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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.

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.

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 δVT /A ≈ 0.24 mm3 /min/cm2 , 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.

We investigate rigorously the behaviour of light propagation in the closed contour of the linear Sagnac effect. Assuming that the local light speed is c in a section of the contour, our approach ma...

We thoroughly examine the role of absolute and relative simultaneity in the interpretation of the Sagnac effect, using an approach that allows for determining the local speed along the light path. If the local speed of light is assumed to be c over the whole closed contour, there is no agreement with the observed result. There is agreement if the local speed is c along an open section of the contour only. Thus a rigorous and coherent interpretation of the Sagnac effect favours absolute over relative simultaneity. The implications for the Lorentz transformations and synchronization by means of the Global Positioning System are considered.

IntroductionThe 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.MethodsA 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.ResultsTo 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.ConclusionsDespite 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.

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.

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&nbsp

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.

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.

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.

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.

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.

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.

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.

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.

Improved knowledge of the electrode-tissue impedance will be useful in optimizing the clinical protocols and resulting efficacy of the existing and emerging approaches to spinal cord stimulation. Toward that end, the complex impedance (amplitude and phase) of in vivo ovine spinal cord tissue was measured at the electrode-pial subdural surface interface from 5 Hz to 1 MHz, and with the bi-polar electrodes oriented both parallel and perpendicular to the rostral-caudal axis of the spinal cord. At stimulation frequencies above 10 kHz, most of the impedance then becomes resistive in nature and the phase diference between the stimulation signal and the resulting current drops to ≈ 10˚, thus maximizing power transfer to the tissues. Also, at these higher frequencies, the current pulse maintains significantly greater fidelity to the shape of the stimulation signal applied across the electrodes. Lastly, there were lower impedances associated with parallel as opposed to perpendicular orientation of the electrodes, thus reflecting the effects of fiber orientation within the spinal cord. Impedance differences of this kind have not been reported with epidural stimulation because of the electrical shunting effects of the intervening layer of relatively high conductivity cerebrospinal fluid. These observations provide a quantitative basis for improved models of spinal cord stimulation and suggest certain advantages for direct intradural stimulation relative to the standard epidural approaches. (Some figures in this article are in colour only in the electronic version)

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.

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.

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.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.All surgical procedures were carried out at the University of Iowa. The gait measurements were made at Iowa State University.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.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.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.

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.

The electric charge–magnetic dipole interaction is considered. If Γem is the electromagnetic and Γmech the mechanical angular momentum, the conservation law for the total angular momentum Γtot holds: Γtot=Γem+Γmech= const., but when the dipole moment varies with time, Γmech is not conserved. We show that the non-conserved Γmech of such a macroscopic isolated system might be experimentally observable. With advanced technology, the strength of the interaction hints to the possibility of novel applications for gyroscopes, such as the electromagnetic top.

We reassess the true roles of the gravitational charge (mass) and the inertial mass in quantum phases acquired in matter-wave interferometry in a gravitational field. The insights gained allow us to address the question of whether gravimetry with atom interferometers is equivalent to a high precision measurement of the relative gravitational time dilation of two clocks separated in space. In particular we show that the gravitational phase is inversely related to the Compton frequency, invalidating the suggested equivalence to a Compton clock. Clarity of arguments is achieved by comparison to a charged matter-wave interferometer. Though quantum states have a similarity to oscillator clocks through the Planck–Einstein–de Broglie relations, it is shown clearly that the claim of greatly enhanced precision over real atomic clock comparison cannot be maintained.

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.

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.

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.

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).

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.

We provide an overview of the fundamental units of physical quantities determined naturally by the values of fundamental constants of nature. We discuss a comparison between the 'Planck units', now widely used in theoretical physics and the pre-quantum 'Stoney units' in which, instead of the Planck constant, the charge of the electron is used with very similar quantitative results. We discuss some of the physical motivation for these special units, attributed much after they were introduced, and also put forth a summary of the arguments supporting various cases for making specific physical interpretations of the meanings of some of these units. The new aspects we discuss are a possible physical basis for the Stoney units, their link to the Planck units, and also the importance of Planck units for thermodynamical quantities in the context of quantum gravity., Comment: 22 pages, 1 table

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.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.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 were90%.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.

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.

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.

Over the past twenty years, there have been several careful experimental, observational and phenomenological investigations aimed at searching for and establishing ever tighter bounds on the possible mass of the photon. There are many fascinating and paradoxical physical implications that would arise from the presence of even a very small value for it, and thus such searches have always been well motivated in terms of the new physics that would result. We provide a brief overview of the theoretical background and classical motivations for this work and the early tests of the exactness of Coulomb’s law that underlie it. We then go on to address the modern situation, in which quantum physics approaches come to attention. Among them we focus especially on the implications that the Aharonov-Bohm and Aharonov-Casher class of effects have on searches for a photon mass. These arise in several different ways and can lead to experiments that might involve the interaction of magnetic dipoles, electric dipoles, or charged particles with suitable potentials. Still other quantum-based approaches employ measurements of the g-factor of the electron. Plausible target sensitivities for limits on the photon mass as sought by the various quantum approaches are in the range of 10-53 to 10-54 g. Possible experimental arrangements for the associated experiments are discussed. We close with an assessment of the state of the art and a prognosis for future work.

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 present the quantum spin as a novel test tool for probing directly the Planck scale space–time foam of quantum gravity. Quantum fluctuations of spatial support for the electric vector associated with the spin-one photon affect its polarization sufficiently to allow us to gain deep insights and unprecedented constraints on the most important and fundamental aspect of quantum gravity — the fluctuating structure of space–time with a Planck scale three-dimensional web. We show that the survival of strong polarization of X-rays and gamma rays from the Crab Nebula rejects the conventional space–time foam at Planck length scale and constrains the microscopic scale of quantum gravitational fluctuations to below 2 × 10-8l P .

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.