Worrell, Gregory A.

Abstract Despite the growing interest in network-guided neuromodulation for epilepsy, uncertainty about the safety and long-term efficacy of thalamocortical stimulation persists. Our evaluation focused on the use of a four-lead open-loop implantable pulse generator for thalamocortical network neuromodulation. We retrospectively reviewed seven patients with diverse seizure networks—poorly localized, regional, or multifocal—undergoing thalamocortical neuromodulation. Employing a four-lead system, electrodes targeted both thalamic and cortical seizure network nodes. We assessed seizure severity, life satisfaction and sleep quality on a 10-point scale, and seizure frequency was assessed via telephone interviews and chart review. Outcomes were assessed by the Wilcoxon sign-rank test at the 0.05 significance level. Seven patients with a median age at implant of 22 years (range 14–42 years) had a median disabling seizure reduction of 93% (range 50–100%, P = 0.0156), with 100% responder rate (≥50% reduction in seizure frequency) after a median of 17 months post-implantation (range 13–60). The median improvement in seizure severity was 3.5 out of 10 points (P = 0.0312), life satisfaction 4.5 points (P = 0.0312) and quality of sleep 3 points (P = 0.062). No perioperative complications occurred. Transient seizure exacerbations (n = 2) and stimulation-related sensory/motor side-effects (n = 2) quickly resolved with parameter adjustments. One patient required surgical revision due to delayed infection. Six patients had permanent electrode placement refined by intracranial EEG trial stimulation; five patients had >90% reduction in seizure frequency during trial stimulation. Thalamocortical network neuromodulation using a four-lead open-loop system is safe and associated with significant improvements in seizure control and patient quality of life. Trial stimulation during intracranial EEG shows promise for enhancing seizure network engagement and parameter optimization but requires further study. Prospective controlled trials are needed to further characterize and validate the efficacy and side-effect profile of thalamocortical network neuromodulation for epilepsy.

AbstractObjectiveThe effects of brain stimulation for diseases like epilepsy are delayed, making stimulation optimization difficult. The parameters for anterior thalamic nuclei (ANT) deep brain stimulation (DBS) for focal drug‐resistant epilepsy management are often restricted to those used in the SANTE landmark trial. There is little evidence regarding effective alternatives, and low‐frequency stimulation is typically neglected. We prospectively compare a widely differing stimulation parameter set to typical settings.MethodsThis randomized, modified crossover, open trial compares the efficacy and safety of an alternative set of parameters using continuous low‐frequency stimulation (cLFS) with a longer pulse width (7 Hz, 200 μs, continuous) compared to SANTE's intermittent high‐frequency stimulation (iHFS) with a short pulse width (145 Hz, 90 μs, cycling 1 min on/5 min off). After 3 months on a randomly assigned first set, patients are switched to the other settings, unless seizure‐free. Patients are re‐evaluated after 3 more months, which marks the completion of the trial. After that, they can either remain on the same settings or switch back.ResultsSixteen patients with a median baseline seizure frequency of 13.8 seizures/month (interquartile range [IQR] = 2.7–22.8) were included in the analysis. At trial completion (median follow‐up = 30 weeks, IQR = 26–35), ANT‐DBS significantly reduced median seizure frequency (62%, IQR = 18–81, Wilcoxon test statistic [W] = 99, p = .008). Both iHFS (33%, IQR = 0–65, W = 81, p = .02) and cLFS (73%, IQR = 30–79, W = 105, p = .001) significantly reduced median seizure frequency. cLFS showed improved median seizure frequency reduction compared to iHFS (W = 63, p = .03) and was not associated with any moderate or severe adverse effects.SignificanceResults support cLFS for ANT‐DBS as a safe and effective alternative to typical iHFS parameters. Stimulation with widely differing parameter sets may be as effective as or, in some situations, more effective than typical stimulation parameters.

Abstract Electrical stimulation is increasingly used to modulate brain networks for clinical purposes. The basic unit of neurostimulation, a single electrical pulse, can travel through white matter to influence connected neuronal populations. However, the mechanisms by which it influences connected populations is not well understood: stimulation may excite, inhibit, or add noise to neuronal population activity. In this study, we investigated how single pulses modulate the neuronal processing of images in a well-controlled visual paradigm. In two human subjects implanted with iEEG electrodes for clinical purposes, single pulses were delivered to electrodes in white matter tracts connected to measurement electrodes in visual cortex. Images appeared on-screen at 0, 100, or 200 ms after each pulse. Using finite impulse response modeling, we decomposed the broadband and evoked potential responses into separate components induced by electrical stimulation and by visual processing. Single pulses induced transient broadband increases followed by suppression, but they did not modulate the visual broadband responses (i.e., stimulation response was additive to visual response). In contrast, single pulses elicited prominent brain stimulation evoked potentials and they modulated the visual evoked potentials. Specifically, visual evoked potentials were larger when stimulation occurred closer to visual onset. This indicates that a single electrical pulse can increase the strength or synchrony of visual inputs. Overall, these findings suggest that the effects of electrical stimulation in the visual system are two-fold: stimulation induces additive effects on broadband power, possibly by adding noise, and it interacts with synchronous visual inputs to amplify them.

Abstract Precise localization of the epileptogenic zone is pivotal for planning minimally invasive surgeries in drug-resistant epilepsy. Here, we present a graph neural network (GNN) framework that integrates interictal intracranial EEG features, electrode topology, and MRI features to automate epilepsy surgery planning. We retrospectively evaluated the model using leave-one-patient-out cross-validation on a dataset of 80 drug-resistant epilepsy patients treated at St. Anne's University Hospital (Brno, Czech Republic), comprising 31 patients with good postsurgical outcomes (Engel I) and 49 with poor outcomes (Engel II–IV). The GNN predictions demonstrated a significantly better (P < 0.05, Mann–Whitney-U test) area under the precision-recall curve in patients with good outcomes (area under the precision-recall curve: 0.69) compared with those with poor outcomes (area under the precision-recall curve: 0.33), indicating that the model captures clinically relevant targets in successful cases. In patients with poor outcomes, the graph neural network proposed alternative intervention sites that diverged from the original clinical plans, highlighting its potential to identify alternative therapeutic targets. We show that topology-aware GNNs significantly outperformed (P < 0.05, Wilcoxon signed-rank test) traditional neural networks while using the same intracranial EEG features, emphasizing the importance of incorporating implantation topology into predictive models. These findings uncover the potential of GNNs to automatically suggest targets for epilepsy surgery, which can assist the clinical team during the planning process.

Abstract Objective Noninvasive brain stimulation (NIBS) provides a treatment option for patients not eligible for surgical intervention or who seek low‐risk approaches and may be used in the hospital, clinic, and at home. Our objective is to summarize our single‐center experience with multiple NIBS approaches for the treatment of focal epilepsy. Methods A retrospective chart review identified drug‐resistant focal epilepsy patients who received NIBS as an epilepsy treatment at Mayo Clinic in Rochester, MN. Patients were typically treated as follows: (1) for TMS, 1 Hz stimulation was applied for five consecutive days in the neuromodulation clinic, (2) for outpatient tDCS, stimulation was applied for five consecutive days in the clinic, followed by optional treatment at home, and (3) for inpatient tDCS, stimulation was applied for three consecutive days. We analyzed continuous EEG data for the inpatient tDCS cohort and available HD‐EEG data for outpatient cohorts to quantify changes in interictal epileptiform discharges (IEDs) as a result of stimulation. Outcomes were assessed at 1 month for TMS and outpatient tDCS and 1 week for inpatient tDCS. Results Twenty‐four patients were treated with TMS ( n = 10) and tDCS ( n = 14, 9 as outpatients). The median age was 40 years (range 15–73). The median seizure reduction following stimulation was 50%. Fourteen patients (58%) were responders to treatment (TMS = 4/10, tDCS Outpatient = 7/9, tDCS Inpatient = 3/5). Five outpatient tDCS participants elected to continue treatment at home. Four TMS and four outpatient tDCS patients underwent high‐density EEG before and after 5 days of therapy. Following stimulation, IED rate was reduced in 4/5 inpatient tDCS patients, 4/4 outpatient tDCS patients, and 4/4 TMS patients. Two patients experienced an increase in seizure frequency (1 following TMS and 1 following outpatient tDCS), which returned to baseline 4–6 weeks after stimulation treatments were discontinued. Significance TMS and tDCS are potential treatment approaches for drug‐resistant focal epilepsy patients in the hospital, clinic, and home. They have a favorable safety profile and can lead to a reduction in IED rates and seizures. These results suggest further studies are needed to examine NIBS as a treatment for epilepsy. Plain Language Summary Noninvasive brain stimulation, such as transcranial magnetic stimulation and transcranial direct current stimulation, offers new treatment options for patients with focal seizures. This study reviewed the experience at Mayo Clinic using noninvasive brain stimulation in the hospital, clinic, and at‐home settings to treat seizures. The results showed an overall 50% median seizure reduction, and 58% of patients had at least a 50% reduction in seizures. Noninvasive brain stimulation is a promising treatment approach with a favorable safety profile.

Abstract The pulvinar has been proposed as an effective neuromodulation target for patients with posterior quadrant and temporal epilepsies. However, the pulvinar has a large tissue volume, multiple subnuclei, and widespread cortical connections. It remains unknown whether electrical stimulation of distinct pulvinar subregions affects the temporal, occipital, and parietal areas differently. To address this gap, we delivered single-pulse electrical stimulation to the pulvinar and measured the resulting brain stimulation evoked potentials in twelve patients undergoing stereotactic EEG for drug-resistant epilepsy. Brain stimulation evoked potentials were parameterized across the occipital, temporal and parietal cortex. Stimulation of the lateral pulvinar elicited significant brain stimulation evoked potentials in striate and extrastriate areas that diminish as stimulation shifts towards the medial pulvinar. Conversely, stimulation of the ventral aspect of the medial pulvinar produced significant lateral temporal evoked potentials, which diminish with lateral pulvinar stimulation. We also found that stimulation of the dorsomedial pulvinar evoked significant parietal responses with limited striate/extrastriate and lateral temporal responses. These results demonstrate that electrical stimulation of specific pulvinar subregions influences distinct occipital, parietal and lateral temporal areas. Selective targeting of pulvinar subregions to maximize seizure network engagement may be essential for individualized treatment of posterior quadrant and temporal epilepsies.