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[Nonspecific brain structures and specialization in the central nervous system].

It has been demonstrated that corticofugal influences may exert selective control of single sensory signals which converge on the neurons of the striatum and other non-specific structures of the brain. This finding suggests that complex sensory image may be formed not by assembling separate elementary signals, but rather by a selective control of these signals into a total sensory inflow within the network brain structures. This conclusion is confirmed by comparative anatomical data. In the phylogenesis of vertebrates, brain structures differentiate presumably into both the specific ones which perform the analysis of only the given kind of information, and those (conventionally described as non-specific) which are specialized on sensory integration and exhibit functional polymodality.

Animals↗
PubMed2026

Causal relationships between somatic movement, brain structures, and mental well-being: A multi-stage Mendelian randomization study.

BACKGROUND: While the relationships between somatic movement, mental well-being, and brain health have been well established, the causal nature and underlying mechanisms of such associations remain incompletely understood. METHODS: By applying multi-stage Mendelian randomization to multi-source summary data derived from genome-wide association studies, we examined the causal effects of 4 somatic movement measures on 2 mental well-being indices and 13 types of brain structures, followed by testing the mediating roles of brain structures in accounting for the causal associations between somatic movement and mental well-being. RESULTS: Two-sample Mendelian randomization revealed that more physical activity was causally associated with greater mental well-being (life satisfaction and positive affect), while more sedentary behavior (longer leisure screen time and more sedentary behavior at work) with lower mental well-being. With respect to brain structures, sedentary behavior was causally linked to decreased volume, surface area, and local gyrification index in distributed cortical regions. Remarkably, decreased surface area of the piriform cortex was found to mediate the causal associations between sedentary behavior and lower mental well-being. CONCLUSIONS: Our findings not only complement and extend earlier reports on the associations of somatic movement with mental well-being and brain health by further resolving the causality but also help elucidate the neural mechanisms by which sedentary behavior adversely affects mental well-being.

Humans↗
PubMed2026

Understanding specificity in immune-brain pathways: A systematic review of differential associations between individual cytokines and brain structure and function measured through magnetic resonance imaging in humans.

Research shows that cytokines are associated with psychiatric disorders, including major depression, and multiple aspects of brain structure and function. Accumulating data suggest that different cytokines may have unique profiles of biological activity, particularly in their neuromodulatory roles, but it is currently unclear whether they have unique associations with specific neural circuits in humans. In this paper, we systematically review magnetic resonance imaging studies conducted with depressed or healthy control human participants under age 65 that examine associations between peripheral cytokines and brain structure and function, with the goal of evaluating evidence for the specificity of these cytokine-brain associations. We find that across multiple measures of brain structure and function, the majority of studies reviewed reported unique associations between individual cytokines and brain outcomes. A synthesis of findings across studies also suggests a preliminary hypothesis of specific associations of interleukin-6 levels in circulation with the default mode network and tumor necrosis factor-alpha with the salience network, which could be tested in future research. We conclude the review with future directions for research that can strengthen understanding of these associations.

Humans↗
PubMed2025

Human development, inequality, and their associations with brain structure across 29 countries.

BACKGROUND: The macro-social and environmental conditions in which people live, such as the level of a country's development or inequality, are associated with brain-related disorders. However, the relationship between these systemic environmental factors and the brain remains unclear. We aimed to determine the association between the level of development and inequality of a country and the brain structure of healthy adults. METHODS: We conducted a cross-sectional study pooling brain imaging (T1-based) data from 145 magnetic resonance imaging (MRI) studies in 7,962 healthy adults (4,110 women) in 29 different countries. We used a meta-regression approach to relate the brain structure to the country's level of development and inequality. RESULTS: Higher human development was consistently associated with larger hippocampi and more expanded global cortical surface area, particularly in frontal areas. Increased inequality was most consistently associated with smaller hippocampal volume and thinner cortical thickness across the brain. CONCLUSIONS: Our results suggest that the macro-economic conditions of a country are reflected in its inhabitants' brains and may explain the different incidence of brain disorders across the world. The observed variability of brain structure in health across countries should be considered when developing tools in the field of personalized or precision medicine that are intended to be used across the world.

Humans↗
PubMed2026

Novel epigenetic loci identified from an epigenome-wide association study underlying brain structural changes in bipolar disorder.

BACKGROUND: DNA methylation influences gene-environment interactions and brain development in bipolar disorder (BD). We aimed to identify BD-associated epigenetic loci and examine their associations with brain structural variation. METHODS: We conducted an epigenome-wide association study (BD group, n = 90; healthy controls group, n = 161) to identify BD-associated DNA methylation loci, and we additionally performed copy number alteration and functional enrichment analyses. The correlations between epigenetic loci and cortical thickness (CT) were assessed using Pearson's partial correlation analysis, and the co-methylation effect of the epigenetic loci identified in the neuroimaging-epigenetic analysis was investigated. FINDINGS: A total of 156 differentially methylated positions (DMPs) and 7 differentially methylated regions were identified, and the genes associated with them were observed to be enriched in biological processes related to muscle hypertrophy and neuronal activity. Significant correlations between the methylation levels of 13 DMPs associated with three genes (miR886, PLEC1, and ICAM5) and the CT of the right postcentral gyrus and inferior frontal gyrus were identified. Specifically, 10 DMPs associated with the CpG island in the upstream region of the miR886 gene showed negative correlations with the right postcentral gyrus CT, implicating miR886-associated CpG-island methylation in regional cortical thinning. CONCLUSION: Epigenetic changes might play an important role in brain structural changes in BD. These multimodal findings nominate miR886-related methylation as a candidate molecular correlate of cortical thinning and warrant replication and mechanistic follow-up in larger, state-diverse cohorts.

Humans↗
PubMed2026

Mapping Focal and Generalized Effects of Common Genetic Variants on Human Brain Structure.

Genome-wide association studies (GWAS) have advanced the quest to understand how specific genetic variants influence human brain structure and function. Recent work has identified hundreds of common variants associated with subcortical brain volumes, sparking interest in how these genetic markers overlap across brain networks. While this can be estimated by hierarchical clustering of the genetic correlation matrix to identify modular patterns of shared architecture, no brain-wide maps of these effects are available. To address this, we computed polygenic scores (PGS) from loci associated with ten brain volume regions of interest (ROIs): nine major subcortical structures and intracranial volume, with each locus weighted by its association with regional volume. In an independent sample from the discovery GWAS, we performed large-scale segmentation of 3D volumetric T1-weighted MRI scans using voxel-based morphometry (VBM) to map 3D profile of regions where gray matter volume (GMV) was associated with each PGS. We found statistically significant, localized effects for PGS defined for the amygdala, thalamus, and basal ganglia, but PGS for brainstem volume was associated with widespread differences throughout the brain. These brain-wide maps reveal patterns consistent with both localized and distributed genetic influences, offering a novel approach to interpret the genomic architecture of brain structure.

GWAS↗
PubMed2026

Causal associations between hormone replacement therapy and brain structure: Evidence from large-scale Mendelian randomization and double machine learning.

BACKGROUND: Hormone replacement therapy (HRT) is widely prescribed for the management of hormone deficiency, particularly during menopause, yet its causal effects on human brain structure remain incompletely understood. Observational studies have reported heterogeneous associations, underscoring the need for robust causal inference. METHODS: We applied an integrated causal framework combining two-sample Mendelian Randomization (MR) and Double Machine Learning (DML) to evaluate the effects of four HRT-related exposures-age at initiation, age at cessation, ever-use of HRT, and a composite medication-based phenotype-on 1366 brain imaging-derived phenotypes from the UK Biobank. Genetic instruments were derived from large-scale GWAS summary statistics, and causal estimates were validated using non-parametric DML models with cross-fitting and performance evaluation. RESULTS: Genetic instruments for age at HRT initiation, age at cessation, and ever-use of HRT were strong (median F-statistics 16.29-36.66). MR analyses identified a causal association between later initiation of HRT and lower orientation dispersion in the right inferior cerebellar peduncle (ubm-a-542; primary finding, no pleiotropy detected). An additional association with the left tapetum FA (ubm-a-243) was identified but exhibited significant directional horizontal pleiotropy (MR-Egger intercept P = 0.001) and is excluded from primary conclusions (Supplementary Note S2). Later cessation of HRT was associated with increased cortical thickness in the left middle occipital gyrus, reduced surface area in the left frontopolar cortex, and increased orientation dispersion in the splenium of the corpus callosum. Ever-use of HRT was causally linked to larger volumes of the right inferior frontal gyrus and right nucleus accumbens. These associations were corroborated by independent DML validation, which provided causally debiased estimates robust to high-dimensional confounding. Results for ukb-b-8080 (median F = 1.45) are provided in Supplementary Note S1 only; weak-instrument bias precludes causal inference. CONCLUSIONS: This study provides genetic-instrument-based and machine-learning-validated evidence for causal associations between HRT exposure-particularly its timing and lifetime use-and specific features of human brain structure, including white-matter microarchitecture, cortical thickness, and regional brain volume. These findings are FDR-controlled within exposures and independently replicated by DML, but require replication in external neuroimaging GWAS cohorts to establish definitive causal conclusions. They highlight the neurobiological relevance of sex steroid exposure and inform future research on brain aging and personalized hormone-based interventions.

Humans↗
PubMed2026

Characterizing the impact of plasma protein levels on human brain structure and disorders leveraging integrative multi-omics analysis.

With recent advances in high-throughput proteomic technologies, population-scale plasma proteomics datasets, often linked to extensive genetic and phenotypic information, have become increasingly accessible. Yet the relationships between circulating protein levels, brain imaging phenotypes, and risk for neurological and psychiatric disorders remain largely unexplored. Proteome-wide association studies offer a promising approach for elucidating biological mechanisms that connect genetic variation to complex brain-related traits and diseases. In this study, we integrated protein quantitative trait loci (pQTLs) from the two largest plasma proteomic resources (the UK Biobank Pharma Proteomics Project [UKB-PPP] and Ferkingstad et al. [deCODE]) with genome-wide association studies of brain imaging-derived phenotypes in UK Biobank using Mendelian randomization and colocalization analyses. We identified 120 cis and 20 trans associations between plasma proteins and imaging phenotypes and validated these findings using brain tissue-derived proteomic and transcriptomic datasets. Multivariable Mendelian randomization revealed eleven plasma proteins (coding genes APOE, ARL3, MICB, NSF, RHOC, RSPO3, ENPP2, BTN2A1, EIF2AK3, MRVI1, and OPLAH) with significant direct effects on the risk of Alzheimer's disease, Parkinson's disease, multiple sclerosis, bipolar disorder, and schizophrenia. Single-cell expression and pathway enrichment analyses further revealed cell-type-specific effects and distinct biological processes underlying these protein-disease associations. Together, these findings demonstrate robust links between plasma protein variation and brain structure, delineate protein-disease pathways, and highlight the cellular and molecular mechanisms that contribute to neurobiological diversity and pathology.

Journal Article↗
PubMed1978

Neuronal, non-neuronal and hybrid forms of enolase in brain: structural, immunological and functional comparisons.

Three forms of the glycolytic enzyme, enolase [2-phospho-D-glycerate hydrolase (E.C. No. 4.2.1.11)] have been prepared from rat whole brain extract. The most acidic enolase form is neuron specific enolase (NSE) which had previously been designated neuron specific protein (NSP). The least acidic form designated non-neuronal enolase (NNE) has been purified and compared structurally, immunologically and functionally to NSE. NNE is a dimer of 86,500 M.W. consistint of two very similar subunits. The data establish that NNE is larger than NSE which has been shown to be composed of two apparently identical 39,000 molecular weight subunits (78,000). NNE is less acidic than NSE having a pI of 5.9 compared to the value of 4.7 for NSE. Structural and immunological analysis establishes that the NNE subunit is distinct from the NSE subunit, and are therfore products of two separate genes. The structural designation of NSE is (gammagamma) and that of NNE (alpha' alpha'). NSE is strictly localized in neurons indicating that the gene coding for the gamma subunit is only expressed in neuronal cells. The intermediate brain enolase form has been partially purified; structural and immunological evidence indicate that it is a hybrid molecule consisting of one NNE subunit and one NSE subunit (alpha'gamma).

Amino Acid Sequence↗
PubMed1979

[Effect of parenterally administered amino acids and protein hydrolysate on the electrical activity of brain structures].

Glycin, glutamic acid or casein hydrolysate induced high frequency and high voltage electrical waves in the brain-stem RF and often in the lateral hypothalamic nucleus and cortex. These changes were more obvious during feeding of the dogs. Sham feeding and parenteral administration of glucose or 0.9% solution of NaCl evoked responses different from the above ones. Gastric secretion stimulated by i.v. administration of nitrous substances by food was not directly related to the above responses either. The impulses responsible for the secretion seem to arise at another level of the brain.

Amino Acids↗
PubMed1979

[Drug-induced influence of the GABA-fluorescence in rat brain structures with some comments on the chemistry of the reaction (author's transl)].

1. GABA was demonstrated in rat brain in fluorescence histochemistry. The alteration by application of submaximal doses of drugs of the distribution and intensity of the transmitter fluorescence was studied in hippocampus and cerebellum. 2. Isonicotinic acid hydrazide and Penicillamine leads to a distinct grain formation and diminishing of the fluorescence product, normally appearing homogenous. These effects are considered to reflect an enzyme (GAD) inhibition. 3. By Cycloserine a distinct increase of the GABA fluorescence is effected, presumably by inhibiting GABA-transaminase-activity. 4. Chloropromazine causes diminishing, grain formation and dislocation as well of the fluorescent product, supposedly due to an affection of the membrane binding properties of GABA. 5. Hypotheses concerning the chemical events of the GABA-reaction are worded.

Animals↗
PubMed1979

[Changes in the millivolt potential of brain structures during micropolarization influencing trace phenomena].

In chronic experiments on monkeys and cats, the effects of intracerebral micropolarization modulating memory processes, on the mV potential of cerebral structures, were studied. A connection was revealed between trace fixing and processes of systemic kindling on the one hand, and the following stabilizing of mV potential, on the other hand. The data obtained suggest that the distant changes of the mV potential reflect a general "tuning" of cerebral systems, are realized by means of specialized regulatory neuronal networks and connected with shifts in metabolic processes.

Animals↗
PubMed2025

Polygenic Associations between Motor Behaviour, Neuromotor Traits, and Active Music Engagement in Four Cohorts.

Phenotypic investigations have shown that actively engaging with music, i.e., playing a musical instrument or singing may be protective of motor decline in aging. For example, music training associated with enhanced sensorimotor skills accompanied by changes in brain structure and function. Although it is possible that the benefits of active music engagement "transfer" to benefits in the motor domain, it is also possible that the genetic architecture of motor behaviour and the motor system structure may influence active music engagement. This study investigated whether polygenic scores (PGS) for five behavioural motor traits, 12 neuromotor structural brain traits, and seven rates of change in brain structure traits trained from existing discovery genome-wide association studies (GWAS) predict active music engagement outcomes in four independent cohorts of unrelated individuals of European ancestry: the Canadian Longitudinal Study on Aging (CLSA; N=22,198), Wisconsin Longitudinal Study (WLS; N=4,605), Vanderbilt's BioVU Repository (BioVU; N=6,150), and Vanderbilt's Online Musicality study (OM; N=1,559). Results were meta-analyzed for each PGS main effect across outcomes and cohorts, revealing that PGS for a faster walking pace was associated with higher amounts of active music engagement. Within CLSA, a higher PGS for walking pace was associated with greater odds of engaging with music. Findings suggest a shared genetic architecture between motor function and active music engagement. Future intervention-based research should consider the genetic underpinnings of motor behavior when evaluating the effects of music engagement on motor function across the lifespan.

BioVU↗