Brain StimulationPub Date : 2025-07-28DOI: 10.1016/j.brs.2025.07.018
Thomas Eckert, Rishishankar Suresh, M S Zobaer, Nathan C Rowland
{"title":"Invasive and Non-invasive Tumor-Treating Electric Field (TTF) Therapy: An Exciting Advance in Oncologic Neuromodulation.","authors":"Thomas Eckert, Rishishankar Suresh, M S Zobaer, Nathan C Rowland","doi":"10.1016/j.brs.2025.07.018","DOIUrl":"https://doi.org/10.1016/j.brs.2025.07.018","url":null,"abstract":"<p><strong>Background: </strong>Tumor-treating fields (TTF) have been shown to slow glioblastoma (GBM) cell growth through mitotic arrest, increased membrane and blood-brain barrier permeability, and other cellular mechanisms. TTF as currently used prolongs GBM survival by 5 months, but there are areas of possible improvement. One of the interesting problems is optimization of TTF delivery to tumor cells, which is attenuated by intervening anatomy and shunting. Current research involving invasive approaches including cranial remodeling, intracortical TTF and intratumoral modulation therapy (IMT) may improve outcomes.</p><p><strong>Objective: </strong>Present the history of TTF and discuss current areas of research with a focus on invasive TTF.</p><p><strong>Methods: </strong>We obtained and analyzed studies referencing TTF, invasive TTF, and any of transcranial electrical stimulation (tES), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), vagus nerve stimulation (VNS), peripheral nervous system (PNS), focused ultrasound (FUS), and transcranial magnetic stimulation (TMS) with respect to mechanism of action or anti-cancer-related effects.</p><p><strong>Results: </strong>Invasive strategies including cranial remodeling and IMT, through stereotaxis like DBS, would help alleviate the current limitations of TTF. In addition, FUS and VNS induce similar blood brain barrier effects and immune modulation as TTF that may enhance and promote an insurmountable host immune response against the immunosuppressive tumor microenvironment.</p><p><strong>Conclusions: </strong>TTF as currently practiced is a remarkable advance in cancer treatment. Improvements which exploit the effects of TTF in combination with other neuromodulatory modalities or in immunotherapy promise to improve this even further.</p>","PeriodicalId":9206,"journal":{"name":"Brain Stimulation","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain StimulationPub Date : 2025-07-28DOI: 10.1016/j.brs.2025.07.008
Han Lu, Shreyash Garg, Maximilian Lenz, Andreas Vlachos
{"title":"Repetitive magnetic stimulation with iTBS600 induces persistent structural and functional plasticity in mouse organotypic slice cultures.","authors":"Han Lu, Shreyash Garg, Maximilian Lenz, Andreas Vlachos","doi":"10.1016/j.brs.2025.07.008","DOIUrl":"https://doi.org/10.1016/j.brs.2025.07.008","url":null,"abstract":"<p><strong>Background: </strong>Repetitive transcranial magnetic stimulation (rTMS) is well known for its ability to induce synaptic plasticity, yet its impact on structural and functional remodeling within stimulated networks remains unclear. This study investigates the cellular and network-level mechanisms of rTMS-induced plasticity using a clinically approved 600-pulse intermittent theta burst stimulation (iTBS600) protocol applied to organotypic brain tissue cultures.</p><p><strong>Methods: </strong>We applied iTBS600 to entorhino-hippocampal organotypic tissue cultures and conducted a 24-hour analysis using c-Fos immunostaining, whole-cell patch-clamp recordings, time-lapse imaging of dendritic spines, and calcium imaging.</p><p><strong>Results: </strong>We observed long-term potentiation (LTP) of excitatory synapses in dentate granule cells, characterized by increased mEPSC frequencies and spine remodeling over time. c-Fos expression in the dentate gyrus was transient and exhibited a clear sensitivity to the orientation of the induced electric field, suggesting a direction-dependent induction of plasticity. Structural remodeling of dendritic spines was temporally linked to enhanced synaptic strength, while spontaneous firing rates remained stable during the early phase in the dentate gyrus, indicating the engagement of homeostatic mechanisms. Despite the widespread electric field generated by rTMS, its effects were spatially and temporally precise, driving Hebbian plasticity and region-specific spine dynamics.</p><p><strong>Conclusions: </strong>These findings provide mechanistic insights into how rTMS-induced LTP promotes targeted plasticity while preserving network stability. Understanding these interactions may help refine stimulation protocols to optimize therapeutic outcomes.</p>","PeriodicalId":9206,"journal":{"name":"Brain Stimulation","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain StimulationPub Date : 2025-07-27DOI: 10.1016/j.brs.2025.07.014
Guilong Tanzhu, Haiqin Peng, Liu Chen, Gang Xiao, Jiaoyang Ning, Ling Chen, Rongrong Zhou
{"title":"Tumor treating fields combined with ionizing radiation inhibit the malignant phenotype of lung cancer brain metastasis cells by suppressing DNA damage repair pathways.","authors":"Guilong Tanzhu, Haiqin Peng, Liu Chen, Gang Xiao, Jiaoyang Ning, Ling Chen, Rongrong Zhou","doi":"10.1016/j.brs.2025.07.014","DOIUrl":"https://doi.org/10.1016/j.brs.2025.07.014","url":null,"abstract":"<p><strong>Background: </strong>Brain metastasis (BrM) is a common complication of advanced tumors with poor prognosis. Although radiotherapy remains a key treatment for BrM, it is plagued by issues such as radiation-induced brain necrosis, neurocognitive impairment, and progress post-treatment. Tumor Treating Fields (TTFields) therapy employs medium frequency (100∼300 kHz) and low intensity (1∼3 v/cm) alternating electric fields to inhibit tumors. We explored the effects and mechanisms of TTFields combined with ionizing radiation (IR) on the malignant phenotype of lung cancer brain metastasis (LCBM) cells, with the aim of advancing the clinical adoption of TTFields.</p><p><strong>Methods: </strong>LCBM cells H1915, PC9-Brm and primary cells were used. The experiment included four groups: Control, 6 Gy, TTFields, and 6 Gy + TTFields group. Cell viability and the number of EDU or Ki67-positive cells, ability of migration and colony formation were assessed; Cell morphology was observed by H&E staining; Bulk transcriptome revealed the potential mechanisms, with the protein levels of differentially expressed genes (DEGs) verified through immunofluorescence assay. DNA damage repair pathways were validated by Western Blot. Additionally, ROS levels, and HO-1 expression were evaluated.</p><p><strong>Results: </strong>The combination of 150 kHz, 2∼2.5 v/cm TTFields and 6 Gy IR effectively suppressed the viability and the number of EDU-positive and Ki67-positive LCBM cells. Following TTFields and IR, the tumor cells exhibited altered morphology and reduced clonogenic and migratory capacities. RNA-seq revealed associations between TTFields combined with IR and various biological processes and mechanisms, including redox reactions (primarily related to mitochondria), DNA replication, transition metal ion transmembrane transport, and heme metabolism. Furthermore, TTFields combined with IR enhanced γH2AX and 53BP1 levels. Increased ROS and HO-1 expression were observed post-treatment. Similarly, LCBM primary cells exhibited decreased Ki67-positive cells along with increased γH2AX and 53BP1 foci following TTFields and IR. TTFields combined with IR exhibited significant suppression on homologous recombination (HR) markers (p-ATM, RAD51), non-homologous end joining (NHEJ) components (DNA-PKcs, KU70, KU80), and microhomology-mediated end joining (MMEJ) effectors (PARP1, p95-NBS1) versus RT alone.</p><p><strong>Conclusions: </strong>TTFields combined with IR effectively inhibits LCBM cells. Mechanistically, this combined treatment enhanced DNA damage, suppressed DNA damage repair, and elevates ROS levels.</p>","PeriodicalId":9206,"journal":{"name":"Brain Stimulation","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain StimulationPub Date : 2025-07-27DOI: 10.1016/j.brs.2025.07.016
Renzo Comolatti, Gabriel Hassan, Ezequiel Mikulan, Simone Russo, Michele A Colombo, Elisabetta Litterio, Giulia Furregoni, Sasha D'Ambrosio, Matteo Fecchio, Sara Parmigiani, Ivana Sartori, Silvia Casarotto, Andrea Pigorini, Marcello Massimini
{"title":"Transcranial magnetic vs intracranial electric stimulation: a direct comparison of their effects via scalp EEG recordings.","authors":"Renzo Comolatti, Gabriel Hassan, Ezequiel Mikulan, Simone Russo, Michele A Colombo, Elisabetta Litterio, Giulia Furregoni, Sasha D'Ambrosio, Matteo Fecchio, Sara Parmigiani, Ivana Sartori, Silvia Casarotto, Andrea Pigorini, Marcello Massimini","doi":"10.1016/j.brs.2025.07.016","DOIUrl":"https://doi.org/10.1016/j.brs.2025.07.016","url":null,"abstract":"<p><strong>Background: </strong>Single-pulse Transcranial Magnetic Stimulation (TMS) and Intracranial Electrical Stimulation (IES) are widely used to probe cortical excitability and connectivity, but their electrophysiological effects have never been compared.</p><p><strong>Objective: </strong>This study aims to fill this gap by using high-density scalp electroencephalogram (hd-EEG) as a common read-out to compare human brain responses to TMS and IES.</p><p><strong>Methods: </strong>The dataset includes TMS-evoked potentials (TEPs) acquired from healthy subjects (n=22) and IES-evoked potentials (IEPs) recorded from drug-resistant epileptic patients (n=31) during wakefulness. In a subset of subjects TEPs (n=12) and IEPs (n=13) were also recorded during NREM sleep. Amplitude, spectral, and spatiotemporal features of TMS and IES responses, as well as their estimated electrical fields, were compared.</p><p><strong>Results: </strong>We observed marked differences between TMS and IES responses. During wakefulness, IEPs are considerably larger, slower and associated with a suppression of cortical activity, whereas TEPs are characterized by multiple waves of recurrent activation. These differences are attenuated in NREM, during which both TMS and IES elicit large EEG responses associated with a prominent suppression of cortical activity. At the global level, the spatiotemporal complexity of the responses to both TMS and IES decreases consistently following the transition from wakefulness to NREM sleep.</p><p><strong>Conclusion: </strong>Despite the limitations due to different subject populations (healthy vs pathological), our findings provide a first reference to parallel non-invasive and invasive brain stimulation and to interpret their differential effects. They also offer important insight on how cortical responsiveness is shaped by inhibition and adaptation mechanisms depending on input parameters and brain states.</p>","PeriodicalId":9206,"journal":{"name":"Brain Stimulation","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain StimulationPub Date : 2025-07-23DOI: 10.1016/j.brs.2025.07.013
Sebastian J Lehmann, Brian D Corneil
{"title":"Continuous theta-burst stimulation of the prefrontal cortex in the macaque monkey: no behavioral evidence for within-target inhibition or neural evidence for cross-hemisphere disinhibition.","authors":"Sebastian J Lehmann, Brian D Corneil","doi":"10.1016/j.brs.2025.07.013","DOIUrl":"https://doi.org/10.1016/j.brs.2025.07.013","url":null,"abstract":"<p><strong>Background: </strong>Continuous theta-burst stimulation (cTBS) can perturb neural activity and behavior by inducing effects that persist beyond the relatively short stimulation period. Although widely used in basic research and clinical settings, there lacks an understanding of the neurophysiological and behavioural effects of cTBS.</p><p><strong>Objectives/hypothesis: </strong>Two assumptions motivating the use of cTBS are that it will i) inhibit neural activity in the targeted area, and ii) consequently disinhibit neural activity in the mirroring region in the contralateral cortex. Here, we test these assumptions in the oculomotor system of healthy rhesus macaques.</p><p><strong>Methods: </strong>In two macaques, we delivered cTBS between blocks of trials where they performed a delayed pro-/anti-saccade task, delivered cTBS to the right PFC (areas 8Ar and 46, which includes the frontal eye fields; 32 cTBS-PFC sessions), to the air as a SHAM control (27 cTBS-SHAM sessions), or to the nearby primary motor cortex as a brain control (21 cTBS-M1 sessions). Across these different types of sessions, we compared changes in oculomotor behavior (reaction times, error rates, peak saccade velocity), and changes in neural activity recorded from the left, contralateral PFC.</p><p><strong>Results: </strong>Despite multiple lines of evidence consistent with TMS influencing neural activity in the cTBS-PFC and cTBS-M1 sessions, we found no behavioral evidence for inhibition of the right PFC in the cTBS-PFC sessions, nor any evidence for contralateral disinhibition in the left PFC.</p><p><strong>Conclusions: </strong>Our results call into question some of the fundamental assumptions underlying the application of cTBS.</p>","PeriodicalId":9206,"journal":{"name":"Brain Stimulation","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain StimulationPub Date : 2025-07-11DOI: 10.1016/j.brs.2025.07.009
Kantapon Pum Wiboonsaksakul, Dale C Roberts, Kathleen E Cullen
{"title":"Removal of stimulation artifacts in high-density Neuropixels recordings using sample clock-synchronized stimulation pulses.","authors":"Kantapon Pum Wiboonsaksakul, Dale C Roberts, Kathleen E Cullen","doi":"10.1016/j.brs.2025.07.009","DOIUrl":"https://doi.org/10.1016/j.brs.2025.07.009","url":null,"abstract":"","PeriodicalId":9206,"journal":{"name":"Brain Stimulation","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brain StimulationPub Date : 2025-07-11DOI: 10.1016/j.brs.2025.07.007
Kristen M Scheitler, Juan M Rojas-Cabrera, Sara A Vettleson-Trutza, Sheng-Ta Tsai, Guillermo K Pons-Monnier, Mohamed M El-Gohary, Ron Scheer, Youngjong Kwak, Damiano G Barone, Charles D Blaha, Tyler S Oesterle, Hojin Shin, Kendall H Lee, Yoonbae Oh
{"title":"Letter to the Editor: Application of a Human Stereotactic System for Image-Guided Deep Brain Stimulation Neurosurgery in a Swine Model.","authors":"Kristen M Scheitler, Juan M Rojas-Cabrera, Sara A Vettleson-Trutza, Sheng-Ta Tsai, Guillermo K Pons-Monnier, Mohamed M El-Gohary, Ron Scheer, Youngjong Kwak, Damiano G Barone, Charles D Blaha, Tyler S Oesterle, Hojin Shin, Kendall H Lee, Yoonbae Oh","doi":"10.1016/j.brs.2025.07.007","DOIUrl":"https://doi.org/10.1016/j.brs.2025.07.007","url":null,"abstract":"","PeriodicalId":9206,"journal":{"name":"Brain Stimulation","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}