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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&nbsp

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.

NEW FINDINGS What is the central question of this research? Does acute spinal cord stimulation increase vascular conductance and decrease muscle sympathetic nerve activity in the lower limbs of humans? What is the main finding and its importance? Acute spinal cord stimulation led to a rapid rise in femoral vascular conductance, and peroneal muscle sympathetic nerve activity demonstrated a delayed reduction that was not associated with the initial increase in femoral vascular conductance. These findings suggest that neural mechanisms in addition to attenuated muscle sympathetic nerve activity might be involved in the initial increase in femoral vascular conductance during acute spinal cord stimulation. ABSTRACT Clinical cases have indicated an increase in peripheral blood flow after continuous epidural spinal cord stimulation (SCS) and that reduced muscle sympathetic nerve activity (MSNA) might be a potential mechanism. However, no studies in humans have directly examined the effects of acute SCS (

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.

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.

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.