The prelimbic division (PrL) of the medial prefrontal cortex is implicated in the pathogenesis of generalised anxiety and chronic pain disorders. This study aimed to investigate the role of PrL N-methyl-D-aspartate (NMDA) receptor signalling in the comorbidity between neuropathic pain and psychiatric disorders. Male Wistar rats were exposed to the Enriched Polygonal Arena Snake-Evoked Panic Test involving confrontation by a constrictor snake. Neuropathy was induced by chronic constriction injury (CCI) of the ischiadicus nerve. Rats subjected to a sham surgical procedure were used as controls. Electrophysiological recordings were performed to assess PrL neuronal activity in CCI and sham-operated rats. Exposure to the threatening environment was conducted 21 days after surgery for 5 min following PrL cortical treatment with vehicle or LY235959 (2, 4, and 8 nmol). Neuronal activity in the PrL cortex was reduced in CCI rats. When confronted with a potential predator, threatened CCI rats exhibited increased emotional defensive responses accompanied by a decrease in mechanical paw withdrawal threshold (MWT), whereas sham-operated animals (without neuropathy) showed an increase in MWT following snake confrontation. Furthermore, NMDA receptor blockade in the PrL cortex with LY235959 reduced both defensive behaviours and mechanical allodynia in threatened animals. These findings suggest that NMDA receptor signalling in the PrL cortex plays a key role in the potentiation and maintenance of the comorbidity between anxiety/panic-like states and chronic neuropathic pain.

This exploratory study aimed to characterize dynamic functional network connectivity (dFNC) alterations in spinal cord injury-induced neuropathic pain (SCI-NP) and dFNC-related metrics as biomarkers for treatment guidance. A total of 23 SCI individuals with NP (SCI-NP), 20 SCI individuals without NP (SCI-N), and 20 healthy controls (HCs) were enrolled. SCI-NP individuals were predominantly chronic (≥12 months post-injury), whereas SCI-N individuals were predominantly acute/subacute (<12 months post-injury). Resting-state fMRI data were analyzed using independent component analysis (ICA) combined with a sliding-window approach to characterize dFNC. Recurring connectivity states were identified using clustering algorithms. Group differences were assessed using ANCOVA, adjusting for age and sex. P values were FDR-corrected for multiple comparisons. Spearman's correlation analyses examined associations between dFNC metrics and pain and clinical scores. Twenty-two whole-brain independent components were identified, and seven functionally meaningful components were selected for dFNC analysis, which revealed six distinct connectivity states. Compared with the SCI-N group, the SCI-NP individuals showed increased State 1 connectivity between the medial visual network (mVN) and sensorimotor network (SMN) and between the default mode network (DMN) and SMN (both p < 0.05, uncorrected), reflecting enhanced cross-modal sensory integration and maladaptive plasticity commonly observed in chronic neuropathic pain. In contrast, State 6 exhibited significantly reduced DMN-visual network (VN) connectivity in the SCI-NP group (p < 0.05, uncorrected), representing a low-interaction resting configuration that may reflect preserved functional segregation preferentially maintained in the SCI-N group. The SCI-NP individuals had shorter mean dwell time (p = 0.04, uncorrected) and fraction of time (p = 0.03, uncorrected) in State 6 relative to SCI-N individuals. None of these differences survived FDR correction.These findings indicate that SCI-NP individuals exhibit state-specific dynamic connectivity disturbances, including maladaptive hyperconnectivity involving sensorimotor, visual, and default mode networks. Metrics of dFNC-including state-specific connectivity and dwell time may serve as sensitive imaging features for guiding targeted rehabilitation strategies in SCI-NP.

Cerebral small vessel disease (CSVD) is a leading cause of vascular cognitive impairment (VCI), characteristically associated with gray matter (GM) loss. However, it remains unclear whether this GM loss exhibits regional interhemispheric asymmetry and how it relates to cognitive function. In this study, 56 CSVD patients and 56 demographically matched healthy controls were included, and structural MRI as well as cognitive and clinical data were collected. Voxel-based morphometry (VBM) and the GM Asymmetry Index (GMAI; calculated as (L-R)/(L + R), higher values indicate relatively greater left-sided GM) were performed using a study-specific symmetric template. Perivascular spaces were also estimated with a deep learning framework. Partial correlations were tested against multi-domain cognitive performance. Compared with controls, CSVD patients exhibited extensive GM reduction in the right superior and middle frontal gyri as well as in the left hippocampus and putamen. Regional GMAI analyses further suggested altered hemispheric GM loss, with leftward shifts (higher GMAI) in the middle temporal gyrus, superior frontal gyrus, and precuneus, and rightward shifts (lower GMAI) in the inferior temporal and fusiform gyri. Additionally, subcortical nuclei exhibited a corresponding leftward lateralization of perivascular space burden. Association analyses showed that right prefrontal volume was positively related to global cognitive scores, whereas left temporal asymmetry tracked cognitive decline. Of note, this right-dominant pattern in prefrontal-related regions is consistent with our activation likelihood estimation meta-analytic re-synthesis of prior VBM evidence and NeuroSynth mapping. Collectively, these findings suggest a distinct topographical vulnerability of the right hemisphere in CSVD and highlight GMAI as a neuroimaging marker for vascular cognitive decline.

Oligodendrocyte-enriched cortical organoids (OCOs) are a powerful platform for modeling oligodendrogenesis in a human cellular context. However, neuronal activity is impaired in conventional culture media, limiting assessment of neuronal function in conjunction with oligodendrocyte biology. To address this, we used a modified BrainPhys medium termed neuronal activity medium (NAM) and defined the optimal developmental window for NAM exposure to generate OCOs with robust neuronal activity (NAM-OCOs). Stage-specific exposure to NAM, prior to oligodendrocyte expansion, leads to enhanced structural complexity, as evidenced by increased organoid size, heightened synaptogenesis, and upregulation of transcripts associated with neuronal morphology. Further, NAM-OCOs display increased cellular heterogeneity, with GABAergic interneurons exhibiting enhanced inhibitory synaptic features and a more advanced developmental transcriptional state, while preserving oligodendrocyte development and oligodendrocyte-axon associations. Altogether, our studies demonstrate that stage-specific exposure to an activity-permissive environment enhances neuronal activity, establishing an OCO model which integrates neuronal activity with oligodendrocyte development and differentiation.

Fracture healing is generally viewed as a local tissue-regeneration process, although skeletal injury can also elicit systemic immune, vascular, and neural responses. We used a stratified analytical strategy combining reanalysis of public transcriptomic datasets, descriptive single-nucleus profiling, and an ordinary differential equation (ODE)-based simulation of fracture healing to examine possible associations between adverse bone phenotypes and Alzheimer disease. In the primary random-effects meta-analysis of three retained human bone-related binary cohorts, 72 prespecified panel genes were measured in all three cohorts; BMP10 and ANGPT1 had the smallest adjusted P values. In the separate GSE48350 whole-brain dataset, 6 of 84 mapped target genes had nominal P < 0.05. Descriptive single-nucleus RNA-sequencing analysis of GSE138852 showed within-dataset, cell-type-specific expression patterns across annotated neural cell populations. The eight-state ODE prototype, built on prespecified assumptions, generated fracture-healing trajectories and scenario-dependent model outputs. Tissue-expression and genetic analyses provided additional exploratory context for the selected genes. These analyses define a hypothesis-generating framework for studying skeletal-neural associations after fracture.

Lafora disease (LD, OMIM#254780) is a rare, devastating form of progressive myoclonus epilepsy characterized by the accumulation of aberrant insoluble forms of glycogen (polyglucosans) in the brain and peripheral tissues. Recently, we reported that neuroinflammation could be considered a second hallmark of LD in mouse models, since brains from LD mice present high levels of proinflammatory cytokines and chemokines, produced by reactive astrocytes and microglia. We also reported that the TNF and IL6/Jak2 signaling pathways were the main contributors to this neuroinflammation, and that there was an infiltration of peripheral CD4+ and CD8+ T-lymphocytes in their brain parenchyma, contributing to neuroinflammation. In this work, we explored whether there was any correlation between the reported inflammation in the brain of LD animals and changes in the populations of peripheral immune cells. By flow cytometry, we observed an upregulation of myeloid cells (CD11b +) along with a decrease in neutrophils (CD11b + Ly6G + high) and in B cells (B220 +). We hypothesize that these alterations may be due to compromised hematopoiesis, disrupted cell survival, or aberrant peripheral cell trafficking, possibly driven by the inflammatory condition and polyglucosan-induced metabolic stress in LD mice.

Chemotherapy has substantially improved cancer survival but is associated with adverse effects such as chemotherapy-induced cognitive impairment (CICI) and peripheral neuropathy (CIPN). Clinically relevant and reliable animal models of chemotherapy-induced neurotoxicity remain limited. We therefore investigated the behavioral and acute neurobiological effects of a clinically inspired multidrug chemotherapy regimen in female C57BL/6J mice. Following four weeks of treatment, thermoception was assessed using the tail flick test, while spatial learning, memory, and reversal learning were evaluated in the Morris water maze. Chemotherapy exposure produced marked and persistent reductions in body weight but did not significantly affect spatial acquisition or spatial memory. Selective treatment-related alterations were observed during early reversal learning, whereas group differences were no longer evident from the second reversal day onward. No statistically detectable treatment-related alterations in tail flick latency were observed. Exploratory immunohistochemical analyses of IBA1, MBP, and SHANK3 measures likewise revealed no significant group differences immediately after treatment. Together, these findings indicate that chemotherapy exposure did not produce a generalized spatial learning or memory deficit but was associated with selective alterations in cognitive flexibility during early adaptation to a relocated platform. The present model may therefore be useful for investigating subtle and temporally specific behavioral consequences of multidrug chemotherapy exposure.

Interpersonal neural synchrony (INS) is widely observed during spoken communication, yet the cognitive and neural processes through which it emerges remain incompletely understood. This review synthesizes evidence on the functional significance, representational organization, and neural implementation of INS and proposes a Hierarchical-Dynamic Integration Model (HDIM) of its formation. HDIM conceptualizes INS as the cross-brain manifestation of ongoing coordination between two interdependent processes: multilevel linguistic alignment and contextual-intentional integration. The hierarchical organization of linguistic alignment encompasses functionally differentiated yet interacting phonological/prosodic, lexical-syntactic, semantic, and higher-order representational levels, without assuming a fixed bottom-up sequence. Its dynamicity arises from recurrent processes of prediction, imitation, and adaptation that continuously regulate interpersonal coordination as communication unfolds. At the neural level, HDIM proposes that linguistic alignment engages distributed bilateral language systems, whereas contextual-intentional integration recruits coordinated activity across language-related and social-cognitive/mentalizing systems. The model yields four empirically testable predictions concerning partial dissociation among representational levels, functional dependencies across levels, temporally differentiated yet interacting regulatory processes, and partner-sensitive integration of linguistic and non-linguistic information. We further identify uneven empirical support across components of the model, together with causal and methodological challenges and limitations in its current scope. We conclude by outlining priorities for causal and interaction-specific testing, computational formalization, and evaluation of the model's boundary conditions and generalizability across communicative contexts.

Intermittent explosive disorder (IED) is characterized by impulsive outbursts of anger and violent behavior, involving dysregulation of limbic circuits underlying emotional and behavioral control. Neuronal nitric oxide synthase (nNOS)-derived nitric oxide may modulate serotonergic neurotransmission involved in anger regulation. Current treatments for IED are limited, and the therapeutic potential of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), a compound with anti-inflammatory and neuroprotective properties, has not been explored for its effects on anger. This study aimed to test the effect of plumbagin on anger-like behavior, focusing on its impact on the nitric oxide and serotonin systems in the amygdala. Herein, we assessed the effects of plumbagin on nNOS expression and nitric oxide levels in the central nucleus of the amygdala (CeA) of rats fasted for 24-hr and subjected to roller rotation and biting activity chambers. The effects of plumbagin, the nNOS inhibitor 7-nitroindazole (7-NI), and their combination were tested through intraperitoneal injections. Intra-CeA administration of 7-NI was also evaluated. nNOS expression, nitric oxide, and serotonin levels in the CeA were measured via immunohistochemistry, RT-qPCR, colorimetric assay, and HPLC, respectively. Rats showed increased roller rotation and biting activity, elevated nNOS expression and nitric oxide concentrations, and decreased serotonin levels in the CeA. The nNOS expression in the basolateral amygdala was unchanged. However, systemic administration of plumbagin, 7-NI, and their combination reversed these changes. Additionally, administration of 7-NI directly in the CeA attenuated the anger-like behavior. Plumbagin might reduce nitric oxide signaling in the CeA, which was accompanied by increased serotonin levels and reduced anger-like behavior.

Depression is a multifactorial neuropsychiatric disorder associated with chronic stress, disrupted neural oscillations and oxidative stress. The present study investigated whether vitamin B6 (Vit B6) enhances the antidepressant efficacy of venlafaxine (VEN) in a chronic unpredictable mild stress (CUMS)-induced model of depression-like behavior in C57BL/6 mice. A total of 72 mice, divided into two subsets, i.e., with and without EEG electrodes, were treated with VEN and Vit B6 alone and in combination for 28 days. The EEG electrode-bearing mice were tested for electrophysiological changes on day 29. Mice without EEG electrodes were tested for behavioral changes during days 29-32, followed by brain isolation on day 33 for biochemical analysis. The CUMS control demonstrated weight loss, anxiety-like activity in light/dark box, and depression-like behavior in sucrose splash, tail suspension and forced swim tests. Moreover, the EEG showed increased theta and reduced alpha and gamma activity. Further, CUMS resulted in marked elevation in brain oxidative stress in terms of elevated malondialdehyde (MDA) and reduced catalase activity. Monotherapy with VEN and Vit B6 partially mitigated these alterations, but the combined treatment restored behavioral performance in light/dark test with increased grooming in the sucrose splash test, while reducing immobility in the tail suspension and forced swim tests. Biochemically, the combined therapy reduced oxidative stress in the brain by reducing MDA and increasing catalase activity. Additionally, the EEG evaluation revealed the restoration of cortical oscillations, attenuation of theta hyperactivity, and increased alpha and gamma band power, indicating improved neuronal synchronization. The study's outcomes suggest that combining vitamin B6 with venlafaxine enhances its antidepressant effects, possibly by modulating oxidative stress and neural circuitry. This combination strategy might be a promising approach to improve therapeutic outcomes in stress-associated depressive disorder.