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Chandan G Reddy,1 John W Miller,1 Kingsley O Abode-Iyamah,1 Sina Safayi,2 Saul Wilson,1 Brian D Dalm,1 Douglas C Fredericks,3 George T Gillies,4 Matthew A Howard III,1 Timothy J Brennan5 1Department of Neurosurgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA; 2Department of Veterinary Clinical Sciences, Iowa State University, Ames, IA, USA; 3Department of Orthopedics and Rehabilitation, University of Iowa Carver College of Medicine, Iowa City, IA, USA; 4Department of Mechanical and Aerospace Engineering, University of Virginia, Charlottesville, VA, USA; 5Department of Anesthesia, University of Iowa Carver College of Medicine, Iowa City, IA, USA Background: It is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise. Purpose: Additionally, the small anatomic scale of current SCS animal models is a barrier to more translational research. Methods: Using chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact. Results: Detectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI. Conclusion: To our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS. Keywords: neuropathic pain, sheep models, gait analysis, spinal cord stimulation, unit recordings

Commonly used arterial respiratory variation metrics are based on mathematical analysis of arterial waveforms in the time domain. Because the shape of the arterial waveform is dependent on the site at which it is measured, we hypothesized that analysis of the arterial waveform in the frequency domain might provide a relatively site-independent means of measuring arterial respiratory variation. Radial and femoral arterial blood pressures were measured in nineteen patients undergoing liver transplantation. Systolic pressure variation (SPV), pulse pressure variation (PPV), area under the curve variation (AUCV), and mean arterial pressure variation (MAPV) at radial and femoral sites were calculated off-line. Two metrics, "Spectral Peak Ratio" (SPeR) and "Spectral Power Ratio" (SPoR) based on ratios of the spectral peak and spectral area (power) at the respiratory and cardiac frequencies, were calculated at both radial and femoral sites. Variance among radial-femoral differences was compared and correlation coefficients describing the relationship between respiratory variation at the radial and femoral sites were developed. The variance in radial-femoral differences were significantly different (p < 0.001). The correlation between radial and femoral estimates of respiratory variation were 0.746, 0.658, 0.858, 0.882, 0.941, and 0.925 for SPV, PPV, AUCV, MAPV, SPeR, and SPoR, respectively. Assuming a PPV treatment threshold of 12 % (or equivalent), differences in treatment decisions based on radial or femoral estimates would arise in 12, 14, 5.4, 5.7, 4.8, and 5.5 % of minutes for SPV, PPV, AUCV, MAPV, spectral peak ratio, and spectral power ratio, respectively. As compared to frequency domain-based estimates of respiratory variation, SPV and PPV are relatively dependent on the anatomic site at which they are measured. Spectral peak and power ratios are relatively site-independent means of measuring respiratory variation, and may offer a useful alternative to time domain-based techniques. [ABSTRACT FROM AUTHOR]

Introduction: We are developing ovine models of spinal cord injury to test novel neuromodulation-based methods on spasticity. The hemisection has been reported in a number of large animal studies. Our aim is to duplicate a hemisection injury in the sheep. Our effort is explored here. Methods and Results : Three sheep underwent hemi-sectioning of the spinal cord. Quantitative gait analysis was completed both pre- and post-injury. While measurable differences in most of the 20 gait metrics were observed, relatively few were above the predicted thresholds based on error levels expected from the data. Variations in severity of injury across the three sheep were observed. Conclusions : The hemisection ovine model of spinal cord injury shows promise as a large-animal platform for developing new therapies for treating spinal cord injuries. While variability in injury severity was observed across animals, as has been observed with weight drop-based SCI models, the hemi-section approach has the advantages of procedural ease and reduced technical complexity.

Objectives: We are in the process of designing and testing an intradural stimulation device that will shorten the distance between the location of the electrode array and the targeted neural tissue, thus improving the efficacy of electrical current delivery. Identifying a biomarker that accurately reflects the response to this intervention is highly valued because of the potential to optimize interventional parameters or predict a response before it is clinically measurable. In this report, we summarize the findings pertaining to the study of biomarkers so that we and others will have an up-to-date reference that critically evaluates the current approaches and select one or several for testing during the development of our device., Materials and Methods: We have conducted a broad survey of the existing literature to catalogue the biomarkers that could be coupled to intradural spinal cord stimulation. We describe in detail some of the most promising biomarkers, existing limitations, and suitability to managing chronic pain., Results: Chronic, intractable pain is an all-encompassing condition that is incurable. Many treatments for managing chronic pain are nonspecific in action and intermittently administered; therefore, patients are particularly susceptible to large fluctuations in pain control over the course of a day. The absence of a reliable biomarker challenges assessment of therapeutic efficacy and contributes to either incomplete and inconsistent pain relief or, alternatively, intolerable side effects. Fluctuations in metabolites or inflammatory markers, signals captured during dynamic imaging, and genomics will likely have a role in governing how a device is modulated., Conclusions: Efforts to identify one or more biomarkers are well underway with some preliminary evidence supporting their efficacy. This has far-reaching implications, including improved outcomes, fewer adverse events, harmonization of treatment and individuals, performance gains, and cost savings. We anticipate that novel biomarkers will be used widely to manage chronic pain., (© 2020 International Neuromodulation Society.)

Objective: The treatment failure rate for spinal cord stimulators (SCS) remains unacceptably high, with reports of removal in up to 30% of patients. The purpose of this study is to perform survival and multivariate regression analyses of patients who have undergone SCS explantation in order to identify patient characteristics that may predict treatment failure., Materials and Methods: We identified 253 patients who underwent SCS placement using current procedural terminology codes in a private health insurance data base spanning 2003-2016. Patient demographics, opioid use, surgical indications, as well as comorbidities were noted. At least 6 months of continuous claims data before and after implantation were required for inclusion. Patients who underwent explantation were defined as those who underwent removal without replacement within 90 days and had at least 90 days of continuous insurance eligibility following removal. Those who underwent removal for infectious reasons were identified with corresponding diagnosis codes., Results: Of the 252 patients who met the inclusion criteria, 17 (6.7%) underwent SCS explantation. Median follow-up time was 2.0 years. Of those who had their system explanted, six patients (2.8%) had their systems removed for infection and 11 (4.3%) for noninfectious reasons. Bivariate analysis revealed that younger age and tobacco use were associated with an increased likelihood of explantation. The Cox proportional hazards analysis demonstrated that younger age, tobacco use, and the presence of "other" mental health disorders were predictive of explantation., Conclusions: In a cohort of SCS patients from multiple institutions, this study demonstrates that explantation for noninfectious reasons is more likely in younger patients, tobacco users, and those with certain psychiatric conditions. With an estimated 10% of patients opting to have their devices removed within 5 years of implantation, refining the ability of clinicians to predict who will see benefit from SCS treatment remains necessary., (© 2020 International Neuromodulation Society.)

Introduction: The introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges., Methods: A review of the available literature relevant to this topic was performed, with particular focus on the pertinent neuroanatomy and uses of spinal cord stimulation systems in the treatment of malignant and nonmalignant gastrointestinal, genitourinary, and chronic pelvic pain., Results: To date, there have been multiple off-label reports testing SCS for refractory gastrointestinal and genitourinary conditions. Though some findings have been favorable for these organs and systems, there is insufficient evidence to make this practice routine. The unique configuration and layout of the pelvic pain pathways may not be ideally treated using traditional SCS implantation techniques, and intradural stimulation may be a viable alternative., Conclusions: Despite the prevalence of visceral pain, the application of neuromodulation therapies, a standard approach for other painful conditions, has received far too little attention, despite promising outcomes from uncontrolled trials. Detailed descriptions of visceral pain pathways may offer several clues that could be used to implement devices tailored to this unique anatomy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We are developing an intradural approach to spinal cord stimulation, where the thin electrode array is affixed stably to the underside of the thoracic spinal dura mater without leakage of cerebrospinal fluid. As part of the design and testing process, we sought to evaluate the potential risk of inadvertent contact of the array with the pial surface of the spinal cord during variations in spinal loading., Methods: As part of the risk assessment process, a 2-part study was undertaken. First, a retrospective review of the imaging studies of 25 patients was done in the supine, 45- and 90-degree positions to measure the positional shift between the T9 and T10 vertebral bodies as a function of spinal angulation. Second, similar measurements were made on a cadaveric model, with and without a prototype intradural stimulator implanted at the T9-T10 position and with and without 13.8 kg (30 lb) of axial spinal loading at the 90-degree orientation., Results: In all cases, the measured relative displacement of the dura mater towards the spinal cord in both the imaging and the cadaveric arms of the study was less than 1 mm., Conclusions: The implantation method for the thin intradural array of the prototype device will ensure that the anatomic separation between it and the pial surface of the spinal cord will be the same as that of the dura mater. Therefore the risk of inadvertent contact will be no greater than that due to the mass effects of standard epidural stimulator implants., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Chronic midline low back pain is the number one reason for disability in the United States despite the prolific use of medical and surgical interventions. Notwithstanding the widespread use of epidural spinal cord stimulators (SCSs), there remains a large portion of the population with inadequate pain control thought to be because of the limited volume of stimulated neural tissue. Intradural SCSs represent an underexplored alternative strategy with the potential to improve selectivity, power efficiency, and efficacy. We studied and carried out development of an intradural form of an SCS. Herein we present the findings of in vivo testing of a prototype intradural SCS in a porcine model., Methods: Six female juvenile pigs underwent surgical investigation. One control animal underwent a laminectomy only, whereas the 5 other animals had implantation of an intradural SCS prototype. One of the prototypes was fully wired to enable acute stimulation and concurrent electromyographic recordings. All animals underwent terminal surgery 3 months postimplantation, with harvesting of the spinal column. Imaging (microcomputed tomography scan) and histopathologic examinations were subsequently performed., Results: All animals survived implantation without evidence of neurologic deficits or infection. Postmortem imaging and histopathologic examination of the spinal column revealed no evidence of spinal cord damage, cerebrospinal fluid fistula formation, abnormal bony overgrowth, or dural defect. Viable dura was present between the intra- and extradural plates of the device. Electromyographic recordings revealed evoked motor units from the stimulator., Conclusions: Chronically implanted intradural device in the porcine model demonstrated safety and feasibility for translation into humans., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction : Translating basic science research into a safe and effective therapy for spinal cord injury (SCI) requires suitable large animal models for testing both implantable devices and biologic approaches to better approximate human anatomy and function. Hemisection lesions, routinely used for investigational purposes in small animals, are less frequently described in large animals that might be appropriate for translational studies. Size constraints of small animals (mice and rats) limits the predictability of the findings when scaled up. Our goal is to review the status of hemisection SCI in large animals across species and time to prepare for the testing of a novel intradural spinal cord stimulation device for control of spasticity in an ovine model. Methods and Results : We surveyed the literature on hemisection in quadrupeds and nonhuman primates, and catalogued the species, protocols and outcomes of the experimental work in this field. Feline, lapine, canine, simian, porcine, ovine and bovine models were the primary focal points. There is a consistent body of literature reporting use of the hemisection approach in large animals, but with differences in surgical technique depending on the goals and nature of the individual studies. While the injuries are not always consistent, the experimental variability is generally lower than that of the contusion-based approach. In general, as the body size of the animal increases, animal care requirements and the associated costs follow. In most cases, this is inversely correlated with the number of animals used in hemisection models. Conclusions : The hemisection approach to modeling SCI is straightforward compared with other methods such as the contusive impact and enables the transection of isolated ascending and descending tracts and segment specific cell bodies. This has certain advantages in models investigating post-injury axonal regrowth. However, this approach is not generally in line with the patho-physiologies encountered in SCI patients. Even so, the ability to achieve more control over the level of injury makes it a useful adjunct to contusive and ischemic approaches, and suggests a useful role in future translational studies.

Objectives: Spinal cord stimulation (SCS) has gained traction as an alternative to chronic opioid therapy in light of the opioid crisis. Prior reports vary widely in their estimates of its effect on opioid consumption. We therefore aimed to address the following questions: 1) Does chronic opioid use change after SCS? 2) Which patient characteristics predict reduced opioid consumption after SCS?, Materials and Methods: Claims from a private health insurance company were used to identify patients with SCS implantation from 2003 to 2014. We required 12 months of continuous data before and after surgery (i.e., a minimum total observation period of two years), and at least two opioid prescription fills in the six months before surgery. Daily morphine equivalent dose (MED) was calculated from prescription medication claims. Diagnosis codes identified common comorbidities., Results: Hundred forty-five patients met inclusion criteria. MED of 65 was the most statistically meaningful preoperative dose threshold. Approximately half of patients decreased opioid use >20% after SCS implantation. Logistic regression analysis revealed age (p = 0.0362), gender (p = 0.0076), and preoperative daily MED < 65 (p = 0.0322) as predictors of meaningful reduction, which was defined as a 20% reduction in MED., Conclusions: With only half of chronic opioid users demonstrating meaningful opioid reduction after SCS implantation, we demonstrate that current SCS technology does not reliably help a larger number of patients reduce opioid usage. Women, older age, and preoperative MED < 65 are predictive of meaningful opioid reduction but only one of these is modifiable. As not all patients saw benefit from their therapies, there is still much room for improvement in the treatment of refractory chronic pain that is associated with failed back surgery syndrome and chronic regional pain syndrome., (© 2019 International Neuromodulation Society.)

Introduction: We are developing a novel intradural spinal cord stimulator for treatment of neuropathic pain and spasticity. A key feature is the means by which it seals the dura mater to prevent leakage of cerebrospinal fluid (CSF). We have built and employed a test rig that enables evaluation of candidate seal materials., Methods: To guide the design of the test rig, we reviewed the literature on neurosurgical durotomies. The test rig has a mock durotomy slot with a dural substitute serving as the surrogate dura mater and water as the CSF. The primary experimental goal was to evaluate the effectiveness of candidate gasket materials as seals against CSF leakage in an implanted prototype device, at both normal and super-physiologic pressures. A secondary goal was to measure the transmembrane flows in a representative dural substitute material, to establish its baseline aqueous transport properties., Results: The seals prevented leakage of water at the implantation site over periods of ≈ ten days, long enough for the scar tissue to form in the clinical situation. The seals also held at water pressure transients approaching 250 mm Hg. The residual volumetric flux of water through the dura substitute membrane (Durepair®) was δV T /A ≈ 0.24 mm 3 /min/cm 2 , consistent with expectations for transport through the porous membrane prior to closure and equalization of internal/external pressures., Conclusions: We have demonstrated the workability of obtaining robust seal against leakage at the implantation site of a novel intradural stimulator using a custom-designed test rig. Extension of the method to in vivo testing in a large animal model will be the next step., (© 2019 International Neuromodulation Society.)

Introduction: Contemporary approaches to surgical site infections have evolved significantly over the last several decades in response to the economic pressures of soaring health care costs and increasing patient expectations of safety. Neurosurgeons face multiple unique challenges when striving to avoid as well as manage surgical implant infections. The tissue compartment, organ system, or joint is characterized by biological factors and physical forces that may not be universally relevant. Such implants, once rare, are now routine. Although the prevention, diagnosis, and treatment of surgical site infections involving neural implants has advanced, guidelines are ever changing, and the incidence still exceeds acceptable levels. We assess the impact of these factors on a new class of implantable neuromodulation devices., Methods: The available evidence along with practice patterns were examined and organized to establish relevant groupings for continuing evaluation and to propose justifiable recommendations for the treatment of infections that might arise in the case of intradural spinal cord stimulators., Results: Few studies in the modern era have systematically evaluated preventive behaviors that were applied to intradural neural implants alone. We anticipate that future efforts will focus even more on the investigation of modifiable factors along a continuum from bacterially repellant implants to weight management. Early diagnosis could offer the best hope for device salvage but to date has been largely understudied., Conclusions: Historically, prevention is the cornerstone to infection mitigation. However, immediate diagnosis and hardware salvage have not received the attention deserved, and that approach may be especially important for intradural devices., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Intradural spinal cord stimulation (SCS) may offer significant therapeutic benefits for those with intractable axial and extremity pain, visceral pain, spasticity, autonomic dysfunction and related disorders. A novel intradural electrical stimulation device, limited by the boundaries of the thecal sac, CSF and spinal cord was developed to test this hypothesis. In order to optimize device function, we have explored finite element modeling (FEM). Methods: COMSOL ® Multiphysics Electrical Currents was used to solve for fields and currents over a geometric model of a spinal cord segment. Cathodic and anodic currents are applied to the center and tips of the T-cross component of the electrode array to shape the stimulation field and constrain charge-balanced cathodic pulses to the target area. Results: Currents from the electrode sites can move the effective stimulation zone horizontally across the cord by a linear step method, which can be diversified considerably to gain greater depth of penetration relative to standard epidural SCS. It is also possible to prevent spread of the target area with no off-target action potential. Conclusion: Finite element modeling of a T-shaped intradural spinal cord stimulator predicts significant gains in field depth and current shaping that are beyond the reach of epidural stimulators. Future studies with in vivo models will investigate how this approach should first be tested in humans.

Introduction: The intrathecal space remains underutilized for diagnostic testing, invasive monitoring or as a pipeline for the delivery of neurological therapeutic agents and devices. The latter including drug infusions, implants for electrical modulation, and a means for maintaining the physiologic pressure column. The reasons for this are many but include unfamiliarity with the central nervous system and the historical risks that continue to overshadow the low complication rates in modern clinical series., Materials and Methods: Our intent in this review is to explore the access devices currently on the market, assess the risk associated with breaching the intrathecal space, and propose a research model for bringing to patients the next generation of intrathecal hardware. For this purpose, we reviewed both historical and contemporary literature that pertains to the access devices and catheters intended for both temporary and permanent implantation and the complications thereof., Results: There are few devices that are currently marketed in the United States or Europe for intrathecal use. Most hew to a relatively fixed design pattern predicated on the dimensions and properties of the thecal sac. All are typically composed of soft silicone, and employ a Tuohy needle for access despite design limitations. In general, these catheters are engineered for durability, ease of use, and regional deployment. Devices on the market with steerability or targeted intrathecal fixation are not yet available. Complications, once a legitimate concern, are now quite rare when recommended techniques are followed., Conclusions: Over the next decade, advances in intrathecal catheter design, access techniques, imaging, and greater understanding of the spinal cord neurophysiology will usher in an era where the intrathecal space is recognized as a highly valued diagnostic and therapeutic target. We anticipate that this will occur in several concurrent phases, each with the potential to accelerate the growth of the others., (© 2017 International Neuromodulation Society.)

Understanding the relevant biophysical properties of the spinal dura mater is essential to the design of medical devices that will directly interact with this membrane or influence the contents of the intradural space. We searched the literature and reviewed the pertinent characteristics for the design, construction, testing, and imaging of novel devices intended to perforate, integrate, adhere or reside within or outside of the spinal dura mater. The spinal dura mater is a thin tubular membrane composed of collagen and elastin fibres that varies in circumference along its length. Its mechanical properties have been well-described, with the longitudinal tensile strength exceeding the transverse strength. Data on the bioelectric, biomagnetic, optical and thermal characteristics of the spinal dura are limited and sometimes taken to be similar to those of water. While various modalities are available to visualise the spinal dura, magnetic resonance remains the best modality to segment its structure. The reaction of the spinal dura to imposition of a foreign body or other manipulations of it may compromise its biomechanical and immune-protective benefits. Therefore, dural sealants and replacements are of particular clinical, research and commercial interest. In conclusion, existing devices that are in clinical use for spinal cord stimulation, intrathecal access or intradural implantation largely adhere to traditional designs and their attendant limitations. However, if future devices are built with an understanding of the dura's properties incorporated more fully into the designs, there is potential for improved performance.

Introduction: Millions of people worldwide suffer with spasticity related to irreversible damage to the brain or spinal cord. Typical antecedent events include stroke, traumatic brain injury, and spinal cord injury, although insidious onset is also common. Regardless of the cause, the resulting spasticity leads to years of disability and reduced quality of life. Many treatments are available to manage spasticity; yet each is fraught with drawbacks including incomplete response, high cost, limited duration, dose-limiting side effects, and periodic maintenance. Spinal cord stimulation (SCS), a once promising therapy for spasticity, has largely been relegated to permanent experimental status., Methods: In this review, our goal is to document and critique the history and assess the development of SCS as a treatment of lower limb spasticity. By incorporating recent discoveries with the insights gained from the early pioneers in this field, we intend to lay the groundwork needed to propose testable hypotheses for future studies., Results: SCS has been tested in over 25 different conditions since a potentially beneficial effect was first reported in 1973. However, the lack of a fully formed understanding of the pathophysiology of spasticity, archaic study methodology, and the early technological limitations of implantable hardware limit the validity of many studies. SCS offers a measure of control for spasticity that cannot be duplicated with other interventions., Conclusions: With improved energy-source miniaturization, tailored control algorithms, novel implant design, and a clearer picture of the pathophysiology of spasticity, we are poised to reintroduce and test SCS in this population., (© 2017 International Neuromodulation Society.)

Objective: To develop a large animal model of spinal cord injury (SCI), for use in translational studies of spinal cord stimulation (SCS) in the treatment of spasticity. We seek to establish thresholds for the SCS parameters associated with reduction of post-SCI spasticity in the pelvic limbs, with implications for patients., Study Design: The weight-drop method was used to create a moderate SCI in adult sheep, leading to mild spasticity in the pelvic limbs. Electrodes for electromyography (EMG) and an epidural spinal cord stimulator were then implanted. Behavioral and electrophysiological data were taken during treadmill ambulation in six animals, and in one animal with and without SCS at 0.1, 0.3, 0.5, and 0.9 V., Setting: All surgical procedures were carried out at the University of Iowa. The gait measurements were made at Iowa State University., Material and Methods: Nine adult female sheep were used in these institutionally approved protocols. Six of them were trained in treadmill ambulation prior to SCI surgeries, and underwent gait analysis pre- and post-SCI. Stretch reflex and H-reflex measurements were also made in conscious animals., Results: Gait analysis revealed repeatable quantitative differences in 20% of the key kinematic parameters of the sheep, pre- and post-SCI. Hock joint angular velocity increased toward the normal pre-injury baseline in the animal with SCS at 0.9 V., Conclusion: The ovine model is workable as a large animal surrogate suitable for translational studies of novel SCS therapies aimed at relieving spasticity in patients with SCI.

Objective: Compare therapeutic response of patients to conventional versus high-frequency spinal cord stimulation (SCS)., Methods: Twelve patients with back and leg pain who met standard clinical criteria for a trial of conventional SCS (low-frequency stimulation [LFS]) participated in a half-day session of high-frequency stimulation (HFS) during their weeklong conventional trial. HFS consisted of frequencies ranging from 50 Hz to 4 kHz, or 100 Hz to10 kHz, at constant voltage settings increasing from 0.5 V to 10 V. Visual Analog Scale scores from 0 to10 were recorded, along with notes of any clinical discomfort and open patient comments., Results: Two of 12 patients had no benefit from either LFS or HFS. In the remaining 10 patients, paresthesias were significantly altered by HFS, and four experienced complete elimination of paresthesias. Five patients preferred HFS to LFS, with an additional three preferring both equally. Abrupt sensation to the onset of HFS was described in six patients, and in ten patients, HFS allowed maximum voltage stimulation of 10 V without discomfort. The four patients who did not have a successful trial of stimulation had significantly longer duration of pain compared to the eight patients who went on to permanent implant (11.2 vs. 4.3 years, P = 0.04)., Conclusions: HFS significantly altered the feeling of paresthesias in the majority of patients (ten of 12), was preferred to LFS in five of 12 patients, and non-inferior to LFS in eight of 12 patients. Both 4 kHz and 10 kHz stimulation allowed patients to benefit from HFS. HFS allowed maximum voltage stimulation without discomfort., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Our laboratories are developing treadmill-based gait analysis employing sheep to investigate potential efficacy of intra-dural spinal cord stimulation in the treatment of spinal cord injury and neuropathic pain. As part of efforts to establish the performance characteristics of the experimental arrangement, this study measured the treadmill speed via a tachometer, video belt-marker timing and ambulation-rate observations of the sheep. The data reveal a 0.1-0.3% residual drift in the baseline (unloaded) treadmill speed which increases with loading, but all three approaches agree on final speed to within 1.7%, at belt speeds of ≈ 4 km/h. Using the tachometer as the standard, the estimated upper limit on uncertainty in the video belt-marker approach is ± 0.18 km h(-1) and the measured uncertainty is ± 0.15 km h(-1). Employment of the latter method in determining timing differences between contralateral hoof strikes by the sheep suggests its utility in assessing severity of SCI and responses to therapeutic interventions.

We are developing a novel intradural spinal cord (SC) stimulator designed to improve the treatment of intractable pain and the sequelae of SC injury. In-vivo ovine models of neuropathic pain and moderate SC injury are being implemented for pre-clinical evaluations of this device, to be carried out via gait analysis before and after induction of the relevant condition. We extend previous studies on other quadrupeds to extract the three-dimensional kinematics of the limbs over the gait cycle of sheep walking on a treadmill. Quantitative measures of thoracic and pelvic limb movements were obtained from 17 animals. We calculated the total-error values to define the analytical performance of our motion capture system for these kinematic variables. The post- vs. pre-injury time delay between contralateral thoracic and pelvic-limb steps for normal and SC-injured sheep increased by ~24s over 100 steps. The pelvic limb hoof velocity during swing phase decreased, while range of pelvic hoof elevation and distance between lateral pelvic hoof placements increased after SC injury. The kinematics measures in a single SC-injured sheep can be objectively defined as changed from the corresponding pre-injury values, implying utility of this method to assess new neuromodulation strategies for specific deficits exhibited by an individual., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This study investigated the use of direct visualization to enhance minimally invasive epicardial procedures. A commercially available miniature camera was placed in a prototype subxiphoid introducer needle and bench top, in vitro and in vivo tests of system performance were made during simulated and actual attempts at pericardial access and cardio-endoscopy. This system had an unshielded field of view of 100° and a resolution of 220 × 224 pixels. When a sleeve used to maintain depth of field was slid past the distal tip of the camera probe, the field of view would decrease by ≈15° per millimetre of sleeve extension, but without loss of image quality. While tests during in vivo subxiphoid access in a porcine model revealed that the pericardial membrane was difficult to localize, the results also showed excellent resolution of the coronary arteries on the epicardial surface. These findings and potential improvements are discussed in detail.

The authors are developing a novel type of spinal cord stimulator, designed to be placed directly on the pial surface of the spinal cord, for more selective activation of target tissues within the dorsal columns. For pre-clinical testing of the device components, an ovine model has been implemented which utilizes the agility and flexibility of a sheep's cervical and upper thoracic regions, thus providing an optimal environment of accelerated stress-cycling on small gauge lead wires implanted along the dorsal spinal columns. The results are presented of representative biomechanical measurements of the angles of rotation and the angular velocities and accelerations associated with the relevant head, neck and upper back motions, and these findings are interpreted in terms of their impact on assessing the robustness of the stimulator implant systems.

Spinal cord stimulation currently relies on extradural electrode arrays that are separated from the spinal cord surface by a highly conducting layer of cerebrospinal fluid. It has recently been suggested that intradural placement of the electrodes in direct contact with the pial surface could greatly enhance the specificity and efficiency of stimulation. The present computational study aims at quantifying and comparing the electrical current distributions as well as the spatial recruitment profiles resulting from extra- and intra-dural electrode arrangements. The electrical potential distribution is calculated using a 3D finite element model of the human thoracic spinal canal. The likely recruitment areas are then obtained using the potential as input to an equivalent circuit model of the pre-threshold axonal response. The results show that the current threshold to recruitment of axons in the dorsal column is more than an order of magnitude smaller for intradural than extradural stimulation. Intradural placement of the electrodes also leads to much higher contrast between the stimulation thresholds for the dorsal root entry zone and the dorsal column, allowing better focusing of the stimulus.

Convection-enhanced delivery (CED) could have clinical applications in the delivery of neuroprotective agents in brain injury states, such as ischaemic stroke. For CED to be safe and effective, a physician must have accurate knowledge of how concentration distributions will be affected by catheter location, flow rate and other similar parameters. In most clinical applications of CED, brain microstructures will be altered by pathological injury processes. Ischaemic stroke and other acute brain injury states are complicated by formation of cytotoxic oedema, in which cellular swelling decreases the fractional volume of the extracellular space (ECS). Such changes would be expected to significantly alter the distribution of neuroprotective agents delivered by CED. Quantitative characterization of these changes will help confirm this prediction and assist in efforts to model the distribution of therapeutic agents. Three-dimensional computational models based on a Nodal Point Integration (NPI) scheme were developed to model infusions in normal brain and brain with cytotoxic oedema. These models were compared to experimental data in which CED was studied in normal brain and in a middle cerebral artery (MCA) occlusion model of cytotoxic oedema. The computational models predicted concentration distributions with reasonable accuracy.

This study develops a means of delivering electrical stimuli directly to the pial surface of the spinal cord for treatment of intractable pain. This intradural implant must remain in direct contact with the cord as it moves within the spinal canal. Therefore, magnetic resonance imaging was used to measure the movement of the spinal cord between neutral and flexed-back positions in a series of volunteers (n = 16). Following flexion of the back, the mean change in the pedicle-to-spinal cord dorsal root entry zone distance at the T10-11 level was (8.5 ± 6.0) mm, i.e. a 71% variation in the range of rostral-caudal movement of the spinal cord across all patients. There will be a large spectrum of spinal cord strains associated with this observed range of rostral-caudal motions, thus calling for suitable axial compliance within the electrode bearing portion of the intradural implant.

Spinal cord stimulation has been utilized for decades in the treatment of numerous conditions such as failed back surgery and phantom limb syndromes, arachnoiditis, cancer pain, and others. The placement of the stimulating electrode array was originally subdural but, to minimize surgical complexity and reduce the risk of certain postsurgical complications, it became exclusively epidural eventually. Here we review the relevant clinical and experimental pathologic findings, including spinal cord compression, infection, hematoma formation, cerebrospinal fluid leakage, chronic fibrosis, and stimulation-induced neurotoxicity, associated with the early approaches to subdural electrical stimulation of the central nervous system, and the spinal cord in particular. These findings may help optimize the safety and efficacy of a new approach to subdural spinal cord stimulation now under development.

We have designed, built, and tested an apparatus used for investigating the biomechanical response of a novel intradural spinal cord stimulator to the simulated physiological movement of the spinal cord within the thecal sac. In this apparatus, the rostral-caudal displacements of an anthropomorphic spinal cord surrogate can be controlled with a resolution of approximately 0.1% of a target value for up to 10(7) lateral movement cycles occurring at a repetition rate of 2 Hz. Using this system, we have been able to determine that the restoring force of the stimulator's suspension system works in concert with the frictional coupling between the electrode array and the surrogate to overcome the 0.42 μN inertial force associated with the lateral motion of the array. The result is a positional stability of the array on the surrogate (in air) of better than 0.2 mm over ~500,000 movement cycles. Design modifications that might lead to improved physiological performance are discussed.

Wireless signal transmission will play a critical role in developing reliable subdural spinal cord stimulation systems. We have developed an approach to inductively coupling signals across the epidural spacing between the pial and epidural surfaces. The major design constraints include tolerance of coil misalignments from spinal cord geometries in addition to reasonable power efficiencies within the expected range of movement. The design of the primary side as a driving circuit is simplified by several turns of commercial magnetic wire, whereas the implanted secondary side is implemented in a micro-planar spiral coil tuned to a resonant frequency of 1.6 MHz. We present the results of wireless inductive coupling experiments that demonstrate the ability to transmit and receive a frequency modulated 1.6 MHz carrier signal between primary and secondary coil antennae scaled to 10 mm. Power delivery is in the range of 400 mW at a link efficiency of 32 % for strong coupling (coil separations of 0.5 mm ) and in the range of 70 mW at 4 % efficiency for weak coupling (coil separations of 10 mm).

The efficacy of spinal cord stimulators is dependent on the ability of the device to functionally activate targeted structures within the spinal cord, while avoiding activation of near-by non-targeted structures. In theory, these objectives can best be achieved by delivering electrical stimuli directly to the surface of the spinal cord. The current experiments were performed to study the influence of different stimulating electrode positions on patterns of spinal cord electrophysiological activation. A custom-designed spinal cord neurostimulator was used to investigate the effects of lead position and stimulus amplitude on cortical electrophysiological responses to spinal cord stimulation. Brain recordings were obtained from subdural grids placed in four adult sheep. We systematically varied the position of the stimulating lead relative to the spinal cord and the voltage delivered by the device at each position, and then examined how these variables influenced cortical responses. A clear relationship was observed between voltage and electrode position, and the magnitude of high gamma-band oscillations. Direct stimulation of the dorsal column contralateral to the grid required the lowest voltage to evoke brain responses to spinal cord stimulation. Given the lower voltage thresholds associated with direct stimulation of the dorsal column, and its possible impact on the therapeutic window, this intradural modality may have particular clinical advantages over standard epidural techniques now in routine use.

We describe a novel spinal cord (SC) stimulator that is designed to overcome a major shortcoming of existing stimulator devices: their restricted capacity to selectively activate targeted axons within the dorsal columns. This device overcomes that limitation by delivering electrical stimuli directly to the pial surface of the SC. Our goal in testing this device was to measure its ability to physiologically activate the SC and examine its capacity to modulate somatosensory evoked potentials (SSEPs) triggered by peripheral stimulation. In this acute study on adult sheep (n = 7), local field potentials were recorded from a grid placed in the subdural space of the right hemisphere during electrical stimulation of the left tibial nerve and the spinal cord. Large amplitude SSEPs (>200 µV) in response to SC stimulation were consistently obtained at stimulation strengths well below the thresholds inducing neural injury. Moreover, stimulation of the dorsal columns with signals employed routinely by devices in standard clinical use, e.g., 50 Hz, 0.2 ms pulse width, produced long-lasting changes (>4.5 h) in the SSEP patterns produced by subsequent tibial nerve stimulation. The results of these acute experiments demonstrate that this device can be safely secured to the SC surface and effectively activate somatosensory pathways.

Background: To improve methods for the treatment of intractable pain, we are developing a novel intradural spinal cord stimulator that could be either attached to the dentate ligaments of the human spinal cord or fitted around the dorsal arc of the cord itself., Purpose: Our goal was to carry out the first in vivo tests of these attachment methods in an ovine model using custom-built devices and instrumentation. For eventual translational studies, we also explored methods of mimicking a human dentate ligament attachment technique in this large animal model., Methods: As a starting point, we investigated details of the gross and histological anatomy of the ovine denticulate ligaments, and compared them with their human counterpart. The gap between the dura and the spinal cord in the sheep is small; hence, the denticulate ligaments are not long enough to accommodate human-scaled attachment clips. Therefore, lateral strips of the spinal-canal dura were fashioned to serve this same device attachment function., Results: This form of dural anchoring was implemented surgically for fixation of a silicone membrane implant that had 12 electrodes, and somatosensory evoked potentials were obtained successfully when stimuli were applied to it. The dorsal arc clamping technique was also implemented., Conclusions: We demonstrated that the dural attachment method is an effective surrogate model for testing the human dentate ligament device fixation technique, and that this mode of fixation was preferable to dorsal arc attachment. The relevant surgical innovations, anatomical findings, and the preliminary electrophysiological data from a pial surface stimulator attached in this way are presented.

We have designed, built and tested an anthropomorphic-scale surrogate spinal canal, for use in preliminary evaluations of the performance characteristics of a novel intradural spinal cord stimulator. The surrogate employs a silicone mock spinal cord with semi-major and semi-minor diameters of 10 and 6 mm, respectively, commensurate with those of actual thoracic-level spinal cord. The axial restoring force provided by the 300 µm thick silicone denticulate ligament constructs on the mock cord is ~ 0.32 N mm(-1) over a 1.5 mm range of displacement, which is within a factor of 2 of that measured by others in human cadaver specimens. Examples of testing protocols of prototype intradural stimulators that employ this device are discussed.

High spinal block is a potentially fatal complication of spinal anesthesia, with an incidence of 0.6 per 1000. Current prevention strategies include decreasing the dose of local anesthetic drug and altering patient positioning such that the location of hyperbaric anesthetic drugs in the neuraxis can be manipulated by gravity. Incorporation of a ferrofluid into a local anesthetic solution, combined with application of an external magnetic field in an in vitro spine model, allowed control of position of a solution of ferrofluid, dye, and local anesthetic against gravity, suggesting an additional mechanism by which anesthesia providers may prevent high spinal block.

We have designed, built and tested a novel device for placing intradural neurmodulator implants directly on the pial surface of the spinal cord. This applier tool is designed for ergonomic handling of delicate electro-mechanical devices such as the Iowa-Patch™ spinal cord stimulator implant, which is aimed at overcoming certain shortcomings in the performance of standard epidural stimulator devices. The applier is approximately 14 cm long, 6 mm in diameter, made of stainless steel components, and has simple and reliable mechanisms for the attachment and release of the implant from it. We describe the design of the device, details of its construction, and its performance during in vivo testing of somatosensory evoked potentials in an ovine model of intradural spinal cord stimulation.

A microfluidic pressure sensor with inductively coupled, wireless readout capability has been developed for integration into cerebrospinal fluid shunt valve implants. The sensor consists of a deformable PDMS film that is bonded over a microfluidic reservoir, forming a fluidic capacitor. Deflection of the capacitor membrane is detected remotely through a shift in the resonance frequency of a micro-fabricated LC circuit. Sensors were fabricated by a combination of conventional MEMS technologies and rapid soft lithography. A direct pattern transfer technique was used to pattern the deformable PDMS film with a metal coating for the capacitive readout. The mechanical response of the fluidic capacitor was characterized by measuring the deflection of the PDMS film using an extrinsic Fabry-Perot interferometer (EFPI), and wireless sensing was demonstrated by the shift in resonance frequency of the sensor via an inductively coupled antenna. The sensor transduces pressure into a change in resonant frequency with sensitivity > 3.4 ppm Pa⁻¹ and responsivity 4.6 kHz Pa⁻¹, over a dynamic range of 0~3 kPa.

We have designed, built and tested a novel spinal cord surrogate that mimics the low-amplitude cardiac-driven pulsations of the human spinal cord, for use in developing intradural implants to be used in a novel form of neuromodulation for the treatment of intractable pain and motor system dysfunction. The silicone surrogate has an oval cross section, 10 mm major axis × 6 mm minor axis, and incorporates a 3 mm diameter × 3 cm long angioplasty balloon that serves as the pulsation actuator. When pneumatically driven at 1 Hz and 1.5 atmospheres (≈ 1140 mm Hg), the surrogate's diametric pulsation is ≈ 100 μm, which corresponds well to in vivo observations. The applications for this surrogate are presented and discussed., (Copyright © 2012 Informa UK, Ltd.)

In the context of intraparenchymal delivery of therapeutic agents into brain parenchyma for the purpose of treating serious brain diseases, we present the scientific and medical need for infusion from a single source to cover a large area of the cerebral cortex, which we refer to as 'surface-contoured distributions' (SCD). The designs of two devices suitable for obtaining such SCD's are described, and the results of preliminary experimental studies with prototypes of them are reported. The studies were done in ex vivo samples of mammalian brain tissues, and histological sections of the brains confirmed that we had covered the large surface area desired. Work to test that the infusate penetrates the thickness of the cortex remains for the future., (Copyright © 2011 Informa UK, Ltd.)

Background: The arterial pulse oximeter, which was introduced clinically in the 1970s, is a convenient, useful, and now ubiquitous anesthesia monitor. Unfortunately, although percent saturation of arterial hemoglobin is, along with cardiac output and concentration of hemoglobin, one of 3 components of oxygen delivery, it does not indicate whether oxygen delivery to a region of interest is adequate. Knowledge of peripheral or regional venous oxygen saturation (Sxvo₂) may lend insight into analysis of regional oxygen supply and demand. Our goal was to assess the suitability of 3 anatomic sites for the transcutaneous assessment of Sxvo₂., Methods: Using a Nonin reflectance oximetry probe (provided by Nonin Medical, Plymouth, MN) placed directly over the antecubital, external jugular, and internal jugular veins in 10 volunteers, we measured the absorbance of red and infrared electromagnetic radiation. We performed fast Fourier transformation on these absorbance waveforms. The ratio of pulsatile absorbance of red and infrared radiation at different frequencies was compared with nonpulsatile absorption, and Sxvo₂ was calculated based on previously derived empiric correlations., Results: Estimates of transcutaneous Sxvo₂ ranged from 41% to 97%, with mean values of 75%, 80%, and 80% at the antecubital, external jugular, and internal jugular veins, respectively. Overall, 93% of predicted Sxvo₂ values were < 90%., Conclusion: Validation and subsequent improvement of this technique requires correlation of our results with venous blood gas measurements, followed by incorporation of technologies from related fields in oximetry (fetal reflectance oximetry and near-infrared spectroscopy), as well as the development of advanced signal processing techniques.

We have designed, built and tested a novel needle for percutaneously accessing the pericardial space. The problem with accessing pericardial space is that the pericardium is against the heart. Our novel device incorporates a single spiral tine at the distal tip of a10-gauge needle, which engages the parietal pericardium tangentially to the surface of the heart. One can then pull the pericardium away, thus minimizing the risk of ventricular perforation associated with oblique axial approaches. Using linear low-density polyethylene film as a surrogate pericardium, we have demonstrated reliable pericardial engagement with successful first-time engagement rates of up to 72% (n = 25 attempts) at approach angles ranging from 0° (normal incidence) to 30°. The associated torques were approximately 1 N mm. The performance limits of the model and the implications for clinical use of such a device are discussed.

We have designed, synthesized, and tested an improved version of our original subxiphoid access system intended to facilitate epicardial electrophysiology. The new version of the system incorporates a precision fiber-optic pressure sensor and a novel signal analysis algorithm for identifying pressure-frequency signatures which, in the clinical setting, may allow for safer access to the pericardial space. Following in vivo studies on ten adult canine models, we analyzed 215 pressure-frequency measurements made at the distal tip of the access needle, of which 98 were from nonpericardial, 112 were from pericardial, and five were from ventricular locations. The needle locations as identified by the algorithm were significantly different from each other (p &lt; 0.01), and the algorithm had improved performance when compared to a standard fast Fourier transform (FFT) analysis of the same data. Moreover, the structure of the algorithm can potentially overcome the time lags intrinsic to FFT analysis such that the needle's location can be determined in near-real time. Hydrodynamic pressure-frequency measurements made during traversal of the pericardial membrane revealed a distinct change in signal structure between the pericardial and nonpericardial anatomy. We present and discuss the design principles, details of construction, and performance characteristics of this system.

We have tested prototypes of a novel coaxial tube catheter in an in vitro gel model of cell delivery into the brain. Devices 1.6 and 2.0 mm outer diameter were used to deliver PC 12 cells (concentration = 10⁶ cells ml⁻¹ at 1 μl min⁻¹ into a 5 ml sandwich of collagen and 0.1% agarose, with and without follow-on infusions of nerve growth factor (NGF). Post-infusion microscopic imaging (40X) at the infusion sites was then carried out over 7-day periods. The results showed that under these experimental conditions, it was possible to use these catheters to deliver cells without either leakage of trapped air into the gel or reflux of the cell suspension along the catheter insertion track. Differentiation of the NGF-treated cells was observed.

We tested a novel neurocatheter in a brain-tissue gel model of drug infusion via convection-enhanced delivery (CED) for the treatment of a variety of neurological diseases. CED is an alternative to systemic administration of agents by intravenous or oral routes, which are often less effective or carry risk of systemic side effects. We investigated two co-axial tube devices, with outer diameters of 1.6 mm and 2.0 mm. Bromophenol blue dye was infused into 400 ml of 0.6% agarose gel at 1 μl/min for 1 h, with/without the inner and outer tubes Luer-locked at the proximal end, with/without the inner tube primed, and with/without the inner tube preloaded into the outer tube upon insertion into the gel. The unlocked, primed, and unloaded configuration produced infusions that resulted in significantly less (p < 0.05) entrapped air escaping into the gel and resulted in no reflux of infusate.

Convection-enhanced delivery (CED) could have clinical application in the delivery of neuroprotective agents following ischemic stroke. However, ischemic brain tissue changes such as cytotoxic edema, in which cellular swelling decreases the fractional volume of the extracellular space, would be expected to significantly alter the distribution of neuroprotective agents delivered by CED. We sought to predict and characterize these effects using the magnetic resonance contrast agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) as a model therapeutic agent. CED was observed using MRI in a normal rat brain and in a middle cerebral artery (MCA) occlusion rat model of brain ischemia. Gd-DTPA was infused to the caudate putamen in the normal rat (n = 6) and MCA occlusion model (n = 6). In each rat, baseline apparent diffusion coefficient images were acquired prior to infusion, and T1 maps were then acquired 13 times throughout the duration of the experiment. These T1 maps were used to compute Gd-DTPA concentrations throughout each brain. In the MCA occlusion group, CED delivered Gd-DTPA to a comparatively larger volume with lower average tissue concentrations. Following the infusion, the total content of Gd-DTPA decreased more slowly in the MCA occlusion group than in the normal group. This quantitative characterization confirms that edematous ischemic tissue changes alter the distribution of agents by CED. These findings may have important implications for CED in the treatment of brain injury, and will assist in future efforts to model the distribution of therapeutic agents.

A common approach to quantify gadolinium (Gd) contrast agents involves measuring the post-contrast change in T1 rate and then using the constant T1 relaxivity R to determine the contrast agent concentration. Because this method is fast and non-invasive, it could be potentially valuable in many areas of brain research. However, to accurately measure contrast agent concentrations in the brain, the T1 relaxivity R of the specific agent must be accurately known. Furthermore, the macromolecular content and compartmentalization of the brain extracellular space (ECS) are expected to significantly alter R from values measured in aqueous solutions. In this study, the T1 relaxivity R of gadolinium-diethylene-triamine penta-acetic acid (Gd-DTPA) was measured following direct interstitial infusions of three different contrast agent concentrations to the parenchyma of rat brains. Changes in magnetic resonance (MR) T1 values were compared to brain slice concentrations determined with inductively coupled plasma atomic emission spectroscopy (ICP-AES) to determine R in 15 rats. Additionally, samples of cerebrospinal fluid, blood and urine were analyzed to evaluate possible Gd-DTPA clearance from the brain. The T1 relaxivity R of Gd-DTPA in the brain ECS was measured to be 5.35 (mM s)(-1) in a 2.4 T field. This value is considerably higher than estimations used in studies by other groups. Measurements of brain Gd-DTPA tissue concentrations using MRI and ICP-AES demonstrated a high degree of coincidence. Clearance of Gd-DTPA was minimal at the time point immediately after infusion. These results suggest that the environment of the brain does in fact significantly affect Gd T1 relaxivity, and that MRI can accurately measure contrast agent concentrations when this relaxivity is well characterized.

Implantation of neural progenitor cells into the central nervous system has attracted strong interest for treatment of a variety of pathologies. The replacement of dopamine-producing neural cells in the brain appears promising for the treatment of patients affected by Parkinson's disease. Previous studies of cell replacement strategies have shown that less than 10% of implanted cells were viable 24-48 hours following implantation. We present the design of an instrumented cell-delivery catheter that has been developed to facilitate the quantification of the cells delivered and determination of viability. The catheter uses a fibre optic probe to perform fluorescence-based cytometric measurements on cells exiting the port at the catheter tip. Results of fluorescence testing data are presented and show that the device can characterize the quantity of cell densities ranging from 60 000 to 600 000 cells ml(-1) with a coefficient of determination of 0.93 (p < 0.05, n = 6).

Background: Nonsurgical subxiphoid pericardial access may be useful in ventricular tachycardia ablation and other electrophysiologic procedures but has a risk of right ventricular puncture., Objective: The purpose of this study was to identify a signature pressure frequency that would help identify the pericardial space and guide access., Methods: The study consisted of 20 patients (8 women and 12 men; mean age 59.1 +/- 14.2 years; left ventricular ejection fraction 25.2% +/- 12.2%; failed 1.8 +/- 0.5 endocardial ablations; unresponsive to 2.0 +/- 1.0 antiarrhythmic drugs; 6 ischemic cardiomyopathy, 12 nonischemic cardiomyopathy, 2 normal heart; 4 previous sternotomy) undergoing epicardial ventricular tachycardia ablation. After pericardial access was obtained, a 10Fr long sheath was used to record pressure inside the pericardium and pleural space. Pressures were analyzed using a fast Fourier transform to identify dominant frequencies in each chamber., Results: Mean pressures in the pleural space and the pericardium were not different (7.7 +/- 1.9 mmHg vs 7.8 +/- 0.9 mmHg, respectively). However, the pericardial space in each patient demonstrated two frequency peaks that correlated with heart rate (1.16 +/- 0.21 Hz) and respiratory rate (0.20 +/- 0.01 Hz), whereas the pleural space in each patient had a single peak correlating with respiratory rate (0.20 +/- 0.01 Hz)., Conclusion: The pericardial space demonstrates a signature pressure frequency that is significantly different from the surrounding space. This difference may make minimally invasive subxiphoid pericardial access safer for nonsurgeons and may have important implications for electrophysiologic procedures., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

We have developed a prototype, in vitro anthropomorphic model for simulating pressure-guided, subxiphoid access procedures done to enable minimally invasive epicardial cardiac procedures including treatments for ventricular tachycardia. Life-size replicas of the heart and lungs were modelled using anatomically accurate surrogates. The dynamic pressure-frequency profiles of simulated pericardial fluid surrounding the water-pumped replica heart were measured and validated against previously acquired human intrapericardial pressure observations (Pearson's r = 0.88, p < 0.001). In replicating access procedures for approaching and entering the pericardial space, the system produced physiologically appropriate pressure measurements at each intermediate point along the needle's insertion pathway. Details of construction and performance are presented and discussed.

We have designed, built, and tested an early prototype of a novel subxiphoid access system intended to facilitate epicardial electrophysiology, but with possible applications elsewhere in the body. The present version of the system consists of a commercially available insertion needle, a miniature pressure sensor and interconnect tubing, read-out electronics to monitor the pressures measured during the access procedure, and a host computer with user-interface software. The nominal resolution of the system is < 0.1 mmHg, and it has deviations from linearity of < 1%. During a pilot series of human clinical studies with this system, as well as in an auxiliary study done with an independent method, we observed that the pericardial space contained pressure-frequency components related to both the heart rate and respiratory rate, while the thorax contained components related only to the respiratory rate, a previously unobserved finding that could facilitate access to the pericardial space. We present and discuss the design principles, details of construction, and performance characteristics of this system.