Theta burst stimulation (TBS) is a promising form of repetitive transcranial magnetic stimulation (rTMS) capable of modulating cortical excitability and intracortical processes, offering therapeutic potential for neurological and psychiatric disorders. However, clinical translation remains limited by high inter-subject and inter-session variability in stimulation effects. To more directly capture cortical responses, there is increased interest in combining TMS with electroencephalography (EEG) to assess TMS-evoked potentials (TEPs) before and after stimulation. As an individual’s neurophysiological state influences stimulation outcomes, this study explores whether pre-stimulation resting-state EEG can predict changes in TEP component amplitudes following intermittent (iTBS) and continuous (cTBS) protocols applied to the left primary motor cortex, using data from fifteen healthy male participants in a randomized, single-blind crossover design. Linear (Lasso regression) and nonlinear (CatBoost regression) models were designed to predict changes in six TEP components (N15, P30, N45, P60, N100, P180). Both models consistently achieved lower mean absolute errors than the random guessing baseline, demonstrating their ability to capture meaningful predictive patterns in cortical responses. The best performing model varied by TEP component and TBS protocol. Incorporating feature deltas (post- vs. pre-stimulation feature difference) did not significantly enhance predictive performance. Feature importance analysis revealed the predictive value of spectral power and connectivity measures. For instance, connectivity between the stimulation site and frontal/parietal regions, together with oscillatory power in frontal and motor areas, often emerged as the top predictors. Given the limited sample size, these findings should be interpreted as exploratory and hypothesis-generating, requiring validation in larger and independent cohorts. The study establishes a framework for predicting individual TEP responses to TBS using machine learning, paving the way for personalized neuromodulation.

RATIONALE:Off-label treatments are often considered to treat refractory status epilepticus (RSE) and superrefractory status epilepticus (SRSE). To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for (S)RSE, we performed a systematic review. MATERIALS AND METHODS:Cessation of (S)RSE after rTMS was extracted as the primary end point from manuscripts describing patients with (S)RSE treated with rTMS. Data relevant to epilepsy history, (S)RSE type and etiology, prior treatment for (S)RSE, prior duration of (S)RSE, rTMS parameters, number of treatment sessions, duration of rTMS protocols, latency to (S)RSE cessation, recurrence rate, adverse events, and long-term outcome were collected as secondary end points. RESULTS:We identified 33 patients; 17 of 33 had epilepsia partialis continua; 7 of 33 had new onset RSE. Data were incomplete in 3 of 33 regarding classification and etiology; 18 of 30 had focal motor status epilepticus (SE), 9 of 30 nonconvulsive SE, and 3 of 30 convulsive SE. The most frequent etiologies were cortical malformation (8/31), stroke (5/31), and genetic mutations (5/31). Median duration of (S)RSE before rTMS was 70 days (range: two-7300, interquartile range = 148, Q1 = 32, Q3 = 180). In 25 of 33 patients (75.8%), rTMS caused cessation of (S)RSE after zero to four days. (S)RSE recurred in eight of 17 patients (47%), for whom follow-up was available. Three deaths occurred from the underlying disease. CONCLUSION:rTMS caused cessation in 75.8% of patients with (S)RSE within four days, with recurrence in 47%. To determine the therapeutic potential of rTMS for patients with (S)RSE, further studies are required given the present findings stem from level IV studies and may have reporting bias.

ObjectivesThis study investigates the way theta burst stimulation (TBS) applied to the motor cortex (M1) affects TMS-evoked potentials (TEPs). There have been few direct comparisons of continuous TBS (cTBS) and intermittent TBS (iTBS), and there is a lack of consensus from existing literature on the induced effects. We performed an exploratory trial to assess the effect of M1-cTBS and M1-iTBS on TEP components.Materials and MethodsIn a cross-over design, 15 participants each completed three experimental sessions with ≥one week in between sessions. The effect of a single TBS train administered over M1 was investigated using TEPs recorded at the same location, 20 to 30 minutes before and in the first 10 minutes after the intervention. In each session, a different type of TBS (cTBS, iTBS, or active control cTBS) was administered in a single-blinded randomized order. For six different TEP components (N15, P30, N45, P60, N100, and P180), amplitude was compared before and after the intervention using cluster-based permutation (CBP) analysis.ResultsWe were unable to identify a significant modulation of any of the six predefined M1 TEP components after a single train of TBS. When waiving statistical correction for multiple testing in view of the exploratory nature of the study, the CBP analysis supports a reduction of the P180 amplitude after iTBS (p = 0.015), whereas no effect was observed after cTBS or in the active control condition. The reduction occurred in ten of 15 subjects, showing intersubject variability.ConclusionsThe observed decrease in the P180 amplitude after iTBS may suggest a neuromodulatory effect of iTBS. Despite methodologic issues related to our study and the potential sensory contamination within this latency range of the TEP, we believe that our finding deserves further investigation in hypothesis-driven trials of adequate power and proper design, focusing on disentanglement between TEPs and peripherally evoked potentials, in addition to indicating reproducibility across sessions and subjects.Clinical Trial RegistrationThe Clinicaltrials.gov registration number for the study is NCT05206162.

BACKGROUND:Epilepsia partialis continua (EPC) is a medication-resistant form of focal status epilepticus (SE), causing significant morbidity. This case series explored whether continuous theta burst stimulation (cTBS) could reduce seizure activity in patients with EPC. METHODS:Three patients with motor EPC (2M/1F) underwent an accelerated cTBS protocol over four consecutive days (five 40-s trains/day, 5Hz bursts, 3 pulses at 50Hz/burst). Stimulation targeted the epileptogenic zone using a figure-of-eight coil at 80% of the resting motor threshold. Electroencephalography (EEG) was conducted before and after each session. Seizure frequency, intensity, adverse events (AEs), seizure diaries, and follow-up data were assessed. RESULTS:cTBS did not interrupt EPC in any patient. One patient reported a 17% reduction in seizure frequency. Another noted mild improvement in shoulder jerks, and a third reported reduced arm tension, though without clinical confirmation. EEG showed no significant changes. One patient experienced seizures during stimulation, and another reported worsening of pre-existing headaches. CONCLUSION:In this small case series, a four-day accelerated cTBS protocol did not yield clinically meaningful seizure control in EPC. Further research is needed to evaluate TMS and TBS in SE and EPC, where a significant treatment gap remains.

Introduction:Repetitive transcranial magnetic stimulation (rTMS) may have anti-epileptic effects, especially in patients with neocortical lesions. Initial clinical trials demonstrated that the duration of the seizure reducing effect is relatively short-lived. In the context of a chronic condition like epilepsy, theta burst stimulation (TBS) may represent a potential solution in optimizing treatment practicality and durability as it was demonstrated to be associated with longer-lasting after-effects. TBS has been studied extensively in diverse neuropsychiatric conditions, but a therapeutic TBS protocol has not previously been applied in epilepsy patients.Materials and methods:We performed a prospective open-label pilot study of 4-day accelerated continuous TBS (cTBS) treatment in patients with neocortical drug-resistant epilepsy (DRE). A treatment session consisted of 5 cTBS trains, each comprising 600 pulses presented in 50 Hz triplet bursts every 200 ms, delivered at 10-min intertrain-intervals, targeted over the epileptic focus (EF) using a neuronavigation-guided figure-of-8 coil. Safety and feasibility, and seizure frequency were assessed as primary and secondary endpoints, respectively, over a 4-week baseline period, a 1-week treatment period and a 7-week follow-up period, using adverse event logging, electro-encephalography, cognitive, and psychological questionnaires and a seizure diary kept by the patients and/or caregivers.Results:Seven subjects (4M:3F; median age 48, interquartile ranges 25) underwent the treatment protocol. Adverse events were reported in all subjects but were mild and transient. No clinical or electrographic seizures were evoked during or immediately following stimulation. No deterioration was found in cognition nor in psycho-emotional well-being following treatment. Treatment burden was acceptable, but seems to depend on clinical effect, duration of ongoing effect and stimulation site. Median weekly seizure frequency and ratio of seizure-free weeks did not change significantly in this small patient cohort.Conclusion:We report the results of the first ever trial of cTBS as a treatment for neocortical DRE. A 4-day accelerated cTBS protocol over the EF appears safe and feasible. Although the design and sample size of this open-label pilot study is unfit to reliably identify a therapeutic effect, results encourage further exploration of cTBS as an anti-epileptic treatment and potential optimization compared to conventional rTMS in a dedicated randomized controlled trial. (clinicaltrials.gov: NCT02635633).

Objectives As a potential treatment for epilepsy, transcutaneous auricular vagus nerve stimulation (taVNS) has yielded inconsistent results. Combining transcranial magnetic stimulation with electromyography (TMS-EMG) and electroencephalography (TMS-EEG) can be used to investigate the effect of interventions on cortical excitability by evaluating changes in motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). The goal of this study is to objectively evaluate the effect of taVNS on cortical excitability with TMS-EMG and TMS-EEG. These findings are expected to provide insight in the mechanism of action and help identify more optimal stimulation paradigms. Materials and Methods In this prospective single-blind cross-over study, 15 healthy male subjects underwent active and sham taVNS for 60 min, using a maximum tolerated stimulation current. Single and paired pulse TMS was delivered over the right-sided motor hotspot to evaluate MEPs and TEPs before and after the intervention. MEP statistical analysis was conducted with a two-way repeated measures ANOVA. TEPs were analyzed with a cluster-based permutation analysis. Linear regression analysis was implemented to investigate an association with stimulation current. Results MEP and TEP measurements were not affected by taVNS in this study. An association was found between taVNS stimulation current and MEP outcome measures indicating a decrease in cortical excitability in participants who tolerated higher taVNS currents. A subanalysis of participants (n = 8) who tolerated a taVNS current >= 2.5 mA showed a significant increase in the resting motor threshold, decrease in MEP amplitude and modulation of the P60 and P180 TEP components. Conclusions taVNS did not affect cortical excitability measurements in the overall population in this study. However, taVNS has the potential to modulate specific markers of cortical excitability in participants who tolerate higher stimulation levels. These findings indicate the need for adequate stimulation protocols based on the recording of objective outcome parameters.

AbstractBackgroundAlthough repetitive transcranial magnetic stimulation (rTMS) has been assessed in epileptic humans, clinical trials in epileptic dogs can provide additional insight.ObjectivesEvaluate the potential antiepileptic effect of rTMS in dogs.AnimalsTwelve client‐owned dogs with drug‐resistant idiopathic epilepsy (IE).MethodsSingle‐blinded randomized sham‐controlled clinical trial (dogs allocated to active or sham rTMS) (I) and open‐labeled uncontrolled clinical trial (dogs received active rTMS after sham rTMS) (II). Monthly seizure frequency (MSF), monthly seizure day frequency (MSDF), and number of cluster seizures (CS) were evaluated for a 3‐month pre‐TMS and post‐rTMS period and safety was assessed. The lasting effect period of rTMS was assessed in each dog treated by active stimulation using the MSF ratio (proportion of post‐TMS to pre‐rTMS MSF) and treatment was considered effective if the ratio was <1.ResultsNo adverse effects were reported. In trial I, MSF and MSDF decreased significantly (P= .04) in the active group (n = 7). In the sham group (n = 5), no significant changes were found (P= .84 and .29, respectively). Cluster seizures did not change significantly in either group. No significant differences were detected between the groups. In trial II, previously sham‐treated dogs (n = 5) received active rTMS and significant decreases in MSF and MSDF were noted (P= .03 and .008, respectively). The overall effect of rTMS lasted for 4 months; thereafter, the MSF ratio was >1.Conclusions and Clinical ImportanceRepetitive transcranial magnetic stimulation may be a safe adjunctive treatment option for dogs with drug‐resistant IE, but large‐scale studies are needed to establish firm conclusions.

BACKGROUND AND PURPOSE:In patients treated with vagus nerve stimulation (VNS) for drug resistant epilepsy (DRE), up to a third of patients will eventually not respond to the therapy. As VNS therapy requires surgery for device implantation, prediction of response prior to surgery is desirable. It is hypothesized that neurophysiological investigations related to the mechanisms of action of VNS may help to differentiate VNS responders from non-responders prior to the initiation of therapy.METHODS:In a prospective series of DRE patients, polysomnography, heart rate variability (HRV) and cognitive event related potentials were recorded. Polysomnography and HRV were repeated after 1 year of treatment with VNS. Polysomnography, HRV and cognitive event related potentials were compared between VNS responders (≥50% reduction in seizure frequency) and non-responders.RESULTS:Fifteen out of 30 patients became VNS responders after 1 year of VNS treatment. Prior to treatment with VNS, the amount of deep sleep (NREM 3), the HRV high frequency (HF) power and the P3b amplitude were significantly different in responders compared to non-responders (P = 0.007; P = 0.001; P = 0.03).CONCLUSION:Three neurophysiological parameters, NREM 3, HRV HF and P3b amplitude, were found to be significantly different in DRE patients who became responders to VNS treatment prior to initiation of their treatment with VNS. These non-invasive recordings may be used as characteristics for response in future studies and help avoid unsuccessful implantations. Mechanistically these findings may be related to changes in brain regions involved in the so-called vagal afferent network.

Although repetitive transcranial magnetic stimulation (rTMS) has been assessed in epileptic humans, clinical trials in epileptic dogs can provide additional insight. Evaluate the potential antiepileptic effect of rTMS in dogs. Twelve client-owned dogs with drug-resistant idiopathic epilepsy (IE). Single-blinded randomized sham-controlled clinical trial (dogs allocated to active or sham rTMS) (I) and open-labeled uncontrolled clinical trial (dogs received active rTMS after sham rTMS) (II). Monthly seizure frequency (MSF), monthly seizure day frequency (MSDF), and number of cluster seizures (CS) were evaluated for a 3-month pre-TMS and post-rTMS period and safety was assessed. The lasting effect period of rTMS was assessed in each dog treated by active stimulation using the MSF ratio (proportion of post-TMS to pre-rTMS MSF) and treatment was considered effective if the ratio was <1. No adverse effects were reported. In trial I, MSF and MSDF decreased significantly ( P = .04) in the active group (n = 7). In the sham group (n = 5), no significant changes were found ( P = .84 and .29, respectively). Cluster seizures did not change significantly in either group. No significant differences were detected between the groups. In trial II, previously sham-treated dogs (n = 5) received active rTMS and significant decreases in MSF and MSDF were noted ( P = .03 and .008, respectively). The overall effect of rTMS lasted for 4 months; thereafter, the MSF ratio was >1. Repetitive transcranial magnetic stimulation may be a safe adjunctive treatment option for dogs with drug-resistant IE, but large-scale studies are needed to establish firm conclusions.

Brain stimulation has emerged as an alternative treatment for patients with refractory epilepsy and an increasing number of trials evaluating its efficacy and safety have been published. Various brain structures have been targeted, focusing either on the ictal onset zone or on remote epileptogenic network structures. This chapter focuses on stimulation of the ictal onset zone. The rationale for these targets and the results obtained in open-label and randomized controlled trials (RCTs), when available, are discussed. It is concluded that promising results have been published, although mainly in open-label trials. More RCTs are needed to establish the value of ictal onset stimulation for the treatment of epilepsy.

Neurostimulation is making its way into the therapeutic armamentarium of the epileptologists, with several invasive neurostimulation modalities available today and several less invasive modalities under investigation. Clinicians will soon face a choice that should not be made randomly. We introduce the concept of a prestimulation evaluation protocol, consisting of a series of rationally chosen investigations that evaluate the presence of biomarkers for response to various neurostimulation therapies. These biomarkers should reflect the susceptibility of the individual’s epileptic network to a given neurostimulation technique. This will require elucidation of the specific mechanism(s) of action of the different neurostimulation modalities. This manuscript provides a hypothetical framework that may be more applicable in the near future when pre-clinical research progresses and can be translated into human applications.

Neurostimulation is making its way into the therapeutic armamentarium of the epileptologists, with several invasive neurostimulation modalities available today and several less invasive modalities under investigation. Clinicians will soon face a choice that should not be made randomly. We introduce the concept of a prestimulation evaluation protocol, consisting of a series of rationally chosen investigations that evaluate the presence of biomarkers for response to various neurostimulation therapies. These biomarkers should reflect the susceptibility of the individual's epileptic network to a given neurostimulation technique. This will require elucidation of the specific mechanism(s) of action of the different neurostimulation modalities. This manuscript provides a hypothetical framework that may be more applicable in the near future when pre-clinical research progresses and can be translated into human applications.