共找到 20 条结果
Chemotherapy drug-induced changes of gene expression in the dorsal root ganglion (DRG) are critical for the genesis of chemotherapy-induced neuropathic pain (CINP). However, the mechanisms driving these changes remain elusive. Here, we report the downregulation of muscleblind-like protein 2 (MBNL2), an RNA-binding protein, in the DRG neurons after intraperitoneal injection of paclitaxel. Rescuing this downregulation blocks an increase of the C-C chemokine receptor type 2 (CCR2) in the DRG and mitigates paclitaxel-induced mechanical allodynia, heat and cold hyperalgesia and ongoing pain. Conversely, DRG downregulation of MBNL2 increases the expression of CCR2 in the DRG neurons and leads to CINP-like symptoms in naïve mice. Mechanistically, paclitaxel-induced downregulation of MBNL2 reduces its binding to the 3'-untranslated region of Ccr2 mRNA, thereby enhancing the stability of Ccr2 mRNA in the DRG. Given that MBNL2 and CCR2 are co-expressed in DRG neurons, these findings suggest that MBNL2 alleviates CINP, likely by destabilizing CCR2 expression in the DRG, and may represent a promising therapeutic strategy for this condition.
The disease-modifying antibody lecanemab for treating Alzheimer's disease (AD) was initially designed to target amyloid-beta (Aβ) protofibrils, i.e. soluble aggregates of Aβ, but it has also been successful in clearing insoluble amyloid plaques in clinical studies. Therefore, this study aimed to investigate how a brain penetrating, bispecific murine variant of lecanemab (RmAb158-scFv8D3) distributes in the brain and interacts with different pools of aggregated Aβ in APP transgenic mice. The alpha-synuclein targeting antibody RmAbSynO2-scFv8D3 was used as control. Further, by performing in vivo high cut-off microdialysis in freely moving animals, brain interstitial fluid (ISF) was continuously collected across 24 h to assess concentrations of free antibody in the brain. Post mortem distribution of the antibodies was analyzed by sequential extraction of brain tissue. RmAb158-scFv8D3 showed rapid ISF clearance as well as a redistribution from brain extracts containing small, soluble Aβ species toward brain extracts containing insoluble, plaque-associated Aβ with time. A treatment effect was detected already at 12 h post injection, whereby the RmAb158-scFv8D3-treated animals showed lower concentrations of the smallest, most soluble Aβ aggregates. Collectively, these findings suggest that within the first 24 h after a single injection of the bispecific RmAb158-scFv8D3 antibody we can capture the antibody's initial brain distribution and interactions with both soluble Aβ aggregates and insoluble, plaque-associated Aβ. These interactions mediate a swift reduction of soluble Aβ, while clearance of insoluble Aβ requires longer treatment time.
Advanced therapies (ATs), including gene and stem cell therapy, hold great potential for preventing and ameliorating many rare neurological disorders (RNDs) in children. These technologies are set to expand across modalities, potentially disrupting and augmenting conventional therapeutic pipelines, with the rapid pace of development highlighting data gaps and implementational challenges. We conducted a two-round modified Delphi study to co-develop a practice framework supporting the safe and effective application of advanced and/or experimental neurotherapeutics for children with rare neurological disorders within a public health ecosystem. The study generated 101 consensus recommendations encompassing criteria to 1) facilitate equitable and timely therapeutic access, 2) optimise transparent communication and shared decision making with families, 3) incorporate disease and patient level considerations for minimising risk and optimising safety within advanced therapeutic research, 4) strengthen resourcing of health systems to enable longitudinal evaluation of treatment effects and safety. Embedding this framework into practice will depend on enhancement of workforce training, establishment of digital infrastructure, fit-for-purpose clinical environments and education and engagement of patients, families and the broader community.
Intravenous (IV) administration of human bone marrow mesenchymal stromal/stem cell-derived small extracellular vesicles (hMSC-sEVs) improves motor recovery in spinal cord-injured rats. We previously observed that daily IV injections over three days were theapeuticaly effective, whereas a single injection with an equivalent total dose was not, indicating that a temporally dispersed regimen is crucial for efficacy. DiR-labeled hMSC-sEVs accumulated in M2 macrophages at the injury site, with excess vesicles cleared via the kidneys within 24 h. To determine whether prolonged continuous delivery can enhance therapeutic outcomes, we compared motor recovery in SCI rats receiving hMSC-sEVs via daily IV injections versus continuous infusion of the same quantity of hMSC-sEVs over 3 or 6 days via osmotic pumps. Continuous intra-jugular IV infusion using an osmotic pump over three days accelerated the onset of motor recovery compared to daily injections. Extending the infusion to six days further enhanced recovery despite the same total dose. Molecular analyses revealed that hMSC-sEVs are enriched in microRNAs targeting fibrosis pathways relative to control serum sEVs. In vitro uptake of hMSC-sEVs by M2 macrophages significantly suppressed the expression of genes associated with extracellular matrix production. Furthermore, MSC-sEV-treated animals showed reductions in fibronectin and collagen 1 and 5 proteins at the lesion site, compared to PBS treated rats. These findings suggest that prolonged continuous infusion of hMSC-sEVs results in greater motor function recovery than daily injections of the same amount, potentially by modulating macrophage-mediated extracellular matrix deposition.
Physical therapy (PT) is commonly used to alleviate specific symptoms of Parkinson's disease (PD). Its efficacy may be enhanced by cortical priming, which aims to improve the brain's responsiveness to rehabilitation. This randomized, double-blind, sham-controlled trial-Stimulation to Enhance Physical Therapy in Parkinson's Disease (STEP-PD)-investigated whether combining PT with intermittent theta-burst stimulation (iTBS) applied over the primary motor cortex (M1-iTBS) could provide additional gains in motor function in patients with PD. Fifty participants with PD received PT combined with either bilateral M1-iTBS or sham-iTBS, twice daily, five days per week for two weeks. The primary outcome was the change in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) in the OFF-medication state, assessed at baseline and immediately post-intervention. Secondary outcomes included the Parkinson's Disease Questionnaire-39 (PDQ-39), and exploratory outcomes included clinical and instrumented assessments of gait and balance, as well as electroencephalography (EEG)-based measures of functional connectivity. Patients receiving PT combined with M1-iTBS showed greater acute improvement in OFF-state MDS-UPDRS III scores compared to those receiving sham stimulation (Δ = -4.60, p = 0.034). There were no significant differences in PDQ-39 scores. Exploratory analyses revealed improved gait stability, fewer falls, and reduced beta-band synchronization on resting-state EEG, suggesting that M1-iTBS may modulate motor networks to facilitate functional recovery. These findings suggest that combining PT with M1-iTBS has promise as an acute cortical priming approach to improve the short-term efficacy of PD rehabilitation, although further research is required to determine the sustainability of these effects.
Isocitrate dehydrogenase (IDH)-mutant gliomas constitute a distinct molecular subtype of diffuse gliomas, characterized by unique biology and relatively favorable clinical outcomes. However, despite their more indolent initial course, these tumors ultimately develop treatment resistance and remain incurable. Standard treatment approaches have relied on surgery followed by radiation and alkylating chemotherapy, which provide meaningful disease control but are associated with cumulative neurocognitive toxicities. The oral mutant IDH inhibitor vorasidenib recently became the first targeted therapy available for IDH-mutant glioma. Based on results of the randomized phase 3 INDIGO trial, vorasidenib was approved by the US Food and Drug Administration in 2024 as a first-line treatment option for grade 2 IDH-mutant glioma following surgery. In this review, we summarize the current therapeutic paradigm for IDH-mutant glioma, including the use of radiation and chemotherapy as well as the evolving role of mutant IDH-targeted therapy. We also highlight emerging therapeutic strategies, including approaches targeting key biologically informed vulnerabilities such as DNA damage repair pathways, cell-cycle and metabolic dependencies, tumor-associated hypermethylation, and anti-tumor immune activation. Collectively, these advances reflect a rapidly evolving treatment landscape driven by improved understanding of IDH biology, and hold promise to overcome therapeutic resistance and improve patient outcomes.
Ischemic stroke poses a substantial clinical and socioeconomic burden due to limited therapeutic efficacy and poor neurological outcomes. To uncover novel gene targets for intervention, we conducted an integrative analysis combining single-cell RNA sequencing with Mendelian randomization using large-scale genomic datasets from the European Bioinformatics Institute (34,593 cases and 624,214 controls), with validation in an independent European Bioinformatics Institute dataset (86,668 cases and 1,503,898 controls) and the UK Biobank (26,052 cases and 487,214 controls). Colocalization analysis identified four core genes-PEBP1, BMP4, APOA1 and CD86-strongly associated with ischemic stroke risk, with a posterior probability of a shared causal variant greater than 0.8. Among them, PEBP1 was markedly upregulated post-ischemia, particularly in endothelial cells, as confirmed by quantitative PCR and immunofluorescence in a middle cerebral artery occlusion model. Both pharmacological inhibition of PEBP1 with FerroLOXIN-1 and AAV-BI30-mediated shRNA knockdown reduced cerebral infarct volume, enhanced neuronal survival, and improved neurological functional recovery. In vitro, FerroLOXIN-1 enhanced cell proliferation and viability under oxygen-glucose deprivation conditions, with potential off-target effects of the interventions validated. Mechanistically, these effects were mediated through activation of the Akt/p38 MAPK signaling cascade. These findings highlight PEBP1 as a central mediator of ischemia-induced neuronal injury and a potential therapeutic target. The convergence of transcriptomic, genetic and experimental validation supports the translational relevance of PEBP1 inhibition in post-stroke neuroregeneration.
Salvage of the ischemic penumbra is critical for improving outcomes after stroke, yet effective molecular targets remain elusive. Therapeutic hypothermia (TH) is a promising neuroprotective strategy, but its precise mechanisms, particularly concerning penumbral salvage, are not fully understood. Here, we demonstrate that TH significantly reduces infarct volume and limits the expansion of the ischemic penumbra in a murine model of transient middle cerebral artery occlusion. Mechanistically, TH exerted its protective effects primarily by suppressing apoptosis rather than other forms of regulated cell death. We identified phosphatidylserine (PS) exposure-a key "eat-me" signal for apoptosis-as a critical target of TH. TH selectively attenuated ischemia-induced PS externalization in neurons both in vivo and in vitro. Furthermore, we found that TH downregulated the expression of the scramblase Xkr8, a major regulator of PS exposure. Inhibition of Xkr8 mimicked the neuroprotective effects of TH, reducing PS exposure and improving neuronal survival, whereas overexpression of Xkr8 mitigated TH-mediated protection in the mouse model. Collectively, our findings reveal that TH protects the ischemic penumbra by inhibiting Xkr8-dependent PS exposure and subsequent apoptotic neuronal death, highlighting Xkr8 as a novel therapeutic target for ischemic stroke.
Migraine is a highly prevalent and disabling neurovascular disorder characterized by recurrent episodes of moderate to severe headache, often accompanied by nausea, photophobia, and phonophobia. A prominent feature of migraine is its disproportionate burden on women, as evidenced by a higher prevalence, frequency and disability, relative to men. These differences are largely attributed to the modulatory effects of sex hormones on migraine pathophysiology. While the cyclic fluctuations of estrogen across reproductive milestones are known to significantly influence migraine onset and severity, far less is known about how sex hormones shape therapeutic response. Currently, the role of hormonal status in determining treatment efficacy remains poorly studied and represents a critical gap in the field. This narrative review synthesizes the current knowledge on the potential mechanisms underlying the higher prevalence in females. It further discusses the sex-specific responses to pharmacological therapies, as well as hormone-based interventions such as contraceptives and hormone replacement therapy. Special attention is given to female-specific migraine phenotypes, such as menstrual migraine, and to therapeutic implications across the female reproductive lifespan. Finally, we identify major gaps in current research and underscore the urgent need for sex- and gender-stratified approaches to optimize treatment and advance precision medicine in migraine care.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the spread of muscle weakness across body regions. ROCK-ALS was a multicenter, placebo-controlled phase 2 trial assessing the safety, tolerability, and efficacy of the Rho kinase inhibitor fasudil in ALS patients. A key exploratory objective was to evaluate fasudil's effect on the spread of muscle weakness using the Motor Unit Number Index (MUNIX), an established, quantitative electrophysiological biomarker of lower motor neuron integrity. MUNIX was assessed in 10 muscles at baseline, day 26, day 90, and day 180. In the present post-hoc analysis, correlations were assessed between baseline serum biomarkers-neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP)-and baseline clinical measures (ALSFRS-R, slow vital capacity, and MUNIX-10 sum scores) as well as their monthly rates of change, to explore potential prognostic relationships. For the analysis of disease spreading, muscles were classified as newly affected based on MUNIX decline relative to contralateral values or prior measurements, using thresholds of ≥10%, ≥20%, or ≥30%. Out of 118 participants included in the intention-to-treat population, 78 had full MUNIX datasets at baseline, and 67 had at least one follow-up. Baseline MUNIX-10 sum scores correlated with subsequent ALSFRS-R decline, suggesting prognostic value. Additionally, at day 90, fasudil significantly reduced the number of newly affected muscles compared to placebo in a dose-dependent manner over different thresholds. This supports MUNIX as a sensitive biomarker for monitoring disease spreading and demonstrates that fasudil may attenuate the progression of lower motor neuron involvement in ALS. Trial registration number: NCT03792490 (ClinicalTrials.gov); 2017-003676-31 (Eudra-CT).
Guillain-Barré syndrome (GBS) is an immune-mediated demyelinating disorder of peripheral nerves with an unclear pathogenesis. This study integrated GBS clinical single-cell data with EAN model transcriptome data, establishing in vivo and in vitro experimental systems to reveal, for the first time, a novel mechanism involving EGR1-ZFP36 and its mediated metabolic reprogramming in GBS pathogenesis. Findings indicated that the transcription factor EGR1 and its predicted target gene ZFP36 were downregulated in both GBS patients and EAN rats. Molecular interaction validation confirmed that EGR1 directly bound to and activated the transcription of ZFP36. Transcriptomic and metabolomic analyses revealed that the EGR1/ZFP36 axis specifically drove macrophage reprogramming toward a glycosphingolipid metabolism-active state. Functionally, EGR1 overexpression promoted the expression of key glycosphingolipid metabolism genes (HEXA, HEXB) by upregulating ZFP36, thereby facilitating polarization toward the anti-inflammatory M2 phenotype. Animal experiments further demonstrated that EGR1 overexpression improved motor function and ameliorated myelin damage in the EAN model, with this protective effect being mediated by ZFP36. Collectively, this study reveals that EGR1 drives glycosphingolipid metabolic reprogramming in monocyte-derived macrophages by transcriptionally activating ZFP36, thereby regulating cellular polarization and participating in the demyelination process of GBS. This discovery not only provides a novel perspective on understanding the immunometabolic mechanisms of GBS but also lays a theoretical foundation for potential therapeutic strategies targeting the EGR1-ZFP36-glycosphingolipid metabolism axis.
Foamy, lipid-laden macrophages are found in multiple sclerosis (MS) lesions, resulting from excessive phagocytosis of myelin debris following demyelination. These lipid-laden macrophages exhibit an inflammatory phenotype, inhibit remyelination, and likely contribute to MS pathology, yet effective therapeutic strategies to target them are lacking. In this study, we sought to better characterize the temporal patterns of myelin debris phagocytosis by human and murine microglia/macrophages, and generate an in vitro model of foamy phagocytes. In addition, given their demonstrated ability to promote lipid efflux in models of other neurological diseases, we investigated cyclodextrins as potential therapeutic agents in MS. We hypothesized that cyclodextrins could lower the accumulation of lipids in foamy macrophages, potentially modulating their inflammatory phenotype. Several in house-synthesized cyclodextrins were evaluated. We found that prolonged application of myelin and inflammatory cytokines produced an inflammatory macrophage phenotype with an MS-like signature, as determined through bulk sequencing analysis. When particular cyclodextrins were applied to these foamy macrophages in culture, there was reduced accumulation of ingested and processed lipids, and altered expression of genes related to inflammatory pathways or wound healing. Our findings suggest that cyclodextrins may modulate the phenotype of inflammatory macrophages, typical of MS pathology, and hold therapeutic potential in MS, warranting further investigation.
Pediatric low-grade gliomas (pLGGs), the most common CNS tumors in children, are increasingly recognized as chronic diseases with prolonged courses and cumulative morbidity. Long-term survival is excellent. Management depends on tumor location and often requires repeated therapy, with risk of long-term functional and neurocognitive impairment. This review synthesizes recent advances in pLGG management, integrating molecular classification, systemic therapies, and emerging diagnostic and surveillance technologies. Treatment advances have been driven by improved molecular characterization, particularly the recognition that most tumors are driven by RAS/MAPK pathway alterations. Integrated histologic-molecular classification has enabled biologically driven risk stratification and adoption of targeted therapies (BRAF, MEK, RAF inhibitors), reshaping treatment for molecularly selected patients. Additionally, recognition of cancer predisposition syndromes and incorporation of germline testing have expanded the scope of clinical decision-making. Emerging technologies including cerebrospinal fluid based liquid biopsy testing, artificial intelligence enabled imaging, advanced metabolic and intraoperative imaging, and digital functional monitoring offer new opportunities to refine diagnosis, surveillance, and response assessments. Despite major progress, challenges remain, including uncertainty about optimal treatment duration and discontinuation, and the management of long-term toxicities from prolonged pathway inhibition. Global disparities in access to molecular diagnostics and targeted therapies, along with financial toxicity from prolonged treatment, hinder equitable precision care. Contemporary pLGG management requires integrating molecular biology, functional outcomes, and long-term surveillance within a multidisciplinary framework. Ongoing research on sequencing, survivorship, and access is essential to improve long-term outcomes.
Cholinergic deficiency is a hallmark neurotransmitter abnormality in Alzheimer's disease (AD) that has traditionally been addressed with cholinesterase inhibitors. In severe AD, butyrylcholinesterase (BuChE) becomes the dominant cholinesterase, suggesting a potential therapeutic target. (-)-N1,N8-bisnorcymserine tartrate (BNC) is a selective BuChE inhibitor designed to address this unmet need. We conducted a phase I, single-center, randomized, double-blind, placebo-controlled, ascending single oral dose clinical trial to evaluate the safety, tolerability, and pharmacokinetics of BNC in 30 healthy volunteers. There were no adverse events (AEs) grade 2 or above or any serious adverse events (SAEs). Most events were mild and self-limited, the most common being asymptomatic bradycardia and headache. The mean AUClast (SD) was 120.98 h∗ng/mL (74.30) for the 40 mg dose, 148.20 h∗ng/mL (99.43) for the 80 mg dose, and 196.33 h∗ng/mL (91.74) for the 120 mg dose. Accordingly, median tmax (range) and mean Cmax (SD) were 1.8 (1.0-5.0) hr and 13.94 (7.64) ng/mL for the 40 mg dose, 1.8 (1.5-5.0) hr and 18.54 (6.44) ng/mL for the 80 mg dose, and 2 (1.0-4.5) hr and 20.93 (5.00) ng/mL for the 120 mg dose. The mean half-life of BNC ranged from 5.5 to 7 h. BNC was safe and well tolerated when administered as a single oral dose of up to 120 mg. This first-in-human, phase I study permits further investigation of this drug as a potential symptomatic treatment for AD. ClinicalTrials.gov, NCT01747213.
Women experience nearly twice the prevalence of depression compared to men and frequently present with comorbid anxiety, with this divergence emerging during adolescence. However, the molecular mechanisms underlying female-specific depression vulnerability remain poorly understood. Here, we found that prenatal stress (PS) induced depressive-like behaviors and selectively downregulated Slit Guidance Ligand 1 (Slit1) expression in the hippocampal dentate gyrus (DG) of female adolescent offspring rats. Furthermore, viral knockdown of Slit1 in the DG induced anxiety- and depressive-like behavioral phenotypes specifically in female rats. In females, Slit1 deficiency reduced the mean fluorescence intensity of the neural stem cell and immature neuron markers Sox2 and DCX in the DG, decreased postsynaptic Homer1, PSD95, and GluA1 expression without affecting Synaptophysin, and diminished the amplitude of sEPSCs. Significantly, the downstream Slit1 effector SLIT-ROBO Rho GTPase-activating protein 2 (Srgap2) was downregulated specifically in Slit1-deficient females. Together, these results suggest that Slit1 disruption selectively affects DG neuroplasticity in females and may contribute to their heightened vulnerability to PS-related depressive-like behaviors, although further mechanistic studies are required to confirm the causal role of Slit1 in these effects.
Chronic craniofacial pain can lead to significant morbidity and reduced quality-of-life. Refractory pain subsequently leads to maladaptive changes within the central nervous system (CNS). It is logical to consider modulation of implicated neural networks to mitigate or reverse these changes in order to alleviate suffering. In this report, we reviewed the current literature in neuromodulation of CNS in facial pain treatment. We conducted PRISMA-compliant systematic review using MEDLINE and EMBASE databases. We included studies applying stimulation to the CNS to treat facial pain. Demographic data, design, duration, participants, clinical details, outcomes, adverse effects were extracted. Out of 1005 unique publications, 57 were included for analysis. Main techniques included were transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), motor cortex stimulation (MCS), deep brain stimulation (DBS), and spinal cord stimulation (SCS). For tDCS, rTMS, and MCS, the main stimulation target was primary motor cortex; while several different DBS targets (e.g., thalamic nuclei, anterior cingulate cortex, periaqueductal grey matter) were studied. While most studies showed improvement in Numeric Rating Scale for pain, values range widely from 11.1% in one MCS study to 90% in one rTMS study, with majority within 20-60%. There is heterogeneity across research designs, including patient selection, outcome measures, and follow-up. Standardized reporting framework is required to allow direct comparison between different modalities within subgroups of facial pain patients.
Exposure of a pathogenic β6/β7 loop neo-epitope has been proposed to contribute to the pathogenesis of misfolded Cu/Zn superoxide dismutase (SOD1) in amyotrophic lateral sclerosis (ALS) by mediating early events in its noxious structural transformation and prion-like activity. Antibody-mediated blockade of this epitope was shown to ameliorate disease phenotype in an ALS animal model. Here, as an alternative strategy, we sought to block this epitope using a small molecule designed to occupy the inter-subunit cavity framed by the two β6/β7 loops. Using a structure-based virtual screen targeting this cavity, we identified a small molecule, N-[3-(3-methylimidazo[2,1-b][1,3]thiazol-6-yl)phenyl]-4-sulfamoylbenzamide (C7), that preferentially bound the native-like conformation of SOD1, reduced β6/β7 loop epitope accessibility, and inhibited irreversible apo-SOD1 misfolding in vitro. Delivered to presymptomatic hSOD1G93A mice via a nanoparticle-based nose-to-brain delivery system, C7 significantly delayed the onset of motor abnormalities and modestly extended survival. At disease onset, spinal cord analysis revealed reduced misfolded SOD1 inclusions and attenuated astro- and microgliosis. Analysis of C7 concentrations in combined brain and spinal cord tissue indicated rapid but saturable nose-to-CNS uptake and slow clearance. Our findings demonstrate that targeting the surface cavity shaped by the β6/β7 loops of SOD1 with a reversibly-binding small molecule can ameliorate ALS-like disease in vivo, potentially by counteracting early misfolding events and/or limiting prion-like propagation of molecular pathology. However, saturable nose-to-CNS uptake of C7 restricts CNS exposure and likely constrains therapeutic efficacy, underscoring the need to define the rate-limiting pharmacokinetic step and to optimize the nanoparticle formulation and/or physicochemical properties of the C7 scaffold.
Focal motor seizures (FMS) are often unresectable because of motor risk. We aimed to evaluate the long-term effectiveness and safety of subthalamic nucleus deep brain stimulation (STN-DBS) in patients with FMS and to identify suitable candidate patients. We analyzed long-term outcomes in 22 patients with FMS treated with STN-DBS, classifying patients as responders (≥50% seizure reduction) or non-responders and relating outcomes to seizure-focus topography using focus-frequency maps and region-of-interest-based volumetrics. In a SEEG cohort of 13 patients with electrodes in the sensorimotor cortex and the STN, including 1 from the DBS cohort, we quantified changes in interictal spike (IIS) rates and broadband (0.5-90 Hz) power spectral density (PSD) across distinct sensorimotor subregions during 100-Hz STN stimulation. At final follow-up (mean 45 months), median seizure reduction was 55%, with 14/22 responders and six patients achieved >90% reduction, including one seizure-free. STN-DBS was well tolerated, with no surgical complications and one explant for infection. Responders' seizure foci clustered in a medial sensorimotor strip comprising the paracentral lobule (PCL), supplementary motor area (SMA) and trunk representations of the precentral and postcentral gyri, and greater involvement of the PCL and trunk areas correlated with better outcome. SEEG analyses showed a global reduction in broadband power but regionally selective suppression of epileptiform activity, confined to the PCL and SMA. Together, STN-DBS appears to be a safe, effective option for FMS, and patients whose seizure foci involve the medial sensorimotor strip may be potential candidates.
Not all patients with acute ischemic stroke (AIS) benefit from endovascular therapy (EVT), particularly in the posterior circulation. This pilot randomized controlled trial evaluated the safety, feasibility, and preliminary efficacy of vertebrobasilar artery cooling infusion (VACI) administered after successful recanalization as a neuroprotective strategy for posterior circulation AIS. Participants were randomly assigned (1:1) to VACI or control. The VACI group received 300 mL of 4 °C saline infused into the vertebral artery at 30 mL/min after thrombectomy, whereas controls received 300 mL of 37 °C saline. All patients received standard guideline-based care. The primary endpoint was symptomatic intracranial hemorrhage (sICH). Secondary endpoints included functional outcomes, infarct volume, mortality, intracranial hemorrhage (ICH), vasospasm, coagulation abnormalities, pneumonia, and urinary tract infection. VACI following EVT appears safe and feasible in posterior circulation AIS and may offer potential neuroprotective benefit. Forty patients were enrolled and analyzed. The incidence of sICH did not differ between groups. Rates of neurological deterioration and other complications were comparable. Favorable trends were observed in the VACI group, including improved early neurological recovery (median NIHSS 6 vs. 12.5) and smaller final infarct volume (9.0 vs. 17.5 mL). Mortality was numerically lower in the VACI group at 90 days (10.0% vs. 20.0%) and at 7 days (5.0% vs. 20.0%). Although differences were not statistically significant, outcomes consistently favored VACI. VACI following EVT appears safe and feasible in posterior circulation AIS and may offer potential neuroprotective benefit.
Drug-resistant epilepsy has traditionally been managed with medications or surgery aimed at removing or destroying epileptogenic tissue. In contrast, electrical brain stimulation seeks to alter dysfunctional neural circuits without tissue destruction. Transcranial magnetic stimulation (TMS) is a particularly attractive approach due to its favorable side-effect profile and robust diagnostic as well as therapeutic capacity. Cortical stimulation by TMS generates quantifiable evoked potentials that provide insights into seizure susceptibility and target engagement by therapeutics. Repetitive TMS (rTMS) has promise as a method for treating seizures, but essential questions remain as to which epilepsy syndromes and which cortical targets will respond to stimulation. Here, we speculate on questions pertaining to diagnostic and therapeutic TMS that may be answered in near-future studies. Will reliable measures to quantify seizure likelihood be available from measures of TMS-EMG or TMS-EEG evoked potentials? Might TMS help optimize other neuromodulation techniques? Can rTMS targeting superficial cortex, either in isolation or coupled with appropriately selected drugs, suppress generalized onset or multifocal seizures? Recent advances highlight the potential of bioelectronic medicine approaches such as TMS.