癫痫的神经调控技术，如深度脑刺激、时间干涉等

超难治性癫痫持续状态(super-refractory status epilepticus, SRSE)是临床急危重症，具有较高的死亡率及致残率。传统抗癫痫药物(ASMs)与麻醉剂输注疗效欠佳。近年来基于癫痫网络理论与神经电生理进展，神经调控技术逐渐成为SRSE多模态治疗的重要策略。因此，本文系统综述侵入性(迷走神经刺激、深部脑刺激、反应性神经刺激)与非侵入性(经颅磁刺激、电休克疗法、经颅直流电刺激)技术的临床证据，旨在阐明神经调控技术对SRSE的治疗效能，以指导SRSE个体化治疗策略的制定，从而提升长期生存质量。

目的：本研究旨在评估迷走神经刺激(VNS)对难治性癫痫(DRE)患者的长期临床结果，并探讨影响VNS疗效的预测因素。方法：我们对2016年8月至2022年12月期间在安徽医科大学第一附属医院接受VNS植入的56例患者的医疗数据进行了回顾性分析。所有患者均进行了至少1年的随访。良好的临床疗效定义为癫痫发作频率降低不低于50%。二元逻辑回归分析用于识别显着影响疗效的变量。结果：我们的研究表明，长期慢性迷走神经刺激后癫痫发作频率显着降低。在最后一次随访时，26名患者(50%)疗效佳，6名(10.7%)患者无癫痫发作。在我们的研究中，二元逻辑回归分析没有发现任何显著影响疗效的预测因素。此外，31名患者(55.4%)报告在最后一次随访时生活质量(QOL)总体改善。植入后32名患者(57.1%)报告了轻微的短暂不良事件，其中最常见的是声音嘶哑。结论：我们的研究结果表明，长期慢性VNS治疗可以有效降低难治性癫痫患者的发作频率。并且观察到QOL的改善。然而，在我们的队列中没有发现显著影响疗效的预测因素。

癫痫的治疗包括药物以及非药物治疗。由于癫痫的致病和治病机制到目前为止，尚未完全清楚，如果采取长期的药物治疗方式，一方面会造成一定程度的资源浪费，另一方面长期的药物治疗会存在一定抗药性和带来某些副作用。就目前而言，手术治疗和借助癫痫治疗仪治疗是非药物治疗的两种主要有效方法。但是，外科手术治疗会对人体造成非常大的伤害，所以不到迫不得已人们通常不会考虑手术治疗。借助癫痫治疗仪辅助治疗就成为了一部分患者的最佳选择之一，其主要治疗方法包括迷走神经刺激术、经颅磁刺激技术和电刺激。一部分癫痫患者选择这些新的治疗方法，并且这些新的治疗方法也可以用于治疗难治的癫痫，或是作为辅助治疗手段。最后对之前的相关研究结果进行了总结，并提出了一些今后的研究方向。

重复性经颅磁刺激(rTMS)作为一种非侵入性神经调控技术，近年来在神经系统疾病治疗领域取得显著进展。本文综述rTMS在神经系统疾病治疗中的研究进展。

无创神经调节技术是治疗神经系统疾病的重要手段，多个研究证明低强度聚集超声(Low-intensity focused ultrasound, LIFU)可应用于多种神经系统疾病，如癫痫、阿尔茨海默病、帕金森病等，并显现出了积极的疗效。LIFU可以穿透颅骨，聚集于大脑深部核团，具有无创、高精确性、高穿透深度等优点。本文通过回顾LIFU的技术进展、作用机制以及在神经系统疾病治疗中的应用，总结了LIFU作为一种新型的无创神经调节技术，在神经系统疾病治疗方面的应用前景。研究表明，LIFU通过靶向调控神经元活性及神经可塑性，可能具有改善神经功能障碍的临床转化价值。本综述为LIFU技术的科学化应用与临床转化研究提供了理论框架与方法学参考。

卒中后癫痫(PSE)是卒中患者常见的严重并发症，显著影响其预后与生活质量。本文系统综述PSE的病理生理机制、诊断技术、治疗策略及预后因素的研究进展。病理生理方面，重点探讨脑损伤后神经递质失衡、离子通道异常、血脑屏障破坏及炎症反应的交互作用；诊断部分，结合脑电图、影像学与血液生物标志物的临床价值与局限性展开分析；治疗策略涵盖抗癫痫药物的选择、神经调控技术的应用及手术干预的适应证；预后部分则从卒中类型、发作特征及治疗依从性等多维度解析影响因素。本文旨在整合现有研究成果，为优化PSE的临床管理及未来的研究方向提供参考。

经颅直流电刺激(transcranial direct current stimulation, tDCS)是一种非侵入性的，利用恒定、低强度直流电(1~2 mA)调节大脑皮层神经元活动的技术。该技术副作用小、操作简便、费用低廉，在临床疾病如癫痫，帕金森，耳鸣、抑郁，精神分裂症，阿兹海默症，成瘾等的治疗中具有广阔的应用前景。本文旨在简要介绍tDCS技术，总结相关的临床应用研究，并指出存在的一些问题以及对未来的展望。

近年来，经皮耳迷走神经刺激(tVNS)作为一种新兴的治疗手段，逐渐引起了医学界的关注。tVNS通过刺激耳部迷走神经，能够有效调节自主神经系统，进而影响多种疾病中的炎症反应。当前的研究显示，tVNS在减轻炎症、改善相关症状方面展现出良好的应用前景。然而，尽管已有一些成功案例，关于其具体作用机制及最佳应用方案仍需深入探讨。此外，临床应用的标准化及效果评估体系的建立也面临挑战。通过综述tVNS在抗炎作用方面的最新研究进展，本文旨在为该领域的未来研究和临床应用提供参考与启示。经皮耳迷走神经刺激属于中医药现代化的典型，该方法在临床治疗一般无需手术，能发挥一定抗炎作用，避免患者面临不良反应风险。经皮耳迷走神经刺激是将自主神经功能调整作为基础，实现外周神经–脑网络–机体调节，对癫痫、抑郁症治疗作用明显。经皮耳迷走神经刺激达到一定抗炎效果，值得临床推广和应用。经针刺和经皮耳迷走神经刺激联合应用后，轻度抑郁症患者的TNF-α、IL-6水平均降低，经神经元、免疫介导和神经内分泌介导的信号通路，能保证炎症水平降低，促使患者的抑郁症状减轻。下文按照文献筛选标准对经皮耳迷走神经刺激的解剖学、抗炎作用机制、治疗的仪器和参数详细分析，明确传统耳穴疗法和经皮耳迷走神经刺激的抗炎作用联系，阐述临床上应用经皮耳迷走神经刺激抗炎作用。

目的：分析我国难治性癫痫高被引文献的剂量特征。方法：检索中国学术期刊全文数据库(CNKI) 2010~2020年的难治性癫痫文献，参照普赖斯定律确定高被引文献，用Excel 2007统计分析被引、年份、期刊、作者、单位、关键词、基金。结果：检出高被引文献321篇，纳入统计200篇，累计被引2318次，篇均被引11.59次；文献数自2010年开始上升，至峰值29篇后又迅速下降为2018年的3篇；文献来自129种期刊，其中《中国实用儿科杂志》、《中国临床神经外科杂志》、《实用医学杂志》稳居文献数、总被引频次、篇均被引频次第一名，文献涉及作者362人、署名404次。累计合作164篇，总合作率82%，作者黄小波、陈文强、李玲的署名数依次居前3名；作者机构涉及179个，其中医院108个(54%)、院校49个(24.5%)，最高产发文机构为首都医科大学，涉及文献13篇。署有首都医科大学、南方医科大学、北京大学、郑州大学文献数居前4位。共涉及关键词330个，787次，篇均关键词3.94个。200篇文献获基金支持的文献共66篇，占33%，累计86项次，篇均1.30项次。结论：CNKI数据库难治性癫痫高被引文献展现出以《中华眼科杂志》、《中国实用儿科杂志》、《中国临床神经外科杂志》、《实用医学杂志》为权威期刊、以医院为核心发文机构、以难治性癫痫主要研究对象、以省部级以上项目为主要资助基金的特征，形成了黄小波、陈文强、李玲等为代表的核心团队，但关键词使用不够规范，资助资金偏少。

Lenox-Gastaut综合征(LGS)是一种儿童期发病，以多种癫痫发作类型、异常脑电图及认知和/或行为障碍为主要特征的癫痫性脑病。大多数LGS患儿为难治性癫痫，常伴有智力障碍及发育迟缓，严重影响患儿的生活质量。在此从病因、发病机制、临床特点、脑电图特征、诊断、治疗及预后等方面进行综述，以期为LGS患儿的诊疗提供思路与参考。

BACKGROUND AND PURPOSE: Neuromodulation of the centromedian nucleus (CM) of the thalamus has shown promise in treating refractory epilepsy, particularly for idiopathic generalized epilepsy and Lennox-Gastaut syndrome. However, precise targeting of CM remains challenging. The combination of deep learning reconstruction (DLR) and fast gray matter acquisition T1 inversion recovery (FGATIR) offers potential improvements in visualization of CM for deep brain stimulation (DBS) targeting. The goal of the study was to evaluate the visualization of the putative CM on DLR-FGATIR and its alignment with atlas-defined CM boundaries, with the aim of facilitating direct targeting of CM for neuromodulation. MATERIALS AND METHODS: This retrospective study included 12 patients with drug-resistant epilepsy treated with thalamic neuromodulation by using DLR-FGATIR for direct targeting. Postcontrast-T1-weighted MRI, DLR-FGATIR, and postoperative CT were coregistered and normalized into Montreal Neurological Institute (MNI) space and compared with the Morel histologic atlas. Contrast-to-noise ratios were measured between CM and neighboring nuclei. CM segmentations were compared between an experienced rater, a trainee rater, the Morel atlas, and the Thalamus Optimized Multi Atlas Segmentation (THOMAS) atlas (derived from expert segmentation of high-field MRI) by using the Sorenson-Dice coefficient (Dice score, a measure of overlap) and volume ratios. The number of electrode contacts within the Morel atlas CM was assessed. RESULTS: On DLR-FGATIR, CM was visible as an ovoid hypointensity in the intralaminar thalamus. Contrast-to-noise ratios were highest (P < .001) for the mediodorsal and medial pulvinar nuclei. Dice score with the Morel atlas CM was higher (median 0.49, interquartile range 0.40–0.58) for the experienced rater (P < .001) than the trainee rater (0.32, 0.19–0.46) and no different (P = .32) than the THOMAS atlas CM (0.56, 0.55–0.58). Both raters and the THOMAS atlas tended to under-segment the lateral portion of the Morel atlas CM, reflected by smaller segmentation volumes (P < .001). All electrodes targeting CM based on DLR-FGATIR traversed the Morel atlas CM. CONCLUSIONS: DLR-FGATIR permitted visualization and delineation of CM commensurate with a group atlas derived from high-field MRI. This technique provided reliable guidance for accurate electrode placement within CM, highlighting its potential use for direct targeting.

The pulvinar nucleus of the thalamus has extensive cortical connections with the temporal, parietal, and occipital lobes. Deep brain stimulation (DBS) targeting the pulvinar nucleus, therefore, carries the potential for therapeutic benefit in patients with drug‐resistant posterior quadrant epilepsy (PQE) and neocortical temporal lobe epilepsy (TLE). Here, we present a single‐center experience of patients managed via bilateral DBS of the pulvinar nucleus.

Introduction Pediatric drug-resistant epilepsy (DRE) is defined as epilepsy that is not controlled by two or more appropriately chosen and dosed anti-seizure medications (ASMs). When alternative therapies or surgical intervention is not viable or efficacious, advanced options like deep brain stimulation (DBS) or responsive neurostimulation (RNS) may be considered. Objective Describe the Stanford early institutional experience with DBS and RNS in pediatric DRE patients. Methods Retrospective chart review of seizure characteristics, prior therapies, neurosurgical operative reports, and postoperative outcome data in pediatric DRE patients who underwent DBS or RNS placement. Results Nine patients had DBS at 16.0 ± 0.9 years and 8 had RNS at 15.3 ± 1.7 years (mean ± SE). DBS targets included the centromedian nucleus of the thalamus (78% of DBS patients), anterior nucleus of the thalamus (11%), and pulvinar (11%). RNS placement was guided by stereo-EEG and/or intracranial monitoring in all RNS patients (100%). RNS targets included specific seizure onset zones (63% of RNS patients), bilateral hippocampi (25%) and bilateral temporal lobes (12%). Only DBS patients had prior trials of ketogenic diet (56%) and VNS therapy (67%). Four DBS patients (44%) had prior neurosurgical interventions, including callosotomy (22%) and focal resection (11%). One RNS patient (13%) and one DBS patient (11%) required revision surgery. Two DBS patients (22%) developed postoperative complications. Three RNS patients (38%) underwent additional resections; one RNS patient had electrocorticography recordings for seizure mapping before surgery. For patients with a follow-up of at ≥1 year (n = 7 for DBS and n = 5 for RNS), all patients had reduced seizure burden. Clinical seizure freedom was achieved in 80% of RNS patients and 20% had a >90% reduction in seizure burden. The majority (71%) of DBS patients had a ≥50% reduction in seizures. No patients experienced no change or worsening of seizure frequency. Conclusion In the early Stanford experience, DBS was used as a palliatively for generalized or mixed DRE refractory to other resective or modulatory approaches. RNS was used for multifocal DRE with a clear seizure focus on stereo-EEG and no prior surgical interventions. Both modalities reduced seizure burden across all patients. RNS offers the additional benefit of providing data to guide future surgical planning.

We sought to perform a systematic review and individual participant data meta‐analysis to identify predictors of treatment response following thalamic neuromodulation in pediatric patients with medically refractory epilepsy. Electronic databases (MEDLINE, Ovid, Embase, and Cochrane) were searched, with no language or data restriction, to identify studies reporting seizure outcomes in pediatric populations following deep brain stimulation (DBS) or responsive neurostimulation (RNS) implantation in thalamic nuclei. Studies featuring individual participant data of patients with primary or secondary generalized drug‐resistant epilepsy were included. Response to therapy was defined as >50% reduction in seizure frequency from baseline. Of 417 citations, 21 articles reporting on 88 participants were eligible. Mean age at implantation was 13.07 ± 3.49 years. Fifty (57%) patients underwent DBS, and 38 (43%) RNS. Sixty (68%) patients were implanted in centromedian nucleus and 23 (26%) in anterior thalamic nucleus, and five (6%) had both targets implanted. Seventy‐four (84%) patients were implanted bilaterally. The median time to last follow‐up was 12 months (interquartile range = 6.75–26.25). Sixty‐nine percent of patients achieved response to treatment. Age, target, modality, and laterality had no significant association with response in univariate logistic regression. Until thalamic neuromodulation gains widespread approval for use in pediatric patients, data on efficacy will continue to be limited to small retrospective cohorts and case series. The inherent bias of these studies can be overcome by using individual participant data. Thalamic neuromodulation appears to be a safe and effective treatment for epilepsy. Larger, prolonged prospective, multicenter studies are warranted to further evaluate the efficacy of DBS over RNS in this patient population where resection for curative intent is not a safe option.

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The precise modulation of electrical activity in specific neuronal populations is paramount for rectifying abnormal neurological functions and is a critical element in the therapeutic arsenal for neurological disorders. However, achieving a balance between minimal invasiveness and robust neuroprotection poses a considerable challenge. Herein, we present a nanoneuromodulation strategy integrating neuroprotective features to effectively address epilepsy with minimal invasiveness and enable wireless functionality. Strategically engineered nanotransducer, adorned with platinum (Pt) decoration with titanium disulfide (TiS2) (TiS2/Pt), enables precise modulation of neuronal electrical activity in vitro and in vivo, ensuring exceptional temporal fidelity under millisecond-precision near-infrared (NIR) light pulses irradiation. Concurrently, TiS2/Pt showcase a pronounced enhancement in enzyme-mimicking activity, offering a robust defense against oxidative neurological injury in vitro. Nanotransducer-enabled wireless neuromodulation with biocatalytic neuroprotective capacity is highly effective in alleviating epileptic high-frequency neural activity and diminishing oxidative stress levels, thereby restoring redox equilibrium. This integrated therapeutic approach reduces the severity of epilepsy, demonstrating minimal invasiveness and obviating the requirements for genetic manipulation and optical fiber implantation, while providing an alternative avenue for neurological disorder treatment.

OBJECTIVE Medically refractory epilepsy (MRE) often requires resection of the seizure onset zone (SOZ) for effective treatment. However, when the SOZ is in functional cortex (FC), achieving complete and safe resection becomes difficult, due to the seizure network overlap with function. The authors aimed to assess the safety and outcomes of a combined approach involving partial resection combined with focal neuromodulation for FC refractory epilepsy. METHODS The authors performed a retrospective analysis of individuals diagnosed with MRE who underwent surgical intervention from January 2015 to December 2022. Patients whose SOZ was located in FC and were treated with resection combined with simultaneous implantation of a focal neuromodulation device (responsive neurostimulation [RNS] device) with more than 12 months of follow-up data were included. All patients underwent a standard epilepsy preoperative assessment including intracranial electroencephalography and extraoperative stimulation mapping. Resections were performed under general anesthesia, followed by the concurrent implantation of an RNS device. RESULTS Seven patients (4 males, median age 32.3 years, all right-handed) were included. The median interval from seizure onset to surgery was 17.4 years. The epileptogenic network included sensorimotor areas (cases 2, 3, and 6), visual cortex (case 1), language areas (cases 4 and 7), and the insula (case 5). The median follow-up was 3 years (range 1-5.8 years). No significant changes in neuropsychological tests were reported. One permanent nondisabling planned neurological deficit (left inferior quadrantanopia) was observed. Six patients had stimulation activated at a median of 4.7 months after resection. All patients achieved good seizure outcomes (5 with Engel class I and 2 with Engel class II outcomes). CONCLUSIONS Maximal safe resection combined with focal neuromodulation presents a promising alternative to stand-alone resections for MRE epileptogenic zones overlapping with functional brain. This combined approach prioritizes the preservation of function while improving seizure outcomes.

Objectives Despite the growing interest in network-guided neuromodulation for epilepsy, uncertainty about the safety and long-term efficacy of thalamocortical stimulation persist. Our evaluation focused on the use of a 4-lead open-loop implantable pulse generator (IPG) for thalamocortical network neuromodulation. Methods We retrospectively reviewed seven subjects with diverse seizure networks (SNs)-poorly localized, regional, or multifocal-undergoing thalamocortical neuromodulation. Employing a 4-lead system, electrodes targeted both thalamic and cortical SN nodes. We assessed seizure severity, life satisfaction, and sleep quality on a 10-point scale, and seizure frequency via telephone interviews and chart review. Six subjects underwent open-loop stimulation trials during intracranial EEG (iEEG) to confirm SN engagement and optimize settings, targeting the suppression of interictal epileptiform discharges (IEDs) and seizures. Outcomes were assessed by Wilcoxon sign-rank test, 0.05 significance level. Results After a median of 17 months post-implantation (range 13-60), subjects had a median disabling seizure reduction of 93% (range 50-100%, p=0.0156), with 100% responder rate ([≥] 50% reduction in seizure frequency). The median improvement in seizure severity was 3.5 out of 10 points (p=0.0312), life satisfaction 4.5 points (p= 0.0312), and quality of sleep 3 points (p=0.062). No perioperative complications occurred. Rare transient seizure exacerbations and stimulation-related sensory/motor side effects resolved with parameter adjustments. One subject required surgical revision due to delayed infection. Six subjects had permanent electrode placement refined by iEEG trial stimulation; five subjects had >90% reduction in seizure frequency during iEEG stimulation. Significance Thalamocortical network neuromodulation using a 4-lead open-loop system is safe, and is associated with significant improvements in seizure control and patient quality of life. Trial stimulation during iEEG shows promise for enhancing SN engagement and parameter optimization, but requires further study. Prospective controlled trials are needed to establish the validity of thalamocortical network neuromodulation for epilepsy.

Racial disparities affect multiple dimensions of epilepsy care including epilepsy surgery. This study aims to further explore these disparities by determining the utilization of invasive neuromodulation devices according to race and ethnicity in a multicenter study of patients living with focal drug‐resistant epilepsy (DRE). We performed a post hoc analysis of the Human Epilepsy Project 2 (HEP2) data. HEP2 is a prospective study of patients living with focal DRE involving 10 sites distributed across the United States. There were no statistical differences in the racial distribution of the study population compared to the US population using census data except for patients reporting more than one race. Of 154 patients enrolled in HEP2, 55 (36%) underwent invasive neuromodulation for DRE management at some point in the course of their epilepsy. Of those, 36 (71%) were patients who identified as White. Patients were significantly less likely to have a device if they identified solely as Black/African American than if they did not (odds ratio = .21, 95% confidence interval = .05–.96, p = .03). Invasive neuromodulation for management of DRE is underutilized in the Black/African American population, indicating a new facet of racial disparities in epilepsy care.

Background. In case of ineffective conservative antiepileptic therapy, surgical treatment aimed at removing the epileptogenic focus may be applied. Resection procedures allow to eliminate seizures in most patients, but in 20–30% cases they persist or recur, thereby proposing to use some neuromodulation.Objective: to assess effectiveness of neuromodulation in patients with drug-resistant epilepsy (DRE) after failed resection surgical interventions.Material and methods. A retrospective data analysis was carried out involving 23 DRE patients who had undergone vagus nerve stimulation (VNS) or deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) or hippocampus (HP) after failed surgeries. The VNS system was implanted in 18 (78.3%) patients, the HP-DBS system – in 3 (13.0%), and the ANT-DBS system – in 2 (8.7%). The results after surgical interventions were assessed according to the Engel scale, VNS therapy – by the McHugh (MH) scale, DBS therapy – by the degree of reduced seizure rate as a percentage. The average follow-up was 56.5 months.Results. Patients with implanted VNS system were found to have the outcome presented as MH Ia–IIb in 3 (16.7%) cases, MH IIIa–IIIb in 10 (55.5%) cases, MH IV–V in 5 (27.8%) cases. In HP-DBS group, 2 out of 3 patients showed a decline in seizure rate by more than 50% from the baseline level, and 1 patient experienced an improvement in seizure severity. In the ANT-DBS group, one patient had a 60% reduction in seizure rate and an improvement in seizure severity, another one showed no change in seizure rate.Conclusion. Neuromodulation in DRE patients can significantly lower seizure rate in more than half of patients after failed surgical treatment.

Anti-seizure medications and deep brain stimulation are widely used therapies to treat seizures; however, both face limitations such as resistance and the unpredictable nature of seizures. Recent advancements, including responsive neural stimulation and on-demand drug release, have been developed to address these challenges. However, a gap remains, as electrical stimulation provides only transient effects while medication has a delayed onset. To bridge this gap, we developed a Bimodal Closed-loop Neurostimulation Implant System that integrates real-time neural recording, immediate electrical stimulation, and on-demand drug release to achieve more effective seizure suppression. This dual-modality system combines rapid electrical intervention with sustained pharmacological treatment to provide comprehensive seizure control. An embedded platform powered by a Long Short-Term Memory network detects seizures and autonomously triggers these interventions. In vivo studies in an epileptic mouse model revealed that electrical stimulation achieved rapid seizure suppression, terminating 75.16% of seizures, with 90% of episodes suppressed within 10 s. The subcutaneous drug capsule provided additional control, with an onset of action approximately 15 min after release. The dual-modality approach bridged the gap between immediate and delayed intervention, stabilizing neural activity and reducing seizure recurrence. Furthermore, we confirmed the long-term viability of neurons, observing no significant changes in morphology or signal quality following stimulation and drug release. These results suggest that the system offers rapid, stable, and minimally invasive seizure control, making it a promising therapeutic tool for epilepsy. By bridging the gap between electrical effects and delayed pharmacological action, the system presents a novel approach to epilepsy management.

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Background: Epilepsy is a widespread neurologic disorder and almost one-third of patients suffer from drug-resistant epilepsy (DRE). Neuromodulation targeting the centromediannucleus of the thalamus (CM) has been showing promising results for patients with generalized DRE who are not surgical candidates. Recently, the effect of CM- deep brain stimulation (DBS) in DRE patients was investigated in the Electrical Stimulation of Thalamus for Epilepsy of Lennox–Gastaut phenotype (ESTEL) trial, a monocentric randomized-controlled study. The same authors described a ‘cold-spot’ and a ‘sweet-spot’, which are defined as the volume of stimulation in the thalamus yielding the least and the best clinical response, respectively. However, it remains unclear which structural connections may contribute to the anti-seizure effect of the stimulation. Objective: We investigated the differences in structural connectivity among CM, the sweet-spot and the cold-spot. Furthermore, we tried to validate our results in a cohort of DRE patients who underwent CM-DBS or CM-RNS (responsive neurostimulation). We hypothesized that the sweet-spot would share similar structural connectivity with responder patients. Methods: By using the software FMRIB Software Library (FSL), probabilistic tractography was performed on 100 subjects from the Human Connectome Project to calculate the probability of connectivity of the whole CM, the sweet-spot and the cold-spot to 45 cortical and subcortical areas. Results among the three seeds were compared with multivariate analysis of variance (MANOVA). Similarly, the structural connectivity of volumes of tissue activated (VTAs) from eight DRE patients was investigated. Patients were divided into responders and non-responders based on the degree of reduction in seizure frequency, and the mean probabilities of connectivity were similarly compared between the two groups. Results: The sweet-spot demonstrated a significantly higher probability of connectivity (p < 0.001) with the precentral gyrus, superior frontal gyrus, and the cerebellum than the whole CM and the cold-spot. Responder patients displayed a higher probability of connectivity with both ipsilateral (p = 0.011) and contralateral cerebellum (p = 0.04) than the non-responders. Conclusion: Cerebellar connections seem to contribute to the beneficial effects of CM-neuromodulation in patients with drug-resistant generalized epilepsy.

Epilepsy is a prevalent and severe neurological disorder and generally requires prolonged electrode implantation and tether brain stimulation in refractory cases. However, implants may cause potential chronic immune inflammation and permanent tissue damage due to material property mismatches with soft brain tissue. Here, we demonstrated a nanomaterial-enabled near-infrared (NIR) neuromodulation approach to provide nongenetic and nonimplantable therapeutic benefits in epilepsy mouse models. Our study showed that crystal-exfoliated photothermal black phosphorus (BP) flakes could enhance neural activity by altering the membrane capacitive currents in hippocampus neurons through NIR photothermal neuromodulation. Optical stimulation facilitated by BP flakes in hippocampal slices evoked action potentials with a high spatiotemporal resolution. Furthermore, BP flake-enabled NIR neuromodulation of hippocampus neural circuits can suppress epileptic signals in epilepsy model mice with minimal invasiveness and high biocompatibility. Consequently, nanomaterial-enabled NIR neuromodulation may open up opportunities for nonimplantable optical therapy of epilepsy in nontransgenic organisms.

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Epilepsy is a common and debilitating neurological disorder, and approximately one-third of affected individuals have ongoing seizures despite appropriate trials of two anti-seizure medications. This population with drug-resistant epilepsy (DRE) may benefit from neurostimulation approaches, such as vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS). In some patient populations, these techniques are FDA-approved for treating DRE. VNS is used as adjuvant therapy for children and adults. Acting via the vagus afferent network, VNS modulates thalamocortical circuits, reducing seizures in approximately 50 % of patients. RNS uses an adaptive (closed-loop) system that records intracranial EEG patterns to activate the stimulation at the appropriate time, being particularly well-suited to treat seizures arising within eloquent cortex. For DBS, the most promising therapeutic targets are the anterior and centromedian nuclei of the thalamus, with anterior nucleus DBS being used for treating focal and secondarily generalized forms of DRE and centromedian nucleus DBS being applied for treating generalized epilepsies such as Lennox-Gastaut syndrome. Here, we discuss the indications, advantages and limitations of VNS, DBS and RNS in treating DRE and summarize the spatial distribution of neuroimaging observations related to epilepsy and stimulation using NeuroQuery and NeuroSynth.

Outcomes following vagus nerve stimulation (VNS) improve over years after implantation in children with drug‐resistant epilepsy. The added value of deep brain stimulation (DBS) instead of continued VNS optimization is unknown. In a prospective, non‐blinded, randomized patient preference trial of 18 children (aged 8–17 years) who did not respond to VNS after at least 1 year, add‐on DBS resulted in greater seizure reduction compared with an additional year of VNS optimization (51.9% vs. 12.3%, p = 0.047). Add‐on DBS also resulted in less bothersome seizures (p = 0.03), but no change in quality of life. DBS may be considered earlier for childhood epilepsy after non‐response to VNS. ANN NEUROL 2024;96:405–411

Short‐term outcomes of deep brain stimulation of the anterior nucleus of the thalamus (ANT‐DBS) were reported for people with drug‐resistant focal epilepsy (PwE). Because long‐term data are still scarce, the Medtronic Registry for Epilepsy (MORE) evaluated clinical routine application of ANT‐DBS.

Background and Objectives The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. Methods MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. Results Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. Discussion The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. Classification of Evidence This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy. Trial Registration Information MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012.

Objective By studying the surgical outcome of deep brain stimulation (DBS) of different target nuclei for patients with refractory epilepsy, we aimed to explore a clinically feasible target nucleus selection strategy. Methods We selected patients with refractory epilepsy who were not eligible for resective surgery. For each patient, we performed DBS on a thalamic nucleus [anterior nucleus of the thalamus (ANT), subthalamic nucleus (STN), centromedian nucleus (CMN), or pulvinar nucleus (PN)] selected based on the location of the patient's epileptogenic zone (EZ) and the possible epileptic network involved. We monitored the clinical outcomes for at least 12 months and analyzed the clinical characteristics and seizure frequency changes to assess the postoperative efficacy of DBS on the different target nuclei. Results Out of the 65 included patients, 46 (70.8%) responded to DBS. Among the 65 patients, 45 underwent ANT-DBS, 29 (64.4%) responded to the treatment, and four (8.9%) of them reported being seizure-free for at least 1 year. Among the patients with temporal lobe epilepsy (TLE, n = 36) and extratemporal lobe epilepsy (ETLE, n = 9), 22 (61.1%) and 7 (77.8%) responded to the treatment, respectively. Among the 45 patients who underwent ANT-DBS, 28 (62%) had focal to bilateral tonic-clonic seizures (FBTCS). Of these 28 patients, 18 (64%) responded to the treatment. Out of the 65 included patients, 16 had EZ related to the sensorimotor cortex and underwent STN-DBS. Among them, 13 (81.3%) responded to the treatment, and two (12.5%) were seizure-free for at least 6 months. Three patients had Lennox–Gastaut syndrome (LGS)-like epilepsy and underwent CMN-DBS; all of them responded to the treatment (seizure frequency reductions: 51.6%, 79.6%, and 79.5%). Finally, one patient with bilateral occipital lobe epilepsy underwent PN-DBS, reducing the seizure frequency by 69.7%. Significance ANT-DBS is effective for patients with TLE or ETLE. In addition, ANT-DBS is effective for patients with FBTCS. STN-DBS might be an optimal treatment for patients with motor seizures, especially when the EZ overlaps the sensorimotor cortex. CMN and PN may be considered modulating targets for patients with LGS-like epilepsy or occipital lobe epilepsy, respectively.

OBJECTIVE Deep brain stimulation (DBS) is a rapidly growing surgical option for patients with drug-resistant epilepsy who are not candidates for resective/ablative surgery. Recent randomized controlled trials have demonstrated efficacy of DBS of the anterior nucleus of the thalamus (ANT), particularly in frontal or temporal epilepsy, whereas DBS of the centromedian (CM) nucleus appears to be most suitable in well-defined generalized epilepsy syndromes. At the authors' institution, DBS candidates who did not fit the populations represented in these trials were managed with DBS of multiple distinct targets, which included ANT, CM, and less-studied nuclei-i.e., mediodorsal nucleus, pulvinar, and subthalamic nucleus. The goal of this study was to present the authors' experience with these types of cases, and to motivate future investigations that can determine the long-term efficacy of multitarget DBS. METHODS This single-center retrospective study of adult patients with drug-resistant epilepsy who underwent multitarget DBS was performed to demonstrate the feasibility and safety of this approach, and to present seizure outcomes. Patients in this cohort had epilepsy with features that were difficult to treat with DBS of the ANT or CM nucleus alone, including multifocal/multilobar, diffuse-onset, and/or posterior-onset seizures; or both generalized and focal seizures. RESULTS Eight patients underwent DBS of 2-3 distinct thalamic/subthalamic nuclei. DBS was performed with 2 electrodes in each hemisphere. All leads in each patient were implanted with either frontal or parietal trajectories. There were no surgical complications. Among those with > 6 months of follow-up (n = 5; range 7-21 months), all patients were responders in terms of overall seizure frequency and/or convulsive seizure frequency (i.e., ≥ 50% reduction). Two patients had adverse stimulation effects, which resolved with further programming. CONCLUSIONS Multitarget DBS is a procedurally feasible and safe treatment strategy to maximize outcomes in patients with complex epilepsy. The authors highlight their approach to inform future studies that are sufficiently powered to assess its efficacy.

Thalamic deep brain stimulation (DBS) is an effective therapeutic option in patients with drug‐resistant epilepsy. Recent DBS devices with sensing capabilities enable chronic, outpatient local field potential (LFP) recordings. Whereas beta oscillations have been demonstrated to be a useful biomarker in movement disorders, the clinical utility of DBS sensing in epilepsy remains unclear. Our aim was to determine LFP features that distinguish ictal from inter‐ictal states, which may aid in tracking seizure outcomes with DBS.

OBJECTIVE Neuromodulation of the centromedian nucleus of the thalamus (CM) has unclear effectiveness in the treatment of drug-resistant epilepsy. Prior reports suggest that it may be more effective in the generalized epilepsies such as Lennox-Gastaut syndrome (LGS). The objective of this study was to determine the outcome of CM deep brain stimulation (DBS) at the authors' institution. METHODS Retrospective chart review was performed for all patients who underwent CM DBS at Emory University, which occurred between December 2018 and May 2021. CM DBS electrodes were implanted using three different surgical methods, including frame-based, robot-assisted, and direct MRI-guided. Seizure frequency, stimulation parameters, and adverse events were recorded from subsequent clinical follow-up visits. RESULTS Fourteen patients underwent CM DBS: 9 had symptomatic generalized epilepsy (including 5 with LGS), 3 had primary or idiopathic generalized epilepsy, and 2 had bifrontal focal epilepsy. At last follow-up (mean [± SEM] 19 ± 5 months, range 4.1-33 months, ≥ 6 months in 11 patients), the median seizure frequency reduction was 91%. Twelve patients (86%) were considered responders (≥ 50% decrease in seizure frequency), including 10 of 12 with generalized epilepsy and both patients with bifrontal epilepsy. Surgical adverse events were rare and included 1 patient with hardware breakage, 1 with a postoperative aspiration event, and 1 with a nonclinically significant intracranial hemorrhage. CONCLUSIONS CM DBS was an effective treatment for drug-resistant generalized and bifrontal epilepsies. Additional studies and analyses may investigate whether CM DBS is best suited for specific epilepsy types, and the relationship of lead location to outcome in different epilepsies.

Estimating the epileptogenic zone network (EZN) is an important part of the diagnosis of drug-resistant focal epilepsy and has a pivotal role in treatment and intervention. Virtual brain twins provide a modeling method for personalized diagnosis and treatment. They integrate patient-specific brain topography with structural connectivity from anatomical neuroimaging such as magnetic resonance imaging, and dynamic activity from functional recordings such as electroencephalography (EEG) and stereo-EEG (SEEG). Seizures show rich spatial and temporal features in functional recordings, which can be exploited to estimate the EZN. Stimulation-induced seizures can provide important and complementary information. Here we consider invasive SEEG stimulation and non-invasive temporal interference stimulation as a complementary approach. This paper offers a high-resolution virtual brain twin framework for EZN diagnosis based on stimulation-induced seizures. It provides an important methodological and conceptual basis to make the transition from invasive to non-invasive diagnosis and treatment of drug-resistant focal epilepsy. A high-resolution virtual brain twin approach is proposed using stimulation-induced seizures to estimate the epileptogenic network, offering a step toward non-invasive diagnosis and treatment of drug-resistant focal epilepsy.

Based on the promising results of randomized controlled trials, deep brain stimulation (DBS) and responsive neurostimulation (RNS) are used increasingly in the treatment of patients with drug‐resistant epilepsy. Drug‐resistant temporal lobe epilepsy (TLE) is an indication for either DBS of the anterior nucleus of the thalamus (ANT) or temporal lobe (TL) RNS, but there are no studies that directly compare the seizure benefits and adverse effects associated with these therapies in this patient population. We, therefore, examined all patients who underwent ANT‐DBS or TL‐RNS for drug‐resistant TLE at our center.

Deep brain stimulation (DBS), specifically thalamic DBS, has achieved promising results to reduce seizure severity and frequency in pharmacoresistant epilepsies, thereby establishing it for clinical use. The mechanisms of action are, however, still unknown. We evidenced the brain networks directly modulated by centromedian (CM) nucleus-DBS and responsible for clinical outcomes in a cohort of patients uniquely diagnosed with generalized pharmacoresistant epilepsy. Preoperative imaging and long-term (2–11 years) clinical data from ten generalized pharmacoresistant epilepsy patients (mean age at surgery = 30.8 ± 5.9 years, 4 female) were evaluated. Volume of tissue activated (VTA) was included as seeds to reconstruct the targeted network to thalamic DBS from diffusion and functional imaging data. CM-DBS clinical outcome improvement (> 50%) appeared in 80% of patients and was tightly related to VTAs interconnected with a reticular system network encompassing sensorimotor and supplementary motor cortices, together with cerebellum/brainstem. Despite methodological differences, both structural and functional connectomes revealed the same targeted network. Our results demonstrate that CM-DBS outcome in generalized pharmacoresistant epilepsy is highly dependent on the individual connectivity profile, involving the cerebello-thalamo-cortical circuits. The proposed framework could be implemented in future studies to refine stereotactic implantation or the parameters for individualized neuromodulation.

Chronic brain recordings suggest that seizure risk is not uniform, but rather varies systematically relative to daily (circadian) and multiday (multidien) cycles. Here, one human and seven dogs with naturally occurring epilepsy had continuous intracranial EEG (median 298 days) using novel implantable sensing and stimulation devices. Two pet dogs and the human subject received concurrent thalamic deep brain stimulation (DBS) over multiple months. All subjects had circadian and multiday cycles in the rate of interictal epileptiform spikes (IES). There was seizure phase locking to circadian and multiday IES cycles in five and seven out of eight subjects, respectively. Thalamic DBS modified circadian (all 3 subjects) and multiday (analysis limited to the human participant) IES cycles. DBS modified seizure clustering and circadian phase locking in the human subject. Multiscale cycles in brain excitability and seizure risk are features of human and canine epilepsy and are modifiable by thalamic DBS.

Highlights • Patients with drug resistant epilepsy refractory to treatment with vagal nerve stimulation benefited from anterior thalamic deep brain stimulation.• We report a combined neuromodulation approach of simultaneous vagal nerve and deep brain stimulation.• Additional studies are needed to assess safety and efficacy of simultaneous VNS and DBS treatment.

Temporal lobe epilepsy (TLE), often associated with cognitive impairment, is one of the most common types of medically refractory epilepsy. Deep brain stimulation (DBS) shows considerable promise for the treatment of TLE. However, the optimal stimulation targets and parameters of DBS to control seizures and related cognitive impairment are still not fully illustrated.

BACKGROUND Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an increasingly utilized treatment of drug-resistant epilepsy. To date, the effect of high-frequency stimulation (HFS) vs low-frequency stimulation (LFS) in ANT DBS is poorly understood. OBJECTIVE To assess differences in the acute effect of LFS vs HFS in ANT DBS utilizing blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI). METHODS In this prospective study of 5 patients with ANT DBS for epilepsy, BOLD activation and deactivation were modeled for 145-Hz and 30-Hz ANT stimulation using an fMRI block design. Data were analyzed with a general linear model and combined via 2-stage mixed-effects analysis. Z-score difference maps were nonparametrically thresholded using cluster threshold of z > 3.1 and a (corrected) cluster significance threshold of P = .05. RESULTS HFS produced significantly greater activation within multiple regions, in particular the limbic and default mode network (DMN). LFS produced minimal activation and failed to produce significant activation within these same networks. HFS produced widespread cortical and subcortical deactivation sparing most of the limbic and DMN regions. Meanwhile, LFS produced deactivation in most DMN and limbic structures. CONCLUSION Our results show that HFS and LFS produce substantial variability in both local and downstream network effects. In particular, largely opposing effects were identified within the limbic network and DMN. These findings may serve as a mechanistic basis for understanding the potential of HFS vs LFS in various epilepsy syndromes.

Abstract BACKGROUND Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an effective therapy for patients with drug-resistant focal epilepsy. Best practices for surgical targeting of the ANT can be refined as new information becomes available regarding effective stimulation sites. OBJECTIVE To conduct a retrospective analysis of the relationship between outcomes (seizure reduction during year 1) and DBS lead locations in subjects from the SANTÉ pivotal trial (Stimulation of ANT for Epilepsy) based upon recent clinical findings. METHODS Postoperative images from SANTÉ subjects (n = 101) were evaluated with respect to lead trajectory relative to defined anatomic landmarks. A qualitative scoring system was used to rate each lead placement for proximity to an identified target region above the junction of the mammillothalamic tract with the ANT. Each subject was assigned a bilateral lead placement score, and these scores were then compared to clinical outcomes. RESULTS Approximately 70% of subjects had “good” bilateral lead placements based upon location with respect to the defined target. These subjects had a much higher probability of being a clinical responder (>50% seizure reduction) than those with scores reflecting suboptimal lead placements (43.5% vs 21.9%, P < .05). CONCLUSION Consistent with experience from more established DBS indications, our findings and other recent reports suggest that there may be specific sites within the ANT that are associated with superior clinical outcomes. It will be important to continue to evaluate these relationships and the evolution of other clinical practices (eg, programming) to further optimize this therapy.

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The centromedian (CM) and anterior nucleus of the thalamus (ANT) are deep brain stimulation (DBS) targets for management of generalized, and focal drug resistant epilepsy (DRE), respectively. We report on a single center retrospective case series of 16 children and adults with DRE who underwent CM with simultaneous ANT (69 %) or CM without simultaneous ANT DBS (31 %). Seizure frequency, epilepsy severity, life satisfaction, and quality of sleep before and after DBS were compared. Baseline median seizure frequency was 323 seizures per month (IQR, 71–563 sz/mo). Median follow up time was 80 months (IQR 37–97 mo). Median seizure frequency reduction was 58 % (IQR 13–87 %, p = 0.002). Ten patients (63 %) reported ≥50 % seizure frequency reduction. Median seizure frequency reduction and responder rate were not significantly different for CM + ANT versus CM only. Seizure severity and life satisfaction were significantly improved. Three patients (19 %) developed device-related side effects, 2 of them (12.5 %) required surgical intervention. In a heterogenous population of children and adults with generalized, multifocal, posterior onset, and poorly localized DRE, CM with or without ANT DBS is feasible, relatively safe and is associated with reduced seizure frequency and severity, as well as improved life satisfaction.

In patients with focal drug-resistant epilepsy, electrical stimulation from intracranial electrodes is frequently used for the localization of seizure onset zones and related pathological networks. The ability of electrically stimulated tissue to generate beta and gamma range oscillations, called rapid-discharges, is a frequent indication of an epileptogenic zone. However, a limit of intracranial stimulation is the fixed physical location and number of implanted electrodes, leaving numerous clinically and functionally relevant brain regions unexplored. Here, we demonstrate an alternative technique relying exclusively on nonpenetrating surface electrodes, namely an orientation-tunable form of temporally-interfering (TI) electric fields to target the CA3 of the mouse hippocampus which focally evokes seizure-like events (SLEs) having the characteristic frequencies of rapid-discharges, but without the necessity of the implanted electrodes. The orientation of the topical electrodes with respect to the orientation of the hippocampus is demonstrated to strongly control the threshold for evoking SLEs. Additionally, we demonstrate the use of square waves as an alternative to sine waves for TI stimulation. An orientation-dependent analysis of classic implanted electrodes to evoke SLEs in the hippocampus is subsequently utilized to support the results of the minimally-invasive temporally-interfering fields. The principles of orientation-tunable TI stimulation seen here can be generally applicable in a wide range of other excitable tissues and brain regions, overcoming several limitations of fixed electrodes which penetrate tissue.

OBJECTIVE We report on the seizure frequency and attention outcome during thalamic centromedian stimulation (CM-DBS) in patients with refractory generalized epilepsy (GE). METHODS Twenty consecutive patients with GE who were submitted to CM-DBS and had at least one year of follow-up were prospectively studied. The CM was targeted bilaterally. Stimulation intensity was ramped up (bipolar, continuous, 130 Hz; 300μsec) until 4.5 V or until side effects developed. Contacts` position was determined on postoperative volumetric MRI scans. Attention was qualitatively evaluated using the SNAP-IV (Swanson, Nolan, and Pelham) questionnaire. Patients were considered responders during CM-DBS if an at least 50% seizure frequency reduction was obtained compared to baseline. RESULTS Median age was 15.5 years (13 males). Median follow-up time was 2.55 years. EEG disclosed generalized spike-and wave discharges in all patients. MRI was normal in 10 patients, showed diffuse atrophy in 6 patients, and showed abnormalities in 4 patients (3 patients had bilateral cortical development abnormalities and one had unilateral hemispheric atrophy). Patients presented with daily multiple seizure types (8 to 66 per day; median: 37), including tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic seizures. Mean DBS intensity was 4.3 V. An insertional effect was noted in 14 patients. CM-DBS was able to significantly reduce the frequency of tonic (p < 0.001), atypical absence seizures (p < 0.001), atonic seizures (p = 0.001) and bilateral generalized tonic-clonic seizures (p = 0.004). One patient became seizure-free. Ninety percent of the patients were considered responders (>50% seizure frequency reduction). All patients showed some improvement in attention. The mean number of items in which improvement was noted in the SNAP-IV questionnaire was 4.8. There was a significant relationship between overall seizure frequency reduction and improvement of attention (p = 0.033). DISCUSSION This prospective, open label study included a large, homogeneous cohort and provided evidence on the efficacy of CM-DBS in reducing the seizure burden and increasing attention in patients with refractory generalized epilepsy.

BACKGROUND Bilateral cyclic high frequency deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces the seizure count in a subset of patients with epilepsy. Detecting stimulation-induced alterations of pathological brain networks may help to unravel the underlying physiological mechanisms related to effective stimulation delivery and optimize target engagement. METHODS We acquired 64-channel electroencephalography during ten ANT-DBS cycles (145Hz, 90μs, 3-5V) of 1-minute ON followed by 5-minutes OFF stimulation to detect changes in cortical activity related to seizure reduction. The study included 14 subjects (three responders, four non-responders, and seven healthy controls). Mixed-model ANOVA tests were used to compare differences in cortical activity between subgroups both ON and OFF stimulation, while investigating frequency-specific effects for the seizure onset zones. RESULTS ANT-DBS had a widespread desynchronization effect on cortical theta and alpha band activity in responders, but not in non-responders. Time domain analysis showed that the stimulation induced reduction in theta-band activity was temporally linked to the stimulation period. Moreover, stimulation induced theta-band desynchronization in the temporal lobe channels correlated significantly with the therapeutic response. Responders to ANT-DBS and healthy-controls had an overall lower level of theta-band activity compared to non-responders. CONCLUSION This study demonstrated that temporal lobe channel theta-band desynchronization may be a predictive physiological hallmark of therapeutic response to ANT-DBS and may be used to improve the functional precision of this intervention by verifying implantation sites, calibrating stimulation contacts, and possibly identifying treatment responders prior to implantation.

Importance A bidirectional brain-computer interface that performs neurostimulation has been shown to improve seizure control in patients with refractory epilepsy, but the therapeutic mechanism is unknown. Objective To investigate whether electrographic effects of responsive neurostimulation (RNS), identified in electrocorticographic (ECOG) recordings from the device, are associated with patient outcomes. Design, Setting, and Participants Retrospective review of ECOG recordings and accompanying clinical meta-data from 11 consecutive patients with focal epilepsy who were implanted with a neurostimulation system between January 28, 2015, and June 6, 2017, with 22 to 112 weeks of follow-up. Recorded ECOG data were obtained from the manufacturer; additional system-generated meta-data, including recording and detection settings, were collected directly from the manufacturer's management system using an in-house, custom-built platform. Electrographic seizure patterns were identified in RNS recordings and evaluated in the time-frequency domain, which was locked to the onset of the seizure pattern. Main Outcomes and Measures Patterns of electrophysiological modulation were identified and then classified according to their latency of onset in relation to triggered stimulation events. Seizure control after RNS implantation was assessed by 3 main variables: mean frequency of seizure occurrence, estimated mean severity of seizures, and mean duration of seizures. Overall seizure outcomes were evaluated by the extended Personal Impact of Epilepsy Scale questionnaires, a patient-reported outcome measure of 3 domains (seizure characteristics, medication adverse effects, and quality of life), with a range of possible scores from 0 to 300 in which lower scores indicate worse status, and the Engel scale, which comprises 4 classes (I-IV) in which lower numbers indicate greater improvement. Results Electrocorticographic data from 11 patients (8 female; mean [range] age, 35 [19-65] years; mean [range] duration of epilepsy, 19 [5-37] years) were analyzed. Two main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network were discovered: direct and indirect effects. Direct effects included ictal inhibition and early frequency modulation but were not associated with improved clinical outcomes (odds ratio [OR], 0.67; 95% CI, 0.06-7.35; P > .99). Only indirect effects-those occurring remote from triggered stimulation-were associated with improved clinical outcomes (OR, infinity; 95% CI, -infinity to infinity; P = .02). These indirect effects included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation. Conclusions and Relevance These findings suggest that RNS effectiveness may be explained by long-term, stimulation-induced modulation of seizure network activity rather than by direct effects on each detected seizure.

We present the findings related to seizure outcome during hippocampal deep brain stimulation (Hip‐DBS) in patients with refractory temporal lobe epilepsy.

Deep brain stimulation (DBS) has provided new treatment options for refractory epilepsy; however, treatment outcomes of DBS in refractory epilepsy patients previously treated with vagus nerve stimulation (VNS) have not been clarified. Herein, treatment outcomes of DBS of the anterior nucleus of the thalamus (ANT-DBS) in patients who had previously experienced VNS failure are reported. Seven patients who had previously experienced VNS failure underwent ANT-DBS device implantation. VNS was turned off before DBS device implantation. Monthly seizure counts starting from baseline to 12–18 months after DBS were analyzed. Five (71.3%) of the 7 patients experienced a >50% reduction of seizure counts after DBS; 1 responder reached a seizure-free status after DBS therapy. Of the 2 nonresponders, 1 subject showed improvement in seizure strength and duration, which lessened the impact of the seizures on the patient’s quality of life. This is the first study in which favorable outcomes of ANT-DBS surgery were observed in individual patients with refractory epilepsy who had not responded to prior VNS. Further studies with a larger number of subjects and longer follow-up period are needed to confirm the feasibility of ANT-DBS in patients who have previously experienced VNS failure.

Abstract BACKGROUND Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) can improve seizure control for patients with drug-resistant epilepsy (DRE). Yet, one cannot overlook the high discrepancy in efficacy among patients, possibly resulting from differences in stimulation site. OBJECTIVE To test the hypothesis that stimulation at the junction of the ANT and mammillothalamic tract (ANT-MTT junction) increases seizure control. METHODS The relationship between seizure control and the location of the active contacts to the ANT-MTT junction was investigated in 20 patients treated with ANT-DBS for DRE. Coordinates and Euclidean distance of the active contacts relative to the ANT-MTT junction were calculated and related to seizure control. Stimulation sites were mapped by modelling the volume of tissue activation (VTA) and generating stimulation heat maps. RESULTS After 1 yr of stimulation, patients had a median 46% reduction in total seizure frequency, 50% were responders, and 20% of patients were seizure-free. The Euclidean distance of the active contacts to the ANT-MTT junction correlates to change in seizure frequency (r2 = 0.24, P = .01) and is ∼30% smaller (P = .015) in responders than in non-responders. VTA models and stimulation heat maps indicate a hot-spot at the ANT-MTT junction for responders, whereas non-responders had no evident hot-spot. CONCLUSION Stimulation at the ANT-MTT junction correlates to increased seizure control. Our findings suggest a relationship between the stimulation site and therapy response in ANT-DBS for epilepsy with a potential role for the MTT. DBS directed at white matter merits further exploration for the treatment of epilepsy.

No abstract available

PURPOSE Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising treatment for refractory epilepsy; however, it remains challenging to successfully target the ANT. The results of Medtronic Registry for Epilepsy (MORE) supported a frontal transventricular(TV) compared to frontal extraventricular (EV) lead trajectory for ANT DBS may have better coverage of the ANT. Here we report the safety and targeting efficacy of a novel, posterior parietal extraventricular (PEV) approach to the ANT. METHODS We conducted a retrospective analysis of ten patients who underwent bilateral ANT DBS (20 total trajectories) for medically-refractory epilepsy. Similar targeting methodology as the MORE trial was used, and the DBS Intrinsic Template Atlas (DISTAL) was utilized for ANT localization and contact position relative to ANT. Clinical data were assessed for DBS targeting efficacy and surgical complications. RESULTS The demonstrated PEV trajectory showed a successful ANT targeting rate of 90% bilaterally. Two or more contacts within ANT were presented in 75% of all leads. Mean contact number in ANT was 2.2+ 1.2. There were no intracranial hemorrhages, cerebrospinal fluid leakage, or permanent neurologic deficits. CONCLUSION In this small series, the novel PEV for ANT DBS is feasible with good targeting accuracy and potential safety advantages. The high accuracy of the PEV trajectory suggests that it is a reasonable alternative trajectory for ANT DBS. Larger studies will be needed to assess this trajectory on clinical outcome of DBS treatment to epilepsy.

No abstract available

OBJECTIVE Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a promising therapy for refractory epilepsy. Unfortunately, the variability in outcomes from ANT DBS is not fully understood. In this pilot study, the authors assess potential differences in functional connectivity related to the volume of tissue activated (VTA) in ANT DBS responders and nonresponders as a means for better understanding the mechanism of action and potentially improving DBS targeting. METHODS This retrospective analysis consisted of 6 patients who underwent ANT DBS for refractory epilepsy. Patients were classified as responders (n = 3) if their seizure frequency decreased by at least 50%. The DBS electrodes were localized postoperatively and VTAs were computationally generated based on DBS programming settings. VTAs were used as seed points for resting-state functional MRI connectivity analysis performed using a control dataset. Differences in cortical connectivity to the VTA were assessed between the responder and nonresponder groups. RESULTS The ANT DBS responders showed greater positive connectivity with the default mode network compared to nonresponders, including the posterior cingulate cortex, medial prefrontal cortex, inferior parietal lobule, and precuneus. Interestingly, there was also a consistent anticorrelation with the hippocampus seen in responders that was not present in nonresponders. CONCLUSIONS Based on their pilot study, the authors observed that successful ANT DBS in patients with epilepsy produces increased connectivity in the default mode network, which the authors hypothesize increases the threshold for seizure propagation. Additionally, an inhibitory effect on the hippocampus mediated through increased hippocampal γ-aminobutyric acid (GABA) concentration may contribute to seizure suppression. Future studies are planned to confirm these findings.

Accurately recognizing artifacts on electroencephalogram (EEG) is necessary to prevent EEG misinterpretation and epilepsy misdiagnosis. EEG artifacts generated by neurostimulation devices (Figures 1 and 2) can be identified based on their unique spatial and frequency properties 1 . VNS and RNS artifacts display an electrical interference-like “spiky” morphology with a distribution that is incom-patible with a cerebral source and frequencies that mirror stimulation settings. DBS artifact features diffuse electrical interference with a relatively monomorphic appearance, and

INTRODUCTION In 2018 the FDA approved the use of anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) for focal epilepsy in response to the results of the Stimulation of the Anterior Nucleus of Thalamus for Epilepsy (SANTÉ) double-blind randomized controlled trial. While generalized epilepsy (GE) was never assessed in this trial, subsequent follow up clarified that focal to bilateral tonic-clonic seizures were reduced in these subjects. In rare cases ANT DBS has nonetheless been pursued for patients with GE. METHODS We report a 27-year-old male with idiopathic GE who was successfully treated with ANT DBS. Prior to DBS, the patient typically had three or four generalized tonic-clonic seizures (GTCS) per week, amongst other seizures, and was refractory to both medication and vagal nerve stimulation (VNS). We also systematically reviewed the literature to understand the extent to which ANT DBS has been used in GE, under what circumstances, and with what results. RESULTS Five years since the introduction of ANT DBS, the patient has remained free of GTCS. Over this time, other seizures were also markedly reduced. For the systematic review, a comprehensive literature search using PubMed, Cochrane, and Google Scholar identified 23 GE patients treated with ANT DBS across 13 publications. 13 patients had patient-specific seizure outcomes reported. Clinical findings, seizure characteristics, and outcomes were summarized, demonstrating that ANT DBS surgery typically occurred after failed VNS and was usually effective, including 3 patients who became free of GTCS. CONCLUSION This anecdotal evidence of effectiveness suggests that some GE networks can be modulated by high-frequency stimulation at the ANT node. When established therapies have failed, ANT DBS is a therapeutic option, but the treatment requires further structured research in treating GE.

Background and Objectives Invasive neurostimulation is rapidly becoming an established option for treatment of neurologic disorders, particularly those that are refractory to pharmacologic treatment. However, there is limited information on the use of neuromodulation during pregnancy. This study explores the safety and clinical outcomes of invasive neuromodulation-specifically vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS)-in pregnant patients with epilepsy and movement disorders. Methods Pregnant patients treated with VNS, DBS, or RNS were identified, and charts were reviewed to extract data on maternal epilepsy/movement disorder, treatment, and pregnancy. Results A total of 14 patients (9 VNS, 3 DBS, 2 RNS) had 22 pregnancies. Neuromodulation indications included focal epilepsy (n = 6: 3 VNS, 2 RNS, 1 DBS), generalized epilepsy (n = 6: all VNS), and Tourette syndrome (n = 2: both DBS). The average age at implantation was 24.7 years for VNS, 29.6 years for DBS, and 28 years for RNS. Pregnancy complications included miscarriages (n = 4 pregnancies; 1 VNS, 2 DBS, 1 RNS), pre-eclampsia with fetal growth restriction (n = 3: 2 VNS, 1 DBS), and gestational diabetes (2 VNS). In addition, 10 pregnancies (8 VNS, 2 RNS) were complicated by seizure exacerbations. Delivery of eight of the pregnancies (5 VNS, 1 DBS, 2 RNS) was by cesarean section. There were no cases of maternal or neonatal mortality, and there were no major congenital malformations. Owing to exacerbated shortness of breath during the third trimester, 1 patient had her VNS turned off. Discussion Pregnancy complications were consistent with previous reports of patients with neurologic disorders. Despite limitations in sample size and confounding factors related to medication use and neurologic diagnosis, our study suggests that implanted neuromodulation devices do not seem to pose a risk of neuromodulation-related teratogenicity. While these data are promising and may provide some reassurance for patient counseling regarding pregnancy, further studies with larger sample sizes are necessary.

INTRODUCTION: Children with drug-resistant epilepsy (DRE) in whom resection or disconnective surgeries are not recommended can still benefit from neurostimulation. Vagus nerve stimulation is FDA-approved for ages = 4, but intracranial stimulators, responsive neurostimulation (RNS) and deep brain stimulation (DBS), are only approved for ages = 18. Studies in adults and early experience in children suggest that intracranial stimulation may be more effective than VNS, but with higher risk. This risk has not been examined in large cohorts. METHODS: This retrospective study examined records of DRE patients who underwent RNS/DBS at Children’s Hospital of Philadelphia from 11/2017–3/2024. DBS electrodes were placed in anterior or centromedian thalamic nuclei. RNS electrodes were placed in seizure foci. RESULTS: 57 patients, age 6–23, underwent intracranial stimulator implantation for DRE, (27 DBS, 30 RNS). Six patients (9.0%) returned to surgery: one surgical site infection requiring explant with successful re-implantation; two experienced traumatic scalp lacerations, one salvaged and another explanted; one underwent wound revision for superficial dehiscence; one underwent explant for multiple sclerosis-related perielectrode inflammation. No patient experienced hemorrhage, hydrocephalus, lead malposition, or long-term stimulation-induced paresthesia, depression, or memory loss. One patient (1.8%) died from sudden unexpected death in epilepsy 28 months post-RNS placement. CONCLUSIONS: This study represents, to the best of our knowledge, the largest single-center series of intracranial stimulation for pediatric DRE. In comparison to established rates of SSI and explant in adults, (12.1%/7.0% in the RNS pivotal trial and 13.3%/8.6% in the DBS SANTE trial), our cohort demonstrated more favorable rates of 1.8%/5.3%. Studies with larger pediatric DRE cohorts are needed with longer follow-up and seizure outcomes to elucidate the risk/benefit balance of intracranial stimulation in children.

OBJECTIVE Children with drug-resistant epilepsy (DRE) in whom resection or disconnective surgeries are not recommended can still benefit from neurostimulation. Vagus nerve stimulation (VNS) is FDA approved for those aged 4 years and older, but intracranial stimulators, that is, responsive neurostimulation (RNS) and deep brain stimulation (DBS) devices, are only approved for those aged 18 years and older. Studies in adults and early experience in children suggest that intracranial stimulation may be more effective than VNS but with higher risk. This risk has not been examined in large pediatric cohorts. This study aimed to evaluate the safety profile of RNS and DBS for pediatric DRE as well as the possible risk factors for wound-related complications. METHODS This retrospective study examined the records of DRE patients who underwent RNS or DBS at Children's Hospital of Philadelphia from November 2017 to March 2024 with at least 6 months of follow-up. DBS electrodes were placed in the anterior or centromedian nucleus of the thalamus. RNS electrodes were placed in seizure foci. RESULTS A total of 54 patients, aged 6-22 years, underwent intracranial stimulator implantation for DRE (24 DBS, 30 RNS). The mean follow-up was 24.4 ± 15.3 months (median 21 months, range 6-69 months). Five (9.3%) patients returned to surgery, 3 (5.6%) of whom required explant and 1 (1.9%) of whom required explant and also had a surgical site infection (SSI). Prior craniotomy was a significant risk factor for wound-related complications (p = 0.0046 in all patients, p = 0.0375 in patients < 18 years). No patient experienced hemorrhage, lead malposition, device malfunction, or long-term stimulation-induced paresthesia, depression, or memory loss. The overall responder rates, defined by achieving 50% or greater reduction in seizure frequency, were 54% in the RNS cohort and 73% in the DBS cohort at the 12-month follow-up. CONCLUSIONS To the best of the authors' knowledge, this study represents the largest single-center series of intracranial stimulation for pediatric DRE. In comparison with established rates of SSI and explant in adults (12% and 7.0% in the RNS pivotal trial and 13% and 8.6% in the DBS SANTE [Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy] trial, respectively), the present cohort demonstrated favorable rates of 1.9% and 5.6%, respectively. Studies with larger pediatric DRE cohorts are needed with longer follow-up and seizure outcomes to elucidate the risk/benefit balance of intracranial stimulation in children.

No abstract available

OBJECTIVE Epilepsy is a prevalent neurological disorder with significant morbidity. Lesional and nonlesional epilepsies, distinguished by the presence or absence of identifiable brain lesions, exhibit differences in patient characteristics and treatment approaches. This study aimed to compare treatment modalities, patient demographic characteristics, and outcomes between lesional and nonlesional epilepsy patients in the United States. METHODS This retrospective study utilized the National Inpatient Sample (NIS) database from 2009 to 2020. Adult patients diagnosed with lesional or nonlesional epilepsy who received vagus nerve stimulation (VNS), responsive neurostimulation (RNS), deep brain stimulation (DBS), resective surgery, radiosurgery, or laser interstitial thermal therapy (LITT) were included. Propensity score matching addressed baseline differences between the groups. Trends in treatment modalities, length of stay, total charges, mortality, and routine discharge were analyzed. RESULTS Lesional epilepsy patients were significantly older, more likely to be male, and had higher comorbidity burdens compared to nonlesional epilepsy patients. Trends in treatment modalities varied, with VNS use declining in nonlesional epilepsy while RNS and LITT increased in both groups. Resective surgery increased in nonlesional epilepsy, while DBS and radiosurgery decreased in both groups. LITT was associated with decreased length of stay. RNS and LITT were associated with a higher likelihood of routine discharge. All surgical interventions were associated with increased total charges. CONCLUSIONS Lesional and nonlesional epilepsy patients exhibit distinct demographic and clinical characteristics, influencing treatment selection and outcomes. The increasing use of RNS and LITT reflects the emergence of new technologies for epilepsy management. These findings highlight the need for tailored treatment approaches based on lesion etiology and individual patient needs. Future research should focus on long-term effectiveness and cost-effectiveness of different surgical interventions for both lesional and nonlesional epilepsy.

OBJECTIVE Neuromodulation is a viable option for patients with drug-resistant epilepsies. We reviewed the management of patients with two deep brain neurostimulators. In addition, patients implanted with a device targeting the centromedian-parafascicular (CM-Pf) nuclear complex supplements this report to provide an illustrative case to implantation and programming a patient with three active devices. METHODS A narrative review using PubMed and Embase identified patients with drug-resistant epilepsy implanted with more than one neurostimulator was performed. Combinations of vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) were identified. We provide a background of a newly reported case of an adult with a triple implant eventually responding to CM-Pf DBS as the third implant following suboptimal benefit from VNS and RNS. RESULTS In review of the literature, dual-device therapy is increasing in reports of use with combinations of VNS, RNS, and DBS to treat patients with drug-resistant epilepsy. We review dual-device implants with thalamic DBS device combinations, functional neural networks, and programming patients with dual devices. CM-Pf is a new target for DBS and has shown a variable response in focal epilepsy. We report the unique case of 28-year-old male with drug-resistant focal epilepsy who experienced a 75% seizure reduction with CM-Pf DBS as his third device after suboptimal responses to VNS and RNS. After 9 months, he also experienced seizure freedom from recurrent focal to bilateral tonic-clonic seizures. No medical or surgical complications or safety issues were encountered. CONCLUSION We demonstrate safety and feasibility in an adult combining active VNS, RNS, and CM-Pf DBS. Patients with dual-device therapy who experience a suboptimal response to initial device use at optimized settings should not be considered a neuromodulation "failure." Strategies to combine devices require a working knowledge of brain networks.

There are three neurostimulation devices available to treat generalized epilepsy: vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). However, the choice between them is unclear due to lack of head‐to‐head comparisons. A systematic comparison of neurostimulation outcomes in generalized epilepsy has not been performed previously. The goal of this meta‐analysis was to determine whether one of these devices is better than the others to treat generalized epilepsy.

Epilepsy is a chronic neurological disorder causing recurrent seizures. Improved diagnosis and management, including high-resolution imaging, genetic testing, and newer antiepileptic drugs with better efficacy and fewer side effects, have enhanced patient outcomes. For those who do not respond well to medication, surgeries like temporal lobe resection, corpus callosotomy, and laser interstitial thermal therapy are effective. Treatments that alter brain communication, such as vagus nerve stimulation (VNS), Deep Brain Stimulation (DBS), and Responsive Neurostimulation (RNS), also help control seizures. Precision medicine chooses the right treatment for each person based on specific biomarkers. Artificial intelligence helps predict seizures and refine treatment plans. Nanotechnology improves how drugs reach the brain and controls their release. These advances integrate medicine, surgery, and technology to provide personalized treatments, improving outcomes for those with epilepsy. Finally, dietary treatments, such as the ketogenic diet and modified Atkins diet, have been successful in reducing seizure activity, especially in children. Additionally, new studies on plant-based treatments have found that several medicinal herbs have antiepileptic properties. This suggests there may be natural alternatives to pharmaceutical drugs. These broad-based advances are a step toward an even broader and more tailored approach to epilepsy treatment, integrating pharmacologic, surgical, and technological progress. Upcoming trials and research must further develop these treatments, holding out new hope for epilepsy sufferers and further enhancing the long-term outlook. This systematic review points to paradigm-breaking progress in the treatment of epilepsy that has revolutionized therapeutic trends from 2001 to 2025. By synthesizing evidence of pharmacological innovation, surgical advancement, neuromodulation innovation, and precision medicine approaches, we seek to bridge crucial knowledge gaps between state-of-the-art research and clinical practice.

INTRODUCTION Epilepsy affects 65 million people globally, with drug-resistant epilepsy (DRE) developing in 30% of patients. Neuromodulation therapies, such as deep brain stimulation (DBS), responsive neurostimulation (RNS), and vagus nerve stimulation (VNS) are attractive treatment options, but assessing efficacy is time consuming. Predictive biomarkers of treatment response may expedite assessment and pave the way for closed-loop strategies that optimize outcomes. This systematic review identifies scalp and intracranial electroencephalography (EEG)-derived biomarkers associated with clinical efficacy in invasive neuromodulation for DRE and explores the impact of preprocessing and methodologic variations on biomarker efficacy. MATERIALS AND METHODS A systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, searching PubMed from 2004 to 2025 for human studies on EEG biomarkers post invasive neuromodulation for people with DRE. Inclusion criteria required ≥four participants, single neuromodulation modalities, and EEG-based measures linked to seizure outcomes. Exclusion criteria eliminated multimodal therapies, craniotomies, and non-English studies. Owing to heterogeneity, qualitative synthesis identified trends, supplemented by an exploratory logistic regression analysis assessing the preprocessing, methodologic, and biomarker type (node-level, edge-level, graph-theory metrics) impacts on biomarker efficacy. RESULTS This review included 30 studies (2005-2024), covering DBS (n = 8), RNS (n = 7), and VNS (n = 15). Ten of 30 studies were of focal DRE; three of 30 studies were generalized DRE, and half of the included studies did not specify whether participants had focal or generalized epilepsy. Biomarkers spanned node-level (eg, interictal epileptiform discharges, spectral power, n = 14), edge-level (eg, phase-amplitude coupling, coherence, n = 13), and graph-theory metrics (n = 3). Key findings were as follows: 1) interictal epileptiform discharge (IED) rate reductions commonly correlate with seizure frequency reduction; 2) short-term changes in the aperiodic parameters appear to be predictive of longer-term clinical outcome; and 3) reduced synchronization is repeatedly associated with improved seizure outcomes across RNS, VNS, and some DBS contexts. Four studies reported early measures (intraoperative or ≤six months post implant) that predicted longer-term seizure outcomes. Exploratory logistic regression suggested nonsignificant trends favoring larger sample sizes, higher sampling rates, data normalization, and edge-level metrics; use of artifact-removal algorithms tended to reduce the likelihood of a reported significant association. All regression estimates were imprecise (nonsignificant, wide 95% CIs) CONCLUSION: In conclusion, EEG-derived biomarkers, particularly IEDs, aperiodic measures, and synchronization measures, show promise for predicting neuromodulation efficacy in DRE. Nonsignificant trends revealed through logistic regression analysis suggest that methodologic and preprocessing variations may influence biomarker predictive efficacy. We would recommend more comprehensive reporting of the signal processing protocols and biomarker performance to enable more robust causal inference.

Nearly 1% of the global population suffers from epilepsy. There are over 65 million people worldwide with epilepsy and approximately 10.5 million of those are children. One third of these people have drug-resistant epilepsy (DRE). Neuromodulation is an adjunct treatment option for these patients. This manuscript aims to describe the history, patient/parent perspective, current use, and future directions of neuromodulation in the management of pediatric DRE. We conducted a nonsystematic search of the literature through different databases as part of the Pediatric State of The Art Symposium at the 2025 American Epilepsy Society meeting in Atlanta. Three neuromodulation therapies, all using implanted devices and electrodes, have been approved by the Food and Drug Administration (FDA) to treat DRE, namely, vagus nerve stimulation (VNS) (1997 and lately 2017), deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) in 2018 (2010 in Europe), and responsive neurostimulation (RNS) in 2013. Only VNS is approved in pediatric patients. Emerging noninvasive neuromodulation modalities such as noninvasive VNS and transcranial magnetic stimulation showed mild adverse effects and exhibit the most encouraging seizure and neurocognitive outcomes to date, but larger multicenter studies are essential before these modalities can be offered and integrated into standard pediatric epilepsy care.

OBJECTIVES Different neurostimulation modalities are available to treat drug-resistant focal epilepsy when surgery is not an option including vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS). Head-to-head comparisons of efficacy do not exist between them nor are likely to be available in the future. We performed a meta-analysis on VNS, RNS, and DBS outcomes to compare seizure reduction efficacy for focal epilepsy. METHODS We systematically reviewed the literature for reported seizure outcomes following implantation with VNS, RNS, and DBS in focal-onset seizures and performed a meta-analysis. Prospective or retrospective clinical studies were included. RESULTS Sufficient data were available at years one (n = 642, two (n = 480), and three (n = 385) for comparing the three modalities with each other. Seizure reduction for the devices at years one, two, and three respectively were: RNS: 66.3%, 56.0%, 68.4%; DBS- 58.4%, 57.5%, 63.8%; VNS 32.9%, 44.4%, 53.5%. Seizure reduction at year one was greater for RNS (p < 0.01) and DBS (p < 0.01) compared to VNS. CONCLUSIONS Our findings indicate the seizure reduction efficacy of RNS is similar to DBS, and both had greater seizure reductions compared to VNS in the first-year post-implantation, with the differences diminishing with longer-term follow-up. SIGNIFICANCE The results help guide neuromodulation treatment in eligible patients with drug-resistant focal epilepsy.

Summarize the current evidence on efficacy and tolerability of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) through a systematic review and meta‐analysis.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug‐resistant epilepsy. Multiple devices are available with long‐term follow‐up and real‐world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS‐ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow‐up for all modalities, albeit in uncontrolled follow‐up or retrospective studies. A significant number of patients experience seizure‐free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved—DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Background and Objectives Surgical and neurostimulator treatments are effective for reducing seizure burden in selected individuals living with drug-resistant epilepsy (DRE). We aimed to determine the presence and key model determinants for cost-effectiveness of these interventions, compared with medical management alone, to assist with decisions about resource allocation. Methods A systematic literature search was conducted on June 1, 2022, using MEDLINE, EMBASE, the NHS Economic Evaluation Database, and the Cost-Effectiveness Analysis database. Included studies were economic evaluations in adult DRE cohorts, comparing surgical and neurostimulator treatments (vagus nerve stimulation [VNS], responsive neurostimulation [RNS], and deep brain stimulation [DBS]) vs medical management alone and reporting cost-benefit analysis, cost-utility, or cost-effectiveness. Exclusion criteria were studies with pediatric cohorts and those published in a language other than English. Three independent reviewers screened, extracted, and assessed data against the Consolidated Health Economic Evaluation Reporting Standards checklist, and a fourth reviewer adjudicated discrepancies. Results Ten studies met inclusion criteria. Seven studies evaluated epilepsy surgery, and 3 evaluated neurostimulation treatments. All relevant studies established that epilepsy surgery is a cost-effective intervention compared with medical management alone, for quality-adjusted life-years and seizure freedom at 2 and 5 years. All relevant studies found neurostimulator treatments to be potentially cost-effective. The incremental cost-effectiveness ratio (ICER), with lower ICER indicating greater cost-effectiveness, was reported for 9 studies and varied between GBP £3,013 and US $61,333. Cost adaptation revealed ICERs from US $170 to US $121,726. Key model determinants included, but were not limited to, improved surgical outcomes and quality of life, reduced surgical and presurgical evaluation costs, higher rates of surgical eligibility after referral and evaluation, epilepsy subtype, less expensive neurostimulator devices with improved longevity, and cost analysis strategy used in the analysis. Discussion There is consistent evidence that epilepsy surgery is a cost-effective treatment of eligible candidates with DRE. Limited evidence suggests that VNS, RNS, and DBS may be cost-effective therapies for DRE, although more health economic evaluations alongside prospective clinical trials are needed to validate these findings. Study Registration Information PROSPERO CRD42021278436.

The experience with neurostimulation for childhood epilepsy is far less extensive than for adults. Nevertheless, the implementation of these techniques could be of great value, especially considering the detrimental effects of ongoing seizures on the developing brain. In this review, we discuss the available evidence for neurostimulation for childhood epilepsy. Vagus nerve stimulation (VNS) is the most studied neurostimulation modality in children. Based on mostly retrospective, open‐label studies, we can conclude that VNS has a similar safety and efficacy profile in children compared to adults. Although there is little available evidence for deep brain stimulation (DBS) and responsive neurostimulation (RNS) in children, both DBS and RNS show promise in reducing seizure frequency with few complications. The implementation of non‐invasive techniques with a more appealing safety profile has gained interest. Small randomized control trials and open‐label studies have investigated transcranial direct current simulation for childhood epilepsy, demonstrating promising but inconsistent findings.

Epilepsy is a serious neurological disorder on the juncture of psychiatry and neurology. It is characterized by recurrent and episodic seizures which are due to excessive discharge by the brain neurons. The therapeutic response failure of more than one or two antiepileptic drugs (AEDs) is the benchmark of refractory or intractable epilepsy. The aim of the study was to determine new approaches which lead towards the treatment of epilepsy. In order to treat focal mesial temporal lobe epilepsy or neocortical epilepsy in adults and any malformation of cortical development such as focal dysplasia surgical resection remains the gold standard treatment. Disconnection procedures such as corpus callosotomy and multiple subpial transections are the best alternative treatment for that patient whose seizure origin is in eloquent cortex or having generalized epilepsy syndromes. Palliative neuromodulation procedures such as Vagus nerve stimulation (VNS), Responsive neurostimulation (RNS) and Deep brain stimulation (DBS) are best approach to treat intractable epileptic patients who are not suitable candidates of surgery.  As the search of better management of epilepsy continues gene therapy and optogenetics gain a momentum in neuroscience.

BACKGROUND Drug-resistant epilepsy (DRE) patients not amenable to epilepsy surgery can benefit from neurostimulation. Few data compare different neuromodulation strategies. OBJECTIVE Compare five invasive neuromodulation strategies for the treatment of DRE: anterior thalamic nuclei deep brain stimulation (ANT-DBS), centromedian thalamic nuclei DBS (CM-DBS), responsive neurostimulation (RNS), chronic subthreshold stimulation (CSS), and vagus nerve stimulation (VNS). METHODS Single center retrospective review and phone survey for patients implanted with invasive neuromodulation for 2004-2021. RESULTS N = 159 (ANT-DBS = 38, CM-DBS = 19, RNS = 30, CSS = 32, VNS = 40). Total median seizure reduction (MSR) was 61 % for the entire cohort (IQR 5-90) and in descending order: CSS (85 %), CM-DBS (63 %), ANT-DBS (52 %), RNS (50 %), and VNS (50 %); p = 0.07. The responder rate was 60 % after a median follow-up time of 26 months. Seizure severity, life satisfaction, and quality of sleep were improved. Cortical stimulation (RNS and CSS) was associated with improved seizure reduction compared to subcortical stimulation (ANT-DBS, CM-DBS, and VNS) (67 % vs. 52 %). Effectiveness was similar for focal epilepsy vs. generalized epilepsy, closed-loop vs. open-loop stimulation, pediatric vs. adult cases, and high frequency (>100 Hz) vs. low frequency (<100 Hz) stimulation settings. Delivered charge per hour varied widely across approaches but was not correlated with improved seizure reduction. CONCLUSIONS Multiple invasive neuromodulation approaches are available to treat DRE, but little evidence compares the approaches. This study used a uniform approach for single-center results and represents an effort to compare neuromodulation approaches.

Epilepsy affects approximately 70 million people worldwide, and it is a significant contributor to the global burden of neurological disorders. Despite the advent of new AEDs, drug resistant-epilepsy continues to affect 30-40% of PWE. Once identified as having drug-resistant epilepsy, these patients should be referred to a comprehensive epilepsy center for evaluation to establish if they are candidates for potential curative surgeries. Unfortunately, a large proportion of patients with drug-resistant epilepsy are poor surgical candidates due to a seizure focus located in eloquent cortex, multifocal epilepsy or inability to identify the zone of ictal onset. An alternative treatment modality for these patients is neuromodulation. Here we present the evidence, indications and safety considerations for the neuromodulation therapies in vagal nerve stimulation (VNS), responsive neurostimulation (RNS), or deep brain stimulation (DBS).

Epilepsy is a neurological disorder that affects more than 70 million people globally. A considerable proportion of epilepsy is resistant to anti-epileptic drugs (AED). For patients with drug-resistant epilepsy (DRE), who are not eligible for resective or ablative surgery, neuromodulation has been a palliative option. Since the approval of vagus nerve stimulation (VNS) in 1997, expansion to include other modalities, such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), has led to improved seizure control in this population. In this article, we discuss the current updates and emerging trends on neuromodulation for epilepsy.

OBJECTIVE Current methods of neuromodulation have been shown to reduce seizures in patients with drug-resistant epilepsy (DRE), and in a small percentage of patients it has rendered them seizure-free when surgical resection is not feasible. While polytherapy with antiseizure medication is not uncommon, dual neurostimulation has received limited attention. We set out to identify trends and changes in the use of dual neurostimulation to understand choosing device combinations. METHODS We reviewed the Mayo Clinic database in Florida of patients who underwent vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) from October, 1998 through September, 2021. The prevalence of active VNS with DBS or RNS was considered dual therapy. RESULTS 131 patients (71 females) underwent 164 VNS-associated procedures, 28 received RNS, and 8 received DBS (6 anterior thalamic, ANT-DBS; 2 CM-DBS). Active dual stimulation occurred in 3/28 RNS patients and 8/8 DBS patients (p=0.006), mean duration of 28 and 16.3 months respectively. VNS-DBS patients were more likely to have a prior response to VNS (p=0.025) and failed more ASMs (p=0.020). The VNS-RNS group had focal seizures more likely to have electroclinical localization (p=0.005) and more frequently underwent invasive EEG monitoring (p=0.026). CONCLUSION The ability to localize was the primary decision-maker in prompting RNS vs. DBS. RNS surgery was more likely to be preceded by invasive EEG monitoring. Prior VNS responsiveness was more prominent in patients with DBS. Dual therapy was safe. Prospective multi-center studies of dual device neuromodulation are needed.

Three neuromodulation therapies, all using implanted device and electrodes, have been approved to treat adults with drug-resistant focal epilepsy, namely, the vagus nerve stimulation in 1995, deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) in 2018 (2010 in Europe), and responsive neurostimulation (RNS) in 2014. Indications for VNS have more recently extended to children down to age of 4. Limited or anecdotal data are available in other epilepsy syndromes and refractory/super-refractory status epilepticus. Overall, neuromodulation therapies are palliative, with only a minority of patients achieving long-term seizure freedom, justifying favoring such treatments in patients who are not good candidates for curative epilepsy surgery. About half of patients implanted with VNS, ANT-DBS, and RNS have 50% or greater reduction in seizures, with long-term data suggesting increased efficacy over time. Besides their impact on seizure frequency, neuromodulation therapies are associated with various benefits and drawbacks in comparison to antiseizure drugs. Yet, we lack high-level evidence to best position each neuromodulation therapy in the treatment pathways of persons with difficult-to-treat epilepsy.

Abstract Aim Vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) all are options for drug-resistant epilepsy (DRE). However, little is known about how the choice of neurostimulation impacts subsequent healthcare costs. Materials and methods We used a large US healthcare claims database to identify all patients with epilepsy who underwent neurostimulation between 2012 and 2019. Eligible patients were identified and stratified based on procedure received (VNS vs. RNS/DBS). VNS patients were matched by propensity scoring to RNS/DBS patients. Use and cost of healthcare resources and pharmacotherapy were ascertained over the 24-month period following neurostimulation, incorporating all-cause and epilepsy-related measures. Disease-related care was defined based on diagnoses of claims for medical care and relevant pharmacotherapies. Results Seven hundred and ninety-two patients met all selection criteria. VNS patients were younger, were prescribed a higher pre-index mean number of anti-seizure medications (ASMs), and had higher pre-index levels of use and cost of epilepsy-related healthcare services. We propensity matched 148 VNS patients to an equal number of RNS/DBS patients. One year following index date (inclusive), mean total all-cause healthcare costs were 50% lower among VNS patients than RNS/DBS patients, and mean epilepsy-related costs were 55% lower; corresponding decreases at the two-year mark were 41% and 48%, respectively. Limitations Some clinical variables, such as seizure frequency and severity, quality of life, and functional status were unavailable in the database, precluding our ability to comprehensively assess differences between devices. Administrative claims data are subject to billing code errors, inaccuracies, and missing data, resulting in possible misclassification and/or unmeasured confounding. Conclusions After matching, VNS was associated with significantly lower all-cause and epilepsy-related costs for the two-year period following implantation. All-cause and epilepsy-related costs remained statistically significantly lower for VNS even after costs of implantation were excluded. PLAIN LANGUAGE SUMMARY For some people with epilepsy, medications do not work very well. For these people, other treatment options exist. One such treatment is neurostimulation. There are three types of neurostimulators—vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS). All three devices are known to reduce seizures in patients who have tried several medications. However, it is not known how these devices impact the costs of care. We compared the use and costs of medical care over 2 years between patients who got VNS and those who got RNS/DBS. Before comparing the groups, we made sure that they were balanced. Patients who got VNS were less likely than patients who got RNS/DBS to go to the hospital during the follow-up period. Patients who got VNS also had lower healthcare costs than patients who got RNS/DBS during follow-up. These differences were seen for all medical care costs. These differences also were seen in the costs of care for epilepsy. Our results suggest that the use of VNS is associated with fewer hospitalizations than RNS/DBS, and also that use of VNS is associated with lower healthcare costs than RNS/DBS.

Closed-loop neuromodulation holds significant promise for treating refractory epilepsy, but the lack of specificity and individualization considerably limits its clinical efficacy. Given the inherent complexity of epilepsy, which involves multiple brain regions and significant interindividual variability, a network-guided, personalized approach is essential. This study aims to develop precise, individualized neuromodulation strategies by leveraging unique brain network characteristics. Using a closed-loop system in chronic temporal lobe epilepsy (cTLE) rats, continuous neural signals were analyzed to identify optimal stimulation targets via the Granger causality (GC) method. Results showed that brain network connectivity remained stable in the short term but changed significantly over time. GC-guided stimulation effectively reduced seizure duration, enhancing <inline-formula> <tex-math notation="LaTeX">$\theta $ </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">$\alpha $ </tex-math></inline-formula> frequency band activity while suppressing <inline-formula> <tex-math notation="LaTeX">$\gamma $ </tex-math></inline-formula> activity. Additionally, targeted stimulation briefly inhibited interictal spikes and suppressed high-frequency oscillations during seizures. These findings highlight the potential for personalized neuromodulation to improve epilepsy treatment outcomes and deepen understanding of its underlying mechanisms.

Interictal epileptiform discharges (IEDs) are expressed in epileptic networks and disrupt cognitive functions. It is unclear whether addressing IED-induced dysfunction could improve epilepsy outcomes, as most therapeutic approaches target seizures. We show, in a kindling model of progressive focal epilepsy, that IEDs produce pathological oscillatory coupling associated with prolonged, hypersynchronous neural spiking in synaptically connected cortex and expand the brain territory capable of generating IEDs. A similar relationship between IED-mediated oscillatory coupling and temporal organization of IEDs across brain regions was identified in human participants with refractory focal epilepsy. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing the spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. These findings suggest that stimulation-based network interventions that normalize interictal dynamics may be an effective treatment of epilepsy and its comorbidities, with a low barrier to clinical translation. Pathological neural communication drives the spread of the epileptic network and contributes to memory impairment in focal epilepsy. The authors show that closed-loop electrical stimulation in rodents can prevent this interaction and preserve long-term memory.

Direct electrical stimulation of the seizure focus can achieve the early termination of epileptic oscillations. However, direct intervention of the hippocampus, the most prevalent seizure focus in temporal lobe epilepsy is thought to be not practicable due to its large size and elongated shape. Here, in a rat model, we report a sequential narrow-field stimulation method for terminating seizures, while focusing stimulus energy at the spatially extensive hippocampal structure. The effects and regional specificity of this method were demonstrated via electrophysiological and biological responses. Our proposed modality demonstrates spatiotemporal preciseness and selectiveness for modulating the pathological target region which may have potential for further investigation as a therapeutic approach. Direct stimulation of the focus of a seizure may have potential for the treatment of epilepsy. Here the authors demonstrate in a rat model a sequential narrow-field stimulation method for terminating seizures.

Epilepsy is a disorder of brain networks, that is usually combined with cognitive and emotional impairment. However, most of the current research on closed-loop pathways in epilepsy is limited to the neuronal level or has focused only on known closed-loop pathways, and studies on abnormalities in closed-loop pathways in epilepsy at the whole-brain network level are lacking. A total of 26 patients with magnetic resonance imaging-negative pharmacoresistant epilepsy (MRIneg-PRE) and 26 healthy controls (HCs) were included in this study. Causal brain networks and temporal-lag brain networks were constructed from resting-state functional MRI data, and the Johnson algorithm was used to identify stable closed-loop pathways. Abnormal closed-loop pathways in the MRIneg-PRE cohort compared with the HC group were identified, and the associations of these pathways with indicators of cognitive and emotional impairments were examined via Pearson correlation analysis. The results revealed that the abnormal stable closed-loop pathways were distributed across the frontal, parietal, and occipital lobes and included altered functional connectivity values both within and between cerebral hemispheres. Four abnormal closed-loop pathways in the occipital lobe were associated with emotional and cognitive impairments. These abnormal pathways may serve as biomarkers for the diagnosis and guidance of individualized treatments for MRIneg-PRE patients.

Abstract A proportional-plus-off control of optogenetic stimulation is implemented using the sample entropy and frequency bands of contralateral depth EEG as the afferent signals for seizure detection and feedback control. The system is tested on mice with mesial temporal epilepsy, induced by lithium-pilocarpine injections. The hippocampus is photic stimulated through an optical fibre inserted using the stereotactic technique, and depth EEG from the hippocampus contralateral to the photic-stimulation site is used to calculate the sample entropy and frequency bands, which, in turn, are utilized to classify the types of seizures. According to a lookup table, the proportional-plus-off controller maps the SEn to the control signal and regulates the intensity of the photic stimulation to the hippocampus. The average rates of correct seizure detection are >90% in both acute and chronic stages. The average rates of successful seizure suppression are 86–98% in the acute stage and 94.3% in the chronic stage. The results indicate that the contralateral sensing and closed-loop proportional-plus-off control of optogenetic stimulation is feasible for seizure control.

Electrical neuromodulation as a palliative treatment has been increasingly used in the control of epilepsy. However, current neuromodulations commonly implement predetermined actuation strategies and lack the capability of self-adaptively adjusting stimulation inputs. In this work, rooted in optimal control theory, we propose a Koopman-MPC framework for real-time closed-loop electrical neuromodulation in epilepsy, which integrates i) a deep Koopman operator based dynamical model to predict the temporal evolution of epileptic electroencephalogram (EEG) with an approximate finite-dimensional linear dynamics and ii) a model predictive control (MPC) module to design optimal seizure suppression strategies. The Koopman operator based linear dynamical model is embedded in the latent state space of the autoencoder neural network, in which we can approximate and update the Koopman operator online. The linear dynamical property of the Koopman operator ensures the convexity of the optimization problem for subsequent MPC control. The proposed deep Koopman operator model shows greater predictive capability than the baseline models (e.g., vector autoregressive model, kernel based method and recurrent neural network (RNN)) in both synthetic and real epileptic EEG data. Moreover, compared with the RNN-MPC framework, our Koopman-MPC framework can suppress seizure dynamics with better computational efficiency in both the Jansen-Rit model and the Epileptor model. Koopman-MPC framework opens a new window for model-based closed-loop neuromodulation and sheds light on nonlinear neurodynamics and feedback control policies.

Despite promising advancements, closed-loop neurostimulation for drug-resistant epilepsy (DRE) still relies on manual tuning and produces variable outcomes, while automated predictable algorithms remain an aspiration. As a fundamental step towards addressing this gap, here we study predictive dynamical models of human intracranial EEG (iEEG) response under parametrically rich neurostimulation. Using data from n = 13 DRE patients, we find that stimulation-triggered switched-linear models with ∼300ms of causal historical dependence best explain evoked iEEG dynamics. These models are highly consistent across different stimulation amplitudes and frequencies, allowing for learning a generalizable model from abundant STIM OFF and limited STIM ON data. Further, evoked iEEG in nearly all subjects exhibited a distance-dependent pattern, whereby stimulation directly impacts the actuation site and nearby regions (≲ 20mm), affects medium-distance regions (20 ∼ 100mm) through network interactions, and hardly reaches more distal areas (≳ 100mm). Peak network interaction occurs at 60∼80mm from the stimulation site. Due to their predictive accuracy and mechanistic interpretability, these models hold significant potential for model-based seizure forecasting and closed-loop neurostimulation design.

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes. Here we hypothesize that stimulation during brain states with less epileptiform activity drives long-term changes that restore healthy brain networks. To test this, we quantified stimulation episodes during low- and high-risk brain states-that is, stimulation during periods with a lower or higher risk of generating epileptiform activity-in a cohort of 40 patients treated with RNS. More frequent stimulation in tonic low-risk states, and out of rhythmic high-risk states, predicted seizure reduction. Additionally, stimulation events were more likely to be phase-locked to prolonged episodes of abnormal activity for intermediate and poor responders when compared to super responders, consistent with the hypothesis that improved outcomes are driven by stimulation during low-risk states. These results support the hypothesis that stimulation during low-risk periods might underlie the mechanisms of RNS, suggesting a relationship between temporal patterns of neuromodulation and plasticity that facilitates long-term seizure reduction.

In closed-loop neuromodulators for epilepsy patients, nonidealities such as common-mode interference (CMI), stimulation artifacts (SA), electrode DC offset (DCO) and 1/f noise bring challenges for the sensing circuit to capture EEG signals (<1 mV) and for the backend classifier to detect patient-specific seizures accurately for precise stimulation. Chopper-stabilized capacitive-coupled instrument amplifiers (CS-CCIA) are widely used to suppress DCO and 1/f noise [1]–[3], and feedforward CM cancelling (CMC) is further added in [2] but still shows limited CMI tolerance (< 650mpp). The SA rejection in [4] requires 3s response time, which is too long for real-time SA rejection. Also, the accurate classifier in [5] operates all the time, resulting in huge digital power (674µW). This work presents an 8-channel closed-loop neuromodulation chipset with 2-level (coars + fine) classification. Applied in a deep-brain stimulation (DBS) system, in vivo measurement verifies that the 2-level classification scheme results in: (1) 35dB SA rejection in 0.5ms; (2) intermittent operation of the fine classifier, achieving ~1.16µW average power for classification. A feedback CMC (FB-CMC) is proposed for the CS-CCIA, achieving CMI tolerance up to 1. 5Vpp.

Epilepsy is a chronic, neurological disorder affecting millions of people every year. The current available pharmacological and surgical treatments are lacking in overall efficacy and cause side-effects like cognitive impairment, depression, tremor, abnormal liver and kidney function. In recent years, the application of optogenetic implants have shown promise to target aberrant neuronal circuits in epilepsy with the advantage of both high spatial and temporal resolution and high cell-specificity, a feature that could tackle both the efficacy and side-effect problems in epilepsy treatment. Optrodes consist of electrodes to record local field potentials and an optical component to modulate neurons via activation of opsin expressed by these neurons. The goal of optogenetics in epilepsy is to interrupt seizure activity in its earliest state, providing a so-called closed-loop therapeutic intervention. The chronic implantation in vivo poses specific demands for the engineering of therapeutic optrodes. Enzymatic degradation and glial encapsulation of implants may compromise long-term recording and sufficient illumination of the opsin-expressing neural tissue. Engineering efforts for optimal optrode design have to be directed towards limitation of the foreign body reaction by reducing the implant’s elastic modulus and overall size, while still providing stable long-term recording and large-area illumination, and guaranteeing successful intracerebral implantation. This paper presents an overview of the challenges and recent advances in the field of electrode design, neural-tissue illumination, and neural-probe implantation, with the goal of identifying a suitable candidate to be incorporated in a therapeutic approach for long-term treatment of epilepsy patients.

The closed-loop electrical stimulation is emerging as a promising neural modulation therapy for refractory epilepsy. However, the efficacy of electrical stimulation is less than optimal and the mechanism of seizure control is still unclear. In this paper, we evaluated the acute seizure control efficacy of the multi-site closed-loop stimulation (MSCLS) in a rodent model with a custom designed closed-loop neurostimulator. A total of 18 rats were injected with kainic-acid in CA3 of the left hippocampus to induce acute temporal lobe seizures. Instead of single target stimulation, four target sites in left hemisphere including CA1 and CA3 of the hippocampus, sub-thalamic nucleus, and M1 region of the motor cortex were selected for both recording and stimulation. A low-cost efficient multi-site seizure detection algorithm was implemented in the neurostimulator for MSCLS. With MSCLS treatment, the rats without status-epilepsy (SE) significantly reduced the seizure duration and the number of generalized seizures in each site. When considering the rats developed SE, the MSCLS could also alleviate the seizure severity, but had little effect on the seizure duration and seizure number. In conclusion, although the efficacy of MSCLS was still limited by the stimulation sites, stimulation parameters, and seizure model chosen in this paper, the MSCLS itself would be a promising direction for the refractory seizure treatment.

Abnormal phase–amplitude coupling (PAC) is a promising biomarker for closed-loop neurostimulation in epilepsy, but robust real-time detection remains challenging. Conventional metrics trade off sensitivity and specificity in low signal-to-noise ratio (SNR) conditions, while statistical normalization methods often introduce prohibitive latency. We presented Confidence-Gated PAC (CG-PAC), a real-time framework that fuses instantaneous signal energy with normalized PAC estimates via a baseline-calibrated Sigmoid gating function. CG-PAC suppresses noise-induced artifacts while preserving genuine coupling. In simulations spanning a range of SNRs and in chronic rat local field potential (LFP) recordings, CG-PAC demonstrated improved robustness and temporal consistency compared to existing methods, achieving an area under the receiver operating characteristic curve (AUROC) of 0.90 for seizure prediction 20–30 s prior to onset. These results highlight CG-PAC as a practical solution for real-time PAC tracking in closed-loop neurostimulation systems.

BACKGROUND Phase-targeted auditory stimulation (PTAS) during sleep has been shown to enhance slow oscillations (SOs) and improve memory consolidation through closed-loop delivery of auditory stimuli at the up-phase of SOs. However, clinical translation of PTAS therapy has been hindered by challenges in the estimation of real-time phase. Our scoping review of 53 PTAS studies identified substantial variability in phase estimation methods and therapeutic outcomes. In particular, there were no validated methods for clinical populations with pathological electroencephalography (EEG) patterns such as persons with epilepsy, where interictal epileptiform discharges (IEDs) compromise the performance of real-time PTAS delivery. NEW METHOD To address critical limitations in the application of existing approaches to the epileptic brain, we developed TWave, a real-time algorithm that integrates wavelet-based phase estimation with predictive modelling and multi-feature validation. TWave is designed to maintain SO phase estimation performance while rejecting pathological EEG artifacts to achieve the temporal precision required for effective PTAS. RESULTS TWave achieved high phase estimation accuracy and precision in healthy adult (mean error=0.11 radians; SD=1.23 radians) and paediatric epilepsy (mean error=0.26 radians; SD=1.22 radians) EEG recordings. Importantly, TWave successfully rejected 83% of IEDs while maintaining sensitivity to SOs. COMPARISON WITH EXISTING ALGORITHMS Benchmarking against four commonly used algorithms demonstrated TWave's superior performance in maintaining phase estimation precision across normative and epilepsy EEG recordings. CONCLUSION The current work accelerates clinical translation of PTAS by providing a validated approach to real-time phase estimation and providing an open-source toolbox to increase reproducibility in sleep modulation research.

No abstract available

Abstract Seizures can emerge from multiple or large foci in temporal lobe epilepsy, complicating focally targeted strategies such as surgical resection or the modulation of the activity of specific hippocampal neuronal populations through genetic or optogenetic techniques. Here, we evaluate a strategy in which optogenetic activation of medial septal GABAergic neurons, which provide extensive projections throughout the hippocampus, is used to control seizures. We utilized the chronic intrahippocampal kainate mouse model of temporal lobe epilepsy, which results in spontaneous seizures and as is often the case in human patients, presents with hippocampal sclerosis. Medial septal GABAergic neuron populations were immunohistochemically labelled and were not reduced in epileptic conditions. Genetic labelling with mRuby of medial septal GABAergic neuron synaptic puncta and imaging across the rostral to caudal extent of the hippocampus, also indicated an unchanged number of putative synapses in epilepsy. Furthermore, optogenetic stimulation of medial septal GABAergic neurons consistently modulated oscillations across multiple hippocampal locations in control and epileptic conditions. Finally, wireless optogenetic stimulation of medial septal GABAergic neurons, upon electrographic detection of spontaneous hippocampal seizures, resulted in reduced seizure durations. We propose medial septal GABAergic neurons as a novel target for optogenetic control of seizures in temporal lobe epilepsy.

Additional treatment options for temporal lobe epilepsy are needed, and potential interventions targeting the cerebellum are of interest. Previous animal work has shown strong inhibition of hippocampal seizures through on-demand optogenetic manipulation of the cerebellum. However, decades of work examining electrical stimulation – a more immediately translatable approach – targeting the cerebellum has produced very mixed results. We were therefore interested in exploring the impact that stimulation parameters may have on seizure outcomes. Using a mouse model of temporal lobe epilepsy, we conducted on-demand electrical stimulation of the cerebellar cortex, and varied stimulation charge, frequency, and pulse width, resulting in over a thousand different potential combinations of settings. To explore this parameter space in an efficient, data-driven, manner, we utilized Bayesian optimization with Gaussian process regression, implemented in Matlab with an Expected Improvement Plus acquisition function. We examined two different fitting conditions and two different electrode orientations. Following the optimization process, we conducted additional on-demand experiments to test the effectiveness of selected settings. Across all animals, we found that Bayesian optimization allowed identification of effective intervention settings. Additionally, generally similar optimal settings were identified across animals, suggesting that personalized optimization may not always be necessary. While optimal settings were consistently effective, stimulation with settings predicted from the Gaussian process regression to be ineffective failed to provide seizure control. Taken together, our results provide a blueprint for exploration of a large parameter space for seizure control, and illustrate that robust inhibition of seizures can be achieved with electrical stimulation of the cerebellum, but only if the correct stimulation parameters are used.

Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, due to its large size and irregular shape. In contrast, the medial septum (MS) is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this ‘proxy intervention’ concept and precisely timed stimulation, we report here that closed-loop MS electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell-type-specific stimulation revealed that precisely timed activation of MS GABAergic neurons underlay the effects. Our concept of phase-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and its current embodiment can be directly translated into clinical application.

Closed-Loop Stimulation of the Medial Septum Terminates Epileptic Seizures Takeuchi Y, Harangozó M, Pedraza L, Földi T, Kozák G, Li Q, Berényi A. Brain. 2021;144(3):885-908. doi:10.1093/brain/awaa450 Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, because of the large size and irregular shape of the hippocampus. In contrast, the medial septum is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this “proxy intervention” concept and precisely timed stimulation, we report here that closed-loop medial septum electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell type-specific stimulation revealed that the precisely timed activation of medial septum GABAergic neurons underlaid the effects. Our concept of time-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and has potential for clinical translation.

The closed-loop brain stimulation technique plays a key role in neural network information processing and therapies of neurological diseases. Transcranial ultrasound stimulation (TUS) is an established neuromodulation method for the neural oscillation in animals or human. All available TUS systems provide brain stimulation in an open-loop pattern. In this study, we developed a closed-loop transcranial ultrasound stimulation (CLTUS) system for real-time non-invasive neuromodulation in vivo. We used the CLTUS system to modulate the neural activities of the hippocampus of a wild-type mouse based on the phase of the theta rhythm recorded at the ultrasound-targeted location. In addition, we modulated the hippocampus of a temporal lobe epilepsy (TLE) mouse. The ultrasound stimulation increased the absolute power and reduced the relative power of the theta rhythm, which were independent of the specific phase of the theta rhythm. Compared with those of a sham stimulation, the latency of epileptic seizures was significantly increased, while the epileptic seizure duration was significantly decreased under the CLTUS. The above results indicate that the CLTUS can be used to not only modulate the neural oscillation through the theta-phase-specific manipulation of the hippocampus but also effectively inhibit the seizure of a TLE mouse in time. CLTUS has large application potentials for the understanding of the causal relationship of neural circuits as well as for timely, effective, and non-invasive therapies of neurological diseases such as epilepsy and Parkinson’s disease.

The Fasciola Cinereum of the Hippocampal Tail as an Interventional Target in Epilepsy Jamiolkowski RM, Nguyen QA, Farrell JS, McGinn RJ, Hartmann DA, Nirschl JJ, Sanchez MI, Buch VP, Soltesz I. Nat Med. 2024 May;30(5):1292–1299. doi: 10.1038/s41591-024-02924-9. Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of 6 patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.

Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of six patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy. The posterior hippocampal tail is an important seizure node in humans and may be a promising interventional target in epilepsy.

To determine if closed‐loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well‐established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory.

Capacitively coupled electrical stimulation modulates neuronal activity through reversible charging and without charge transfer reactions. This represents a promising and safe neuromodulation scheme but achieving wireless and high capacitive charge density injection remains challenging. Here, we developed a topological fibrous-architecture sonocapacitor (SonoCap) that assembled from piezoelectric-dielectric composite nanosphere (UCapT) and two-dimensional cellulose. UCapT features a unique piezoelectric core-hollow cavity-dielectric cage structure that can efficiently couples ultrasound excitation to achieve piezoelectric electron-capacitance transfer, and its highly assembled SonoCap achieves cumulative charge storage, a high ion-accessible surface area, and macroscopic softness, thereby enabling wireless and high capacitive charge density injection. SonoCap can achieve a capacitive charge density output of up to 9.7 mC cm−2 under 0.63 W cm−2 ultrasound excitation, while generating a negligible Faradaic charge of 2 nC cm−2. We demonstrated that SonoCap can transcranially and epidurally modulate neural circuit dynamics in rat and pig brains, without introducing intracerebral foreign bodies and maintaining ventricular homeostasis. By integrating a deep learning-based closed-loop diagnostic system, on-demand, wireless, and epidural capacitive electrical stimulation treatment for temporal lobe epilepsy can be achieved. The design concept of SonoCap is expected to inspire expanding development of functional capacitive stimulators, potentially promoting the widespread application of capacitive electrical neuromodulation. Achieving wireless and high charge density neural stimulation remains challenging. To address this issue, the authors develop a sonocapacitor from piezoelectric-dielectric composite nanospheres and two-dimensional cellulose.

OBJECTIVE Refractory temporal lobe epilepsy (TLE) with recurring seizures causing continuing pathological changes in neural reorganization. There is an incomplete understanding of how spatiotemporal electrophysiological characteristics changes during the development of TLE. Long-term multi-site epilepsy patients' data is hard to obtain. Thus, our study relied on animal models to reveal the changes in electrophysiological and epileptic network characteristics systematically. METHODS Long-term local field potentials (LFPs) were recorded over a period of 1 to 4 months from 6 pilocarpine-treated TLE rats. We compared variations of seizure onset zone (SOZ), seizure onset pattern (SOP), the latency of seizure onsets, and functional connectivity network from 10-channel LFPs between the early and late stages. Moreover, three machine learning classifiers trained by early-stage data were used to test seizure detection performance in the late stage. RESULTS Compared to the early stage, the earliest seizure onset was more frequently detected in hippocampus areas in the late stage. The latency of seizure onsets between electrodes became shorter. Low-voltage fast activity (LVFA) was the most common SOP and the proportion of it increased in the late stage. Different brain states were observed during seizures using Granger causality (GC). Moreover, seizure detection classifiers trained by early-stage data were less accurate when tested in late-stage data. SIGNIFICANCE Neuromodulation especially closed-loop deep brain stimulation (DBS) is effective in the treatment of refractory TLE. Although the frequency or amplitude of the stimulation is generally adjusted in existing closed-loop DBS devices in clinical usage, the adjustment rarely considers the pathological progression of chronic TLE. This suggests that an important factor affecting the therapeutic effect of neuromodulation may have been overlooked. The present study reveals time-varying electrophysiological and epileptic network properties in chronic TLE rats and indicates that classifiers of seizure detection and neuromodulation parameters might be designed to adapt to the current state dynamically with the progression of epilepsy.

Human Cortical Interneurons Optimized for Grafting Specifically Integrate, Abort Seizures, and Display Prolonged Efficacy Without Over-Inhibition Zhu Q, Mishra A, Park JS, Liu D, Le DT, Gonzalez SZ, Anderson-Crannage M, Park JM, Park G-H, Tarbay L, Daneshvar K, Brandenburg M, Signoretti C, Zinski A, Gardner E-J, Zheng KL, Abani CP, Hu C, Beaudreault CP, Zhang X-L, Stanton PK, Cho J-H, Velíšek L, Velíšková J, Javed S, Leonard CS, Kim H-Y, Chung S. Neuron. 2023;111(6):807-823.e7. ISSN 0896-6273. doi:10.1016/j.neuron.2022.12.014 Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control, and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, providing further evidence that this treatment for epilepsy could reliably help patients suffering from intractable epilepsy.

Closed-Loop Direct Control of Seizure Focus in a Rodent Model of Temporal Lobe Epilepsy via Localized Electric Fields Applied Sequentially Kang W, Ju C, Joo J, Lee J, Shon Y-M, Park S-M. Nat Commun. 2022;13(1):7805. doi:10.1038/s41467-022-35540-7 Direct electrical stimulation of the seizure focus can achieve the early termination of epileptic oscillations. However, direct intervention of the hippocampus, the most prevalent seizure focus in temporal lobe epilepsy is thought to be not practicable due to its large size and elongated shape. Here, in a rat model, we report a sequential narrow-field stimulation method for terminating seizures, while focusing stimulus energy at the spatially extensive hippocampal structure. The effects and regional specificity of this method were demonstrated via electrophysiological and biological responses. Our proposed modality demonstrates spatiotemporal preciseness and selectiveness for modulating the pathological target region which may have potential for further investigation as a therapeutic approach.

No abstract available

Implantable brain stimulation devices continue to be developed to treat and monitor brain conditions. As the complexity of these devices grows to include adaptive neuromodulation therapy, validating the operation and verifying the correctness of these systems becomes more complicated. The new complexities lie in the functioning of the device being dependent on the interaction with the patient and environmental factors such as noise and artifacts. Here, we present a hardware-in-the-loop (HIL) testing framework that employs computational models of pathological neural dynamics to test adaptive deep brain stimulation (DBS) devices prior to animal or human testing. A brain stimulation and recording electrode array is placed in the saline tank and connected to an adaptive neuromodulation system that measures and processes the synthetic signals and delivers stimulation back into the saline tank. A data acquisition system is used to detect the stimulation and provide feedback to the computational model in order to simulate the effects of stimulation on the neural dynamics. In this study, we used real-time computational models to emulate the dynamics of epileptic seizures observed in the anterior nucleus of the thalamus (ANT) in epilepsy patients and beta band (11-35 Hz) oscillations observed in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients. These models simulated neuronal responses to electrical stimulation pulses and the saline tank tested hardware interactions between the detection algorithms and stimulation interference. We tested and validated the operation of adaptive DBS algorithms for seizure and beta band power suppression embedded in an implantable DBS system (Medtronic Summit RC+S). This study highlights the utility of the proposed hardware-in-the-loop framework to systematically test the adaptive DBS systems in the presence of system aggressors such as environmental noise and stimulation-induced electrical artifacts. This testing procedure can help ensure correctness and robustness of adaptive DBS devices prior to animal and human testing.

OBJECTIVE To characterize ictal high-frequency activity (HFA, 80-500 Hz) within the limbic thalami and correlate HFA with seizure onset patterns in patients with temporal lobe epilepsy (TLE). METHODS Patients with TLE undergoing stereoelectroencephalography (SEEG) for presurgical workup were prospectively recruited for electrode implantation in one of the anterior (AN), centromedian (CeM), or mediodorsal (MD) thalamic nuclei. HFA was computed by three complementary methods: (1.) power-spectral density (PSD), (2.) power-law based (i.e., 1/f) regression, and (3.) envelope-based (ENV) power analysis. Electrographic onset patterns in the seizure onset zone were classified in three distinct patterns, including low amplitude fast activity (LAFA). RESULTS From 11 patients, 44 seizures were analyzed. Ictal HFA was observed in all three thalamic nuclei. HFA was greatest during ictal onset in the AN and MD and greatest during termination in the CeM (P < 0.001). LAFA-onset seizures were associated with earlier peak HFA compared to those with other onset patterns (P = 0.006). CONCLUSIONS Dynamics of ictal HFA seem to vary by thalamic subnuclei. AN and MD may facilitate seizure propagation while CeM may play a role in termination. LAFA-onset seizures rapidly propagate to the thalamus. SIGNIFICANCE Characterizing nucleus-specific ictal dynamics of neural activities facilitates precise therapy for epilepsy treatment with closed-loop deep brain stimulation.

Purpose of the Review Intracranial neurostimulation is a well-established treatment of neurologic conditions such as drug-resistant epilepsy (DRE) and movement disorders, and there is emerging evidence for using deep brain stimulation to treat obsessive-compulsive disorder (OCD) and depression. Nearly all published reports of intracranial neurostimulation have focused on implanting a single device to treat a single condition. The purpose of this review was to educate neurology clinicians on the background literature informing dual treatment of 2 comorbid neuropsychiatric conditions epilepsy and OCD, discuss ethical and logistical challenges to dual neuropsychiatric treatment with a single device, and demonstrate the promise and pitfalls of this approach through discussion of the first-in-human closed-looped responsive neurostimulator (RNS) implanted to treat both DRE (on-label) and OCD (off-label). Recent Findings We report the first implantation of an intracranial closed-loop neurostimulation device (the RNS system) with the primary goal of treating DRE and a secondary exploratory goal of managing treatment-refractory OCD. The RNS system detects electrophysiologic activity and delivers electrical stimulation through 1 or 2 electrodes implanted into a patient's seizure-onset zones (SOZs). In this case report, we describe a patient with treatment-refractory epilepsy and OCD where the first lead was implanted in the right superior temporal gyrus to target the most active SOZ based on stereotactic EEG (sEEG) recordings and semiology. The second lead was implanted to target the right anterior peri-insular region (a secondary SOZ on sEEG) with the distal-most contacts in the right nucleus accumbens, a putative target for OCD neurostimulation treatment. The RNS system was programmed to detect and record the unique electrophysiologic signature of both the patient's seizures and compulsions and then deliver tailored electrical pulses to disrupt the pathologic circuitry. Summary Dual treatment of refractory focal epilepsy and OCD with an intracranial closed-loop neurostimulation device is feasible, safe, and potentially effective. However, there are logistical challenges and ethical considerations to this novel approach to treatment, which require complex care coordination by a large multidisciplinary team.

Temporal lobe epilepsy is the most common type of epilepsy in adults, is often medically refractory, and due to broad actions and long-time scales, current systemic treatments have major negative side-effects. However, temporal lobe seizures tend to arise from discrete regions before overt clinical behaviour, making temporally and spatially specific treatment theoretically possible. Here we report the arrest of spontaneous seizures using a real-time, closed-loop, response system and in vivo optogenetics in a mouse model of temporal lobe epilepsy. Either optogenetic inhibition of excitatory principal cells, or activation of a subpopulation of GABAergic cells representing <5% of hippocampal neurons, stops seizures rapidly upon light application. These results demonstrate that spontaneous temporal lobe seizures can be detected and terminated by modulating specific cell populations in a spatially restricted manner. A clinical approach built on these principles may overcome many of the side-effects of currently available treatment options. Temporal lobe epilepsy in adults does not always respond to treatment. Krook-Magnuson and colleagues use optogenetics to inhibit and activate excitatory and inhibitory neurons, respectively, in a mouse model of temporal lobe epilepsy, and find that they can stop seizures on a moment-to-moment basis.

BACKGROUND Patients with refractory, bilateral, multifocal epilepsy have few treatment options that typically include a combination of antiseizure medications (ASMs) and vagus nerve stimulation (VNS). A man in his 40s presented with epilepsy refractory to a combination of five ASMs plus VNS; he was still experiencing 7–10 seizures per week. His seizure network involved multiple foci in both frontal and temporal lobes. Bilateral depth electrodes were implanted into the centromedian/parafascicular (CM/PF) complex of the thalamus and connected to the responsive neurostimulation (RNS) system for closed-loop stimulation and neurophysiological monitoring. OBSERVATIONS The patient reported clear improvement in his seizures since the procedure, with a markedly reduced number of seizures and decreased seizure intensity. He also reported stretches of seizure freedom not typical of his preoperative baseline, and his remaining seizures were milder, more often with preserved awareness. Generalized seizures with loss of consciousness have decreased to about one per month. RNS data confirmed a right-sided predominance of the bilateral seizure onsets. LESSONS In this patient with multifocal, bilateral frontotemporal epilepsy, RNS of the CM/PF thalamic complex combined with VNS was found to be beneficial. The RNS device was able to detect seizures propagating through the thalamus, and stimulation produced a decrease in seizure burden and intensity.

OBJECTIVES This study investigated 1) epileptiform activity propagation triggered by intrahippocampal kainic acid (KA) injections, 2) whether low-frequency probing stimulation applied to the ipsilateral amygdaloid complex (AMY) would affect propagation, and 3) whether distinct temporal patterns of electrical stimulation applied to the contralateral amygdaloid complex interfere with the interhemispheric propagation pattern. MATERIALS AND METHODS Electrical stimulation (ES) comprised a 100-μs pulse of 500 μA applied to the AMY. The Probing protocol applied a 2000-millisecond interpulse-interval (IPI) ES ipsilateral to KA injection. The Propagation protocol ES was applied contralateral to KA injection using temporally coded ES patterns: periodic stimulation (PS, with fixed 250-millisecond IPI or nonperiodic stimulation [NPS], power-law distributed IPIs constrained by a maximum of 4 pulses/s). Continuous local-field electrophysiologic data were recorded from AMY and hippocampus sites in both hemispheres. RESULTS Our results show that probing stimulation to the ipsilateral amygdala does not interfere with the seizure propagation pattern; however, independent contralateral seizures were observed. Our data show that NPS treatment, but not PS, interferes with propagation to the contralateral hemisphere even when applied before KA injection: seizure duration, energy, and total number of seizures were significantly reduced. Seizure causality analysis between channels also shows significant differences between PS and NPS treatments. CONCLUSION These data corroborate that KA injection seizures, even during status epilepticus, are not restricted to injection foci. Our data show promising perspectives on designing a closed-loop solution using 0.5-Hz probing stimulation to predict seizures and temporally coded stimulation to modulate seizure propagation.

Introduction One-third of patients with epilepsy continue to have seizures despite antiepileptic medications. Some of these refractory patients may not be candidates for surgical resection primarily because the seizure onset zones (SOZs) involve both hemispheres or are located in eloquent areas. The NeuroPace Responsive Neurostimulation System (RNS) is a closed-loop device that uses programmable detection and stimulation to tailor therapy to a patient's individual neurophysiology. Here, we present our single-center experience with the use of RNS in thalamic nuclei to provide long-term seizure control in patients with refractory epilepsy. Methods We performed a prospective single-center study of consecutive refractory epilepsy patients who underwent RNS system implantation in the anterior (ANT) and centromedian (CM) thalamic nuclei from September 2015 to December 2020. Patients were followed postoperatively to evaluate seizure freedom and complications. Results Twenty-three patients underwent placement of 36 RNS thalamic leads (CM = 27 leads, ANT = 9 leads). Mean age at implant was 18.8 ± 11.2 years (range 7.8–62 years-old). Two patients (8.7%) developed infections: 1 improved with antibiotic treatments alone, and 1 required removal with eventual replacement of the system to recover the therapeutic benefit. Mean time from RNS implantation to last follow-up was 22.3 months. Based on overall reduction of seizure frequency, 2 patients (8.7%) had no- to <25% improvement, 6 patients (26.1%) had 25–49% improvement, 14 patients (60.9%) had 50–99% improvement, and 1 patient (4.3%) became seizure-free. All patients reported significant improvement in seizure duration and severity, and 17 patients (74%) reported improved post-ictal state. There was a trend for subjects with SOZs located in the temporal lobe to achieve better outcomes after thalamic RNS compared to those with extratemporal SOZs. Of note, seizure etiology was syndromic in 12 cases (52.2%), and 7 patients (30.4%) had undergone resection/disconnection surgery prior to thalamic RNS therapy. Conclusion Thalamic RNS achieved ≥50% seizure control in ~65% of patients. Infections were the most common complication. This therapeutic modality may be particularly useful for patients affected by aggressive epilepsy syndromes since a young age, those whose seizure foci are located in the mesial temporal lobe, and those who have failed prior surgical interventions.

This work explores the potential utility of neural network classifiers for real-time classification of field-potential based biomarkers in next-generation responsive neuromodulation systems. Compared to classical filter-based classifiers, neural networks offer an ease of patient-specific parameter tuning, promising to reduce the burden of programming on clinicians. The paper explores a compact, feed-forward neural network architecture of only dozens of units for seizure-state classification in refractory epilepsy. The proposed classifier offers comparable accuracy to filter classifiers on clinician-labelled data, while reducing detection latency. As a trade-off to classical methods, the paper focuses on keeping the complexity of the architecture minimal, to accommodate the on-board computational constraints of implantable pulse generator systems.

Neuromodulation techniques have emerged as promising approaches for treating a wide range of neurological disorders, precisely delivering electrical stimulation to modulate abnormal neuronal activity. While leveraging the unique capabilities of artificial intelligence (AI) holds immense potential for responsive neurostimulation, it appears as an extremely challenging proposition where real-time (low-latency) processing, low power consumption, and heat constraints are limiting factors. The use of sophisticated AI-driven models for personalized neurostimulation depends on back-telemetry of data to external systems (e.g. cloud-based medical mesosystems and ecosystems). While this can be a solution, integrating continuous learning within implantable neuromodulation devices for several applications, such as seizure prediction in epilepsy, is an open question. We believe neuromorphic architectures hold an outstanding potential to open new avenues for sophisticated on-chip analysis of neural signals and AI-driven personalized treatments. With more than three orders of magnitude reduction in the total data required for data processing and feature extraction, the high power- and memory-efficiency of neuromorphic computing to hardware-firmware co-design can be considered as the solution-in-the-making to resource-constraint implantable neuromodulation systems. This perspective introduces the concept of Neuromorphic Neuromodulation, a new breed of closed-loop responsive feedback system. It highlights its potential to revolutionize implantable brain-machine microsystems for patient-specific treatment

Objective. While ultrasound is largely established for use in diagnostic imaging and heating therapies, its application for neuromodulation is relatively new and not well understood. The objective of the present study was to investigate issues related to interactions between focused acoustic beams and brain tissues to better understand possible limitations of transcranial ultrasound for neuromodulation. Approach. A computational model of transcranial focused ultrasound was constructed and validated against bench top experimental data. The models were then incrementally extended to address and investigate a number of issues related to the use of ultrasound for neuromodulation. These included the effect of variations in skull geometry and gyral anatomy, as well as the effect of transmission across multiple tissue and media layers, such as scalp, skull, CSF, and gray/white matter on ultrasound insertion behavior. In addition, a sensitivity analysis was run to characterize the influence of acoustic properties of intracranial tissues. Finally, the heating associated with ultrasonic stimulation waveforms designed for neuromodulation was modeled. Main results. Depending on factors such as acoustic frequency, the insertion behavior of a transcranial focused ultrasound beam is only subtly influenced by the geometry and acoustic properties of the underlying tissues. Significance. These issues are critical for the refinement of device design and the overall advancement of ultrasound methods for noninvasive neuromodulation.

Epilepsy is a neurological illness that is characterised by continuous spasms of shaking, sometimes known as convulsions. Although there are effective treatments for epilepsy, such as drugs and surgery, there is still a group of individuals who have intractable epilepsy that fails to respond to standard methods. Intractable epilepsy is a severe neurological illness that ripples across the globe and impacts millions of individuals. It is extremely difficult to control intractable epilepsy, which is defined as the lack of response to two or more standard antiepileptic medication treatments. In recent years, the use of programmable electrical stimulation of the brain has shown promise as a digital treatment strategy for lowering seizure frequency in individuals with intractable epilepsy. In this research, the use of Amenable Neurostimulation (ANS) as part of a digital treatment strategy to intractable epilepsy is investigated. When applied to the brain, ANS uses a closed-loop system to selectively stimulate neurons in the affected areas, therefore lowering the frequency of seizures. In addition, the report describes the design and execution of a pilot research employing ANS to treat intractable epilepsy, including patient selection criteria, device settings, and outcome measures. The findings of this pilot research point to the possibility that ANS might be a realistic and successful therapy option for people afflicted with intractable epilepsy. This paper demonstrated the prospects of digital medicines in treating complicated neurological illnesses and recommends future routes for research and development in this field.

We define and explain the quasistatic approximation (QSA) as applied to field modeling for electrical and magnetic stimulation. Neuromodulation analysis pipelines include discrete stages, and QSA is applied specifically when calculating the electric and magnetic fields generated in tissues by a given stimulation dose. QSA simplifies the modeling equations to support tractable analysis, enhanced understanding, and computational efficiency. The application of QSA in neuro-modulation is based on four underlying assumptions: (A1) no wave propagation or self-induction in tissue, (A2) linear tissue properties, (A3) purely resistive tissue, and (A4) non-dispersive tissue. As a consequence of these assumptions, each tissue is assigned a fixed conductivity, and the simplified equations (e.g., Laplace's equation) are solved for the spatial distribution of the field, which is separated from the field's temporal waveform. Recognizing that electrical tissue properties may be more complex, we explain how QSA can be embedded in parallel or iterative pipelines to model frequency dependence or nonlinearity of conductivity. We survey the history and validity of QSA across specific applications, such as microstimulation, deep brain stimulation, spinal cord stimulation, transcranial electrical stimulation, and transcranial magnetic stimulation. The precise definition and explanation of QSA in neuromodulation are essential for rigor when using QSA models or testing their limits.

In the emerging research field of bioelectronic medicine, it has been indicated that neuromodulation of the Vagus Nerve (VN) has the potential to treat various conditions such as epilepsy, depression, and autoimmune diseases. In order to reduce side effects, as well as to increase the effectiveness of the delivered therapy, subfascicle stimulation specificity is required. In the electrical domain, increasing spatial selectivity can only be achieved using invasive and potentially damaging approaches like compressive forces or nerve penetration. To avoid these invasive methods, while obtaining a high spatial selectivity, a 2 mm diameter extraneural cuff-shaped proof-of-concept design with integrated Lead Zirconate Titanate (PZT) based ultrasound (US) transducers is proposed in this paper. For the development of the proposed concept, wafer-level microfabrication techniques are employed. Moreover, acoustic measurements are performed on the device, in order to characterize the ultrasonic beam profiles of the integrated PZT-based US transducers. A focal spot size of around 200 μm by 200 μm is measured for the proposed cuff. Moreover, the curvature of the device leads to constructive interference of the US waves originating from multiple PZT-based US transducers, which in turn leads to an increase of 45% in focal pressure compared to the focal pressure of a single PZT-based US transducer. Integrating PZT-based US transducers in an extraneural cuff-shaped design has the potential to achieve high-precision US neuromodulation of the Vagus Nerve without requiring intraneural implantation.

Neuromorphic engineering makes use of mixed-signal analog and digital circuits to directly emulate the computational principles of biological brains. Such electronic systems offer a high degree of adaptability, robustness, and energy efficiency across a wide range of tasks, from edge computing to robotics. Within this context, we investigate a key feature of biological neurons: their ability to carry out robust and reliable computation by adapting their input response and spiking pattern to context through neuromodulation. Achieving analogous levels of robustness and adaptation in neuromorphic circuits through modulatory mechanisms is a largely unexplored path. We present a novel current-mode neuron design that supports robust neuromodulation with minimal model complexity, compatible with standard CMOS technologies. We first introduce a mathematical model of the circuit and provide tools to analyze and tune the neuron behavior; we then demonstrate both theoretically and experimentally the biologically plausible neuromodulation adaptation capabilities of the circuit over a wide range of parameters. All the theoretical predictions were verified in experiments on a low-power 180 nm CMOS implementation of the proposed neuron circuit. Due to the analog underlying feedback structure, the proposed adaptive neuromodulable neuron exhibits a high degree of robustness, flexibility, and scalability across operating ranges of currents and temperatures, making it a perfect candidate for real-world neuromorphic applications.

As neurostimulation devices increasingly incorporate closed-loop functionality, the greater design complexity brings additional requirements for risk management and special considerations to optimise benefit. This manuscript creates a common framework upon which all current and planned neuromodulation-based physiological closed-loop controllers (PCLCs) can be mapped including integration of the Technical Considerations of Medical Devices with Physiologic Closed-Loop Control Technology guidance published in 2023 by the United States Food and Drug Administration (FDA), a classification of feedback (reactive) and feedforward (predictive) biomarkers, and control systems theory. We explain risk management in the context of this framework and illustrate its applications for three exemplary technologies. This manuscript serves as guidance to the emerging field of PCLCs in neuromodulation, mitigating risk through standardized nomenclature and a systematic outline for rigorous device development, testing, and implementation.

Epilepsy is the fourth most common neurological disorder and affects people of all ages worldwide. Deep Brain Stimulation (DBS) has emerged as an alternative treatment option when anti-epileptic drugs or resective surgery cannot lead to satisfactory outcomes. To facilitate the planning of the procedure and for its standardization, it is desirable to develop an algorithm to automatically localize the DBS stimulation target, i.e., Anterior Nucleus of Thalamus (ANT), which is a challenging target to plan. In this work, we perform an extensive comparative study by benchmarking various localization methods for ANT-DBS. Specifically, the methods involved in this study include traditional registration method and deep-learning-based methods including heatmap matching and differentiable spatial to numerical transform (DSNT). Our experimental results show that the deep-learning (DL)-based localization methods that are trained with pseudo labels can achieve a performance that is comparable to the inter-rater and intra-rater variability and that they are orders of magnitude faster than traditional methods.

During the last three decades, many studies have been conducted in the field of treatment with non-invasive methods. In this way, researchers try to use alternative methods including the use of electromagnetic waves in the treatment of diseases. As a result, the therapeutic use of electromagnetic waves in the treatment of neurological diseases has made significant progress. Among the various techniques that have revolutionized the non-invasive treatment of neurological disorders, there is a remarkable technique called Repetitive Transcranial Magnetic Stimulation (rTMS). On the other hand, there is a wide range of neurological conditions (like epilepsy) that are somewhat drug-resistant or can only be controlled with high-risk treatments. In this article, the effect of rTMS on epilepsy is investigated.

Targeted electrical stimulation of the brain perturbs neural networks and modulates their rhythmic activity both at the site of stimulation and at remote brain regions. Understanding, or even predicting, this neuromodulatory effect is crucial for any therapeutic use of brain stimulation. To this end, we analyzed the stimulation responses in 131 stimulation sessions across 66 patients with focal epilepsy recorded through intracranial EEG (iEEG). We considered functional and structural connectivity features as predictors of the response at every iEEG contact. Taking advantage of multiple recordings over days, we also investigated how slow changes in interictal functional connectivity (FC) ahead of the stimulation relate to stimulation responses. The results reveal that, indeed, this long-term variability of FC exhibits strong association with the stimulation-induced increases in delta and theta band power. Furthermore, we show through cross-validation that long-term variability of FC improves prediction of responses above the performance of spatial predictors alone. These findings can enhance the patient-specific design of effective neuromodulatory protocols for therapeutic interventions.

Focal epilepsy is a devastating neurological disorder that affects an overwhelming number of patients worldwide, many of whom prove resistant to medication. The efficacy of current innovative technologies for the treatment of these patients has been stalled by the lack of accurate and effective methods to fuse multimodal neuroimaging data to map anatomical targets driving seizure dynamics. Here we propose a parsimonious model that explains how large-scale anatomical networks and shared genetic constraints shape inter-regional communication in focal epilepsy. In extensive ECoG recordings acquired from a group of patients with medically refractory focal-onset epilepsy, we find that ictal and preictal functional brain network dynamics can be accurately predicted from features of brain anatomy and geometry, patterns of white matter connectivity, and constraints complicit in patterns of gene coexpression, all of which are conserved across healthy adult populations. Moreover, we uncover evidence that markers of non-conserved architecture, potentially driven by idiosyncratic pathology of single subjects, are most prevalent in high frequency ictal dynamics and low frequency preictal dynamics. Finally, we find that ictal dynamics are better predicted by white matter features and more poorly predicted by geometry and genetic constraints than preictal dynamics, suggesting that the functional brain network dynamics manifest in seizures rely on - and may directly propagate along - underlying white matter structure that is largely conserved across humans. Broadly, our work offers insights into the generic architectural principles of the human brain that impact seizure dynamics, and could be extended to further our understanding, models, and predictions of subject-level pathology and response to intervention.

The ability to modulate brain states using targeted stimulation is increasingly being employed to treat neurological disorders and to enhance human performance. Despite the growing interest in brain stimulation as a form of neuromodulation, much remains unknown about the network-level impact of these focal perturbations. To study the system wide impact of regional stimulation, we employ a data-driven computational model of nonlinear brain dynamics to systematically explore the effects of targeted stimulation. Validating predictions from network control theory, we uncover the relationship between regional controllability and the focal versus global impact of stimulation, and we relate these findings to differences in the underlying network architecture. Finally, by mapping brain regions to cognitive systems, we observe that the default mode system imparts large global change despite being highly constrained by structural connectivity. This work forms an important step towards the development of personalized stimulation protocols for medical treatment or performance enhancement.

For decades, focal non-invasive neuromodulation of deep brain regions has not been possible because of the steep depth-focality trade-off of conventional non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) or classical transcranial electric stimulation (tES). Deep brain stimulation has therefore largely relied on invasive approaches in clinical populations, requiring surgery. Transcranial Temporal Interference Stimulation (tTIS) has recently emerged as a promising method to overcome this challenge and allows for the first time focal non-invasive electrical deep brain stimulation. The method, which was first validated through computational modeling and rodent work, has now been successfully translated to humans to target deep brain regions such as the hippocampus or striatum. In this Perspective, we present current evidence for tTIS-based neuromodulation, underlying mechanisms and discuss future developments of this promising technology. More specifically, we highlight key opportunities and challenges for fundamental neuroscience as well as for the design of new interventions in neuropsychiatric disorders. We also discuss the status of understanding and challenges regarding the basic mechanisms of action of tTIS and possible lines of technological innovation to optimize stimulation, in particular in terms of intensity and focality. Overall, we suggest that following the first proof-of-concepts, an important multidisciplinary research effort is now required to further validate the use of tTIS in multiple applications, understand its underlying principles and optimize the technology in the view of a wider scientific and clinical deployment.

The coordinated activity of neural populations underlies myriad brain functions. Manipulating this activity using brain stimulation techniques has great potential for scientific and clinical applications, as it provides a tool to causally influence brain function. The state of the brain affects how neural populations respond to incoming sensory stimuli. Thus, taking into account pre-stimulation neural population activity may be crucial to achieve a desired causal manipulation using stimulation. In this work, we propose Online MicroStimulation Optimization (OMiSO), a brain stimulation framework that leverages brain state information to find stimulation parameters that can drive neural population activity toward specified states. OMiSO includes two key advances: i) it leverages the pre-stimulation brain state to choose optimal stimulation parameters, and ii) it adaptively refines the choice of those parameters by considering newly-observed stimulation responses. We tested OMiSO by applying intracortical electrical microstimulation in a monkey and found that it outperformed competing methods that do not incorporate these advances. Taken together, OMiSO provides greater accuracy in achieving specified activity states, thereby advancing neuromodulation technologies for understanding the brain and for treating brain disorders.

Essential Tremor is the most common neurological movement disorder. This progressive disease causes uncontrollable rhythmic motions -most often affecting the patient's dominant upper extremity- that occur during volitional movement and make it difficult for the patient to perform everyday tasks. Medication may also become ineffective as the disorder progresses. For many patients, deep brain stimulation (DBS) of the thalamus is an effective means of treating this condition when medication fails. In current use, however, clinicians set the patient's stimulator to apply stimulation at all times- whether it is needed or not. This practice leads to excess power use, and more rapid depletion of batteries that require surgical replacement. In the work described here, for the first time, neural sensing of movement (using chronically-implanted cortical electrodes) is used to enable or disable stimulation for tremor. Therapeutic stimulation is delivered only when the patient is actively using their effected limb, thereby reducing the total stimulation applied, and potentially extending the lifetime of surgically-implanted batteries. This work, which involves both implanted and external subsystems, paves the way for the future fully-implanted closed-loop deep brain stimulators.

Epilepsy is a chronic neurological disorder with a significant prevalence. However, there is still no adequate technological support to enable epilepsy detection and continuous outpatient monitoring in everyday life. Hyperdimensional (HD) computing is an interesting alternative for wearable devices, characterized by a much simpler learning process and also lower memory requirements. In this work, we demonstrate a few additional aspects in which HD computing, and the way its models are built and stored, can be used for further understanding, comparing, and creating more advanced machine learning models for epilepsy detection. These possibilities are not feasible with other state-of-the-art models, such as random forests or neural networks. We compare inter-subject similarity of models per different classes (seizure and non-seizure), then study the process of creation of generalized models from personalized ones, and in the end, how to combine personalized and generalized models to create hybrid models. This results in improved epilepsy detection performance. We also tested knowledge transfer between models created on two different datasets. Finally, all those examples could be highly interesting not only from an engineering perspective to create better models for wearables, but also from a neurological perspective to better understand individual epilepsy patterns.

The Epilepsies are a common, chronic neurological disorder affecting more than 50 million individuals across the globe. It is characterized by unprovoked, recurring (similar or different type) seizures which are commonly diagnosed through clinical EEGs. Good-quality, open-access and free EEG data can act as a catalyst for on-going state-of-the-art (SOTA) research works for detection, prediction and management of epilepsy and seizures. They can also aid in improving the quality of life (QOL) of these diseased individuals and contribute research in healthcare multimedia, data analytics and Artificial Intelligence (AI) in personalized medicine. This paper presents widely used, available, open and free EEG datasets available for epilepsy and seizure diagnosis. A brief comparison and discussion of open and private datasets has also been done. Such datasets will help in development and evaluation of automatic computer-aided system in healthcare.

Recently Transformer and Convolution neural network (CNN) based models have shown promising results in EEG signal processing. Transformer models can capture the global dependencies in EEG signals through a self-attention mechanism, while CNN models can capture local features such as sawtooth waves. In this work, we propose an end-to-end neural epilepsy detection model, EENED, that combines CNN and Transformer. Specifically, by introducing the convolution module into the Transformer encoder, EENED can learn the time-dependent relationship of the patient's EEG signal features and notice local EEG abnormal mutations closely related to epilepsy, such as the appearance of spikes and the sprinkling of sharp and slow waves. Our proposed framework combines the ability of Transformer and CNN to capture different scale features of EEG signals and holds promise for improving the accuracy and reliability of epilepsy detection. Our source code will be released soon on GitHub.

Closed-loop neural stimulation provides novel therapies for neurological diseases such as Parkinson's disease (PD), but it is not yet clear whether artificial intelligence (AI) techniques can tailor closed-loop stimulation to individual patients or identify new therapies. Progress requires us to address a number of translational issues, including sample efficiency, training time, and minimizing loop latency such that stimulation may be shaped in response to changing brain activity. We propose temporal basis function models (TBFMs) to address these difficulties, and explore this approach in the context of excitatory optogenetic stimulation. We demonstrate the ability of TBF models to provide a single-trial, spatiotemporal forward prediction of the effect of optogenetic stimulation on local field potentials (LFPs) measured in two non-human primates. We further use simulations to demonstrate the use of TBF models for closed-loop stimulation, driving neural activity towards target patterns. The simplicity of TBF models allow them to be sample efficient, rapid to train (2-4min), and low latency (0.2ms) on desktop CPUs. We demonstrate the model on 40 sessions of previously published excitatory optogenetic stimulation data. For each session, the model required 15-20min of data collection to successfully model the remainder of the session. It achieved a prediction accuracy comparable to a baseline nonlinear dynamical systems model that requires hours to train, and superior accuracy to a linear state-space model. In our simulations, it also successfully allowed a closed-loop stimulator to control a neural circuit. Our approach begins to bridge the translational gap between complex AI-based approaches to modeling dynamical systems and the vision of using such forward prediction models to develop novel, clinically useful closed-loop stimulation protocols.

Neuromodulation, as defined as the use of electrical stimulation by implanted stimulators to treat various neurological conditions, has developed gradually from long experience with electrical stimulation of the nervous system. Indications are still evolving, and the field is advancing at an ever increasing rate.

Epilepsy is a neurological disorder consisting of recurrent seizures, resulting from excessive, uncontrolled electrical activity in the brain. Epilepsy treatment is successful in the majority of the cases; however; still one third of the epilepsy patients are refractory to treatment. Besides the ongoing research on the efficacy of antiepileptic treatments in suppressing seizures (anti-seizure effect), we want to seek for therapies that can lead to plastic, neuromodulatory changes in the epileptic network. Neuropharmacological therapy with levetiracetam (LEV) and vagus nerve stimulation (VNS) are two novel treatments for refractory epilepsy. LEV acts rapidly on seizures in both animal models and humans. In addition, preclinical studies suggest that LEV may have antiepileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression. VNS as well can have an immediate effect on seizures in epilepsy models and patients with, in addition, a cumulative effect after prolonged treatment. Studies in man are hampered by the heterogeneity of patient populations and the difficulty to study therapy-related effects in a systematic way. Therefore, investigation was performed utilizing two rodent models mimicking epilepsy in humans. Genetic absence epilepsy rats from Strasbourg (GAERS) have inborn absence epilepsy and Fast rats have a genetically determined sensitivity for electrical amygdala kindling, which is an excellent model of temporal lobe epilepsy. Our findings support the hypothesis that treatment with LEV and VNS can be considered as neuromodulatory: changes are induced in central nervous system function or organization as a result of influencing and initiating neurophysiological signals.

Optogenetic neuromodulation techniques, which have emerged during the last 15 years, have considerably enhanced our ability to probe the functioning of neural circuits by allowing the excitation and inhibition of genetically-defined neuronal populations using light. Having gained tremendous popularity in the field of fundamental neuroscience, these techniques are now opening new therapeutic avenues. Optogenetic neuromodulation is a method of choice for studying the physiopathology of neurological and neuropsychiatric disorders in a range of animal models, and could accelerate the discovery of new therapeutic strategies. New therapeutic protocols employing optogenetic neuromodulation may also emerge in the near future, offering promising alternative approaches for disorders which lack appropriate treatments, such as pharmacoresistant epilepsy and inherited retinal degeneration.

Kindling is an animal model of epilepsy produced by focal electrical stimulation of the brain. This chapter: describes the kindling phenomenon; considers the validity of kindling as an animal model and proposes a hypothesis as to how kindling might contribute to human epileptogenesis; presents a critical review of current insights into the underlying mechanisms; and emphasizes that, if progress is to be made in understanding the mechanisms, the network of brain structures underlying kindling must be elucidated. Recent investigations directly related to the network issue are considered, namely studies demonstrating that a brainstem structure, the substantia nigra (SN), can regulate the kindled seizure threshold. Thus, either microinjection of a GABA receptor agonist or a GABA transaminase inhibitor into SN, but not into nearby sites, elevates kindled-seizure threshold. Likewise, destruction of SN, but not of adjacent structures, is associated with an increase of kindled-seizure threshold. These treatments suppress not only clonic motor seizures, but also complex partial seizures and afterdischarge at the site of stimulation. These findings demonstrate that the SN can regulate the intrinsic neuronal excitability of forebrain structures. A hypothesis is advanced that generation of a complex partial seizure requires activation of neurons in the SN which in turn feed back through polysynaptic connections to influence neurons at the site of seizure origin. This nigral influence on neurons at the site of seizure origin is either a direct excitation or a disinhibition. Thus, the seizure represents reverberatory activity within a network of brain structures which includes the SN. Other investigators have proposed that the centrencephalic system subserved seizure propagation; the relationship of the hypothesis proposed here to these earlier ideas is discussed.

Sleep and epilepsy are mutually related in a complex, bidirectional manner. However, our understanding of this relationship remains unclear. The literatures of the neurobiological basis of the interactions between sleep and epilepsy indicate that non rapid eye movement sleep and idiopathic generalized epilepsy share the same thalamocortical networks. Most of neurotransmitters and neuromodulators such as adenosine, melatonin, prostaglandin D2, serotonin, and histamine are found to regulate the sleep-wake behavior and also considered to have antiepilepsy effects; antiepileptic drugs, in turn, also have effects on sleep. Furthermore, many drugs that regulate the sleep-wake cycle can also serve as potential antiseizure agents. The nonpharmacological management of epilepsy including ketogenic diet, epilepsy surgery, neurostimulation can also influence sleep. In this paper, we address the issues involved in these phenomena and also discuss the various therapies used to modify them.

Brain stimulation has, for many decades, been considered as a potential solution for the unmet needs of the many people living with drug-resistant epilepsy. Clinically, there are several different approaches in use, including vagus nerve stimulation, deep brain stimulation of the thalamus, and responsive neurostimulation. Across populations of patients, all deliver reductions in seizure load and sudden unexpected death in epilepsy risk, yet do so variably, and the improvements seem incremental rather than transformative. In contrast, within the field of experimental neuroscience, the transformational impact of optogenetic stimulation is evident; by providing a means to control subsets of neurons in isolation, it has revolutionized our ability to dissect out the functional relations within neuronal microcircuits. It is worth asking, therefore, how preclinical optogenetics research could advance clinical practice in epilepsy? Here, we review the state of the clinical field, and the recent progress in preclinical animal research. We report various breakthrough results, including the development of new models of seizure initiation, its use for seizure prediction, and for fast, closed-loop control of pathological brain rhythms, and what these experiments tell us about epileptic pathophysiology. Finally, we consider how these preclinical research advances may be translated into clinical practice.

Deep brain stimulation has demonstrated efficacy in reducing seizure frequency in patients with drug-resistant epilepsy who may otherwise not be candidates for other surgical procedures. Recently, a clinical device that can monitor neural activity in the form of local field potentials around the deep brain stimulator lead implant site has been introduced. While this technology has been clinically adopted in other disorders treated with deep brain stimulation, such as Parkinson's disease, its application in epilepsy remains unclear. Previous research using investigational devices has suggested that specific frequency bands may correlate with clinical response to deep brain stimulation in epilepsy, but features of the clinical device may prevent its use. The authors present their experience with using this technology in epilepsy patients and describe some of its limitations. Ultimately, novel biomarkers will need to be identified to elucidate how neural activity at deep brain stimulation sites may change with clinical response.

Intracranial neuromodulation is an evolving therapy for patients with drug-resistant epilepsy (DRE). Deep brain stimulation (DBS) is now available as a therapy for patients with DRE and focal-onset seizures in select health care systems; however, there remains a substantial need of efficacy data before DBS can be more widely adopted into routine clinical practice. This review and commentary focuses on a particular shifting paradigm: DBS as a therapy for children with generalized-onset seizures.

Deep brain stimulation has been used in increasing frequency to treat refractory epilepsy. Different targets have been tried, and different epileptic syndromes have been addressed in different ways. We describe the current targeting techniques for the structures presently most often implanted, namely the anterior nucleus of the thalamus, the centromedian nucleus of the thalamus, and the hippocampus.

Epilepsy affects approximately 50 million people worldwide, with around 30 % not responding to antiepileptic drugs. Neuromodulation therapies, such as deep brain stimulation (DBS), are increasingly crucial for managing poorly controlled epilepsy. This study conducted a meta-analysis following PRISMA guidelines, systematically searching PubMed, Scopus, and Web of Science databases for studies on DBS in refractory epilepsy patients. Out of an initial 568 papers screened by title and abstract, 49 studies met the inclusion criteria, involving a total of 682 patients. Various DBS interventions were analyzed, targeting regions such as the anterior nucleus of the thalamus, centromedian thalamic nucleus, and hypothalamus, with diverse stimulation parameters, including voltage, frequency, and stimulation type. The analysis revealed that these parameters significantly impacted treatment success, with moderate variability among studies. This meta-analysis underscores the importance of tailored DBS parameters to improve outcomes in patients with drug-resistant epilepsy, highlighting DBS as a promising treatment approach.

We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

Antiepileptic drugs prevent morbidity and death in a large number of patients suffering from epilepsy. However, it is estimated that approximately 30% of epileptic patients will not have adequate seizure control with medication alone. Resection of epileptogenic cortex may be indicated in medically refractory cases with a discrete seizure focus in noneloquent cortex. For patients in whom resection is not an option, deep brain stimulation (DBS) may be an effective means of seizure control. Deep brain stimulation targets for treating seizures primarily include the thalamic nuclei, hippocampus, subthalamic nucleus, and cerebellum. A variety of stimulation parameters have been studied, and more recent advances in electrical stimulation to treat epilepsy include responsive neurostimulation. Data suggest that DBS is effective for treating drug-resistant epilepsy.

A variety of treatment modalities currently exist for epilepsy, a debilitating disorder. With the emergence of drug-resistant epilepsy, however, new options are being explored. Deep brain stimulation is a neuromodulation technique that can prove to be a ground-breaking treatment option for pediatric epilepsy. It employs a neurosurgical method in which electrodes are implanted within the brain that send impulses to control abnormal brain activity. Significant gaps exist in literature, thereby emphasizing the importance of further research in this promising approach.

Neuromodulation has taken a foothold in the landscape of surgical treatment for medically refractory epilepsies and offers additional surgical treatment options for patients who are not candidates for resective/ablative surgery. Approximately one third of patients with epilepsy suffer with medication-refractory epilepsy. A persistent underuse of epilepsy surgery exists. Neuromodulation treatments including deep brain stimulation (DBS) expand the surgical options for patients with epilepsy and provide options for patients who are not candidates for resective surgery. DBS of the bilateral anterior nucleus of the thalamus is an Food and Drug Administration-approved, safe, and efficacious treatment option for patients with refractory focal epilepsy. The purpose of this consensus position statement is to summarize evidence, provide recommendations, and identify indications and populations for future investigation in DBS for epilepsy. The recommendations of the American Society of Functional and Stereotactic Neurosurgeons are based on several randomized and blinded clinical trials with high-quality data to support the use of DBS to the anterior nucleus of the thalamus for the treatment of refractory focal-onset seizures.

DBS has been a possible therapy for epilepsy for more than 30 years, and now it is moving to the point of clinical utility. Animal models have shown efficacy of DBS at several brain regions, although not all animal studies have shown efficacy. Clinically, an array of sites have been explored, including the cerebellum, anterior nucleus of the thalamus, CM nucleus, hippocampus, subthalamic nucleus, brainstem, and corpus callosum; direct stimulation of the cortex has also been explored. Interest in evaluating these sites for treatment of epilepsy has been enhanced by the success of vagus nerve stimulation for epilepsy and DBS for movement disorders. Literature consists of mostly small and uncontrolled studies that are subject to limitations in interpretation. A pivotal large, double-blind controlled trial of anterior nucleus of the thalamus has recently been completed, and it showed efficacy for partial seizures with or without secondary generalization.28 A controlled trial for RNS is underway.57 In addition, pilot studies of hippocampal stimulation 41,43 are expected to lead to more definitive trials of this site.Brain stimulation for epilepsy holds several challenges for the future. Mechanisms of DBS are poorly understood, although investigations are actively being pursued. Little is known about optimal stimulation parameters. DBS has been little examined in cases of intractable generalized epilepsy. Because DBS carries some risk, mainly of hemorrhage and infection, clinicians will need to develop an effective method of identifying the best candidates. DBS is palliative rather than curative, but experience suggests that this relatively new therapy may be of benefit to some people with otherwise untreatable epilepsy.

Deep brain stimulation (DBS) of the thalamic nuclei for the treatment of drug-resistant epilepsy (DRE) has been investigated for decades. In recent years, DBS targeting the anterior nucleus of the thalamus (ANT) was approved by CE and FDA for the treatment of focal-onset DRE in light of the results from the multicentric randomized controlled SANTE trial. However, stereotactic targeting of thalamic nuclei is not straightforward because of the low contrast definition among thalamic nuclei on the current MRI sequences. When the FGATIR sequence is added to the preoperative MRI protocol, the mammillothalamic tract can be identified and used as a visible landmark to directly target ANT. According to the current evidence, the trans-ventricular trajectory allows the placement of stimulating contact into the nucleus more frequently than the trans-cortical trajectory. Another thalamic nucleus whose stimulation for the treatment of generalized DRE is receiving increasing attention is the centromedian nucleus (CM). CM-DBS seems to be particularly efficacious in patients suffering from Lennox-Gastault syndrome (LGS) and the recent monocentric randomized controlled ESTEL trial also described a beneficial "sweet-spot". However, CM targeting is still based on indirect stereotactic coordinates, since acquisition times and post-processing techniques of the actual MRI sequences are not applicable in clinical practice. Moreover, the results of the ESTEL trial await confirmation from similar studies accounting for epileptic syndromes other than LGS. Therefore, novel neuroimaging approaches are advisable to improve the surgical targeting of CM and potentially tailor the stimulation based on the patient's specific epileptic phenotype.

Responsive neurostimulation (RNS) has recently emerged as a safe and effective treatment for some patients with medically refractory focal epilepsy who are not candidates for surgical resection. Responsive neurostimulation involves an implanted neurostimulator and intracranial leads that detect incipient seizures and respond with electrical counterstimulation. Over 1800 patients have been treated with RNS since its FDA approval in 2013. Despite its widespread use, however, RNS presents distinct challenges for clinicians. What types of patients are most well-suited for treatment with RNS? Given the availability of two other neurostimulation modalities, vagus nerve stimulation (VNS) and thalamic deep brain stimulation (DBS), what patient characteristics favor or disfavor RNS? Once RNS candidates are identified, lead placement presents another challenge. Unlike VNS and thalamic DBS, which both involve prespecified electrode locations, RNS involves intracranial strip and/or depth electrodes that can be flexibly configured based on knowledge of the seizure onset zone. The efficacy of RNS may depend on optimal lead configuration, but there are few resources to guide clinicians in formulating lead placement strategies. Here, we address these challenges, first by reviewing clinical trial data supporting the safety and efficacy of RNS. Then, through a series of clinical vignettes from our center, we provide a framework for RNS patient selection. For each clinical scenario, we illustrate typical strategies for RNS lead placement. We outline considerations for choosing among available neurostimulation devices based on their intrinsic features. For example, a unique feature of RNS is that the neurostimulator provides chronic electrocorticography (ECoG), which has powerful diagnostic potential. We highlight emerging applications of chronic ECoG, and we discuss how the limitations of RNS will inform development of next-generation devices.

Epilepsy is a common neurological condition in children. It is usually amenable to drug therapy. However, nearly one-third of patients may be refractory to antiseizure drugs. Poor compliance and nonepileptic events should be ruled out as possible causes of drug-resistant epilepsy (DRE). After failing adequate trials of two appropriate antiseizure drugs, patients with focal DRE or poorly classifiable epilepsy or epileptic encephalopathy with focal electro-clinical features should be worked up for surgical candidacy. A randomized controlled trial provided a class I evidence for epilepsy surgery in pediatric DRE. Pre-surgical screening workup typically includes a high-resolution epilepsy protocol brain magnetic resonance imaging (MRI) and a high-quality in-patient video electroencephalography evaluation. Advanced investigations such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetoencephalography (MEG) may be required in selected cases especially when brain MRI is normal, and further evidence for anatomo-electro-clinical concordance is necessary to refine candidacy for surgery and surgical strategy. Some children may also need functional MRI to map eloquent regions of interest such as motor, sensory, and language functions to avoid unacceptable neurological deficits after surgery. Selected children may need invasive long-term electroencephalographic monitoring using stereotactically implanted intracranial depth electrodes or subdural grids. Surgical options include resective surgeries (lesionectomy, lobectomy, multilobar resections) and disconnective surgeries (corpus callosotomy, etc.) with the potential to obtain seizure freedom. Other surgical procedures, typically considered to be palliative are neuromodulation [deep brain stimulation (DBS), vagal nerve stimulation (VNS), and responsive neural stimulation (RNS)]. DBS and RNS are currently not approved in children. Pediatric DRE should be evaluated early considering the risk of epileptic encephalopathy and negative impact on cognition.

Epilepsy is a chronic neurological disorder frequently requiring lifelong treatment. In 70% of epilepsy patients, seizures are well controlled by antiepileptic medications. About 30% of epilepsy patients remain refractory to medical treatments and may need surgical interventions for better seizure control. Unfortunately and not infrequently, surgical intervention is not feasible due to various reasons such as multiple seizure foci, not resectable focus because of eloquent cortex location, or inability to tolerate surgery due to ongoing concomitant medical conditions. Neurostimulation devices have provided possible seizure control for refractory epilepsy patients who are not candidates for surgical intervention. Among them, vagal nerve stimulation (VNS) has been the oldest, in use since 1997. VNS was followed by responsive nerve stimulation (RNS) after obtaining FDA approval in 2013. Deep brain stimulation (DBS) has not yet met approval in the USA, but has been in clinical practice in Europe since 2010. Neurostimulation devices vary in how they are inserted and their mechanisms of action. VNS has been easily accepted by patients since it is placed extracranially. By contrast, DBS and RNS require invasive procedures for intracranial implantation. As use of these devices will continue to increase in the foreseeable future, we aimed to contribute to the foundation for new research to expand on current knowledge and practice by reviewing the current status of the literature.

Dravet syndrome (DS) is a refractory developmental and epileptic encephalopathy (EE) with a variety of comorbidities, including cognitive impairment, autism-like behavior, speech dysfunction, and ataxia, which can seriously affect the quality of life of patients and impose a great burden on society and their families. Currently, the pharmacological therapy is patient dependent and may work or not. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), responsive neurostimulation (RNS), and chronic subthreshold cortical stimulation (CSCS), have become common adjuvant therapies for neurological diseases, but their efficacy in the treatment of DS is unknown. We searched Web of Science, PubMed, and SpringerLink for all published cases related to the neuromodulation techniques of DS until January 15, 2022. The systematic review was supplemented with relevant articles from the references. The results reported by each study were summarized narratively. The Web of science, PubMed and SpringerLink search yielded 258 items. A total of 16 studies published between 2016 and 2021 met the final inclusion criteria. Overall, 16 articles (109 cases) were included in this study, among which fifteen (107 patients) were involved VNS, and one (2 patients) was involved DBS. After VNS implantation, seizures were reduced to ≥50% in 60 cases (56%), seizure free were found in 8 cases (7.5%). Only two DS patients received DBS treatment, and the initial outcomes of DBS implantation were unsatisfactory. The seizures significantly improved over time for both DBS patients after the addition of antiepileptic drugs. More than half of the DS patients benefited from VNS, and VNS may be effective in the treatment of DS. However, it is important to note that VNS does not guarantee improvement of seizures, and there is a risk of infection and subsequent device failure. Although DBS is a safe and effective strategy for the treatment of refractory epilepsy, the role of DBS in DS needs further study, as the sample size was small. Thus far, there is no strong evidence for the role of DBS in DS.

The study aims to evaluate the efficacy of neuromodulatory strategies for people who have drug-resistant epilepsy (DRE). We searched electronic repositories, including PubMed, Web of Science, Embase, and the Cochrane Library, for randomized controlled trials, their ensuing open-label extension studies, and prospective studies focusing on surgical or neuromodulation interventions for people with DRE. We used seizure frequency reduction as the primary outcome. A single-arm meta-analysis synthesized data across all studies to assess treatment effectiveness at multiple time points. A network meta-analysis evaluated the efficacy of diverse therapies in randomized controlled trials. Grading of Recommendations, Assessment, Development, and Evaluations was applied to evaluate the overall quality of the evidence. Twenty-eight studies representing 2936 individuals underwent 10 treatments were included. Based on the cumulative ranking in the network meta-analysis, the top 3 neuromodulatory options were deep brain stimulation (DBS) with 27% probability, responsive neurostimulation (RNS) with 22.91%, and transcranial direct current stimulation with 24.31%. In the single-arm meta-analysis, in the short-to-medium term, seizure control is more effective with RNS than with invasive vagus nerve stimulation (inVNS), which in turn is slightly more effective than DBS, though the differences are minimal. However, in the long term, inVNS appears to be less effective than both DBS and RNS. Trigeminal nerve stimulation, transcranial magnetic stimulation, and transcranial alternating current stimulation did not demonstrate significant seizure frequency reduction. Regarding long-term efficacy, RNS and DBS outperformed inVNS. While transcranial direct current stimulation and transcutaneous auricular VNS showed promise for treating DRE, further studies are needed to confirm their long-term efficacy.

Neuromodulation is a treatment strategy that is increasingly being utilized in those suffering from drug-resistant epilepsy who are not appropriate for resective surgery. The number of double-blinded RCTs demonstrating the efficacy of neurostimulation in persons with epilepsy is increasing. Although reductions in seizure frequency is common in these trials, obtaining seizure freedom is rare. Invasive neuromodulation procedures (DBS, VNS, and RNS) have been approved as therapeutic measures. However, further investigations are necessary to delineate effective targeting, minimize side effects that are related to chronic implantation and to improve the cost effectiveness of these devices. The RCTs of non-invasive modes of neuromodulation whilst showing much promise (tDCS, eTNS, rTMS), require larger powered studies as well as studies that focus at better targeting techniques. We provide a review of double-blinded randomized clinical trials that have been conducted for neuromodulation in epilepsy.

Various neurostimulation modalities have emerged in the field of epilepsy. Despite the fact that delivery of an electrical current to the hyperexcitable epileptic brain might, at first, seem contradictory, neurostimulation has become an established therapeutic option with a promising efficacy and adverse effects profile. In "responsive" neurostimulation the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or even prevent an upcoming seizure. The design of technology required for responsive stimulation is more challenging compared with devices for open-loop neurostimulation. The achievement of therapeutic success is dependent on adequate sensing and stimulation algorithms and a fast coupling between both. The benefits of delivering current only at the time of an approaching seizure merit further investigation. Current experience with responsive neurostimulation in epilepsy is still limited, but seems promising.

Thalamic neuromodulation can be an effective therapeutic option for select patients with medically refractory epilepsy. However, successful outcome depends on several factors, beginning with appropriate patient and thalamic target selection. Among thalamic targets, the anterior (ANT) and centromedian (CeM) nuclei have the greatest clinical evidence for efficacy. However, the place of thalamic neuromodulation in the treatment armamentarium for intractable seizures is at the tail end of a long list of options. It's relative efficacy, if any, in relation to other treatment modalities however, can be inferred. As we will discuss, considerable work remains to be done in optimal targeting of thalamic nuclei, appropriate to the epilepsy syndrome and seizure type of the individual patient, which may change our current understanding of the place of thalamic neuromodulation on a range of treatment modality efficacies. Currently, it appears that ANT DBS is most efficacious for limbic epilepsies whereas CM, for generalized, multifocal (especially frontotemporal) epilepsies. Based on controlled studies, the efficacy of ANT and CeM DBS is roughly in line with other neuromodulatory therapies (i.e. RNS, VNS) when assessed within the cohort of patients for which the therapy is indicated. Much improvement is needed to render thalamic DBS more efficacious, and use of optimal targeting strategies, especially direct targeting, can positively affect outcomes. Thalamic neuromodulation is still in its infancy; however, clinical advances in this therapy are being realized.

Lennox-Gastaut syndrome (LGS) is a childhood onset developmental and epileptic encephalopathy characterized by multiple seizure types that are often refractory to traditional antiseizure medications. Neuromodulation therapies including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) have emerged as potential treatment options, but their comparative efficacy remains unclear. We conducted a systematic review and meta-analysis of studies reporting outcomes of neuromodulation therapies in patients with LGS. A comprehensive search of electronic databases was performed through July 26, 2024. The primary outcome was the proportion of patients achieving ≥50% seizure reduction. Random-effects models were used to calculate pooled estimates, and meta-regression analyses were performed to identify potential effect modifiers. Fifty-four studies comprising 1350 patients were included in the analysis (VNS: 37 studies, 1242 patients; DBS: 11 studies, 81 patients; RNS: six studies, 27 patients). The overall pooled responder rate was 55.4% (95% confidence interval [CI] = 48.0%-62.8%). DBS showed the highest responder rate (69.7%, 95% CI = 51.3-88.1%), followed by RNS (63.0%, 95% CI = 30.9-95.1%) and VNS (50.6%, 95% CI = 43.0-58.2%). Meta-regression analysis revealed that intervention type was a significant moderator of treatment effect, with VNS showing significantly lower efficacy compared to DBS (p = .0305). In the DBS subgroup, a later onset of epilepsy was a significant positive predictor of response (p = .0051). Twenty studies qualitatively described quality-of-life outcomes, most commonly noting improved alertness and attention, although heterogeneous assessments precluded meta-analysis. Twenty-seven studies reported complications; VNS was linked to stimulation-related side effects, whereas DBS and RNS had higher rates of serious device-related issues. This meta-analysis suggests that all three neuromodulation therapies are effective for seizure reduction in LGS, with DBS and RNS demonstrating potentially superior efficacy compared to VNS. These findings may help guide treatment selection for patients with LGS, although prospective comparative studies are needed.

Epilepsy is a common neurological disease impacting both patients and healthcare systems. Approximately one third of patients have drug-resistant epilepsy (DRE) and are candidates for surgical options. However, only a small percentage undergo surgical treatment due to factors such as patient misconception/fear of surgery, healthcare disparities in epilepsy care, complex presurgical evaluation, primary care knowledge gap, and lack of systemic structures to allow effective coordination between referring physician and surgical epilepsy centers. Resective surgical treatments are superior to medication management for DRE patients in terms of seizure outcomes but may be less palatable to patients. There have been major advancements in minimally invasive surgeries (MIS) and neuromodulation techniques that may allay these concerns. Both epilepsy MIS and neuromodulation have shown promising seizure outcomes while minimizing complications. Minimally invasive methods include Laser Interstitial Thermal Therapy (LITT), RadioFrequency Ablation (RFA), Stereotactic RadioSurgery (SRS). Neuromodulation methods, which are more palliative, include Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), and Responsive Neurostimulation System (RNS). This review will discuss the role of these techniques in varied epilepsy subtypes, their effectiveness in improving seizure control, and adverse outcomes.

Non-invasive brain stimulation (NIBS) methods carry particular appeal as non-pharmacological approaches to inducing or improving sleep. However, intense research efforts to use transcranial magnetic stimulation (TMS) and electrical stimulation (tES) for sleep modulation have not yet delivered evidence-based NIBS treatments in sleep medicine. The main obstacles lie in insufficiently robust stimulation protocols that affect neurophysiological and self-reported sleep parameters, inadequately controlled-and explained-placebo effects, and heterogeneity in patient populations and outcome parameters. Recent technological advances, e.g., transcranial ultrasound stimulation (TUS) and temporal interference stimulation (TIS), make deep brain structures feasible targets. Real-time approaches, e.g., closed-loop auditory stimulation (CLAS), demonstrate efficacious modulation of different sleep oscillations by tuning stimulation to ongoing brain activity. The identification of sleep-regulatory regions and cell types in the cerebral cortex and thalamus provides new specific targets. To turn this neuroscientific progress into therapeutic advancement, conceptual reframing is warranted. Chronic insomnia may not be optimally suited to demonstrate NIBS efficacy due to the mismatch between self-reported symptoms and polysomnographic sleep parameters. More feasible initial approaches could be to (1) modulate specific sleep oscillations to promote specific sleep functions, (2) modify nightmares and traumatic memories with targeted memory reactivation, (3) increase 'wake intensity' in patients with depression to improve daytime fatigue and elevate sleep pressure and (4) disrupt pathological activity in sleep-dependent epilepsies. Effective treatments in these areas of sleep medicine seem in reach but require rigorously designed clinical trials to identify which NIBS strategies bring real benefit in sleep medicine.

目的：系统评价经颅直流电刺激(transcranial Direct Current Stimulation, tDCS)对癫痫发作控制及精神共病(抑郁、焦虑)与认知功能结局的疗效与安全性。方法：检索PubMed、Embase、Web of Science与Cochrane Library自建库至2025年10月31日的人体研究，提取刺激参数与主要/次要结局，并对随机对照试验采用Cochrane随机试验偏倚风险评估工具(Risk of Bias 2.0, RoB 2.0)评价方法学质量。结果：阴极tDCS在药物难治性癫痫(Drug-Resistant Epilepsy, DRE)中可短期降低发作频率并抑制发作间期痫样放电(interictal Epileptiform Discharges, IEDs)，证据主要来自DRE中的局灶性癫痫；严重不良事件罕见；情绪与认知结局证据有限且异质性较大。结论：tDCS可作为药物难治性局灶性癫痫的辅助治疗，但疗效维持、最佳参数与反应预测仍需多中心长期研究验证。

Neuromodulation is an increasingly utilized therapy for the treatment of people with drug-resistant epilepsy. To date, the most common and effective target has been the thalamus, which is known to play a key role in multiple forms of epilepsy. Neuroimaging has facilitated rapid developments in the understanding of functional targets, surgical and programming techniques, and the effects of thalamic stimulation. In this review, the role of neuroimaging in neuromodulation is explored. First, the structural and functional changes of the thalamus in common epilepsy syndromes are discussed as the rationale for neuromodulation of the thalamus. Next, methods for imaging different thalamic nuclei are presented, as well as rationale for the need of direct surgical targeting rather than reliance on traditional stereotactic coordinates. Lastly, we discuss the potential role of neuroimaging in assessing the effects of thalamic stimulation and as a potential biomarker for neuromodulation outcomes.

Lennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), have emerged as important treatment options for patients with LGS who do not respond adequately to antiseizure medications. This review, developed with input from the Pediatric Epilepsy Research Consortium (PERC) LGS Special Interest Group, provides practical guidance for clinicians on the use of these neuromodulation approaches in patients with LGS. We discuss patient selection criteria, expected seizure and non-seizure outcomes, potential complications, and device management considerations for each technique. The review also covers initiation and titration strategies, ongoing care requirements, and emerging data on combining multiple neuromodulation modalities. While all three approaches can reduce seizure frequency in patients with LGS, with commonly reported responder rates ranging from 50 % to 60 %, their impacts on cognition, behavior and quality of life are more variable. Careful patient selection, individualized programming, and long-term follow-up are essential to optimize outcomes with neuromodulation in this challenging patient population. Further research is needed to identify optimal candidates, determine the ideal timing during patients' clinical course to consider neuromodulation, develop standardized outcome measures, and evaluate the comparative effectiveness and cost-effectiveness of different neuromodulation techniques for LGS.

Abstract Background: Surgical treatment of generalized drug-resistant epilepsy (DRE), lacking a clearly resectable epileptogenic focus, presents a formidable clinical challenge. Inadequately treated generalized DRE is associated with neurological deficits, impaired neurodevelopment, poor quality of life, and lifelong educational and occupational difficulties. Over the last half-century, various neurosurgical interventions have been introduced for the management of generalized DRE. These include longstanding and well-established disconnection procedures, which have evolved over time to reduce surgical morbidity, as well as more recent options such as neuromodulation through surgically implanted devices. As technological advances and evidence for their use continue to grow, clinical decision-making has become increasingly nuanced. Summary: This narrative review synthesizes contemporary neurosurgical strategies for the management of generalized DRE, focusing on two principal categories of intervention: disconnection procedures (e.g., corpus callosotomy) and neuromodulation therapies (e.g., vagus nerve stimulation, deep brain stimulation, responsive neurostimulation). We provide an updated summary of their indications, efficacy, and complications, supported by recent clinical data. In addition, we offer an evidence-based clinical framework to assist with patient selection and presurgical counselling in specialized epilepsy centers. The review also addresses emerging technologies and ongoing innovations, including minimally invasive techniques and closed-loop stimulation systems. Key Messages: Neurosurgical intervention is a viable treatment option for patients with generalized DRE who have failed medical therapy, with evidence supporting its role in reducing seizure burden and improving overall quality of life. Disconnection procedures remain highly effective, especially for individuals with frequent drop attacks or developmental and epileptic encephalopathies, though patient selection is critical to minimize neurocognitive risks. Neuromodulation therapies are increasingly used in both pediatric and adult populations, offering less invasive and more adaptable alternatives. As treatment options expand, clinical decision-making has become more complex and must be guided by seizure characteristics, imaging findings, and individualized patient goals.

OBJECTIVES Generalized and multifocal forms of drug-resistant epilepsy are highly prevalent but have limited treatment options. Centromedian nucleus (CMN) thalamic neuromodulation has emerged as an effective treatment for these epilepsies, but head-to-head neuromodulation modality trials do not exist, and optimal stimulation parameters are not established. MATERIALS AND METHODS Using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, we conducted a systematic review by searching PubMed and Embase for peer-reviewed studies of bilateral CMN deep brain stimulation (DBS) or responsive neurostimulation (RNS) for generalized and/or multifocal epilepsy. From studies that met the inclusion criteria, we extracted individual patient data and used a mixed-effects model to compare seizure frequency reduction (SR) of modalities and for DBS, across different stimulation frequencies. RESULTS A total of 25 studies with 192 total patients were included. DBS and RNS yielded comparable SR (76.8% vs 66.7%, respectively, p = 0.1). Within the DBS cohort, high-frequency (>100 Hz) stimulation was more effective for SR by 20.16% (CI: 6.49-33.83) than low-frequency stimulation. Patients with Lennox-Gastaut Syndrome (LGS) had 13.37% lower SR (CI: -26.17 to -0.56) than did those without this diagnosis. Longer follow-up duration (≥18 months) was associated with 12.60% greater SR (CI: 2.53-22.68). CONCLUSIONS For CMN thalamic neuromodulation in patients with multifocal or generalized epilepsy, modality type (RNS vs DBS) may matter less for SR than may underlying diagnosis (LGS vs not LGS), stimulation parameters (high- vs low-frequency), and treatment duration. These findings have implications for the therapeutic mechanism(s) of thalamic neuromodulation and motivate further study of optimal stimulation approaches.

This is a summary of the three commercially available neuromodulation devices for refractory epilepsy, highlighting their use in children. The article offers a high-level review of the proposed mechanisms of vagus nerve stimulation, responsive neurostimulation, and deep brain stimulation, the pivotal trials leading to their approval for use in the United States, as well as their efficacy and associated adverse effects.

Abstract Background: Epilepsy is one of the most prevalent chronic neurological disorders, with approximately 30% of patients not responding to medical treatment. In selected cases, drug-resistant epilepsy can be safely managed with neuromodulation, leading to a significant reduction in disease burden. Summary: Experimental evidence has demonstrated that the primary neuromodulation modalities, vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), can modulate various brain circuits and reduce epileptic activity by decreasing neuronal hypersynchronization through multiple mechanisms at the molecular, cellular, and network levels. However, clear criteria for selecting among devices, determining optimal stimulation targets, and defining effective parameters to improve outcomes remain elusive. Key Messages: Neuromodulation represents a promising treatment strategy for drug-resistant epilepsy. Nevertheless, further research is essential to refine clinical decision-making. In this review, we discuss the evolution of neuromodulation technologies, with a focus on the indications, advantages, disadvantages, and future directions of VNS, DBS, and RNS.

Non-invasive neuromodulation presents as an exciting potential adjunctive therapy for people with drug-resistant epilepsy (DRE). A major advantage of this approach is the absence of the neurocognitive and systemic adverse events commonly associated with anti-seizure medications (ASM), and the significant risks that accompany both resective epilepsy surgery and invasive neuromodulation techniques. The proposed systematic review and meta-analysis will investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), low-intensity focused ultrasound (LI-FUS), transcutaneous vagus nerve stimulation (tVNS), and trigeminal nerve stimulation (TNS) for seizure reduction amongst patients diagnosed with DRE, with comparisons also being made between intervention types where applicable. Both immediate and long-term adverse events will also be discussed to offer greater insight into its use as a safe, viable, and reliable method of seizure control. The study’s secondary aim will be to identify optimal stimulation parameters to better inform future clinical trial protocols and to maximise treatment efficacy in clinical applications. PubMed, OVID Embase, OVID Medline, and Web of Science will be searched for studies investigating the efficacy and safety of non-invasive nerve and brain stimulation techniques for the management of DRE. Two authors will independently screen relevant studies in Covidence, extract data, and assess risks of bias, with discrepancies being resolved by a third reviewer. The primary outcome will be seizure reduction, measured by mean/median change in seizure frequency and responder rate. Secondary outcomes will include the percentage of patients reporting specified adverse events. A meta-analysis will assess the primary outcome. Subgroup analyses will be performed to investigate potential sources of heterogeneity and the optimal protocol settings for each intervention. Sensitivity analyses will also be conducted to evaluate the robustness of the results. This study will analyse all relevant non-invasive brain and nerve stimulation methods using a consistent protocol, uniquely allowing for rigorous comparisons and result-pooling to evaluate the overall efficacy and safety of each stimulation method. Additionally, it will identify optimal stimulation parameters, where possible, to facilitate the use of these methods in future trials and clinical applications. PROSPERO CRD42023446051.

No abstract available

In patients with an unresectable epileptic focus, such as an undefined focus or epileptic focus within functional areas, various neuromodulation therapies, including vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation, have been adopted as alternative treatment modalities. Vagus nerve stimulation, the earliest approved neuromodulation therapy in Japan, may be indicated irrespective of the epilepsy type and offers several advantages, including craniotomy not being required; however, its efficacy remains limited. Among deep brain stimulation targets, the anterior nucleus of the thalamus has the most established efficacy, and anterior nucleus of the thalamus-deep brain stimulation has been covered by the national health insurance system of Japan for the treatment of epilepsy since 2023. It is considered to be particularly effective for seizures originating from the limbic structures. Although it is not approved for insurance coverage in either Japan or the United States, another effective target is the centromedian nucleus of the thalamus, particularly for generalized epilepsies, including Lennox-Gastaut syndrome. While evidence is limited, deep brain stimulation targeting the hippocampus, subthalamic nucleus, pulvinar nucleus, posteromedial hypothalamus, nucleus accumbens, and cerebellum has also been reported. Responsive neurostimulation, though not yet approved in Japan, records electroencephalographic activity via intracranial electrodes and delivers automatic electrical stimulation upon seizure detection. It is useful for patients with an unresectable seizure focus, that is, eloquent cortex involvement or bilateral temporal lobe epilepsy. This review outlines neuromodulation therapies for epilepsy.

Neuromodulation via Responsive Neurostimulation (RNS) or Deep Brain Stimulation (DBS) is an emerging treatment strategy for pediatric drug‐resistant epilepsy (DRE). Knowledge gaps exist in patient selection, surgical technique, and perioperative care. Here, we use an expert survey to clarify practices. Thirty‐two members of the Pediatric Epilepsy Research Consortium were surveyed using REDCap. Respondents were from 17 pediatric epilepsy centers (missing data in one): Four centers implant RNS only while 13 implant both RNS and DBS. Thirteen RNS programs commenced in or before 2020, and 10 of 12 DBS programs began thereafter. The busiest six centers implant 6–10 new RNS devices per year; all DBS programs implant <5 annually. The youngest RNS patient was 3 years old. Most centers (11/12) utilize MP2RAGE and/or FGATIR sequences for planning. Centromedian thalamic nuclei were the unanimous target for Lennox–Gastaut syndrome. Surgeon exposure to neuromodulation occurred mostly in clinical practice (14/17). Clinically significant hemorrhage (n = 2) or infection (n = 3) were rare. Meaningful seizure reduction (>50%) was reported by 81% (13/16) of centers. RNS and DBS are rapidly evolving treatment modalities for safe and effective treatment of pediatric DRE. There is increasing interest in multicenter collaboration to gain knowledge and facilitate dialogue.

Thalamic neuromodulation has emerged as a treatment option for drug-resistant epilepsy (DRE) with widespread and/or undefined epileptogenic networks. While deep brain stimulation (DBS) and responsive neurostimulation (RNS) depth electrodes offer means for electrical stimulation of the thalamus in adult patients with DRE, the application of thalamic neuromodulation in pediatric epilepsy remains limited. To address this gap, the Neuromodulation Expert Collaborative was established within the Pediatric Epilepsy Research Consortium (PERC) Epilepsy Surgery Special Interest Group. In this expert review, existing evidence and recommendations for thalamic neuromodulation modalities using DBS and RNS are summarized, with a focus on the anterior (ANT), centromedian(CMN), and pulvinar nuclei of the thalamus. To-date, only DBS of the ANT is FDA approved for treatment of DRE in adult patients based on the results of the pivotal SANTE (Stimulation of the Anterior Nucleus of Thalamus for Epilepsy) study. Evidence for other thalamic neurmodulation indications and targets is less abundant. Despite the lack of evidence, positive responses to thalamic stimulation in adults with DRE have led to its off-label use in pediatric patients. Although caution is warranted due to differences between pediatric and adult epilepsy, the efficacy and safety of pediatric neuromodulation appear comparable to that in adults. Indeed, CMN stimulation is increasingly accepted for generalized and diffuse onset epilepsies, with recent completion of one randomized trial. There is also growing interest in using pulvinar stimulation for temporal plus and posterior quadrant epilepsies with one ongoing clinical trial in Europe. The future of thalamic neuromodulation holds promise for revolutionizing the treatment landscape of childhood epilepsy. Ongoing research, technological advancements, and collaborative efforts are poised to refine and improve thalamic neuromodulation strategies, ultimately enhancing the quality of life for children with DRE.

No abstract available

Epilepsy is a severe, relapsing, and multifactorial neurological disorder. Studies regarding the accurate diagnosis, prognosis, and in-depth pathogenesis are crucial for the precise and effective treatment of epilepsy. The pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression, protein expression, ion channel activity, energy metabolites, and gut microbiota composition. Satisfactory results are lacking for conventional treatments for epilepsy. Surgical resection of lesions, drug therapy, and non-drug interventions are mainly used in clinical practice to treat pain associated with epilepsy. Non-pharmacological treatments, such as a ketogenic diet, gene therapy for nerve regeneration, and neural regulation, are currently areas of research focus. This review provides a comprehensive overview of the pathogenesis, diagnostic methods, and treatments of epilepsy. It also elaborates on the theoretical basis, treatment modes, and effects of invasive nerve stimulation in neurotherapy, including percutaneous vagus nerve stimulation, deep brain electrical stimulation, repetitive nerve electrical stimulation, in addition to non-invasive transcranial magnetic stimulation and transcranial direct current stimulation. Numerous studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic seizures. Additionally, many new technologies for the diagnosis and treatment of epilepsy are being explored. However, current research is mainly focused on analyzing patients’ clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level, which has led to a lack of consensus regarding the mechanisms related to the disease.

Neuromodulation (neurostimulation) is a relatively new and rapidly growing treatment for refractory epilepsy. Three varieties are approved in the US: vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS). This article reviews thalamic DBS for epilepsy. Among many thalamic sub-nuclei, DBS for epilepsy has been targeted to the anterior nucleus (ANT), centromedian nucleus (CM), dorsomedial nucleus (DM) and pulvinar (PULV). Only ANT is FDA-approved, based upon a controlled clinical trial. Bilateral stimulation of ANT reduced seizures by 40.5% at three months in the controlled phase (p = .038) and 75% by 5 years in the uncontrolled phase. Side effects related to paresthesias, acute hemorrhage, infection, occasional increased seizures, and usually transient effects on mood and memory. Efficacy was best documented for focal onset seizures in temporal or frontal lobe. CM stimulation may be useful for generalized or multifocal seizures and PULV for posterior limbic seizures. Mechanisms of DBS for epilepsy are largely unknown, but animal work points to changes in receptors, channels, neurotransmitters, synapses, network connectivity and neurogenesis. Personalization of therapies, in terms of connectivity of the seizure onset zone to the thalamic sub- nucleus and individual characteristics of the seizures, might lead to improved efficacy. Many questions remain about DBS, including the best candidates for different types of neuromodulation, the best targets, the best stimulation parameters, how to minimize side effects and how to deliver current noninvasively. Despite the questions, neuromodulation provides useful new opportunities to treat people with refractory seizures not responding to medicines and not amenable to resective surgery.

Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug‐resistant epilepsy (DRE). The primary goal of this systematic review and meta‐analysis is to describe recent advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty‐four articles were included in the meta‐analysis (23 for anterior thalamic nucleus [ANT], 8 for centromedian thalamic nucleus [CMT], and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta‐analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.

Drug-resistant epilepsy, characterized by ongoing seizures despite appropriate trials of anti-seizure medications, affects approximately one-third of people with epilepsy. Brain stimulation has recently become available as an alternative treatment option to reduce symptomatic seizures in short and long-term follow-up studies. Several questions remain on how to optimally develop patient-specific treatments and manage therapy over the long term. This review aims to discuss the clinical use and mechanisms of action of Responsive Neural Stimulation and Deep Brain Stimulation in the treatment of epilepsy and highlight recent advances that may both improve outcomes and present new challenges. Finally, a rational approach to device selection is presented based on current mechanistic understanding, clinical evidence, and device features.

Deep brain stimulation of the subthalamic nucleus (STN‐DBS) is a promising palliative option for patients with refractory epilepsy. However, crucial questions remain unanswered: Which patients are the optimal candidates? How, where, and when to stimulate the STN? And what is the mechanism of STN‐DBS action on epilepsy? Thus, we reviewed the clinical evidence on the antiepileptic effects of STN‐DBS and its possible mechanisms on drug‐resistant epilepsy, its safety, and the factors influencing stimulation outcomes. This information may guide clinical decision‐making. In addition, based on the current knowledge on the effect of STN‐DBS on epilepsy, we suggest research that needs to be carried out in the future.

Advances in device technology have created greater flexibility in treating seizures as emergent properties of networks that exist on a local to global continuum. All patients with drug-resistant epilepsy are potential surgical candidates, given that intracranial neuromodulation through deep brain stimulation and responsive neurostimulation can reduce seizures and improve quality of life, even in multifocal and generalized epilepsies. To achieve this goal, indications and strategies for diagnostic epilepsy surgery are evolving. This article describes the state-of-the-art in epilepsy surgery and related changes in how we define indications for diagnostic and therapeutic surgical intervention.

Background Deep brain stimulation (DBS) is an effective treatment for movement disorders and neurological/psychiatric disorders. DBS has been approved for the control of Parkinson disease (PD) and epilepsy. Objectives A systematic review and possible future direction of DBS system studies is performed in the open loop and closed-loop configuration on PD and epilepsy. Methods We searched Google Scholar database for DBS system and development. DBS search results were categorized into clinical device and research system from the open-loop and closed-loop perspectives. Results We performed literature review for DBS on PD and epilepsy in terms of system development by the open loop and closed-loop configuration. This study described development and trends for DBS in terms of electrode, recording, stimulation, and signal processing. The closed-loop DBS system raised a more attention in recent researches. Conclusion We overviewed development and progress of DBS. Our results suggest that the closed-loop DBS is important for PD and epilepsy.

Introduction: Deep brain stimulation is a safe and effective neurointerventional technique for the treatment of movement disorders. Electrical stimulation of subcortical structures may exert a control on seizure generators initiating epileptic activities. The aim of this review is to present the targets of the deep brain stimulation for the treatment of drug-resistant epilepsy. Methods: We performed a structured review of the literature from 1980 to 2018 using Medline and PubMed. Articles assessing the impact of deep brain stimulation on seizure frequency in patients with DRE were selected. Meta-analyses, randomized controlled trials, and observational studies were included. Results: To date, deep brain stimulation of various neural targets has been investigated in animal experiments and humans. This article presents the use of stimulation of the anterior and centromedian nucleus of the thalamus, hippocampus, basal ganglia, cerebellum and hypothalamus. Anterior thalamic stimulation has demonstrated efficacy and there is evidence to recommend it as the target of choice. Conclusion: Deep brain stimulation for seizures may be an option in patients with drug-resistant epilepsy. Anterior thalamic nucleus stimulation could be recommended over other targets.

OBJECTIVE Drug-resistant epilepsy (DRE) presents a therapeutic challenge in children, necessitating the consideration of multiple treatment options. Although deep brain stimulation (DBS) has been studied in adults with DRE, little evidence is available to guide clinicians regarding the application of this potentially valuable tool in children. Here, the authors present the first systematic review aimed at understanding the safety and efficacy of DBS for DRE in pediatric populations, emphasizing patient selection, device placement and programming, and seizure outcomes. METHODS The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendations. Relevant articles were identified from 3 electronic databases (MEDLINE, Embase, and Cochrane CENTRAL) from their inception to November 17, 2017. Inclusion criteria of individual studies were 1) diagnosis of DRE; 2) treatment with DBS; 3) inclusion of at least 1 pediatric patient (age ≤ 18 years); and 4) patient-specific data. Exclusion criteria for the systematic review included 1) missing data for age, DBS target, or seizure freedom; 2) nonhuman subjects; and 3) editorials, abstracts, review articles, and dissertations. RESULTS This review identified 21 studies and 40 unique pediatric patients (ages 4–18 years) who received DBS treatment for epilepsy. There were 18 patients with electrodes placed in the bilateral or unilateral centromedian nucleus of the thalamus (CM) electrodes, 8 patients with bilateral anterior thalamic nucleus (ATN) electrodes, 5 patients with bilateral and unilateral hippocampal electrodes, 3 patients with bilateral subthalamic nucleus (STN) and 1 patient with unilateral STN electrodes, 2 patients with bilateral posteromedial hypothalamus electrodes, 2 patients with unilateral mammillothalamic tract electrodes, and 1 patient with caudal zona incerta electrode placement. Overall, 5 of the 40 (12.5%) patients had an International League Against Epilepsy class I (i.e., seizure-free) outcome, and 34 of the 40 (85%) patients had seizure reduction with DBS stimulation. CONCLUSIONS DBS is an alternative or adjuvant treatment for children with DRE. Prospective registries and future clinical trials are needed to identify the optimal DBS target, although favorable outcomes are reported with both CM and ATN in children. ABBREVIATIONS ATN = anterior thalamic nucleus; CM = centromedian nucleus of the thalamus; DBS = deep brain stimulation; DRE = drug-resistant epilepsy; RNS = responsive neurostimulation; STN = subthalamic nucleus; VNS = vagus nerve stimulation.

No abstract available

Neurostimulation in epilepsy is a long standing established concept, and through experimental and clinical uses, our understanding of neurostimulation and neuromodulation has grown substantially. Noninvasive brain stimulation techniques use electromagnetic principles to noninvasively modulate brain activity in a spatiotemporally targeted manner. This review focused on the two predominant forms of noninvasive neurostimulation: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, and their current applications in the diagnosis and management of epilepsy. A number of small randomized sham-controlled studies suggest that both TMS and transcranial direct current stimulation may have a beneficial effect in decreasing seizure frequency in patients with medically refractory epilepsy, without significant side effects. Small pilot studies also suggest that TMS in combination with EEG may be used to develop quantitative biomarkers of cortical hyperexcitability in patients with epilepsy. Furthermore, TMS is already Food and Drug Administration-cleared for presurgical mapping of eloquent cortex, and preliminary studies suggest that navigated TMS represents a highly valuable clinical supplement for preoperative functional planning. Transcranial magnetic stimulation and transcranial direct current stimulation have shown great potential benefit for patients with epilepsy; however, further large multicenter randomized sham-controlled studies are needed to better optimize stimulation settings and protocols, define mechanisms of action, assess long-term effects, and clearly define roles and determine efficacy.

The efficacy and safety of deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) for epilepsy (SANTE) trial was demonstrated by a randomized trial by Fisher et al. (2010). Based on this trial, the U.S. Food and Drug Administration recently granted approval for DBS therapy for epilepsy; the indication is as follows: "Bilateral stimulation of the anterior nucleus of the thalamus (ANT) for epilepsy is indicated as an adjunctive therapy for reducing the frequency of seizures in individuals 18 years of age or older diagnosed with epilepsy characterized by partial onset seizures with or without secondary generalization that are refractory to three or more antiepileptic medications". This paper reviews the experimental data and the clinical experience using DBS for the treatment of epilepsy. "This article is part of the Supplement issue Neurostimulation for Epilepsy."

Abstract Although electricity has been used in medicine for thousands of years, bioelectronic medicine for treating epilepsy has become increasingly common in recent years. Invasive neurostimulation centers primarily around three approaches: vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS). These approaches differ by target (e.g., cranial nerve, cortex, or thalamus) and stimulation parameters (e.g., triggered stimulation or continuous stimulation). Although typically noncurative, these approaches can dramatically reduce the seizure burden and offer patients new treatment options. There remains much to be understood about optimal targets and individualized stimulation protocols. Objective markers of seizure burden and biomarkers that quickly quantify neural excitability are still needed. In the future, bioelectronic medicine could become a curative approach that remodels neural networks to reduce pathological activity.

Objective Bilateral temporal lobe epilepsy represents a subset of patients with medically intractable epilepsy that is particularly difficult to treat. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of three neuromodulation techniques-Vagus Nerve Stimulation (VNS), Responsive Neurostimulation (RNS), and Deep Brain Stimulation (DBS)-in refractory BTLE. Methods In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a thorough electronic literature search using Ovid MEDLINE, Ovid Embase, and PubMed databases. Data from the selected studies were extracted, analyzed, and a quality assessment was performed. Meta-analysis was performed comparing mean seizure reduction rates in VNS, RNS, and DBS. Results Twenty studies (4 VNS, 7 RNS, 9 DBS) involving 142 BTLE patients were included in the systematic review. Meta-analysis of 12 studies (2 VNS, 5 RNS, 5 DBS) revealed comparable efficacy between VNS (61.69%), RNS (67.51%), and DBS (66.68%), with no statistically significant difference (p = 0.932) between the modalities. All three techniques demonstrated efficacy in seizure reduction. Additionally, complication rates did not significantly differ between VNS, RNS, and DBS. (p = 0.85). Conclusion This study provides a comprehensive assessment of existing data regarding the use of neuromodulation in refractory BTLE. VNS, RNS, and DBS demonstrated comparable efficacy, supporting their consideration in treatment planning. Clinical decision-making should weigh factors such as surgical candidacy, patient preferences, comorbidities, and side effect profiles. Further research, including standardized reporting and head-to-head trials, is vital for optimizing treatment protocols and expanding our understanding of neuromodulation's impact on seizure reduction, quality of life, and cognitive outcomes in patients with BTLE.

Introduction and Objective. Drug-resistant epilepsy (DRE) is a serious therapeutic challenge, as approximately 30% of epileptic patients do not achieve sustained seizure control despite using at least two appropriately selected antiepileptic drugs. Although pharmacotherapy is the basis of treatment, some patients need new solutions. The aim of this study is to present current therapeutic options for DRE, as well as promising drugs being tested in clinical trials. Review Methods. The review article was compiled mainly on the basis of the PubMed database and the ClinicalTrials.gov website. Most of the articles included were published between 2018–2025. Brief description of the state of knowledge. In recent years, new therapeutic approaches have been investigated. Among a variety of treatment strategies studied, add-on therapy, dietary approaches including ketogenic diet (KD) and continuously improved neurostimulation techniques (DBS, VNS, RNS) are interventions of high clinical significance. Add-on therapy involves introducing additional drugs to the treatment regimen in order to reduce the number and severity of seizures, improve quality of life, prolong seizure-free periods and increase safety. Moreover, numerous international clinical trials on drugs and other treatments for DRE are being conducted, the results of which in the near future may possibly become available to a wider group of patients. Summary. Due to drug resistance in the treatment of epilepsy, there is a constant need to search for new, complex therapeutic methods that ensure better control of the disease.

Epilepsy is a complex neurological disorder affecting millions worldwide, with a substantial number of patients facing drug-resistant epilepsy. This comprehensive review explores innovative therapies for epilepsy management, focusing on their principles, clinical evidence, and potential applications. Traditional antiseizure medications (ASMs) form the cornerstone of epilepsy treatment, but their limitations necessitate alternative approaches. The review delves into cutting-edge therapies such as responsive neurostimulation (RNS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), highlighting their mechanisms of action and promising clinical outcomes. Additionally, the potential of gene therapies and optogenetics in epilepsy research is discussed, revealing groundbreaking findings that shed light on seizure mechanisms. Insights into cannabidiol (CBD) and the ketogenic diet as adjunctive therapies further broaden the spectrum of epilepsy management. Challenges in achieving seizure control with traditional therapies, including treatment resistance and individual variability, are addressed. The importance of staying updated with emerging trends in epilepsy management is emphasized, along with the hope for improved therapeutic options. Future research directions, such as combining therapies, AI applications, and non-invasive optogenetics, hold promise for personalized and effective epilepsy treatment. As the field advances, collaboration among researchers of natural and synthetic biochemistry, clinicians from different streams and various forms of medicine, and patients will drive progress toward better seizure control and a higher quality of life for individuals living with epilepsy.

Nearly 1% of the global population suffers from epilepsy. Drug‐resistant epilepsy (DRE) affects one‐third of epileptic patients who are unable to treat their condition with existing drugs. For the treatment of DRE, neuromodulation offers a lot of potential. The background, mechanism, indication, application, efficacy, and safety of each technique are briefly described in this narrative review, with an emphasis on three approved neuromodulation therapies: vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (ANT‐DBS), and closed‐loop responsive neurostimulation (RNS). Neuromodulatory approaches involving direct or induced electrical currents have been developed to lessen seizure frequency and duration in patients with DRE since the notion of electrical stimulation as a therapy for neurologic diseases originated in the early nineteenth century. Although few people have attained total seizure independence for more than 12 months using these treatments, more than half have benefitted from a 50% drop in seizure frequency over time. Although promising outcomes in adults and children with DRE have been achieved, challenges such as heterogeneity among epilepsy types and etiologies, optimization of stimulation parameters, a lack of biomarkers to predict response to neuromodulation therapies, high‐level evidence to aid decision‐making, and direct comparisons between neuromodulatory approaches remain. To solve these existing gaps, authorize new kinds of neuromodulation, and develop personalized closed‐loop treatments, further research is needed. Finally, both invasive and non‐invasive neuromodulation seems to be safe. Implantation‐related adverse events for invasive stimulation primarily include infection and pain at the implant site. Intracranial hemorrhage is a frequent adverse event for DBS and RNS. Other stimulation‐specific side‐effects are mild with non‐invasive stimulation.

The aim of this research is to explore the efficacy and safety of neurostimulation techniques, particularly responsive neurostimulation, in treating medically refractory epilepsy. The study reviews relevant literature, discusses the mechanisms of action, and presents evidence of reduced seizure frequency and improved quality of life in patients receiving neurostimulation. To evaluate invasive Neuromodulation’s efficiency for medically refractory epilepsy, we searched databases like Google Scholar, Medline, and Elsevier using keywords ‘Neuromodulation and epilepsy’. Numerous relevant results emerged. We conducted rapid abstract reviews to identify key articles, cross-referencing for valuable references, ensuring a comprehensive analysis of pertinent research. Neuromodulation techniques, particularly VNS, DBS, and RNS, offer promising therapeutic options for medically refractory epilepsy. Ongoing research and clinical trials are vital for refining these treatments, adapting them for diverse populations, and enhancing outcomes. The potential to improve patients’ quality of life through innovative approaches is encouraging, driving further progress in neuromodulation.

Epilepsy is the most common brain disorder around the world. The main treatments of epilepsy are through drug treatment or epilepsy surgery. However, examples of EEG-based neuromodulation treatments, such as Vagus nerve stimulation (VNS), thalamic deep brain stimulation (DBS), and responsive neuro-stimulation (RNS), are also promising therapeutic methods nowadays. The aim of the paper is to recognize the effectiveness and potential risks of the three techniques. By carrying out randomized multicenter double-blind trials, this research studied the effectiveness of VNS, RNS, and DBS by measuring the median seizure reduction rate, rate of the responder, and proportion of seizure-free patients; the sudden unexpected death in epilepsy (SUDEP) of the treated patients; and the possible side effects that each treatment may cause. This review paper discusses the classification of epilepsy, common treatment methods for epilepsy, previous studies related to the three techniques, and data collected from the randomized multicenter double-blind trials. All in all, the result suggested that for short-term treatment, DBS may be the most effective method, but for long-term treatment, RNS may be more recommended. As the SUDEP rates for all three methods are lower than the SUDEP rate for epilepsy surgery, EEG-based neuromodulation techniques may become the main treatment for epilepsy in the future.

Neurostimulation for epilepsy refers to the application of electricity to affect the central nervous system, with the goal of reducing seizure frequency and severity. We review the available evidence for the use of neurostimulation to treat pediatric epilepsy, including vagus nerve stimulation (VNS), responsive neurostimulation (RNS), deep brain stimulation (DBS), chronic subthreshold cortical stimulation (CSCS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). We consider possible mechanisms of action and safety concerns, and we propose a methodology for selecting between available options. In general, we find neurostimulation is safe and effective, although any high quality evidence applying neurostimulation to pediatrics is lacking. Further research is needed to understand neuromodulatory systems, and to identify biomarkers of response in order to establish optimal stimulation paradigms.

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BACKGROUND Several types of palliative surgery to treat drug resistant epilepsy (DRE) have been reported, but the evidence that is currently available is insufficient to help physicians redirect DRE patients to the most appropriate kind of surgery. METHODS A systematic search in the PubMed and Scopus databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines to compare different clinical features, outcomes and complications of adult patients submitted to callosotomy, vagal nerve stimulation (VNS), multiple subpial transections (MST), deep brain stimulation (DBS) or responsive neurostimulation (RNS). RESULTS After screening 3447 articles, 36 studies were selected, including the data of 1628 patients: 76 were treated with callosotomy, 659 were treated with VNS, 416 were treated with DBS, and 477 were treated with RNS. No studies including patients treated with MST met the inclusion criteria. The global weighted average seizure frequency reduction was 50.23%, while the global responder rate was 52.12%. There were significant differences among the palliative surgical procedures in term of clinical features of patients and epilepsy, seizure frequency reduction and percentage of responders. Complications were differently distributed as well. CONCLUSIONS Our analysis highlights the necessity of prospective studies, possibly randomized controlled trials, to compare different forms of palliative epilepsy surgery. Moreover, by identifying the outcome predictors associated with each technique, the "best responder" may be profiled for each procedure.

BACKGROUND The cognitive impacts of resective surgery for epilepsy have been well-studied. While seizure outcomes for less invasive, neuromodulatory treatments are promising, there is a paucity of data for cognitive outcomes. METHODS Medline, EMBASE, and the Cochrane Library were searched on November 2019. Inclusion criteria were studies reporting cognitive outcomes following chronic (>6 months) vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS) for epilepsy in at least five patients. Studies reporting acute on-off effects of stimulation were also included. Studies were screened, extracted of data, and assessed for bias using the Joanna Briggs Institute Critical Appraisal Tools by two independent reviewers. Prospero ID: CRD42020184432. RESULTS Of 8443 studies screened, 29 studies were included. Nineteen investigated the effects of chronic stimulation (11 VNS, 6 DBS, 2 RNS): 10 (53 %) reported no change compared to preoperative baseline; 8 (42 %) reported some improvement in one or more cognitive domain; 1 (5%) reported decline. Ten investigated the effects of acute stimulation (5 VNS, 5 DBS): 3 (30 %) reported no change; 4 reported improvement (40 %); 3 (30 %) reported decline. Eight (28 %) did not report statistical analysis. CONCLUSIONS Long-term cognitive outcomes are at least stable following VNS, DBS and RNS. Acute effects of stimulation are less clear. However, data are limited by number, size, and quality. More robust evidence is needed to properly assess the cognitive effects of each of these treatments.

Driven by its proven therapeutic efficacy in treating movement disorders and psychiatric conditions, neurostimulation has emerged as a promising intervention for intractable epilepsy. Researchers envision an advanced implantable device capable of long-term neuronal monitoring, high spatio-temporal resolution data processing, and timely responsive neurostimulation upon seizure detection. However, the stringent energy constraints of implantable devices and significant inter-patient variability in neural activity pose substantial challenges and opportunities for biomedical circuits and systems researchers. For seizure detection, various ASIC solutions employing both deterministic and data-driven algorithms have been developed. These solutions leverage a subset of numerous signal features (spanning time and frequency domains) and classifiers (such as SVMs, DNNs, SNNs) to achieve notable success in terms of detection accuracy, latency, and energy efficiency. Implementations vary widely in computational approaches (digital, mixed-signal, analog, spike-based), training strategies (online versus offline), and application targets (patient-specific versus cross-patient). In terms of treatment, recent efforts have focused on the personalization of stimulation waveforms to enhance therapeutic efficacy. This personalization faces complex challenges, including a limited understanding of how stimulation parameters influence neuronal activity, the lack of a comprehensive brain model to capture its intricate electrochemical dynamics, and recording neural signals in the presence of stimulation artifacts. This review provides a comprehensive overview of the field, detailing the foundational principles, recent advancements, and ongoing challenges in enhancing the diagnostic accuracy, treatment efficacy, and energy efficiency of implantable patient-optimized neurostimulators. We also discuss potential future directions, emphasizing the need for standardized performance metrics, advanced computational models, and adaptive stimulation protocols to realize the full potential of this transformative technology.

Temporal interference stimulation (TIS) is a novel non‐invasive neuromodulation technique enabling targeted stimulation of deep brain structures with enhanced focality. By applying multiple high‐frequency (≥ 1 kHz) electric fields with a small frequency difference (Δf), TIS generates a low‐frequency amplitude‐modulated envelope at the interference focus, modulating neural activity while minimizing superficial stimulation. Since its introduction, research has rapidly explored TIS's computational foundations, biophysical mechanisms, experimental validation, and therapeutic potential. This review synthesizes advancements, detailing computational optimization strategies for personalized targeting and dynamical modeling insights into neuronal mechanisms like nonlinear ion channel rectification, which underpin TIS efficacy. Preclinical and human studies validating functional outcomes (e.g., memory, motor) and assessing the safety profile are evaluated, confirming TIS's ability to modulate deep targets like the hippocampus and striatum. TIS is compared with conventional tES and invasive DBS, highlighting its unique advantages (non‐invasive depth access) and limitations (lower focal intensity, modeling complexity). Emerging clinical applications in disorders like Alzheimer's, Parkinson's, epilepsy, and depression are discussed. Future directions focus on refining protocols, enhancing personalization (e.g., multi‐channel, closed‐loop), and establishing long‐term safety/efficacy. This review consolidates multidisciplinary findings to advance TIS translation from experimental concepts toward clinical reality as a potentially transformative neuromodulation tool.

SUMMARY Responsive neurostimulation and deep brain stimulation have emerged as effective intracranial neuromodulation therapies for drug-resistant epilepsy when surgical resection is not an option. However, programming these devices presents unique challenges in epilepsy. Without immediate feedback and a vast programming space, clinicians are often tasked with fine-tuning device settings without clear, mechanistic guidance and limited clinical time. Recent efforts toward individualized programming have shown promise, including the use of nonstandard parameter sets, target-specific stimulation strategies, and patient-tailored adaptations while avoiding unintended interference with critical functions such as emotional regulation. Emerging research in programming is shifting beyond the one-size-fits-all protocols, incorporating closed-loop biomarkers, integrating multimodal data and predictive modeling that hold promise for improving seizure control and reducing adverse effects. This review synthesizes current evidence on standard and individualized programming approaches for deep brain stimulation and responsive neurostimulation in epilepsy, highlighting practical strategies, clinical outcomes, and insights from recent studies. Although emerging tools such as biomarker-guided programming and predictive modeling are gaining interest, the focus of this review is on existing clinical literature shaping programming today.

Non-invasive brain imaging techniques allow understanding the behavior and macro changes in the brain to determine the progress of a disease. However, computational pathology provides a deeper understanding of brain disorders at cellular level, able to consolidate a diagnosis and make the bridge between the medical image and the omics analysis. In traditional histopathology, histology slides are visually inspected, under the microscope, by trained pathologists. This process is time-consuming and labor-intensive; therefore, the emergence of Computational Pathology has triggered great hope to ease this tedious task and make it more robust. This chapter focuses on understanding the state-of-the-art machine learning techniques used to analyze whole slide images within the context of brain disorders. We present a selective set of remarkable machine learning algorithms providing discriminative approaches and quality results on brain disorders. These methodologies are applied to different tasks, such as monitoring mechanisms contributing to disease progression and patient survival rates, analyzing morphological phenotypes for classification and quantitative assessment of disease, improving clinical care, diagnosing tumor specimens, and intraoperative interpretation. Thanks to the recent progress in machine learning algorithms for high-content image processing, computational pathology marks the rise of a new generation of medical discoveries and clinical protocols, including in brain disorders.

Deep Brain Stimulation (DBS) is a highly effective treatment for Parkinson's Disease (PD). Recent research uses reinforcement learning (RL) for DBS, with RL agents modulating the stimulation frequency and amplitude. But, these models rely on biomarkers that are not measurable in patients and are only present in brain-on-chip (BoC) simulations. In this work, we present an RL-based DBS approach that adapts these stimulation parameters according to brain activity measurable in vivo. Using a TD3 based RL agent trained on a model of the basal ganglia region of the brain, we see a greater suppression of biomarkers correlated with PD severity compared to modern clinical DBS implementations. Our agent outperforms the standard clinical approaches in suppressing PD biomarkers while relying on information that can be measured in a real world environment, thereby opening up the possibility of training personalized RL agents specific to individual patient needs.

Electroencephalography (EEG) signals contain rich temporal-spectral structure but are difficult to model due to noise, subject variability, and multi-scale dynamics. Lightweight deep learning models have shown promise, yet many either rely solely on local convolutions or require heavy recurrent modules. This paper presents PaperNet, a compact hybrid architecture that combines temporal convolutions, a channel-wise residual attention module, and a lightweight bidirectional recurrent block which is used for short-window classification. Using the publicly available BEED: Bangalore EEG Epilepsy Dataset, we evaluate PaperNet under a clearly defined subject-independent training protocol and compare it against established and widely used lightweight baselines. The model achieves a macro-F1 of 0.96 on the held-out test set with approximately 0.6M parameters, while maintaining balanced performance across all four classes. An ablation study demonstrates the contribution of temporal convolutions, residual attention, and recurrent aggregation. Channel-wise attention weights further offer insights into electrode relevance. Computational profiling shows that PaperNet remains efficient enough for practical deployment on resource-constrained systems through out the whole process. These results indicate that carefully combining temporal filtering, channel reweighting, and recurrent context modeling can yield strong EEG classification performance without excessive computational cost.

Deep brain stimulation (DBS) has been used in the treatment of motor diseases with remarkable safety and efficacy, which abet the interest of its application in the management of other neurologic and psychiatric disorders such as epilepsy. Experimental data demonstrated that electric current could modulate distinct brain circuits and decrease the neuronal hypersynchronization seen in epileptic activity. The ability to carefully choose the most suitable anatomical target as well as to define the most reasonable stimulation parameters is highly dependable on the comprehension of the underlying mechanisms of action, which remain unclear. This review aimed to explore the relevant clinical data regarding the use of DBS in the treatment of refractory epilepsy.

Deep brain stimulation (DBS) in drug-resistant epilepsy has been applied to several brain targets. However, its exact mechanism of action is not known, and the diversity of targets makes it difficult to know the degree of evidence that supports its use. A review of the literature on DBS for drug-resistant epilepsy was conducted. The efficacy of DBS in drug-resistant epilepsy seems to be mediated by a desynchronisation of neuronal activity at the epileptogenic focus or a modulation of the «circuitopathies» that exist in epilepsy, depending on the target. In DBS multiple cortical and subcortical structures have been used, but class I evidence exists only for DBS of the anterior nucleus of the thalamus. DBS in epilepsy is still under investigation, with class I evidence for DBS of the anterior nucleus of the thalamus. The rest of the targets have yielded variable results that must be confirmed with randomised designs in larger series. Estimulación cerebral profunda en la epilepsia farmacorresistente. Introducción. La estimulación cerebral profunda (ECP) en la epilepsia farmacorresistente se ha aplicado en varias dianas cerebrales. Sin embargo, su mecanismo de acción no se conoce con exactitud, y la diversidad de dianas hace difícil conocer el grado de evidencia que apoya su utilización. Desarrollo. Se realiza una revisión bibliográfica sobre la ECP para la epilepsia farmacorresistente. La eficacia de la ECP en la epilepsia farmacorresistente parece mediada por una desincronización de la actividad neuronal en el foco epileptógeno o una modulación de las circuitopatías que existen en la epilepsia, dependiendo de la diana. En la ECP se han utilizado múltiples estructuras corticales y subcorticales, pero solamente la ECP del núcleo anterior del tálamo tiene una evidencia de clase I. Conclusiones. La ECP en la epilepsia es aún objeto de investigación, con evidencia de clase I en la ECP del núcleo anterior del tálamo. El resto de las dianas ha arrojado resultados variables que deben confirmarse con diseños aleatorizados en series de mayor tamaño.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus is an FDA-approved therapy for drug-resistant focal epilepsy. Recent advances in device technology, thalamic stereotactic-EEG, and chronic sensing have deepened our understanding of corticothalamic networks in epilepsy and identified promising biomarkers to guide and personalize DBS. In this review, we examine electrophysiological, imaging, and clinical biomarkers relevant to epilepsy DBS, with a focus on their potential to support seizure detection, target engagement, network excitability tracking, and seizure risk forecasting. We highlight emerging insights from thalamic sEEG, including both passive recordings and active stimulation protocols, which enable mapping and modulation of large-scale brain networks. The capabilities of clinical sensing-enabled DBS systems are reviewed. As device functionality and biomarker discovery evolve, concerted translational efforts are needed to realize a new paradigm of personalized DBS in epilepsy.

Brain stimulation is increasingly used in epilepsy patients with insufficient therapeutic response to pharmacological treatment. Whereas vagus nerve stimulation with implanted devices has been used in large and heterogeneous patient groups, new devices also enable targeted brain stimulation at the site of seizure generation (responsive neurostimulation) or at network hubs (thalamic stimulation). Both responsive neurostimulation systems targeting the epileptic focus and the latest vagus nerve stimulators are intended to stimulate during the ictal phase to disrupt clinical seizure manifestation of reduce seizure severity. Furthermore, transcutaneous stimulation approaches are now available, although their efficacy remains uncertain. This review explains the concepts underlying brain stimulation, provides an overview of efficacy and tolerability data and discusses the rational use of the growing spectrum of neuromodulatory strategies available.

Cognitive dysfunction is one of the common comorbidities of epilepsy. More than 60 % of epilepsy patients may experience impairment in learning, memory, attention, and executive control. At present, it can only control the symptoms of seizures, and there is no specific treatment for cognitive impairment. Deep brain stimulation (DBS) has been used to treat intractable epilepsy, with proven safety. Recently data suggests that DBS can not only improve the seizure control, but also improved cognitive function. This review summarizes the effects of DBS on cognitive impairment in epilepsy, including the current status and application of DBS, the influence of different DBS targets on brain of DBS on cognitive impairment in epilepsy, the possible mechanisms of DBS on cognitive impairment and its future prospects. It provides a theoretical basis for its further clinical application in epilepsy patients with cognitive dysfunction.

To review the therapeutic effects of deep brain stimulation of the anterior nuclei of the thalamus (ANT-DBS) and the predictors of its effectiveness, safety, and adverse effects. A comprehensive search of the medical literature (PubMed) was conducted to identify relevant articles investigating ANT-DBS therapy for epilepsy. Out of 332 references, 77 focused on focal epilepsies were reviewed. The DBS effect is probably due to decreased synchronization of epileptic activity in the cortex. The potential mechanisms from cellular to brain network levels are presented. The ANT might participate actively in the network elaborating focal seizures. The effects of ANT-DBS differed in various studies; ANT-DBS was linked with a 41% seizure frequency reduction at 1 year, 69% at 5 years, and 75% at 7 years. The most frequently reported adverse effects, depression and memory impairment, were considered non-serious in the long-term follow-up view. ANT-DBS also has been used in a few cases to treat status epilepticus. We reviewed the clinical literature and identified several factors that may predict seizure outcome following DBS therapy. More large-scale trials are required since there is a need to explore stimulation settings, apply patient-tailored therapy, and identify the presurgical predictors of patient response. A critical review of the published literature on ANT-DBS in focal epilepsy is presented. ANT-DBS mechanisms are not fully understood; possible explanations are provided. Biomarkers of ANT-DBS effectiveness may lead to patient-tailored therapy.

Three neuromodulation therapies have been appropriately tested and approved in refractory focal epilepsies: vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS), and closed-loop responsive neurostimulation of the epileptogenic zone or zones. These therapies are primarily palliative. Only a few individuals have achieved complete freedom from seizures for more than 12 months with these therapies, whereas more than half have benefited from long-term reduction in seizure frequency of more than 50%. Implantation-related adverse events primarily include infection and pain at the implant site. Intracranial haemorrhage is a frequent adverse event for ANT-DBS and responsive neurostimulation. Other stimulation-specific side-effects are observed with VNS and ANT-DBS. Biomarkers to predict response to neuromodulation therapies are not available, and high-level evidence to aid decision making about when and for whom these therapies should be preferred over other antiepileptic treatments is scant. Future studies are thus needed to address these shortfalls in knowledge, approve other forms of neuromodulation, and develop personalised closed-loop therapies with embedded machine learning. Until then, neuromodulation could be considered for individuals with intractable seizures, ideally after the possibility of curative surgical treatment has been carefully assessed and ruled out or judged less appropriate.