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.
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.
Background and Objective Schizophrenia (SCZ) is a severe mental disorder, and its pathological mechanism is closely associated with neuronal ferroptosis. Metformin (Met) has a well–defined anti–ferroptotic effect. Therefore, this study aimed to investigate whether Met improves neuronal injury and behavioral abnormalities in MK-801-induced SCZ-like mice by inhibiting neuronal ferroptosis. Methods Mice received dizocilpine (MK-801) to induce a SCZ-like phenotype. The behavioral activities of mice were evaluated using the open field test, Morris water maze test, and forced swim test. Neuronal injury in the hippocampus was evaluated by Nissl staining. The mitochondrial structure in the hippocampal tissue was observed using transmission electron microscopy. Ferroptosis was assessed by measuring the levels of glutathione (GSH), malondialdehyde (MDA), and Fe2⁺; lipid peroxidation; mitochondrial membrane potential; and p53, SLC7A11, and GPX4 expression in the hippocampus. Results Hippocampal neurons in MK–801–induced SCZ-like mice exhibited typical ferroptotic characteristics, including obvious neuronal injury; reduced mitochondrial membrane potential, GSH, SLC7A11, and GPX4 levels; and elevated lipid peroxidation, MDA, Fe2⁺, and p53 levels. Met intervention significantly reversed these ferroptosis–related indicators and inhibited hippocampal neuronal ferroptosis. Furthermore, Met alleviated MK-801-induced ferroptosis in HT22 cells. Behavioral results revealed that Met ameliorated behavioral abnormalities in the MK-801-treated mice. The ferroptosis inducer RSL3 partially reversed the behavioral improvements induced by Met. Further studies demonstrated that risperidone (RIS) or Met alone alleviated behavioral abnormalities in MK-801-induced SCZ-like mice, whereas their combined treatment produced greater improvement than either monotherapy. Conclusion Met can alleviate neuronal damage and cognitive dysfunction in MK–801–induced SCZ-like mice, at least in part, by inhibiting neuronal ferroptosis. Moreover, combined treatment with Met and RIS is more effective.
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.
