrhosis: A magnetic resonance imaging study. / ä¹™åž‹è‚ç‚ŽåŽè‚ç¡¬åŒ–æ‚£è€ è„‘çš®å±‚ä¸‹ç»“æž„ä½“ç§¯æ”¹å˜çš„MRIç ”ç©¶.

OBJECTIVES: To investigate volume changes of subcortical structures in patients with post-hepatitis B cirrhosis. METHODS: Thirty patients with post-hepatitis B cirrhosis (the cirrhosis group) and 24 age- and sex-matched healthy controls (the control group) were enrolled in this prospective study. All subjects underwent neuropsychological tests, blood biochemical determinations, and cerebral MRI. Volumes of 18 selected subcortical structures were automatically segmented and analyzed by the FreeSurfer. In the cirrhosis group, the relationships between abnormal subcortical volumes and clinical index or neurocognitive performance were investigated. The relationships between globus pallidus volumes and pallidal hyperintensity were also examined. RESULTS: Compared with the healthy controls, patients with post-hepatitis B cirrhosis displayed smaller bilateral putamen, amygdala, and nucleus accumbens volumes and larger bilateral globus pallidus volumes (P<0.001 or P=0.001). In the cirrhosis group, the volumes of left putamen and amygdala were negatively correlated with the number connection test-A (NCT-A)(left putamen r=-0.410, P=0.034; left amygdala r=-0.439, P=0.022), and the volumes of bilateral globus pallidus were positively correlated with pallidal index (PI) (left globus pallidus r=0.889, P<0.001; right globus pallidus r=0.900, P<0.001). CONCLUSIONS: Abnormalities of subcortical volumes appear bilaterally symmetrical in patients with post-hepatitis B cirrhosis. Atrophy of left putamen and amygdala might contribute to poor neurocognitive performance, and the manganese deposition might contribute to the increased globus pallidus volumes in patients with post-hepatitis B cirrhosis.

Combined fractional anisotropy and subcortical volumetric abnormalities in healthy immigrants to high altitude: A longitudinal study.

The study of individuals at high-altitude (HA) exposure provides an important opportunity for unraveling physiological and psychological mechanism of brain underlying hypoxia condition. However, this has rarely been assessed longitudinally. We aim to explore the cognitive and cerebral microstructural alterations after chronic HA exposure. We recruited 49 college freshmen who immigrated to Tibet and followed up for 2 years. Control group consisted of 49 gender and age-matched subjects from sea level. Neuropsychological tests were also conducted to determine whether the subjects' cognitive function had changed in response to chronic HA exposure. Surface-based cortical and subcortical volumes were calculated from structural magnetic resonance imaging data, and tract-based spatial statistics (TBSS) analysis of white matter (WM) fractional anisotropy (FA) based on diffusion weighted images were performed. Compared to healthy controls, the high-altitude exposed individuals showed significantly lower accuracy and longer reaction times in memory tests. Significantly decreased gray matter volume in the caudate region and significant FA changes in multiple WM tracts were observed for HA immigrants. Furthermore, differences in subcortical volume and WM integration were found to be significantly correlated with the cognitive changes after 2 years' HA exposure. Cognitive functions such as working memory and psychomotor function were found to be impaired during chronic HA. Differences of brain subcortical volumes and WM integration between HA and sea-level participants indicated potential impairments in the brain structural modifications and microstructural integrity of WM tracts after HA exposure.

Parsing neurodevelopmental features of irritability and anxiety: Replication and validation of a latent variable approach.

Irritability and anxiety are two common clinical phenotypes that involve high-arousal negative affect states (anger and fear), and that frequently co-occur. Elucidating how these two forms of emotion dysregulation relate to perturbed neurodevelopment may benefit from alternate phenotyping strategies. One such strategy applies a bifactor latent variable approach that can parse shared versus unique mechanisms of these two phenotypes. Here, we aim to replicate and extend this approach and examine associations with neural structure in a large transdiagnostic sample of youth (N = 331; M = 13.57, SD = 2.69 years old; 45.92% male). FreeSurfer was used to extract cortical thickness, cortical surface area, and subcortical volume. The current findings replicated the bifactor model and demonstrate measurement invariance as a function of youth age and sex. There were no associations of youth's factor scores with cortical thickness, surface area, or subcortical volume. However, we found strong convergent and divergent validity between parent-reported irritability and anxiety factors with clinician-rated symptoms and impairment. A general negative affectivity factor was robustly associated with overall functional impairment across symptom domains. Together, these results support the utility of the bifactor model as an alternative phenotyping strategy for irritability and anxiety, which may aid in the development of targeted treatments.

Disease-specific patterns of cortical and subcortical degeneration in a longitudinal study of Alzheimer's disease and behavioural-variant frontotemporal dementia.

BACKGROUND: Clinical differentiation between Alzheimer's disease (AD) and behavioural-variant frontotemporal dementia (bvFTD) is challenging due to overlapping clinical features at presentation. Whilst diagnostic criteria for both disorders incorporate evidence of frontal and temporal cortical atrophy, understanding of the progression of atrophy in these disorders is limited. This study aimed to elucidate common and disease-specific progressive changes in cortical and subcortical brain structures in AD and bvFTD. METHODS: Forty-one AD, 37 bvFTD and 33 healthy controls underwent baseline MRI and of these longitudinal follow-up was obtained for 20AD and 20 bvFTD (1 to 4years). A total of 87 AD and 70 bvFTD consecutive scans were included in the study. The trajectories of progression in cortical and subcortical structures were identified with FreeSurfer and linear mixed effect modelling. RESULTS: The results uncovered cortical and subcortical disease-specific trajectories of neurodegeneration in AD and bvFTD. Specifically, direct comparisons between patient groups revealed that over time AD showed greater cortical atrophy in the inferior parietal and posterior cingulate cortex than bvFTD. Conversely, bvFTD patients showed greater atrophy in the striatum than AD over time. CONCLUSIONS: These results indicate that atrophy in the posterior cingulate and the striatum diverges with disease progression in these dementia syndromes and may represent a potential diagnostic biomarker for tracking rates of progression of AD and bvFTD. These findings may help inform future drug trials by identifying appropriate outcome measures to quantify drug efficacy and their ability to modulate disease progression over time.

Subcortical shape analysis of progressive mild cognitive impairment in Parkinson's disease.

BACKGROUND: Cortical neural correlates of ongoing cognitive decline in Parkinson's disease (PD) have been suggested; however, the role of subcortical structures in longitudinal change of cognitive dysfunction in PD has not been fully investigated. Here, we used automatic analysis to explore subcortical brain structures in patients with PD with mild cognitive impairment that converts into PD with dementia. METHODS: One hundred eighty-two patients with PD with mild cognitive impairment were classified as PD with mild cognitive impairment converters (n = 74) or nonconverters (n = 108), depending on whether they were subsequently diagnosed with dementia in PD. We used surface-based analysis to compare atrophic changes of subcortical brain structures between PD with mild cognitive impairment converters and nonconverters. RESULTS: PD with mild cognitive impairment converters had lower cognitive composite scores in the attention and frontal executive domains than did nonconverters. Subcortical shape analysis revealed that PD with mild cognitive impairment converters had smaller local shape volumes than did nonconverters in the bilateral thalamus, right caudate, and right hippocampus. Logistic regression analysis showed that local shape volumes in the bilateral thalamus and right caudate were significant independent predictors of PD with mild cognitive impairment converters. In the PD with mild cognitive impairment converter group, thalamic local shape volume was associated with semantic fluency and attentional composite score. CONCLUSIONS: The present data suggest that the local shape volumes of deep subcortical structures, especially in the caudate and thalamus, may serve as important predictors of the development of dementia in patients with PD. © 2017 International Parkinson and Movement Disorder Society.

Early developmental gene enhancers affect subcortical volumes in the adult human brain.

Genome-wide association screens aim to identify common genetic variants contributing to the phenotypic variability of complex traits, such as human height or brain morphology. The identified genetic variants are mostly within noncoding genomic regions and the biology of the genotype-phenotype association typically remains unclear. In this article, we propose a complementary targeted strategy to reveal the genetic underpinnings of variability in subcortical brain volumes, by specifically selecting genomic loci that are experimentally validated forebrain enhancers, active in early embryonic development. We hypothesized that genetic variation within these enhancers may affect the development and ultimately the structure of subcortical brain regions in adults. We tested whether variants in forebrain enhancer regions showed an overall enrichment of association with volumetric variation in subcortical structures of >13,000 healthy adults. We observed significant enrichment of genomic loci that affect the volume of the hippocampus within forebrain enhancers (empirical P = 0.0015), a finding which robustly passed the adjusted threshold for testing of multiple brain phenotypes (cutoff of P < 0.0083 at an alpha of 0.05). In analyses of individual single nucleotide polymorphisms (SNPs), we identified an association upstream of the ID2 gene with rs7588305 and variation in hippocampal volume. This SNP-based association survived multiple-testing correction for the number of SNPs analyzed but not for the number of subcortical structures. Targeting known regulatory regions offers a way to understand the underlying biology that connects genotypes to phenotypes, particularly in the context of neuroimaging genetics. This biology-driven approach generates testable hypotheses regarding the functional biology of identified associations. Hum Brain Mapp 37:1788-1800, 2016. © 2016 Wiley Periodicals, Inc.

Reliability and statistical power analysis of cortical and subcortical FreeSurfer metrics in a large sample of healthy elderly.

FreeSurfer is a tool to quantify cortical and subcortical brain anatomy automatically and noninvasively. Previous studies have reported reliability and statistical power analyses in relatively small samples or only selected one aspect of brain anatomy. Here, we investigated reliability and statistical power of cortical thickness, surface area, volume, and the volume of subcortical structures in a large sample (N=189) of healthy elderly subjects (64+ years). Reliability (intraclass correlation coefficient) of cortical and subcortical parameters is generally high (cortical: ICCs>0.87, subcortical: ICCs>0.95). Surface-based smoothing increases reliability of cortical thickness maps, while it decreases reliability of cortical surface area and volume. Nevertheless, statistical power of all measures benefits from smoothing. When aiming to detect a 10% difference between groups, the number of subjects required to test effects with sufficient power over the entire cortex varies between cortical measures (cortical thickness: N=39, surface area: N=21, volume: N=81; 10mm smoothing, power=0.8, α=0.05). For subcortical regions this number is between 16 and 76 subjects, depending on the region. We also demonstrate the advantage of within-subject designs over between-subject designs. Furthermore, we publicly provide a tool that allows researchers to perform a priori power analysis and sensitivity analysis to help evaluate previously published studies and to design future studies with sufficient statistical power.

A longitudinal study of brain atrophy over two years in community-dwelling older individuals.

Most previous neuroimaging studies of age-related brain structural changes in older individuals have been cross-sectional and/or restricted to clinical samples. The present study of 345 community-dwelling non-demented individuals aged 70-90years aimed to examine age-related brain volumetric changes over two years. T1-weighted magnetic resonance imaging scans were obtained at baseline and at 2-year follow-up and analyzed using the FMRIB Software Library and FreeSurfer to investigate cortical thickness and shape and volumetric changes of subcortical structures. The results showed significant atrophy across much of the cerebral cortex with bilateral transverse temporal regions shrinking the fastest. Atrophy was also found in a number of subcortical structures, including the CA1 and subiculum subfields of the hippocampus. In some regions, such as left and right entorhinal cortices, right hippocampus and right precentral area, the rate of atrophy increased with age. Our analysis also showed that rostral middle frontal regions were thicker bilaterally in older participants, which may indicate its ability to compensate for medial temporal lobe atrophy. Compared to men, women had thicker cortical regions but greater rates of cortical atrophy. Women also had smaller subcortical structures. A longer period of education was associated with greater thickness in a number of cortical regions. Our results suggest a pattern of brain atrophy with non-demented people that resembles a less extreme form of the changes associated with Alzheimer's disease (AD).

Subcortical and cerebellar volume differences in bilingual and monolingual children: An ABCD study.

Research suggests that bilingual children experience an extension or delay in the closing of the sensitive/critical period of language development due to multiple language exposure. Moreover, bilingual experience may impact the development of subcortical regions, although these conclusions are drawn from research with adults, as there is a scarcity of research during late childhood and early adolescence. The current study included 1215 bilingual and 5894 monolingual children from the ABCD Study to examine the relationship between subcortical volume and English vocabulary in heritage Spanish bilingual and English monolingual children, as well as volumetric differences between the language groups. We also examined the unique effects of language usage in bilingual children's subcortical volumes. In general, bilingual children had less cerebellar volume and greater volume in the putamen, thalamus, and globus pallidus than monolingual children. English vocabulary was positively related to volume in the cerebellum, thalamus, caudate, putamen, nucleus accumbens, and right pallidum in all children. Moreover, the positive relationship between vocabulary and volume in the nucleus accumbens was stronger for monolingual adolescents than bilingual adolescents. The results are somewhat in line with existing literature on the dynamic volume adaptation of subcortical brain regions due to bilingual development and experience. Future research is needed to further explore these regions longitudinally across development to examine structural changes in bilingual brains.

Clinical and neuroimaging correlates in a pilot randomized trial of aerobic exercise for major depression.

BACKGROUND: Aerobic exercise (AE) combined with pharmacotherapy is known to reduce depressive symptoms; however, studies have not focused on long-term AE for volumetric changes of brain regions (amygdala, thalamus, and nucleus accumbens [NAcc]) linked to the control of affective responses and hopelessness in individuals with major depression (MD). In addition, AE with motor complexity (AEMC) would be more effective than AE in causing brain plasticity. We compared the effects of 24 weeks of AE and AEMC combined with pharmacotherapy on clinical and volumetric outcomes in individuals with MD. METHODS: Forty medicated individuals with MD were randomly assigned to nonexercising control (C), AE, and AEMC groups. The training groups exercised for 60 min, twice a week for 24 weeks. Clinical and volumetric outcomes were assessed before and after the 24 weeks. Effect size (ES) and confidence interval (CI) were calculated for within-group and between-groups changes. RESULTS: AE and AEMC reduced hopelessness (ES = -0.73 and ES = -0.62, respectively) and increased affective responses (ES = 1.24 and ES = 1.56, respectively). Only AE increased amygdala (ES = 0.27 left and ES = 0.34 right), thalamus (ES = 0.33 left and ES = 0.26 right) and left NAcc (ES = 0.54) volumes. AE was more effective than the C group in reducing hopelessness and causing brain plasticity. The changes in the right amygdala volume showed a strong trend in explaining 72 % of the changes in affective responses following AE (p = 0.06). LIMITATION: Lack of posttraining follow-up and small sample size. CONCLUSION: These preliminary data indicate that AE combined with pharmacotherapy can cause clinical improvement and brain plasticity in individuals with MD.

Shared Genetic Architecture Among Gastrointestinal Diseases, Schizophrenia, and Brain Subcortical Volumes.

BACKGROUND AND HYPOTHESIS: The gut-brain axis plays important roles in both gastrointestinal diseases (GI diseases) and schizophrenia (SCZ). Moreover, both GI diseases and SCZ exhibit notable abnormalities in brain subcortical volumes. However, the genetic mechanisms underlying the comorbidity of these diseases and the shared alterations in brain subcortical volumes remain unclear. STUDY DESIGN: Using the genome-wide association studies data of SCZ, 14 brain subcortical volumes, and 8 GI diseases, the global polygenic overlap and local genetic correlations were identified, as well as the shared genetic variants among those phenotypes. Furthermore, we conducted multi-trait colocalization analyses to bolster our findings. Functional annotations, cell-type enrichment, and protein-protein interaction (PPI) analyses were carried out to reveal the critical etiology and pathology mechanisms. STUDY RESULTS: The global polygenic overlap and local genetic correlations informed the close relationships between SCZ and both GI diseases and brain subcortical volumes. Moreover, 84 unique lead-shared variants were identified. The associated genes were linked to vital biological processes within the immune system. Additionally, significant correlations were observed with key immune cells and the PPI analysis identified several histone-associated hub genes. These findings highlighted the pivotal roles played by the immune system for both SCZ and GI diseases, along with the shared alterations in brain subcortical volumes. CONCLUSIONS: These findings revealed the shared genetic architecture contributing to SCZ and GI diseases, as well as their shared alterations in brain subcortical volumes. These insights have substantial implications for the concurrent development of intervention and therapy targets for these diseases.

Subcortical volumes in offspring with a multigenerational family history of depression - A study across two cohorts.

BACKGROUND: Having multiple previous generations with depression in the family increases offspring risk for psychopathology. Parental depression has been associated with smaller subcortical brain volumes in their children, but whether two prior generations with depression is associated with further decreases is unclear. METHODS: Using two independent cohorts, 1) a Three-Generation Study (TGS, N = 65) with direct clinical interviews of adults and children across all three generations, and 2) the Adolescent Brain Cognitive Development Study (ABCD, N = 10,626) of 9-10 year-old children with family history assessed by a caregiver, we tested whether having more generations of depression in the family was associated with smaller subcortical volumes (using structural MRI). RESULTS: In TGS, caudate, pallidum and putamen showed decreasing volumes with higher familial risk for depression. Having a parent and a grandparent with depression was associated with decreased volume compared to having no familial depression in these regions. Putamen volume was associated with depression at eight-year follow-up. In ABCD, smaller pallidum and putamen were associated with family history, which was driven by parental depression, regardless of grandparental depression. LIMITATIONS: Discrepancies between cohorts could be due to interview type (clinical or self-report) and informant (individual or common informant), sample size or age. Future analyses of follow-up ABCD waves will be able to assess whether effects of grandparental depression on brain markers become more apparent as the children enter young adulthood. CONCLUSIONS: Basal ganglia regional volumes are significantly smaller in offspring with a family history of depression in two independent cohorts.