Xiquan Hu

Background: Autophagy-lysosomal dysfunction contributes to lipid droplet (LD) accumulation, which drives pathological progression in Alzheimer's disease (AD). Exercise is reported to restore autophagy-lysosomal function and attenuate cognitive impairment in AD, but its regulation of LD deposition remains unknown. Methods: 5×FAD transgenic mice underwent a three-month exercise intervention. Cognitive and emotional behaviors were assessed using the Morris water maze, novel object recognition, and open field test. LD deposition was evaluated by oil red O and BODIPY staining. Proteomic sequencing was performed to identify proteins affected by exercise. Pathological changes were examined by immunofluorescence, western blotting, and transmission electron microscopy. Intracerebroventricular injection of AAV was used to overexpress or knock down microglial TMEM9 to investigate the mechanisms by which physical exercise affects behavior and pathology in AD. In vitro, BV2 cells were cultured and incubated with oligomeric amyloid-β (oAβ), with or without oleic acid to induce LD formation. Chloroquine and rapamycin, which regulate autophagy-lysosomal function, were used to examine the effects of LDs on mitochondrial integrity under glucose deprivation conditions. Lentiviral or plasmid transfection was used to explore the key role of TMEM9 in regulating lipophagy, and the interaction between TMEM9 and ATP6AP1 was detected by co-immunoprecipitation. Clinically, plasma TMEM9 and ATP6AP1 levels in AD patients were measured by ELISA, and receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance. Results: Exercise mitigated cerebral LD deposition through enhanced lipophagy, preserving mitochondrial integrity and attenuating cognitive decline. Mechanistically, exercise suppressed microglial TMEM9 expression, restoring LD degradation. Tmem9 downregulation facilitated LKB1 lysosomal translocation, activating AMPK signaling. In vitro, oleic acid-induced LDs preserved mitochondrial membrane potential and increased ATP production in BV2 microglia under glucose deprivation and oAβ exposure. Tmem9 overexpression exacerbated lipophagy impairment and mitochondrial dysfunction, whereas Tmem9 knockdown enhanced lipophagy and cytoprotection. Aβ clearance was negatively regulated by TMEM9. Clinically, AD patients exhibited characteristic Aβ deposition and glucose hypometabolism, with plasma TMEM9 levels strongly correlating with p-tau217 progression. Plasma TMEM9 and the TMEM9/ATP6AP1 ratio emerged as potential AD diagnostic biomarkers (AUC=0.791 and 0.853, respectively). Conclusion: These findings establish exercise-induced TMEM9 inhibition as a novel therapeutic strategy targeting lipidostasis to combat AD progression.

Objective: This study aimed to evaluate the efficacy of brain‐computer interface (BCI)‐controlled exoskeleton training on lower‐limb functional recovery, psychological outcomes, and neural plasticity in patients with spinal cord injury (SCI). Methods: We conducted a single‐center, prospective, randomized, single‐blind pilot trial (ChiCTR2300074503) including 21 patients with SCI. Participants were randomized to a BCI‐exoskeleton group (B + E, n = 10) or an exoskeleton‐only group (E, n = 11) for lower‐limb training. Both groups received conventional rehabilitation plus 30 minutes of training, 6 days per week, for 4 weeks. The primary outcomes were Walking Index for Spinal Cord Injury II (WISCI II) scoring. Secondary outcomes included Lower Extremity Motor Score (LEMS), Spinal Cord Independence Measure version III (SCIM III), International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR‐SCIFRS), 10‐Meter Walk Test (10MWT), 6‐Minute Walk Test (6MWT), and Hospital Anxiety and Depression Scale (HADS). Cortical plasticity was assessed by electroencephalography (EEG) and magnetic resonance imaging (MRI). Results: The B + E group showed a significant improvement in LEMS ( p = 0.003), whereas both groups improved in IANR‐SCIFRS ( p < 0.05). The B + E group demonstrated significant within‐group gains in walking speed (10MWT, p < 0.001) and endurance (6MWT, p = 0.031), although between‐group differences were not significant. Compared with the E group, the B + E group had larger reductions in HADS scores ( p = 0.003). EEG analyses revealed stronger μ/β desynchronization and increased network efficiency, whereas MRI showed no structural changes. Interpretation: BCI‐controlled exoskeleton training enhanced motor function, walking performance, and depressive symptoms more than exoskeleton training alone, likely through cortical reorganization. Extended training may further consolidate these benefits, supporting BCI‐exoskeleton integration as a promising rehabilitation strategy for SCI. ANN NEUROL 2026;99:1124–1138

Recent advances in transcranial ultrasound stimulation (TUS) pulsed at 40 Hz have demonstrated the potential to ameliorate cognitive deficits in mouse models of Alzheimer’s disease. However, technical barriers remain as general anesthesia is required for mice, which restricts the accurate elucidation of biological mechanisms and behavioral effects under awake physiological conditions. Here, we report a wearable, free-moving ultrasound stimulation system that delivers TUS pulsed at 40 Hz to female 5xFAD transgenic mice to systematically evaluate the behavioral outcomes and underlying mechanistic pathways. Among the treatment groups, a 14-d regimen at an acoustic intensity of 2.14 W/cm ² yielded the optimal cognitive outcome in Alzheimer’s disease mice, which was consistently verified across Y-maze and Morris water maze tests. Additionally, this group showed reduced Aβ plaque deposition and increased plaque-associated microglial activity. Furthermore, enhanced gamma oscillations in the hippocampus were detected following treatment. RNA sequencing revealed modulation of innate immune and inflammatory pathways. Corresponding molecular analysis demonstrated a marked down-regulation in RIPK1 , phosphorylated NF-κB , and necroptosis markers, alongside reductions in key pro-inflammatory cytokines ( IL-6 , IL-1β , and TNF-α ). Collectively, our findings suggest that the cognitive improvement observed after treatment with TUS pulsed at 40 Hz may be linked to the modulation of neuroinflammatory and necroptotic pathways, possibly involving RIPK1 / NF-κB signaling.

Accurately assessing and detecting residual awareness in patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state (MCS) remains significant challenges. We aimed to investigate the whole-brain and network characteristics based on resting-state functional near-infrared spectroscopy (fNIRS) in patients with disorders of consciousness (DOC). Additionally, we sought to identify specific biomarkers to differentiate MCS from VS/UWS and evaluate their classification performance. For DOC patients, the Coma Recovery Scale-Revised (CRS-R) assessment was conducted, and all participants underwent a 5-min resting-state fNIRS recording. Functional connectivity features based on region of interest, channel, and network analyses were calculated to explore significant differences between healthy adults and DOC, as well as MCS patients and VS/UWS patients. Pearson correlation analysis was then performed to examine the relationship between fNIRS features and CRS-R scores. Receiver operating characteristic analysis and linear support vector machines were employed to assess classification performance. We included 52 DOC patients (n = 26 for MCS and n = 26 for VS/UWS) and 49 healthy controls in the final analysis. Compared to healthy controls, DOC patients showed widespread impairments in both whole-brain and network-based functional connectivity. Additionally, VS/UWS patients exhibited significantly reduced functional connectivity compared to MCS patients, including connectivity between the prefrontal cortex, premotor cortex, sensorimotor regions, and Wernicke’s area (p < 0.01), as well as within auditory, frontoparietal, and default mode network (p < 0.05). Some of these connectivity differences were found to correlate with the total CRS-R score, as well as the visual, motor, and verbal subscale scores (p < 0.05). In terms of classification performance for distinguishing MCS from VS/UWS patients, the functional connectivity between channel 4 and channel 29 showed the highest accuracy among whole-brain features, with a classification accuracy of 76.92% and an area under the curve (AUC) of 0.818. Among the resting-state network features, the auditory network exhibited the highest accuracy, achieving 73.08% with an AUC of 0.803. fNIRS could effectively detect abnormal brain network functional connectivity in DOC patients and could provide valuable insights for differentiating MCS and VS/UWS patients.

Background: Discourse impairment significantly affects communication effectiveness. For a comprehensive understanding of pathological discourse behaviour, documentation of typical discourse production is essential. However, reference data from Mandarin speakers have not been previously available. Aims: This study sought to: (1) develop preliminary reference data for the Mandarin‐speaking population to characterise discourse performance elicited by the picnic scene picture description task from the Western Aphasia Battery (WAB) and explore the relationship between demographic variables (i.e., age, education, gender) and discourse performance; (2) examine how persons with anomic aphasia differ from healthy adults on discourse measures. Method and Procedure: We recruited 207 healthy Mandarin‐speaking adults to establish the reference data. The picture description task of the WAB was administered to all participants. Effects of age, gender, and years of education on discourse performance were examined. Additionally, the microstructural discourse variables of 11 individuals with anomic aphasia were compared with those of 11 age‐, gender‐, and education‐matched healthy adults. Outcomes and Results: Preliminary reference data were obtained. Findings in healthy controls revealed statistically significant effects of age and education on syntactic complexity (mean length of utterance) and communication efficiency (correct information units per minute). Age significantly impacted transmission effectiveness (percentage of correct information units). Education level significantly influenced lexical diversity (the moving‐average type‐token ratio). Individuals with anomic aphasia performed more poorly than healthy controls on most discourse measures. Conclusions and Implications: To our knowledge, this study provides the first reference data for analysing discourse production in the WAB picture description task among the Mandarin‐speaking population. Persons with anomic aphasia underperformed healthy controls on most of the discourse measures. The findings contribute to improving microstructural evaluation of discourse impairment in clinical settings, particularly for persons anomic with aphasia. WHAT THIS PAPER ADDS: What is already known on the subject Discourse analysis is becoming an area of growing interest. Microstructural measures reveal discourse deficits in aphasia that standardised tests may fail to detect. However, the absence of reference data in Mandarin for healthy adults presents a notable constraint that prevents the in‐depth assessment of discourse in clinical settings. What this paper adds to the existing knowledge This study established preliminary reference data for the Mandarin‐speaking population using the WAB picnic scene description task while examining the influence of demographic factors (age, education, gender) on discourse performance. The study compared discourse measures between healthy controls and persons with anomic aphasia. Findings demonstrated that age and education significantly influenced discourse performance in healthy participants. Significant differences were observed in most discourse measures between the control and anomic aphasia groups. What are the potential or actual clinical implications for this work? The reference data from this study enables clinicians to better understand and interpret the discourse abilities of persons with aphasia by identifying both specific measures and the extent to which these individuals exhibit discourse impairments compared to healthy controls. Microstructural discourse measures can be employed to compare the discourse abilities of healthy controls and individuals with aphasia.

We explore cerebral reorganization in patients with spinal cord injury (SCI) using structural and functional magnetic resonance imaging (fMRI) to investigate regions relative to the prognosis of sensory-motor ability within SCI patients. Thirty right-handed SCI patients and 30 gender- and age-matched healthy controls (HCs) were included. Gray matter volume (GMV) changes in SCI patients were observed and the amplitude of low-frequency fluctuations (ALFF) values within regions with significant differences in GMV were calculated. These altered gray matter regions were used as regions of interest (ROIs) for functional connectivity (FC) analysis to detect related functional changes. Additionally, the Granger causality analysis (GCA) was used to study alterations in effective connectivity (EC) within the brain. The potential association between all the above MRI values with the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) scores was investigated through partial correlation analysis. SCI patients showed reduced GMV in bilateral putamen compared to the HCs. Meanwhile, significant lower FC were found between the bilateral putamen and the right superior parietal gyrus, whereas significant higher FC were found between the right putamen and the bilateral precuneus in patients with SCI. GCA revealed enhanced EC from the left precuneus to the right putamen. The degree of functional alterations with the putamen might hint at the level of sensory-motor function of patients following SCI. When multisensory integration was decreased due to disease, the increased connection between the precuneus and the putamen might serve a role in SCI recovery by increasing visuospatial integration.

JOURNAL/nrgr/04.03/01300535-202606000-00053/figure1/v/2026-04-16T195327Z/r/image-tiff White matter injury is a key factor impacting stroke recovery. Physical exercise can promote white matter repair. Immune cells, especially regulatory T (Treg) cells, contribute to strengthening white matter integrity, yet little is known about the underlying mechanism. To examine this, we established a transient middle cerebral artery occlusion male mouse model. We found that physical exercise elevated brain Treg cells, thereby enhancing neurological recovery, reducing neuroinflammation, promoting myelin debris clearance, and accelerating white matter repair. Depletion of Treg cells caused a decrease in these positive effects of physical exercise. Mechanistically, the rise in osteopontin triggered by physical exercise is dampened when Treg cells are depleted. In addition, Treg-conditioned medium reduced oxygen–glucose deprivation/re-oxygenation-induced microglial inflammation and enhanced phagocytosis, which could be blocked by osteopontin antibodies. Importantly, although Treg infusion could mimic the protective effects of physical exercise, osteopontin blockade partially countered the effects of physical exercise and Treg cells. Finally, our sequencing data revealed a marked upregulation of C–X–C motif chemokine ligand 12 (CXCL12) mRNA expression subsequent to physical exercise, which was confirmed at the protein level. Stimulation of Treg cells with stroke brain lysates increased C–X–C motif chemokine receptor 4 (CXCR4) expression, indicating a potential role for the CXCL12–CXCR4 axis in recruiting Treg cells. These findings suggest that physical exercise promotes white matter repair after ischemic stroke by Treg cells.