Pub Date : 2025-12-21DOI: 10.1016/j.brainres.2025.150120
Desmond Agboada , Roman Rethwilm , Manuel Kuder , Wolfgang Mack , Wolfgang Seiberl
Background
Conventional TMS devices are limited in the number of variations of pulse parameters they produce, which limits the extension of TMS application. Recently, however, successful attempts have been made to introduce next-generation (next-gen) TMS devices with adjustable pulse parameters. Although research using these devices is still in its infancy, a systematic synthesis of the direction of results is valuable to identify the current progress and some limitations of these technologies which can guide further studies in the field.
Objective
This review aims to investigate the influence of pulse parameters (width, shape, and current direction) of next-gen TMS devices on corticospinal excitability and the induction of neuroplasticity.
Methods
Using the PRISMA method of reporting systematic reviews, we searched major biomedical databases − PubMed (n = 84), Web of Science (n = 141), Scopus (n = 111) and APA PsychInfo (n = 27) for literature, with 21 studies included in this review.
Results
Compared to conventional TMS devices, next-generation TMS devices were more efficient in many neurophysiological measurements. For plasticity inducing protocols, both inhibitory and facilitatory protocols showed enhanced respective inhibitory and excitatory after-effects with increasing pulse width. The new near-rectangular pulse shape moreover induced stronger inhibitory after-effects compared to conventional pulses.
Conclusions
Next-generation devices expand the parameter space of TMS. Further studies are however needed to explore the full potential of these next-gen devices, especially in non-motor brain regions.
Significance
Next-gen TMS devices do hold a promise in the optimization of the neuromodulatory effects of TMS.
{"title":"A systematic review of the effect of pulse parameters of next-generation TMS devices on corticospinal excitability and neuroplasticity","authors":"Desmond Agboada , Roman Rethwilm , Manuel Kuder , Wolfgang Mack , Wolfgang Seiberl","doi":"10.1016/j.brainres.2025.150120","DOIUrl":"10.1016/j.brainres.2025.150120","url":null,"abstract":"<div><h3>Background</h3><div>Conventional TMS devices are limited in the number of variations of pulse parameters they produce, which limits the extension of TMS application. Recently, however, successful attempts have been made to introduce next-generation (next-gen) TMS devices with adjustable pulse parameters. Although research using these devices is still in its infancy, a systematic synthesis of the direction of results is valuable to identify the current progress and some limitations of these technologies which can guide further studies in the field.</div></div><div><h3>Objective</h3><div>This review aims to investigate the influence of pulse parameters (width, shape, and current direction) of next-gen TMS devices on corticospinal excitability and the induction of neuroplasticity.</div></div><div><h3>Methods</h3><div>Using the PRISMA method of reporting systematic reviews, we searched major biomedical databases − PubMed (n = 84), Web of Science (n = 141), Scopus (n = 111) and APA PsychInfo (n = 27) for literature, with 21 studies included in this review.</div></div><div><h3>Results</h3><div>Compared to conventional TMS devices, next-generation TMS devices were more efficient in many neurophysiological measurements. For plasticity inducing protocols, both inhibitory and facilitatory protocols showed enhanced respective inhibitory and excitatory after-effects with increasing pulse width. The new near-rectangular pulse shape moreover induced stronger inhibitory after-effects compared to conventional pulses.</div></div><div><h3>Conclusions</h3><div>Next-generation devices expand the parameter space of TMS. Further studies are however needed to explore the full potential of these next-gen devices, especially in non-motor brain regions.</div></div><div><h3>Significance</h3><div>Next-gen TMS devices do hold a promise in the optimization of the neuromodulatory effects of TMS.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150120"},"PeriodicalIF":2.6,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145817731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.brainres.2025.150122
Zina Li , Jichan Nian , Shuiyan Li , Zhiqing Deng , Hang Wu , Haili Zhong , Xiyan Huang , Pengmin Qin , Jinhui Wang , Qiuyou Xie , Juan Chen
The Minimally Conscious State (MCS) is a condition in which a patient, following a brain injury, exhibits minimal yet definite behavioral evidence of awareness, representing a crucial transitional state between unconsciousness and the full emergence of consciousness. Assessing preserved cognitive function, particularly visual function, is crucial for diagnosis and rehabilitation, given that vision is the primary source of sensory input. While MCS patients consistently exhibit visual behaviors, such as sustained fixation or pursuit eye movements, previous neuroimaging studies have treated the visual network as a monolith, leaving it unclear which part of their visual cortical neural networks is affected or preserved. Here, we investigated the visual neural network of patients, encompassing 38 visual cortical subregions, from the primary visual cortex (V1), which processes low-level features (e.g., contrast, orientation), to higher-level visual regions that mediate object recognition and visual attention. Threshold-free network-based statistical analysis revealed that inter-hemispheric connectivity is significantly decreased, while intra-hemispheric connectivity is largely preserved in the visual network of MCS patients. Graph-based analysis showed a longer characteristic path length in them, indicating impaired global integration. Nodal analysis revealed that the primary visual cortex (V1) is a more critical hub for information transfer, while the middle and high-level visual areas are less essential in MCS patients than in HCs. These findings provide a detailed characterization of the functional connectivity and topological properties of the visual cortical network in MCS patients, offering crucial insights for stimulus selection when using visual stimulation in rehabilitation and for assessing other cognitive functions.
{"title":"Functional connectivity and graphical topological properties of the visual cortical network of minimally conscious state (MCS) patients","authors":"Zina Li , Jichan Nian , Shuiyan Li , Zhiqing Deng , Hang Wu , Haili Zhong , Xiyan Huang , Pengmin Qin , Jinhui Wang , Qiuyou Xie , Juan Chen","doi":"10.1016/j.brainres.2025.150122","DOIUrl":"10.1016/j.brainres.2025.150122","url":null,"abstract":"<div><div>The Minimally Conscious State (MCS) is a condition in which a patient, following a brain injury, exhibits minimal yet definite behavioral evidence of awareness, representing a crucial transitional state between unconsciousness and the full emergence of consciousness. Assessing preserved cognitive function, particularly visual function, is crucial for diagnosis and rehabilitation, given that vision is the primary source of sensory input. While MCS patients consistently exhibit visual behaviors, such as sustained fixation or pursuit eye movements, previous neuroimaging studies have treated the visual network as a monolith, leaving it unclear which part of their visual cortical neural networks is affected or preserved. Here, we investigated the visual neural network of patients, encompassing 38 visual cortical subregions, from the primary visual cortex (V1), which processes low-level features (e.g., contrast, orientation), to higher-level visual regions that mediate object recognition and visual attention. Threshold-free network-based statistical analysis revealed that inter-hemispheric connectivity is significantly decreased, while intra-hemispheric connectivity is largely preserved in the visual network of MCS patients. Graph-based analysis showed a longer characteristic path length in them, indicating impaired global integration. Nodal analysis revealed that the primary visual cortex (V1) is a more critical hub for information transfer, while the middle and high-level visual areas are less essential in MCS patients than in HCs. These findings provide a detailed characterization of the functional connectivity and topological properties of the visual cortical network in MCS patients, offering crucial insights for stimulus selection when using visual stimulation in rehabilitation and for assessing other cognitive functions.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150122"},"PeriodicalIF":2.6,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leucine-rich repeat neuronal protein 3 (LRRN3) is a multifunctional transmembrane protein with a crucial role in intracellular signal transduction. It is expressed at high levels in neurons. LRRN3 expression has been shown to be associated with Parkinson’s disease (PD) and aging. It is involved in regulating cellular energy metabolism. However, the specific mechanism involved remains undetermined. In this study, we investigated whether LRRN3 can regulate the expression of the key glycolytic enzymes HK2 and LDHA as well as lactate levels. We also studied the expression of the apoptosis-related regulatory factors Bax and Bcl-2 and the mitochondrial structure. We found that LRRN3 can inhibit the expression of HK2 and LDHA and reduce lactate levels in PD models. LRRN3 rescued apoptotic cells, reversed mitochondrial structure damage, and alleviated motor deficits in PD mice. When glycolysis was inhibited in mice treated with 2-deoxy-D-glucose, apoptosis, mitochondrial structure damage, and motor deficits were reversed. Mechanistically, LRRN3 targets and inhibits glycolytic enzymes to enhance lactate homeostasis, ultimately exerting a protective effect on dopaminergic (DA) neurons. Our data indicate that LRRN3 can protect DA neurons by suppressing glycolysis. It holds promise as a potential therapeutic target for PD.
{"title":"LRRN3 protects dopaminergic neurons by inhibiting glycolysis in Parkinson’s disease","authors":"Jinzhao Gao, Kunpeng Qin, Wenke Xian, Jiwen Ren, Anmu Xie, Binghui Hou","doi":"10.1016/j.brainres.2025.150119","DOIUrl":"10.1016/j.brainres.2025.150119","url":null,"abstract":"<div><div>Leucine-rich repeat neuronal protein 3 (LRRN3) is a multifunctional transmembrane protein with a crucial role in intracellular signal transduction. It is expressed at high levels in neurons. LRRN3 expression has been shown to be associated with Parkinson’s disease (PD) and aging. It is involved in regulating cellular energy metabolism. However, the specific mechanism involved remains undetermined. In this study, we investigated whether LRRN3 can regulate the expression of the key glycolytic enzymes HK2 and LDHA as well as lactate levels. We also studied the expression of the apoptosis-related regulatory factors Bax and Bcl-2 and the mitochondrial structure. We found that LRRN3 can inhibit the expression of HK2 and LDHA and reduce lactate levels in PD models. LRRN3 rescued apoptotic cells, reversed mitochondrial structure damage, and alleviated motor deficits in PD mice. When glycolysis was inhibited in mice treated with 2-deoxy-D-glucose, apoptosis, mitochondrial structure damage, and motor deficits were reversed. Mechanistically, LRRN3 targets and inhibits glycolytic enzymes to enhance lactate homeostasis, ultimately exerting a protective effect on dopaminergic (DA) neurons. Our data indicate that LRRN3 can protect DA neurons by suppressing glycolysis. It holds promise as a potential therapeutic target for PD.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150119"},"PeriodicalIF":2.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.brainres.2025.150118
Andrew M. Victoria , Haley E. Capeci , Jade A. Steber , Hailey M. Donald , Piper L. Rennerfeldt , Jeffrey P. Cheng , Eleni H. Moschonas , Corina O. Bondi , Anthony E. Kline
Environmental enrichment (EE) promotes neurobehavioral recovery after traumatic brain injury (TBI). However, most preclinical studies initiate EE immediately after injury, which contrasts with delayed rehabilitation in the clinic. To better model clinical practice, we delayed the onset of EE and administered amantadine (AMT), which exhibits indirect dopaminergic effects, acutely as a therapeutic bridge. We hypothesized that this temporally sequenced combination therapy would improve neurobehavioral outcomes more than either treatment alone. Post-natal day 21 male rats received a controlled cortical impact or sham surgery and housed in standard (STD) conditions. Beginning 24 h post-surgery, daily intraperitoneal injections of AMT (20 mg/kg) or saline vehicle (VEH; 1 mL/kg) were provided for 7 days (bridge phase). On post-operative day 8, a subset transitioned to abbreviated EE (6 h/day). Vestibulomotor (beam-balance), cognition (spatial learning/memory), and affect (shock probe defensive burying) were assessed on days 8–12, 14–20, and 23, respectively. Hippocampal neuron survival was quantified on day 24. EE, regardless of AMT or VEH treatment, and AMT in STD housing, improved motor and cognitive outcomes versus VEH + STD (p < 0.05). Additionally, AMT + EE outperformed VEH + EE in spatial learning and improved memory retention relative to AMT + STD (p < 0.05). All treatment groups engaged quicker with the shock probe and increased burying behavior compared to VEH + STD. Additionally, the AMT + EE group spent more time burying the probe than the AMT + STD and VEH + EE groups (p < 0.05) and did not differ from SHAM controls (p > 0.05). Both EE groups had more CA3 neurons compared to the STD-housed groups (p < 0.05), while no difference in CA1 neurons was observed among the groups (p > 0.05). Overall, these findings reveal that acute AMT treatment augments the efficacy of delayed and abbreviated EE, particularly in cognitive and affective domains, which support the hypothesis. This temporally staged combination therapy may more accurately model clinical care and lead to greater improvement after TBI.
{"title":"Bridging the gap: Acute amantadine augments the neurorehabilitative efficacy of delayed and abbreviated environmental enrichment in a pediatric traumatic brain injury model","authors":"Andrew M. Victoria , Haley E. Capeci , Jade A. Steber , Hailey M. Donald , Piper L. Rennerfeldt , Jeffrey P. Cheng , Eleni H. Moschonas , Corina O. Bondi , Anthony E. Kline","doi":"10.1016/j.brainres.2025.150118","DOIUrl":"10.1016/j.brainres.2025.150118","url":null,"abstract":"<div><div>Environmental enrichment (EE) promotes neurobehavioral recovery after traumatic brain injury (TBI). However, most preclinical studies initiate EE immediately after injury, which contrasts with delayed rehabilitation in the clinic. To better model clinical practice, we delayed the onset of EE and administered amantadine (AMT), which exhibits indirect dopaminergic effects, acutely as a therapeutic bridge. We hypothesized that this temporally sequenced combination therapy would improve neurobehavioral outcomes more than either treatment alone. Post-natal day 21 male rats received a controlled cortical impact or sham surgery and housed in standard (STD) conditions. Beginning 24 h post-surgery, daily intraperitoneal injections of AMT (20 mg/kg) or saline vehicle (VEH; 1 mL/kg) were provided for 7 days (bridge phase). On post-operative day 8, a subset transitioned to abbreviated EE (6 h/day). Vestibulomotor (beam-balance), cognition (spatial learning/memory), and affect (shock probe defensive burying) were assessed on days 8–12, 14–20, and 23, respectively. Hippocampal neuron survival was quantified on day 24. EE, regardless of AMT or VEH treatment, and AMT in STD housing, improved motor and cognitive outcomes versus VEH + STD (<em>p</em> < 0.05). Additionally, AMT + EE outperformed VEH + EE in spatial learning and improved memory retention relative to AMT + STD (<em>p</em> < 0.05). All treatment groups engaged quicker with the shock probe and increased burying behavior compared to VEH + STD. Additionally, the AMT + EE group spent more time burying the probe than the AMT + STD and VEH + EE groups (<em>p</em> < 0.05) and did not differ from SHAM controls (<em>p</em> > 0.05). Both EE groups had more CA3 neurons compared to the STD-housed groups (<em>p</em> < 0.05), while no difference in CA1 neurons was observed among the groups (<em>p</em> > 0.05). Overall, these findings reveal that acute AMT treatment augments the efficacy of delayed and abbreviated EE, particularly in cognitive and affective domains, which support the hypothesis. This temporally staged combination therapy may more accurately model clinical care and lead to greater improvement after TBI.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150118"},"PeriodicalIF":2.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.brainres.2025.150115
Caiti-Erin Talty , Susan F. Murphy , Pamela J. VandeVord
Traumatic brain injury (TBI) is a leading cause of disability worldwide, with approximately 50 % of individuals with mild TBI experiencing persistent, debilitating symptoms. Clinical findings have demonstrated that females are more likely than males to develop chronic symptoms and tend to report greater symptom severity. Despite this, the pathophysiological mechanisms underlying these sex-specific chronic outcomes remain poorly understood. Using a clinically-relevant preclinical model of closed-head controlled impact in adult female rats, we examined affective-like behavior alterations up to twelve weeks post-injury. Injured animals exhibited early increases in risk-taking and disinhibition behaviors, followed by decreased social novelty preference and evidence of increased grooming behavior at eight weeks. Glutamatergic protein expression was measured in the frontal cortex and hippocampus at twelve weeks to assess glutamatergic alterations associated with chronic behavioral outcomes. TBI resulted in elevated expression of N-methyl-D-aspartate receptor subunits GluN1, GluN2A, and GluN2B, along with a decreased GluN2A:GluN2B ratio in the frontal cortex. Additionally, glutamate transporters GLT-1 and GLAST were upregulated in the hippocampus and frontal cortex, respectively. Together, these findings demonstrated that females exhibited dynamic behavioral changes accompanied by region-specific upregulation of glutamatergic signaling proteins. Further investigations are warranted to investigate circuit-level glutamatergic dysfunction and its potential role as a mechanistic driver of chronic TBI-related deficits in females.
外伤性脑损伤（TBI）是世界范围内致残的主要原因，大约50%的轻度TBI患者会出现持续的、使人衰弱的症状。临床研究结果表明，女性比男性更容易出现慢性症状，而且往往报告的症状更严重。尽管如此，这些性别特异性慢性结果的病理生理机制仍然知之甚少。使用与临床相关的成年雌性大鼠闭头控制撞击的临床前模型，我们检查了损伤后12周的情感样行为改变。受伤的动物表现出冒险行为和去抑制行为的早期增加，随后是社会新奇偏好的减少和8周时梳理行为的增加。在12周时测量额叶皮层和海马体中的谷氨酸能蛋白表达，以评估与慢性行为结果相关的谷氨酸能改变。脑外伤导致n -甲基- d -天冬氨酸受体亚基GluN1、GluN2A和GluN2B的表达升高，GluN2A:GluN2B比值降低。此外，海马和额叶皮层的谷氨酸转运体GLT-1和GLAST分别上调。总之，这些发现表明，雌性表现出动态的行为变化，并伴有区域特异性的谷氨酸信号蛋白上调。有必要进一步研究回路水平的谷氨酸能功能障碍及其作为女性慢性创伤性脑损伤相关缺陷的机制驱动因素的潜在作用。
{"title":"Chronic dynamic behavioral changes and upregulation of glutamatergic signaling proteins following traumatic brain injury in females","authors":"Caiti-Erin Talty , Susan F. Murphy , Pamela J. VandeVord","doi":"10.1016/j.brainres.2025.150115","DOIUrl":"10.1016/j.brainres.2025.150115","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a leading cause of disability worldwide, with approximately 50 % of individuals with mild TBI experiencing persistent, debilitating symptoms. Clinical findings have demonstrated that females are more likely than males to develop chronic symptoms and tend to report greater symptom severity. Despite this, the pathophysiological mechanisms underlying these sex-specific chronic outcomes remain poorly understood. Using a clinically-relevant preclinical model of closed-head controlled impact in adult female rats, we examined affective-like behavior alterations up to twelve weeks post-injury. Injured animals exhibited early increases in risk-taking and disinhibition behaviors, followed by decreased social novelty preference and evidence of increased grooming behavior at eight weeks. Glutamatergic protein expression was measured in the frontal cortex and hippocampus at twelve weeks to assess glutamatergic alterations associated with chronic behavioral outcomes. TBI resulted in elevated expression of N-methyl-D-aspartate receptor subunits GluN1, GluN2A, and GluN2B, along with a decreased GluN2A:GluN2B ratio in the frontal cortex. Additionally, glutamate transporters GLT-1 and GLAST were upregulated in the hippocampus and frontal cortex, respectively. Together, these findings demonstrated that females exhibited dynamic behavioral changes accompanied by region-specific upregulation of glutamatergic signaling proteins. Further investigations are warranted to investigate circuit-level glutamatergic dysfunction and its potential role as a mechanistic driver of chronic TBI-related deficits in females.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150115"},"PeriodicalIF":2.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.brainres.2025.150116
You-hai Hua , Xin-yue Huang , Jing-jing Ma , Jin Wu , Zeng-hui Zhou
Objective
Neuroinflammation driven by microglial hyperactivation plays a critical role in Parkinson’s disease (PD). Ezetimibe, a cholesterol absorption inhibitor widely used for hyperlipidemia, has recently been implicated in neuroprotection. However, its impact on microglial activation in PD remains poorly understood. This study aimed to investigate the therapeutic potential and mechanisms of ezetimibe in modulating microglial activation in PD model.
Methods
Network pharmacology was employed to predict ezetimibe targets in PD, followed by validation in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Protein–protein interaction (PPI) analysis and Gene Ontology (GO) enrichment were used to identify relevant pathways. Molecular docking assessed ezetimibe-TLR4 binding. The effects of ezetimibe on pro-inflammatory mediator production, TLR4/JNK signaling, and microglia-induced dopaminergic neurotoxicity were evaluated using western blotting, qPCR, ELISA, and BV2–SH-SY5Y co-culture assays.
Results
Network pharmacology identified 53 common targets between ezetimibe and PD, with TLR4, TNF, and IL-1β as hub genes enriched in inflammatory processes. In BV2 cells, ezetimibe markedly reduced LPS-induced expression and secretion of iNOS, COX-2, Nitric oxide (NO), and IL-6 at both protein and transcriptional levels. Molecular docking revealed a strong binding affinity of ezetimibe to TLR4, although ezetimibe did not alter the basal expression of TLR4. Mechanistically, ezetimibe pretreatment suppressed LPS-induced JNK phosphorylation and AP-1 transcriptional activity, key downstream events of TLR4 activation. Consistently, pharmacological inhibition of TLR4 with TLR4-IN-C34 did not produce additional anti-inflammatory effects, confirming that ezetimibe acts through the TLR4 signaling pathway. Moreover, conditioned medium from ezetimibe-pretreated BV2 cells significantly reduced SH-SY5Y neuronal death, as indicated by decreased PI staining, LDH release, CCK8 assay, tyrosine hydroxylase (TH) protein levels and caspase-3 activation.
Conclusion
Ezetimibe suppresses microglial activation by targeting the TLR4/JNK pathway, thereby alleviating dopaminergic neuronal death. These findings highlight ezetimibe as a promising candidate for repurposing in PD therapy.
目的：由小胶质细胞过度激活驱动的神经炎症在帕金森病（PD）中起关键作用。依折替米贝是一种广泛用于高脂血症的胆固醇吸收抑制剂，最近被认为与神经保护有关。然而，其对PD中小胶质细胞激活的影响仍然知之甚少。本研究旨在探讨依折麦布调节PD模型小胶质细胞活化的治疗潜力和机制。方法采用网络药理学方法预测依zetimibe在PD中的靶点，然后在脂多糖（LPS）刺激的BV2小胶质细胞中进行验证。通过蛋白-蛋白相互作用（PPI）分析和基因本体（GO）富集来确定相关途径。分子对接评估ezetimibe-TLR4结合。采用western blotting、qPCR、ELISA和BV2-SH-SY5Y共培养试验评估依泽替米贝对促炎介质产生、TLR4/JNK信号传导和小胶质细胞诱导的多巴胺能神经毒性的影响。结果网络药理学鉴定了依zetimibe和PD之间的53个共同靶点，其中TLR4、TNF和IL-1β是炎症过程中富集的中心基因。在BV2细胞中，依zetimibe在蛋白和转录水平上显著降低lps诱导的iNOS、COX-2、一氧化氮（NO）和IL-6的表达和分泌。分子对接显示ezetimibe与TLR4有很强的结合亲和力，尽管ezetimibe没有改变TLR4的基础表达。在机制上，依zetimibe预处理抑制了lps诱导的JNK磷酸化和AP-1转录活性，这是TLR4激活的关键下游事件。与此一致的是，TLR4- in - c34对TLR4的药理学抑制并未产生额外的抗炎作用，证实依折麦贝是通过TLR4信号通路起作用的。此外，ezetimibe预处理BV2细胞的条件培养基显著降低了SH-SY5Y神经元的死亡，PI染色、LDH释放、CCK8检测、酪氨酸羟化酶（TH）蛋白水平和caspase-3激活均有所降低。结论依折替米贝通过TLR4/JNK通路抑制小胶质细胞的激活，从而减轻多巴胺能神经元的死亡。这些发现突出了依折麦布在帕金森病治疗中的应用前景。
{"title":"Ezetimibe mitigates microglial activation in Parkinson’s disease via TLR4/JNK pathway inhibition: evidence from network pharmacology and experimental validation","authors":"You-hai Hua , Xin-yue Huang , Jing-jing Ma , Jin Wu , Zeng-hui Zhou","doi":"10.1016/j.brainres.2025.150116","DOIUrl":"10.1016/j.brainres.2025.150116","url":null,"abstract":"<div><h3>Objective</h3><div>Neuroinflammation driven by microglial hyperactivation plays a critical role in Parkinson’s disease (PD). Ezetimibe, a cholesterol absorption inhibitor widely used for hyperlipidemia, has recently been implicated in neuroprotection. However, its impact on microglial activation in PD remains poorly understood. This study aimed to investigate the therapeutic potential and mechanisms of ezetimibe in modulating microglial activation in PD model.</div></div><div><h3>Methods</h3><div>Network pharmacology was employed to predict ezetimibe targets in PD, followed by validation in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Protein–protein interaction (PPI) analysis and Gene Ontology (GO) enrichment were used to identify relevant pathways. Molecular docking assessed ezetimibe-TLR4 binding. The effects of ezetimibe on pro-inflammatory mediator production, TLR4/JNK signaling, and microglia-induced dopaminergic neurotoxicity were evaluated using western blotting, qPCR, ELISA, and BV2–SH-SY5Y co-culture assays.</div></div><div><h3>Results</h3><div>Network pharmacology identified 53 common targets between ezetimibe and PD, with TLR4, TNF, and IL-1β as hub genes enriched in inflammatory processes. In BV2 cells, ezetimibe markedly reduced LPS-induced expression and secretion of iNOS, COX-2, Nitric oxide (NO), and IL-6 at both protein and transcriptional levels. Molecular docking revealed a strong binding affinity of ezetimibe to TLR4, although ezetimibe did not alter the basal expression of TLR4. Mechanistically, ezetimibe pretreatment suppressed LPS-induced JNK phosphorylation and AP-1 transcriptional activity, key downstream events of TLR4 activation. Consistently, pharmacological inhibition of TLR4 with TLR4-IN-C34 did not produce additional anti-inflammatory effects, confirming that ezetimibe acts through the TLR4 signaling pathway. Moreover, conditioned medium from ezetimibe-pretreated BV2 cells significantly reduced SH-SY5Y neuronal death, as indicated by decreased PI staining, LDH release, CCK8 assay, tyrosine hydroxylase (TH) protein levels and caspase-3 activation.</div></div><div><h3>Conclusion</h3><div>Ezetimibe suppresses microglial activation by targeting the TLR4/JNK pathway, thereby alleviating dopaminergic neuronal death. These findings highlight ezetimibe as a promising candidate for repurposing in PD therapy.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150116"},"PeriodicalIF":2.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145789795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1016/j.brainres.2025.150114
Muhammad Maaz Amjad , Hadiya Javed , Muhammad Zuhaz Azeem , Tuyyab Anwer , Bilal Wazir Khan , Muhammad Huzaifa Khattak , Umer Zaryab Khan , Muhammad Ahmed Zahoor , Zobia Tabassum , Muhammad Ehsan , Hafiza Sidra , Habeeb Ahmad , Sarmad Nazir , Komal Khan
Background
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, repetitive behaviors, and loss of interests. Despite the use of conventional treatment such as medication and behavioral therapy, many children and adolescents still experience significant functional impairments. Recent advances in noninvasive brain stimulation have raised the interest of transcranial direct current stimulation (tDCS) in addressing core symptoms of ASD.
Methods
A comprehensive literature search of databases PubMed, Cochrane Library, and Google Scholar for relevant studies was conducted until March 28, 2025. A total of 1,443 records were identified. After duplicate removal and application of inclusion and exclusion criteria, 11 studies contributed to the Meta-analyses, while 28 studies were eligible for the systematic review.
Results
In addressing clinical outcomes, tDCS yielded significant improvement in social communication, the pooled data from 4 studies showed significant improvement in social communication (SMD = − 0.66, 95 % CI [−0.94, −0.39] and p < 0.00001), social awareness was also improved with tDCS (SMD = −0.60; 95 % CI [−1.12, −0.07] and p = 0.03) however, language skill showed no significant improvement (SMD = −0.11; 95 % CI [-0.44, 0.21] and p = 0.50). Moreover, tDCS also showed enhancement in restrictive repetitive behaviors (SMD = −0.60, 95 % CI [−0.85, −0.34] and p < 0.00001). In addition, tDCS generated robust improvements in behavioral symptoms and regulations (SMD = −0.65; 95 % CI [−0.98, −0.32] and p < 0.001). Finally, for overall symptom severity reduction in ASD by tDCS, assessed by SRS score, exhibited statistical improvements (SMD = −0.64; 95 % CI [−0.89, −0.39] and p < 0.00001). However, the pooled analysis of 5 studies assessing ATEC score demonstrated no statistically significant difference (SMD = −0.61; 95 % CI [−1.34, 0.11] and p = 0.10) with high heterogeneity (p = 0.0006, I2 = 80 %). To overcome heterogeneity, we performed a sensitivity analysis, which made the result significant (SMD = −0.95; 95 % CI [−1.41, −0.49] and p < 0.0001) with low heterogeneity (p = 0.16, I2 = 42 %).
Conclusion
tDCS appears to be a promising noninvasive therapy for improving social and behavioral symptoms of ASD. However, large-scale, multi-center RCTs with standardized protocols and longer follow-up durations are essential to determine optimal stimulation parameters and to identify which patients will benefit the most from it.
{"title":"Efficacy of transcranial direct current stimulation in children and adolescents with autism spectrum disorder: A systematic review and meta-analysis","authors":"Muhammad Maaz Amjad , Hadiya Javed , Muhammad Zuhaz Azeem , Tuyyab Anwer , Bilal Wazir Khan , Muhammad Huzaifa Khattak , Umer Zaryab Khan , Muhammad Ahmed Zahoor , Zobia Tabassum , Muhammad Ehsan , Hafiza Sidra , Habeeb Ahmad , Sarmad Nazir , Komal Khan","doi":"10.1016/j.brainres.2025.150114","DOIUrl":"10.1016/j.brainres.2025.150114","url":null,"abstract":"<div><h3>Background</h3><div>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, repetitive behaviors, and loss of interests. Despite the use of conventional treatment such as medication and behavioral therapy, many children and adolescents still experience significant functional impairments. Recent advances in noninvasive brain stimulation have raised the interest of transcranial direct current stimulation (tDCS) in addressing core symptoms of ASD.</div></div><div><h3>Methods</h3><div>A comprehensive literature search of databases PubMed, Cochrane Library, and Google Scholar for relevant studies was conducted until March 28, 2025. A total of 1,443 records were identified. After duplicate removal and application of inclusion and exclusion criteria, 11 studies contributed to the Meta-analyses, while 28 studies were eligible for the systematic review.</div></div><div><h3>Results</h3><div>In addressing clinical outcomes, tDCS yielded significant improvement in social communication, the pooled data from 4 studies showed significant improvement in social communication (SMD = − 0.66, 95 % CI [−0.94, −0.39] and p < 0.00001), social awareness was also improved with tDCS (SMD = −0.60; 95 % CI [−1.12, −0.07] and p = 0.03) however, language skill showed no significant improvement (SMD = −0.11; 95 % CI [-0.44, 0.21] and p = 0.50). Moreover, tDCS also showed enhancement in restrictive repetitive behaviors (SMD = −0.60, 95 % CI [−0.85, −0.34] and p < 0.00001). In addition, tDCS generated robust improvements in behavioral symptoms and regulations (SMD = −0.65; 95 % CI [−0.98, −0.32] and p < 0.001). Finally, for overall symptom severity reduction in ASD by tDCS, assessed by SRS score, exhibited statistical improvements (SMD = −0.64; 95 % CI [−0.89, −0.39] and p < 0.00001). However, the pooled analysis of 5 studies assessing ATEC score demonstrated no statistically significant difference (SMD = −0.61; 95 % CI [−1.34, 0.11] and p = 0.10) with high heterogeneity (p = 0.0006, I2 = 80 %). To overcome heterogeneity, we performed a sensitivity analysis, which made the result significant (SMD = −0.95; 95 % CI [−1.41, −0.49] and p < 0.0001) with low heterogeneity (p = 0.16, I2 = 42 %).</div></div><div><h3>Conclusion</h3><div>tDCS appears to be a promising noninvasive therapy for improving social and behavioral symptoms of ASD. However, large-scale, multi-center RCTs with standardized protocols and longer follow-up durations are essential to determine optimal stimulation parameters and to identify which patients will benefit the most from it.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150114"},"PeriodicalIF":2.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-16DOI: 10.1016/j.brainres.2025.150117
Suman Rekha Dip, Hemant Kumar Meena
Early and accurate identification of Brain Tumors (BT) is one of the most challenging problems due to the complex, non-Euclidean, and irregular characteristics of brain MRI data. Graph Signal Processing (GSP) offers a robust framework for accurately depicting irregular neighborhood connectivities by modeling brain images as signals on graphs and enables the simultaneous analysis of both the spatial and spectral characteristics of the data. A key aspect of GSP is the construction of an appropriate graph, and thus the performance of the resultant graph-based representation and algorithms depends on the definition of the graph used. However, defining such graphs across diverse application domains is often complex. Ideally, the constructed graph should allow the data to exhibit smoothness or regularity over its topology. To overcome this issue, this study discusses the graph Laplacian, or graph topologies, allowing the brain MRI data to vary smoothly across the graph. We utilize this foundation by employing three forms of the graph Laplacian matrix, such as unnormalized, normalized, and random walk, to extract a discriminative Graph Laplacian Spectral (GLS) feature that accurately represents tumor-induced modifications in brain structure. Experimental evaluations of the Br35H and Kaggle-4600 MRI datasets demonstrate that an unnormalized Laplacian-based GLS feature achieves classification accuracies of 98.33% for Br35H and 98.21% for Kaggle-4600, while maintaining minimal computational cost. These classification results validate the potential of GSP and graph topology learning to improve BT detection by providing a highly effective method of modeling the inherent connectivity of brain tissue. Furthermore, the implementation of the proposed framework on the PYNQ-ZU platform has validated the suitability of our framework for efficient and real-time BT classification.
{"title":"Hardware-based brain tumor classification using graph Laplacian spectral features","authors":"Suman Rekha Dip, Hemant Kumar Meena","doi":"10.1016/j.brainres.2025.150117","DOIUrl":"10.1016/j.brainres.2025.150117","url":null,"abstract":"<div><div>Early and accurate identification of Brain Tumors (BT) is one of the most challenging problems due to the complex, non-Euclidean, and irregular characteristics of brain MRI data. Graph Signal Processing (GSP) offers a robust framework for accurately depicting irregular neighborhood connectivities by modeling brain images as signals on graphs and enables the simultaneous analysis of both the spatial and spectral characteristics of the data. A key aspect of GSP is the construction of an appropriate graph, and thus the performance of the resultant graph-based representation and algorithms depends on the definition of the graph used. However, defining such graphs across diverse application domains is often complex. Ideally, the constructed graph should allow the data to exhibit smoothness or regularity over its topology. To overcome this issue, this study discusses the graph Laplacian, or graph topologies, allowing the brain MRI data to vary smoothly across the graph. We utilize this foundation by employing three forms of the graph Laplacian matrix, such as unnormalized, normalized, and random walk, to extract a discriminative Graph Laplacian Spectral (GLS) feature that accurately represents tumor-induced modifications in brain structure. Experimental evaluations of the Br35H and Kaggle-4600 MRI datasets demonstrate that an unnormalized Laplacian-based GLS feature achieves classification accuracies of 98.33% for Br35H and 98.21% for Kaggle-4600, while maintaining minimal computational cost. These classification results validate the potential of GSP and graph topology learning to improve BT detection by providing a highly effective method of modeling the inherent connectivity of brain tissue. Furthermore, the implementation of the proposed framework on the PYNQ-ZU platform has validated the suitability of our framework for efficient and real-time BT classification.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150117"},"PeriodicalIF":2.6,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-15DOI: 10.1016/j.brainres.2025.150113
Thatiany Souza Marinho, Julie Oliveira A. Bittencourt, Marcia Barbosa Aguila, Carlos A. Mandarim-de-Lacerda
Obesity, diabetes, and menopause impair hypothalamic regulation of energy balance by inducing inflammation, cellular stress, and disruption of neuropeptide signaling. In a female mouse model combining these conditions, we investigated whether tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, restores hypothalamic homeostasis by integrating gene and protein expression analyses. Ovariectomized and sham-operated mice were fed either a control or high-fat, high-sucrose diet and then treated with tirzepatide for four weeks. Metabolic and hormonal stress induced robust activation of inflammatory pathways, elevated cytokine and chemokine expression, marked endoplasmic reticulum stress, and enhanced microglial reactivity, accompanied by a shift toward appetite-stimulating neuropeptides and reduced expression of appetite-suppressing neuropeptides. Tirzepatide produced broad hypothalamic benefits, markedly suppressing inflammatory and stress-related markers, reprogramming microglia toward an anti-inflammatory phenotype, and restoring neuropeptide balance by reducing agouti-related peptide and neuropeptide Y while increasing proopiomelanocortin and melanocortin 4 receptor expression. Treatment also lowered suppressor of cytokine signaling 3 and normalized doublecortin expression, indicating enhanced neuronal plasticity and recovery of hypothalamic circuitry. Multivariate analysis demonstrated that tirzepatide shifted the overall hypothalamic molecular profile of obese-diabetic and ovariectomized mice to that of control groups, highlighting coordinated improvement across inflammatory, glial, and neuropeptidergic pathways. In conclusion, these findings show that tirzepatide exerts potent and broad central nervous system actions capable of counteracting hypothalamic inflammation, cellular stress, microglial activation, and neuropeptide dysregulation under severe metabolic–hormonal challenge, supporting its therapeutic potential to restore hypothalamic integrity and metabolic control in obesity and diabetes during menopause.
{"title":"Tirzepatide reverses hypothalamic inflammation, cellular stress, and neuropeptide imbalance in metabolic–menopausal dysfunction","authors":"Thatiany Souza Marinho, Julie Oliveira A. Bittencourt, Marcia Barbosa Aguila, Carlos A. Mandarim-de-Lacerda","doi":"10.1016/j.brainres.2025.150113","DOIUrl":"10.1016/j.brainres.2025.150113","url":null,"abstract":"<div><div>Obesity, diabetes, and menopause impair hypothalamic regulation of energy balance by inducing inflammation, cellular stress, and disruption of neuropeptide signaling. In a female mouse model combining these conditions, we investigated whether tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, restores hypothalamic homeostasis by integrating gene and protein expression analyses. Ovariectomized and sham-operated mice were fed either a control or high-fat, high-sucrose diet and then treated with tirzepatide for four weeks. Metabolic and hormonal stress induced robust activation of inflammatory pathways, elevated cytokine and chemokine expression, marked endoplasmic reticulum stress, and enhanced microglial reactivity, accompanied by a shift toward appetite-stimulating neuropeptides and reduced expression of appetite-suppressing neuropeptides. Tirzepatide produced broad hypothalamic benefits, markedly suppressing inflammatory and stress-related markers, reprogramming microglia toward an anti-inflammatory phenotype, and restoring neuropeptide balance by reducing agouti-related peptide and neuropeptide Y while increasing proopiomelanocortin and melanocortin 4 receptor expression. Treatment also lowered suppressor of cytokine signaling 3 and normalized doublecortin expression, indicating enhanced neuronal plasticity and recovery of hypothalamic circuitry. Multivariate analysis demonstrated that tirzepatide shifted the overall hypothalamic molecular profile of obese-diabetic and ovariectomized mice to that of control groups, highlighting coordinated improvement across inflammatory, glial, and neuropeptidergic pathways. In conclusion, these findings show that tirzepatide exerts potent and broad central nervous system actions capable of counteracting hypothalamic inflammation, cellular stress, microglial activation, and neuropeptide dysregulation under severe metabolic–hormonal challenge, supporting its therapeutic potential to restore hypothalamic integrity and metabolic control in obesity and diabetes during menopause.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1872 ","pages":"Article 150113"},"PeriodicalIF":2.6,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-13DOI: 10.1016/j.brainres.2025.150106
Nian Li , Liqin Zhang , Xu Tian , Yang Zhao , Guodong Feng , Zhiqiang Gao
Introduction
This study investigates the role of central nervous system networks outside the auditory system in the development of tinnitus.
Methods
Twenty Sprague-Dawley rats were exposed to 96 dB SPL narrowband noise (right ear, 1 h); nine unexposed rats served as controls. Tinnitus presence was evaluated through gap prepulse inhibition of acoustic startle (GPIAS-PPI), which divided the exposed rats into tinnitus (ET, n = 8) and non-tinnitus (ENT, n = 12) groups. The auditory brainstem response (ABR) was utilized to evaluate hearing thresholds and wave I parameters. Resting-state fMRI (rs-fMRI) revealed significant increases/decreases in resting-state indices, including the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and functional connectivity.
Results
ABR exhibited no intergroup threshold differences. Post-exposure, ET and ENT groups exhibited a decrease in click-evoked wave I amplitude compared to pre-exposure levels, along with an increase in 8 kHz wave I amplitude compared to controls. Rs-fMRI revealed that the ET group had increased ALFF in the entorhinal cortex, amygdala, hippocampus, and superior colliculus, and decreased ALFF in the cingulate and prelimbic cortices. The ENT group showed increased cerebellar activity and decreased basal forebrain activity. ReHo was elevated in the ET group’s entorhinal/amygdala and reduced in the cingulate cortex, whereas the ENT group showed reduced basal forebrain/striatum ReHo. ET weakened amygdala-sensory connections and ENT enhanced basal forebrain-cingulate/sensory connectivity.
Conclusion
Noise-exposed rats with/without tinnitus exhibit distinct neural activity/connectivity patterns, supporting a noise-cancellation gating mechanism. Compensatory prelimbic cortex/striatum connectivity may prevent tinnitus in the ENT group. Further research should target noise elimination pathways and the hippocampal/entorhinal roles in “abnormal auditory memory.”
前言：本研究探讨了听觉系统外中枢神经网络在耳鸣发展中的作用。方法：将20只Sprague-Dawley大鼠暴露于96 dB SPL的窄带噪声（右耳，1 h）；9只未暴露的大鼠作为对照。通过间隙预脉冲声惊吓抑制法（GPIAS-PPI）评估耳鸣是否存在，将暴露大鼠分为耳鸣组（ET组，n = 8）和非耳鸣组（ENT组，n = 12）。听觉脑干反应（ABR）用于评估听力阈值和波I参数。静息状态fMRI （rs-fMRI）显示静息状态指标显著增加/减少，包括低频波动幅度（ALFF）、区域均匀性（ReHo）和功能连通性。结果：ABR无组间阈值差异。与暴露前相比，暴露后、ET和ENT组的点击诱发波I振幅下降，与对照组相比，8 kHz波I振幅增加。Rs-fMRI显示，ET组内嗅皮层、杏仁核、海马和上丘ALFF升高，扣带皮层和边缘前皮层ALFF降低。耳鼻喉科组小脑活动增加，基底前脑活动减少。ET组内嗅/杏仁核的ReHo升高，扣带皮层的ReHo降低，而耳鼻喉科组基底前脑/纹状体的ReHo降低。ET削弱了杏仁核-感觉连接，而耳鼻喉科增强了基底前脑-扣带/感觉连接。结论：噪声暴露大鼠有/无耳鸣表现出明显的神经活动/连接模式，支持噪声消除门控机制。代偿性边缘皮层/纹状体连接可预防耳鼻喉科组的耳鸣。进一步的研究应该针对噪音消除途径和海马/内嗅在“异常听觉记忆”中的作用。
{"title":"Differential neural activity and connectivity patterns in rats with and without noise-induced tinnitus","authors":"Nian Li , Liqin Zhang , Xu Tian , Yang Zhao , Guodong Feng , Zhiqiang Gao","doi":"10.1016/j.brainres.2025.150106","DOIUrl":"10.1016/j.brainres.2025.150106","url":null,"abstract":"<div><h3>Introduction</h3><div>This study investigates the role of central nervous system networks outside the auditory system in the development of tinnitus.</div></div><div><h3>Methods</h3><div>Twenty Sprague-Dawley rats were exposed to 96 dB SPL narrowband noise (right ear, 1 h); nine unexposed rats served as controls. Tinnitus presence was evaluated through gap prepulse inhibition of acoustic startle (GPIAS-PPI), which divided the exposed rats into tinnitus (ET, n = 8) and non-tinnitus (ENT, n = 12) groups. The auditory brainstem response (ABR) was utilized to evaluate hearing thresholds and wave I parameters. Resting-state fMRI (rs-fMRI) revealed significant increases/decreases in resting-state indices, including the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and functional connectivity.</div></div><div><h3>Results</h3><div>ABR exhibited no intergroup threshold differences. Post-exposure, ET and ENT groups exhibited a decrease in click-evoked wave I amplitude compared to pre-exposure levels, along with an increase in 8 kHz wave I amplitude compared to controls. Rs-fMRI revealed that the ET group had increased ALFF in the entorhinal cortex, amygdala, hippocampus, and superior colliculus, and decreased ALFF in the cingulate and prelimbic cortices. The ENT group showed increased cerebellar activity and decreased basal forebrain activity. ReHo was elevated in the ET group’s entorhinal/amygdala and reduced in the cingulate cortex, whereas the ENT group showed reduced basal forebrain/striatum ReHo. ET weakened amygdala-sensory connections and ENT enhanced basal forebrain-cingulate/sensory connectivity.</div></div><div><h3>Conclusion</h3><div>Noise-exposed rats with/without tinnitus exhibit distinct neural activity/connectivity patterns, supporting a noise-cancellation gating mechanism. Compensatory prelimbic cortex/striatum connectivity may prevent tinnitus in the ENT group. Further research should target noise elimination pathways and the hippocampal/entorhinal roles in “abnormal auditory memory.”</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1872 ","pages":"Article 150106"},"PeriodicalIF":2.6,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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