A Prelimbic Cortex-Thalamus Circuit Bidirectionally Regulates Innate and Stress-Induced Anxiety-Like Behavior.

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.

The radiological characteristics, tertiary lymphoid structures, and survival status associated with EGFR mutation in patients with subsolid nodules like stage I-II LUAD.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for the patients with subsolid nodule in early lung cancer stage is not routinely. The clinical value and impact in patients with EGFR mutation on survival outcomes is further needed to be elucidated to decide whether the application of EGFR-TKIs was appropriate in early lung adenocarcinoma (LUAD) stage appearing as subsolid nodules. MATERIALS AND METHODS: The inclusion of patients exhibiting clinical staging of IA-IIB subsolid nodules. Clinical information, computed tomography (CT) features before surgical resection and pathological characteristics including tertiary lymphoid structures of the tumors were recorded for further exploration of correlation with EGFR mutation and prognosis. RESULTS: Finally, 325 patients were enrolled into this study, with an average age of 56.8 ± 9.8 years. There are 173 patients (53.2%) harboring EGFR mutation. Logistic regression model analysis showed that female (OR = 1.944, p = 0.015), mix ground glass nodule (OR = 2.071, p = 0.003, bubble-like lucency (OR = 1.991, p = 0.003) were significant risk factors of EGFR mutations. Additionally, EGFR mutations were negatively correlated with TLS presence and density. Prognosis analysis showed that the presence of TLS was associated with better recurrence-free survival (RFS)(p = 0.03) while EGFR mutations were associated with worse RFS(p = 0.01). The RFS in patients with TLS was considerably excel those without TLS within EGFR wild type group(p = 0.018). Multivariate analyses confirmed that EGFR mutation was an independent prognostic predictor for RFS (HR = 3.205, p = 0.037). CONCLUSIONS: In early-phase LUADs, subsolid nodules with EGFR mutation had specific clinical and radiological signatures. EGFR mutation was associated with worse survival outcomes and negatively correlated with TLS, which might weaken the positive impact of TLS on prognosis. Highly attention should be paid to the use of EGFR-TKI for further treatment as agents in early LUAD patients who carrying EGFR mutation.

Disturbed Dynamic Brain Activity and Neurovascular Coupling in End-Stage Renal Disease Assessed With MRI.

BACKGROUND: Pathophysiological mechanisms underlying cognitive impairment in end-stage renal disease (ESRD) remain unclear, with limited studies on the temporal variability of neural activity and its coupling with regional perfusion. PURPOSE: To assess neural activity and neurovascular coupling (NVC) in ESRD patients, evaluate the classification performance of these abnormalities, and explore their relationships with cognitive function. STUDY TYPE: Prospective. POPULATION: Exactly 33 ESRD patients and 35 age, sex, and education matched healthy controls (HCs). FIELD STRENGTH/SEQUENCE: The 3.0T/3D pseudo-continuous arterial spin labeling, resting-state functional MRI, and 3D-T1 weighted structural imaging. ASSESSMENT: Dynamic (dfALFF) and static (sfALFF) fractional amplitude of low-frequency fluctuations and cerebral blood flow (CBF) were assessed. CBF-fALFF correlation coefficients and CBF/fALFF ratio were determined for ESRD patients and HCs. Their ability to distinguish ESRD patients from HCs was evaluated, alongside assessment of cerebral small vessel disease (CSVD) MRI features. All participants underwent blood biochemical and neuropsychological tests to evaluate cognitive decline. STATISTICAL TESTS: Chi-squared test, two-sample t-test, Mann-Whitney U tests, covariance analysis, partial correlation analysis, family-wise error, false discovery rate, Bonferroni correction, area under the receiver operating characteristic curve (AUC) and multivariate pattern analysis. P < 0.05 denoted statistical significance. RESULTS: ESRD patients exhibited higher dfALFF in triangular part of left inferior frontal gyrus (IFGtriang) and left middle temporal gyrus, lower CBF/dfALFF ratio in multiple brain regions, and decreased CBF/sfALFF ratio in bilateral superior temporal gyrus (STG). Compared with CBF/sfALFF ratio, dfALFF, and sfALFF, CBF/dfALFF ratio (AUC = 0.916) achieved the most powerful classification performance in distinguishing ESRD patients from HCs. In ESRD patients, decreased CBF/fALFF ratio correlated with more severe renal impairment, increased CSVD burden, and cognitive decline (0.4 < |r| < 0.6). DATA CONCLUSION: ESRD patients exhibited abnormal dynamic brain activity and impaired NVC, with dynamic features demonstrating superior discriminative capacity and CBF/dfALFF ratio showing powerful classification performance. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Association between neutrophil-to-high-density lipoprotein cholesterol ratio and metabolic dysfunction-associated steatotic liver disease and liver fibrosis in the US population: a nationally representative cross-sectional study using NHANES data from 2017 to 2020.

BACKGROUND: The neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) has emerged as a promising biomarker for assessing inflammation and lipid dysregulation. Increasing evidence indicates that these metabolic disturbances play a crucial role in the development of metabolic dysfunction-associated steatotic liver disease(MASLD). This study aims to investigate the association between NHR, MASLD, and liver fibrosis. METHODS: This cross-sectional study analyzed data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES). Weighted multivariate logistic regression models were used to investigate the association between NHR and both MASLD and liver fibrosis. Smoothed curve fitting and threshold effect analysis were performed to detect potential nonlinear relationships. Subgroup analyses were conducted to assess the consistency of these associations across different groups. RESULTS: The study involved 4,761 participants. We observed a significant positive association between NHR and MASLD (OR = 1.20, 95% CI: 1.09-1.31). However, there was no significant association between NHR and liver fibrosis (OR = 1.01; 95% CI: 0.94-1.09). The analysis of smoothed curve fitting and threshold effect revealed an inverted U-shaped relationship between NHR and MASLD, with a turning point at 5.63. CONCLUSION: Our findings indicate a positive correlation between elevated NHR levels and MASLD prevalence. However, we did not observe a significant association between NHR and liver fibrosis prevalence. Further prospective research is needed to validate these findings in a longitudinal setting.

Connectome-based predictive modeling predicts paranoid ideation in young men with paranoid personality disorder: a resting-state functional magnetic resonance imaging study.

Paranoid personality disorder (PPD), a mental disorder that affects interpersonal relationships and work, is frequently neglected during diagnosis and evaluation at the individual-level. This preliminary study aimed to investigate whether connectome-based predictive modeling (CPM) can predict paranoia scores of young men with PPD using whole-brain resting-state functional connectivity (rs-FC). College students with paranoid tendencies were screened using paranoia scores ≥60 derived from the Minnesota Multiphasic Personality Inventory; 18 participants were ultimately diagnosed with PPD according to the Diagnostic and Statistical Manual of Mental Disorders and subsequently underwent resting-state functional magnetic resonance imaging. Whole-brain rs-FC was constructed, and the ability of this rs-FC to predict paranoia scores was evaluated using CPM. The significance of the models was assessed using permutation tests. The model constructed based on the negative prediction network involving the limbic system-temporal lobe was observed to have significant predictive ability for paranoia scores, whereas the model constructed using the positive and combined prediction network had no significant predictive ability. In conclusion, using CPM, whole-brain rs-FC predicted the paranoia score of patients with PPD. The limbic system-temporal lobe FC pattern is expected to become an important neurological marker for evaluating paranoid ideation.

Static and Dynamic Characteristics of Functional Network Connectivity in Neurologically Asymptomatic Patients Undergoing Maintenance Hemodialysis: A Resting-State Functional MRI Study.

BACKGROUND: The characteristics of static functional network connectivity (sFNC) and dynamic FNC (dFNC) in neurologically asymptomatic patients undergoing maintenance hemodialysis are unknown. Elucidating these characteristics may improve our understanding of the mechanisms of neuropathological damage in these patients. PURPOSE: To explore the static and dynamic characteristics of FNC in neurologically asymptomatic patients undergoing maintenance hemodialysis and the relationship between FNC-related parameters with the neuropsychological scores and blood biomarkers. STUDY TYPE: Retrospective. POPULATION: A total of 23 neurologically asymptomatic patients undergoing maintenance hemodialysis and 25 healthy controls matched for age, sex, and years of education. FIELD STRENGTH/SEQUENCE: A 3.0 T MRI/functional MRI and three-dimensional-T1 structural imaging ASSESSMENT: Independent components; spatial map intensity; sFNC and dFNC strengths; and time attribute parameters (mean dwell time, fractional window, and number of transitions) were determined. Neuropsychological tests were performed. Blood biochemical tests were performed for the patients but not healthy controls. STATISTICAL TESTS: Chi-squared test, one-sample t-test, two-sample t-test, partial correlation analysis, and family-wise error and false discovery rate correction. P < 0.05 denoted statistical significance. RESULTS: Significant group differences in the strengths of sFNC and dFNC between networks were found. The sFNC strength between the visual and sensorimotor networks was significantly associated with the global cognitive function score (i.e. the Montreal Cognitive Assessment [MoCA]) (r = 0.606). The sFNC strength between the salience and default mode networks was significantly associated with anxiety scores (r = 0.458). In state 1, positive correlations were found between the mean dwell time and backward digital span task score (r = 0.562), fractional window and MoCA score (r = 0.576), and fractional window and backward digital span task score (r = 0.592). DATA CONCLUSION: Neurologically asymptomatic patients undergoing maintenance hemodialysis had defective sFNC and dFNC. Our results provide a new perspective on the mechanism of neuropathological damage in patients undergoing maintenance hemodialysis. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

PV network plasticity mediated by neuregulin1-ErbB4 signalling controls fear extinction.

Neuroplasticity in the medial prefrontal cortex (mPFC) is essential for fear extinction, the process of which forms the basis of the general therapeutic process used to treat human fear disorders. However, the underlying molecules and local circuit elements controlling neuronal activity and concomitant induction of plasticity remain unclear. Here we show that sustained plasticity of the parvalbumin (PV) neuronal network in the infralimbic (IL) mPFC is required for fear extinction in adult male mice and identify the involvement of neuregulin 1-ErbB4 signalling in PV network plasticity-mediated fear extinction. Moreover, regulation of fear extinction by basal medial amygdala (BMA)-projecting IL neurons is dependent on PV network configuration. Together, these results uncover the local molecular circuit mechanisms underlying mPFC-mediated top-down control of fear extinction, suggesting alterative therapeutic approaches to treat fear disorders.

Evaluation of diffuse glioma grade and proliferation activity by different diffusion-weighted-imaging models including diffusion kurtosis imaging (DKI) and mean apparent propagator (MAP) MRI.

PURPOSE: To evaluate two advanced diffusion models, diffusion kurtosis imaging and the newly proposed mean apparent propagation factor-magnetic resonance imaging, in the grading of gliomas and the assessing of their proliferative activity. METHODS: Fifty-nine patients with clinically diagnosed and pathologically proven gliomas were enrolled in this retrospective study. All patients underwent DKI and MAP-MRI scans. Manually outline the ROI of the tumour parenchyma. After delineation, the imaging parameters were extracted using only the data from within the ROI including mean diffusion kurtosis (MK), return-to-origin probability (RTOP), Q-space inverse variance (QIV) and non-Gaussian index (NG), and the differences in each parameter in the classification of glioma were compared. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of these parameters. RESULTS: MK, NG, RTOP and QIV were significantly different amongst the different grades of glioma. MK, NG and RTOP had excellent diagnostic value in differentiating high-grade from low-grade glioma, with largest areas under the curve (AUCs; 0.929, 0.933 and 0.819, respectively; P < 0.01). MK and NG had the largest AUCs (0.912 and 0.904) when differentiating grade II tumours from III tumours (P < 0.01) and large AUCs (0.791 and 0.786) when differentiating grade III from grade IV tumours. Correlation analysis of tumour proliferation activity showed that MK, NG and QIV were strongly correlated with the Ki-67 LI (P < 0.001). CONCLUSION: MK, RTOP and NG can effectively represent the microstructure of these altered tumours. Multimodal diffusion-weighted imaging is valuable for the preoperative evaluation of glioma grade and tumour proliferative activity.

Identification of proline, 1-pyrroline-5-carboxylate and glutamic acid as biomarkers of depression reflecting brain metabolism using carboxylomics, a new metabolomics method.

AIM: Depression is a psychiatric disease which is accompanied by metabolic disorder. Though depression has been widely studied, its metabolism is yet to be illustrated. We aimed to manifest the underlying mechanisms to diagnose depression. METHODS: One hundred thirty serum samples, including 65 patients and 65 healthy controls from different hospitals (training and validation cohorts), were recruited into the research. Sensitive Profiling for ChemoSelective Derivatization Carboxylomics (SPCSDCarboxyl) was applied to deeply hunt for the differential metabolites. Then, the serum, CSF, and hippocampus from depression rat models (CUMS group) were used to further confirm the results. Additionally, the co-occurrence between enzymes and biomarkers, as well as the combinatorial marker panel and the correlation of biomarkers among serum, CSF, or hippocampus were elucidated. RESULTS: Two hundred eight metabolites were identified from the sera of patients. Proline, 1-pyrroline-5-carboxylate (P5C), and glutamic acid could discriminate patients from healthy humans and were confirmed to be the potential biomarkers. After further validation through CUMS rats, proline, and P5C were enriched, while glutamic acid was depleted in the CUMS group. The co-occurrence analysis of enzymes and biomarkers indicated that they could be used for the diagnosis of depression. Moreover, the combinatorial marker panel and the correlation analysis of biomarkers between serum and CSF or between serum and hippocampus revealed that serum could be an alternative approach to directly reflect the potential physiological mechanisms and diagnose depression instead of brain samples. CONCLUSION: These integrated methods may facilitate the identification of biomarkers and help manifest the underlying mechanisms of depression.

Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy.

OBJECTIVE: Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota. DESIGN: Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed. RESULTS: We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders. CONCLUSION: Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.