Ventral Diencephalon Research Articles

Age-related volume decrease in subcortical gray matter is a part of healthy brain aging in men.

With the global population aging, the number of individuals over 60 is expected to double by 2050. Brain volume increases until age 13, stabilizes between 18 and 35, then declines by 0.2% annually. Magnetic resonance imaging (MRI) studies highlight significant gray matter atrophy, necessitating differentiation between normal aging and neurodegeneration. This study assessed the impact of aging on subcortical gray matter in healthy males to identify biomarkers of physiological aging. A retrospective study of 106 healthy males who underwent brain MRI from 2012 to 2016, divided into two age groups: younger and older than 35years. MRI scans were performed using a 3T machine, and volumetric analysis was conducted with VolBrain software. Subcortical gray matter volumes were compared between groups. The Shapiro-Wilk test evaluated normality. Student's t-test and Mann-Whitney U test were used for statistical analysis, with significance defined as p < 0.05. Total intracranial volume was comparable between age groups (p = 0.527). Significant volume reductions (p < 0.05) were observed in subcortical gray matter structures, including the nucleus accumbens, caudate nucleus, globus pallidus, putamen, thalamus, and ventral diencephalon, particularly on the right side in the elderly group. Subcortical gray matter volume in healthy males shows significant differences between older and younger individuals (p < 0.05), with asymmetrical reduction and certain structures on the right aging more rapidly. These findings are significant for distinguishing healthy aging from neurodegeneration.

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Scalable Hypothalamic Arcuate Neuron Differentiation from Human Pluripotent Stem Cells Suitable for Modeling Metabolic and Reproductive Disorders.

The hypothalamus, composed of several nuclei, is essential for maintaining our body's homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.

Investigating the genetic relationship of intracranial and subcortical brain volumes with depression and other psychiatric disorders

Abstract Depression is one of the most common mental health disorders worldwide, yet its neurobiological mechanisms remain poorly understood. Structural brain differences in subcortical limbic regions are thought to be implicated in the pathology of depression. We leveraged genome-wide association studies (GWAS) summary-level data to explore the molecular pathways underlying the relationship between genetic risk for depression and intracranial and subcortical brain volumes measured via magnetic resonance imaging. At the whole-genome level, we identified a negative genetic correlation (rG) between depression and the volume of the ventral diencephalon (rG = -0.08), which remained significant after adjusting for multiple testing. We observed nominal (P &amp;lt; 0.05) positive genetic correlations between depression and the volumes of the caudate nucleus (rG = 0.06) and the putamen (rG = 0.06), while hippocampal volume displayed a negative genetic correlation (rG = -0.06) with depression. Pairwise GWAS analyses uncovered 104 genome segments with genetic variants influencing the aetiology of depression and at least one brain volume at the local genetic level. Gene association analyses of these genomic segments suggest putative links with dopamine neurotransmission, mesocorticolimbic functional connectivity, GABAergic transmission, and the insulin signalling pathway. Sensitivity analyses showed that the volume of the ventral diencephalon is also negatively correlated with bipolar disorder and schizophrenia; however, most of the genes associated with depression and brain volumes are specific for depression and do not replicate when investigating bipolar disorder or schizophrenia with brain volumes. We observed negative phenotypic correlations between depression and intracranial and subcortical brain volumes. Overall, our findings contribute to our understanding of the neurobiology of depression and suggest that, besides the known role of the hippocampus, other subcortical structures might also play essential roles in the aetiology of depression.

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Comparison of detailed brain volume measurements in schizophrenia with healthy individuals

Aims: This study aims to provide insights into the preliminary and definitive diagnosis, treatment modalities, and elucidation of the underlying pathophysiological mechanisms of schizophrenia, alongside ongoing research efforts. Methods: This retrospective study examined a cohort of 31 patients (17 male, 14 female) diagnosed with schizophrenia according to the criteria specified in the Diagnostic and Statistical Manual of Mental Disorders (DSM V) at the Psychiatry Clinic of the University Hospital. The healthy control group, comprising 31 individuals (17 male, 14 female), was selected from archived records at the same hospital, with sociodemographic characteristics matching those of the patient group. High-resolution T1-weighted MRI images of the individuals were analyzed using the VolBrain AssemblyNet program. Results: It has been observed that the volumes of various brain structures, including white matter (WM), gray matter (GM), subcortical GM, cortical GM, WM+GM, IC, total cerebrum, right cerebrum, left cerebrum, cerebrum WM, cerebrum GM, are significantly reduced (p&lt;0.05) in patients diagnosed with schizophrenia compared to healthy controls. Additionally, volumes of cerebellar WM, GM, vermis, brainstem, accumbens, hippocampus, thalamus, ventral diencephalon (DC), amygdala, and basal forebrain were found to be decreased in schizophrenia patients compared to healthy controls. Conversely, volumes of the pallidum, caudate, putamen, inferior lateral ventricle, lateral ventricle, third ventricle, fourth ventricle, and CSF were observed to be increased. Conclusion: These findings underscore the widespread nature of neuroanatomical alterations in schizophrenia and highlight the importance of understanding these changes for elucidating the disorder's pathophysiology and developing targeted therapeutic interventions. Further research is warranted to explore the interplay of genetic, developmental, and environmental factors in schizophrenia.

Longitudinal Neuroanatomical Increases from Early to One-Year Postpartum.

Preclinical studies have provided causal evidence that the postpartum period involves regional neuroanatomical changes in 'maternal' brain regions to support the transition to offspring caregiving. Few studies, in humans, have examined neuroanatomical changes from early to one-year postpartum with longitudinal neuroimaging data and their association with postpartum mood changes. In this study, we examined longitudinal changes in surface morphometry (cortical thickness and surface area) in regions previously implicated in the transition to parenthood. We also examined longitudinal volumetric neuroanatomical changes in three subcortical regions of the maternal brain: the hippocampus, amygdala, and ventral diencephalon. Twenty-four participants underwent longitudinal structural magnetic resonance imaging at 2-4 weeks and 1 year postpartum. Cortical thickness increased from early to one-year postpartum in the left (p = .003, Bonferroni corrected) and right (p = .02, Bonferroni corrected) superior frontal gyrus. No significant increases (or decreases) were observed in these regions for surface area. Volumetric increases, across the postpartum period, were found in the left amygdala (p = .001, Bonferroni corrected) and right ventral diencephalon (p = .01, Bonferroni corrected). An exploratory analysis of depressive symptoms found reductions in depressive symptoms from early postpartum to one-year postpartum were associated with greater cortical thickness in the superior frontal gyrus for both the left (p = .02) and right (p = .02) hemispheres. The findings expand our evidence of the neuroanatomical changes that occur across the postpartum period in humans and motivate future studies to examine how mood changes across this period are associated with cortical thickness of the superior frontal gyrus.

Polygenic architecture of brain structure and function, behaviors, and psychopathologies in children.

The human brain undergoes structural and functional changes during childhood, a critical period in cognitive and behavioral development. Understanding the genetic architecture of the brain development in children can offer valuable insights into the development of the brain, cognition, and behaviors. Here, we integrated brain imaging-genetic-phenotype data from over 8,600 preadolescent children of diverse ethnic backgrounds using multivariate statistical techniques. We found a low-to-moderate level of SNP-based heritability in most IDPs, which is lower compared to the adult brain. Using sparse generalized canonical correlation analysis (SGCCA), we identified several covariation patterns among genome-wide polygenic scores (GPSs) of 29 traits, 7 different modalities of brain imaging-derived phenotypes (IDPs), and 266 cognitive and psychological phenotype data. In structural MRI, significant positive associations were observed between total grey matter volume, left ventral diencephalon volume, surface area of right accumbens and the GPSs of cognition-related traits. Conversely, negative associations were found with the GPSs of ADHD, depression and neuroticism. Additionally, we identified a significant positive association between educational attainment GPS and regional brain activation during the N-back task. The BMI GPS showed a positive association with fractional anisotropy (FA) of connectivity between the cerebellum cortex and amygdala in diffusion MRI, while the GPSs for educational attainment and cannabis use were negatively associated with the same IDPs. Our GPS-based prediction models revealed substantial genetic contributions to cognitive variability, while the genetic basis for many mental and behavioral phenotypes remained elusive. This study delivers a comprehensive map of the relationships between genetic profiles, neuroanatomical diversity, and the spectrum of cognitive and behavioral traits in preadolescence.

Smaller subcortical volume relates to greater weight gain in girls with initially healthy weight.

Among 3614 youth who were 9 to 12 years old and initially did not have overweight or obesity (12% [n = 385] developed overweight or obesity), we examined the natural progression of weight gain and brain structure development during a 2-year period with a high risk for obesity (e.g., pre- and early adolescence) to determine the following: 1) whether variation in maturational trajectories of the brain regions contributes to weight gain; and/or 2) whether weight gain contributes to altered brain development. Data were gathered from the Adolescent Brain Cognitive Development (ABCD) Study. Linear mixed-effects regression models controlled for puberty, caregiver education, handedness, and intracranial volume (random effects: magnetic resonance scanner [MRI] scanner and participant). Because pubertal development occurs earlier in girls, analyses were stratified by sex. For girls, but not boys, independent of puberty, greater increases in BMI were driven by smaller volumes over time in the bilateral accumbens, amygdala, hippocampus, and thalamus, right caudate and ventral diencephalon, and left pallidum (all p < 0.05). The results suggest a potential phenotype for identifying obesity risk because underlying differences among regions involved in food intake were related to greater weight gain in girls, but not in boys. Importantly, 2 years of weight gain may not be sufficient to alter brain development, highlighting early puberty as a critical time to prevent negative neurological outcomes.

Sex versus gender associations with brain structure

In contrast to sex (a biological distinction), little is known about the associations between gender (a societal construct) and brain structure in the general population. In response to this knowledge gap, we examined the associations of sex vs. gender with FreeSurfer-generated cortical thickness and proportion-adjusted subcortical brain volume regions-of-interest (ROIs) in healthy adults (n = 88) screened for general medical conditions, mental illness, substance abuse, and intracranial pathologies. Gender role endorsement was assessed using the well-established and validated Bem Sex Role Inventory. For our main objectives, we calculated a continuum score as a composite measure of gender. For our secondary objectives, we examined sex-specific associations of the masculine vs. feminine gender role endorsement domains with brain structural outcomes. We found that female sex, independent of continuum scores, was associated with larger proportion-adjusted volumes for the basal ganglia, hippocampus, and ventral diencephalon. Higher continuum scores, independent of sex, were associated with thicker cortical thickness for the left and right superior frontal cortex, caudal and rostral middle frontal cortex, and right pars orbitalis. Female sex and higher continuum scores were independently associated with larger corpus callosum volumes. Post-hoc testing showed sex-specific associations between higher femininity scores and thicker prefrontal cortical thickness for the ROIs in females, but not in males. In conclusion, sex and gender showed semi-independent associations with brain structure in a general population sample. Our research supports the disaggregation of sex and gender to provide a more nuanced perspective on brain structural differences between men and women.

Atypical social cognition processing in bulimia nervosa: an fMRI study of patients thinking of others' mental states.

Feeding and eating disorders are severe mental disorders that gravely affect patients' lives. In particular, patients with anorexia nervosa (AN) or bulimia nervosa (BN) appear to have poor social cognition. Many studies have shown the relationship between poor social cognition and brain responses in AN. However, few studies have examined the relationship between social cognition and BN. Therefore, we examined which brain regions impact the ability for social cognition in patients with BN. We used task-based functional magnetic resonance imaging (fMRI) to examine brain responses during a social cognition task and the Reading Mind in the Eyes Test (RMET). During the fMRI, 22 women with BN and 22 healthy women (HW) took the RMET. Participants also completed the eating disorder clinical measures Bulimic Investigatory Test, Edinburgh (BITE) and Eating Disorders Examination Questionnaire (EDE-Q), the Patient Health Questionnaire (PHQ-9) measure of depression; and the Generalized Anxiety Disorder (GAD-7) measure of anxiety. No difference was observed in the RMET scores between women with BN and HW. Both groups showed activation in brain regions specific to social cognition. During the task, no differences were shown between the groups in the BOLD signal (p < 0.05, familywise error correctedfor multiple comparisons). However, there was a tendency of more robust activation in the right angular gyrus, ventral diencephalon, thalamus proper, temporal pole, and middle temporal gyrus in BN (p < 0.001, uncorrectedfor multiple comparisons). Moreover, HW showed a positive correlation between RMET scores and the activation of two regions: medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC); however, no significant correlation was observed in women with BN. While activation in the mPFC and ACC positively correlated to the RMET scores in HW, no correlation was observed in BN patients. Therefore, women with BN might display modulated neural processing when thinking of others' mental states. Further examination is needed to investigate neural processing in BN patients to better understand their social cognition abilities. UMIN, UMIN000010220. Registered 13 March 2013, https://rctportal.niph.go.jp/s/detail/um?trial_id=UMIN000010220.

Staging of progressive supranuclear palsy-Richardson syndrome using MRI brain charts for the human lifespan.

Brain charts for the human lifespan have been recently proposed to build dynamic models of brain anatomy in normal aging and various neurological conditions. They offer new possibilities to quantify neuroanatomical changes from preclinical stages to death, where longitudinal MRI data are not available. In this study, we used brain charts to model the progression of brain atrophy in progressive supranuclear palsy-Richardson syndrome. We combined multiple datasets (n = 8170 quality controlled MRI of healthy subjects from 22 cohorts covering the entire lifespan, and n = 62 MRI of progressive supranuclear palsy-Richardson syndrome patients from the Four Repeat Tauopathy Neuroimaging Initiative (4RTNI)) to extrapolate lifetime volumetric models of healthy and progressive supranuclear palsy-Richardson syndrome brain structures. We then mapped in time and space the sequential divergence between healthy and progressive supranuclear palsy-Richardson syndrome charts. We found six major consecutive stages of atrophy progression: (i) ventral diencephalon (including subthalamic nuclei, substantia nigra, and red nuclei), (ii) pallidum, (iii) brainstem, striatum and amygdala, (iv) thalamus, (v) frontal lobe, and (vi) occipital lobe. The three structures with the most severe atrophy over time were the thalamus, followed by the pallidum and the brainstem. These results match the neuropathological staging of tauopathy progression in progressive supranuclear palsy-Richardson syndrome, where the pathology is supposed to start in the pallido-nigro-luysian system and spreads rostrally via the striatum and the amygdala to the cerebral cortex, and caudally to the brainstem. This study supports the use of brain charts for the human lifespan to study the progression of neurodegenerative diseases, especially in the absence of specific biomarkers as in PSP.

A structural equation modeling approach using behavioral and neuroimaging markers in major depressive disorder

Major depressive disorder (MDD) has consistently proven to be a multifactorial and highly comorbid disease. Despite recent depression-related research demonstrating causalities between MDD-related factors and a small number of variables, including brain structural changes, a high-statistical power analysis of the various factors is yet to be conducted. We retrospectively analyzed data from 155 participants (84 healthy controls and 71 patients with MDD). We used magnetic resonance imaging and diffusion tensor imaging data, scales assessing childhood trauma, depression severity, cognitive dysfunction, impulsivity, and suicidal ideation. To simultaneously evaluate the causalities between multivariable, we implemented two types of MDD-specified structural equation models (SEM), the behavioral and neurobehavioral models. Behavioral SEM showed significant results in the MDD group: Comparative Fit Index [CFI] = 1.000, Root Mean Square Error of Approximation [RMSEA]) = 0.000), with a strong correlation in the scales for childhood trauma, depression severity, suicidal ideation, impulsivity, and cognitive dysfunction. Based on behavioral SEM, we established neurobehavioral models showing the best-fit in MDD, especially including the right cingulate cortex, central to the posterior corpus callosum, right putamen, pallidum, whole brainstem, and ventral diencephalon, including the thalamus (CFI >0.96, RMSEA <0.05). Our MDD-specific model revealed that the limbic-associated regions are strongly connected with childhood trauma rather than depression severity, and that they independently affect suicidal ideation and cognitive dysfunction. Furthermore, cognitive dysfunction could affect impulsivity.

CXCL12 promotes the crossing of retinal ganglion cell axons at the optic chiasm.

Binocular vision requires the segregation of retinal ganglion cell (RGC) axons extending from the retina into the ipsilateral and contralateral optic tracts. RGC axon segregation occurs at the optic chiasm, which forms at the ventral diencephalon midline. Using expression analyses, retinal explants and genetically modified mice, we demonstrate that CXCL12 (SDF1) is required for axon segregation at the optic chiasm. CXCL12 is expressed by the meninges bordering the optic pathway, and CXCR4 by both ipsilaterally and contralaterally projecting RGCs. CXCL12 or ventral diencephalon meninges potently promoted axon outgrowth from both ipsilaterally and contralaterally projecting RGCs. Further, a higher proportion of axons projected ipsilaterally in mice lacking CXCL12 or its receptor CXCR4 compared with wild-type mice as a result of misrouting of presumptive contralaterally specified RGC axons. Although RGCs also expressed the alternative CXCL12 receptor ACKR3, the optic chiasm developed normally in mice lacking ACKR3. Our data support a model whereby meningeal-derived CXCL12 helps drive axon growth from CXCR4-expressing RGCs towards the diencephalon midline, enabling contralateral axon growth. These findings further our understanding of the molecular and cellular mechanisms controlling optic pathway development.

Volumetric brain assessment of long-term head and neck cancer survivors

BackgroundRadiation therapy (RT) for locally advanced head and neck cancer (HNC) often exposes subcortical brain structures to radiation. We performed this study to assess region-specific brain volumetrics in a population of long term HNC survivors. Methods and MaterialsForty HNC survivors were enrolled at a mean of 6.4 years from completion of RT. Patients underwent a research MRI protocol that included a 3D T1- weighted whole-brain scan on a 3 Tesla MRI scanner. Voxel based morphometry was performed using the Computational Anatomy Toolbox with the Neuromorphometrics atlas. Healthy controls from the Human Connectome Project were used as a comparison cohort. Study participants also completed a comprehensive neurocognitive assessment. ResultsThe final study cohort consisted of 38 participants after excluding 2 participants due to image quality. HNC survivors displayed widespread reduction in gray matter (GM) brain region volumes that included bilateral medial frontal cortex, temporal lobe, hippocampus, supplemental motor area, and cerebellum. Greater radiation exposure was associated with reduced GM volume in the left ventral diencephalon (r = -0.512, p = 0.003). Associations between cognition and regional GM volumes were identified for motor coordination and bilateral cerebellum (left, r = 0.444, p = 0.009; right, r = 0.372, p = 0.030), confrontation naming and left amygdala (r = 0.382, p = 0.026), verbal memory and bilateral thalamus (left, r = 0.435, p = 0.010; right, r = 0.424, p = 0.012), right amygdala (r = 0.339, p = 0.050), and right putamen (r = 0.364, p = 0.034). ConclusionsReductions in GM were observed within this cohort of primarily non-nasopharyngeal HNC survivors as compared to a control sample. GM volumes were associated with performance in multiple cognitive domains. Results of this exploratory study support the need for investigation of anatomic brain changes as an important translational corollary to cognitive problems among HNC survivors.

Individual differences in rhythm perception modulate music-related motor learning: a neurobehavioral training study with children

Rhythm and motor function are intrinsically linked to each other and to music, but the rhythm-motor interplay during music training, and the corresponding brain mechanisms, are underexplored. In a longitudinal training study with children, we examined the role of rhythm predisposition in the fine motor improvements arising from music training, and which brain regions would be implicated. Fifty-seven 8-year-olds were assigned to either a 6-month music training (n = 21), sports training (n = 18), or a control group (n = 18). They performed rhythm and motor tasks, and structural brain scans before and after training were collected. Better ability to perceive rhythm before training was related to less gray matter volume in regions of the cerebellum, fusiform gyrus, supramarginal gyrus, ventral diencephalon, amygdala, and inferior/middle temporal gyri. Music training improved motor performance, and greater improvements correlated with better pre-training rhythm discrimination. Music training also induced a loss of gray matter volume in the left cerebellum and fusiform gyrus, and volume loss correlated with higher motor gains. No such effects were found in the sports and control groups. In summary, children with finer-tuned rhythm perception abilities were prone to finer motor improvements through music training, and this rhythm-motor link was to some extent subserved by the left cerebellum and fusiform gyrus. These findings have implications for models on music-related plasticity and rhythm cognition, and for programs targeting motor function.

Both clinically informed and brain region agnostic approaches identify neuroimaging derived phenotypes associated with genetically regulated gene expression of late‐onset Alzheimer’s disease genes

AbstractBackgroundGenetically regulated gene expression (GReX) data leverages expression quantitative trait loci to investigate the genetic mechanism of Alzheimer’s disease (AD). This study utilized the GReX‐mediated neuro‐imaging derived phenotypes (NIDPs), summary features derived from brain imaging modalities, as an endophenotype to identify brain regions associated with late‐onset AD (LOAD) via gene expression.MethodThis study contained brain region‐agnostic and region‐informed approaches. Both approaches utilized a set of 25 genes causally associated with LOAD in our previous cross‐tissue transcriptome‐wide association studies (TWAS) (Chen et al., 2021) to identify LOAD‐associated GReX‐mediated NIDPs. We leveraged the UK Biobank (UKBB) neuroimaging TWAS resource to provide GReX‐mediated NIDP information. Region‐agnostic: We assessed associations between GReX of LOAD genes and T1‐derived cortical and subcortical grey matter NIDPs from the UKBB neuroimaging TWAS. Region‐informed: We identified a set of AD‐associated cortical grey matter NIDPs from diagnosed AD patients (Westman et al., 2013). Next, we subset the UKBB neuroimaging TWAS data to those describing associations between GReX of LOAD genes and the selected AD NIDPs.A Benjamini‐Hochberg FDR p‐value threshold of 0.05 was used to establish statistical significance, and causal inference testing on associations between GReX of LOAD genes and NIDPs was conducted by implementing MR‐JTI in both approaches.Result Region‐agnostic: This approach found associations between GReX of 8 LOAD‐associated genes and 14 NIDPs (Figure 1). The most significant association is the GreX of ZNF296 and the right pars opercularis of the inferior frontal cortex, which replicated across 16 different tissues. Region‐informed: A single highly significant causal association between the GReX of PSMC3 and the ventral diencephalon was identified and replicated in gene expression models of 3 different bansal ganglia‐derived tissue models.ConclusionOur study shows the highly significant causal association between the GReX of ZNF296 and the right pars opercularis on LOAD through the region‐agnostic approach and the strong causal association between the GReX of PSMC3 and the ventral diencephalon on LOAD in AD‐associated region‐informed analyses. Our methodologies provide opportunities to explore brain regions associated with LOAD that are mediated by GReX of AD‐associated genes illuminating the impact of LOAD‐associated genes on gene expression and brain physiology.

Relating neighborhood deprivation to childhood obesity in the ABCD study: Evidence for theories of neuroinflammation and neuronal stress.

We evaluated whether relationships between area deprivation (ADI), body mass index (BMI) and brain structure (e.g., cortical thickness, subcortical volume) during preadolescence supported the immunologic model of self-regulation failure (NI) and/or neuronal stress (NS) theories of overeating. The NI theory proposes that ADI causes structural alteration in the brain due to the neuroinflammatory effects of overeating unhealthy foods. The NS theory proposes that ADI-related stress negatively impacts brain structure, which causes stress-related overeating and subsequent obesity. Data were gathered from the Adolescent Brain Cognitive Development Study (9 to 12 years old; n = 3,087, 51% male). Linear mixed-effects models identified brain regions that were associated with both ADI and BMI; longitudinal associations were evaluated with mediation models. The NI model included ADI and BMI at 9 to 10 years old and brain data at 11 to 12 years old. The NS model included ADI and brain data at 9 to 10 years old and BMI at 11 to 12 years old. BMI at 9 to 10 years old partially mediated the relationship between ADI and ventral diencephalon (DC) volume at 11 to 12 years old. Additionally, the ventral DC at 9 to 10 years old partially mediated the relationship between ADI and BMI at 11 to 12 years old, even in youth who at baseline, were of a healthy weight. Results were unchanged when controlling for differences in brain structure and weight across the 2-years. Greater area deprivation may indicate fewer access to resources that support healthy development, like nutritious food and nonstressful environments. Our findings provide evidence in support of the NI and NS theories of overeating, specifically, with greater ADI influencing health outcomes of obesity via brain structure alterations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Low bone mineral density is associated with gray matter volume decrease in UK Biobank.

Previous research has found an association of low bone mineral density (BMD) and regional gray matter (GM) volume loss in Alzheimer's disease (AD). We were interested whether BMD is associated with GM volume decrease in brains of a healthy elderly population from the UK Biobank. T1-weighted images from 5,518 women (MAge = 70.20, SD = 3.54; age range: 65-82 years) and 7,595 men (MAge = 70.84, SD = 3.68; age range: 65-82 years) without neurological or psychiatric impairments were included in voxel-based morphometry (VBM) analysis in CAT12 with threshold-free-cluster-enhancement (TFCE) across the whole brain. We found a significant decrease of GM volume in women in the superior frontal gyri, middle temporal gyri, fusiform gyri, temporal poles, cingulate gyri, precunei, right parahippocampal gyrus and right hippocampus, right ventral diencephalon, and right pre- and postcentral gyrus. Only small effects were found in men in subcallosal area, left basal forebrain and entorhinal area. BMD is associated with low GM volume in women but less in men in regions afflicted in the early-stages of AD even in a sample without neurodegenerative diseases.

The sequence of regional structural disconnectivity due to multiple sclerosis lesions.

Prediction of disease progression is challenging in multiple sclerosis as the sequence of lesion development and retention of inflammation within a subset of chronic lesions is heterogeneous among patients. We investigated the sequence of lesion-related regional structural disconnectivity across the spectrum of disability and cognitive impairment in multiple sclerosis. In a full cohort of 482 multiple sclerosis patients (age: 41.83 ± 11.63 years, 71.57% females), the Expanded Disability Status Scale was used to classify patients into (i) no or mild (Expanded Disability Status Scale <3) versus (ii) moderate or severe disability groups (Expanded Disability Status Scale ≥3). In 363 out of 482 patients, quantitative susceptibility mapping was used to identify paramagnetic rim lesions, which are maintained by a rim of iron-laden innate immune cells. In 171 out of 482 patients, Brief International Cognitive Assessment was used to identify subjects as being cognitively preserved or impaired. Network Modification Tool was used to estimate the regional structural disconnectivity due to multiple sclerosis lesions. Discriminative event-based modelling was applied to investigate the sequence of regional structural disconnectivity due to (i) all representative T2 fluid-attenuated inversion recovery lesions, (ii) paramagnetic rim lesions versus non-paramagnetic rim lesions separately across disability groups ('no to mild disability' to 'moderate to severe disability'), (iii) all representative T2 fluid-attenuated inversion recovery lesions and (iv) paramagnetic rim lesions versus non-paramagnetic rim lesions separately across cognitive status ('cognitively preserved' to 'cognitively impaired'). In the full cohort, structural disconnection in the ventral attention and subcortical networks, particularly in the supramarginal and putamen regions, was an early biomarker of moderate or severe disability. The earliest biomarkers of disability progression were structural disconnections due to paramagnetic rim lesions in the motor-related regions. Subcortical structural disconnection, particularly in the ventral diencephalon and thalamus regions, was an early biomarker of cognitive impairment. Our data-driven model revealed that the structural disconnection in the subcortical regions, particularly in the thalamus, is an early biomarker for both disability and cognitive impairment in multiple sclerosis. Paramagnetic rim lesions-related structural disconnection in the motor cortex may identify the patients at risk for moderate or severe disability in multiple sclerosis. Such information might be used to identify people with multiple sclerosis who have an increased risk of disability progression or cognitive decline in order to provide personalized treatment plans.