Pub Date : 2025-10-09DOI: 10.1016/j.eplepsyres.2025.107676
Yun-Ju Hsieh , Fang-Chia Chang , Chiung-Hui Liu , Yi-Tse Hsiao , Wen-Chieh Liao , Ru-Yin Tsai , Ciptasari Prabawanti , Chih-Li Lin , Ching-Sui Hung , Ying-Jui Ho
An imbalance between excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmitters is a key mechanism in epilepsy. Astrocytic glutamate transporter-1 (GLT-1) helps reuptake glutamate in the synaptic cleft to maintain glutamate concentration and prevent neuronal hyperactivity. Sulbactam (SUL), a β-lactam drug, increases GLT-1 expression. Valproate (VPA) is a first-line antiepileptic drug. The current study evaluated the effects of SUL and VPA on histology and electroencephalography in a pentylenetetrazol (PTZ)-induced epilepsy rat model.
Male Wistar rats received intraperitoneal injection of PTZ (20–35 mg/kg, every other day) for 25 days (13 injections in total) to establish an epilepsy model. From day 26, saline, SUL (50 or 150 mg/kg), VPA (50 mg/kg), or a combination of SUL and VPA was intraperitoneally administered daily for 25 days. Electroencephalography recordings were taken on day 46 or 47. Brains were used for histological analyses.
Electrophysiological results indicated that during the PTZ challenge session, the epilepsy group had significantly more spikes and seizures and higher delta, theta, and beta power compared with the control group. SUL at 150 mg/kg and the combination of SUL (50 mg/kg) and VPA (50 mg/kg) significantly reduced the numbers of spikes and seizures. SUL at both 50 and 150 mg/kg and the combination of SUL (50 mg/kg) and VPA (50 mg/kg) significantly inhibited the increase in delta, theta, and beta power. In terms of histology, the epilepsy group exhibited lower neuronal density in the hippocampus, lower GLT-1 expression in astrocytes, lower GABAergic density, and hyperactivity in the subthalamic nucleus. These neurophysiological impairments were restored by treatment with SUL and a combination of SUL and VPA. The results suggest that SUL increases GLT-1 expression in astrocytes and the number of GABAergic neurons, indicating it holds potential as an antiepileptic treatment.
{"title":"Histological and electrophysiological effects of sulbactam and valproate in the PTZ-induced epileptic rat model","authors":"Yun-Ju Hsieh , Fang-Chia Chang , Chiung-Hui Liu , Yi-Tse Hsiao , Wen-Chieh Liao , Ru-Yin Tsai , Ciptasari Prabawanti , Chih-Li Lin , Ching-Sui Hung , Ying-Jui Ho","doi":"10.1016/j.eplepsyres.2025.107676","DOIUrl":"10.1016/j.eplepsyres.2025.107676","url":null,"abstract":"<div><div>An imbalance between excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmitters is a key mechanism in epilepsy. Astrocytic glutamate transporter-1 (GLT-1) helps reuptake glutamate in the synaptic cleft to maintain glutamate concentration and prevent neuronal hyperactivity. Sulbactam (SUL), a β-lactam drug, increases GLT-1 expression. Valproate (VPA) is a first-line antiepileptic drug. The current study evaluated the effects of SUL and VPA on histology and electroencephalography in a pentylenetetrazol (PTZ)-induced epilepsy rat model.</div><div>Male Wistar rats received intraperitoneal injection of PTZ (20–35 mg/kg, every other day) for 25 days (13 injections in total) to establish an epilepsy model. From day 26, saline, SUL (50 or 150 mg/kg), VPA (50 mg/kg), or a combination of SUL and VPA was intraperitoneally administered daily for 25 days. Electroencephalography recordings were taken on day 46 or 47. Brains were used for histological analyses.</div><div>Electrophysiological results indicated that during the PTZ challenge session, the epilepsy group had significantly more spikes and seizures and higher delta, theta, and beta power compared with the control group. SUL at 150 mg/kg and the combination of SUL (50 mg/kg) and VPA (50 mg/kg) significantly reduced the numbers of spikes and seizures. SUL at both 50 and 150 mg/kg and the combination of SUL (50 mg/kg) and VPA (50 mg/kg) significantly inhibited the increase in delta, theta, and beta power. In terms of histology, the epilepsy group exhibited lower neuronal density in the hippocampus, lower GLT-1 expression in astrocytes, lower GABAergic density, and hyperactivity in the subthalamic nucleus. These neurophysiological impairments were restored by treatment with SUL and a combination of SUL and VPA. The results suggest that SUL increases GLT-1 expression in astrocytes and the number of GABAergic neurons, indicating it holds potential as an antiepileptic treatment.</div></div>","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"218 ","pages":"Article 107676"},"PeriodicalIF":2.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344419","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 : 2025-10-08DOI: 10.1016/j.eplepsyres.2025.107674
Arkansh Sharma , Vinay Suresh
{"title":"Comment on the meta-analysis comparing phenobarbital and valproate for the treatment of generalized convulsive status epilepticus","authors":"Arkansh Sharma , Vinay Suresh","doi":"10.1016/j.eplepsyres.2025.107674","DOIUrl":"10.1016/j.eplepsyres.2025.107674","url":null,"abstract":"","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"217 ","pages":"Article 107674"},"PeriodicalIF":2.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274154","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 : 2025-10-03DOI: 10.1016/j.eplepsyres.2025.107670
Emma Acerbo , Thomas Eggers , Alejandra M. Fernandez , Robert E. Gross , Claire-Anne Gutekunst
Epilepsy affects approximately 1 % of the global population, presenting as a complex and heterogeneous disorder characterized by spontaneous, recurrent seizures. Focal onset seizures comprise half of all epilepsy cases. Mesial temporal lobe epilepsy (MTLE), the most prevalent form of focal seizures in adults, originates in the temporal lobe and is challenging to manage with standard antiseizure medications. Deep brain stimulation (DBS) targeting the anterior nucleus of the thalamus (ANT) has emerged as a therapeutic option for drug-resistant cases. Although clinical effects are well documented, pre-clinical research remains limited. To date, only 28 studies have been published, mostly in rodents and few in primates and sheep. This narrative review examines the anatomical organization of the ANT across human, rodent, and non-human primate models and synthesizes findings from the preclinical studies investigating ANT-DBS in experimental MTLE animal models. Collectively, these studies demonstrate an approximate 50 % reduction in seizure frequency, mirroring recent clinical outcomes. However, the majority of studies have focused on high-frequency stimulation (>100 Hz), with few exploring multiple stimulation frequencies. Additionally, outcomes from intermittent ON/OFF stimulation were inconclusive or showed worsening effects in two out of three studies. Thus, several crucial parameters, including stimulation frequency, pattern, and other variables remain inadequately explored in preclinical MTLE models yet hold potential to enhance therapeutic efficacy and patient outcomes.
{"title":"Deep brain stimulation of the anterior nucleus of the thalamus in animal models of mesial temporal lobe epilepsy: A literature review","authors":"Emma Acerbo , Thomas Eggers , Alejandra M. Fernandez , Robert E. Gross , Claire-Anne Gutekunst","doi":"10.1016/j.eplepsyres.2025.107670","DOIUrl":"10.1016/j.eplepsyres.2025.107670","url":null,"abstract":"<div><div>Epilepsy affects approximately 1 % of the global population, presenting as a complex and heterogeneous disorder characterized by spontaneous, recurrent seizures. Focal onset seizures comprise half of all epilepsy cases. Mesial temporal lobe epilepsy (MTLE), the most prevalent form of focal seizures in adults, originates in the temporal lobe and is challenging to manage with standard antiseizure medications. Deep brain stimulation (DBS) targeting the anterior nucleus of the thalamus (ANT) has emerged as a therapeutic option for drug-resistant cases. Although clinical effects are well documented, pre-clinical research remains limited. To date, only 28 studies have been published, mostly in rodents and few in primates and sheep. This narrative review examines the anatomical organization of the ANT across human, rodent, and non-human primate models and synthesizes findings from the preclinical studies investigating ANT-DBS in experimental MTLE animal models. Collectively, these studies demonstrate an approximate 50 % reduction in seizure frequency, mirroring recent clinical outcomes. However, the majority of studies have focused on high-frequency stimulation (>100 Hz), with few exploring multiple stimulation frequencies. Additionally, outcomes from intermittent ON/OFF stimulation were inconclusive or showed worsening effects in two out of three studies. Thus, several crucial parameters, including stimulation frequency, pattern, and other variables remain inadequately explored in preclinical MTLE models yet hold potential to enhance therapeutic efficacy and patient outcomes.</div></div>","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"218 ","pages":"Article 107670"},"PeriodicalIF":2.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265974","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 : 2025-10-03DOI: 10.1016/j.eplepsyres.2025.107672
Rachana Mehta, Ranjana Sah
{"title":"Comment on \"Seizure outcome and anti-seizure medication use in post-stroke epilepsy: A retrospective cohort study\"","authors":"Rachana Mehta, Ranjana Sah","doi":"10.1016/j.eplepsyres.2025.107672","DOIUrl":"10.1016/j.eplepsyres.2025.107672","url":null,"abstract":"","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"218 ","pages":"Article 107672"},"PeriodicalIF":2.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244010","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 : 2025-10-03DOI: 10.1016/j.eplepsyres.2025.107675
Umair Ul Haq, Neha Majeed, Nisha Kumari, Anushe Saleh, Amna Tariq, Saad Masood, Junaid Imran, Safa Siddique Ali ansari, Hamzah Naushad Siddiqui, Muhammad Wasey Arshad, Muhammad Aamir, Abdul Rehman Shah Syed, Satesh Kumar, Mahima Khatri, Maria Rasheed
{"title":"Phenobarbital versus valproate for generalized convulsive status epilepticus in adults. An updated systematic review and meta-analysis","authors":"Umair Ul Haq, Neha Majeed, Nisha Kumari, Anushe Saleh, Amna Tariq, Saad Masood, Junaid Imran, Safa Siddique Ali ansari, Hamzah Naushad Siddiqui, Muhammad Wasey Arshad, Muhammad Aamir, Abdul Rehman Shah Syed, Satesh Kumar, Mahima Khatri, Maria Rasheed","doi":"10.1016/j.eplepsyres.2025.107675","DOIUrl":"10.1016/j.eplepsyres.2025.107675","url":null,"abstract":"","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"217 ","pages":"Article 107675"},"PeriodicalIF":2.0,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231822","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 : 2025-09-25DOI: 10.1016/j.eplepsyres.2025.107668
Haoyu Liu , Qiannan Song , Jiayi Jin , Hong Chen
<div><h3>Background</h3><div>cAMP response element-binding protein 3-like transcription factor 4 (CREB3L4) serves as an important transcriptional regulatory factor and plays a crucial role in neurological diseases, however, its specific mechanism in epilepsy pathogenesis remains unclear. This study aims to investigate the role of the CREB3L4-Sirtuin 4 (SIRT4) regulatory axis in epilepsy pathogenesis and its effects on γ-aminobutyric acid GABA/glutamate balance and mitochondrial function.</div></div><div><h3>Methods</h3><div>A classical epilepsy animal model was established, and quantitative real-time PCR, Western blot, and immunofluorescence staining techniques were employed to detect the expression changes of CREB3L4 and SIRT4 in the epilepsy model. CREB3L4 expression levels were modulated through lentivirus-mediated gene overexpression and RNA interference techniques to observe their effects on epileptic behavioral manifestations. ELISA was used to detect GABA and glutamate contents in brain tissues, and the GABA/glutamate ratio was calculated.</div></div><div><h3>Results</h3><div>CREB3L4 expression was downregulated 3.2-fold in the epilepsy model (1.026 ± 0.051–0.325 ± 0.028, p < 0.001), with 1.8-fold decreased GABA/glutamate ratio (1.065 ± 0.063–0.581 ± 0.046, p < 0.001). CREB3L4 overexpression upregulated SIRT4 mRNA 3.5-fold (0.185 ± 0.051–0.643 ± 0.039, p < 0.01) and reduced seizure frequency 2.0-fold (67.6 ± 3.1–34.4 ± 2.4 seizures, p < 0.001) and severity 2.2-fold (4.3 ± 0.3–2.0 ± 0.3 grade, p < 0.001). Conversely, CREB3L4 silencing exacerbated epilepsy progression, increasing seizure frequency 1.4-fold (58.7 ± 2.7–79.3 ± 4.2 seizures, p < 0.001) and severity 1.3-fold (3.7 ± 0.3–4.7 ± 0.2 grade, p < 0.001), with 2.2-fold decreased GABA/glutamate ratio (0.639 ± 0.051–0.288 ± 0.041, p < 0.001). Mechanistic studies demonstrated that CREB3L4 overexpression improved mitochondrial function through SIRT4 upregulation, thereby maintaining mitochondrial homeostasis. Meanwhile, activation of the CREB3L4-SIRT4 axis effectively increased brain tissue GABA content, improved the GABA/glutamate ratio, and restored neurotransmitter balance. Rescue experiments demonstrated that SIRT4 silencing (3.1-fold knockdown) significantly attenuated CREB3L4's neuroprotective effects, increasing seizure severity 1.6-fold (3.0 ± 0.5–4.8 ± 0.2 grade, p < 0.01), frequency 1.7-fold (43.2 ± 3.1–74.7 ± 4.2 seizures, p < 0.001), and reducing GABA/glutamate ratio 1.6-fold (1.81 ± 0.05–1.12 ± 0.05, p < 0.001), confirming SIRT4 as the key downstream mediator.</div></div><div><h3>Conclusion</h3><div>This study elucidates the important role of the CREB3L4-SIRT4 regulatory axis in epilepsy pathogenesis, revealing the molecular mechanism by which CREB3L4 transcriptionally activates SIRT4, subsequently regulates GABA/glutamate balance and maintains mitochondrial homeostasis, ultimately suppressing seizures and associated pathophysiological damage.</
{"title":"CREB3L4 upregulates SIRT4 expression to increase GABA/glutamate ratio and mitochondrial homeostasis for epilepsy suppression","authors":"Haoyu Liu , Qiannan Song , Jiayi Jin , Hong Chen","doi":"10.1016/j.eplepsyres.2025.107668","DOIUrl":"10.1016/j.eplepsyres.2025.107668","url":null,"abstract":"<div><h3>Background</h3><div>cAMP response element-binding protein 3-like transcription factor 4 (CREB3L4) serves as an important transcriptional regulatory factor and plays a crucial role in neurological diseases, however, its specific mechanism in epilepsy pathogenesis remains unclear. This study aims to investigate the role of the CREB3L4-Sirtuin 4 (SIRT4) regulatory axis in epilepsy pathogenesis and its effects on γ-aminobutyric acid GABA/glutamate balance and mitochondrial function.</div></div><div><h3>Methods</h3><div>A classical epilepsy animal model was established, and quantitative real-time PCR, Western blot, and immunofluorescence staining techniques were employed to detect the expression changes of CREB3L4 and SIRT4 in the epilepsy model. CREB3L4 expression levels were modulated through lentivirus-mediated gene overexpression and RNA interference techniques to observe their effects on epileptic behavioral manifestations. ELISA was used to detect GABA and glutamate contents in brain tissues, and the GABA/glutamate ratio was calculated.</div></div><div><h3>Results</h3><div>CREB3L4 expression was downregulated 3.2-fold in the epilepsy model (1.026 ± 0.051–0.325 ± 0.028, p < 0.001), with 1.8-fold decreased GABA/glutamate ratio (1.065 ± 0.063–0.581 ± 0.046, p < 0.001). CREB3L4 overexpression upregulated SIRT4 mRNA 3.5-fold (0.185 ± 0.051–0.643 ± 0.039, p < 0.01) and reduced seizure frequency 2.0-fold (67.6 ± 3.1–34.4 ± 2.4 seizures, p < 0.001) and severity 2.2-fold (4.3 ± 0.3–2.0 ± 0.3 grade, p < 0.001). Conversely, CREB3L4 silencing exacerbated epilepsy progression, increasing seizure frequency 1.4-fold (58.7 ± 2.7–79.3 ± 4.2 seizures, p < 0.001) and severity 1.3-fold (3.7 ± 0.3–4.7 ± 0.2 grade, p < 0.001), with 2.2-fold decreased GABA/glutamate ratio (0.639 ± 0.051–0.288 ± 0.041, p < 0.001). Mechanistic studies demonstrated that CREB3L4 overexpression improved mitochondrial function through SIRT4 upregulation, thereby maintaining mitochondrial homeostasis. Meanwhile, activation of the CREB3L4-SIRT4 axis effectively increased brain tissue GABA content, improved the GABA/glutamate ratio, and restored neurotransmitter balance. Rescue experiments demonstrated that SIRT4 silencing (3.1-fold knockdown) significantly attenuated CREB3L4's neuroprotective effects, increasing seizure severity 1.6-fold (3.0 ± 0.5–4.8 ± 0.2 grade, p < 0.01), frequency 1.7-fold (43.2 ± 3.1–74.7 ± 4.2 seizures, p < 0.001), and reducing GABA/glutamate ratio 1.6-fold (1.81 ± 0.05–1.12 ± 0.05, p < 0.001), confirming SIRT4 as the key downstream mediator.</div></div><div><h3>Conclusion</h3><div>This study elucidates the important role of the CREB3L4-SIRT4 regulatory axis in epilepsy pathogenesis, revealing the molecular mechanism by which CREB3L4 transcriptionally activates SIRT4, subsequently regulates GABA/glutamate balance and maintains mitochondrial homeostasis, ultimately suppressing seizures and associated pathophysiological damage.</","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"218 ","pages":"Article 107668"},"PeriodicalIF":2.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154691","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 : 2025-09-25DOI: 10.1016/j.eplepsyres.2025.107669
Giovanni Battista Dell’Isola , Margherita Siciliano , Gianluca D’Onofrio , Pietro Ferrara , Pasquale Striano , Marco Carotenuto , Alberto Verrotti
Neurological and neuropsychiatric disorders, particularly drug-resistant epilepsies and rare genetic syndromes such as CDKL5 deficiency disorder, pose significant therapeutic challenges. Ganaxolone (GNX), a synthetic neurosteroid and positive allosteric modulator of GABA-A receptors, has emerged as a promising treatment option due to its unique pharmacological properties. This review explores GNX's pharmacokinetic profile, preclinical evidence, and clinical applications. Preclinical studies have demonstrated its efficacy in reducing seizure frequency and severity across various epilepsy models, including amygdala kindling and status epilepticus, as well as its neuroprotective effects in hypoxic-ischemic encephalopathy. Clinical trials have confirmed GNX's benefits, particularly in CDD, where it significantly reduces seizure frequency, leading to its FDA and EMA approval. Additionally, GNX has shown potential in focal epilepsy, status epilepticus, and other drug-resistant epilepsies, although with variable results. Beyond epilepsy, GNX's modulation of GABAergic signaling suggests potential applications in neuropsychiatric conditions. Its favorable safety profile further supports its therapeutic value.
{"title":"Ganaxolone in Epilepsy: Insights into a Neurosteroid-Based Therapy","authors":"Giovanni Battista Dell’Isola , Margherita Siciliano , Gianluca D’Onofrio , Pietro Ferrara , Pasquale Striano , Marco Carotenuto , Alberto Verrotti","doi":"10.1016/j.eplepsyres.2025.107669","DOIUrl":"10.1016/j.eplepsyres.2025.107669","url":null,"abstract":"<div><div>Neurological and neuropsychiatric disorders, particularly drug-resistant epilepsies and rare genetic syndromes such as CDKL5 deficiency disorder, pose significant therapeutic challenges. Ganaxolone (GNX), a synthetic neurosteroid and positive allosteric modulator of GABA-A receptors, has emerged as a promising treatment option due to its unique pharmacological properties. This review explores GNX's pharmacokinetic profile, preclinical evidence, and clinical applications. Preclinical studies have demonstrated its efficacy in reducing seizure frequency and severity across various epilepsy models, including amygdala kindling and status epilepticus, as well as its neuroprotective effects in hypoxic-ischemic encephalopathy. Clinical trials have confirmed GNX's benefits, particularly in CDD, where it significantly reduces seizure frequency, leading to its FDA and EMA approval. Additionally, GNX has shown potential in focal epilepsy, status epilepticus, and other drug-resistant epilepsies, although with variable results. Beyond epilepsy, GNX's modulation of GABAergic signaling suggests potential applications in neuropsychiatric conditions. Its favorable safety profile further supports its therapeutic value.</div></div>","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"218 ","pages":"Article 107669"},"PeriodicalIF":2.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205979","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 : 2025-09-19DOI: 10.1016/j.eplepsyres.2025.107665
Ahmed Ameen Fateh , Abla Smahi , Muhammad Hassan , Cristina Cañete-Massé , Adam A.Q. Mohammed , Feng Yue , Zhanqi Hu , Hongwu Zeng
Background
Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTs) is a dominant childhood epilepsy form characterized by seizures originating from the brain’s centrotemporal region. Crucially, unlocking the neural dynamics and mechanisms underlying SeLECTs paves the way for potent diagnostic and therapeutic strategies. Our work investigates dynamic functional connectivity (dFC) variability in the thalamocortical circuit in SeLECTs individuals, thereby shedding light on the temporal dynamics and anomaly in connectivity patterns tied to seizure occurrence and propagation.
Methods
Utilizing resting-state functional magnetic resonance imaging (rs-fMRI) data from 45 SeLECTs patients and 55 healthy controls (HCs), dynamic changes in functional connectivity (FC) across various brain regions were examined over time. We selected 16 thalamic seeds to delve into dFC variability using a sliding window approach. We also evaluated clinical data from both groups to discern its correlation with dFC variability. As a final step, a Support Vector Machine (SVM) was employed for classification analysis to demonstrate the potential use of dFC variability as a distinguishing feature between SeLECTs patients and HCs.
Results
t-test analysis manifested significant variances in dFC variability between SeLECTs and HCs groups related to thalamus seeds, also showing a correlation between VCI and certain areas. Out of 16 thalamus seeds, significant variances emerged in 9 seeds. Specifically, an increase in dFC variability was observed between the right occipital thalamus seed and the right precentral gyrus in SeLECTs patients, implying a positive connectivity alteration. On the other hand, a lowered dFC was observed between the right inferior prefrontal thalamus seed and the left cuneus, reflecting a reduction in their connectivity strength.
Conclusion
Our study underscores the significance of dFC variability within the thalamocortical circuit in SeLECTs individuals. The noticeable aberrant connectivity patterns enrich our understanding of temporal dynamics linked to SeLECTs seizure occurrence and propagation, thereby contributing to understanding SeLECTs pathophysiology. These insights may steer the development of precise diagnostic and therapeutic strategies for this widespread childhood epilepsy.
{"title":"Dynamic functional connectivity variability in the thalamocortical circuit: Insights from Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTs)","authors":"Ahmed Ameen Fateh , Abla Smahi , Muhammad Hassan , Cristina Cañete-Massé , Adam A.Q. Mohammed , Feng Yue , Zhanqi Hu , Hongwu Zeng","doi":"10.1016/j.eplepsyres.2025.107665","DOIUrl":"10.1016/j.eplepsyres.2025.107665","url":null,"abstract":"<div><h3>Background</h3><div>Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTs) is a dominant childhood epilepsy form characterized by seizures originating from the brain’s centrotemporal region. Crucially, unlocking the neural dynamics and mechanisms underlying SeLECTs paves the way for potent diagnostic and therapeutic strategies. Our work investigates dynamic functional connectivity (dFC) variability in the thalamocortical circuit in SeLECTs individuals, thereby shedding light on the temporal dynamics and anomaly in connectivity patterns tied to seizure occurrence and propagation.</div></div><div><h3>Methods</h3><div>Utilizing resting-state functional magnetic resonance imaging (rs-fMRI) data from 45 SeLECTs patients and 55 healthy controls (HCs), dynamic changes in functional connectivity (FC) across various brain regions were examined over time. We selected 16 thalamic seeds to delve into dFC variability using a sliding window approach. We also evaluated clinical data from both groups to discern its correlation with dFC variability. As a final step, a Support Vector Machine (SVM) was employed for classification analysis to demonstrate the potential use of dFC variability as a distinguishing feature between SeLECTs patients and HCs.</div></div><div><h3>Results</h3><div>t-test analysis manifested significant variances in dFC variability between SeLECTs and HCs groups related to thalamus seeds, also showing a correlation between VCI and certain areas. Out of 16 thalamus seeds, significant variances emerged in 9 seeds. Specifically, an increase in dFC variability was observed between the right occipital thalamus seed and the right precentral gyrus in SeLECTs patients, implying a positive connectivity alteration. On the other hand, a lowered dFC was observed between the right inferior prefrontal thalamus seed and the left cuneus, reflecting a reduction in their connectivity strength.</div></div><div><h3>Conclusion</h3><div>Our study underscores the significance of dFC variability within the thalamocortical circuit in SeLECTs individuals. The noticeable aberrant connectivity patterns enrich our understanding of temporal dynamics linked to SeLECTs seizure occurrence and propagation, thereby contributing to understanding SeLECTs pathophysiology. These insights may steer the development of precise diagnostic and therapeutic strategies for this widespread childhood epilepsy.</div></div>","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"218 ","pages":"Article 107665"},"PeriodicalIF":2.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145104430","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 : 2025-09-19DOI: 10.1016/j.eplepsyres.2025.107667
Noora Puhakka , Mette Heiskanen , Xavier Ekolle Ndode-Ekane , Idrish Ali , Cesar Santana-Gomez , Shalini Das Gupta , Meheli Banerjee , Pedro Andrade , Riikka Immonen , Pablo Casillas-Espinosa , Gregory Smith , Rhys D. Brady , Juliana Silva , Emma Braine , Matthew R. Hudson , Glen R. Yamakawa , Nigel C. Jones , Sandy R. Shultz , Neil G. Harris , David K. Wright , Asla Pitkänen
Objective
To analyze the success of harmonization and standardization of plasma miRNA biomarker discovery and validation for post-traumatic epilepsy (PTE) in the EpiBioS4Rx international multicenter project.
Methods
Adult male Sprague-Dawley rats were randomized to lateral fluid-percussion-induced traumatic brain injury (TBI) or sham operation at three study sites (Finland, Australia, USA). Video-electroencephalogram (vEEG) was performed in the 7th post-injury month to detect spontaneous seizures. Tail vein plasma was collected at baseline and 48 h after TBI for microRNA (miRNA) analysis. Common data elements were generated to document and monitor pre-analytic activities, including housing conditions, post-injury care, blood sampling, plasma preparation, plasma quality, storage, and shipping. miRNA analysis was performed using droplet digital PCR (ddPCR) at one study site (Finland) with on-site standardized procedures.
Results
The 2-day miRNA levels were successfully measured in 85 % (209/245) of the rats included in the final analysis cohort. Exclusions were related to small sample volume, hemolysis, and failed RNA extraction for ddPCR. Most of the pre-analytical factors leading to sample exclusions were related to non-optimal plasma pipetting. We also recognized gaps in data entry and monitoring of personnel training.
Conclusions
Our study demonstrates that conducting a successful plasma miRNA biomarker analysis requires procedural harmonization between laboratories, protocol standardization, inclusion and analysis of quality controls, training of researchers, and continuous monitoring of adherence to pre-agreed protocols.
{"title":"Standardization of preclinical methodologies for discovery and validation of circulating microRNA biomarkers for post-traumatic epileptogenesis – Lessons learned from the EpiBioS4Rx Project 1","authors":"Noora Puhakka , Mette Heiskanen , Xavier Ekolle Ndode-Ekane , Idrish Ali , Cesar Santana-Gomez , Shalini Das Gupta , Meheli Banerjee , Pedro Andrade , Riikka Immonen , Pablo Casillas-Espinosa , Gregory Smith , Rhys D. Brady , Juliana Silva , Emma Braine , Matthew R. Hudson , Glen R. Yamakawa , Nigel C. Jones , Sandy R. Shultz , Neil G. Harris , David K. Wright , Asla Pitkänen","doi":"10.1016/j.eplepsyres.2025.107667","DOIUrl":"10.1016/j.eplepsyres.2025.107667","url":null,"abstract":"<div><h3>Objective</h3><div>To analyze the success of harmonization and standardization of plasma miRNA biomarker discovery and validation for post-traumatic epilepsy (PTE) in the EpiBioS4Rx international multicenter project.</div></div><div><h3>Methods</h3><div>Adult male Sprague-Dawley rats were randomized to lateral fluid-percussion-induced traumatic brain injury (TBI) or sham operation at three study sites (Finland, Australia, USA). Video-electroencephalogram (vEEG) was performed in the 7th post-injury month to detect spontaneous seizures. Tail vein plasma was collected at baseline and 48 h after TBI for microRNA (miRNA) analysis. Common data elements were generated to document and monitor pre-analytic activities, including housing conditions, post-injury care, blood sampling, plasma preparation, plasma quality, storage, and shipping. miRNA analysis was performed using droplet digital PCR (ddPCR) at one study site (Finland) with on-site standardized procedures.</div></div><div><h3>Results</h3><div>The 2-day miRNA levels were successfully measured in 85 % (209/245) of the rats included in the final analysis cohort. Exclusions were related to small sample volume, hemolysis, and failed RNA extraction for ddPCR. Most of the pre-analytical factors leading to sample exclusions were related to non-optimal plasma pipetting. We also recognized gaps in data entry and monitoring of personnel training.</div></div><div><h3>Conclusions</h3><div>Our study demonstrates that conducting a successful plasma miRNA biomarker analysis requires procedural harmonization between laboratories, protocol standardization, inclusion and analysis of quality controls, training of researchers, and continuous monitoring of adherence to pre-agreed protocols.</div></div>","PeriodicalId":11914,"journal":{"name":"Epilepsy Research","volume":"218 ","pages":"Article 107667"},"PeriodicalIF":2.0,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108996","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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