Individual Brain Research Articles

Multiple-system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50-60 years and leading to death within a decade1-3. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar α-synuclein (aSyn)4-8, the formation of which shows parallels with prion propagation9,10. While fibrils extracted from brains of individuals with MSA have been structurally characterized11, their ability to replicate in a protein-only manner has been questioned12, and their ability to induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain 1B13,14, assembled from recombinant human aSyn, self-replicates in vitro and induces GCIs in mice15-suggesting direct relevance to MSA-but lacks scrutiny at the atomic scale. Here we report high-resolution structural analyses of 1B fibrils and of fibrils extracted from diseased mice injected with 1B that developed GCIs (1BP). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Notably, the structures of 1B and 1BP are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from patients with MSA11. Moreover, reinjection of crude mouse brain homogenates containing 1BP into new mice reproduces the same MSA-like pathology induced by the parent synthetic seed 1B. Our findings identify 1B as a synthetic pathogen capable of self-replication in vivo and reveal structural features of 1B and 1BP that may underlie MSA pathology, offering insights for therapeutic strategies.

We assessed the effect of the 5-HT1A receptor (R) antagonist WAY100,635 on motor behaviors, object place learning and the regional levels of dopamine (DA), serotonin (5-HT) and their metabolites in the rat brain. After a single dose of either WAY100,635 (0.4 mg/kg) or vehicle (0.9% NaCl), recognition memory was assessed together with motor/exploratory behaviors. After sacrifice, regional DA, 5-HT and metabolite levels were determined with HPLC. Overall activity and exploratory behavior were reduced by WAY100,635. Object place recognition did not differ between treatments. WAY100,635 promoted DA metabolization (1) by both monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) in cingulate, caudateputamen, thalamus and cerebellum, (2) solely by MAO in dorsal hippocampus and (3) solely by COMT in ventral hippocampus and brainstem, but suppressed DA metabolization (by both MAO and COMT) in nucleus accumbens. It promoted 5-HT metabolization (by MAO) in cingulate, caudateputamen, dorsal hippocampus and brainstem, but suppressed it in nucleus accumbens, thalamus and cerebellum. WAY100,635 altered activity and exploratory behavior as well as the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways.

The objective of this study was to define the molecular neuroanatomy of the human habenula (Hb) and identify transcriptomic differences between brains of individuals with schizophrenia and nonpsychiatric control brains. This study utilized Hb-enriched postmortem human brain tissue. Single-nucleus RNA sequencing (snRNA-seq) was conducted to identify molecularly defined Hb cell types (N=7 donors), and single-molecule fluorescent in situ hybridization (smFISH) was performed to validate cell types and map their spatial locations (N=5 independent donors). Bulk RNA sequencing (RNA-seq) (schizophrenia, N=35; nonpsychiatric control, N=33) and cell type deconvolution were used to identify differentially expressed genes (DEGs), which were then compared to dorsolateral prefrontal cortex, hippocampus, and caudate schizophrenia DEGs. Expression quantitative trait loci (eQTLs) and schizophrenia risk colocalization analyses were performed. snRNA-seq identified 17 cell type clusters across 16,437 nuclei, including three medial and seven lateral Hb populations, several of which were conserved in rodents. smFISH validated snRNA-seq Hb cell types and depicted their spatial organization. Bulk RNA-seq analyses yielded 173 schizophrenia-associated DEGs (false discovery rate<0.1), of which 129 (75%) were unique to Hb-enriched tissue. eQTL analysis identified 717 independent single-nucleotide polymorphism (SNP)-gene pairs (false discovery rate<0.05). Of these, 16 pairs included a SNP that is a schizophrenia risk variant, and seven different pairs included a schizophrenia DEG. eQTL and schizophrenia risk colocalization analysis identified 16 colocalized genes, nine of which have not been previously identified. These results identify topographically organized cell types with distinct molecular signatures in the human habenula and demonstrate unique genetic differences associated with schizophrenia, thereby providing novel molecular insights into the role of the habenula in neuropsychiatric disorders.

Butyrylcholinesterase (BChE) plays a pivotal role in the progression of Alzheimer's disease. Empirical research demonstrated a fundamental alteration in the role of BChE concerning the reduction of cholinergic neurotransmission within the brains of individuals at advanced stages of Alzheimer's. This study focuses on developing potent inhibitors for Butyrylcholinesterase (BChE) in the context of Alzheimer's disease (AD) treatment. Building upon previous research, a series of 44 aromatic tertiary amine-based compounds was investigated. Starting with ADME-Tox studies, the pharmacokinetic and pharmacodynamic properties of the compounds were analyzed to select promising candidates for BChE inhibition, which is a crucial factor in AD pathology. Molecular docking analyses identified compound M18 as the most promising candidate, and further compounds (X9 and X10) were proposed based on M18's chemical structure. These compounds displayed superior properties in terms of binding energies and hydrogen bonds in comparison to M18. The Molecular Dynamics (MD) simulations, which are over a 500 ns timeframe, confirmed the conformational stability of compounds X9 and X10, compared to M18. Overall, the stated results suggest that the proposed compounds, including X9 and X10 specifically, have a significant potential as candidates for BChE inhibition. This presents a promising avenue for therapeutic intervention in Alzheimer's disease.

Irisin/BDNF pathway dysfunction subserves anorexia nervosa pathophysiology.

Sensory processing sensitivity: theory, evidence, and directions.

A pilot study of inter-regional phase amplitude coupling as comorbid depression biomarker in temporal lobe epilepsy.

How are systems supporting high-level cognition organized in the human brain? We hypothesize that cognitive processes involved in understanding people and places are implemented by distinct neural systems with parallel anatomical organization. We test this hypothesis using precision neuroimaging of individual human brains on diverse tasks involving perception and cognition in the domains of familiar people, places, and objects. We find that thinking about people and places elicits responses in distinct areas of high-level association cortex within the default mode network, spanning the frontal, parietal, and temporal lobes. Person- and place-preferring brain regions are systematically spatially adjacent across cortical zones. These areas have strongly domain-specific response profiles across visual, semantic, and episodic tasks and are specifically functionally connected to other parts of association cortex with like domain preference. Social and spatial networks remain anatomically separated at the apex of a unimodal-to-transmodal gradient across cortex and include regions with anatomical connections to the hippocampal formation. These results demonstrate the existence of parallel, domain-specific networks reaching the cortical apex.

Emerging Roles of Chromatin-Associated lncRNAs in 3-Dimensional Chromatin Remodeling and Heterochromatinization: Implications for Major Depressive Disorder.

Aberrant phosphorylation, which is absent in healthy brains but present exclusively in the brains of individuals with Alzheimer's disease (AD), plays a critical role in AD development. It causes the dissociation of tau protein from microtubules, followed by the aggregation of tau protein into brain-toxic oligomers and fibrils. In our previous study, we investigated the impact of abnormal phosphorylation at S289 (pS289) on the oligomerization of tau repeat R2 peptides. In this work, we continue to investigate the effect of aberrant phosphorylation at residue S293 (pS293) on the R2 peptides. Our result indicated that pS293 also promotes oligomerization, which is similar to pS289. Both the phosphorylation-enhanced intramolecular and intermolecular interactions and β-sheet formation of phosphorylated R2 compared to that of the wild type. We observed that Na+ can bridge two pS293 residues to form pS293--Na+-pS293 triad in the R2 dimer, a phenomenon also observed for the pS289 R2 dimer. However, the impact of pS293 was different from that of pS289 in terms of the secondary structural profile of both monomeric and dimeric R2 peptides. Our findings suggest that phosphorylation at S293 should be taken into consideration in the inhibitor screening of tau oligomerization.

Abstract The neural organization of cognitive control has been extensively studied using neuroimaging methods, but this organization is still not well understood. We argue that two factors may have contributed to this elusiveness. First, most previous research has relied on group-averaged results, which may provide a misleading representation of individual brains. Second, most fMRI studies study the brain only under a limited number of conditions, making it challenging to provide fine-grained distinctions in the functions associated with specific regions. Recent precision neuroimaging approaches have demonstrated substantial promise in furthering understanding of the human brain through repeated sampling of individual participants. However, most precision imaging work still relies on resting-state fMRI or a small number of tasks. In the present study, we demonstrate the utility of a novel dense imaging approach, which combines precision neuroimaging with an unusually large task battery. We demonstrate that patterns of neural activity associated with cognitive control tasks are significantly more similar within-person than between people, even after controlling for anatomical similarity, suggesting that these patterns are person-specific and reliable. In addition, we demonstrate that within-person and between-person similarity changes significantly across tasks, suggesting that some tasks may be more suited for exploring individual differences in cognitive control than others. Together, our findings highlight the potential value of a precision approach and the benefit of using a large number of tasks to further understanding of cognitive control.

Individual brain activity patterns derived from electroencephalogram (EEG) data offer a unique source for personal identification, introducing a novel approach to the field. Autoencoders are well-known machine learning models that automate feature extraction, which is a crucial step in biometric identification. Among various types of autoencoders, the domain-adaptive autoencoder (DAAE) is explored for feature extraction. The extracted latent features are employed by four machine learning classifiers, KNN, ANN, SVM and RF, for personal identification. Two domain adaptation approaches were presented. The proposed frameworks were evaluated in a longitudinal setting, using three types of EEG recordings: resting state, auditory and cognitive stimuli. Model performance was assessed through experiments involving seven-, five- and two-subject classification tasks. The highest identification accuracy, 100%, was achieved by the SVM-based model in the two-subject experiment, using features extracted with the uniform referential DAAE. Similarly, the RF-based model attained an accuracy of 99.84% in the two-subject experiment when trained on features obtained from the softmin referential DAAE. As expected, accuracy declined with an increasing number of subjects in the dataset, reflecting the difficulty of multi-subject classification.

Acrolein, an α,β-unsaturated aldehyde and reactive oxygen species (ROS), originates from both endogenous mechanisms, such as lipid peroxidation, and exogenous sources, including the decomposition of organic matter. Elevated levels of acrolein are detected in the brains of individuals with Alzheimer's and Parkinson's diseases, as well as those with traumatic brain or spinal cord injuries. Environmental exposure, including smoking and industrial emissions, further contribute to acrolein accumulation. Despite their recognized immediate neurotoxic effects, the chronic implications on neurodegeneration remain elusive. To elucidate these effects, human induced pluripotent stem cell (hiPSC)-derived human cortical neurons (∼Day 60 postdifferentiation) were subjected to 0, 1, and 10 μM concentrations of acrolein for 2 days following a nonexposure relaxation period (7 days) to assess the persistence of the resulting phenotypes. Immunofluorescence and calcium imaging demonstrated sustained alterations in the synaptic density and neuronal activity in acrolein-exposed differentiated neurons. Moreover, a persistent and dose-dependent neuronal hyperactivity was identified through microelectrode array analysis. Acrolein exposure also precipitated sustained elevations in Alzheimer's Disease-related phosphorylated Tau (p-tau) pathology and mitochondrial stress, along with diminished cellular resilience to subsequent stressors. Collectively, these findings support a persistent neurotoxic effect of acrolein, highlighting its potential implications for neurodegenerative disorders.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impaired social interaction, and restricted and repetitive patterns of behavior. ASD presents as a clinical spectrum, with variable levels of severity and multiple co-occurring conditions. The etiology of ASD may involve hundreds of genes and there is evidence that neurotransmitter and synaptic (NS) pathways are implicated. Proton Magnetic Resonance Spectroscopy (1H-MRS) has made it possible to study the concentration of brain neurometabolites and compare their levels in the brains of ASD and control individuals. We integrated genetic variants in NS genes with 1H-MRS analysis, and identified 12 predicted damaging variants (PDVs) in 12 NS genes in 10 ASD individuals, most mapping to genes involved in Gamma-aminobutyric acid (GABA) and glutamate pathways. Total creatine (tCr) and total N-acetyl aspartate (tNAA), markers of bioenergetics and neuronal metabolism, respectively, were lower in ASD patients with genetic alterations in NS genes compared to a control group without ASD. We conclude that PDVs in NS genes that are important for the regulation of glutamate or involved in GABAergic functions are associated with neurometabolic alterations, and that dysfunction in glutamatergic and/or GABAergic pathways may be implicated as these pathways are linked to the metabolic measures altered in cases.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-20090-x.

Schizophrenia is a complex neuropsychiatric disorder characterized by significant heterogeneity, posing a challenge for accurate classification using neuroimaging data. Graph convolutional networks (GCNs) have emerged as a promising approach for leveraging the inherent graph structure of brain connectivity to discriminate between patients with schizophrenia and healthy controls. However, existing GCN-based methods often struggle to capture the subtle neuroimaging differences associated with the disorder. To address these limitations, we propose a novel GCN framework (MSN-GCN) that integrates morphometric similarity networks (MSN) derived from structural MRI scans. Our method involves constructing individual brain graphs based on multiple morphometric features, including cortical thickness, surface area, gray matter volume, mean curvature, and Gaussian curvature. These individual graphs are then combined into a population-level graph that incorporates both topological and phenotypic information. By employing a variational edge learning approach, our model adaptively optimizes the edge weights to capture the complex relationships between brain structure and schizophrenia. We evaluated our proposed method on a large, multi-site dataset comprising 377 schizophrenia patients and 590 healthy controls. Experimental results demonstrate superior classification performance compared to state-of-the-art methods, achieving a mean accuracy of 80.85%. Notably, the superior temporal gyrus emerged as a key region contributing to classification. Significant differences in the clustering coefficient of the superior temporal gyrus, postcentral gyrus, and lateral occipital cortex between patients and healthy controls, and their correlations with negative symptoms were detected in post-hoc analyses. These findings demonstrate the potential of MSN-GCN for accurate schizophrenia detection and provide valuable insights into the neural correlates of the disorder.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-19894-8.

Transcriptional specialization shapes abnormal cortical morphological similarity gradients in Wilson's disease.

Cognitive prediction using regional connectivities and network biomarkers in Alzheimer's disease.

MR-guided graph learning of 18F-florbetapir PET enables accurate and interpretable Alzheimer's disease staging.

To compare the effects of low-load (LL) blood flow restriction (BFR) and high-load (HL) training on cortical activation and the specific contributions of individual brain regions to functional recovery in stroke patients. Sixty-six patients with ischemic stroke were divided into BFR (30% one-repetition maximum [1RM]), matched LL, or HL (80% 1RM) groups. Patients underwent a four-week supervised cycling program, and oxyhemoglobin (HbO) concentrations were assessed during the first session and after the program via functional near-infrared spectroscopy (fNIRS). Muscle performance was characterized by the rectus femoris muscle cross-sectional area (CSA), knee extensor peak torque (PT), and Fugl-Meyer lower extremity (FMLE) scores. Compared with the LL group, the BFR and HL groups presented significant brain activation (increased HbO concentration) during the first session (P < 0.05). Following the 4-week intervention, the BFR and HL groups presented greater changes in the HbO concentration (ΔHbO), PT and FMLE scores than did the LL group (P < 0.05). The ΔHbO values in the primary motor cortex (M1), premotor cortex and supplementary motor area (PMC-SMA) of the affected hemisphere (AH) were considerably greater than those in the unaffected hemisphere (P < 0.05), whereas there was no difference in the dorsolateral prefrontal cortex (DLPFC). Changes in PT (mean r = 0.51 [range = 0.46-0.55]; P < 0.05) and FMLE scores (mean r = 0.54 [range = 0.48-0.62]; P < 0.05) were positively correlated with the AH M1 and PMC-SMA ΔHbO across groups. By actively manipulating the M1 and PMC-SMA, LL-BFR and HL training yield comparable short-term improvements in central and peripheral performance after stroke. (Registry: Chinese Clinical Trial Registry; ChiCTR2400087378).

AimsTo compare the effects of low-load (LL) blood flow restriction (BFR) and high-load (HL) training on cortical activation and the specific contributions of individual brain regions to functional recovery in stroke patients.MethodsSixty-six patients with ischemic stroke were divided into BFR (30% one-repetition maximum [1RM]), matched LL, or HL (80% 1RM) groups. Patients underwent a four-week supervised cycling program, and oxyhemoglobin (HbO) concentrations were assessed during the first session and after the program via functional near-infrared spectroscopy (fNIRS). Muscle performance was characterized by the rectus femoris muscle cross-sectional area (CSA), knee extensor peak torque (PT), and Fugl–Meyer lower extremity (FMLE) scores.ResultsCompared with the LL group, the BFR and HL groups presented significant brain activation (increased HbO concentration) during the first session (P < 0.05). Following the 4-week intervention, the BFR and HL groups presented greater changes in the HbO concentration (ΔHbO), PT and FMLE scores than did the LL group (P < 0.05). The ΔHbO values in the primary motor cortex (M1), premotor cortex and supplementary motor area (PMC-SMA) of the affected hemisphere (AH) were considerably greater than those in the unaffected hemisphere (P < 0.05), whereas there was no difference in the dorsolateral prefrontal cortex (DLPFC). Changes in PT (mean r = 0.51 [range = 0.46–0.55]; P < 0.05) and FMLE scores (mean r = 0.54 [range = 0.48–0.62]; P < 0.05) were positively correlated with the AH M1 and PMC-SMA ΔHbO across groups.Conclusions and ImplicationsBy actively manipulating the M1 and PMC-SMA, LL-BFR and HL training yield comparable short-term improvements in central and peripheral performance after stroke. (Registry: Chinese Clinical Trial Registry; ChiCTR2400087378).