Brain Research Bulletin[JOURNAL]
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200 papers
High-frequency rTMS applied to the right hemisphere promotes aphasia recovery and brain microstructural changes in subacute stroke.
Yu Q, Sun Y, Ju X … +3 more , Liu K, Feng Q, Xu X
Brain Res Bull · 2026 May · PMID 41912097 · Publisher ↗
BACKGROUND: The role of the right hemisphere in post-stroke aphasia (PSA) remains one of the key controversies in contemporary neuroscience. While accumulating evidence has demonstrated the clinical potential of repetiti...
BACKGROUND: The role of the right hemisphere in post-stroke aphasia (PSA) remains one of the key controversies in contemporary neuroscience. While accumulating evidence has demonstrated the clinical potential of repetitive transcranial magnetic stimulation (rTMS) for the management of PSA, consensus regarding optimal stimulation strategies has not yet been established. The present study aimed to investigate the therapeutic effects of high-frequency rTMS applied to the right hemisphere in patients with PSA. METHODS: Sixty-one patients with PSA were enrolled in this study. Language function was assessed before and following the rehabilitation regimen. Among the participants, 32 received adjunctive rTMS in combination with language therapy, while the remaining 29 received language therapy alone. Microstructural changes in the bilateral neural pathways were assessed using diffusion tensor imaging (DTI). Correlation analyses were conducted to investigate the potential relationships between the DTI indices of tract integrity and improvements in language performance. RESULTS: High-frequency rTMS significantly improved language performance across language domains (Δ: speech, 28.51%; comprehension, 25.08%; repetition, 24.25%; naming, 19.36%; and fluency, 28.48%). Notably, microstructural integrity was significantly enhanced specifically in the right-hemispheric tracts, including the arcuate fasciculus (Δ FA = 3.53%), the second branch of the superior longitudinal fasciculus (Δ FA = 5.60%), the inferior frontal-occipital fasciculus (Δ FA = 5.50%), the frontal aslant tract (Δ FA = 5.60%), and the extreme capsule (Δ FA = 5.58%), with no comparable changes in the left hemisphere. Moreover, multiple linear regression analyses revealed that these structural changes in the right tracts were significantly associated with language improvement. CONCLUSIONS: High-frequency rTMS applied to the right hemisphere facilitates the recovery of PSA, potentially driven by the involvement of right-hemispheric neural tracts, highlighting the therapeutic potential of right hemisphere-targeted rTMS as a viable rehabilitation strategy for PSA during the early stage of stroke.
Identification of potential drug targets for delirium from genetic insights: A Mendelian randomization study.
Geng YN, Dong X, Liu Y … +1 more , Dong Y
Brain Res Bull · 2026 May · PMID 41905541 · Publisher ↗
Delirium, a prevalent acute cerebral disorder, currently lacks effective pharmacological interventions despite its substantial clinical impact. Leveraging genetic insights represents a valuable approach for advancing the...
Delirium, a prevalent acute cerebral disorder, currently lacks effective pharmacological interventions despite its substantial clinical impact. Leveraging genetic insights represents a valuable approach for advancing therapeutic discovery. This study used Mendelian randomization (MR) to systematically screen druggable genes and prioritize genetic targets for delirium. Among 5883 druggable genes examined, we identified 11 genes with causal evidence supporting their role in delirium susceptibility, of which 5 were further supported by summary-data-based MR (SMR) and HEIDI tests. PSORS1C3 demonstrated significant genetic colocalization with delirium risk (PP.H4 = 0.746), strongly implicating its potential causal role. We also conducted an exploratory two-step MR mediation analysis and found that the genetically proxied expression of POU5F1 and PSORS1C3 may reduce delirium risk potentially by regulating white matter structural connectivity between the left hemisphere salience/ventral attention network and the default mode network. However, these mediation findings are preliminary and require validation in independent cohorts with non-overlapping samples. In conclusion, this study prioritizes PSORS1C3 and POU5F1 as high-confidence candidate genes for delirium susceptibility, providing a genetic foundation for future functional studies and guiding subsequent drug repurposing investigations.
Vitamin B12 attenuates post-ischemic brain fibrotic remodeling and suppresses MAPK1 signaling in male rats.
Wu H, Zhou L, Cai X … +10 more , Ren Y, Zhao Y, Yang Q, Wang J, Tan Y, Wang Y, Xiao F, Xu X, Huang J, Yang Q
Brain Res Bull · 2026 May · PMID 41905540 · Publisher ↗
Ischemic stroke (IS) is a major global cause of mortality and disability, with fibrotic scar formation during disease progression markedly restricting neurological recovery. Vitamin B12 (cobalamin) has been shown to impr...
Ischemic stroke (IS) is a major global cause of mortality and disability, with fibrotic scar formation during disease progression markedly restricting neurological recovery. Vitamin B12 (cobalamin) has been shown to improve short-term stroke outcomes; however, its regulatory role in long-term fibrotic remodeling, particularly its capacity to modulate specific molecular pathways, is incompletely understood. The present study integrated network pharmacology with drug-target Mendelian randomization (MR) to identify pivotal vitamin B12-related targets involved in post-ischemic fibrosis, yielding three candidate genes-ALDH2, CD40, and mitogen-activated protein kinase 1 (MAPK1). These targets were subsequently validated through molecular docking, molecular dynamics simulation, nomogram prediction, and in vivo experiments using the middle cerebral artery occlusion/reperfusion (MCAO/R) rat model. The findings suggested that ALDH2 and CD40 act as protective factors, whereas MAPK1 serves as a risk-susceptible driver of post-ischemic fibrotic remodeling. Reverse MR emphasized MAPK1 as the most influential contributor to disease progression among these targets. In subacute MCAO/R male rats, vitamin B12 administration markedly suppressed MAPK1 expression, attenuated the expression of key fibrosis indicators (fibronectin, type I collagen, and alpha-smooth muscle actin), and improved motor recovery. Mechanistic analyses suggest that vitamin B12 may limit fibrotic scar deposition by coordinating a "metabolism-immune-matrix" regulatory network centered on MAPK1. These results provide a robust theoretical foundation for applying vitamin B12-based strategies to counteract post-ischemic fibrosis and establish MAPK1 as a promising therapeutic target for enhancing long-term neurological recovery in ischemic stroke.
Poly I:C-induced maternal immune activation causes schizophrenia- like memory and prepulse inhibition deficits in the offspring by upregulating IL-6.
Luo Y, Chen D, Yu Y … +2 more , Zhang M, Fan N
Brain Res Bull · 2026 May · PMID 41895382 · Publisher ↗
Poly I:C-induced maternal immune activation(MIA) during gestation increases the risk of schizophrenia-like behaviors in the offspring. However, the molecular mechanism of poly I:C MIA-induced schizophrenia-like behaviors...
Poly I:C-induced maternal immune activation(MIA) during gestation increases the risk of schizophrenia-like behaviors in the offspring. However, the molecular mechanism of poly I:C MIA-induced schizophrenia-like behaviors in the offspring is not well clarified. Available evidence showed that patients with schizophrenia have higher IL-6 levels in the blood and cerebrospinal fluid, which is correlated with psychotic and cognitive impairments. Previous findings suggest a key role for IL-6 in poly I:C MIA-induced schizophrenia-like abnormal behaviors. In the present study, we found that prenatal poly I:C exposure at gestational day (GD) 9 increased the expression of IL-6 and IL-6Rα and led to impaired prepulse inhibition (PPI) and recognition memory in adolescent and adult offspring. We also found that the expression and phosphorylation of IKKα/β, NF-κB, JAK2, and STAT3, the upstream and downstream signal molecules of IL-6, were increased in adolescent and adult offspring of poly I:C-treated mothers at GD 9. The increases in the expression of IL-6, IL-6Rα, IKKα/β, NF-κB, JAK2, and STAT3 and the impairments in PPI and recognition memory were alleviated by IL-6 blockade. These results suggest that IL-6 may be a potential mediator between NF-κB and JAK/STAT cross-talk, thereby contributing to poly I:C MIA-induced impairments in PPI and recognition memory in offspring. Our findings show that blocking of IL-6 could ameliorate prenatal poly I:C exposure-induced schizophrenia-like impairments in adolescent and adult offspring. Our study provides additional insight that targeting IL-6 is a potential strategy for treating poly I:C MIA-induced schizophrenia-like behaviors and behavioral deficits in schizophrenia.
Spiral ligament dysfunction and endocochlear potential loss drive hearing impairment in Niemann-Pick C1 mice.
Miwa T, Yamada Y, Ishii A … +11 more , Shirakawa A, Tanaka M, Kondo Y, Takeo T, Nakagata N, Takeda H, Higaki K, Ikeda R, Matsuo M, Irie T, Ishitsuka Y
Brain Res Bull · 2026 May · PMID 41895381 · Publisher ↗
BACKGROUND: Sensorineural hearing loss is increasingly recognized in Niemann-Pick disease type C (NPC), but the underlying cochlear lesion remains undefined. While prior work emphasized hair-cell (HC) involvement, whethe...
BACKGROUND: Sensorineural hearing loss is increasingly recognized in Niemann-Pick disease type C (NPC), but the underlying cochlear lesion remains undefined. While prior work emphasized hair-cell (HC) involvement, whether auditory dysfunction instead arises from lateral-wall failure and endocochlear potential (EP) decline is unknown. METHODS: Npc1 mice and littermate controls underwent auditory function test and electrophysiological recordings at postnatal day (P) 35 and P63. Cochlear cytoarchitecture was evaluated using immunohistochemistry and transmission electron microscopy (TEM). To probe cell-type susceptibility, NPC1 was inhibited in Spiral ligament (SLi)-like fibrocytes, HC-like HEI-OC1 cells in vitro. RESULTS: Npc1 mice showed elevated low-frequency auditory brainstem response (ABR) thresholds at P35, progressing to pan-frequency impairment and prolonged ABR wave IV-V latencies by P63. HCs, stereocilia bundles, and spiral ganglion cells were preserved. In contrast, EP was markedly reduced. Na⁺/K⁺-ATPase α1 and connexin-26 immunolabeling in the SLi decreased significantly without strial thinning, indicating impaired ion recycling and gap-junction coupling. Filipin staining and TEM revealed progressive free-cholesterol accumulation and vacuolar inclusions in SLi fibrocytes and supporting cells, with secondary involvement of HC regions. In vitro, NPC1 inhibition increased cholesterol in SLi-like fibrocytes but not in HEI-OC1 cells. CONCLUSIONS: NPC-related hearing loss arises primarily from SLi dysfunction and EP failure, with secondary HC compromise, rather than degeneration. These findings reposition NPC hearing loss as a disorder of cochlear homeostasis and identify EP preservation and correction of cholesterol trafficking as rational therapeutic targets. Early auditory monitoring may improve clinical outcomes.
Giving old drugs new life: Disulfiram alleviates microglial pyroptosis and disulfidptosis-like cytoskeletal/mitochondrial alterations in cerebral ischemia-reperfusion injury.
Zhou C, Liang TS, Zhan YB … +4 more , Fu SS, Xu JP, Zhao YQ, Zheng ZQ
Brain Res Bull · 2026 May · PMID 41895380 · Publisher ↗
BACKGROUND: The cerebral ischemia-reperfusion injury (CIRI) induced by endovascular treatment represents a research challenge. Microglial pyroptosis plays a critical role in the neuroinflammatory damage associated with C...
BACKGROUND: The cerebral ischemia-reperfusion injury (CIRI) induced by endovascular treatment represents a research challenge. Microglial pyroptosis plays a critical role in the neuroinflammatory damage associated with CIRI. Gasdermin D (GSDMD) is a key executor of pyroptosis, mediating plasma membrane rupture. Interestingly, research on pyroptosis has long focused on cell membrane rupture. We further hypothesize that cytoskeletal collapse during pyroptosis may facilitate cell rupture. This new perspective will contribute to a comprehensive understanding of the mechanisms of morphological changes during pyroptosis. Recent research has proposed disulfidptosis, an emerging form of cell death characterized by cytoskeletal collapse. Therefore, we speculated that disulfidptosis might occur concurrently with pyroptosis-associated cell rupture, and investigated whether disulfiram (DSL) could inhibit microglial pyroptosis and the associated disulfidptosis-related changes in a CIRI model. MATERIALS: Middle cerebral artery occlusion (MCAO) was established on rats, and the optimal dosage of DSL was determined. Neurological function, infarct volume, vascular diameter, cellular morphology, and key molecular mediators of microglial pyroptosis and disulfidptosis were tested. Furthermore, microglial mitochondrial fragmentation was investigated at the subcellular structural level. RESULTS: High-dose DSL (500 mg·Kgd) significantly improved neurological function in rats. Moreover, high-dose DSL reduced infarct size and attenuated cellular shrinkage in the ischemic penumbra. GSDMD and SLC7A11 were co-localized in microglia. DSL suppressed the expression of pyroptosis-related proteins, including GSDMD-N-terminal, caspase-1 p10, and cleaved caspase-11. In addition, DSL mitigated SLC7A11 loss and inhibited the expression of NOX4 and ARP2. At the mitochondrial level, DSL alleviated microglial mitochondrial fragmentation and downregulated the expression of DRP1 and VDAC1. CONCLUSION: Following CIRI, disulfiram suppressed pyroptosis by inhibiting the caspase-1/11-GSDMD pathway and attenuated disulfidptosis-like changes via modulation of the SLC7A11-NOX4-ARP2 axis, suggesting its potential neuroprotective effect.
Independent Association of hippocampal perivascular spaces with memory function in Type 2 diabetes.
Pan P, Li L, Zhang D … +4 more , Tang M, Lei X, Zhang X, Gao J
Brain Res Bull · 2026 May · PMID 41887294 · Publisher ↗
OBJECTIVE: To investigate the associations of hippocampal perivascular space (H-PVS) volume and hippocampal volume with memory function in patients with type 2 diabetes mellitus (T2DM), and to compare their independent c...
OBJECTIVE: To investigate the associations of hippocampal perivascular space (H-PVS) volume and hippocampal volume with memory function in patients with type 2 diabetes mellitus (T2DM), and to compare their independent contributions to cognitive impairment. METHODS: A total of 75 cognitively normal patients (T2DM-NC) and 70 cognitively impaired patients (T2DM-CI) with T2DM were included, along with 79 healthy controls (HCs) matched for age, sex, and education. All participants underwent brain MRI scans and neuropsychological assessments. Multiple linear regression analyses were conducted in the T2DM group to assess the independent associations of H-PVS and hippocampal volumes with general cognitive and memory function. RESULTS: Compared with HCs, the T2DM-CI group exhibited significantly larger H-PVS (P < 0.001) and choroid plexus volumes (P = 0.001). In patients with T2DM, H-PVS volume was not associated with hippocampal volume but was positively correlated with choroid plexus volume (P = 0.008). Multiple linearregression analysis showed that H-PVS volume was independently associated with memory function (β = -0. 212, P = 0. 033) in patients with T2DM, but not with the general cognitive function (P = 0.117). Hippocampal volume was not independently associated with either general cognitive function (P = 0.150) or memory function (P = 0.081). CONCLUSION: H-PVS volume is independently associated with memory function in patients with T2DM, beyond the effects of hippocampal atrophy, suggesting that H-PVS volume may serve as a novel imaging biomarker for early identification of memory impairment in this population.
Corrigendum to "Electrical stimulation of olfactory bulb downregulates RGMa expression after ischemia/reperfusion injury in rats" [Brain Res. Bull. 86 (2011) 254-261].
Zhang G, Zhang JH, Feng J … +3 more , Li Q, Wu X, Qin X
Brain Res Bull · 2026 May · PMID 41876307 · Publisher ↗
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Altered cortical morphometric similarity and associated transcriptional signatures and neurodevelopmental outcome in infants with external hydrocephalus.
Sun Y, Zhao H, Yin Y … +8 more , Zhang G, Zhang Y, Huang T, Zhang H, Zheng C, Pei N, Zhao C, Jin C
Brain Res Bull · 2026 May · PMID 41876047 · Publisher ↗
OBJECTIVE: External hydrocephalus (EH) is associated with subsequent neurodevelopmental delays, potentially resulting from the excessive cerebrospinal fluid-disrupted cortical development. This study aims to investigate...
OBJECTIVE: External hydrocephalus (EH) is associated with subsequent neurodevelopmental delays, potentially resulting from the excessive cerebrospinal fluid-disrupted cortical development. This study aims to investigate early alterations in the morphometric similarity network (MSN) and corresponding regional transcriptional expression patterns in relation to subsequent motor and speech delays in EH infants. MATERIALS AND METHODS: This retrospective study recruited 127 EH infants, identified through routine MRI within 1 year after birth, whose neurodevelopmental outcomes were assessed at 1-4 years of age. Early alterations in morphometric similarity (MS) were identified using multiple linear regression. MS alterations-related genes were examined by partial least squares regression. RESULTS: We found that MS significantly increased in the left inferior parietal region and decreased in the right banks of the superior temporal sulcus in EH infants with subsequent motor delay. MS alterations-related genes were enriched in immune pathways. These genes were primarily involved in microglial cells. Notably, these genes showed a significant overlap with those associated with autism spectrum disorder (ASD) and schizophrenia (all p<0.05). CONCLUSION: Early MS alterations in EH infants may serve as predictors of subsequent motor and speech delays, and are associated with genes enriched in immune pathways, overlapping with those implicated in ASD and schizophrenia.
Probiotics reverse prenatal stress-induced anxiety and memory impairment in rats through gut-hippocampus axis regulation.
Bidgoli FA, Salami M, Mirzaei H … +1 more , Talaei SA
Brain Res Bull · 2026 Jun · PMID 41876046 · Publisher ↗
Prenatal stress is a significant risk factor that can lead to neurobehavioral deficits in offspring. In the present study, we examined the effects of a probiotic mixture on anxiety, memory, and underlying possible molecu...
Prenatal stress is a significant risk factor that can lead to neurobehavioral deficits in offspring. In the present study, we examined the effects of a probiotic mixture on anxiety, memory, and underlying possible molecular pathways in prenatally stressed rats. Male offspring exposed to chronic unpredictable stress (CUS) during fetal life were received either saline (CUS+SAL) or a probiotic mixture (CUS+PRO) for 30 days post-weaning. Non-stressed controls were also given either saline (CON+SAL) or probiotics (CON+PRO). The passive avoidance test and the elevated zero maze test were used to assess avoidance memory and anxiety-like behavior, respectively. In comparison to the CON+SAL controls, the CUS+SAL group exhibited significant anxiety-like behavior and impaired avoidance memory. At a molecular level, the behavioral impairments were accompanied by increased serum levels of the oxidant, MDA, and decreased serum levels of antioxidants, TAC, GSH, and SOD, upregulation of the hippocampal serotonin receptor Htr1a gene, while downregulation of microRNAs miR-26a and miR-320-3p, reduced BDNF, and increased Bax/Bcl-2 ratio apoptosis in the duodenum. Probiotics effectively mitigated these alterations. The intervention improved behavioral functions, normalized oxidative and antioxidative stress markers, and restored the expression of Htr1a and miR-320-3p to near-normal levels, while miR-26a expression remained unaffected by the treatment. It also enhanced the Bax/Bcl-2 ratio and increased BDNF content. Interestingly, unstressed control rats were unresponsive to the probiotic treatment. Conclusively, probiotic supplementation sufficiently alleviates the adverse effects of fetal life stress, possibly by affecting the gut-brain axis, highlighting the importance of beneficial bacteria in neurobehavioral development and maintenance.
Ketamine-induced changes in accumbal glutamate and their association with altered states of consciousness.
Gubser LP, Trippel AS, Zoelch N … +2 more , Engeli EJE, Herdener M
Brain Res Bull · 2026 May · PMID 41871813 · Publisher ↗
Ketamine has been shown to modulate glutamate signaling in animals and may therefore have the potential to restore glutamate imbalances in the brain. Impaired glutamate homeostasis has been implicated in mental health di...
Ketamine has been shown to modulate glutamate signaling in animals and may therefore have the potential to restore glutamate imbalances in the brain. Impaired glutamate homeostasis has been implicated in mental health disorders such as substance use disorders (SUDs). Thus, we investigated ketamine's potential to increase glutamate levels in the nucleus accumbens (NAc), a key region for the development and maintenance of SUD. We further examined whether glutamate changes are associated with ketamine's potential to induce altered states of consciousness. A single intravenous dose of R,S-ketamine (0.71 mg/kg bodyweight) was administered to 10 healthy volunteers over 40 min. Glutamate levels were measured by using a tailored proton magnetic resonance spectroscopy (H-MRS) sequence in the left NAc on a 3 T scanner, before and during the infusion. Subjective effects were measured by using the Five-Dimensional Altered States of Consciousness (5D-ASC) questionnaire. Glutamate levels were considered from the overall spectrum average (22 min) as well as three shorter, overlapping sub-blocks (each 10 min), to capture the progression of glutamate over time. Mean glutamate levels in the NAc were not significantly altered between baseline and ketamine H-MRS measurement. However, glutamate changes were positively associated with anxious ego dissolution and reductions in vigilance. In conclusion, ketamine did not significantly increase glutamate levels across our sample of 10 healthy volunteers, but individual glutamate changes induced by ketamine correlate with anxious ego dissolution and reductions in vigilance, indicating that ketamine-induced glutamate alterations in the NAc underly specific alterations in perception and consciousness.
Association of maternal antenatal distress with child amygdala-prefrontal cortex functional connectivity at 2-3 years in a South African birth cohort study.
Miles M, Wedderburn CJ, Fairchild G … +13 more , Lake MT, Narr KL, Joshi S, Lawrence M, Hoffman N, Groenewold NA, Barnett W, du Plessis S, Ipser J, Halligan SL, Zar HJ, Stein DJ, Donald KA
Brain Res Bull · 2026 May · PMID 41865903 · Publisher ↗
Maternal antenatal psychological distress can negatively affect child development, particularly in low- and middle-income countries (LMICs) where women are at heightened risk for distress. This study examined the associa...
Maternal antenatal psychological distress can negatively affect child development, particularly in low- and middle-income countries (LMICs) where women are at heightened risk for distress. This study examined the association between maternal antenatal distress and child amygdala-prefrontal cortex functional connectivity in a South African birth cohort using resting-state fMRI. Children aged 2-3 years who were either exposed to maternal distress in utero (n = 27) or unexposed (n = 85) were analyzed using region-of-interest analysis. Multivariate analysis of covariance assessed group differences, adjusting for confounders, and Pearson correlations examined associations with externalizing behaviors 6-18 months later across the whole sample (n = 111). Exposed children showed weaker amygdala-medial PFC and amygdala-lateral PFC connectivity than unexposed peers (medial PFC: mean=0.099 vs 0.164, p = 0.034; lateral PFC: mean=0.095 vs 0.132, p = 0.025). These differences were significant in boys only (medial PFC: p = 0.016; lateral PFC: p = 0.019). Additionally, hippocampus-PFC connectivity at ages 2-3 was negatively associated with later externalizing behaviors. Findings suggest exposure to maternal psychological distress in utero impacts amygdala-PFC connectivity in early childhood, while exploratory associations between hippocampus-PFC and externalizing behavior point to potential links with later behavioral outcomes. Understanding these neural correlates may inform early interventions to disrupt intergenerational transmission of psychological risk.
Dexmedetomidine ameliorates postoperative delirium-like behavior in aged mice by restoring microglial autophagy via MAPK14 inhibition.
Yao J, Feng T, Chen Y … +7 more , Wang J, Zhu Y, Lan Z, Liu F, Zhang Y, Li Q, Huang L
Brain Res Bull · 2026 Apr · PMID 41865902 · Publisher ↗
Postoperative delirium (POD) is a serious complication in elderly patients undergoing surgery; however, its underlying mechanisms remain poorly understood. In this study, we investigated whether dexmedetomidine (DEX) ame...
Postoperative delirium (POD) is a serious complication in elderly patients undergoing surgery; however, its underlying mechanisms remain poorly understood. In this study, we investigated whether dexmedetomidine (DEX) ameliorates POD-like behavior by regulating microglial autophagy through the MAPK14 pathway. DEX targets were identified through transcriptomic analysis, and MAPK14 was validated as a key mediator by using molecular docking. In vitro experiments employed LPS-stimulated BV2 microglia to evaluate the effects of DEX on apoptosis (flow cytometry) and autophagy (transmission electron microscopy, BCL-2/Beclin-1/LC3-II/p62). In the aged C57BL/6 J mouse model of anesthesia/surgery-induced POD, animals received intraperitoneal injections of DEX or MAPK14 overexpression, followed by behavioral tests (open-field test and Y-maze test). Subsequently, hippocampal tissue was subjected to enzyme-linked immunosorbent assay and Western blot analyses to assess the levels of inflammatory factors and autophagy. DEX treatment effectively inhibited LPS-induced apoptosis in BV2 microglia while enhancing autophagy, as evidenced by increased LC3-II and Beclin-1 expression and decreased p62 and Bcl-2 levels. In the aged mouse POD model, DEX administration significantly reduced levels of neuroinflammatory factors and S100β while protecting against neuronal damage in the hippocampal CA1 and dentate gyrus regions. Behavioral assessments revealed substantial cognitive improvements in DEX-treated aged mice with delirium-like phenotype. All these therapeutic effects were abolished by MAPK14 overexpression. DEX attenuates POD by inhibiting MAPK14 to restore microglial autophagy and suppress neuroinflammation, thereby offering a novel therapeutic strategy for elderly patients. Furthermore, MAPK14 activation may serve as a biomarker for DEX responsiveness.
Sex-dependent hemodynamic responses in the whole brain during single-session fNIRS neurofeedback.
Wu P, Wei M, Li Y … +5 more , Bi Y, Xue Y, Zhao X, Wang C, Jiang W
Brain Res Bull · 2026 Apr · PMID 41865901 · Publisher ↗
BACKGROUND: Functional near-infrared spectroscopy-based neurofeedback (fNIRS-NF) training shows potential for improving cognitive function. However, current paradigms often overlook individual differences-particularly ge...
BACKGROUND: Functional near-infrared spectroscopy-based neurofeedback (fNIRS-NF) training shows potential for improving cognitive function. However, current paradigms often overlook individual differences-particularly gender-specific effects on neuroplastic responses. This study investigates gender's role by analyzing brain functional characteristics during neurofeedback training across genders. METHODS: A total of 38 subjects (20 males and 18 females) were included in this study. All subjects completed neuropsychological tests, followed by a single NIRS-NF training session targeting the bilateral dorsolateral prefrontal cortex (DLPFC). RESULTS: No significant differences were observed in demographic data, neuropsychological test scores, or neurofeedback training scores between the male and female groups (p > 0.05). During neurofeedback training, the target brain region was primarily activated in the left DLPFC, with no difference in activation patterns between the two groups (p > 0.05, FDR corrected). Functional connectivity analysis revealed that males exhibited higher whole-brain connectivity strength than females (p < 0.05, FDR corrected). Specifically, the connectivity strength between the prefrontal lobe and right parietal lobe (r = 0.420，p = 0.008), as well as between the prefrontal lobe and posterior frontal area (r = 0.383，p = 0.017), was positively correlated with neurofeedback training scores. CONCLUSIONS: This study confirms that individuals can successfully achieve regulation of the target brain region through a single session of neurofeedback, while highlighting the necessity of considering gender-specific brain network characteristics in the development of personalized neurofeedback paradigms.
Transcranial ultrasound stimulation and vagus nerve stimulation: Potential therapeutic strategies for Alzheimer's disease.
Wang B, Cheng K, Chen Z … +3 more , Chen Y, Wang Z, Ni J
Brain Res Bull · 2026 Apr · PMID 41864514 · Publisher ↗
Alzheimer's disease (AD) is a complex neurodegenerative disorder with limited efficacy from existing medications and conventional neuromodulation therapies. In recent years, emerging neuromodulation techniques have demon...
Alzheimer's disease (AD) is a complex neurodegenerative disorder with limited efficacy from existing medications and conventional neuromodulation therapies. In recent years, emerging neuromodulation techniques have demonstrated promising therapeutic potential. This review focuses on exploring the therapeutic value of transcranial ultrasound stimulation (TUS) and vagus nerve stimulation (VNS) for AD. We systematically review the evidence for these techniques in AD basic research and clinical practice, elucidating their unique mechanisms of action. The review further contrasts the advantages of TUS and VNS over traditional AD therapies and explores their potential for synergistic application with conventional treatments. Finally, we propose future research directions, including combined VNS and TUS treatment strategies based on complementary mechanisms, aiming to provide theoretical foundations for developing multi-targeted, personalized AD therapies.
Altered functional connectivity within the pain connectome in type 2 diabetic patients with painful peripheral neuropathy: Evidence from pain matrix hubs.
Yang J, He M, Liu X … +8 more , Zhou J, Zhang X, Li J, Shao X, Feng F, Guan Y, Li W, Zhang W
Brain Res Bull · 2026 May · PMID 41864513 · Publisher ↗
OBJECTIVE: We investigated the pain connectome in patients with diabetic peripheral neuropathy (DPN), particularly those with neuropathic pain, by characterizing functional interactions within the traditional pain matrix...
OBJECTIVE: We investigated the pain connectome in patients with diabetic peripheral neuropathy (DPN), particularly those with neuropathic pain, by characterizing functional interactions within the traditional pain matrix and across large-scale brain networks. METHODS: Sixty-two patients with type 2 diabetes mellitus (25 without DPN, 20 with painless DPN, and 17 with painful DPN) and 33 healthy controls were enrolled in this study. All participants underwent resting-state functional MRI, and region of interest (ROI)-to-ROI functional connectivity (FC) analysis was performed within predefined core regions of the pain matrix, supplemented by group independent component analysis to evaluate interactions between pain related networks. Partial correlation analyses were conducted to assess associations between connectivity strength and pain-related measures, peripheral nerve function, and neuropsychological outcomes. RESULTS: Compared with HCs, patients with painful DPN showed presented decreased FC between the amygdala and the anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), thalamus, and periaqueductal gray (PAG), as well as between the thalamus and PAG. Higher peak pain scores and lower Douleur Neuropathique 4 questionnaire (DN4) questionnaire scores were associated with lower FC in these pathways (all P < 0.05). Lower FC in these pathways (except FC between the amygdala and the PAG) was also associated with poorer peripheral nerve functions (all P < 0.05). Higher anxiety levels were associated with increased FC between the right amygdala and the right ACC (r = 0.600, P = 0.023). CONCLUSIONS: Patients with painful DPN exhibit distinct FC alterations, and the amygdala may play a key role in pain perception and emotional regulation in the neuropathic pathophysiology of DPN.
LncRNA 4930544M13Rik-201 regulates CACNA2D1 expression via interacting with hnRNPA2B1 to promote neuropathic pain following nerve injury.
Fang Z, Liu F, Tang Q … +7 more , Liu Y, Peng Y, Zheng Z, Li Q, Zhang Y, Wang H, Shen J
Brain Res Bull · 2026 May · PMID 41864512 · Publisher ↗
Long non-coding RNAs (lncRNAs) have recently been reported to play a crucial role in neuropathic pain (NP). However, whether lncRNA 4930544M13Rik-201, a significantly up-regulated lncRNA in peripheral ganglia following n...
Long non-coding RNAs (lncRNAs) have recently been reported to play a crucial role in neuropathic pain (NP). However, whether lncRNA 4930544M13Rik-201, a significantly up-regulated lncRNA in peripheral ganglia following nerve injury, contributes to NP is not elucidated. This study aimed to investigate the role and mechanism of 4930544M13Rik-201 in NP. In the current study, the head withdrawal threshold (HWT) of mice following infraorbital nerve chronic constriction injury (CCI-ION) was assessed using behavioral tests to evaluate the presence of neuropathic pain. To elucidate the underlying mechanisms, RT-qPCR, western blotting, RNA pull-down, RNA immunoprecipitation, immunofluorescence, and fluorescence in situ hybridization were performed. It was found that 4930544M13Rik-201 was predominantly located in the nuclei of neurons in the trigeminal ganglion (TG). Silencing 4930544M13Rik-201 alleviated mechanical allodynia, while overexpression of 4930544M13Rik-201 in the wild-type mice caused orofacial allodynia. Notably, 4930544M13Rik-201 increased the stabilization of calcium voltage-gated channel auxiliary subunit alpha 2 delta 1 (Cacna2d1) mRNA and protein expression via interacting with heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). Furthermore, inhibition of CACNA2D1 and silencing of hnRNPA2B1 alleviated the allodynia and expression of 4930544M13Rik-201. In conclusion, these results suggest that 4930544M13Rik-201 promotes NP by upregulating Cacna2d1 expression via binding to hnRNPA2B1 following nerve injury.
Macrophage membrane-camouflaged nanoparticles for synergistic gene-phototherapy in glioblastoma.
Lin G, Cai W, Zheng Z … +1 more , Lin Y
Brain Res Bull · 2026 Apr · PMID 41862139 · Publisher ↗
BACKGROUND: Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. Its treatment efficacy is largely limited by the blood-brain barrier (BBB). Given their excellent capacity to penetrate...
BACKGROUND: Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. Its treatment efficacy is largely limited by the blood-brain barrier (BBB). Given their excellent capacity to penetrate the BBB, macrophage membrane (MM)-modified nanomedicine systems represent a promising strategy to overcome this obstacle. METHODS: MM-camouflaged nanoparticles (NPs) (siSTAT3-IR780@M) were prepared by co-loading the photosensitizer IR780 with siSTAT3 via electrostatic adsorption, followed by camouflage with an MM. Their physical characteristics were characterized by transmission electron microscopy, dynamic light scattering, and ultraviolet-visible (UV-Vis) spectroscopy. Biosafety and BBB penetration were evaluated through hemolysis, CCK-8, cellular uptake assays, and an in vitro BBB model. In vitro antitumor effects were assessed via DCFH-DA probe, western blot, and Annexin V/PI staining. In vivo biodistribution, antitumor efficacy, and biosafety were investigated using a xenograft GBM nude mouse model and IVIS imaging. RESULTS: The fabricated siSTAT3-IR780@M NPs exhibited a spherical morphology, favorable photodynamic properties, and a uniform size distribution. In vitro, these NPs efficiently enhanced uptake by U87 MG cells, effectively traversed the BBB model, significantly elevated intracellular reactive oxygen species levels, suppressed STAT3 protein expression, and induced apoptosis. In vivo, the NPs showed significant accumulation in brain tumor tissues. Upon near-infrared irradiation, tumor growth was substantially inhibited without inducing obvious adverse effects. CONCLUSION: siSTAT3-IR780@M NPs demonstrate excellent BBB penetration and tumor-targeting ability. They synergistically enhance GBM treatment through combining gene silencing and photodynamic therapy. This study highlights the strong potential of siSTAT3-IR780@M for clinical translation.
Byakangelicin attenuates vascular dementia by modulating the KDR-NOS3 axis: An integration of network pharmacology and experimental validation.
Wang L, Yan Y, Qiao Y … +4 more , Guo T, Wang L, Zhang Y, Yang G
Brain Res Bull · 2026 Apr · PMID 41856256 · Publisher ↗
Vascular dementia (VaD) is a major cause of cognitive impairment with limited treatment options. Byakangelicin (Byn), a natural coumarin compound, has shown potential neuroprotective effects, but its mechanism in VaD rem...
Vascular dementia (VaD) is a major cause of cognitive impairment with limited treatment options. Byakangelicin (Byn), a natural coumarin compound, has shown potential neuroprotective effects, but its mechanism in VaD remains unclear. This study employed an integrated approach combining network pharmacology, molecular docking, and experimental validation to investigate Byn's therapeutic action. Network analysis prioritized KDR and NOS3 as core targets, which was corroborated by molecular docking. In a 2-VO-induced VaD rat model, Byn administration dose-dependently improved cognitive function, alleviated hippocampal damage, and reduced neuroinflammation. Mechanistically, Byn upregulated the KDR-NOS3 axis, enhanced Akt/eNOS phosphorylation, and suppressed apoptotic signaling. Critically, the protective effects of Byn were abolished by co-administration of KDR or NOS3 inhibitors. Our findings reveal that byakangelicin attenuates VaD by modulating the KDR-NOS3 signaling pathway, offering a promising therapeutic strategy and a solid mechanistic basis for further drug development.
Effects of Sulbactam on behavioral and neuronal deficits in an MPTP-induced Parkinson's disease rat model.
Yang SC, Tsou SH, Liao WC … +6 more , Hsieh YJ, Pan HH, Bellesi M, Weng JC, Hung CS, Ho YJ
Brain Res Bull · 2026 Apr · PMID 41856255 · Publisher ↗
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor impairments, often culminating in dementia. Glutamatergic hyperactivation and γ-aminobutyric acid (GABA) decline co...
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor impairments, often culminating in dementia. Glutamatergic hyperactivation and γ-aminobutyric acid (GABA) decline contribute to dopaminergic degeneration, highlighting these systems as therapeutic targets. Sulbactam (SUX), a β-lactamase inhibitor, enhances astrocytic glutamate transporter 1 (GLT-1) expression, facilitating glutamate clearance and potentially conferring neuroprotection. We investigated SUX effects on behavioral outcomes, neurotransmitter systems, and neurogenesis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats received bilateral MPTP injections into the substantia nigra pars compacta, followed by daily saline, SUX (50 mg/kg), levodopa (L-dopa; 4 mg/kg), or SUX+L-dopa for 18 or 25 days. Behavioral assessments included spontaneous locomotion, anxiety, working memory, and object recognition. Histological analyses evaluated dopaminergic integrity, subthalamic nucleus activity, neuronal density, neurogenesis, and astrocytic counts. PD rats exhibited motor, emotional, and cognitive deficits, accompanied by dopaminergic neuron loss, subthalamic hyperactivation, and reduced hippocampal neurogenesis. L-dopa improved only object recognition, whereas SUX alone or combined with L-dopa reduced anxiety, enhanced cognition, and mitigated neuronal loss. SUX-treated healthy rats also demonstrated superior memory retention. No significant hippocampal GABAergic alterations were observed. This study provides the first evidence that SUX exerts neuroprotective and pro-neurogenic effects while alleviating emotional and cognitive deficits in PD rats. Restoration of GLT-1-expressing astrocytes may underlie these benefits, supporting SUX as a promising candidate for PD therapy.
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