Models Of Spinal Cord Stimulation Research Articles

Evoked compound action potential (ECAP)-controlled closed-loop spinal cord stimulation in an experimental model of neuropathic pain in rats

BackgroundPreclinical models of spinal cord stimulation (SCS) are lacking objective measurements to inform translationally applicable SCS parameters. The evoked compound action potential (ECAP) represents a measure of dorsal column fiber activation. This measure approximates the onset of SCS-induced sensations in humans and provides effective analgesia when used with ECAP-controlled closed-loop (CL)-SCS systems. Therefore, ECAPs may provide an objective surrogate for SCS dose in preclinical models that may support better understanding of SCS mechanisms and further translations to the clinics. This study assessed, for the first time, the feasibility of recording ECAPs and applying ECAP-controlled CL-SCS in freely behaving rats subjected to an experimental model of neuropathic pain.MethodsAdult male Sprague–Dawley rats (200–300 g) were subjected to spared nerve injury (SNI). A custom-made six-contact lead was implanted epidurally covering T11-L3, as confirmed by computed tomography or X-ray. A specially designed multi-channel system was used to record ECAPs and to apply ECAP-controlled CL-SCS for 30 min at 50 Hz 200 µs. The responses of dorsal column fibers to SCS were characterized and sensitivity towards mechanical and cold stimuli were assessed to determine analgesic effects from ECAP-controlled CL-SCS. Comparisons between SNI rats and their controls as well as between stimulation parameters were made using omnibus analysis of variance (ANOVA) tests and t-tests.ResultsThe recorded ECAPs showed the characteristic triphasic morphology and the ECAP amplitude (mV) increased as higher currents (mA) were applied in both SNI animals and controls (SNI SCS-ON and sham SCS-ON). Importantly, the use of ECAP-based SCS dose, implemented in ECAP-controlled CL-SCS, significantly reduced mechanical and cold hypersensitivity in SNI SCS-ON animals through the constant and controlled activation of dorsal column fibers. An analysis of conduction velocities of the evoked signals confirmed the involvement of large, myelinated fibers.ConclusionsThe use of ECAP-based SCS dose implemented in ECAP-controlled CL-SCS produced analgesia in animals subjected to an experimental model of neuropathic pain. This approach may offer a better method for translating SCS parameters between species that will improve understanding of the mechanisms of SCS action to further advance future clinical applications.

Neurostimulation in the patient with chronic pain: forecasting the future with data from the present – data-driven analysis or just dreams?

Chronic pain involves a structured and individualized development of neurophysiological and biological responses. The final expression in each patient correlates with diverse expressions of mediators and activations of different transmission...

Bioheat Model of Spinal Column Heating During High-Density Spinal Cord Stimulation

IntroductionHigh-density (HD) spinal cord stimulation (SCS) delivers higher charge per time by increasing frequency and/or pulse duration, thus increasing stimulation energy. Previously, through phantom studies and computational modeling, we demonstrated that stimulation energy drives spinal tissue heating during kHz SCS. In this study, we predicted temperature increases in the spinal cord by HD SCS, the first step in considering the potential impact of heating on clinical outcomes. Materials and MethodsWe adapted a high-resolution computer-aided design–derived spinal cord model, both with and without a lead encapsulation layer, and applied bioheat transfer finite element method multiphysics to predict temperature increases during SCS. We simulated HD SCS using a commercial SCS lead (eight contacts) with clinically relevant intensities (voltage-controlled: 0.5–7 Vrms) and electrode configuration (proximal bipolar, distal bipolar, guarded tripolar [+−+], and guarded quadripolar [+−−+]). Results were compared with the conventional and 10-kHz SCS (current-controlled). ResultsHD SCS waveform energy (reflecting charge per second) governs joule heating in the spinal tissues, increasing temperature supralinearly with stimulation root mean square. Electrode configuration and tissue properties (an encapsulation layer) influence peak tissue temperature increase—but in a manner distinct for voltage-controlled (HD SCS) compared with current-controlled (conventional/10-kHz SCS) stimulation. Therefore, depending on conditions, HD SCS could produce heating greater than that of 10-kHz SCS. For example, with an encapsulation layer, using guarded tripolar configuration (500-Hz, 250-μs pulse width, 5-Vpeak HD SCS), the peak temperature increases were 0.36 °C at the spinal cord and 1.78 °C in the epidural space. ConclusionsAs a direct consequence of the higher charge, HD SCS increases tissue heating; voltage-controlled stimulation introduces special dependencies on electrode configuration and lead encapsulation (reflected in impedance). If validated with an in vivo measurement as a possible mechanism of action of SCS, bioheat models of HD SCS serve as tools for programming optimization.

ID:16342 Electrically Evoked Compound Action Potentials in a Rat Model of Spinal Cord Stimulation

Spinal evoked compound action potentials (ECAPs) quantify the relationship between the stimulation delivered during spinal cord stimulation (SCS) and the neural recruitment of Aβ-fibers in dorsal columns (DCs)1,2. This relationship has important clinical implications for the treatment of chronic pain in humans. We therefore assessed the feasibility of recording and characterizing ECAPs from DC axons in rats to develop pre-clinical models of therapeutic SCS. We also aimed to quantify the relationship between ECAP and motor thresholds (ECAPTs and MTs) to identify novel stimulation methods for rodents that would better reproduce clinical SCS procedures.

ID:16278 Assessing Thresholds for Activation of the Pain Pathways in a Rodent Model of SCS

Neuromodulation approaches like spinal cord stimulation (SCS) are increasingly being applied as alternatives to the traditional pharmacologic treatments of chronic pain1. Tonic electrical stimulation of the spinal cord is most often applied through epidural electrodes, but in addition to putatively exciting the dorsal columns, it can induce paresthesia in many patients sometimes limiting therapeutic efficacy1. As a result, alternative, ‘paresthesia-free’ stimulation paradigms such as burst2 and high frequency stimulation are gaining popularity.

Development of Machine Learning-Based Models to Predict Treatment Response to Spinal Cord Stimulation.

Despite spinal cord stimulation's (SCS) proven efficacy, failure rates are high with no clear understanding of which patients benefit long term. Currently, patient selection for SCS is based on the subjective experience of the implanting physician. To develop machine learning (ML)-based predictive models of long-term SCS response. A combined unsupervised (clustering) and supervised (classification) ML technique was applied on a prospectively collected cohort of 151 patients, which included 31 features. Clusters identified using unsupervised K-means clustering were fitted with individualized predictive models of logistic regression, random forest, and XGBoost. Two distinct clusters were found, and patients in the cohorts significantly differed in age, duration of chronic pain, preoperative numeric rating scale, and preoperative pain catastrophizing scale scores. Using the 10 most influential features, logistic regression predictive models with a nested cross-validation demonstrated the highest overall performance with the area under the curve of 0.757 and 0.708 for each respective cluster. This combined unsupervised-supervised learning approach yielded high predictive performance, suggesting that advanced ML-derived approaches have potential to be used as a functional clinical tool to improve long-term SCS outcomes. Further studies are needed for optimization and external validation of these models.

Electrically Evoked Compound Action Potentials in Spinal Cord Stimulation: Implications for Preclinical Research Models

ObjectivesThe study aimed to assess the feasibility of recording electrically evoked compound action potentials (ECAPs) from the rat spinal cord. To achieve this, we characterized electrophysiological responses of dorsal column (DC) axons from electrical stimulation and quantified the relationship between ECAP and motor thresholds (ECAPTs and MTs). Material and MethodsNaïve, anesthetized, and freely behaving rats were implanted with a custom-made epidural spinal cord stimulation (SCS) lead. Epidural stimulation and recordings were performed on the same lead using specifically designed equipment. ResultsThe ECAPs recorded from the rat spinal cord demonstrated the expected triphasic morphology. Using 20 μsec pulse duration and 2 Hz frequency rate, the current required in anesthetized rats to generate ECAPs was 0.13 ± 0.02 mA, while the average current required to observe MT was 1.49 ± 0.14 mA. In unanesthetized rats, the average current required to generate ECAPs was 0.09 ± 0.02 mA, while the average current required to observe MT was 0.27 ± 0.04 mA. Thus, there was a significant difference between the ECAPT and MT in both anesthetized and unanesthetized rats (MT was 13.39 ± 2.40 and 2.84 ± 0.33 times higher than ECAPT, respectively). Signal analysis revealed average conduction velocities (CVs) suggesting that predominantly large, myelinated fibers were activated. In addition, a morphometric evaluation of spinal cord slices indicated that the custom-made lead may preferentially activate DC axons. ConclusionsThis is the first evidence demonstrating the feasibility of recording ECAPs from the rat spinal cord, which may be more useful in determining parameters of SCS in preclinical SCS models than MTs. Thus, this approach may allow for the development of a novel model of SCS in rats with chronic pain that will translate better between animals and humans.

Simulation study of spinal cord stimulation evoked compound action potential

Spinal cord stimulation (SCS) for pain is usually implanted as an open loop system using unchanged parameters. To avoid the under and over stimulation caused by lead migration, evoked compound action potentials (ECAP) is used as feedback signal to change the stimulating parameters. This study established a simulation model of ECAP recording to investigate the relationship between ECAP component and dorsal column (DC) fiber recruitment. Finite element model of SCS and multi-compartment model of sensory fiber were coupled to calculate the single fiber action potential (SFAP) caused by single fiber in different spinal cord regions. The synthetized ECAP, superimposition of SFAP, could be considered as an index of DC fiber excitation degree, because the position of crests and amplitude of ECAP corresponds to different fiber diameters. When 10% or less DC fibers were excited, the crests corresponded to fibers with large diameters. When 20% or more DC fibers were excited, ECAP showed a slow conduction crest, which corresponded to fibers with small diameters. The amplitude of this slow conduction crest increased as the stimulating intensity increased while the amplitude of the fast conduction crest almost remained unchanged. Therefore, the simulated ECAP signal in this paper could be used to evaluate the degree of excitation of DC fibers. This SCS-ECAP model may provide theoretical basis for future clinical application of close loop SCS base on ECAP.

Patient-Specific Analysis of Neural Activation During Spinal Cord Stimulation for Pain

Despite the widespread use of spinal cord stimulation (SCS) for chronic pain management, its neuromodulatory effects remain poorly understood. Computational models provide a valuable tool to study SCS and its effects on axonal pathways within the spinal cord. However, these models must include sufficient detail to correlate model predictions with clinical effects, including patient-specific data. Therefore, the goal of this study was to investigate axonal activation at clinically relevant SCS parameters using a computer model that incorporated patient-specific anatomy and electrode locations. We developed a patient-specific computer model for a patient undergoing SCS to treat chronic pain. This computer model consisted of two main components: 1) finite element model of the extracellular voltages generated by SCS and 2) multicompartment cable models of axons in the spinal cord. To determine the potential significance of a patient-specific approach, we also performed simulations with standard canonical models of SCS. We used the computer models to estimate axonal activation at clinically measured sensory, comfort, and discomfort thresholds. The patient-specific and canonical models predicted significantly different axonal activation. Relative to the canonical models, the patient-specific model predicted sensory threshold estimates that were more consistent with the corresponding clinical measurements. These results suggest that it is important to account for sources of interpatient variability (e.g., anatomy, electrode locations) in model-based analysis of SCS. This study demonstrates the potential for patient-specific computer models to quantitatively describe the axonal response to SCS and to address scientific questions related to clinical SCS.

Realistic anatomically detailed open-source spinal cord stimulation (RADO-SCS) model

Objective. Computational current flow models of spinal cord stimulation (SCS) are widely used in device development, clinical trial design, and patient programming. Proprietary models of varied sophistication have been developed. An open-source model with state-of-the-art precision would serve as a standard for SCS simulation. Approach. We developed a sophisticated SCS modeling platform, named Realistic Anatomically Detailed Open-Source Spinal Cord Stimulation (RADO-SCS) model. This platform consists of realistic and detailed spinal cord and ancillary tissues anatomy derived based on prior imaging and cadaveric studies. In our finite element model of the T9-T11 spine levels, we represented the following tissues: vertebrae, intervertebral disc, epidural space, epidural space vasculature, dura mater, dural sac, intraforaminal tissue, cerebrospinal fluid (CSF), whitematter, spinal cord vasculature, Lissauer’s tract, gray matter, dorsal and ventral roots and rootlets, dorsal root ganglion (DRG), sympathetic chain (trunk and ganglion), thoracic aorta and its branching, peripheral vasculature, and soft tissues (thorax). As an exemplary application to illustrate the model workflow, we simulated a bipolar SCS montage and calculated the corresponding activation thresholds for individual axons populating the spinal cord. Main results. RADO-SCS provides state-of-the-art precision across 19 tissue compartments. The resulting model calculations of the electric fields generated in the white-matter and gray matter, and the axonal activation thresholds are broadly consistent with prior simulations. Significance. The RADO-SCS can be used to simulate any SCS approach with both unprecedented resolution (precision) and transparency (reproducibility). Freely-available online, the RADO-SCS will be updated continuously with version control.

Phrenic motor neuron activation using temporal interference stimulation

Based on deep brain stimulation data, we are using a method called temporal interference (T‐I) stimulation to activate phrenic motor neurons in adult rats. The premise is to target the deep ventral motor pools of the spinal cord with two high frequency but low amplitude electrical waveforms. The waveforms are delivered at kilohertz frequencies that are well above values that directly stimulate neurons, and amplitudes insufficient to activate neurons until the electric field combine in the tissue. The frequency of the two waveforms is offset by a small amount (e.g. 1–5 Hz), and where the two electrical fields combine to form a difference‐frequency time‐modulated signal in the tissue, neuronal populations are recruited. This work tested the hypotheses that 1) T‐I stimulation using epidural electrodes can activate phrenic motoneurons via direct depolarization, and 2) T‐I stimulation using percutaneously electrodes in the neck can activate the diaphragm and sustain breathing after opioid overdose. For epidural stimulation, electrodes were placed at C3 and experiments were conducted in ventilated, urethane anesthetized adult rats. Initial experiments showed that a pair of electrodes, one medial and one lateral, over the left hemicord was sufficient to enable diaphragm activation via T‐I. Intraspinal delivery of CNQX and AP5 was used to block excitatory synaptic inputs to phrenic motoneurons, confirmed by a complete cessation of endgoenous diaphragm activity. Under these conditions, epidural T‐I (5000Hz and 5001Hz 360–1800μA) could activate the diaphragm, but the response was attenuated by 50–75% as compared to pre‐drug conditions. Blocking inhibitory synaptic inputs using strychnine and bicuculline increased the impact of epidural T‐I by 100–170%. Opioid overdose (fentanyl, 30mcg/kg) in spontaneously breathing rats produced severe hypoventilation and mortality in 4 of 4 cases. However, when T‐I stimulation was given via intramuscular wires placed in the neck (5000Hz and 5001Hz 8–10mA), 4 of 4 rats survived the fentanyl overdose and were able to eventually resume spontaneous breathing. Ongoing efforts by our group are aimed at understanding the flow of electrical current in the spinal cord during epidural and percutaneous delivery to T‐I. To this end, in silico models of spinal cord stimulation are being developed using the Sim4Life software (image‐based electromagnetic and neural simulations in a rat anatomical model with detailed spinal cord structures). The modeling data are intended to help refine the electrode design, placement, and stimulation parameters, to minimize off‐target muscle activation. At this time, we conclude that 1) epidural T‐I of the cervical spinal cord can activate phrenic motoneurons by a combination of pre‐ and post‐synaptic inputs, and 2) percutaneous T‐I is capable of producing airflow which can sustain life through opioid overdose.Support or Funding InformationF31 HL145831‐01 (MDS), R21‐NS109571 (DDF)

Evoked Potentials Recorded From the Spinal Cord During Neurostimulation for Pain: A Computational Modeling Study

Spinal cord stimulation (SCS) for pain is typically implemented in an open-loop manner using parameters that remain largely unchanged. To improve the overall efficacy and consistency of SCS, one closed-loop approach proposes to use evoked compound action potentials (ECAPs) recorded from the SCS lead(s) as a feedback control signal to guide parameter selection. The goal of this study was to use a computational modeling approach to investigate the source of these ECAP recordings and technical and physiological factors that affect their composition. We developed a computational model that coupled a finite element model of lower thoracic SCS with multicompartment models of sensory axons within the spinal cord. We used a reciprocity-based approach to calculate SCS-induced ECAPs recorded from the SCS lead. Our model ECAPs contained a triphasic, P1, N1, P2 morphology. The model P2-N1 amplitudes and conduction velocities agreed with previous experimental data from human subjects. Model results suggested that the ECAPs are dominated by the activation of axons with diameters 8.7-10.0 μm located in the dorsal aspect of the spinal cord. We also observed changes in the ECAP amplitude and shape due to the electrode location relative to the vertebrae and spinal cord. Our modeling results suggest that clinically effective SCS relies on the activation of numerous axons within a narrow fiber diameter range and that several factors affect the composition of the ECAP recordings. These results can improve how we interpret and implement these recordings in a potential closed-loop approach to SCS.

The Quasi-uniform assumption for Spinal Cord Stimulation translational research

BackgroundQuasi-uniform assumption is a general theory that postulates local electric field predicts neuronal activation. Computational current flow model of spinal cord stimulation (SCS) of humans and animal models inform how the quasi-uniform assumption can support scaling neuromodulation dose between humans and translational animal. New methodHere we developed finite element models of cat and rat SCS, and brain slice, alongside SCS models. Boundary conditions related to species specific electrode dimensions applied, and electric fields per unit current (mA) predicted. ResultsClinically and across animal, electric fields change abruptly over small distance compared to the neuronal morphology, such that each neuron is exposed to multiple electric fields. Per unit current, electric fields generally decrease with body mass, but not necessarily and proportionally across tissues. Peak electric field in dorsal column rat and cat were ∼17x and ∼1x of clinical values, for scaled electrodes and equal current. Within the spinal cord, the electric field for rat, cat, and human decreased to 50% of peak value caudo-rostrally (C5–C6) at 0.48 mm, 3.2 mm, and 8 mm, and mediolaterally at 0.14 mm, 2.3 mm, and 3.1 mm. Because these space constants are different, electric field across species cannot be matched without selecting a region of interest (ROI). Comparison with existing methodThis is the first computational model to support scaling neuromodulation dose between humans and translational animal. ConclusionsInter-species reproduction of the electric field profile across the entire surface of neuron populations is intractable. Approximating quasi-uniform electric field in a ROI is a rational step to translational scaling.

Assessment of axonal recruitment using model-guided preclinical spinal cord stimulation in the ex vivo adult mouse spinal cord

Spinal cord stimulation (SCS) is used clinically to limit chronic pain, but fundamental questions remain on the identity of axonal populations recruited. We developed an ex vivo adult mouse spinal cord preparation to assess recruitment following delivery of clinically analogous stimuli determined by downscaling a finite element model of clinical SCS. Analogous electric field distributions were generated with 300-µm × 300-µm electrodes positioned 200 µm above the dorsal column (DC) with stimulation between 50 and 200 µA. We compared axonal recruitment using electrodes of comparable size and stimulus amplitudes when contacting the caudal thoracic DC and at 200 or 600 μm above. Antidromic responses recorded distally from the DC, the adjacent Lissauer tract (LT), and in dorsal roots (DRs) were found to be amplitude and site dependent. Responses in the DC included a unique component not seen in DRs, having the lowest SCS recruitment amplitude and fastest conduction velocity. At 200 μm above, mean cathodic SCS recruitment threshold for axons in DRs and LT were 2.6 and 4.4 times higher, respectively, than DC threshold. SCS recruited primary afferents in all (up to 8) caudal segments sampled. Whereas A and C fibers could be recruited at nearby segments, only A fiber recruitment and synaptically mediated dorsal root reflexes were observed in more distant (lumbar) segments. In sum, clinically analogous SCS led to multisegmental recruitment of several somatosensory-encoding axonal populations. Most striking is the possibility that the lowest threshold recruitment of a nonprimary afferent population in the DC are postsynaptic dorsal column tract cells (PSDCs) projecting to gracile nuclei.NEW & NOTEWORTHY Spinal cord stimulation (SCS) is used clinically to control pain. To identify axonal populations recruited, finite element modeling identified scaling parameters to deliver clinically analogous SCS in an ex vivo adult mouse spinal cord preparation. Results showed that SCS first recruited an axonal population in the dorsal column at a threshold severalfold lower than primary afferents. These putative postsynaptic dorsal column tract cells may represent a previously unconsidered population responsible for SCS-induced paresthesias necessary for analgesia.

An Intermediate Animal Model of Spinal Cord Stimulation.

Spinal cord injuries (SCI) result in the loss of movement and sensory feedback as well as organs dysfunctions. For example, nearly all SCI subjects loose their bladder control and are prone to kidney failure if they do not proceed to intermittent (self-) catheterization. Electrical stimulation of the sacral spinal roots with an implantable neuroprosthesis is a promising approach, with commercialized products, to restore continence and control micturition. However, many persons do not ask for this intervention since a surgical deafferentation is needed and the loss of sensory functions and reflexes become serious side effects of this procedure. Recent results renewed interest in spinal cord stimulation. Stimulation of existing pre-cabled neural networks involved in physiological processes regulation is suspected to enable synergic recruitment of spinal fibers. The development of direct spinal stimulation strategies aiming at bladder and bowel functions restoration would therefore appear as a credible alternative to existent solutions. However, a lack of suitable large animal model complicates these kinds of studies. In this article, we propose a new animal model of spinal stimulation -pig- and will briefly introduce results from one first acute experimental validation session.

High-Frequency Stimulation of Dorsal Column Axons: Potential Underlying Mechanism of Paresthesia-Free Neuropathic Pain Relief

Spinal cord stimulation (SCS) treats neuropathic pain through retrograde stimulation of dorsal column axons and their inhibitory effects on wide dynamic range (WDR) neurons. Typical SCS uses frequencies from 50-100 Hz. Newer stimulation paradigms use high-frequency stimulation (HFS) up to 10 kHz and produce pain relief but without paresthesia. Our hypothesis is that HFS preferentially blocks larger diameter axons (12-15 µm) based on dynamics of ion channel gates and the electric potential gradient seen along the axon, resulting in inhibition of WDR cells without paresthesia. We input field potential values from a finite element model of SCS into an active axon model with ion channel subcomponents for fiber diameters 1-20 µm and simulated dynamics on a 0.001 msec time scale. Assuming some degree of wave rectification seen at the axon, action potential (AP) blockade occurs as hypothesized, preferentially in larger over smaller diameters with blockade in most medium and large diameters occurring between 4.5 and 10 kHz. Simulations show both ion channel gate and virtual anode dynamics are necessary. At clinical HFS frequencies and pulse widths, HFS preferentially blocks larger-diameter fibers and concomitantly recruits medium and smaller fibers. These effects are a result of interaction between ion gate dynamics and the "activating function" (AF) deriving from current distribution over the axon. The larger fibers that cause paresthesia in low-frequency simulation are blocked, while medium and smaller fibers are recruited, leading to paresthesia-free neuropathic pain relief by inhibiting WDR cells.

(399) Patient-specific computer models of spinal cord stimulation for chronic pain management

(399) Patient-specific computer models of spinal cord stimulation for chronic pain management

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.

Spinal Cord Stimulation

Spinal Cord Stimulation

The effects of modulating stimulation parameters of spinal cord stimulation (SCS) and glial activity in animals with neuropathic pain

Spinal cord stimulation is (SCS) is an effective treatment for the management of chronic intractable neuropathic pain. We therefore used an animal model of SCS to modulate frequency (4Hz vs. 60Hz), duration (30m vs. 6h), or intensity (50%, 75%, or 90% MT) in animals with neuropathic pain. To elucidate potential mechanisms modulated by SCS we examined immunoreactivity for glial markers in the spinal cord in animals with SCS compared to those with sham SCS. Neuropathic pain was induced in Sprague-Dawley rats using the spared nerve injury model (SNI).