Aura Kullmann

Deep brain stimulation (DBS), a proven treatment for movement disorders, also holds promise for the treatment of psychiatric and cognitive conditions. However, for DBS to be clinically effective, it may require DBS technology that can alter or trigger stimulation in response to changes in biomarkers sensed from the patient’s brain. A growing body of evidence suggests that such adaptive DBS is feasible, it might achieve clinical effects that are not possible with standard continuous DBS and that some of the best biomarkers are signals from the cerebral cortex. Yet capturing those markers requires the placement of cortex-optimized electrodes in addition to standard electrodes for DBS. In this Perspective we argue that the need for cortical biomarkers in adaptive DBS and the unfortunate convergence of regulatory and financial factors underpinning the unavailability of cortical electrodes for chronic uses threatens to slow down or stall research on adaptive DBS and propose public–private partnerships as a potential solution to such a critical technological gap.

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.

Purpose: Substantive evidence supports a role of chronic stress in the development, maintenance, and even enhancement of functional bladder disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). Increased urinary frequency and bladder hyperalgesia have been reported in rodents exposed to a chronic stress paradigm. Here, we utilized a water avoidance stress (WAS) model in rodents to investigate the effect of chronic stress on vascular perfusion and angiogenesis.Methods: Female Wistar-Kyoto rats were exposed to WAS for 10 consecutive days. Bladder neck tissues were analyzed by western immunoblot for vascular endothelial growth factor (VEGF) and nerve growth factor precursor (proNGF). Vascular perfusion was assessed by fluorescent microangiography followed by Hypoxyprobe testing to identify regions of tissue hypoxia.Results: The expression of VEGF and proNGF in the bladder neck mucosa was significantly higher in the WAS rats than in the controls. There was a trend toward increased vascular perfusion, but without a statistically significant difference from the control group. The WAS rats displayed a 1.6-fold increase in perfusion. Additionally, a greater abundance of vessels was observed in the WAS rats, most notably in the microvasculature.Conclusions: These findings show that chronic psychological stress induces factors that can lead to increased microvasculature formation, especially around the bladder neck, the region that contains most nociceptive bladder afferents. These findings may indicate a link between angiogenesis and other inflammatory factors that contribute to structural changes and pain in IC/BPS.

Subdural electrode arrays are used for monitoring cortical activity and functional brain mapping in patients with seizures. Until recently, the only commercially available arrays were silicone-based, whose thickness and lack of conformability could impact their performance. We designed, characterized, manufactured, and obtained FDA clearance for 29-day clinical use (510(k) K192764) of a new thin-film polyimide-based electrode array. This study describes the electrochemical characterization undertaken to evaluate the quality and reliability of electrical signal recordings and stimulation of these new arrays. Two testing paradigms were performed: a short-term active soak with electrical stimulation and a 29-day passive soak. Before and after each testing paradigm, the arrays were evaluated for their electrical performance using Electrochemical Impedance Spectroscopy (EIS), Cyclic Voltammetry (CV) and Voltage Transients (VT). In all tests, the impedance remained within an acceptable range across all frequencies. The different CV curves showed no significant changes in shape or area, which is indicative of stable electrode material. The electrode polarization remained within appropriate limits to avoid hydrolysis.

Stereo-electroencephalography (sEEG) guided radiofrequency thermocoagulation (RFTC, also called RF ablation) is a procedure in which sEEG electrodes implanted for the evaluation of the seizure onset zone (SOZ) are used for tissue lesioning. The procedure has been performed since the early 2000s, on hundreds of patients in centres across the world. Candidates for RFTC are drug-resistant epilepsy (DRE) patients for which resective surgery carries a high risk of subsequent deficits. This study describes the results of RFTC at their centre. The study is a retrospective analysis of patients evaluated with sEEG over the course of 7 years, between February 2013 and December 2020. Out of 84 sEEG evaluated patients, 55 (65%) have RFTC performed. The analysis presented in the paper encompasses 31 patients with MRI negative findings. Follow-up was 30.9 months (range 7.1-69.8 months). The results showed that at the last follow-up, 14 patients (45.2%) had at least a 50% reduction in seizure frequency, and 8 (25.8%) were seizure-free. There were mild, temporary complications. Similar to other studies, this study confirms that sEEG-RFTC is a safe procedure and leads to a good response in many cases of MRI-negative focal epilepsy. What this study emphasises, is that “a nonnegligible proportion of patients may benefit from this procedure”, therefore it is important to consider sEEG guided RFTC as a one stage, much less invasive approach that uses electrodes already implanted, and performs thermolesions based on direct sEEG data.

Purpose: Lower urinary tract symptoms are known to significantly increase with age, negatively impacting quality of life and self-reliance. The urothelium fulfills crucial tasks, serving as a barrier protecting the underlying bladder tissue from the harsh chemical composition of urine, and exhibits signaling properties via the release of mediators within the bladder wall that affect bladder functioning. Aging is associated with detrimental changes in cellular health, in part by increasing oxidative stress in the bladder mucosa, and more specifically the urothelium. This, in turn, may impact urothelial mitochondrial health and bioenergetics.Methods: We collected mucosal tissue samples from both young (3–4 months old) and aged (25–30 months old) rats. Tissue was evaluated for p21-Arc, nitrotyrosine, and cytochrome C expression by western immunoblotting. Urothelial cells were cultured for single-cell imaging to analyze basal levels of reactive oxygen species and the mitochondrial membrane potential. Mitochondrial bioenergetics and cellular respiration were investigated by the Seahorse assay, and measurements of adenosine triphosphate release were made using the luciferin-luciferase assay.Results: Aging was associated with a significant increase in biomarkers of cellular senescence, oxidative stress, and basal levels of reactive oxygen species. The mitochondrial membrane potential was significantly lower in urothelial cell cultures from aged animals, and cultures from aged animals showed a significant decrease in mitochondrial bioenergetics.Conclusions: Aging-related increases in oxidative stress and excessive reactive oxygen species may be contributing factors underlying lower urinary tract symptoms in older adults. The mechanisms outlined in this study could be utilized to identify novel pharmaceutical targets to improve aging-associated bladder dysfunction.

Subdural strip and grid invasive electroencephalography electrodes are routinely used for surgical evaluation of patients with drug-resistant epilepsy (DRE). Although these electrodes have been in the United States market for decades (first FDA clearance 1985), their fabrication, materials, and properties have hardly changed. Existing commercially available electrodes are made of silicone, are thick (>0.5 mm), and do not optimally conform to brain convolutions. New thin-film polyimide electrodes (0.08 mm) have been manufactured to address these issues. While different thin-film electrodes are available for research use, to date, only one electrode is cleared by Food and Drug Administration (FDA) for use in clinical practice. This study describes the biocompatibility tests that led to this clearance. Biocompatibility was tested using standard methods according to International Organization for Standardization (ISO) 10993. Electrodes and appropriate control materials were bent, folded, and placed in the appropriate extraction vehicles, or implanted. The extracts were used for in vitro and in vivo tests, to assess the effects of any potential extractable and leachable materials that may be toxic to the body. In vitro studies included cytotoxicity tested in L929 cell line, genotoxicity tested using mouse lymphoma assay (MLA) and Ames assay, and hemolysis tested in rabbit whole blood samples. The results indicated that the electrodes were non-cytotoxic, non-mutagenic, non-clastogenic, and non-hemolytic. In vivo studies included sensitization tested in guinea pigs, irritation tested in rabbits, acute systemic toxicity testing in mice, pyrogenicity tested in rabbits, and a prolonged 28-day subdural implant in sheep. The results indicated that the electrodes induced no sensitization and irritation, no weight loss, and no temperature increase. Histological examination of the sheep brain tissue showed no or minimal immune cell accumulation, necrosis, neovascularization, fibrosis, and astrocyte infiltration, with no differences from the control material. In summary, biocompatibility studies indicated that these new thin-film electrodes are appropriate for human use. As a result, the electrodes were cleared by the FDA for use in clinical practice [510(k) K192764], making it the first thin-film subdural electrode to progress from research to clinic. Its readiness as a commercial product ensures availability to all patients undergoing surgical evaluation for DRE.

This study analyzed changes in the National Association of Epilepsy Centers (NAEC)-accredited epilepsy centers between 2012 and 2019. The results showed increases in the number of centers, epileptologists and staff members, epilepsy monitoring unit (EMU) admission, EMU beds, and new technology. There was also an increase in procedures involving more complex surgeries using newer technology, including laser interstitial thermal therapy (LITT), responsive neurostimulation (RNS), and intracranial EEG monitoring without resection. Despite these increases, the overall rate of epilepsy surgery did not change. Patients with seizures are first evaluated by primary care doctors or neurologists and typically treated with medication. In about 1/3 of them, medication does not work. Ideally, these patients should be recommended to the NAEC-accredited epilepsy centers for further evaluation and treatment. However, the rate of recommendation is low. This study, by providing comprehensive data on epilepsy center characteristics and available procedures, could help increase patient referrals. Future studies are required to better understand the influence of epilepsy center characteristics on testing, treatment, and outcomes.

This paper describes a two-stage stereoelectroencephalography (sEEG)-guided radio frequency (RF) ablation in children 3-16 years old (n=9) with drug-resistant epilepsy due to tuberous sclerosis. The tumor size ranged from 1.2cm to 3.95cm, visible in the MRI. The first stage sEEG located the pathogenic nodules, mapped functional cortical areas that couldn’t be ablated without causing functional deficits, and coagulated most nodules. The number of coagulations per patient was 1-13. The second stage sEEG was performed in four children who still had seizures, at an interval of 10 days to 13 months. Multiple sEEG electrodes were implanted according to the size, shape, and location of pathogenic nodules identified in the first stage. The electrodes were implanted to form a high-density three-dimensional cross-bonding to cover a sufficiently large ablation volume, necessary for the elimination of the nodules. The outcome was that seven of the nine children were seizure-free; two were still experiencing seizures at the last follow-up. This paper established the feasibility of ablations using sEEG electrodes specifically implanted to cover large volumes. In many countries, ablations for tuberous sclerosis are typically performed using laser interstitial thermal therapy (LITT), which produces large volume ablations. The procedure involves expensive equipment, a laser, and MRI. In countries where resources are scarce and the availability of lasers and MRI suites is reduced, the method described in this paper provides a good alternative with favorable outcomes.