Assessing expert reliability in determining intracranial EEG channel quality and introducing the automated bad channel detection algorithm.

Objective.To evaluate the inter- and intra-rater reliability for the identification of bad channels among neurologists, EEG Technologists, and naïve research personnel, and to compare their performance with the automated bad channel detection (ABCD) algorithm for detecting bad channels.Approach.Six Neurologists, ten EEG Technologists, and six naïve research personnel (22 raters in total) were asked to rate 1440 real intracranial EEG channels as good or bad. Intra- and interrater kappa statistics were calculated for each group. We then compared each group to the ABCD algorithm which uses spectral and temporal domain features to classify channels as good or bad.Main results.Analysis of channel ratings from our participants revealed variable intra-rater reliability within each group, with no significant differences across groups. Inter-rater reliability was moderate among neurologists and EEG Technologists but minimal among naïve participants. Neurologists demonstrated a slightly higher consistency in ratings than EEG Technologists. Both groups occasionally misclassified flat channels as good, and participants generally focused on low-frequency content for their assessments. The ABCD algorithm, in contrast, relied more on high-frequency content. A logistic regression model showed a linear relationship between the algorithm's ratings and user responses for predominantly good channels, but less so for channels rated as bad. Sensitivity and specificity analyses further highlighted differences in rating patterns among the groups, with neurologists showing higher sensitivity and naïve personnel higher specificity.Significance.Our study reveals the bias in human assessments of intracranial electroencephalography (iEEG) data quality and the tendency of even experienced professionals to overlook certain bad channels, highlighting the need for standardized, unbiased methods. The ABCD algorithm, outperforming human raters, suggests the potential of automated solutions for more reliable iEEG interpretation and seizure characterization, offering a reliable approach free from human biases.

Friendship Homophily Trajectories among Asian American Youth from High School to College.

Friendship racial homophily, the tendency to form friendships with individuals who share the same racial background, is a normative developmental phenomenon that holds particular significance for youth of color in a racialized society. Yet, there exists a paucity of longitudinal research elucidating the stability and change of friendship racial composition across developmental span. This study aimed to examine the friendship racial homophily trajectories over a six-year period encompassing four time points. The sample comprised 437 Asian American youth (MAge = 16.52, SDAge = 1.36, 53% female), with 197 Filipino and 240 Korean participants. Using logistic multilevel modeling analyses, it was found that both Filipino and Korean American youth demonstrated an increase in friendship racial homophily from high school to college, but that Filipino youth overall reported lower levels of racial homophily compared to their Korean counterparts. The study findings also pinpointed several influential factors impacting these trajectories, including proficiency in heritage languages, ethnic identity, and encounters with racial discrimination from both White Americans and other People of Color. These results highlight the continuous evolution of friendship racial composition from high school to college and emphasize the crucial role of ethnic identity and experiences of discrimination in influencing these dynamics, with ethnic identity exerting more enduring effects and experiences of discrimination showing more situational impacts on the levels of racial homophily.

A toolkit for planning and implementing acute febrile illness (AFI) surveillance.

Acute febrile illness (AFI) is a broad clinical syndrome with a wide range of potential infectious etiologies. The lack of accessible, standardized approaches to conducting AFI etiologic investigations has contributed to significant global gaps in data on the epidemiology of AFI. Based on lessons learned from years of supporting AFI sentinel surveillance worldwide, the U.S. Centers for Disease Control and Prevention developed the toolkit for planning and implementing AFI surveillance, described here. This toolkit provides a comprehensive yet flexible framework to guide researchers, public health officials, and other implementers in developing a strategy to identify and/or monitor the potential causes of AFI. The toolkit comprises a cohesive set of planning aids and supporting materials, including an implementation framework, generic protocol, several generic forms (including screening, case report, specimen collection and testing, and informed consent and assent), and a generic data dictionary. These materials incorporate key elements intended to harmonize approaches for AFI surveillance, as well as setting-specific components and considerations for adaptation based on local surveillance objectives and limitations. Appropriate adaptation and implementation of this toolkit may generate data that expand the global AFI knowledge base, strengthen countries' surveillance and laboratory capacity, and enhance outbreak detection and response efforts.

Implantation accuracy of novel polyimide stereotactic electroencephalographic depth electrodes-a human cadaveric study.

Introduction: Stereoelectroencephalography (sEEG) is a minimally invasive procedure that uses depth electrodes stereotactically implanted into brain structures to map the origin and propagation of seizures in epileptic patients. Implantation accuracy of sEEG electrodes plays a critical role in the safety and efficacy of the procedure. This study used human cadaver heads, simulating clinical practice, to evaluate (1) neurosurgeon's ability to implant a new thin-film polyimide sEEG electrode according to the instructions for use (IFU), and (2) implantation accuracy. Methods: Four neurosurgeons (users) implanted 24 sEEG electrodes into two cadaver heads with the aid of the ROSA robotic system. Usability was evaluated using a questionnaire that assessed completion of all procedure steps per IFU and user errors. For implantation accuracy evaluation, planned electrode trajectories were compared with post-implantation trajectories after fusion of pre- and postoperative computer tomography (CT) images. Implantation accuracy was quantified using the Euclidean distance for entry point error (EPE) and target point error (TPE). Results: All sEEG electrodes were successfully placed following the IFU without user errors, and post-implant survey of users showed favorable handling characteristics. The EPE was 1.28 ± 0.86 mm and TPE was 1.61 ± 0.89 mm. Long trajectories (>50 mm) had significantly larger EPEs and TPEs than short trajectories (<50 mm), and no differences were found between orthogonal and oblique trajectories. Accuracies were similar or superior to those reported in the literature when using similar experimental conditions, and in the same range as those reported in patients. Discussion: The results demonstrate that newly developed polyimide sEEG electrodes can be implanted as accurately as similar devices in the marker without user errors when following the IFU in a simulated clinical environment. The human cadaver ex-vivo test system provided a realistic test system, owing to the size, anatomy and similarity of tissue composition to that of the live human brain.

Neural signal data collection and analysis of Percept™ PC BrainSense recordings for thalamic stimulation in epilepsy.

Deep brain stimulation (DBS) using Medtronic's Percept™ PC implantable pulse generator is FDA-approved for treating Parkinson's disease (PD), essential tremor, dystonia, obsessive compulsive disorder, and epilepsy. Percept™ PC enables simultaneous recording of neural signals from the same lead used for stimulation. Many Percept™ PC sensing features were built with PD patients in mind, but these features are potentially useful to refine therapies for many different disease processes. When starting our ongoing epilepsy research study, we found it difficult to find detailed descriptions about these features and have compiled information from multiple sources to understand it as a tool, particularly for use in patients other than those with PD. Here we provide a tutorial for scientists and physicians interested in using Percept™ PC's features and provide examples of how neural time series data is often represented and saved. We address characteristics of the recorded signals and discuss Percept™ PC hardware and software capabilities in data pre-processing, signal filtering, and DBS lead performance. We explain the power spectrum of the data and how it is shaped by the filter response of Percept™ PC as well as the aliasing of the stimulation due to digitally sampling the data. We present Percept™ PC's ability to extract biomarkers that may be used to optimize stimulation therapy. We show how differences in lead type affects noise characteristics of the implanted leads from seven epilepsy patients enrolled in our clinical trial. Percept™ PC has sufficient signal-to-noise ratio, sampling capabilities, and stimulus artifact rejection for neural activity recording. Limitations in sampling rate, potential artifacts during stimulation, and shortening of battery life when monitoring neural activity at home were observed. Despite these limitations, Percept™ PC demonstrates potential as a useful tool for recording neural activity in order to optimize stimulation therapies to personalize treatment.

Paradoxical Modulation of STN ß-Band Activity with Medication Compared to Deep Brain Stimulation.

BACKGROUND: Excessive subthalamic nucleus (STN) ß-band (13-35 Hz) synchronized oscillations has garnered interest as a biomarker for characterizing disease state and developing adaptive stimulation systems for Parkinson's disease (PD). OBJECTIVES: To report on a patient with abnormal treatment-responsive modulation in the ß-band. METHODS: We examined STN local field potentials from an externalized deep brain stimulation (DBS) lead while assessing PD motor signs in four conditions (OFF, MEDS, DBS, and MEDS+DBS). RESULTS: The patient presented here exhibited a paradoxical increase in ß power following administration of levodopa and pramipexole (MEDS), but an attenuation in ß power during DBS and MEDS+DBS despite clinical improvement of 50% or greater under all three therapeutic conditions. CONCLUSIONS: This case highlights the need for further study on the role of ß oscillations in the pathophysiology of PD and the importance of personalized approaches to the development of ß or other biomarker-based DBS closed loop algorithms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neurosurgery residency match for international medical graduates in the United States.

OBJECTIVE: Training of international medical graduates (IMGs) offers opportunities for the US neurosurgery community to engage the global talent pool and impact national and international healthcare. Here, the authors analyzed the time trend of IMGs matching into US neurosurgery programs and identified potential opportunities for enhancing IMG engagement. METHODS: The authors analyzed the National Resident Matching Program (NRMP) match results, NRMP program director (PD) surveys, and applicant surveys from 2013 to 2022. Regression methods were used to analyze time trends. RESULTS: Between 2013 and 2022, the number of US neurosurgery residency positions increased by 17.6% (from 204 to 240). During this period, the percentage of IMGs matching into neurosurgery increased from 3.5% to 7%, translating into a 6.8% increase in the likelihood of a successful IMG match per year (95% CI 0.3%-13.8%, p = 0.042). The likelihoods of a successful match for US MDs and IMGs scoring > 260 on the USMLE Step 1 were > 90% and approximately 55%, respectively. In PD surveys, approximately 90% of PDs indicated that they seldom/never interview or rank IMGs. In terms of factors that influenced the PD decision for interviewing/ranking, IMGs are disadvantaged in several categories, including the ability to secure an audition elective/rotation, and proper letters of recommendation, as well as the influence of the culture on the preconceived perception of poor interpersonal skills. CONCLUSIONS: The number of IMGs matching successfully in neurosurgery has increased marginally during the past decade. The authors outline the challenges that IMGs encounter in this process and suggest strategies for considerations of IMG training in NRMP-associated institutions.

Incremental Utility of First-Pass Perfusion CMR for Prognostic Risk Stratification of Cancer-Associated Cardiac Masses.

BACKGROUND: Cardiac magnetic resonance (CMR) differentiates cardiac metastasis (CMET) and cardiac thrombus (CTHR) based on tissue characteristics stemming from vascularity on late gadolinium enhancement (LGE). Perfusion CMR can assess magnitude of vascularity; utility for cardiac masses (CMASS) is unknown. OBJECTIVES: This study sought to determine if perfusion CMR provides diagnostic and prognostic utility for CMASS beyond binary differentiation of CMET and CTHR. METHODS: The population comprised adult cancer patients with CMASS on CMR; CMET and CTHR were defined using LGE-CMR: CMASS+ patients were matched to CMASS- control subjects for cancer type/stage. First-pass perfusion CMR was interpreted visually and semiquantitatively for CMASS vascularity, including contrast enhancement ratio (CER) (plateau vs baseline) and contrast uptake rate (CUR) (slope). Follow-up was performed for all-cause mortality. RESULTS: A total of 462 cancer patients were studied, including patients with (CMET = 173, CTHR = 69) and without CMASS on LGE-CMR. On perfusion CMR, CER and CUR were higher within CMET vs CTHR (P < 0.001); CUR yielded better performance (AUC: 0.89-0.93) than CER (AUC: 0.66-0.72) (both P < 0.001) to differentiate LGE-CMR-evidenced CMET and CTHR, although both CUR (P = 0.10) and CER (P = 0.01) typically misclassified CMET with minimal enhancement. During follow-up, mortality among CMET patients was high but variable; 47% of patients were alive 1 year post-CMR. Patients with semiquantitative perfusion CMR-evidenced CMET had higher mortality than control subjects (HR: 1.42 [95% CI: 1.06-1.90]; P = 0.02), paralleling visual perfusion CMR (HR: 1.47 [95% CI: 1.12-1.94]; P = 0.006) and LGE-CMR (HR: 1.52 [95% CI: 1.16-2.00]; P = 0.003). Among patients with CMET on LGE-CMR, mortality was highest among patients (P = 0.002) with lesions in the bottom perfusion (CER) tertile, corresponding to low vascularity. Among CMET and cancer-matched control subjects, mortality was equivalent (P = NS) among patients with lesions in the upper CER tertile (corresponding to higher lesion vascularity). Conversely, patients with CMET in the middle (P = 0.03) and lowest (lowest vascularity) (P = 0.001) CER tertiles had increased mortality. CONCLUSIONS: Perfusion CMR yields prognostic utility that complements LGE-CMR: Among cancer patients with LGE-CMR defined CMET, mortality increases in proportion to magnitude of lesion hypoperfusion.

Low-frequency deep brain stimulation reveals resonant beta-band evoked oscillations in the pallidum of Parkinson's Disease patients.

Introduction: Evidence suggests that spontaneous beta band (11-35 Hz) oscillations in the basal ganglia thalamocortical (BGTC) circuit are linked to Parkinson's disease (PD) pathophysiology. Previous studies on neural responses in the motor cortex evoked by electrical stimulation in the subthalamic nucleus have suggested that circuit resonance may underlie the generation of spontaneous and stimulation-evoked beta oscillations in PD. Whether these stimulation-evoked, resonant oscillations are present across PD patients in the internal segment of the globus pallidus (GPi), a primary output nucleus in the BGTC circuit, is yet to be determined. Methods: We characterized spontaneous and stimulation-evoked local field potentials (LFPs) in the GPi of four PD patients (five hemispheres) using deep brain stimulation (DBS) leads externalized after DBS implantation surgery. Results: Our analyses show that low-frequency (2-4 Hz) stimulation in the GPi evoked long-latency (>50 ms) beta-band neural responses in the GPi in 4/5 hemispheres. We demonstrated that neural sources generating both stimulation-evoked and spontaneous beta oscillations were correlated in their frequency content and spatial localization. Discussion: Our results support the hypothesis that the same neuronal population and resonance phenomenon in the BGTC circuit generates both spontaneous and evoked pallidal beta oscillations. These data also support the development of closed-loop control systems that modulate the GPi spontaneous oscillations across PD patients using beta band stimulation-evoked responses.

Frequency settings of subthalamic nucleus DBS for Parkinson's disease: A systematic review and network meta-analysis.

INTRODUCTION: Deep Brain Stimulation (DBS) is an effective treatment for the motor symptoms of Parkinson's Disease. The targeted physiological structure for lead location is commonly the subthalamic nucleus (STN). The efficacy of DBS for improving motor symptoms is assessed via the Unified Parkinson's Disease Rating III Scale (UPDRS-III). In this study, we sought to compare the efficacy of frequency settings utilized for STN-DBS. METHODS: Following PRISMA Guidelines, a search on PUBMED and MEDLINE was performed to include full-length randomized controlled trials evaluating STN-DBS. The frequency stimulation parameters and Unified Parkinson's Disease Rating Scale (UPDRS-III) outcomes were extracted in the search. High-frequency stimulation (HFS) was defined as ≥100 Hz and low-frequency stimulation (LFS) was defined as <100 Hz. A frequentist network meta-analysis was performed with odds ratios (OR) and pooling performed using the Mantel-Haenszel method. Statistics are presented as OR [95% CI]. RESULTS: 15 studies consisting of 298 patients were included for analysis. Bilateral HFS -0.68 [-0.89; -0.46] was associated with better UPDRS-III scores compared to bilateral LFS. On the other hand, bilateral LFS with medications (MEDS) was favored over HFS with MEDS (-0.28 [-0.63; 0.07]). Bilateral LFS and MEDS, HFS and MEDS, stimulation (STIM) OFF MEDS ON, HFS, LFS, STIM OFF MEDS OFF UPDRS outcomes were ranked from best to worst outcomes. DISCUSSION: The outcomes of this study suggest that bilateral HFS has better utility for those with no response to medication, while LFS has additive benefits to medication by improving unique symptoms via different neurophysiological mechanisms.

COVID-19-Related Racial Discrimination during Lockdown and Its Impact on Asian American Women.

During the lockdown period of the COVID-19 pandemic, Asian American (AA) women have experienced a surge in anti-Asian hate crimes and racial discrimination, and a majority of studies have quantitatively shown the negative impact of these incidents on Asian Americans' well-being. Our research expands on the existing literature by qualitatively investigating types of COVID-19-related racial discrimination during lockdown and its impacts on changes in emotions, behaviors, well-being, and racial identity development among AA women. This study covered two timepoints (December 2019 to May 2020) and the data were collected using an open-ended survey with 40 AA women. Thematic analysis identified core themes related to types of racial discrimination, emotional and behavioral changes, and racial identity status that emerged due to COVID-19-related racial discrimination experiences. The findings shed light on the long-lasting impacts of racial discrimination on AA women's overall well-being and dynamic development of racial identity. Altogether, our findings underscore the need for systematic forms of advocacy to combat anti-Asian racism and call for solidarity for AA women's well-being.

Cultural family processes, depressive symptoms, and suicidal ideation: A longitudinal study of Asian American youths.

INTRODUCTION: This prospective study examined the direct and interactive effects of depressive symptoms and cultural family processes (i.e., intergenerational cultural conflict, academic parental control, cultural socialization parenting) on Asian American youths' suicidal ideation from adolescence to young adulthood. METHODS: We utilized three-wave data of 408 Korean American and 378 Filipino American youths (M = 15.00 years, SD = 1.91 at Wave 1). For each ethnicity, we tested (1) whether depressive symptoms and cultural family processes predicted past-year suicidal ideation; and (2) whether cultural family processes moderated the depressive symptom-suicidal ideation link. RESULTS: Across ethnicities, depressive symptoms significantly predicted suicidal ideation after controlling for cultural family processes. For Filipino youths, intergenerational cultural conflict significantly predicted suicidal ideation after controlling depressive symptoms and exacerbated the depressive symptom-suicidal ideation link. For Filipino youths, depressive symptoms were significantly associated with suicidal ideation only at lower levels of cultural socialization parenting. For Korean youths, academic parental control exacerbated the depressive symptom-suicidal ideation link. CONCLUSION: Findings suggest that while depressive symptoms have a robust effect on Asian American youths' suicidal ideation, this effect may be moderated by cultural family processes. Different findings for Korean and Filipino youths highlight the importance of disaggregating analyses by ethnicity to guide prevention efforts.

Highly Ordered Small Molecule Organic Semiconductor Thin-Films Enabling Complex, High-Performance Multi-Junction Devices.

Organic semiconductors have opened up many new electronic applications, enabled by properties like flexibility, low-cost manufacturing, and biocompatibility, as well as improved ecological sustainability due to low energy use during manufacturing. Most current devices are made of highly disordered thin-films, leading to poor transport properties and, ultimately, reduced device performance as well. Here, we discuss techniques to prepare highly ordered thin-films of organic semiconductors to realize fast and highly efficient devices as well as novel device types. We discuss the various methods that can be implemented to achieve such highly ordered layers compatible with standard semiconductor manufacturing processes and suitable for complex devices. A special focus is put on approaches utilizing thermal treatment of amorphous layers of small molecules to create crystalline thin-films. This technique has first been demonstrated for rubrene─an organic semiconductor with excellent transport properties─and extended to some other molecular structures. We discuss recent experiments that show that these highly ordered layers show excellent lateral and vertical mobilities and can be electrically doped to achieve high n- and p-type conductivities. With these achievements, it is possible to integrate these highly ordered layers into specialized devices, such as high-frequency diodes or completely new device principles for organics, e.g., bipolar transistors.

WITHDRAWN: Laterality and frequency settings of subthalamic nucleus DBS for Parkinson's disease: A systematic review and network meta-analysis.

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Correlates of Stigma Toward Mental Health Service Use Among Filipino Americans and Korean Americans.

Asian Americans are less likely than Whites to seek mental care and when they do, there is a substantial delay in help-seeking. Stigma associated with mental health service use is one of the major barriers to help-seeking among Asian Americans. However, few studies have examined multi-layered contextual predictors of stigma to examine joint as well as unique contributions of each predictor. Using a cross-sectional study of 376 Filipino and 412 Korean American parents from the Midwestern U.S., we investigated how individual, familial, ethnic cultural, and macro level factors were associated with stigma among immigrant parents. The findings from hierarchical regressions suggest that familial and ethnic cultural factors are prominent predictors of stigma among Korean Americans, whereas macro level factors are particularly pertinent to Filipino Americans. This study highlights the significance of subgroup specific interventions to be effective in addressing unmet mental care needs in distinct subgroups of Asian Americans.

Posterior vitreous cortex hyalocytes visualization in asymmetric pigmented paravenous chorioretinal atrophy (PPCRA) using en face OCT.

Purpose: Pigmented paravenous chorioretinal atrophy (PPCRA) is a rare retinal disease with inflammatory or infectious associations affecting the retinal pigment epithelium (RPE) and choriocapillaris. While the clinical manifestations and imaging findings are well-documented in the literature, no reports exist describing potential biomarkers of intraocular inflammation or ischemia in this condition, such as the presence of posterior vitreous cortex hyalocytes. Observations: We report a case of a 26-year-old female who presented with progressive peripheral vision loss in both eyes over one year. Dilated fundus examination revealed bilateral, asymmetric bone-spicule pigmentary changes along the retinal veins, which appeared more advanced in the left eye. Optical coherence tomography (OCT) revealed the presence of numerous hyalocytes in both eyes 3 µm anterior to the inner limiting membrane (ILM). The morphology of the hyalocytes differed between the two eyes, suggesting different levels of activation related to the stage of the disease. Specifically, the left eye, with more advanced disease, exhibited hyalocytes with multiple elongated processes consistent with a quiescent state, whereas the right eye, with the less advanced disease state, exhibited amoeboid-appearing hyalocytes suggestive of more active inflammation. Conclusions: This case illustrates how hyalocyte morphology may reflect the underlying activity of an indolent retinal degeneration and provide a useful biomarker of disease progression.

Papers and patents are becoming less disruptive over time.

Theories of scientific and technological change view discovery and invention as endogenous processes1,2, wherein previous accumulated knowledge enables future progress by allowing researchers to, in Newton's words, 'stand on the shoulders of giants'3-7. Recent decades have witnessed exponential growth in the volume of new scientific and technological knowledge, thereby creating conditions that should be ripe for major advances8,9. Yet contrary to this view, studies suggest that progress is slowing in several major fields10,11. Here, we analyse these claims at scale across six decades, using data on 45 million papers and 3.9 million patents from six large-scale datasets, together with a new quantitative metric-the CD index12-that characterizes how papers and patents change networks of citations in science and technology. We find that papers and patents are increasingly less likely to break with the past in ways that push science and technology in new directions. This pattern holds universally across fields and is robust across multiple different citation- and text-based metrics1,13-17. Subsequently, we link this decline in disruptiveness to a narrowing in the use of previous knowledge, allowing us to reconcile the patterns we observe with the 'shoulders of giants' view. We find that the observed declines are unlikely to be driven by changes in the quality of published science, citation practices or field-specific factors. Overall, our results suggest that slowing rates of disruption may reflect a fundamental shift in the nature of science and technology.

Structured deep embedding model to generate composite clinical indices from electronic health records for early detection of pancreatic cancer.

The high-dimensionality, complexity, and irregularity of electronic health records (EHR) data create significant challenges for both simplified and comprehensive health assessments, prohibiting an efficient extraction of actionable insights by clinicians. If we can provide human decision-makers with a simplified set of interpretable composite indices (i.e., combining information about groups of related measures into single representative values), it will facilitate effective clinical decision-making. In this study, we built a structured deep embedding model aimed at reducing the dimensionality of the input variables by grouping related measurements as determined by domain experts (e.g., clinicians). Our results suggest that composite indices representing liver function may consistently be the most important factor in the early detection of pancreatic cancer (PC). We propose our model as a basis for leveraging deep learning toward developing composite indices from EHR for predicting health outcomes, including but not limited to various cancers, with clinically meaningful interpretations.

Clinical Benefit of Vagus Nerve Stimulation for Epilepsy: Assessment of Randomized Controlled Trials and Prospective Non-Randomized Studies.

We examined the efficacy of vagal nerve stimulation (VNS) for patients suffering from medically intractable epilepsy. Four randomized controlled trials (RCTs - 3 adult RCTs and 1 pediatric RCT) were identified in our comprehensive literature search. Across the 4 studies, high frequency VNS stimulation (frequency >20 Hz) consistently achieved a greater seizure frequency reduction (23.4-33.1%) relative to low frequency VNS stimulation (1 Hz, .6-15.2%). We identified 2 RCTs examining whether the parameters of stimulation influenced seizure control. These studies reported that VNS achieved seizure control comparable to those reported by the first 4 RCTs (22-43% seizure frequency reduction), irrespective of the parameters utilized for VNS stimulation. In terms of VNS associated morbidity, these morbidities were consistently higher in adults who underwent high frequency VNS stimulation (eg dysphonia 37-66%, dyspnea 6-25.3%). However, no such differences were observed in the pediatric population. Moreover, <2% of patients withdrew from the RCTs/prospective studies due to intolerable symptoms. To provide an assessment of how the risks and benefits of VNS impact the patient experience, 1 study assessed the well-being of enrolled patients (as a secondary end point) and found VNS was associated with an overall improvement in well-being. Consistent with this observation, we identified a prospective, non-randomized study that demonstrated improved quality of life for epilepsy patients managed with VNS and best medical practice relative to best medical practice alone. In aggregate, these RCT studies support the efficacy and benefit of VNS as a neuro-modulatory platform in the management of a subset of medically refractory epilepsy patients.