Neurophysiological outcomes that sustained clinically significant improvements over 3 years of physiologic ECAP-controlled closed-loop spinal cord stimulation for the treatment of chronic pain.

INTRODUCTION: A novel, spinal cord stimulation (SCS) system with a physiologic closed-loop (CL) feedback mechanism controlled by evoked compound action potentials (ECAPs) enables the optimization of physiologic neural dose and the accuracy of the stimulation, not possible with any other commercially available SCS systems. The report of objective spinal cord measurements is essential to increase the transparency and reproducibility of SCS therapy. Here, we report a cohort of the EVOKE double-blind randomized controlled trial treated with CL-SCS for 36 months to evaluate the ECAP dose and accuracy that sustained the durability of clinical improvements. METHODS: 41 patients randomized to CL-SCS remained in their treatment allocation and were followed up through 36 months. Objective neurophysiological data, including measures of spinal cord activation, were analyzed. Pain relief was assessed by determining the proportion of patients with ≥50% and ≥80% reduction in overall back and leg pain. RESULTS: The performance of the feedback loop resulted in high-dose accuracy by keeping the elicited ECAP within 4µV of the target ECAP set on the system across all timepoints. Percent time stimulating above the ECAP threshold was >98%, and the ECAP dose was ≥19.3µV. Most patients obtained ≥50% reduction (83%) and ≥80% reduction (59%) in overall back and leg pain with a sustained response observed in the rates between 3-month and 36-month follow-up (p=0.083 and p=0.405, respectively). CONCLUSION: The results suggest that a physiological adherence to supra-ECAP threshold therapy that generates pain inhibition provided by ECAP-controlled CL-SCS leads to durable improvements in pain intensity with no evidence of loss of therapeutic effect through 36-month follow-up.

ECAP-controlled closed-loop versus open-loop SCS for the treatment of chronic pain: 36-month results of the EVOKE blinded randomized clinical trial.

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p<0.001) and ≥80% reduction (CL-SCS=49.3%, OL-SCS=31.3%; difference: 17.9, 95% CI 1.6% to 34.2%, p=0.032) in overall back and leg pain intensity. Clinically meaningful improvements from baseline were observed at 36 months in both CL-SCS and OL-SCS groups in all other patient-reported outcomes with greater levels of improvement with CL-SCS. A greater proportion of patients with CL-SCS were holistic treatment responders at 36-month follow-up (44.8% vs 28.4%), with a greater cumulative responder score for CL-SCS patients. Greater neural activation and accuracy were observed with CL-SCS. There were no differences between CL-SCS and OL-SCS groups in adverse events. No explants due to loss of efficacy were observed in the CL-SCS group. CONCLUSION: This long-term evaluation with objective measurement of SCS therapy demonstrated that ECAP-controlled CL-SCS resulted in sustained, durable pain relief and superior holistic treatment response through 36 months. Greater neural activation and increased accuracy of therapy delivery were observed with ECAP-controlled CL-SCS than OL-SCS. TRIAL REGISTRATION NUMBER: NCT02924129.

Evaluation of Intracellular Metabolism of Methotrexate in Hepatocytes and Embryonic Kidney Cells based on Folylpolyglutamate Synthetase and Gamma-Glutamyl Hydrolase Expression.

BACKGROUND: Methotrexate (MTX) is a common folic acid antagonist in clinical medicine, easily inducing a common adverse side effect of liver and kidney injury. It has been found that the expression of Folylpolyglutamate Synthetase (FPGS) and gamma-Glutamyl Hydrolase (GGH) may be closely related to that of related proteins to affect the intracellular metabolism of MTX. OBJECTIVE: The relationship between FPGS/GGH and MTXPGs accumulation in liver and kidney cells was explored by adjusting the expression of FPGS and GGH in cells using UPLC-MS/MS quantitative technology. METHOD: Based on UPLC-MS/MS quantitative techniques, the relationship between MTXPGs accumulation and FPGS/GGH in hepatocytes and embryonic kidney cells was explored by adjusting the expression of FPGS and GGH, and the effect of FPGS/GGH on the intracellular toxicity of MTX was comprehensively analyzed. RESULT: The results showed that the difference in methotrexate polyglutamates (MTXPGs) accumulation in liver and kidney cells was related to the difference in FPGS and GGH expression. The expression of FPGS interacted with that of GGH. These results suggest that the protein abundance ratio of FPGS to GGH (FPGS/GGH) has more potential to be used as a predictor of MTX efficacy than the FPGS or GGH single protein index. This can effectively avoid liver and kidney damage caused by MTX and guides the rational use of drugs in MTX. CONCLUSION: The results prove that there is a positive correlation between the FPGS/GGH and the accumulation of MTXPGS in liver and kidney cells. Summarily, the FPGS/GGH is expected to be a predictor for MTXPGs accumulation and provides an effective method to evaluate the toxicity caused by MTX.

Impact of Long-Term Evoked Compound Action Potential Controlled Closed-Loop Spinal Cord Stimulation on Sleep Quality in Patients With Chronic Pain: An EVOKE Randomized Controlled Trial Study Subanalysis.

OBJECTIVE: Spinal cord stimulation (SCS) is considered an effective interventional nonpharmacologic treatment option for several chronic pain conditions. Here we present the effects of the novel evoked compound action potential (ECAP) controlled closed-loop (ECAP-CL) SCS system on long-term sleep quality outcomes from the EVOKE study. MATERIALS AND METHODS: The EVOKE study is a double-blind, randomized, controlled clinical trial conducted at 13 sites in the United States (N = 134 patients). The clinical trial utilized SCS to manage chronic pain and compared novel ECAP-CL technology to open-loop SCS. Additionally, sleep quality data was collected using the Pittsburgh Sleep Quality Index (PSQI) at baseline and all study visits. RESULTS: The mean PSQI global score for ECAP-CL patients at baseline was 14.0 (n = 62; ± 0.5, SD 3.8), indicating poor sleep quality. Clinically meaningful and statistically significant reductions (p < 0.001) in the global PSQI scores were noted at 12 months (n = 55; 5.7 ± 0.6, SD 4.2). A total of 76.4% of ECAP-CL patients met or exceeded Minimal Clinically Important Difference from baseline in PSQI at 12 months. Additionally, 30.9% of ECAP-CL patients achieved "good sleep quality" scores (PSQI ≤ 5), and 29.1% achieved sleep quality remission. "Normative" sleep scores were observed in 29.6% of ECAP-CL patients at 12 months, and these scores were better than the US general population. Additionally, ECAP-CL patients achieved statistically significant changes from baseline (p < 0.01) across all seven subcomponent scores of PSQI at 12 months. CONCLUSIONS: ECAP-CL SCS elicits consistent neural activation of the target leading to less variability in long-term therapy delivery. In the EVOKE study, this resulted in ECAP-CL patients demonstrating clinically superior and sustained pain relief. Results from this study provide new evidence of long-term improvement in sleep quality and quantity in patients with chronic pain resulting from the use of this novel ECAP-CL SCS technology. CLINICAL TRAIL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02924129.

Detrusor Pressure Estimation from Single-Channel Urodynamics.

Urodynamics is the current gold-standard for diagnosing lower urinary tract dysfunction, but uses non-physiologically fast, retrograde cystometric filling to obtain a brief snapshot of bladder function. Ambulatory urodynamics allows physicians to evaluate bladder function during natural filling over longer periods of time, but artifacts generated from patient movement necessitate the use of an abdominal pressure sensor, which makes long-term monitoring and feedback for closed-loop treatment impractical. In this paper, we analyze the characteristics of single-channel bladder pressure signals from human and feline datasets, and present an algorithm designed to estimate detrusor pressure, which is useful for diagnosis and treatment. We utilize multiresolution analysis techniques to maximize the attenuation of probable abdominal pressure components in the vesical pressure signal. Results indicate a strong correlation, averaging 0.895 ± 0.121 (N = 40) and 0.812 ± 0.113 (N = 16) between the estimated detrusor pressure obtained by the proposed method and recorded urodynamic data from human and feline subjects, respectively. Clinical Relevance- This work establishes that signal pro-cessing techniques may be applied to vesical pressure alone to accurately reconstruct pressures generated independently by the detrusor muscle. This is relevant for emerging sensors that measure vesical pressure alone or for data analysis of bladder pressure in ambulatory subjects which contains significant abdominal pressure artifacts.

Closed-loop sacral neuromodulation for bladder function using dorsal root ganglia sensory feedback in an anesthetized feline model.

Overactive bladder patients suffer from a frequent, uncontrollable urge to urinate, which can lead to a poor quality of life. We aim to improve open-loop sacral neuromodulation therapy by developing a conditional stimulation paradigm using neural recordings from dorsal root ganglia (DRG) as sensory feedback. Experiments were performed in 5 anesthetized felines. We implemented a Kalman filter-based algorithm to estimate the bladder pressure in real-time using sacral-level DRG neural recordings and initiated sacral root electrical stimulation when the algorithm detected an increase in bladder pressure. Closed-loop neuromodulation was performed during continuous cystometry and compared to bladder fills with continuous and no stimulation. Overall, closed-loop stimulation increased bladder capacity by 13.8% over no stimulation (p < 0.001) and reduced stimulation time versus continuous stimulation by 57.7%. High-confidence bladder single units had a reduced sensitivity during stimulation, with lower linear trendline fits and higher pressure thresholds for firing observed during stimulation trials. This study demonstrates the utility of decoding bladder pressure from neural activity for closed-loop control of sacral neuromodulation. An underlying mechanism for sacral neuromodulation may be a reduction in bladder sensory neuron activity during stimulation. Real-time validation during behavioral studies is necessary prior to clinical translation of closed-loop sacral neuromodulation.

Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial.

Importance: Chronic pain is debilitating and profoundly affects health-related quality of life. Spinal cord stimulation (SCS) is a well-established therapy for chronic pain; however, SCS has been limited by the inability to directly measure the elicited neural response, precluding confirmation of neural activation and continuous therapy. A novel SCS system measures the evoked compound action potentials (ECAPs) to produce a real-time physiological closed-loop control system. Objective: To determine whether ECAP-controlled, closed-loop SCS is associated with better outcomes compared with fixed-output, open-loop SCS at 24 months following implant. Design, Setting, and Participants: The Evoke study was a double-blind, randomized, controlled, parallel arm clinical trial with 36 months of follow-up. Participants were enrolled from February 2017 to 2018, and the study was conducted at 13 US investigation sites. SCS candidates with chronic, intractable back and leg pain refractory to conservative therapy, who consented, were screened. Key eligibility criteria included overall, back, and leg pain visual analog scale score of 60 mm or more; Oswestry Disability Index score of 41 to 80; stable pain medications; and no previous SCS. Analysis took place from October 2020 to April 2021. Interventions: ECAP-controlled, closed-loop SCS was compared with fixed-output, open-loop SCS. Main Outcomes and Measures: Reported here are the 24-month outcomes of the trial, which include all randomized patients in the primary and safety analyses. The primary outcome was a reduction of 50% or more in overall back and leg pain assessed at 3 and 12 months (previously published). Results: Of 134 randomized patients, 65 (48.5%) were female and the mean (SD) age was 55.2 (10.6) years. At 24 months, significantly more closed-loop than open-loop patients were responders (≥50% reduction) in overall pain (53 of 67 [79.1%] in the closed-loop group; 36 of 67 [53.7%] in the open-loop group; difference, 25.4% [95% CI, 10.0%-40.8%]; P = .001). There was no difference in safety profiles between groups (difference in rate of study-related adverse events: 6.0 [95% CI, -7.8 to 19.7]). Improvements were also observed in health-related quality of life, physical and emotional functioning, and sleep, in parallel with opioid reduction or elimination. Objective neurophysiological measurements substantiated the clinical outcomes and provided evidence of activation of inhibitory pain mechanisms. Conclusions and Relevance: ECAP-controlled, closed-loop SCS, which elicited a more consistent neural response, was associated with sustained superior pain relief at 24 months, consistent with the 3- and 12-month outcomes.

Sharpened and Mechanically Durable Carbon Fiber Electrode Arrays for Neural Recording.

Bioelectric medicine treatments target disorders of the nervous system unresponsive to pharmacological methods. While current stimulation paradigms effectively treat many disorders, the underlying mechanisms are relatively unknown, and current neuroscience recording electrodes are often limited in their specificity to gross averages across many neurons or axons. Here, we develop a novel, durable carbon fiber electrode array adaptable to many neural structures for precise neural recording. Carbon fibers ( [Formula: see text] diameter) were sharpened using a reproducible blowtorchmethod that uses the reflection of fibers against the surface of a water bath. The arrays were developed by partially embedding carbon fibers in medical-grade silicone to improve durability. We recorded acute spontaneous electrophysiology from the rat cervical vagus nerve (CVN), feline dorsal root ganglia (DRG), and rat brain. Blowtorching resulted in fibers of 72.3 ± 33.5-degree tip angle with [Formula: see text] exposed carbon. Observable neural clusters were recorded using sharpened carbon fiber electrodes fromrat CVN ( [Formula: see text]), feline DRG ( [Formula: see text]), and rat brain ( [Formula: see text]). Recordings from the feline DRG included physiologically relevant signals from increased bladder pressure and cutaneous brushing. These results suggest that this carbon fiber array is a uniquely durable and adaptable neural recordingdevice. In the future, this device may be useful as a bioelectric medicine tool for diagnosis and closed-loop neural control of therapeutic treatments and monitoring systems.

Studies on the intracellular accumulation process of methotrexate and its correlation with the key protein using an LC-MS/MS method: a novel way to realize prospective individualized medication.

High-dose methotrexate (HDMTX) combined with leucovorin (LV) is the first-line drug therapy for many kinds of malignant tumors. However, the specific treatment plans, such as dosage and duration of administration, are usually formulated according to the clinician's experience and therapeutic drug monitoring (TDM) of methotrexate in patients' plasma, which are responsible for strong individual differences of drug usage. A large number of studies have shown that methotrexate targets the inside of the cell. The key cytotoxic component is the methotrexate polyglutamates (MTXPGs) in the cell. The concentration of methotrexate in plasma does not reflect the efficacy and side effects well. Based on mass spectrometry technology, we developed and validated an accurate, sensitive, and stable method to quantify the intracellular MTX (MTXPG1) and its metabolites MTXPG2-7 simultaneously. The lower limit of quantification was 0.100 ng/ml, and the run time was only 3 min. Moreover, our team has already developed two LC-MS/MS-based methods to respectively quantify methotrexate in plasma samples and two key proteins (γ-glutamyl hydrolase [GGH] and folylpolyglutamate synthetase [FPGS]) in peripheral blood mononuclear cells (PBMC). Through these highly sensitive and accurate approaches, we have gained a deep understanding of the whole pharmacokinetic process of MTX and explored the key factors affecting the accumulation process of intracellular active components (MTXPGs). Based on this research, it is possible to find a more effective way to provide an accurate reference for clinical drug use than traditional therapeutic drug monitoring (TDM).

Bladder pressure encoding by sacral dorsal root ganglion fibres: implications for decoding.

Objective.We aim at characterising the encoding of bladder pressure (intravesical pressure) by a population of sensory fibres. This research is motivated by the possibility to restore bladder function in elderly patients or after spinal cord injury using implanted devices, so called bioelectronic medicines. For these devices, nerve-based estimation of intravesical pressure can enable a personalized and on-demand stimulation paradigm, which has promise of being more effective and efficient. In this context, a better understanding of the encoding strategies employed by the body might in the future be exploited by informed decoding algorithms that enable a precise and robust bladder-pressure estimation.Approach.To this end, we apply information theory to microelectrode-array recordings from the cat sacral dorsal root ganglion while filling the bladder, conduct surrogate data studies to augment the data we have, and finally decode pressure in a simple informed approach.Main results.We find an encoding scheme by different main bladder neuron types that we divide into three response types (slow tonic, phasic, and derivative fibres). We show that an encoding by different bladder neuron types, each represented by multiple cells, offers reliability through within-type redundancy and high information rates through semi-independence of different types. Our subsequent decoding study shows a more robust decoding from mean responses of homogeneous cell pools.Significance.We have here, for the first time, established a link between an information theoretic analysis of the encoding of intravesical pressure by a population of sensory neurons to an informed decoding paradigm. We show that even a simple adapted decoder can exploit the redundancy in the population to be more robust against cell loss. This work thus paves the way towards principled encoding studies in the periphery and towards a new generation of informed peripheral nerve decoders for bioelectronic medicines.

Anesthetic agents affect urodynamic parameters and anesthetic depth at doses necessary to facilitate preclinical testing in felines.

Urodynamic studies, used to understand bladder function, diagnose bladder disease, and develop treatments for dysfunctions, are ideally performed with awake subjects. However, in small and medium-sized animal models, anesthesia is often required for these procedures and can be a research confounder. This study compared the effects of select survival agents (dexmedetomidine, alfaxalone, and propofol) on urodynamic (Δpressure, bladder capacity, bladder compliance, non-voiding contractions, bladder pressure slopes) and anesthetic (change in heart rate [∆HR], average heart rate [HR], reflexes, induction/recovery times) parameters in repeated cystometrograms across five adult male cats. The urodynamic parameters under isoflurane and α-chloralose were also examined in terminal procedures for four cats. Δpressure was greatest with propofol, bladder capacity was highest with α-chloralose, non-voiding contractions were greatest with α-chloralose. Propofol and dexmedetomidine had the highest bladder pressure slopes during the initial and final portions of the cystometrograms respectively. Cats progressed to a deeper plane of anesthesia (lower HR, smaller ΔHR, decreased reflexes) under dexmedetomidine, compared to propofol and alfaxalone. Time to induction was shortest with propofol, and time to recovery was shortest with dexmedetomidine. These agent-specific differences in urodynamic and anesthetic parameters in cats will facilitate appropriate study-specific anesthetic choices.

Real-Time Bladder Pressure Estimation for Closed-Loop Control in a Detrusor Overactivity Model.

Overactive bladder (OAB) patients suffer from a frequent urge to urinate, which can lead to a poor quality of life. Current neurostimulation therapy uses open-loop electrical stimulation to alleviate symptoms. Continuous stimulation facilitates habituation of neural pathways and consumes battery power. Sensory feedback-based closed-loop stimulation may offer greater clinical benefit by driving bladder relaxation only when bladder contractions are detected, leading to increased bladder capacity. Effective delivery of such sensory feedback, particularly in real-time, is necessary to accomplish this goal. We implemented a Kalman filter-based model to estimate bladder pressure in real-time using unsorted neural recordings from sacral-level dorsal root ganglia, achieving a 0.88 ± 0.16 correlation coefficient fit across 35 normal and simulated OAB bladder fills in five experiments. We also demonstrated closed-loop neuromodulation using the estimated pressure to trigger pudendal nerve stimulation, which increased bladder capacity by 40% in two trials. An offline analysis indicated that unsorted neural signals had a similar stability over time as compared to sorted single units, which would require a higher computational load. We believe this paper demonstrates the utility of decoding bladder pressure from neural activity for closed-loop control; however, real-time validation during behavioral studies is necessary prior to clinical translation.

Evaluation of Decoding Algorithms for Estimating Bladder Pressure from Dorsal Root Ganglia Neural Recordings.

A closed-loop device for bladder control may offer greater clinical benefit compared to current open-loop stimulation devices. Previous studies have demonstrated the feasibility of using single-unit recordings from sacral-level dorsal root ganglia (DRG) for decoding bladder pressure. Automatic online sorting, to differentiate single units, can be computationally heavy and unreliable, in contrast to simple multi-unit thresholded activity. In this study, the feasibility of using DRG multi-unit recordings to decode bladder pressure was examined. A broad range of feature selection methods and three algorithms (multivariate linear regression, basic Kalman filter, and a nonlinear autoregressive moving average model) were used to create training models and provide validation fits to bladder pressure for data collected in seven anesthetized feline experiments. A non-linear autoregressive moving average (NARMA) model with regularization provided the most accurate bladder pressure estimate, based on normalized root-mean-squared error, NRMSE, (17 ± 7%). A basic Kalman filter yielded the highest similarity to the bladder pressure with an average correlation coefficient, CC, of 0.81 ± 0.13. The best algorithm set (based on NRMSE) was further evaluated on data obtained from a chronic feline experiment. Testing results yielded a NRMSE and CC of 10.7% and 0.61, respectively from a model that was trained on data recorded 2 weeks prior. From offline analysis, implementation of NARMA in a closed-loop scheme for detecting bladder contractions would provide a robust control signal. Ultimate integration of closed-loop algorithms in bladder neuroprostheses will require evaluations of parameter and signal stability over time.