Sina Safayi

Soft-coupling suspension system for an intradural spinal cord stimulator: Biophysical performance characteristics

We have characterized the mechanical compliance of an improved version of the suspension system used to position the electrode-bearing membrane of an intradural neuromodulator on the dorsal pial surface of the spinal cord. Over the compression span of 5 mm, it exhibited a restoring force of 2.4 μN μm−1 and a mean pressure of 0.5 mm Hg (=66 Pa) on the surface below it, well within the range of normal intrathecal pressures. We have implanted prototype devices employing this suspension and a novel device fixation technique in a chronic ovine model of spinal cord stimulation and found that it maintains stable contact at the electrode-pia interface without lead fracture, as determined by measurement of the inter-contact impedances.

Biomechanical performance of an ovine model of intradural spinal cord stimulation

Abstract 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.

Revisiting intradural spinal cord stimulation: an introduction to a novel intradural spinal cord stimulation device

Abstract Background: Spinal cord stimulation has been in use for decades and is growing as a therapeutic treatment option. A significant problem arising from the epidural location of the lead is electrical shunting through the cerebrospinal fluid, providing sub-optimal delivery of the electrical current specifically to the Aβ fibers of the dorsal column. Objective: Our goal is to design a safe and effective intradural spinal cord stimulator (SCS) that places the stimulating electrodes directly against the pia similar to what is currently employed with the auditory brainstem implant. Methods: We have reviewed the literature on the early original intradural SCSs and designed, built, and tested an improved device that seeks to overcome the limitations the existing epidural stimulators. Results: In particular, we have shown that the present design of our device allows for motion of the spinal cord without the device being displaced itself, exerts a surface pressure on the spinal cord surface that is below what would cause ischemia or vessel injury, activates somato-sensory evoked potentials at a lower threshold than epidural stimulation, and (iv) does not cause deleterious neurological deficits in a chronic ovine model of intradural stimulator implantation. Conclusion: While further studies to prove long-term safety and durability of the device are underway, we believe that revisiting an intradural approach to spinal cord stimulation may continue to improve our ability to treat certain chronic pain states and possibly the spasticity associated with spinal cord injuries.

Kinematic analysis of the gait of adult sheep during treadmill locomotion: Parameter values, allowable total error, and potential for use in evaluating spinal cord injury

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.

An ovine model of spinal cord injury.

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.

Treadmill measures of ambulation rates in ovine models of spinal cord injury and neuropathic pain

Abstract 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.

Ovine model of neuropathic pain for assessing mechanisms of spinal cord stimulation therapy via dorsal horn recordings, von Frey filaments, and gait analysis

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.

When neuroscience met clinical pathology: partitioning experimental variation to aid data interpretation in neuroscience

In animal experiments, neuroscientists typically assess the effectiveness of interventions by comparing the average response of groups of treated and untreated animals. While providing useful insights, focusing only on group effects risks overemphasis of small, statistically significant but physiologically unimportant, differences. Such differences can be created by analytical variability or physiological within‐individual variation, especially if the number of animals in each group is small enough that one or two outlier values can have considerable impact on the summary measures for the group. Physicians face a similar dilemma when comparing two results from the same patient. To determine whether the change between two values reflects disease progression or known analytical and physiological variation, the magnitude of the difference between two results is compared to the reference change value. These values are generated by quantifying analytical and within‐individual variation, and differences between two results from the same patient are considered clinically meaningful only if they exceed the combined effect of these two sources of ‘noise’. In this article, we describe how the reference change interval can be applied within neuroscience. This form of analysis provides a measure of outcome at an individual level that complements traditional group‐level comparisons, and therefore, introduction of this technique into neuroscience can enrich interpretation of experimental data. It can also safeguard against some of the possible misinterpretations that may occur during analysis of the small experimental groups that are common in neuroscience and, by illuminating analytical error, may aid in design of more efficient experimental methods.