Coordinated movement relies on the proper integration of multiple neural circuits. Motor training can alter the excitability of neural circuits controlling movement, but the pathway-specific effects to the lower limb of motor skill versus isometric resistance training remain unclear. Here, we tested how single 30-minute sessions of cue-paced motor skill and isometric resistance training modulate corticospinal, reticulospinal, and spinal excitability in unimpaired adults (N = 23). Using motor-evoked potentials via transcranial magnetic stimulation, we found motor skill training increased corticospinal excitability, while isometric resistance training did not. In contrast, by assessing reticulospinal tract excitability by StartReact responses and measuring spinal excitability with H/M ratios, F-wave response amplitude, and persistence, we found that each tract’s excitability remained largely unchanged. These results suggest that short-term motor skill training selectively enhances corticospinal tract excitability without a measurable impact on spinal or reticulospinal circuits. These results highlight the influence of task complexity on distal lower limb excitability and provide a framework for evaluating neural adaptations across corticospinal, reticulospinal, and spinal circuits.
{"title":"Transient effects in corticospinal and reticulospinal tract excitability induced by motor skill and isometric resistance training","authors":"Rachel Hawthorn , Natalie Phelps , Carolyn Atkinson , Rodolfo Keesey , Zachary Seitz , Haolin Nie , Ismael Seáñez","doi":"10.1016/j.brainres.2025.150132","DOIUrl":"10.1016/j.brainres.2025.150132","url":null,"abstract":"<div><div>Coordinated movement relies on the proper integration of multiple neural circuits. Motor training can alter the excitability of neural circuits controlling movement, but the pathway-specific effects to the lower limb of motor skill versus isometric resistance training remain unclear. Here, we tested how single 30-minute sessions of cue-paced motor skill and isometric resistance training modulate corticospinal, reticulospinal, and spinal excitability in unimpaired adults (N = 23). Using motor-evoked potentials via transcranial magnetic stimulation, we found motor skill training increased corticospinal excitability, while isometric resistance training did not. In contrast, by assessing reticulospinal tract excitability by StartReact responses and measuring spinal excitability with H/M ratios, F-wave response amplitude, and persistence, we found that each tract’s excitability remained largely unchanged. These results suggest that short-term motor skill training selectively enhances corticospinal tract excitability without a measurable impact on spinal or reticulospinal circuits. These results highlight the influence of task complexity on distal lower limb excitability and provide a framework for evaluating neural adaptations across corticospinal, reticulospinal, and spinal circuits.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1874 ","pages":"Article 150132"},"PeriodicalIF":2.6,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892024","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 : 2025-12-31DOI: 10.1016/j.brainres.2025.150139
Paulina Borkowska , Aleksandra Krawczyk , Malgorzata Kowalczyk , Aleksandra Zielinska , Dariusz Kusmierz , Magdalena B. Rother , Monika Paul-Samojedny
Background
Neurological disorders cause over 11 million deaths annually worldwide, highlighting the urgent need for new therapeutic strategies to improve current treatment outcomes. Nerve growth factor (NGF) is a key regulator of neuronal survival, and modifying mesenchymal stem cells (MSC) to enhance their neurotrophic activity is a promising therapeutic strategy. However, the broader molecular consequences of NGF overexpression in MSC remain unclear. This study examined how NGF overexpression affects neurotrophin secretion and apoptosis-related protein expression in Wharton’s jelly MSC (WJ-MSC).
Methods
WJ-MSC were lentivirally transduced to overexpress NGF and differentiated for 12 days. NGF, BDNF, TrkA, TrkB, IL-13, and TNF-α were quantified using ELISA (n = 3 biological replicates; assays in duplicate). Thirty-five apoptosis-related proteins were assessed using the Proteome Profiler Human Apoptosis Array (assays in duplicate). Data were analyzed using one-way ANOVA or multiple t-test.
Results
NGF overexpression increased extracellular NGF (↑∼220 %, p < 0.0001) and reduced BDNF secretion (↓∼35 %, p < 0.05). Soluble phosphorylated TrkA/TrkB increased significantly in supernatants (↑30–60 %, p < 0.05). IL-13 rose modestly without statistical significance, and TNF-α remained undetectable. Early proteome changes showed upregulation of pro-apoptotic proteins (p21 ↑97 %, phospho-p53 ↑30 %) with concurrent reductions in anti-apoptotic markers (BCL2 ↓66 %, HSP60 ↓58 %). After 12 days, the apoptotic profile remained predominantly pro-apoptotic, despite selective increases in BCLXL (↑92 %), clusterin (↑102 %), and survivin (↑38 %) indicating only partial compensatory responses.
Conclusions
NGF overexpression enhances neurotrophin-related signaling but produces a sustained pro-apoptotic shift in WJ-MSC, suggesting limited benefit for cell survival. These findings require confirmation using functional apoptosis assays and in vivo models.
{"title":"The impact of NGF overexpression on proteome profile in WJ-MSC cultures","authors":"Paulina Borkowska , Aleksandra Krawczyk , Malgorzata Kowalczyk , Aleksandra Zielinska , Dariusz Kusmierz , Magdalena B. Rother , Monika Paul-Samojedny","doi":"10.1016/j.brainres.2025.150139","DOIUrl":"10.1016/j.brainres.2025.150139","url":null,"abstract":"<div><h3>Background</h3><div>Neurological disorders cause over 11 million deaths annually worldwide, highlighting the urgent need for new therapeutic strategies to improve current treatment outcomes. Nerve growth factor (NGF) is a key regulator of neuronal survival, and modifying mesenchymal stem cells (MSC) to enhance their neurotrophic activity is a promising therapeutic strategy. However, the broader molecular consequences of NGF overexpression in MSC remain unclear. This study examined how NGF overexpression affects neurotrophin secretion and apoptosis-related protein expression in Wharton’s jelly MSC (WJ-MSC).</div></div><div><h3>Methods</h3><div>WJ-MSC were lentivirally transduced to overexpress NGF and differentiated for 12 days. NGF, BDNF, TrkA, TrkB, IL-13, and TNF-α were quantified using ELISA (n = 3 biological replicates; assays in duplicate). Thirty-five apoptosis-related proteins were assessed using the Proteome Profiler Human Apoptosis Array (assays in duplicate). Data were analyzed using one-way ANOVA or multiple <em>t</em>-test.</div></div><div><h3>Results</h3><div>NGF overexpression increased extracellular NGF (↑∼220 %, p < 0.0001) and reduced BDNF secretion (↓∼35 %, p < 0.05). Soluble phosphorylated TrkA/TrkB increased significantly in supernatants (↑30–60 %, p < 0.05). IL-13 rose modestly without statistical significance, and TNF-α remained undetectable. Early proteome changes showed upregulation of pro-apoptotic proteins (p21 ↑97 %, phospho-p53 ↑30 %) with concurrent reductions in anti-apoptotic markers (BCL2 ↓66 %, HSP60 ↓58 %). After 12 days, the apoptotic profile remained predominantly pro-apoptotic, despite selective increases in BCLXL (↑92 %), clusterin (↑102 %), and survivin (↑38 %) indicating only partial compensatory responses.</div></div><div><h3>Conclusions</h3><div>NGF overexpression enhances neurotrophin-related signaling but produces a sustained pro-apoptotic shift in WJ-MSC, suggesting limited benefit for cell survival. These findings require confirmation using functional apoptosis assays and in vivo models.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1874 ","pages":"Article 150139"},"PeriodicalIF":2.6,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892064","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 : 2025-12-30DOI: 10.1016/j.brainres.2025.150137
Haniyeh Soheil Beygi , Ali Shahraki , Roghayeh Sheervalilou
Background and aim
Glioblastoma (GBM) is a lethal brain cancer demanding novel therapeutic targets. This study integrated bioinformatics to identify hub genes and dysregulated pathways in GBM.
Methods
Gene expression profiles (GSE108474: 221 GBM, 28 normal samples) were analyzed using R (Limma, clusterProfiler, BioBase). Differentially expressed genes (DEGs) were defined by |logFC| > 1 and adjusted p < 0.01. Gene Ontology (GO) and KEGG pathway enrichment (p < 0.05), protein–protein interaction network construction (STRING/Cytoscape), and hub gene validation using TCGA-GBM/GTEx data (GEPIA2; 163 tumor, 207 normal) were performed. Immune infiltration (xCell algorithm; 64 cell types) and prognostic significance (Kaplan-Meier/log-rank tests) were assessed.
Results
We identified 5,710 DEGs, significantly enriched in actin cytoskeleton regulation. Eleven hub genes were validated: upregulated (PECAM1, PXDN, RPL27, RPL12, EIF3B, ENG, TGFB2, THBS1) and downregulated (CAMK2B, FGF22, RASGRF1). Hub genes correlated strongly with immunosuppressive cells: FGF22 and CAMK2B negatively correlated with M2 macrophages, while PECAM1, PXDN, RPL27, and ENG positively correlated. Consistent correlations were observed with B cells and regulatory T cells. Survival analysis revealed high THBS1 expression associated with poorer overall survival (HR = 1.4, p < 0.05) and disease-free survival (HR = 1.9, p < 0.05). Elevated ENG also reduced disease-free survival (HR = 1.7, p < 0.05).
Conclusion
THBS1 and ENG are significant prognostic biomarkers and potential therapeutic targets in GBM. Their strong correlation with immunosuppressive M2 macrophage infiltration implicates actin cytoskeleton remodeling pathways in GBM-mediated immune evasion. Targeting these hub genes may disrupt critical tumor microenvironment interactions, offering new avenues for therapy.
{"title":"Identification of hub genes and signaling pathways as possible therapeutic targets in human glioblastoma: evidenced by bioinformatics analysis","authors":"Haniyeh Soheil Beygi , Ali Shahraki , Roghayeh Sheervalilou","doi":"10.1016/j.brainres.2025.150137","DOIUrl":"10.1016/j.brainres.2025.150137","url":null,"abstract":"<div><h3>Background and aim</h3><div>Glioblastoma (GBM) is a lethal brain cancer demanding novel therapeutic targets. This study integrated bioinformatics to identify hub genes and dysregulated pathways in GBM.</div></div><div><h3>Methods</h3><div>Gene expression profiles (GSE108474: 221 GBM, 28 normal samples) were analyzed using R (Limma, clusterProfiler, BioBase). Differentially expressed genes (DEGs) were defined by |logFC| > 1 and adjusted p < 0.01. Gene Ontology (GO) and KEGG pathway enrichment (p < 0.05), protein–protein interaction network construction (STRING/Cytoscape), and hub gene validation using TCGA-GBM/GTEx data (GEPIA2; 163 tumor, 207 normal) were performed. Immune infiltration (xCell algorithm; 64 cell types) and prognostic significance (Kaplan-Meier/log-rank tests) were assessed.</div></div><div><h3>Results</h3><div>We identified 5,710 DEGs, significantly enriched in actin cytoskeleton regulation. Eleven hub genes were validated: upregulated (PECAM1, PXDN, RPL27, RPL12, EIF3B, ENG, TGFB2, THBS1) and downregulated (CAMK2B, FGF22, RASGRF1). Hub genes correlated strongly with immunosuppressive cells: FGF22 and CAMK2B negatively correlated with M2 macrophages, while PECAM1, PXDN, RPL27, and ENG positively correlated. Consistent correlations were observed with B cells and regulatory T cells. Survival analysis revealed high THBS1 expression associated with poorer overall survival (HR = 1.4, p < 0.05) and disease-free survival (HR = 1.9, p < 0.05). Elevated ENG also reduced disease-free survival (HR = 1.7, p < 0.05).</div></div><div><h3>Conclusion</h3><div>THBS1 and ENG are significant prognostic biomarkers and potential therapeutic targets in GBM. Their strong correlation with immunosuppressive M2 macrophage infiltration implicates actin cytoskeleton remodeling pathways in GBM-mediated immune evasion. Targeting these hub genes may disrupt critical tumor microenvironment interactions, offering new avenues for therapy.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1874 ","pages":"Article 150137"},"PeriodicalIF":2.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888615","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 : 2025-12-27DOI: 10.1016/j.brainres.2025.150136
Øyvind A. Høydal , Runa R.G. Notøy , Kjetil L. Høydal
With a rising prevalence of the major mood disorders, recent years have seen a growing interest in the potential therapeutic value of lifestyle practises such as exercise and thermotherapy. While the beneficial effects of exercise on mental health are now well documented, the potential benefits of thermotherapy are less studied. Similarly to exercise, passive heat- and cold exposure may induce physiological responses which counteract the pathophysiological underpinnings of mood disorders such as depression and anxiety. Thus, for prevention or treatment of mood disorders, thermotherapy could complement exercise or be a viable alternative for people with injuries or disability. Here, we first review physiological adaptations to passive heat- or cold treatment in the context of hypotheses for the pathogenesis of depression. Next, we review clinical interventions investigating effects of passive heat- or cold treatment on depressive disorder, before ending with a discussion of future directions.
{"title":"Can thermotherapy mitigate depression? A review of physiological adaptations and clinical evidence","authors":"Øyvind A. Høydal , Runa R.G. Notøy , Kjetil L. Høydal","doi":"10.1016/j.brainres.2025.150136","DOIUrl":"10.1016/j.brainres.2025.150136","url":null,"abstract":"<div><div>With a rising prevalence of the major mood disorders, recent years have seen a growing interest in the potential therapeutic value of lifestyle practises such as exercise and thermotherapy. While the beneficial effects of exercise on mental health are now well documented, the potential benefits of thermotherapy<!--> <!-->are less studied. Similarly to exercise, passive heat- and cold exposure may induce physiological responses which counteract the pathophysiological underpinnings of mood disorders such as depression and anxiety. Thus, for prevention or treatment of mood disorders, thermotherapy could complement exercise or be a viable alternative for people with injuries or disability. Here, we first review physiological adaptations to passive heat- or cold treatment in the context of hypotheses for the<!--> <!-->pathogenesis of depression. Next, we review clinical interventions investigating effects of passive heat- or cold treatment on depressive disorder, before ending with a discussion of future directions.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150136"},"PeriodicalIF":2.6,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145854423","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}
Neurodegenerative disorders—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—are increasingly understood to have origins in early neurodevelopmental disturbances. This review examines how genetic, epigenetic, and environmental factors impact brain development during critical periods, predisposing individuals to neurodegeneration later in life. Prenatal and early-life exposures such as maternal stress, malnutrition, infection, and environmental toxins can alter key developmental processes, leading to long-term vulnerability. Mechanistic pathways linking early-life disruptions to neurodegenerative outcomes include persistent mitochondrial dysfunction, chronic neuroinflammation, increased oxidative stress, and aberrant synaptic pruning, all of which contribute to progressive neuronal damage and dysfunction. The gut-brain axis is also discussed as a key intermediary, where early microbiota dysbiosis alters neuroimmune signaling and inflammatory responses, modulating susceptibility to age-related neurological disorders. In this context, the review highlights emerging molecular and imaging biomarkers capable of detecting subtle neurodevelopmental deviations that may precede clinical symptoms by decades. The paper emphasizes the need for early-life interventions, including maternal nutritional optimization, management of prenatal stress, and microbiome-targeted strategies, as potential tools to reduce long-term neurological risk. Furthermore, it proposes the integration of precision medicine approaches aimed at individualized risk assessment and therapeutic targeting of developmental pathways. Adopting a lifespan perspective, this review argues for a paradigm shift from reactive to preventive strategies in neurology. Understanding the developmental roots of neurodegeneration opens new avenues for research and intervention, enabling resilience and reducing disease burden through early diagnostics and tailored therapeutics across the lifespan.
{"title":"Neurodevelopmental origins of neurodegeneration: a lifespan perspective on brain vulnerability","authors":"Spandana Rajendra Kopalli , Nasir Vadia , Pooja Varma , Swati Mishra , Neha Joshi , Pooja Bansal , Shaker Al-Hasnaawei , Ashish Singh Chauhan , Hardik Jain , Deepak Nathiya , Anita Devi , Hanish Singh Jayasingh Chellammal , Priyanka Gupta , Pranay Wal , Sushruta Koppula","doi":"10.1016/j.brainres.2025.150134","DOIUrl":"10.1016/j.brainres.2025.150134","url":null,"abstract":"<div><div>Neurodegenerative disorders—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—are increasingly understood to have origins in early neurodevelopmental disturbances. This review examines how genetic, epigenetic, and environmental factors impact brain development during critical periods, predisposing individuals to neurodegeneration later in life. Prenatal and early-life exposures such as maternal stress, malnutrition, infection, and environmental toxins can alter key developmental processes, leading to long-term vulnerability. Mechanistic pathways linking early-life disruptions to neurodegenerative outcomes include persistent mitochondrial dysfunction, chronic neuroinflammation, increased oxidative stress, and aberrant synaptic pruning, all of which contribute to progressive neuronal damage and dysfunction. The gut-brain axis is also discussed as a key intermediary, where early microbiota dysbiosis alters neuroimmune signaling and inflammatory responses, modulating susceptibility to age-related neurological disorders. In this context, the review highlights emerging molecular and imaging biomarkers capable of detecting subtle neurodevelopmental deviations that may precede clinical symptoms by decades. The paper emphasizes the need for early-life interventions, including maternal nutritional optimization, management of prenatal stress, and microbiome-targeted strategies, as potential tools to reduce long-term neurological risk. Furthermore, it proposes the integration of precision medicine approaches aimed at individualized risk assessment and therapeutic targeting of developmental pathways. Adopting a lifespan perspective, this review argues for a paradigm shift from reactive to preventive strategies in neurology. Understanding the developmental roots of neurodegeneration opens new avenues for research and intervention, enabling resilience and reducing disease burden through early diagnostics and tailored therapeutics across the lifespan.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150134"},"PeriodicalIF":2.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848897","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 : 2025-12-24DOI: 10.1016/j.brainres.2025.150135
Cinthia Coria-Lucero , Mariana Lopez , Sandra Gomez-Mejiba , Dario Ramirez , María Belén Delsouc , Marilina Casais , Richard Alba , Jorge Leporatti , Silvia Delgado , Ana Cecilia Anzulovich , Lorena Navigatore-Fonzo
Alzheimer’s dementia (AD) is a neurodegenerative disorder that causes memory loss and dementia in older adults. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, oxidative damage, neuroinflammation, synaptic loss and neuronal cell death. The accumulation of Aβ in the brain plays a key role in the pathogenesis of AD. Elevated levels of Aβ causes an increase in oxidative damage and neuroinflammation both are considered key factors in the progression of AD. Also patients with Alzheimer’s show alterations in their circadian rhythms. Our objectives were (a) to analyze whether inflammation and cognition-related factors exhibit a day-night variation, (b) to verify whether antioxidant enzymes expression and activity exhibit a daily rhythm in the rat temporal cortex and (c) to evaluate the effects of an intracerebroventricular injection of Aβ-amyloid (1–42) aggregates on those temporal profiles. Four-month old males Holtzman rats were used in this study. Groups were defined as: 1) control 2) Aβ-injected. Rats were maintained under 12 h-Light:12 h-Dark conditions with food ad-libitum. Our results showed temporal patterns of nitrites, iNOS, catalase and glutathione peroxidase expression and activity, as well as Rc3 and Gap-43 mRNA, in the rat temporal cortex. An i.c.v. injection of Aβ abolishes the temporal pattern of Rc3 and Gap-43 mRNA. Also increased the rhythm’s mesor of NO and iNOS levels, reduced the mesor of CAT activity rhythms, and changed the phase of GPx activity patterns. These alterations in the temporal patterns of inflammation and redox status-related factors would affect cellular clock activity and consequently cognitive performance.
{"title":"Daily temporal organization of inflammation and cognition-related factors and antioxidant enzymes are modified by an intracerebroventricular injection of amyloid-beta peptide (1–42) aggregates in the rat temporal cortex","authors":"Cinthia Coria-Lucero , Mariana Lopez , Sandra Gomez-Mejiba , Dario Ramirez , María Belén Delsouc , Marilina Casais , Richard Alba , Jorge Leporatti , Silvia Delgado , Ana Cecilia Anzulovich , Lorena Navigatore-Fonzo","doi":"10.1016/j.brainres.2025.150135","DOIUrl":"10.1016/j.brainres.2025.150135","url":null,"abstract":"<div><div>Alzheimer’s dementia (AD) is a neurodegenerative disorder that causes memory loss and dementia in older adults. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, oxidative damage, neuroinflammation, synaptic loss and neuronal cell death. The accumulation of Aβ in the brain plays a key role in the pathogenesis of AD. Elevated levels of Aβ causes an increase in oxidative damage and neuroinflammation both are considered key factors in the progression of AD. Also patients with Alzheimer’s show alterations in their circadian rhythms. Our objectives were (a) to analyze whether inflammation and cognition-related factors exhibit a day-night variation, (b) to verify whether antioxidant enzymes expression and activity exhibit a daily rhythm in the rat temporal cortex and (c) to evaluate the effects of an intracerebroventricular injection of Aβ-amyloid (1–42) aggregates on those temporal profiles. Four-month old males Holtzman rats were used in this study. Groups were defined as: 1) control 2) Aβ-injected. Rats were maintained under 12 h-Light:12 h-Dark conditions with food ad-libitum. Our results showed temporal patterns of nitrites, iNOS, catalase and glutathione peroxidase expression and activity, as well as Rc3 and Gap-43 mRNA, in the rat temporal cortex. An i.c.v. injection of Aβ abolishes the temporal pattern of Rc3 and Gap-43 mRNA. Also increased the rhythm’s mesor of NO and iNOS levels, reduced the mesor of CAT activity rhythms, and changed the phase of GPx activity patterns. These alterations in the temporal patterns of inflammation and redox status-related factors would affect cellular clock activity and consequently cognitive performance.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1874 ","pages":"Article 150135"},"PeriodicalIF":2.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843530","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 : 2025-12-23DOI: 10.1016/j.brainres.2025.150133
Zhi Wen , Yuan-Zhi He , Zhan-Xiang Hu , Xin Huang , Bao-jun Xie
Parkinson’s disease (PD) is characterized by widespread motor and non-motor impairments; however, the temporal dynamics underlying these functional disruptions remain unclear. The intrinsic neural timescale (INT), a novel neuroimaging metric that reflects the capacity of brain regions to integrate information over time, provides new insights into cortical hierarchy and dysfunction. In this study, we examined voxel-wise and network-level alterations in INT among PD patients using resting-state fMRI and integrated their molecular correlates with transcriptomic data from the Allen Human Brain Atlas and PET-derived neurotransmitter receptor maps. Our analysis revealed localized reductions in INT in the left insula, Rolandic operculum, and middle temporal gyrus in PD, while large-scale network hierarchies remained preserved. Partial least squares regression analysis indicated that changes in INT were significantly associated with spatial gene expression gradients, particularly those involving immune-metabolic stress and synaptic maintenance. Furthermore, cell-type enrichment analysis identified excitatory and inhibitory neurons as key cellular contributors. Notably, INT alterations correlated with cortical GABAA receptor density, suggesting a role for inhibitory neurotransmission in temporal integration deficits. These findings highlight a multiscale pathophysiological framework linking functional brain dynamics, molecular architecture, and neurochemical modulation in PD.
{"title":"Molecular and neurochemical underpinnings of altered intrinsic neural timescales in Parkinson’s disease: a multimodal imaging and transcriptomics study","authors":"Zhi Wen , Yuan-Zhi He , Zhan-Xiang Hu , Xin Huang , Bao-jun Xie","doi":"10.1016/j.brainres.2025.150133","DOIUrl":"10.1016/j.brainres.2025.150133","url":null,"abstract":"<div><div>Parkinson’s disease (PD) is characterized by widespread motor and non-motor impairments; however, the temporal dynamics underlying these functional disruptions remain unclear. The intrinsic neural timescale (INT), a novel neuroimaging metric that reflects the capacity of brain regions to integrate information over time, provides new insights into cortical hierarchy and dysfunction. In this study, we examined voxel-wise and network-level alterations in INT among PD patients using resting-state fMRI and integrated their molecular correlates with transcriptomic data from the Allen Human Brain Atlas and PET-derived neurotransmitter receptor maps. Our analysis revealed localized reductions in INT in the left insula, Rolandic operculum, and middle temporal gyrus in PD, while large-scale network hierarchies remained preserved. Partial least squares regression analysis indicated that changes in INT were significantly associated with spatial gene expression gradients, particularly those involving immune-metabolic stress and synaptic maintenance. Furthermore, cell-type enrichment analysis identified excitatory and inhibitory neurons as key cellular contributors. Notably, INT alterations correlated with cortical GABAA receptor density, suggesting a role for inhibitory neurotransmission in temporal integration deficits. These findings highlight a multiscale pathophysiological framework linking functional brain dynamics, molecular architecture, and neurochemical modulation in PD.</div></div>","PeriodicalId":9083,"journal":{"name":"Brain Research","volume":"1873 ","pages":"Article 150133"},"PeriodicalIF":2.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833011","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 : 2025-12-21DOI: 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}
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