Xingyue Hu

Background: Obsessive‒compulsive disorder is a chronic, disabling mental disorder. While repetitive transcranial magnetic stimulation has emerged as a promising neuromodulation intervention for psychiatric disorders, its efficacy in treatment-naïve obsessive‒compulsive disorder patients remains understudied.

Background: Functional movement disorders (FMDs) are common within functional neurological disorders, yet understudied in Asian populations, particularly in China. Understanding FMDs across diverse cultural and ethnic contexts is crucial for elucidating disease mechanisms and optimizing treatment strategies. This study aimed to characterize FMDs among Chinese Han individuals and identify key prognostic factors. Methods: We enrolled 119 FMD patients from 22 centers across China. Data collected included demographics, clinical manifestations, neuropsychological assessments, and treatment details. Statistical analyses including ANOVA, chi‐square tests, logistic regression, and so on were used to analyze the clinical characteristics and potential prognostic predictors of FMD patients in China. Results: Patients showed a mean onset age of 45.3 years, female (58.8%), and a possible bimodal age distribution (peaks at 20–30 and ≥ 60 years). Mixed phenotypes (32.8%) and tremor (29.4%) were most common, with high rates of anxiety (61.3%) and depression (53.8%), and 38.7% clinical symptom remission. Physical therapy may be a potential protective factor (OR = 0.077, p < 0.001), while trauma history (OR = 7.863, p = 0.002) and higher baseline CGI scores (OR = 1.933, p = 0.002) predicted poorer outcomes. Conclusion: This first multi‐center study of FMDs in China highlights a potential tendency toward a bimodal distribution, female predominance, and abnormal scores on psychiatric scales. Notably, physical therapy represents a potential protective factor, while trauma history may be a risk factor. Our findings identify the clinical profile and prognostic factors of FMDs in the Chinese population, offering valuable insights for clinical practice and future research.

Neutrophils are among the earliest and most abundant immune cells infiltrating the brain following ischemic stroke, aggravating neuroinflammation through the formation of neutrophil extracellular traps (NETs). Pyroptosis, an inflammasome-mediated form of programmed cell death, occurs in post-stroke brain tissue and amplifies inflammation by releasing proinflammatory mediators, propagating the inflammatory cascade. However, the mechanistic link between NETs and pyroptosis remains unclear. This study demonstrated significantly elevated NET levels in arterial blood at the infarct site compared with venous or femoral arterial blood in stroke patients. A positive correlation was observed between the 24-h change in NIHSS score (NIHSS_baseline - NIHSS24h) and the difference in arterial citrullinated histone 3 (CitH3)-DNA (NETs) levels between the infarct site and femoral artery (NET_{sinfarct site} - NET_{sfemoral artery}). In a murine stroke model, NETs were detected in the brain parenchyma. Pharmacological inhibition of NET formation with GSK484, a selective protein-arginine deiminase type 4 antagonist, suppressed NET production, reduced absent in melanoma 2 (AIM2) inflammasome expression, and improved neurological outcomes in mice following stroke. AIM2 knockdown in brain tissue achieved similar neuroprotective effects. In both BV2 cells and stroke-induced mice, NETs triggered AIM2-dependent pyroptosis. These findings suggest that neutrophils in peripheral blood infiltrate the brain parenchyma to generate NETs, activating the AIM2 inflammasome in microglia and exacerbating stroke-induced brain injury through pyroptosis. Targeting NET formation or AIM2 inflammasome activation represents a potential therapeutic strategy for attenuating post-stroke neuroinflammation and secondary neuronal damage.

Background Large duplications or triplications involving the 13q33-34 chromosomal region, which encompass the COL4A1 and COL4A2 genes, have been reported in association with cerebral small vessel disease (CSVD) in a few patients. Herein, we report an additional case of CSVD linked to a duplication of COL4A1 and COL4A2 and provide a detailed summary of the associated clinical and MRI findings. Methods A patient with CSVD underwent detailed clinical and neuroimaging evaluations. Targeted next-generation sequencing (NGS) and copy number variation sequencing (CNV-seq) based on whole genome sequencing were used to identify the genetic basis of the disease. Results The patient experienced his first ischemic stroke at age 51. Cranial MRI revealed extensive acute and chronic lacunar infarcts and white matter hyperintensities across both cerebral hemispheres, with involvement of the anterior temporal lobe and the external capsule. Bilateral thalamic microbleeds were also noted. The clinical features and MRI findings are similar to those observed in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Targeted NGS and CNV-seq analysis identified a duplication in the region of chromosome 13, which included the COL4A1 and COL4A2 genes. Conclusions This case provides further evidence supporting the association of CNVs in COL4A1 and COL4A2 with CSVD. When hereditary CSVD is suspected and no micro-mutations in CSVD-associated genes are identified, CNV analysis of the 13q region should be considered.

Background Recently, mutations affecting a microRNA-29 (miR-29)-binding site in the 3’-untranslated region of COL4A1 have been identified as a cause of pontine autosomal dominant microangiopathy with leukoencephalopathy (PADMAL) and hereditary multi-infarct dementia (hMID) of the Swedish type. PADMAL and Swedish hMID are extremely rare disorders with no de novo mutations previously reported. Methods A patient with cerebral small vessel disease underwent comprehensive neurological examinations, neuroimaging analysis, and whole-exome sequencing. Co-segregation analysis was performed on his family, and haplotype analysis was conducted to confirm the biological relationship. Results The patient experienced recurrent ischemic strokes since age 32. Brain MRI showed multiple acute and chronic lacunar infarcts in the pons and bilateral cerebral hemispheres. A previously reported pathogenic mutation of PADMAL, COL4A1 c.*32G > T, was identified and found to be absent in both parents. Identity testing confirmed the biological parentage, classifying the c.*32G > T variant as a de novo mutation. Conclusions The discovery of PADMAL in a patient with a de novo mutation indicates that COL4A1 gene miR-29-binding site variant sequencing should be considered in patients exhibiting typical clinical and MRI features, even if there is no family history.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant inherited vascular disorder that can involve multiple organs, thus can be associated with so many clinical departments that proper screening and diagnosis of HHT are needed for providing better management of both patients and their family members. We present a 58-year-old female patient with recurrent paradoxical brain embolism due to HHT. She received aspirin therapy and underwent pulmonary arteriovenous malformation embolization, recovering well and discharged 3 days postoperatively. Though ischemic stroke caused by HHT-induced vascular disorders has been reported, our patient presented with both recurrent paradoxical brain embolisms and radiologic findings of bilateral globus pallidus manganese deposition at the same time, a combination rarely reported. We also review the literature on the clinical features and management of HHT for prompt diagnosis of this genetic disease behind paradoxical embolism. When patients with ischemic stroke, especially recurrent ischemic stroke, have combined arteriovenous malformations (AVMs) in single or multiple organs, or clues for AVMs like manganese deposition in globus pallidus, genetic diseases such as HHT may be the reason for ischemic stroke and shouldn’t be missed in the evaluation of embolic sources.

Background: Subdural hematoma (SDH) is a potentially life-threatening complication in patients with spontaneous intracranial hypotension (SIH). Though bed rest is the basis of conservative treatment, no clear evidence exists regarding the association between bed rest and the later complication of SDH in these patients.Objectives: This study aimed to evaluate the association between bed rest and SDH development in patients with SIH. StudyDesign: A retrospective study was conducted from March 2013 through December 2019. Four hundred twenty adult patients diagnosed with SIH were enrolled. Clinical presentations and radiographic findings were recorded. The cumulative duration of bed rest in hours was used to measure the bed rest length. The clinical outcomes during follow-up were assessed.Methods: Categorical data were compared using ?(2) tests; continuous data were compared using the Mann-Whitney U test or Kruskal-Wallis test. A backwards stepwise Cox proportional hazard regression model adjusted with confounders which differed between SDH and non-SDH in univariate analysis was used to estimate the risk of cumulative duration of bed rest for SDH. A stratified Cox regression was performed to exclude the effect of the treatment algorithm.Results: Of the 420 patients with SIH, 88 (21%) were in the SDH Group and 332 (79%) were in the non-SDH (NSDH) Group. The cumulative duration of bed rest in hours was a protective factor for SDH in SIH (Hazard Ratio [HR] = 0.997; P < 0.001). A stratified Cox regression analysis showed that the cumulative duration of bed rest remained a protective factor for SDH both in patients who received conservative treatment before admission (HR = 0.997; P < 0.001) and in those who did not (HR = 0.996; P = 0.061). Age (HR = 1.029, 95% CI, 1.009-1.050; P = 0.004) and orthostatic headache (HR = 4.770, 95% 95% CI, 2.177-10.450; P < 0.001) were risk factors for SDH in SIH. The clinical outcomes, including length of hospital stay, epidural blood patch (EBP) therapy, and repeated EBP therapy, were higher in the SDH Group. The revisit rate was similar between the 2 groups. Limitations: Retrospective studies are susceptible to different radiological procedures and therapeutic strategies. A bed rest score based on a patient's memory is susceptible to recognition and reporting bias. This is a single-center study and the sample size is not large. The validity of the bed rest scale has not been previously evaluated in any other study.Conclusions: Bed rest was a protective factor for SDH in patients with SIH. With more time and proper treatment, patients with SIH who have an SDH can achieve good prognosis in the long term.

Backgrounds: Botulinum toxin type A (BoNT/A) is extensively applied in spasticity and dystonia as it cleaves synaptosome-associated protein 25 (SNAP25) in the presynaptic terminals, thereby inhibiting neurotransmission. An increasing number of randomized clinical trials have suggested that glabellar BoNT/A injection improves depressive symptoms in patients with major depressive disorder (MDD). However, the underlying neuronal circuitry of BoNT/A-regulated depression remains largely uncharacterized. Results: Here, we modeled MDD using mice subjected to chronic restraint stress (CRS). By pre-injecting BoNT/A into the unilateral whisker intrinsic musculature (WIM), and performing behavioral testing, we showed that pre-injection of BoNT/A attenuated despair- and anhedonia-like phenotypes in CRS mice. By applying immunostaining of BoNT/A-cleaved SNAP25 (cl.SNAP25₁₉₇), subcellular spatial localization of SNAP25 with markers of cholinergic neurons (ChAT) and post-synaptic membrane (PSD95), and injection of monosynaptic retrograde tracer CTB-488-mixed BoNT/A to label the primary nucleus of the WIM, we demonstrated that BoNT/A axonal retrograde transported to the soma of whisker-innervating facial motoneurons (wFMNs) and subsequent transcytosis to synaptic terminals of second-order neurons induced central effects. Furthermore, using transsynaptic retrograde and monosynaptic antegrade viral neural circuit tracing with c-Fos brain mapping and co-staining of neural markers, we observed that the CRS-induced expression of c-Fos and CaMKII double-positive neurons in the ventrolateral periaqueductal grey (vlPAG), which sent afferents to wFMNs, was down-regulated 3 weeks after BoNT/A facial pre-administration. Strikingly, the repeated and targeted silencing of the wFMNs-projecting CaMKII-positive neurons in vlPAG with a chemogenetic approach via stereotactic injection of recombinant adeno-associated virus into specific brain regions of CRS mice mimicked the antidepressant-like action of BoNT/A pre-treatment. Conversely, repeated chemogenetic activation of this potential subpopulation counteracted the BoNT/A-improved significant antidepressant behavior. Conclusion: We reported for the first time that BoNT/A inhibited the wFMNs-projecting vlPAG excitatory neurons through axonal retrograde transport and cell-to-cell transcytosis from the injected location of the WIM to regulate depressive-like phenotypes of CRS mice. For the limited and the reversibility of side effects, BoNT/A has substantial advantages and potential application in MDD.

Background and purpose: Neutrophil extracellular traps (NETs) are special web-like structures that can be generated in both infectious and noninfectious diseases. Previous studies showed that reactive oxygen species (ROS) were crucial in the formation of NETs (NETosis). The purpose of this study is to evaluate the effect of (+)-borneol, an antioxidant, on NETosis.Methods: Human neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) to induce NETosis in vitro. Neutrophils treated with (+)-borneol at three different time points (−30 min, 0, and 30 min) associated with PMA stimulation were used to examine the effect of (+)-borneol on the formation of NETs. The ROS generation of neutrophils was also measured to explore the potential mechanism of the inhibitory effect of (+)-borneol on NETosis.Results: (+)-Borneol pretreatment inhibited NETosis induced by PMA. Immunofluorescence staining visualized and confirmed the inhibitory effect. (+)-Borneol inhibited the burst of ROS in neutrophils caused by PMA. Suppressing NADPH oxidase or protein kinase C (PKC) eliminated the effect of (+)-borneol on NETosis. Moreover, inhibiting Toll-like receptor 2 (TLR2) led to increased NETosis which can be inhibited by (+)-borneol.Conclusion: (+)-Borneol decreases the ROS level in activated neutrophils and inhibits NETosis triggered by PMA stimulation in vitro. (+)-Borneol therapy may be effective in some NET-dependent conditions.