Lundstrom, Brian N.

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.

Importance The role and safety of transcranial electrical stimulation (tES) for treating depressive disorders remain under evaluation. Objective To evaluate tES treatment in patients with major depressive disorder (MDD) and comorbid depressive conditions. Data Sources A search of MEDLINE, Embase, Cochrane, APA PsycINFO, and Scopus databases was conducted from inception to September 17, 2024. Study Selection Randomized clinical trials (RCTs) of adults with MDD, depression with psychiatric comorbidities (DPC), or depression with medical comorbidities (DMC), treated with transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or transcranial random noise stimulation (tRNS), compared with sham or other treatments were included. Data Extraction and Synthesis Independent reviewers extracted data in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, with random-effects meta-analysis used for pooling. Main Outcomes and Measures Primary outcomes were depression severity, response and remission rates, and adverse events. Standardized mean differences (SMDs) were reported for continuous outcomes, and odds ratios (ORs) were reported for categorical outcomes. Quality of evidence (QOE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. Results The meta-analysis included 5522 participants from 114 study groups from 88 RCTs (3198 female [58.9%]; mean [range] age, 43.1 [19.4-76.9] years). Most studies (104 study groups from 79 RCTs [91.2%]) evaluated tDCS, while 7 study groups from 6 RCTs (6.1%) evaluated tACS, and 3 study groups from 3 RCTs (2.7%) evaluated tRNS. tES was associated with reduced depressive symptoms (SMD = −0.59; 95% CI, −0.83 to −0.35; low QOE) and improvement in DMC (SMD = −1.05; 95% CI, −1.67 to −0.43; low QOE) and DPC (SMD = −0.78; 95% CI, −1.27 to −0.29; low QOE) compared with MDD (SMD = −0.22; 95% CI, −0.44 to 0.01; low QOE). tDCS was associated with reduced depression in DMC (SMD = −1.05; 95% CI, −1.70 to −0.40; very low QOE) and DPC (SMD = −0.88; 95% CI, −1.40 to −0.36; low QOE) but not MDD. tACS was associated with improved MDD symptoms (SMD = −0.58; 95% CI, −0.96 to −0.20; high QOE) and response rates (OR, 2.07; 95% CI, 1.34 to 3.19; high QOE). Combined tDCS and medication was associated with reduced symptoms (SMD = −0.51; 95% CI, −0.90 to −0.13; moderate QOE) and increased response (OR, 2.25; 95% CI, 1.08 to 4.65; high QOE) in MDD. tDCS combined with psychotherapy was not associated with improvement. Subgroup analysis showed that anodal left dorsolateral prefrontal cortex DCS was associated with improved outcomes. Mild to moderate adverse events were more frequent in tES groups. Conclusions and Relevance In this systematic review and meta-analysis, tDCS was associated with improvement in depression among patients with DMC and DPC (with smaller benefits in MDD), tACS was associated with improved MDD outcomes (while tRNS had insufficient evidence) in smaller samples, and combined tDCS and medication was associated with improvement in depression. These findings suggest that tES is well-tolerated overall, with only mild to moderate adverse events, and that future research should optimize stimulation parameters and individualize tES interventions.

Summary: Epilepsy neuromodulation treatment failure is a significant challenge, with multiple possible causes. The responsive neurostimulation (RNS) system delivers stimulation from a single current source, and the relative flow of the electrical current through each stimulating contact is inversely proportional to the relative impedance of each contact. Current shunting through low-impedance contacts (i.e., intraventricular contacts) can divert therapy away from the intended targets and may be a cause of treatment failure. We present a case of a patient with bitemporal epilepsy and bitemporal encephaloceles, with poor response to bilateral mesial temporal RNS, who completed stereotactic EEG (sEEG) monitoring to investigate the possible causes of treatment failure. The sEEG was safely completed without damaging the RNS device. The sEEG recorded independent bitemporal interictal epileptiform discharges and seizures, which did not arise from sampled encephalocele regions. The sEEG-recorded RNS stimulation artifact was reduced in the left mesial temporal region relative to the right, which suggested potential current shunting through the right-sided contacts. Impedance measurements confirmed several low-impedance contacts from the right lead, with associated intraventricular position on imaging. At last follow up, 161 days after replacement of the right lead, the patient experienced an additional 58% reduction in seizure burden. Effective therapy delivery by single-current-source neurostimulation systems, such as RNS, critically depends on relative electrode impedances. Current shunting through low-impedance contacts is an underappreciated potential cause of treatment failure. Routine impedance assessments and individualized stimulation programs are recommended to avoid unintended current diversion. Concurrent sEEG monitoring and active RNS are feasible and can characterize stimulation effects.

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 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.

AbstractObjectiveNeuromodulation for pediatric refractory epilepsy (PRE) is preferred when the seizure onset zone is not amenable to surgical resection, due to multifocal onset or involvement of eloquent cortex. Given its rapidly evolving landscape, we describe our institutional experience with neurostimulation therapies including deep brain stimulation (DBS) of the anterior nucleus (DBS‐ANT), the centromedian nucleus (DBS‐CM), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS) to treat PRE.MethodsA retrospective chart review was conducted to identify pediatric patients (≤18 years of age) who presented to our institution with PRE. Patients were included who had at least 1 year of follow‐up after neurostimulation was started. Patients with ≥50% seizure frequency reduction at last follow‐up compared to baseline were classified as responders.ResultsA total of 35 patients (21 females) were included in the series. Nine patients underwent DBS‐ANT, 9 underwent DBS‐CM (+ ANT in 7 patients), 5 underwent RNS, and 12 underwent CSS. The median age at seizure onset and surgery was 8 and 16 years, respectively. Structural lesions were the most common etiology of epilepsy (54%). Eighteen patients had prior interventions and 13 received invasive EEG. Post‐operative complications following neurostimulation implantation were noted in three patients (9%). However, no permanent deficits were noted. Median follow‐up time was 46 months (range 13–162 months). Twenty‐three patients (59%) were responders (3/9 DBS‐ANT; 7/9 DBS‐CM; 4/5 RNS; 9/12 CSS). Further, median seizure reduction was 25% (DBS‐ANT), 89% (DBS‐CM), 87% (RNS), and 88% (CSS) across the cohort. Six patients (17%) had improved subjective neurocognitive outcomes while the other 29 had stable neurocognitive outcomes.SignificanceDBS, RNS, and CSS are safe and effective options for PRE. An understanding of treatment approaches can optimize results by tailoring therapy to individual patients.Plain Language SummaryThis study investigates the use of various neurostimulation therapies for treating pediatric refractory epilepsy (PRE) including deep brain stimulation (DBS), responsive neurostimulation (RNS), and chronic subthreshold stimulation (CSS). Overall, neuromodulation was found to be effective in reducing seizures in most patients, with 59% of patients showing at least a 50% reduction in seizure frequency. Additionally, the treatments were generally safe, with few complications and no instances of permanent deficits.