Closed-loop stimulation in periods with less epileptiform activity drives improved epilepsy outcomes.

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

Local accumbens in vivo imaging during deep brain stimulation reveals a strategy-dependent amelioration of hedonic feeding.

Impulsive overeating is a common, disabling feature of eating disorders. Both continuous deep brain stimulation (DBS) and responsive DBS, which limits current delivery to pathological brain states, have emerged as potential therapies. We used in vivo fiber photometry in wild-type, Drd1-cre, and A2a-cre mice to 1) assay subtype-specific medium spiny neuron (MSN) activity of the nucleus accumbens (NAc) during hedonic feeding of high-fat food, and 2) examine DBS strategy-specific effects on NAc activity. D1, but not D2, NAc GCaMP activity increased immediately prior to high-fat food approach. Responsive DBS triggered a GCaMP surge throughout the stimulation period and durably reduced high-fat intake. However, with continuous DBS, this surge decayed, and high-fat intake reemerged. Our results argue for a stimulation strategy-dependent modulation of D1 MSNs with a more sustained decrease in consumption with responsive DBS. This study illustrates the important role in vivo imaging can play in understanding effects of such novel therapies.

Predictors of therapeutic response following thalamic neuromodulation for drug-resistant pediatric epilepsy: A systematic review and individual patient data meta-analysis.

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

National 22-year epilepsy surgery landscape shows increasing open and minimally invasive pediatric epilepsy surgery.

OBJECTIVES: A surgical "treatment gap" in pediatric epilepsy persists despite the demonstrated safety and effectiveness of surgery. For this reason, the national surgical landscape should be investigated such that an updated assessment may more appropriately guide health care efforts. METHODS: In our retrospective cross-sectional observational study, the National Inpatient Sample (NIS) database was queried for individuals 0 to <18 years of age who had an International Classification of Diseases (ICD) code for drug-resistant epilepsy (DRE). This cohort was then split into a medical group and a surgical group. The former was defined by ICD codes for -DRE without an accompanying surgical code, and the latter was defined by DRE and one of the following epilepsy surgeries: any open surgery; laser interstitial thermal therapy (LITT); vagus nerve stimulation; or responsive neurostimulation (RNS) from 1998 to 2020. Demographic variables of age, gender, race, insurance type, hospital charge, and hospital characteristics were analyzed between surgical options. Continuous variables were analyzed with weight-adjusted quantile regression analysis, and categorical variables were analyzed by weight-adjusted counts with percentages and compared with weight-adjusted chi-square test results. RESULTS: These data indicate an increase in epilepsy surgeries over a 22-year period, primarily due to a statistically significant increase in open surgery and a non-significant increase in minimally invasive techniques, such as LITT and RNS. There are significant differences in age, race, gender, insurance type, median household income, Elixhauser index, hospital setting, and size between the medical and surgical groups, as well as the procedure performed. SIGNIFICANCE: An increase in open surgery and minimally invasive surgeries (LITT and RNS) account for the overall rise in pediatric epilepsy surgery over the last 22 years. A positive inflection point in open surgery is seen in 2005. Socioeconomic disparities exist between medical and surgical groups. Patient and hospital sociodemographics show significant differences between the procedure performed. Further efforts are required to close the surgical "treatment gap."

Racial disparities in the utilization of invasive neuromodulation devices for the treatment of drug-resistant focal epilepsy.

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

Optimization of closed-loop electrical stimulation enables robust cerebellar-directed seizure control.

Additional treatment options for temporal lobe epilepsy are needed, and potential interventions targeting the cerebellum are of interest. Previous animal work has shown strong inhibition of hippocampal seizures through on-demand optogenetic manipulation of the cerebellum. However, decades of work examining electrical stimulation-a more immediately translatable approach-targeting the cerebellum has produced very mixed results. We were therefore interested in exploring the impact that stimulation parameters may have on seizure outcomes. Using a mouse model of temporal lobe epilepsy, we conducted on-demand electrical stimulation of the cerebellar cortex, and varied stimulation charge, frequency and pulse width, resulting in over 1000 different potential combinations of settings. To explore this parameter space in an efficient, data-driven, manner, we utilized Bayesian optimization with Gaussian process regression, implemented in MATLAB with an Expected Improvement Plus acquisition function. We examined three different fitting conditions and two different electrode orientations. Following the optimization process, we conducted additional on-demand experiments to test the effectiveness of selected settings. Regardless of experimental setup, we found that Bayesian optimization allowed identification of effective intervention settings. Additionally, generally similar optimal settings were identified across animals, suggesting that personalized optimization may not always be necessary. While optimal settings were effective, stimulation with settings predicted from the Gaussian process regression to be ineffective failed to provide seizure control. Taken together, our results provide a blueprint for exploration of a large parameter space for seizure control and illustrate that robust inhibition of seizures can be achieved with electrical stimulation of the cerebellum, but only if the correct stimulation parameters are used.

Optogenetic stimulation of the superior colliculus suppresses genetic absence seizures.

While anti-seizure medications are effective for many patients, nearly one-third of individuals have seizures that are refractory to pharmacotherapy. Prior studies using evoked preclinical seizure models have shown that pharmacological activation or excitatory optogenetic stimulation of the deep and intermediate layers of the superior colliculus (DLSC) display multi-potent anti-seizure effects. Here we monitored and modulated DLSC activity to suppress spontaneous seizures in the WAG/Rij genetic model of absence epilepsy. Female and male WAG/Rij adult rats were employed as study subjects. For electrophysiology studies, we recorded single unit activity from microwire arrays placed within the DLSC. For optogenetic experiments, animals were injected with virus coding for channelrhodopsin-2 or a control vector, and we compared the efficacy of continuous neuromodulation to that of closed-loop neuromodulation paradigms. For each, we compared three stimulation frequencies on a within-subject basis (5, 20, 100 Hz). For closed-loop stimulation, we detected seizures in real time based on the EEG power within the characteristic frequency band of spike-and-wave discharges (SWDs). We quantified the number and duration of each SWD during each 2 h-observation period. Following completion of the experiment, virus expression and fibre-optic placement was confirmed. We found that single-unit activity within the DLSC decreased seconds prior to SWD onset and increased during and after seizures. Nearly 40% of neurons displayed suppression of firing in response to the start of SWDs. Continuous optogenetic stimulation of the DLSC (at each of the three frequencies) resulted in a significant reduction of SWDs in males and was without effect in females. In contrast, closed-loop neuromodulation was effective in both females and males at all three frequencies. These data demonstrate that activity within the DLSC is suppressed prior to SWD onset, increases at SWD onset, and that excitatory optogenetic stimulation of the DLSC exerts anti-seizure effects against absence seizures. The striking difference between open- and closed-loop neuromodulation approaches underscores the importance of the stimulation paradigm in determining therapeutic effects.

Patient experiences of resection versus responsive neurostimulation for drug-resistant epilepsy.

This study explored illness experiences and decision-making among patients with epilepsy who underwent two different types of surgical interventions: resection versus implantation of the NeuroPace Responsive Neurostimulation System (RNS). We recruited 31 participants from a level four epilepsy center in an academic medical institution. We observed 22 patient clinic visits (resection: n = 10, RNS: n = 12) and conducted 18 in-depth patient interviews (resection: n = seven, RNS: n = 11); most visits and interviews included patient caregivers. Using an applied ethnographic approach, we identified three major themes in the experiences of resection versus RNS patients. First, for patients in both cohorts, the therapeutic journey was circuitous in ways that defied standardized first-, second-, and third- line of care models. Second, in conceptualizing risk, resection patients emphasized the permanent loss of "taking out" brain tissue whereas RNS patients highlighted the reversibility of "putting in" a device. Lastly, in considering benefit, resection patients perceived their surgery as potentially curative while RNS patients understood implantation as primarily palliative with possible additional diagnostic benefit from chronic electrocorticography. Insight into the perspectives of patients and caregivers may help identify key topics for counseling and exploration by clinicians.

The role of neuromodulation in the management of drug-resistant epilepsy.

Drug-resistant epilepsy (DRE) poses significant challenges in terms of effective management and seizure control. Neuromodulation techniques have emerged as promising solutions for individuals who are unresponsive to pharmacological treatments, especially for those who are not good surgical candidates for surgical resection or laser interstitial therapy (LiTT). Currently, there are three neuromodulation techniques that are FDA-approved for the management of DRE. These include vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). Device selection, optimal time, and DBS and RNS target selection can also be challenging. In general, the number and localizability of the epileptic foci, alongside the comorbidities manifested by the patients, substantially influence the selection process. In the past, the general axiom was that DBS and VNS can be used for generalized and localized focal seizures, while RNS is typically reserved for patients with one or two highly localized epileptic foci, especially if they are in eloquent areas of the brain. Nowadays, with the advance in our understanding of thalamic involvement in DRE, RNS is also very effective for general non-focal epilepsy. In this review, we will discuss the underlying mechanisms of action, patient selection criteria, and the evidence supporting the use of each technique. Additionally, we explore emerging technologies and novel approaches in neuromodulation, such as closed-loop systems. Moreover, we examine the challenges and limitations associated with neuromodulation therapies, including adverse effects, complications, and the need for further long-term studies. This comprehensive review aims to provide valuable insights on present and future use of neuromodulation.

Disparities in Access to Deep Brain Stimulation and Responsive Neurostimulation Approaches to Drug-Resistant Epilepsy.

BACKGROUND: Epilepsy affects 1% to 2% of the global population, and those who are resistant to medical treatment may be candidates for neuromodulation. In select populations, brain stimulation approaches including deep brain stimulation (DBS) and responsive neurostimulation (RNS) are used. Although studies have shown that patients from Black, Hispanic, lower income, and rural communities have less access to epilepsy care and have lower rates of epilepsy surgery, disparities in the use of brain stimulation for epilepsy treatment are currently not known. MATERIALS AND METHODS: We queried the US National Inpatient Sample data base from January 1, 2014 to December 31, 2019 for all patients discharged with an International Classification of Diseases (ICD) Ninth Revision or ICD Tenth Revision diagnosis of drug-resistant epilepsy. Among these patients discharged, the rates of brain stimulation treatment, including DBS and RNS, were reported in each subgroup of race, ethnicity, and insurance. To generate national estimates, all analyses were weighted. RESULTS: A total of 237,895 patients discharged with drug-resistant epilepsy were identified, of whom 4,925 (2.1%) received brain stimulation treatment for drug-resistant epilepsy. Black patients (n = 420, 0.9%, odds ratio [OR] = 0.51, 95% CI [0.40, 0.64]) were less likely to receive brain stimulation treatment than were White patients (n = 3300, 2.4%). There was no significant difference between Asian (n = 105, 2.3%, OR = 0.80, 95% CI [0.53, 1.33]) and Hispanic (n = 655, 2.6%, OR = 0.95, 95% CI [0.77, 1.17]) patients and White patients. No significant difference was observed between female (n = 2515, 2.1%, OR = 1.02, 95% CI [0.89, 1.17]) and male (n = 2410, 2.0%) patients either. Patients with Medicare (n = 1150, 1.2%, OR = 0.69, 95% CI [0.57, 0.84]) or Medicaid (n = 1150, 1.8%, OR = 0.52, 95% CI [0.44, 0.62]) were less likely to receive brain stimulation treatment than were those with private insurance as the primary payer (n = 2370, 3.9%). CONCLUSIONS: We discovered significant disparities in the use of brain stimulation treatments for drug-resistant epilepsy based on race and insurance status. More research will be required to determine the cause of these disparities.

Stimulation better targets fast-ripple generating networks in super responders to the responsive neurostimulator system.

How responsive neurostimulation (RNS) decreases seizure frequency is unclear. Stimulation may alter epileptic networks during inter-ictal epochs. Definitions of the epileptic network vary but fast ripples (FRs) may be an important substrate. We, therefore, examined whether stimulation of FR-generating networks differed in RNS super responders and intermediate responders. In 10 patients, with subsequent RNS placement, we detected FRs from stereo-electroencephalography (SEEG) contacts during pre-surgical evaluation. The normalized coordinates of the SEEG contacts were compared with those of the eight RNS contacts, and RNS-stimulated SEEG contacts were defined as those within 1.5 cm3 of the RNS contacts. We compared the post-RNS placement seizure outcome to (1) the ratio of stimulated SEEG contacts in the seizure-onset zone (SOZ stimulation ratio [SR]); (2) the ratio of FR events on stimulated contacts (FR SR); and (3) the global efficiency of the FR temporal correlational network on stimulated contacts (FR SGe). We found that the SOZ SR (p = .18) and FR SR (p = .06) did not differ in the RNS super responders and intermediate responders, but the FR SGe did (p = .02). In super responders, highly active desynchronous sites of the FR network were stimulated. RNS that better targets FR networks, as compared to the SOZ, may reduce epileptogenicity more.

Responsive neurostimulation with low-frequency stimulation.

Deep brain stimulation and responsive neurostimulation (RNS) use high-frequency stimulation (HFS) per the pivotal trials and manufacturer-recommended therapy protocols. However, not all patients respond to HFS. In this retrospective case series, 10 patients implanted with the RNS System were programmed with low-frequency stimulation (LFS) to treat their seizures; nine of these patients were previously treated with HFS (100 Hz or greater). LFS was defined as frequency < 10 Hz. Burst duration was increased to at least 1000 ms. With HFS, patients had a median seizure reduction (MSR) of 13% (interquartile range [IQR] = -67 to 54) after a median of 19 months (IQR = 8-49). In contrast, LFS was associated with a 67% MSR (IQR = 13-95) when compared to HFS and 76% MSR (IQR = 43-91) when compared to baseline prior to implantation. Charge delivered per hour and pulses per day were not significantly different between HFS and LFS, although time stimulated per day was longer for LFS (228 min) than for HFS (7 min). There were no LFS-specific adverse effects reported by any of the patients. LFS could represent an alternative, effective method for delivering stimulation in focal drug-resistant epilepsy patients treated with the RNS System.

Chronic intracranial recordings after resection for epilepsy reveal a "running down" of epileptiform activity.

We describe an electrical "running down" phenomenon and also a consistent spectral change (in the aperiodic component of the power spectrum) derived from chronic interictal electrocorticography (ECoG) after surgery in a patient with drug-resistant epilepsy. These data were recorded using a closed-loop neurostimulation system that was implanted after resection. The patient has been seizure-free for 2.5 years since resection without requiring the neurostimulator to be turned on to stimulate. Concurrently, there was an exponential decrease in the number of epileptiform electrographic detections recorded by the device, particularly over the first 26 weeks, indicative of an electrical running down phenomenon as the brain adapted to an extended period of seizure freedom. We also find that the aperiodic exponent of the power spectrum gradually decreases over time. The aperiodic component of intracranial ECoG may represent a novel marker of epileptogenicity, independent of seizures.

Towards network-guided neuromodulation for epilepsy.

Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce seizures in adults with focal-onset epilepsy; and there is emerging evidence for their efficacy in children and generalized-onset seizure disorders. The convergence of these advancing fields is driving an era of 'network-guided neuromodulation' for epilepsy. In this review, we distil the current literature on network mechanisms underlying neurostimulation for epilepsy. We discuss the modulation of key 'propagation points' in the epileptogenic network, focusing primarily on thalamic nuclei targeted in current clinical practice. These include (i) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (ii) the centromedian nucleus of the thalamus, a target for both deep brain stimulation and responsive neurostimulation in generalized-onset epilepsies. We discuss briefly the networks associated with other emerging neuromodulation targets, such as the pulvinar of the thalamus, piriform cortex, septal area, subthalamic nucleus, cerebellum and others. We report synergistic findings garnered from multiple modalities of investigation that have revealed structural and functional networks associated with these propagation points - including scalp and invasive EEG, and diffusion and functional MRI. We also report on intracranial recordings from implanted devices which provide us data on the dynamic networks we are aiming to modulate. Finally, we review the continuing evolution of network-guided neuromodulation for epilepsy to accelerate progress towards two translational goals: (i) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (ii) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizure propagation through mapping and modulation of each patients' individual epileptogenic networks.

Efficacy of different strategies of responsive neurostimulation on seizure control and their association with acute neurophysiological effects in rats.

Responsive neurostimulation (RNS) has shown promising but limited efficacy in the treatment of drug-resistant epilepsy. The clinical utility of RNS is hindered by the incomplete understanding of the mechanism behind its therapeutic effects. Thus, assessing the acute effects of responsive stimulation (AERS) based on intracranial EEG recordings in the temporal lobe epilepsy rat model may provide a better understanding of the potential therapeutic mechanisms underlying the antiepileptic effect of RNS. Furthermore, clarifying the correlation between AERS and seizure severity may help guide the optimization of RNS parameter settings. In this study, RNS with high (130 Hz) and low frequencies (5 Hz) was applied to the subiculum (SUB) and CA1. To quantify the changes induced by RNS, we calculated the AERS during synchronization by Granger causality and analyzed the band power ratio in the classic power band after different stimulations were delivered in the interictal and seizure onset periods, respectively. This demonstrates that only targets combined with an appropriate stimulation frequency could be efficient for seizure control. High-frequency stimulation of CA1 significantly shortened the ongoing seizure duration, which may be causally related to increased synchronization after stimulation. Both high-frequency stimulation of the CA1 and low-frequency stimulation delivered to the SUB reduced seizure frequency, and the reduced seizure risk may correlate with the change in power ratio near the theta band. It indicated that different stimulations may control seizures in diverse manners, perhaps with disparate mechanisms. More focus should be placed on understanding the correlation between seizure severity and synchronization and rhythm around theta bands to simplify the process of parameter optimization.

The effect of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes in drug-resistant epilepsy.

OBJECTIVE: The impact of responsive neurostimulation (RNS) on neuropsychiatric and psychosocial outcomes has not been extensively evaluated outside of the original clinical trials and post-approval studies. The goal of this study was to ascertain the potential real-world effects of RNS on cognitive, psychiatric, and quality of life (QOL) outcomes in relation to seizure outcomes by examining 50 patients undergoing RNS implantation for drug-resistant epilepsy (DRE). METHODS: We performed a retrospective review of all patients treated at our institution with RNS for DRE with at least 12 months of follow-up. In addition to baseline demographic and disease-related characteristics, we collected cognitive (Full-Scale Intelligence Quotient, Verbal Comprehension, and Perceptual Reasoning Index), psychiatric (Beck Depression and Anxiety Inventory Scores), and QOL (QOLIE-31) outcomes at 6 and 12 months after RNS implantation and correlated them with seizure outcomes. RESULTS: Fifty patients (median age 39.5 years, 64% female) were treated with RNS for DRE in our institution from 2005 to 2020. Of the 37 of them who had well-documented pre and post-implantation seizure diaries, the 6-month median seizure frequency reduction was 88%, the response rate (50% or greater seizure frequency reduction) was 78%, and 32% of patients were free of disabling seizures in this timeframe. There was no statistically significant difference at a group level in any of the evaluated cognitive, psychiatric, and QOL outcomes at 6 and 12 months post-implantation compared to the pre-implantation baseline, irrespective of seizure outcomes, although a subset of patients experienced a decline in mood or cognitive variables. SIGNIFICANCE: Responsive neurostimulation does not appear to have a statistically significant negative or positive impact on neuropsychiatric and psychosocial status at the group level. We observed significant variability in outcome, with a minority of patients experiencing worse behavioral outcomes, which seemed related to RNS implantation. Careful outcome monitoring is required to identify the subset of patients experiencing a poor response and to make appropriate adjustments in care.

Distinct Biomarkers of ANT Stimulation and Seizure Freedom in an Epilepsy Patient with Ambulatory Hippocampal Electrocorticography.

INTRODUCTION: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) and responsive neurostimulation (RNS) of the hippocampus are the predominant approaches to brain stimulation for treating mesial temporal lobe epilepsy (MTLE). Both are similarly effective at reducing seizures in drug-resistant patients, but the underlying mechanisms are poorly understood. In rare cases where it is clinically indicated to use RNS and DBS simultaneously, ambulatory electrophysiology from RNS may provide the opportunity to measure the effects of ANT DBS in the putative seizure onset zone and identify biomarkers associated with clinical improvement. Here, one such patient became seizure free, allowing us to identify and compare the changes in hippocampal electrophysiology associated with ANT stimulation and seizure freedom. METHODS: Ambulatory electrocorticography and clinical history were retrospectively analyzed for a patient treated with RNS and DBS for MTLE. DBS artifacts were used to identify ANT stimulation periods on RNS recordings and measure peri-stimulus electrographic changes. Clinical history was used to determine the chronic electrographic changes associated with seizure freedom. RESULTS: ANT stimulation acutely suppressed hippocampal gamma (25-90Hz) power, with minimal theta (4-8Hz) suppression and without clear effects on seizure frequency. Eventually, the patient became seizure free alongside the emergence of chronic gamma increase and theta suppression, which started at the same time as clobazam was introduced. Both seizure freedom and the associated electrophysiology persisted after inadvertent DBS discontinuation, further implicating the clobazam relationship. Unexpectedly, RNS detections and long episodes increased, although they were not considered to be electrographic seizures, and the patient remained clinically seizure free. CONCLUSION: ANT stimulation and seizure freedom were associated with distinct, dissimilar spectral changes in RNS-derived electrophysiology. The time course of these changes supported a new medication as the most likely cause of clinical improvement. Broadly, this work showcases the use of RNS recordings to interpret the effects of multimodal therapy. Specifically, it lends additional credence to hippocampal theta suppression as a biomarker previously associated with seizure reduction in RNS patients.

Evidence for Thalamic Responsive Neurostimulation in Treatment of Adult and Pediatric Epilepsy.

Responsive neurostimulation (RNS) has well-established efficacy in patients with identifiable seizure foci. Emerging evidence suggests the feasibility of expanding this treatment to patients with nonfocal or multifocal epileptic profiles with thalamic targeting. Our institution performed two successful implantations of thalamic RNS (tRNS) targeting the centromedian nucleus of the thalamus (CMT), and 1-year postoperative outcomes are provided. Additionally, a literature review of all reported tRNS was conducted. Publications were excluded if they did not include demographic data and/or epilepsy outcomes at follow-up. In the literature, 19 adult and 3 pediatric cases were identified. These cases were analyzed for outcome, indications, previous operations, and surgical practice variations. Both of our patients had failed multiple previous pharmacological and neurosurgical interventions for epilepsy. Case #1 underwent tRNS with bilateral CMT stimulation. Case #2 underwent tRNS with simultaneous right CMT and right insular stimulation, although an additional lead was placed in the left CMT and left capped for potential future use. Each has achieved ≥90% reduction in seizure burden and approach seizure freedom. 71% of patients in the literature review had multifocal, bilateral, or cryptogenic seizure onset. Three patients were implanted for Lennox Gastaut (2 of 3 are pediatric). 16 patients underwent an average of 1.6 failed procedures prior to successful tRNS implantation. Taken together, the 21 adult patients reviewed have experienced an average seizure reduction of 77% at the latest follow-up. 95% of the adult patients reported in the literature experienced >50% reduction in seizure activity following tRNS and 52% experienced ≥90% reduction in seizure burden following tRNS. Pediatric patients have experienced 70-100% improvement.

Publication Rates and Characteristics of Clinical Trials in Deep Brain and Responsive Neurostimulation.

INTRODUCTION: Prompt dissemination of clinical trial results is essential for ensuring the safety and efficacy of intracranial neurostimulation treatments, including deep brain stimulation (DBS) and responsive neurostimulation (RNS). However, the frequency and completeness of results publication, and reasons for reporting delays, are unknown. Moreover, the patient populations, targeted anatomical locations, and stimulation parameters should be clearly reported for both reproducibility and to identify lacunae in trial design. Here, we examine DBS and RNS trials from 1997 to 2022, chart their characteristics, and examine rates and predictors of results reporting. METHODS: Trials were identified using ClinicalTrials.gov. Associated publications were identified using ClinicalTrials.gov and PubMed.gov. Pearson's χ2 tests were used to assess differences in trial characteristics between published and unpublished trials. RESULTS: Across 449 trials, representing a cumulative cohort of 42,769 patient interventions, there were 37 therapeutic indications and 44 stimulation targets. The most common indication and target were Parkinson's disease (40.55%) and the subthalamic nucleus (35.88%), respectively. Only 0.89% of trials were in pediatric patients (11.58% were mixed pediatric and adult). Explored targets represented 75% of potential basal ganglia targets but only 29% of potential thalamic targets. Allowing a 1-year grace period after trial completion, 34/169 (20.12%) had results reported on ClinicalTrials.gov, and 107/169 (63.31%) were published. ∼80% of published trials included details about stimulation parameters used. Published and unpublished trials did not significantly differ by trial characteristics. CONCLUSION: We highlight key knowledge and performance gaps in DBS and RNS trial research. Over one-third of trials remain unpublished >1 year after completion; pediatric trials are scarce; most of the thalamus remains unexplored; about one-in-five trials fail to report stimulation parameters; and movement disorders comprise the most studied indications.

Ambulatory Local Field Potential Recordings from the Thalamus in Epilepsy: A Feasibility Study.

INTRODUCTION: Stimulation of the thalamus is gaining favor in the treatment of medically refractory multifocal and generalized epilepsy. Implanted brain stimulators capable of recording ambulatory local field potentials (LFPs) have recently been introduced, but there is little information to guide their use in thalamic stimulation for epilepsy. This study sought to assess the feasibility of chronically recording ambulatory interictal LFP from the thalamus in patients with epilepsy. METHODS: In this pilot study, ambulatory LFP was recorded from patients who underwent sensing-enabled deep brain stimulation (DBS, 2 participants) or responsive neurostimulation (RNS, 3 participants) targeting the anterior nucleus of the thalamus (ANT, 2 electrodes), centromedian nucleus (CM, 7 electrodes), or medial pulvinar (PuM, 1 electrode) for multifocal or generalized epilepsy. Time-domain and frequency-domain LFP was investigated for epileptiform discharges, spectral peaks, circadian variation, and peri-ictal patterns. RESULTS: Thalamic interictal discharges were visible on ambulatory recordings from both DBS and RNS. At-home interictal frequency-domain data could be extracted from both devices. Spectral peaks were noted at 10-15 Hz in CM, 6-11 Hz in ANT, and 19-24 Hz in PuM but varied in prominence and were not visible in all electrodes. In CM, 10-15 Hz power exhibited circadian variation and was attenuated by eye opening. CONCLUSION: Chronic ambulatory recording of thalamic LFP is feasible. Common spectral peaks can be observed but vary between electrodes and across neural states. DBS and RNS devices provide a wealth of complementary data that have the potential to better inform thalamic stimulation for epilepsy.