It is shown that TLE patients have structural changes in two brain regions, the posterior cingulate cortex and dorsolateral prefrontal cortex, linked to slower processing speed and poorer working memory, which helps explain how microscopic gene patterns may contribute to large‐scale brain changes and cognitive difficulties in TLE.
Abstract
Abstract Objective Widespread cognitive deficits in temporal lobe epilepsy (TLE) are associated with macroscale brain structural changes. However, the correlation between the changes in the cortical morphological similarity of the TLE and gene expression remains unclear. Methods Structural magnetic resonance imaging (MRI) was collected from 31 TLE patients and 35 healthy controls to construct an individual‐level Morphometric INverse Divergence (MIND) network. Changes in cortical morphological similarity attributable to TLE and their cognitive correlates were assessed. Using a public transcriptional dataset, we linked TLE‐related structural changes to specific gene expression and biological pathways. Results TLE patients exhibited macroscopic morphological changes in the posterior cingulate cortex and dorsolateral prefrontal cortex, which were associated with cognitive impairments such as processing speed and working memory. Notably, TLE‐related MIND changes were spatially correlated with the expression of epilepsy‐associated genes, which were predominantly enriched in biological processes including cellular regulation and synaptic transmission. Significance MIND reveals macroscopic morphometric abnormalities of TLE. The microscopic transcriptional patterns have facilitated the understanding of the molecular mechanisms underlying cortical susceptibility. Plain Language Summary TLE patients often have memory and thinking problems. This study used brain scans to show that TLE patients have structural changes in two brain regions, the posterior cingulate cortex and dorsolateral prefrontal cortex. These changes are linked to slower processing speed and poorer working memory. Importantly, the brain changes were spatially related to the activity of TLE susceptibility genes involved in cell regulation and signal transmission between neurons. This helps explain how microscopic gene patterns may contribute to large‐scale brain changes and cognitive difficulties in TLE.
Background Temporal lobe epilepsy (TLE) is increasingly recognized as a network disorder, yet reported regional intrinsic neural activity alterations from resting-state fMRI studies remain spatially heterogeneous. This study aimed to determine whether these heterogeneous alterations converge onto a shared functional network and to characterize its normative transcriptomic and neurochemical correlates. Methods Using a coordinate-based network mapping approach (functional connectivity network mapping, FCNM), we delineated a common brain network functionally connected to regional intrinsic neural activity alterations reported across 20 published neuroimaging studies. The robustness of the resulting network was assessed in an independent cross-scanner validation connectome and across different seed sizes. We further characterized this TLE-related network by correlating its spatial topography with microscale gene expression data from the Allen Human Brain Atlas (AHBA) and with normative neurotransmitter receptor and transporter distributions derived from the JuSpace toolbox. Results Twenty studies comprising 345 foci of regional intrinsic neural activity alteration in TLE were included. The FCNM analysis revealed that heterogeneous regional alterations in TLE converged onto a common functional brain network. This network exhibited the greatest spatial overlap with the default mode network (DMN), while also showing substantial overlap with the limbic network (LN). Transcriptomic analysis revealed that the network’s topography was spatially correlated with gene expression profiles significantly enriched in adaptive immune response pathways, particularly antigen processing and presentation. Neurochemically, the TLE-related network exhibited a significant positive spatial correlation with the distribution of the 5-hydroxytryptamine receptor 1A (5-HT1A). Conclusion Our findings reconcile previously inconsistent reports of regional intrinsic neural activity alterations in TLE by demonstrating their convergence onto a shared brain network, primarily the DMN and LN. By linking this TLE-related network to specific normative transcriptomic and neurochemical signatures, we propose a multi-scale neurobiological framework for the disorder. These findings should be interpreted as spatial associations based on normative datasets rather than direct evidence of disease-specific molecular alterations. This framework reframes TLE from a collection of disparate regional changes toward a core network dysfunction with distinct molecular correlates, thereby opening new avenues for targeted, network-based interventions.
Liang-Liang Ma, Lingling Yang, Bao-Zhen Zhou et al.· Frontiers in Molecular Neuro...· 0 citations
A hypometabolic gradient is identified in TLE, which covaries with cytoarchitectonic organization, microstructural changes, and hippocampal-neocortical interactions and provides a biologically grounded framework for precise surgical planning, emphasizing that targeting severe hypometabolism may optimize prognosis.
J. Mo, F. Fadaie, J. Lam et al.· medRxiv· 0 citations
These findings provide robust evidence that multiscale MRI profiling can identify FCD signatures and contribute to in-vivo subtyping and the novel use of myeloarchitecture profiling and contextualization with macro-scale brain gradients provides new avenues to understand intracortical alterations and the embedding of FCD lesions into broader organizational patterns.
E. Sahlas, Judy Chen, Arielle Dascal et al.· bioRxiv· 0 citations
BACKGROUND
Primary angle-closure glaucoma (PACG) induces widespread central nervous system remodeling. However, the molecular, cellular, and neurochemical architectures driving macroscopic functional synchronization abnormalities in PACG remain unexplored.
METHODS
We employed a multiscale imaging-transcriptomics framework. Resting-state functional MRI was used to evaluate regional homogeneity (ReHo) in 44 PACG patients and 57 healthy controls. Voxel-wise ReHo alterations were spatially linked to whole-brain gene expression profiles from the Allen Human Brain Atlas, canonical cell-type-specific expression data, and multimodal PET neurotransmitter maps.
RESULTS
PACG patients exhibited decreased ReHo in the primary visual cortex and compensatory increases across widespread subcortical and higher-order associative cortices. These macroscopic ReHo alterations significantly covaried with a specific transcriptional profile characterized by the upregulation of stress response and extracellular matrix remodeling pathways, alongside the downregulation of synaptic transmission. Cellular enrichment analysis revealed that these transcriptomic signatures were highly specifically localized to the neurovascular and glial axis (astrocytes, endothelial cells, and oligodendrocytes) rather than neuronal lineages. Furthermore, the ReHo abnormality map was significantly coupled with the spatial distribution of multiple neurotransmitters, particularly dopamine, gamma-aminobutyric acid, and serotonin receptors.
CONCLUSION
This study provides multidimensional evidence that PACG-induced functional synchronization alterations are tightly constrained by underlying transcriptomic gradients, glial-vascular networks, and neurochemical architectures, reinforcing the conceptualization of PACG as a systemic central neurodegenerative disease.
Xian-Sheng Liu, Zirui Zheng, Cao Jie· NeuroReport· 0 citations
Two biologically distinct PD subtypes are identified with divergent molecular architecture and systemic neurodegeneration beyond conventional motor phenotyping beyond conventional motor phenotyping.
M. Bianco, Camilla Calomino, Maria Celeste Bonacci et al.· International Journal of Mol...· 0 citations
BACKGROUND
Schizophrenia is increasingly conceptualized as a disorder of large-scale brain network organization arising from atypical neurodevelopment. However, the relationship between early-emerging cortical folding patterns and the maturation of the structural connectome remains poorly understood.
METHODS
We introduced a sulcal morphology-centered framework that integrated normative modeling of sulcal width with diffusion-derived structural connectivity and cortical transcriptomics in a large multisite cohort (n=5,392; 377 schizophrenia). Deviations from normative folding patterns were mapped to the structural connectome and the Allen Human Brain Atlas.
RESULTS
Individuals with schizophrenia exhibited widespread sulcal widening (30/40 sulci), primarily in frontal, temporal, and occipital regions. Nodal vulnerability followed a clear topological principle: sulci with higher degree centrality (sulcal network hubs) showed disproportionately greater widening (pspin=0.02). Transcriptomic integration identified a gene expression profile explaining 56.5% of the spatial variance in sulcal abnormalities (p =0.049). This profile was significantly enriched for synaptic signaling and energy metabolism genes, showed adult-onset expression bias, and was associated with common cross-disorder genetic risk. Conversely, genes with the opposite spatial weight showed significant prenatal expression bias and enrichment for rare disruptive variants associated with autism spectrum disorder.
CONCLUSIONS
These findings demonstrate that aberrant cortical folding in schizophrenia is constrained by network topology and molecular architecture. By linking macroscopic folding to metabolic and synaptic pathways, this work establishes sulcal morphology as a mechanistically grounded biomarker that may help differentiate the neurodevelopmental trajectories of psychiatric disorders.
J. González-Peñas, H. Schnack, Carmen Rueda Hernández et al.· Biological Psychiatry· 0 citations
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