Prediction error (PE) signals support feedback evaluation and adaptive updating, and are closely linked to medial frontal theta dynamics, particularly within dorsal anterior cingulate cortex (dACC)-centered networks. However, evidence linking these oscillatory mechanisms to the modulation of PE encoding remains limited. Here, we tested whether theta-band modulation of a dACC-centered medial frontal network altered trial-level PE encoding during food-reward processing. In a single-blind, sham-controlled pre–post design, individuals with elevated food addiction symptoms performed a food incentive-delay task while undergoing electroencephalographic recordings combined with theta-band temporal interference stimulation. Single-trial analyses revealed that feedback-related negativity (FRN) amplitudes varied as a function of both behavioral and model-derived prediction errors. Critically, theta-band modulation altered FRN–PE coupling, with the effect most pronounced for unfavorable outcomes, whereas anticipatory activity remained unchanged. These findings support the hypothesis that theta-band modulation can alter feedback-related PE encoding within this population and task context.
As an integrative center of the limbic system, the amygdala and its subfields participate in diverse neural functions and demonstrate heterogeneous structural changes in various neurological disorders. In this study, three-dimensional T1-weighted MRI data from 22,258 healthy participants were analyzed using normative modeling to establish normative references for the volumes of the amygdala and its subfields. These models elucidated the developmental and aging curves of the amygdala and identified distinct ages at peak volume across subfields, ranging from 24.6 to 43.7 years. Based on these references, individual centile scores were calculated for 4132 patients with mild cognitive impairment, Alzheimer’s disease, Parkinson’s disease, cerebral small vessel disease, multiple sclerosis, and neuromyelitis optica spectrum disorder. These centile scores not only captured disease-specific deviation patterns of the amygdala subfields but also demonstrated utility in disease classification. Moreover, the centile scores correlated with clinical measures of cognitive function, emotional state, and motor performance across disorders. These findings suggest that normative references of the amygdala subfields provide insights into cross-disease alteration patterns and offer potential neuroimaging biomarkers to aid differential diagnosis and clinical assessment.
Cystatin C (CysC) is emerging as a key regulator and intercellular signaling mediator within the neuro-glial-vascular unit (NGVU). This review comprehensively examines its multifaceted roles across NGVU components, detailing mechanisms by which CysC preserves blood–brain barrier integrity, modulates neuroinflammation, and influences pathological protein aggregation. Rather than providing a merely descriptive catalogue, we emphasize its context-dependent nature. In cerebrovascular and neurodegenerative diseases, CysC exhibits functional duality along the neuron–glia axis, either restraining or perpetuating inflammation and proteinopathy depending on cellular context and disease stage. Similarly, along the endothelial–oligodendrocyte precursor cell crosstalk, its coordination of angiogenesis and myelination may shift from protective to detrimental under chronic hypoperfusion. We evaluate its dual utility as a clinical biomarker and therapeutic target, addressing challenges in brain delivery, target selectivity, and safety. This integrative synthesis provides a critical perspective on unresolved controversies and future research priorities regarding CysC in neurological disorders.
Aging is a risk factor for neurodegenerative disorders, but the molecular link between neuronal aging and neurodegeneration remains unclear. Huntington's disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms. Striatal medium spiny neurons (MSNs) are mainly affected in HD, but how aging contributes to MSN degeneration remains uncertain. Using directly converted MSNs from fibroblasts of HD patients (HD-MSNs), we studied age-related pathological features, including neuronal cell death, mutant huntingtin (mHTT) aggregation, and DNA damage in HD. In this study, through transcriptomic analysis of longitudinally aged MSNs and HD-MSNs, we identified four upstream regulators, NFKB1, SOD1, IRF3, and REST, that modulate downstream gene expression in aged MSNs. Among these, knocking down NFKB1 significantly reduced HD pathologies in HD-MSNs, while overexpressing NFKB1 reversed these protective effects. Overall, these results identify NFKB1 as a key age-associated upstream regulator whose downregulation confers neuronal resilience and is a potential therapeutic target in HD.
