Comparative Efficacy of Interventions for Drug-Resistant Epilepsy: A Network Meta-analysis

Comparative Efficacy of Interventions for Drug-Resistant Epilepsy: A Network Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Comparative Efficacy of Interventions for Drug-Resistant Epilepsy: A Network Meta-analysis Parnian Eslahi, Maryam moghbel baerz, Mehrdad Roozbeh, Shahab Lotfinia This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8515031/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Drug-resistant epilepsy remains difficult to manage when medications and surgical resection are ineffective or unsuitable. Several neurostimulation approaches are now used as alternative treatments, yet their comparative effectiveness has not been clearly established. Methods A systematic search of PubMed، Web of Science، and Scopus identified 435 studies, of which 16 randomized or quasi-randomized controlled trials fulfilled eligibility criteria for inclusion in a network meta-analysis. The primary outcome was the proportion of participants achieving at least a 50 percent reduction in seizure frequency. A random-effects network meta-analysis integrated direct and indirect evidence, with assessment of heterogeneity, global and local inconsistency, and potential small-study effects. Study quality was evaluated using the Newcastle–Ottawa Scale. Results The network showed high coherence with minimal inconsistency. Noninvasive methods particularly repetitive transcranial magnetic stimulation، transcranial direct current stimulation، and external trigeminal nerve stimulation produced the strongest seizure-reduction effects. Deep brain stimulation and vagus nerve stimulation offered moderate but consistent benefits, while responsive neurostimulation showed weaker short-term efficacy within the limited randomized evidence. Precision for several modalities remained constrained by the small number of eligible trials. Conclusion This analysis provides an integrated comparison of neurostimulation approaches for drug-resistant epilepsy and highlights the promising therapeutic potential of several noninvasive modalities. Larger randomized studies with standardized stimulation parameters, extended follow-up, and mechanistic biomarkers are needed to refine treatment selection and optimize long-term clinical outcomes. drug-resistant epilepsy neurostimulation therapies deep brain stimulation vagus nerve stimulation responsive neurostimulation repetitive transcranial magnetic stimulation transcranial direct current stimulation transcranial alternating current stimulation external trigeminal nerve stimulation network meta-analysis seizure reduction Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Epilepsy affects approximately 50 million individuals worldwide, representing about 1% of the global population. According to the International League Against Epilepsy (ILAE), drug-resistant epilepsy (DRE) is defined as the failure to achieve sustained seizure freedom after adequate trials of at least two appropriately chosen and tolerated anti-seizure medications (ASMs)( 1 ). The prevalence of DRE ranges from 13.7% in community-based studies to 36.3% in clinic-based cohorts ( 2 ). DRE is associated with increased risk of premature mortality due to Sudden Unexpected Death in Epilepsy (SUDEP)( 3 ). Patients with DRE account for the major burden of epilepsy ( 4 ) because they experience high rates of medical comorbidities ( 5 , 6 ), psychological dysfunction ( 7 ), social stigma ( 8 ), impaired quality of life, and elevated mortality ( 9 ), leading to a reduced life expectancy ( 10 ). Although diagnostic procedures and therapeutic interventions including medical, surgical, and neuromodulation treatments carry inherent risks ( 11 – 13 ), these risks are generally outweighed by the consequences of uncontrolled seizures ( 3 ). Despite the substantial burden associated with DRE, evidence directly comparing anti-seizure medications remains limited. Evidence from head-to-head comparative trials of ASMs in DRE remains limited. Most available data are extrapolated from monotherapy studies aimed at demonstrating non-inferiority. The SANAD and SANAD II pragmatic trials compared first-line treatments for focal and generalized epilepsies but were not double-blind ( 14 , 15 ). Only one randomized, double-blind study has directly compared adjunctive therapies in DRE, showing that pregabalin was non-inferior to levetiracetam for ≥ 50% seizure reduction, with comparable tolerability. No significant differences were found in secondary outcomes ( 16 ). For patients who do not achieve adequate seizure control with pharmacological treatments, several alternative therapeutic modalities are available, including surgical and neuromodulatory approaches. Multiple treatment options exist for patients with persistent seizures, including surgical, neuromodulatory, and non-invasive approaches. Resective procedures such as temporal lobectomy, selective amygdalohippocampectomy, extratemporal resections, and hemispherectomy can be curative, whereas palliative disconnective surgeries (corpus callosotomy, multiple subpial transections, and hemispherotomy) aim to reduce seizure spread ( 17 , 18 ). Deep brain stimulation (DBS) has shown long-term seizure reductions of up to 75%, independent of prior VNS or surgery ( 19 ). Responsive neurostimulation (RNS), approved in 2014, delivers targeted stimulation upon detection of epileptiform activity and has demonstrated a median 75% seizure reduction with a 73% responder rate in extended follow-up studies ( 20 ). For patients who are not candidates for resective surgery, vagus nerve stimulation (VNS) provides a less invasive option, yielding responder rates above 50% but relatively low seizure-free rates (< 10% ( 21 – 23 ); it is generally well tolerated and may have mood-enhancing effects ( 24 ). In addition to invasive neuromodulation strategies, non-invasive brain stimulation techniques have also been explored. Non-invasive brain stimulation (NIBS) techniques including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) modulate cortical excitability and have shown variable antiseizure effects in open-label studies ( 25 – 28 ). While generally safe and well tolerated, the evidence remains insufficient to confirm their efficacy, underscoring the need for further research ( 29 ). Given the limited head-to-head evidence and the diverse therapeutic landscape, network meta-analysis (NMA) provides a robust framework for synthesizing direct and indirect comparisons across multiple interventions. Therefore, this study aimed to compare the efficacy of available treatment modalities for DRE using network meta-analysis to identify the most effective options and guide clinical decision-making. 2. Method We conducted this network meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ( 30 ). As this study is based exclusively on previously published data, it did not involve any new research involving human participants. The protocol for this network meta-analysis was prospectively registered on the Open Science Framework (OSF; Registration DOI: 10.17605/OSF.IO/SB3WN ). The flow diagram of the study demonstrated in Fig. 1 . 2.1. Search strategy We systematically searched PubMed, Web of Science, and Scopus from inception to November 2025. The search was restricted to English-language publications. A comprehensive search strategy was developed using controlled vocabulary and free-text terms related to drug-resistant epilepsy and therapeutic interventions. The following key terms and their variants were used: (“drug-resistant epilepsy”, “refractory epilepsy”, “intractable epilepsy”, “treatment-resistant epilepsy”, “pharmacoresistant epilepsy”), combined with terms for interventions including anti-seizure medications (e.g., levetiracetam, pregabalin, lamotrigine, carbamazepine, valproate, topiramate, lacosamide, perampanel), epilepsy surgery (temporal lobectomy, selective amygdalohippocampectomy, extratemporal resection, lesionectomy, corpus callosotomy, multiple subpial transections, hemispherotomy), neuromodulation (vagus nerve stimulation [VNS], deep brain stimulation [DBS], responsive neurostimulation [RNS]), non-invasive brain stimulation (rTMS, tDCS), and dietary therapies (ketogenic diet, modified Atkins diet). 2.2. Eligibility Criteria We included randomized, double-blind, placebo-controlled, add-on clinical trials that evaluated the efficacy and safety of therapeutic interventions for patients with DRE. High-quality clinical studies published in English were eligible, including randomized controlled trials (RCTs) and cohort studies with Newcastle–Ottawa Scale (NOS) scores ≥ 5 ( 31 ). Eligible RCTs compared an intervention against placebo, standard care, or another active intervention and included only adult populations. Studies were required to report seizure frequency or responder-rate outcomes. 2.3. Study selection We conducted an extensive literature search to identify studies that met the objectives of this review. During the screening process, two independent reviewers performed an initial assessment of titles and abstracts to determine relevance. Full texts of potentially eligible studies were then evaluated to confirm inclusion. Any disagreements between reviewers were resolved through discussion and, when necessary, consultation with a third researcher to reach consensus. We excluded studies that met any of the following conditions: review articles, conference abstracts, editorials, or other non-original reports; studies that did not report seizure frequency or responder-rate outcomes; trials in which ASMs were not stable before enrollment or throughout the treatment period; studies lacking a placebo or appropriate control group; and cohort studies, as well as randomized controlled trials judged to be of low quality based on the Cochrane Risk of Bias assessment. 2.4. Outcome measures The primary outcome was the proportion of patients achieving a ≥ 50% reduction in seizure frequency from baseline (responder rate), which served as the main quantitative measure for the network meta-analysis. For each eligible study, we extracted the following data: the number of participants in the active treatment group and the corresponding number of responders, as well as the number of participants in the control group (placebo or comparator) and their respective responder counts. 2.5. Statistical Analysis Statistical analyses were performed in R v4.5.2 using the netmeta package. A frequentist random-effects network meta-analysis was used to integrate direct and indirect comparisons across interventions. Effect sizes were calculated as odds ratios (ORs) with 95% confidence intervals (CIs), and sham served as the common reference comparator because all included studies were sham-controlled. Between-study heterogeneity was assessed using τ² and I² statistics. In addition to conventional CIs, 95% prediction intervals (PIs) were computed to estimate the expected range of effect sizes in future studies, accounting for heterogeneity. Treatment ranking was performed using P-scores, reflecting the probability that each intervention is among the most effective options in the network. Network coherence was evaluated using both global (design-by-treatment interaction) and local (node-splitting) inconsistency tests. Small-study effects and potential publication bias were examined using comparison-adjusted funnel plots and Egger’s regression test. No meaningful inconsistency or publication bias was detected. 3. Results 3.1. Study Characteristics Sixteen randomized controlled trials evaluating eight neuromodulatory interventions were included in the network meta-analysis. All studies incorporated both an active intervention arm and a sham control, producing a fully connected network. Sample sizes ranged from small, exploratory trials (e.g., ENTS, tACS, RNS) to larger studies examining tDCS, VNS, and DBS. Assessment of study quality using the Newcastle–Ottawa Scale (NOS) showed that all included trials met acceptable methodological standards, with scores ranging from 6 to 8. Most studies scored 7 or 8, indicating generally moderate to high quality, and no study fell below the predefined inclusion threshold. Table 1 summarizes the characteristics of included studies and treatment arms. Table 1 Characteristics of Included Studies and Treatment Arms Study Active Intervention Number of Participants (Active) Responders (Active) Control Intervention Number of Participants (Control) Responders (Control) NOS Scoring Cukiert 2017 DBS 8 7 sham 8 1 6 Herrman 2019 DBS 8 4 sham 10 0 6 SANTE 2010 DBS 54 29 sham 55 25 7 Pivotal 2011 RNS 97 28 sham 90 24 8 Rezakhani 2022 tDCS 10 10 sham 10 0 8 Zoghi 2016 tDCS 16 8 sham 7 1 8 SanJuan 2017 tDCS 8 5 sham 8 2 7 Assenza 2016 tDCS 2 2 sham 2 0 8 Tekturk 2016 tDCS 12 10 sham 12 2 7 Yang 2019 tDCS 25 17 sham 21 5 7 Yang 2023 VNS 100 45 sham 50 8 8 Rong 2015 VNS 98 38 sham 46 14 8 SanJuan 2022 tACS 9 3 sham 7 1 8 Sun 2012 rTMS 31 26 sham 29 5 7 Ashour 2019 rTMS 16 14 sham 14 7 7 Gil-Lopez 2019 ENTS 17 10 sham 15 0 7 Note. All trials include sham as the reference comparator. Abbreviations: DBS, deep brain stimulation; RNS, responsive neurostimulation; tDCS, transcranial direct current stimulation; VNS, vagus nerve stimulation; tACS, transcranial alternating current stimulation; rTMS, repetitive transcranial magnetic stimulation; ENTS, external trigeminal nerve stimulation. 3.2. Network Geometry The network consisted of eight active interventions, each compared directly with sham, forming a star-shaped structure without disconnected components. The highest number of comparisons was available for tDCS and DBS (Fig. 2 ). 3.3. Network Meta-analysis Random-effects network estimates indicated substantial variability across treatments. ENTS demonstrated the largest pooled effect relative to sham, followed by rTMS and tDCS. DBS produced a moderate treatment effect, whereas VNS, tACS, and RNS showed smaller or uncertain effects. Numerical results are summarized in Table 2/Fig. 3 . Table 2. Network Meta-analysis ORs (Random-Effects Model) vs Sham Treatment OR 95% CI Lower 95% CI Upper p-value ENTS 43.40 1.49 1267.16 .028 rTMS 14.46 2.95 70.73 .001 tDCS 11.83 3.69 37.91 <.001 DBS 4.16 0.99 17.43 .051 tACS 3.00 0.15 60.04 .47 VNS 2.46 0.69 8.74 .16 RNS 1.12 0.20 6.28 .90 sham Reference — — — Abbreviations: DBS, deep brain stimulation; RNS, responsive neurostimulation; tDCS, transcranial direct current stimulation; VNS, vagus nerve stimulation; tACS, transcranial alternating current stimulation; rTMS, repetitive transcranial magnetic stimulation; ENTS, external trigeminal nerve stimulation. 3.4 Treatment Ranking (P-scores) P-score analysis supported the magnitude ordering of treatments. ENTS, rTMS, and tDCS ranked highest. Table 3 presents the ranking values; Fig 4 displays the barplot. Table 3. P-score Ranking of Neuromodulation Treatments Rank Treatment P-score 1 ENTS 0.879 2 rTMS 0.785 3 tDCS 0.753 4 DBS 0.500 5 tACS 0.422 6 VNS 0.367 7 RNS 0.179 8 sham 0.116 Abbreviations: DBS, deep brain stimulation; RNS, responsive neurostimulation; tDCS, transcranial direct current stimulation; VNS, vagus nerve stimulation; tACS, transcranial alternating current stimulation; rTMS, repetitive transcranial magnetic stimulation; ENTS, external trigeminal nerve stimulation. 3.5 Prediction Intervals Prediction intervals (PIs) quantified expected treatment effects in future trials. rTMS and tDCS retained favorable effects even after accounting for heterogeneity, whereas PIs for DBS, RNS, VNS, and tACS crossed unity. ENTS displayed a wide PI reflecting imprecision. Table 4 provides the complete PI results. Table 4. Network ORs with 95% Prediction Intervals (Random-Effects Model) Treatment OR PI Lower PI Upper ENTS 43.40 0.582 3238.38 rTMS 14.46 1.068 195.73 tDCS 11.83 1.200 116.65 DBS 4.16 0.347 49.84 tACS 3.00 0.059 151.68 VNS 2.46 0.232 26.06 RNS 1.12 0.073 16.98 Abbreviations: DBS, deep brain stimulation; RNS, responsive neurostimulation; tDCS, transcranial direct current stimulation; VNS, vagus nerve stimulation; tACS, transcranial alternating current stimulation; rTMS, repetitive transcranial magnetic stimulation; ENTS, external trigeminal nerve stimulation. 3.6 Assessment of Consistency and Heterogeneity Global and local inconsistency testing showed no evidence of disagreement between direct and indirect estimates. The total heterogeneity was moderate (τ² = 0.67; I² = 48.6%). No design-level or comparison-level inconsistencies were detected (Fig 5). 3.7 Small-Study Effects Egger's regression test indicated no significant small-study effects (p = .955). Visual inspection of the comparison-adjusted funnel plot confirmed the absence of clear asymmetry. 4. Discussion This network meta-analysis synthesized evidence from 16 randomized and quasi-randomized clinical trials evaluating multiple neurostimulation modalities for DRE. By integrating both direct and indirect comparisons across diverse interventions, the analysis provides a comprehensive comparative assessment of their relative therapeutic efficacy. The results demonstrate clinically meaningful differences among modalities, with several techniques showing substantially higher responder rates compared with others. Consistency assessments supported the robustness of the network. The global test for inconsistency revealed no significant disagreement between direct and indirect evidence, and design-by-treatment decomposition indicated that the small amount of heterogeneity observed was driven primarily by DBS sham comparisons without compromising overall network stability. Local inconsistency analysis showed no problematic loops, and the consistency model remained appropriate. Furthermore, evaluation of publication bias using comparison-adjusted funnel plots and Egger's regression revealed no evidence of small-study effects. Although the number of trials for certain modalities (particularly ENTS and tACS) was limited, the absence of funnel plot asymmetry increases confidence in the reliability of the findings. Across the network, ENTS, rTMS, and tDCS ranked as the most effective modalities, with the highest P-scores, suggesting they consistently outperformed other treatments in achieving responder status. The large estimated effect of ENTS should be interpreted with caution, as its confidence interval was wide and prediction interval substantially broader, reflecting imprecision and the limited sample contributing to that comparison. Nonetheless, the observed magnitude suggests potential benefit that warrants confirmation through larger controlled trials. ENTS targets the supraorbital branches of the ophthalmic division of the trigeminal nerve on both sides of the forehead. Sensory input from these fibers is relayed to the trigeminal sensory nuclei in the brainstem, which project upward through the trigeminal lemniscus to the ventral posteromedial nucleus of the thalamus and subsequently to somatosensory cortical regions (32, 33). Beyond these ascending pathways, trigeminal nuclei have strong functional interactions with brainstem modulatory structures, particularly the locus coeruleus. This noradrenergic nucleus sends widespread projections to limbic and cortical areas including the dorsal and ventral hippocampus and is thought to play a key role in how ENTS influences broader neural networks. Modulation of these thalamocortical and noradrenergic circuits has been proposed as a central mechanism through which ENTS may exert antiseizure effects (32, 34). This network-level modulation may help dampen pathological synchronization and enhance inhibitory control within seizure-prone circuits, offering a plausible explanation for its observed therapeutic signal in DRE. However, the scarcity of trials and heterogeneity of protocols likely contributed to the variability seen in treatment effects. rTMS and tDCS showed more stable and precise estimates, with both demonstrating clear superiority over sham stimulation. The robustness of their effects, supported by moderate prediction intervals, suggests that these techniques may be promising candidates for broader implementation or further clinical evaluation. rTMS and tDCS influence cortical excitability through complementary neurophysiological mechanisms. rTMS induces transient electric fields powerful enough to elicit action potentials and produce frequency-dependent after-effects, with high-frequency protocols generally enhancing excitability and low-frequency stimulation exerting inhibitory influences. These modulatory effects have been linked to LTP/LTD-like synaptic plasticity through changes in glutamatergic transmission, NMDA receptor activation, and GABAergic inhibition (35, 36). In contrast, tDCS applies weak, steady electrical currents that shift resting membrane potentials toward depolarization or hyperpolarization without directly triggering neuronal firing. Prolonged stimulation can induce sustained neuroplastic changes mediated by voltage-gated ion channels and downstream mechanisms that resemble early stages of synaptic potentiation or depression (37, 38). Both techniques also modulate distributed cortical–subcortical networks rather than isolated cortical sites, engaging neuromodulatory systems and altering task-dependent neural processing in behaviorally relevant circuits (39). In drug-resistant epilepsy, these neuromodulatory effects can reduce cortical hyperexcitability and disrupt pathological synchronization within epileptogenic networks, thereby lowering seizure propensity. By shifting the excitability balance toward more stable and less synchronized cortical states, rTMS and tDCS may attenuate abnormal network dynamics that underlie refractory seizures. DBS and VNS yielded moderate benefits relative to sham, consistent with previous literature demonstrating their long-term efficacy in reducing seizure burden. However, their relative position within the network placed them below the noninvasive cortical stimulation modalities. This pattern may reflect differences in sample characteristics, stimulation parameters, or methodological heterogeneity across the included studies. VNS modulates seizure activity through activation of the vagus afferent network, beginning with projections from the cervical vagus nerve to the nucleus tractus solitarius and subsequently to key brainstem neuromodulatory centers, including the locus coeruleus and dorsal raphe nucleus (40). These ascending pathways exert widespread effects on thalamic and cortical regions, promoting desynchronization of epileptiform activity (41, 42) and altering thalamocortical dynamics that are linked to treatment responsiveness (43, 44). DBS, in contrast, acts by directly modulating subcortical nodes within epileptogenic networks. Stimulation of the anterior nucleus of the thalamus (ANT) influences limbic–hippocampal circuitry involved in focal and secondarily generalized seizures (45, 46), with evidence suggesting reduced pathological connectivity and network hyperexcitability following stimulation (47, 48). Through these complementary mechanisms ascending neuromodulatory modulation in VNS and direct thalamic network regulation in DBS both approaches help decrease synchronization within epileptogenic circuits and improve seizure control in drug-resistant epilepsy. RNS ranked lower within the network, likely due to the small number of trials available for pooling under the sham-controlled design and substantial heterogeneity observed. RNS operates as a closed-loop system that continuously monitors electrocorticographic activity at one or two seizure foci and delivers brief stimulation only when abnormal epileptiform patterns are detected (51, 52). This targeted, event-triggered intervention disrupts early pathological synchronization and leads to gradual long-term modulation of local network excitability, with chronic recordings showing reductions in interictal activity and improved baseline EEG patterns over time (53, 54). Compared with open-loop modalities such as VNS and DBS, RNS delivers far less total daily stimulation while achieving comparable long-term seizure control, as it acts directly at the seizure onset zone only when abnormal activity emerges (19). RNS may appear less effective in this network meta-analysis because its therapeutic benefits accumulate gradually over many months to years, whereas the included randomized trials typically evaluate short-term responder rates. Moreover, RNS relies on individualized detection and stimulation parameters that require extended optimization, making early treatment effects modest compared with open-loop modalities that deliver continuous stimulation from the outset. Taken together, these findings underscore the variability in neuromodulation treatment responses and indicate that noninvasive stimulation techniques may achieve effects comparable to or in some cases exceeding those of invasive approaches. However, several limitations should be considered when interpreting these results. First, the evidence base consisted of heterogeneous study designs and diverse stimulation protocols, which may have influenced the comparative estimates. Second, the number of available randomized trials for certain interventions particularly external trigeminal nerve stimulation، transcranial alternating current stimulation، and responsive neurostimulation was limited, resulting in imprecision and wide prediction intervals. In addition, although DBS has a large and mature body of literature, most DBS studies are single-arm or lack a sham comparator and therefore could not be included in the present network; this exclusion of a substantial portion of the DBS evidence base may affect the apparent relative performance of the modality. Third, variability in baseline seizure frequency, epilepsy etiology, and concomitant medication regimens across trials may have introduced residual confounding. Finally, although overall inconsistency was low, the network relied predominantly on sham-controlled two-arm studies, which restricted the ability to model more complex indirect pathways and potentially reduced the richness of network connections. This study also possesses several important strengths that enhance the reliability and interpretability of the findings. First, the use of a network meta-analytic framework allowed for the integration of both direct and indirect evidence, enabling a comprehensive comparison of multiple neuromodulation modalities within a unified analytic structure. Second, all included trials used sham-controlled designs, providing a consistent and rigorous reference comparator across interventions and reducing the risk of performance and detection bias. Third, the analysis applied robust statistical approaches including random-effects models, P-score ranking, prediction intervals, and formal assessments of heterogeneity, inconsistency, and small-study effects supporting the stability of the results. Finally, by focusing on responder-rate outcomes and extracting detailed arm-level data, the study facilitated a clinically meaningful evaluation of therapeutic effects across invasive and noninvasive techniques in drug-resistant epilepsy. In conclusion, this network meta-analysis offers a comprehensive comparative evaluation of neuromodulation strategies for DRE and indicates that rTMS, tDCS, and ENTS may provide the strongest short-term therapeutic effects relative to sham stimulation and several established approaches. DBS and VNS demonstrated moderate yet consistent efficacy, whereas RNS showed comparatively smaller early benefits within the randomized evidence base, likely reflecting its gradual, optimization-dependent mode of action. Future research should prioritize larger head-to-head randomized trials, harmonized stimulation protocols, and standardized outcome measures to enhance comparability across modalities. Incorporating long-term follow-up data, patient-centered metrics, and mechanistic biomarkers will be essential for identifying which neuromodulation approaches yield the most durable and clinically meaningful seizure control. 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Med Hypotheses 74(5):855–856 Warsi NM, Yan H, Wong SM, Yau I, Breitbart S, Go C et al (2023) Vagus Nerve Stimulation Modulates Phase-Amplitude Coupling in Thalamic Local Field Potentials. Neuromodulation 26(3):601–606 Liu WC, Mosier K, Kalnin AJ, Marks D (2003) BOLD fMRI activation induced by vagus nerve stimulation in seizure patients. J Neurol Neurosurg Psychiatry 74(6):811–813 Warsi NM, Yan H, Suresh H, Wong SM, Arski ON, Gorodetsky C et al (2022) The anterior and centromedian thalamus: Anatomy, function, and dysfunction in epilepsy. Epilepsy Res 182:106913 Aggleton JP, O'Mara SM, Vann SD, Wright NF, Tsanov M, Erichsen JT (2010) Hippocampal-anterior thalamic pathways for memory: uncovering a network of direct and indirect actions. Eur J Neurosci 31(12):2292–2307 Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM et al (2015) Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology 84(10):1017–1025 Laxpati NG, Kasoff WS, Gross RE (2014) Deep brain stimulation for the treatment of epilepsy: circuits, targets, and trials. Neurotherapeutics 11(3):508–526 Agashe S, Burkholder D, Starnes K, Van Gompel JJ, Lundstrom BN, Worrell GA, Gregg NM (2022) Centromedian Nucleus of the Thalamus Deep Brain Stimulation for Genetic Generalized Epilepsy: A Case Report and Review of Literature. Front Hum Neurosci 16:858413 Dalic LJ, Warren AEL, Bulluss KJ, Thevathasan W, Roten A, Churilov L, Archer JS (2022) DBS of Thalamic Centromedian Nucleus for Lennox-Gastaut Syndrome (ESTEL Trial). Ann Neurol 91(2):253–267 Kassiri H, Muneeb A, Salahi R, Dabbaghian A (2024) Closed-Loop Implantable Neurostimulators for Individualized Treatment of Intractable Epilepsy: A Review of Recent Developments, Ongoing Challenges, and Future Opportunities. IEEE Trans Biomed Circuits Syst 18(6):1268–1295 Murro A, Park Y, Bergey G, Kossoff E, Ritzl E, Karceski S et al (2003) Multicenter study of acute responsive stimulation in patients with intractable epilepsy. Epilepsia 44(Supplement 9):326 Kossoff EH, Ritzl EK, Politsky JM, Murro AM, Smith JR, Duckrow RB et al (2004) Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia 45(12):1560–1567 Esteller R, Echauz J, Tcheng T (eds) (2004) Comparison of line length feature before and after brain electrical stimulation in epileptic patients. The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society; : IEEE Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8515031","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":569100752,"identity":"509cbac2-fd37-422a-a769-c7abfca1baab","order_by":0,"name":"Parnian Eslahi","email":"","orcid":"","institution":"Shahid Beheshti University of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Parnian","middleName":"","lastName":"Eslahi","suffix":""},{"id":569100753,"identity":"2cdafce7-9301-4925-9abd-0ba6cf2fd2d0","order_by":1,"name":"Maryam moghbel baerz","email":"","orcid":"","institution":"Shahid Beheshti University of 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10:29:40","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":137966,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8515031/v1/f4b07e836bcf3a589a0f5b7f.html"},{"id":99692101,"identity":"74c3519b-9af9-4253-af7a-5a04694b31b9","added_by":"auto","created_at":"2026-01-07 10:29:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":170445,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8515031/v1/f79cd3905218aa373a909d57.png"},{"id":99692103,"identity":"134524f2-6121-4f82-a9bc-77a1856b8261","added_by":"auto","created_at":"2026-01-07 10:29:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":123179,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork geometry of included trials. Graphical representation of the treatment network. Nodes reflect interventions and their sample sizes; edges represent direct comparisons, showing that all active treatments are connected through sham controls.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8515031/v1/1424b44c5e4d3cbef280dd73.png"},{"id":99692104,"identity":"805a94e7-fd8b-47a1-8a61-1d2f7d23ba41","added_by":"auto","created_at":"2026-01-07 10:29:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":274505,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of network meta-analysis. Odds ratios (ORs) with 95% confidence intervals for each neuromodulation treatment versus sham. Interventions with OR\u0026gt;1 indicate greater response rates than sham.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8515031/v1/b345139ffdc024ddc2de0cd0.png"},{"id":99795097,"identity":"cd93321e-ac97-4621-bba3-c2c28f080b4b","added_by":"auto","created_at":"2026-01-08 13:36:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44883,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment ranking based on P-scores. P-score ranking of all interventions, indicating the probability of each treatment being among the most effective options.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8515031/v1/a6b41c41a9a205bc129b936c.png"},{"id":99692107,"identity":"74821751-1308-426f-a1a7-190df9c5404c","added_by":"auto","created_at":"2026-01-07 10:29:39","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":107298,"visible":true,"origin":"","legend":"\u003cp\u003eComparison-adjusted funnel plot. Assessment of small-study effects and publication bias. The largely symmetric distribution indicates no evidence of systematic bias.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8515031/v1/a3496f180cd42868f664ae4b.png"},{"id":99805027,"identity":"47692964-b24d-4436-8878-0b79efbbd92a","added_by":"auto","created_at":"2026-01-08 14:15:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1417024,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8515031/v1/fb5c63be-b646-473a-a430-e20d17f6f11a.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eComparative Efficacy of Interventions for Drug-Resistant Epilepsy: A Network Meta-analysis\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eEpilepsy affects approximately 50\u0026nbsp;million individuals worldwide, representing about 1% of the global population. According to the International League Against Epilepsy (ILAE), drug-resistant epilepsy (DRE) is defined as the failure to achieve sustained seizure freedom after adequate trials of at least two appropriately chosen and tolerated anti-seizure medications (ASMs)(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The prevalence of DRE ranges from 13.7% in community-based studies to 36.3% in clinic-based cohorts (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). DRE is associated with increased risk of premature mortality due to Sudden Unexpected Death in Epilepsy (SUDEP)(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatients with DRE account for the major burden of epilepsy (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) because they experience high rates of medical comorbidities (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), psychological dysfunction (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), social stigma (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), impaired quality of life, and elevated mortality (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), leading to a reduced life expectancy (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Although diagnostic procedures and therapeutic interventions including medical, surgical, and neuromodulation treatments carry inherent risks (\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), these risks are generally outweighed by the consequences of uncontrolled seizures (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Despite the substantial burden associated with DRE, evidence directly comparing anti-seizure medications remains limited.\u003c/p\u003e \u003cp\u003eEvidence from head-to-head comparative trials of ASMs in DRE remains limited. Most available data are extrapolated from monotherapy studies aimed at demonstrating non-inferiority. The SANAD and SANAD II pragmatic trials compared first-line treatments for focal and generalized epilepsies but were not double-blind (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Only one randomized, double-blind study has directly compared adjunctive therapies in DRE, showing that pregabalin was non-inferior to levetiracetam for \u0026ge;\u0026thinsp;50% seizure reduction, with comparable tolerability. No significant differences were found in secondary outcomes (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). For patients who do not achieve adequate seizure control with pharmacological treatments, several alternative therapeutic modalities are available, including surgical and neuromodulatory approaches.\u003c/p\u003e \u003cp\u003eMultiple treatment options exist for patients with persistent seizures, including surgical, neuromodulatory, and non-invasive approaches. Resective procedures such as temporal lobectomy, selective amygdalohippocampectomy, extratemporal resections, and hemispherectomy can be curative, whereas palliative disconnective surgeries (corpus callosotomy, multiple subpial transections, and hemispherotomy) aim to reduce seizure spread (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Deep brain stimulation (DBS) has shown long-term seizure reductions of up to 75%, independent of prior VNS or surgery (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Responsive neurostimulation (RNS), approved in 2014, delivers targeted stimulation upon detection of epileptiform activity and has demonstrated a median 75% seizure reduction with a 73% responder rate in extended follow-up studies (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). For patients who are not candidates for resective surgery, vagus nerve stimulation (VNS) provides a less invasive option, yielding responder rates above 50% but relatively low seizure-free rates (\u0026lt;\u0026thinsp;10% (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e); it is generally well tolerated and may have mood-enhancing effects (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). In addition to invasive neuromodulation strategies, non-invasive brain stimulation techniques have also been explored.\u003c/p\u003e \u003cp\u003eNon-invasive brain stimulation (NIBS) techniques including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) modulate cortical excitability and have shown variable antiseizure effects in open-label studies (\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). While generally safe and well tolerated, the evidence remains insufficient to confirm their efficacy, underscoring the need for further research (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGiven the limited head-to-head evidence and the diverse therapeutic landscape, network meta-analysis (NMA) provides a robust framework for synthesizing direct and indirect comparisons across multiple interventions. Therefore, this study aimed to compare the efficacy of available treatment modalities for DRE using network meta-analysis to identify the most effective options and guide clinical decision-making.\u003c/p\u003e"},{"header":"2. Method","content":"\u003cp\u003eWe conducted this network meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). As this study is based exclusively on previously published data, it did not involve any new research involving human participants. The protocol for this network meta-analysis was prospectively registered on the Open Science Framework (OSF; Registration DOI: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.17605/OSF.IO/SB3WN\u003c/span\u003e\u003cspan address=\"10.17605/OSF.IO/SB3WN\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The flow diagram of the study demonstrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Search strategy\u003c/h2\u003e \u003cp\u003eWe systematically searched PubMed, Web of Science, and Scopus from inception to November 2025. The search was restricted to English-language publications. A comprehensive search strategy was developed using controlled vocabulary and free-text terms related to drug-resistant epilepsy and therapeutic interventions.\u003c/p\u003e \u003cp\u003eThe following key terms and their variants were used: (\u0026ldquo;drug-resistant epilepsy\u0026rdquo;, \u0026ldquo;refractory epilepsy\u0026rdquo;, \u0026ldquo;intractable epilepsy\u0026rdquo;, \u0026ldquo;treatment-resistant epilepsy\u0026rdquo;, \u0026ldquo;pharmacoresistant epilepsy\u0026rdquo;), combined with terms for interventions including anti-seizure medications (e.g., levetiracetam, pregabalin, lamotrigine, carbamazepine, valproate, topiramate, lacosamide, perampanel), epilepsy surgery (temporal lobectomy, selective amygdalohippocampectomy, extratemporal resection, lesionectomy, corpus callosotomy, multiple subpial transections, hemispherotomy), neuromodulation (vagus nerve stimulation [VNS], deep brain stimulation [DBS], responsive neurostimulation [RNS]), non-invasive brain stimulation (rTMS, tDCS), and dietary therapies (ketogenic diet, modified Atkins diet).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Eligibility Criteria\u003c/h2\u003e \u003cp\u003eWe included randomized, double-blind, placebo-controlled, add-on clinical trials that evaluated the efficacy and safety of therapeutic interventions for patients with DRE. High-quality clinical studies published in English were eligible, including randomized controlled trials (RCTs) and cohort studies with Newcastle\u0026ndash;Ottawa Scale (NOS) scores\u0026thinsp;\u0026ge;\u0026thinsp;5 (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Eligible RCTs compared an intervention against placebo, standard care, or another active intervention and included only adult populations. Studies were required to report seizure frequency or responder-rate outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Study selection\u003c/h2\u003e \u003cp\u003e We conducted an extensive literature search to identify studies that met the objectives of this review. During the screening process, two independent reviewers performed an initial assessment of titles and abstracts to determine relevance. Full texts of potentially eligible studies were then evaluated to confirm inclusion. Any disagreements between reviewers were resolved through discussion and, when necessary, consultation with a third researcher to reach consensus.\u003c/p\u003e \u003cp\u003eWe excluded studies that met any of the following conditions: review articles, conference abstracts, editorials, or other non-original reports; studies that did not report seizure frequency or responder-rate outcomes; trials in which ASMs were not stable before enrollment or throughout the treatment period; studies lacking a placebo or appropriate control group; and cohort studies, as well as randomized controlled trials judged to be of low quality based on the Cochrane Risk of Bias assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Outcome measures\u003c/h2\u003e \u003cp\u003eThe primary outcome was the proportion of patients achieving a\u0026thinsp;\u0026ge;\u0026thinsp;50% reduction in seizure frequency from baseline (responder rate), which served as the main quantitative measure for the network meta-analysis. For each eligible study, we extracted the following data: the number of participants in the active treatment group and the corresponding number of responders, as well as the number of participants in the control group (placebo or comparator) and their respective responder counts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Statistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed in R v4.5.2 using the netmeta package. A frequentist random-effects network meta-analysis was used to integrate direct and indirect comparisons across interventions. Effect sizes were calculated as odds ratios (ORs) with 95% confidence intervals (CIs), and sham served as the common reference comparator because all included studies were sham-controlled. Between-study heterogeneity was assessed using τ\u0026sup2; and I\u0026sup2; statistics. In addition to conventional CIs, 95% prediction intervals (PIs) were computed to estimate the expected range of effect sizes in future studies, accounting for heterogeneity. Treatment ranking was performed using P-scores, reflecting the probability that each intervention is among the most effective options in the network. Network coherence was evaluated using both global (design-by-treatment interaction) and local (node-splitting) inconsistency tests. Small-study effects and potential publication bias were examined using comparison-adjusted funnel plots and Egger\u0026rsquo;s regression test. No meaningful inconsistency or publication bias was detected.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Study Characteristics\u003c/h2\u003e \u003cp\u003eSixteen randomized controlled trials evaluating eight neuromodulatory interventions were included in the network meta-analysis. All studies incorporated both an active intervention arm and a sham control, producing a fully connected network. Sample sizes ranged from small, exploratory trials (e.g., ENTS, tACS, RNS) to larger studies examining tDCS, VNS, and DBS. Assessment of study quality using the Newcastle\u0026ndash;Ottawa Scale (NOS) showed that all included trials met acceptable methodological standards, with scores ranging from 6 to 8. Most studies scored 7 or 8, indicating generally moderate to high quality, and no study fell below the predefined inclusion threshold. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the characteristics of included studies and treatment arms.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of Included Studies and Treatment Arms\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eActive Intervention\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNumber of Participants (Active)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eResponders (Active)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eControl Intervention\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNumber of Participants (Control)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eResponders (Control)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNOS Scoring\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCukiert 2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDBS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHerrman 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDBS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSANTE 2010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDBS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePivotal 2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRezakhani 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etDCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZoghi 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etDCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSanJuan 2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etDCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAssenza 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etDCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTekturk 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etDCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYang 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etDCS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYang 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRong 2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSanJuan 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003etACS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun 2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003erTMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAshour 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003erTMS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGil-Lopez 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eENTS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esham\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eNote. All trials include sham as the reference comparator. Abbreviations: DBS, deep brain stimulation; RNS, responsive neurostimulation; tDCS, transcranial direct current stimulation; VNS, vagus nerve stimulation; tACS, transcranial alternating current stimulation; rTMS, repetitive transcranial magnetic stimulation; ENTS, external trigeminal nerve stimulation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Network Geometry\u003c/h2\u003e \u003cp\u003eThe network consisted of eight active interventions, each compared directly with sham, forming a star-shaped structure without disconnected components. The highest number of comparisons was available for tDCS and DBS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Network Meta-analysis\u003c/h2\u003e \u003cp\u003eRandom-effects network estimates indicated substantial variability across treatments. ENTS demonstrated the largest pooled effect relative to sham, followed by rTMS and tDCS. DBS produced a moderate treatment effect, whereas VNS, tACS, and RNS showed smaller or uncertain effects. Numerical results are summarized in Table\u0026nbsp;2/Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \n\u003cp\u003e\u003cstrong\u003eTable 2. Network Meta-analysis ORs (Random-Effects Model) vs Sham\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e95% CI Lower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e95% CI Upper\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eENTS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e43.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e1.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e1267.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003erTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e14.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e2.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e70.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003etDCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e11.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e3.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e37.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eDBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e4.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e17.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e.051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003etACS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e60.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eVNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e2.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e8.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e6.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003esham\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 20%;\"\u003e\n \u003cp\u003e\u0026mdash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DBS, deep brain stimulation; RNS, responsive neurostimulation; tDCS, transcranial direct current stimulation; VNS, vagus nerve stimulation; tACS, transcranial alternating current stimulation; rTMS, repetitive transcranial magnetic stimulation; ENTS, external trigeminal nerve stimulation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Treatment Ranking (P-scores)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eP-score analysis supported the magnitude ordering of treatments. ENTS, rTMS, and tDCS ranked highest. Table \u003cstrong\u003e3\u003c/strong\u003e presents the ranking values; Fig 4 displays the barplot.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. P-score Ranking of Neuromodulation Treatments\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eRank\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eP-score\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eENTS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0.879\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003erTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0.785\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003etDCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0.753\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eDBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0.500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003etACS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0.422\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eVNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0.367\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003eRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003esham\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e0.116\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations: DBS, deep brain stimulation; RNS, responsive neurostimulation; tDCS, transcranial direct current stimulation; VNS, vagus nerve stimulation; tACS, transcranial alternating current stimulation; rTMS, repetitive transcranial magnetic stimulation; ENTS, external trigeminal nerve stimulation.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5 Prediction Intervals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrediction intervals (PIs) quantified expected treatment effects in future trials. rTMS and tDCS retained favorable effects even after accounting for heterogeneity, whereas PIs for DBS, RNS, VNS, and tACS crossed unity. ENTS displayed a wide PI reflecting imprecision. Table \u003cstrong\u003e4\u003c/strong\u003e provides the complete PI results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Network ORs with 95% Prediction Intervals (Random-Effects Model)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003ePI Lower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003ePI Upper\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eENTS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e43.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.582\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e3238.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003erTMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e14.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e1.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e195.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003etDCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e11.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e1.200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e116.65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eDBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e4.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e49.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003etACS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e151.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eVNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e2.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.232\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e26.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eRNS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e16.98\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DBS, deep brain stimulation; RNS, responsive neurostimulation; tDCS, transcranial direct current stimulation; VNS, vagus nerve stimulation; tACS, transcranial alternating current stimulation; rTMS, repetitive transcranial magnetic stimulation; ENTS, external trigeminal nerve stimulation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.6 Assessment of Consistency and Heterogeneity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGlobal and local inconsistency testing showed no evidence of disagreement between direct and indirect estimates. The total heterogeneity was moderate (\u0026tau;\u0026sup2; = 0.67; I\u0026sup2; = 48.6%). No design-level or comparison-level inconsistencies were detected (Fig 5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.7 Small-Study Effects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEgger\u0026apos;s regression test indicated no significant small-study effects (p = .955). Visual inspection of the comparison-adjusted funnel plot confirmed the absence of clear asymmetry.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis network meta-analysis synthesized evidence from 16 randomized and quasi-randomized clinical trials evaluating multiple neurostimulation modalities for DRE. By integrating both direct and indirect comparisons across diverse interventions, the analysis provides a comprehensive comparative assessment of their relative therapeutic efficacy. The results demonstrate clinically meaningful differences among modalities, with several techniques showing substantially higher responder rates compared with others.\u003c/p\u003e\n\u003cp\u003eConsistency assessments supported the robustness of the network. The global test for inconsistency revealed no significant disagreement between direct and indirect evidence, and design-by-treatment decomposition indicated that the small amount of heterogeneity observed was driven primarily by DBS sham comparisons without compromising overall network stability. Local inconsistency analysis showed no problematic loops, and the consistency model remained appropriate. Furthermore, evaluation of publication bias using comparison-adjusted funnel plots and Egger\u0026apos;s regression revealed no evidence of small-study effects. Although the number of trials for certain modalities (particularly ENTS and tACS) was limited, the absence of funnel plot asymmetry increases confidence in the reliability of the findings.\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eAcross the network, ENTS, rTMS, and tDCS ranked as the most effective modalities, with the highest P-scores, suggesting they consistently outperformed other treatments in achieving responder status.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe large estimated effect of ENTS should be interpreted with caution, as its confidence interval was wide and prediction interval substantially broader, reflecting imprecision and the limited sample contributing to that comparison. Nonetheless, the observed magnitude suggests potential benefit that warrants confirmation through larger controlled trials. ENTS targets the supraorbital branches of the ophthalmic division of the trigeminal nerve on both sides of the forehead. Sensory input from these fibers is relayed to the trigeminal sensory nuclei in the brainstem, which project upward through the trigeminal lemniscus to the ventral posteromedial nucleus of the thalamus and subsequently to somatosensory cortical regions (32, 33). Beyond these ascending pathways, trigeminal nuclei have strong functional interactions with brainstem modulatory structures, particularly the locus coeruleus. This noradrenergic nucleus sends widespread projections to limbic and cortical areas including the dorsal and ventral hippocampus and is thought to play a key role in how ENTS influences broader neural networks. Modulation of these thalamocortical and noradrenergic circuits has been proposed as a central mechanism through which ENTS may exert antiseizure effects (32, 34). This network-level modulation may help dampen pathological synchronization and enhance inhibitory control within seizure-prone circuits, offering a plausible explanation for its observed therapeutic signal in DRE. However, the scarcity of trials and heterogeneity of protocols likely contributed to the variability seen in treatment effects.\u003c/p\u003e\n\u003cp\u003erTMS and tDCS showed more stable and precise estimates, with both demonstrating clear superiority over sham stimulation. The robustness of their effects, supported by moderate prediction intervals, suggests that these techniques may be promising candidates for broader implementation or further clinical evaluation. rTMS and tDCS influence cortical excitability through complementary neurophysiological mechanisms. rTMS induces transient electric fields powerful enough to elicit action potentials and produce frequency-dependent after-effects, with high-frequency protocols generally enhancing excitability and low-frequency stimulation exerting inhibitory influences. These modulatory effects have been linked to LTP/LTD-like synaptic plasticity through changes in glutamatergic transmission, NMDA receptor activation, and GABAergic inhibition (35, 36). In contrast, tDCS applies weak, steady electrical currents that shift resting membrane potentials toward depolarization or hyperpolarization without directly triggering neuronal firing. Prolonged stimulation can induce sustained neuroplastic changes mediated by voltage-gated ion channels and downstream mechanisms that resemble early stages of synaptic potentiation or depression (37, 38). Both techniques also modulate distributed cortical\u0026ndash;subcortical networks rather than isolated cortical sites, engaging neuromodulatory systems and altering task-dependent neural processing in behaviorally relevant circuits (39).\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eIn drug-resistant epilepsy, these neuromodulatory effects can reduce cortical hyperexcitability and disrupt pathological synchronization within epileptogenic networks, thereby lowering seizure propensity. By shifting the excitability balance toward more stable and less synchronized cortical states, rTMS and tDCS may attenuate abnormal network dynamics that underlie refractory seizures.\u003c/p\u003e\n\u003cp\u003eDBS and VNS yielded moderate benefits relative to sham, consistent with previous literature demonstrating their long-term efficacy in reducing seizure burden. However, their relative position within the network placed them below the noninvasive cortical stimulation modalities. This pattern may reflect differences in sample characteristics, stimulation parameters, or methodological heterogeneity across the included studies. VNS modulates seizure activity through activation of the vagus afferent network, beginning with projections from the cervical vagus nerve to the nucleus tractus solitarius and subsequently to key brainstem neuromodulatory centers, including the locus coeruleus and dorsal raphe nucleus (40). These ascending pathways exert widespread effects on thalamic and cortical regions, promoting desynchronization of epileptiform activity (41, 42) and altering thalamocortical dynamics that are linked to treatment responsiveness (43, 44). DBS, in contrast, acts by directly modulating subcortical nodes within epileptogenic networks. Stimulation of the anterior nucleus of the thalamus (ANT) influences limbic\u0026ndash;hippocampal circuitry involved in focal and secondarily generalized seizures (45, 46), with evidence suggesting reduced pathological connectivity and network hyperexcitability following stimulation (47, 48). Through these complementary mechanisms\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eascending neuromodulatory modulation in VNS and direct thalamic network regulation in DBS\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eboth approaches help decrease synchronization within epileptogenic circuits and improve seizure control in drug-resistant epilepsy.\u003c/p\u003e\n\u003cp\u003eRNS ranked lower within the network, likely due to the small number of trials available for pooling under the sham-controlled design and substantial heterogeneity observed. RNS operates as a closed-loop system that continuously monitors electrocorticographic activity at one or two seizure foci and delivers brief stimulation only when abnormal epileptiform patterns are detected (51, 52). This targeted, event-triggered intervention disrupts early pathological synchronization and leads to gradual long-term modulation of local network excitability, with chronic recordings showing reductions in interictal activity and improved baseline EEG patterns over time (53, 54). Compared with open-loop modalities such as VNS and DBS, RNS delivers far less total daily stimulation while achieving comparable long-term seizure control, as it acts directly at the seizure onset zone only when abnormal activity emerges (19). RNS may appear less effective in this network meta-analysis because its therapeutic benefits accumulate gradually over many months to years, whereas the included randomized trials typically evaluate short-term responder rates. Moreover, RNS relies on individualized detection and stimulation parameters that require extended optimization, making early treatment effects modest compared with open-loop modalities that deliver continuous stimulation from the outset.\u003c/p\u003e\n\u003cp\u003eTaken together, these findings underscore the variability in neuromodulation treatment responses and indicate that noninvasive stimulation techniques may achieve effects comparable to\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eor in some cases exceeding\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003ethose of invasive approaches. However, several limitations should be considered when interpreting these results. First, the evidence base consisted of heterogeneous study designs and diverse stimulation protocols, which may have influenced the comparative estimates. Second, the number of available randomized trials for certain interventions\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eparticularly external trigeminal nerve stimulation، transcranial alternating current stimulation، and responsive neurostimulation\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003ewas limited, resulting in imprecision and wide prediction intervals. In addition, although DBS has a large and mature body of literature, most DBS studies are single-arm or lack a sham comparator and therefore could not be included in the present network; this exclusion of a substantial portion of the DBS evidence base may affect the apparent relative performance of the modality. Third, variability in baseline seizure frequency, epilepsy etiology, and concomitant medication regimens across trials may have introduced residual confounding. Finally, although overall inconsistency was low, the network relied predominantly on sham-controlled two-arm studies, which restricted the ability to model more complex indirect pathways and potentially reduced the richness of network connections.\u003c/p\u003e\n\u003cp\u003eThis study also possesses several important strengths that enhance the reliability and interpretability of the findings. First, the use of a network meta-analytic framework allowed for the integration of both direct and indirect evidence, enabling a comprehensive comparison of multiple neuromodulation modalities within a unified analytic structure. Second, all included trials used sham-controlled designs, providing a consistent and rigorous reference comparator across interventions and reducing the risk of performance and detection bias. Third, the analysis applied robust statistical approaches including random-effects models, P-score ranking, prediction intervals, and formal assessments of heterogeneity, inconsistency, and small-study effects supporting the stability of the results. Finally, by focusing on responder-rate outcomes and extracting detailed arm-level data, the study facilitated a clinically meaningful evaluation of therapeutic effects across invasive and noninvasive techniques in drug-resistant epilepsy.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this network meta-analysis offers a comprehensive comparative evaluation of neuromodulation strategies for DRE and indicates that rTMS, tDCS, and ENTS may provide the strongest short-term therapeutic effects relative to sham stimulation and several established approaches. DBS and VNS demonstrated moderate yet consistent efficacy, whereas RNS showed comparatively smaller early benefits within the randomized evidence base, likely reflecting its gradual, optimization-dependent mode of action. Future research should prioritize larger head-to-head randomized trials, harmonized stimulation protocols, and standardized outcome measures to enhance comparability across modalities. Incorporating long-term follow-up data, patient-centered metrics, and mechanistic biomarkers will be essential for identifying which neuromodulation approaches yield the most durable and clinically meaningful seizure control.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G et al (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51(6):1069\u0026ndash;1077\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSultana B, Panzini MA, Veilleux Carpentier A, Comtois J, Rioux B, Gore G et al (2021) Incidence and Prevalence of Drug-Resistant Epilepsy: A Systematic Review and Meta-analysis. Neurology 96(17):805\u0026ndash;817\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N et al (2014) The consequences of refractory epilepsy and its treatment. Epilepsy Behav 37:59\u0026ndash;70\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrganization WH (2008) The global burden of disease: 2004 update. World Health Organ. ;14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaitatzis A, Johnson AL, Chadwick DW, Shorvon SD, Sander JW (2004) Life expectancy in people with newly diagnosed epilepsy. 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Neuroscience 18(2):291\u0026ndash;306\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoughlin SE, Foote SL, Grzanna R (1986) Efferent projections of nucleus locus coeruleus: morphologic subpopulations have different efferent targets. Neuroscience 18(2):307\u0026ndash;319\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang Y-Z, Chen R-S, Rothwell JC, Wen H-Y (2007) The after-effect of human theta burst stimulation is NMDA receptor dependent. Clin Neurophysiol 118(5):1028\u0026ndash;1032\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNitsche MA, Liebetanz D, Antal A, Lang N, Tergau F, Paulus W (2003) Modulation of cortical excitability by weak direct current stimulation\u0026ndash;technical, safety and functional aspects. Suppl Clin Neurophysiol 56:255\u0026ndash;276\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNitsche MA, Paulus W (2000) Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol 527(Pt 3):633\u0026ndash;639\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStagg CJ, Nitsche MA (2011) Physiological basis of transcranial direct current stimulation. Neuroscientist 17(1):37\u0026ndash;53\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePolania R, Nitsche MA, Ruff CC (2018) Studying and modifying brain function with non-invasive brain stimulation. Nat Neurosci 21(2):174\u0026ndash;187\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHachem LD, Wong SM, Ibrahim GM (2018) The vagus afferent network: emerging role in translational connectomics. Neurosurg Focus 45(3):E2\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFraschini M, Puligheddu M, Demuru M, Polizzi L, Maleci A, Tamburini G et al (2013) VNS induced desynchronization in gamma bands correlates with positive clinical outcome in temporal lobe pharmacoresistant epilepsy. Neurosci Lett 536:14\u0026ndash;18\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJaseja H (2010) EEG-desynchronization as the major mechanism of anti-epileptic action of vagal nerve stimulation in patients with intractable seizures: clinical neurophysiological evidence. Med Hypotheses 74(5):855\u0026ndash;856\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWarsi NM, Yan H, Wong SM, Yau I, Breitbart S, Go C et al (2023) Vagus Nerve Stimulation Modulates Phase-Amplitude Coupling in Thalamic Local Field Potentials. 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Front Hum Neurosci 16:858413\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDalic LJ, Warren AEL, Bulluss KJ, Thevathasan W, Roten A, Churilov L, Archer JS (2022) DBS of Thalamic Centromedian Nucleus for Lennox-Gastaut Syndrome (ESTEL Trial). Ann Neurol 91(2):253\u0026ndash;267\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKassiri H, Muneeb A, Salahi R, Dabbaghian A (2024) Closed-Loop Implantable Neurostimulators for Individualized Treatment of Intractable Epilepsy: A Review of Recent Developments, Ongoing Challenges, and Future Opportunities. IEEE Trans Biomed Circuits Syst 18(6):1268\u0026ndash;1295\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMurro A, Park Y, Bergey G, Kossoff E, Ritzl E, Karceski S et al (2003) Multicenter study of acute responsive stimulation in patients with intractable epilepsy. Epilepsia 44(Supplement 9):326\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKossoff EH, Ritzl EK, Politsky JM, Murro AM, Smith JR, Duckrow RB et al (2004) Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia 45(12):1560\u0026ndash;1567\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEsteller R, Echauz J, Tcheng T (eds) (2004) Comparison of line length feature before and after brain electrical stimulation in epileptic patients. The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society; : IEEE\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Shahid Beheshti University of Medical Sciences","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"drug-resistant epilepsy, neurostimulation therapies, deep brain stimulation, vagus nerve stimulation, responsive neurostimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, external trigeminal nerve stimulation, network meta-analysis, seizure reduction","lastPublishedDoi":"10.21203/rs.3.rs-8515031/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8515031/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDrug-resistant epilepsy remains difficult to manage when medications and surgical resection are ineffective or unsuitable. Several neurostimulation approaches are now used as alternative treatments, yet their comparative effectiveness has not been clearly established.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA systematic search of PubMed، Web of Science، and Scopus identified 435 studies, of which 16 randomized or quasi-randomized controlled trials fulfilled eligibility criteria for inclusion in a network meta-analysis. The primary outcome was the proportion of participants achieving at least a 50 percent reduction in seizure frequency. A random-effects network meta-analysis integrated direct and indirect evidence, with assessment of heterogeneity, global and local inconsistency, and potential small-study effects. Study quality was evaluated using the Newcastle\u0026ndash;Ottawa Scale.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe network showed high coherence with minimal inconsistency. Noninvasive methods particularly repetitive transcranial magnetic stimulation، transcranial direct current stimulation، and external trigeminal nerve stimulation produced the strongest seizure-reduction effects. Deep brain stimulation and vagus nerve stimulation offered moderate but consistent benefits, while responsive neurostimulation showed weaker short-term efficacy within the limited randomized evidence. Precision for several modalities remained constrained by the small number of eligible trials.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis analysis provides an integrated comparison of neurostimulation approaches for drug-resistant epilepsy and highlights the promising therapeutic potential of several noninvasive modalities. Larger randomized studies with standardized stimulation parameters, extended follow-up, and mechanistic biomarkers are needed to refine treatment selection and optimize long-term clinical outcomes.\u003c/p\u003e","manuscriptTitle":"Comparative Efficacy of Interventions for Drug-Resistant Epilepsy: A Network Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-07 10:29:34","doi":"10.21203/rs.3.rs-8515031/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9fe81e8c-fcbd-4e28-933f-307d9feb2719","owner":[],"postedDate":"January 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-07T10:29:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-07 10:29:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8515031","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8515031","identity":"rs-8515031","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}