4379462 multi-electrode catheter assembly for spinal cord stimulation

Spinal Cord Stimulation and Evidence-Based Medicine—Cui Bono

Spinal dorsal column stimulation (DCS) modulates sensory transmission, including pain, at the dorsal horn of the cord. However, the mechanisms of DCS modulatory actions and the effects of anesthetics on these mechanisms remain to be investigated. We studied the effects of isoflurane (1.0% and 2.0%) on conditioned inhibition, the amplitude decrease of the spinal cord potentials (SCPs) after a conditioning volley (DCS), in the ketamine-anesthetized rat by recording the sharp negative (N) and slow positive (P) waves of the SCPs evoked by conditioning dorsal column (DC) and testing segmental stimulations. The N wave is believed to be the synchronized activity of the dorsal horn neurons, and the P wave, primary afferent depolarization (PAD), reflecting presynaptic inhibition. The P potentials evoked by either DC or segmental stimulation were depressed by isoflurane, whereas the N waves remained unchanged, indicating that the pharmacological characteristics of these N and P waves are similar between DC-evoked and segmentally evoked SCPs. The conditioned inhibition of segmental N and P waves by DC stimulation was almost completely suppressed by 2.0% isoflurane. The conditioned inhibition of the segmental N wave was not changed by spinal cord transection, whereas the conditioned inhibition of the segmental P wave was decreased. The results indicate that isoflurane depresses presynaptic inhibition without affecting the synchronized activity of dorsal horn neurons and, most profoundly, depresses the conditioned inhibition by DC stimulation of the dorsal horn neurons and PAD. Further, the results indicate that conditioned inhibition by DC stimulation of PAD receives a facilitatory influence from the supraspinal structures, whereas that of the synchronized activity of the dorsal horn neurons does not. To investigate how anesthetics affect supraspinal modulation of sensory transmission in the spinal cord, the spinal cord potential (SCP) evoked by dorsal cord stimulation (DCS) and segmentally evoked SCP conditioned by DCS were recorded in intact and spinal cord-transected rats during isoflurane anesthesia.

Editorial| April 2023 Modulating the Cardiac Autonomic Nervous System: Stay Close to My Heart or Keep Your Distance? This article has an Audio Podcast Karsten Bartels, M.D., Ph.D., M.B.A.; Karsten Bartels, M.D., Ph.D., M.B.A. 1Department of Anesthesiology, University of Nebraska Medical Center, Omaha, Nebraska; Outcomes Research Consortium, Cleveland, Ohio. https://orcid.org/0000-0003-2028-4664 Search for other works by this author on: This Site PubMed Google Scholar Amanda A. Fox, M.D., M.P.H. Amanda A. Fox, M.D., M.P.H. 2Department of Anesthesiology and Pain Management, and McDermott Center for Human Growth and Development/Center for Human Genetics, University of Texas Southwestern Medical Center, Dallas, Texas. Search for other works by this author on: This Site PubMed Google Scholar Author and Article Information This editorial accompanies the article on p. 372. Accepted for publication February 1, 2023. Address correspondence to Dr. Bartels: karbartels@unmc.edu Anesthesiology April 2023, Vol. 138, 348–350. https://doi.org/10.1097/ALN.0000000000004529 Connected Content Article: GABAergic Signaling during Spinal Cord Stimulation Reduces Cardiac Arrhythmias in a Porcine Model Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Search Site Citation Karsten Bartels, Amanda A. Fox; Modulating the Cardiac Autonomic Nervous System: Stay Close to My Heart or Keep Your Distance?. Anesthesiology 2023; 138:348–350 doi: https://doi.org/10.1097/ALN.0000000000004529 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll PublicationsAnesthesiology Search Advanced Search Topics: autonomic nervous system, heart Perioperative cardiac protection research is needed to determine how to prevent and mitigate cardiac injury that can lead to cardiovascular morbidity and mortality. In this month’s issue of Anesthesiology, Howard-Quijano et al.1 report effects of high thoracic spinal cord stimulation on decreasing sympathetic stimulation of the heart and corresponding ventricular arrhythmias. What is particularly meaningful about this paper is that the authors do experiments on Yorkshire pigs in order to define the biology underlying the favorable cardiac effects of high thoracic spinal cord stimulation. In their manuscript, the authors report findings from an elegant sequence of experiments demonstrating specifically that (1) spinal cord stimulation therapy during cardiac ischemia resulted in fewer ventricular arrhythmias, (2) intrathecal γ-aminobutyric acid type A (GABAA) and γ-aminobutyric acid type B (GABAB) receptor blockade eliminated the protective effects of spinal cord stimulation, (3) intrathecal administration of γ-aminobutyric acid (GABA) transaminase... You do not currently have access to this content.

Paclitaxel-induced peripheral neuropathy (PIPN) is a common dose-limiting side effect of this cancer treatment drug. Spinal cord stimulation (SCS) has demonstrated efficacy for attenuating some neuropathic pain conditions. We aim to examine the inhibitory effect of SCS on the development of PIPN pain and changes of gene expression in the spinal cord in male rats after SCS. We examined whether traditional SCS (50 Hz, 6-8 h/session daily for 14 consecutive days) administered during paclitaxel treatment (1.5 mg/kg, i.p.) attenuates PIPN-related pain behavior. After SCS treatment, we performed RNA-seq of the lumbar spinal cord to examine which genes are differentially expressed after PIPN with and without SCS. Compared to rats treated with paclitaxel alone (n = 7) or sham SCS (n = 6), SCS treatment (n = 11) significantly inhibited the development of paclitaxel-induced mechanical and cold hypersensitivity, without altering open-field exploratory behavior. RNA-seq showed that SCS induced upregulation of 836 genes and downregulation of 230 genes in the spinal cord of paclitaxel-treated rats (n = 3) as compared to sham SCS (n = 5). Spinal cord stimulation upregulated immune responses in paclitaxel-treated rats, including transcription of astrocyte- and microglial-related genes, but repressed transcription of multiple gene networks associated with synapse transmission, neuron projection development, γ-aminobutyric acid reuptake, and neuronal plasticity. Our findings suggest that traditional SCS may attenuate the development of pain-related behaviors in PIPN rats, possibly by causing aggregate inhibition of synaptic plasticity through upregulation and downregulation of gene networks in the spinal cord.

Complex regional pain syndrome I (reflex sympathetic dystrophy).

PurposeElectrical epidural spinal cord stimulation (SCS) is used as a treatment for chronic pain as well as to partially restore motor function after a spinal cord injury. Monitoring the spinal cord activity during SCS with fMRI could provide important and objective measures of integrative responses to treatment. Unfortunately, spinal cord fMRI is severely challenged by motion and susceptibility artifacts induced by the implanted electrode and bones. This pilot study introduces multi‐band sweep imaging with Fourier transformation (MB‐SWIFT) technique for spinal cord fMRI during SCS in rats. Given the close to zero acquisition delay and high bandwidth in 3 dimensions, MB‐SWIFT is demonstrated to be highly tolerant to motion and susceptibility‐induced artifacts and thus holds promise for fMRI during SCS.MethodsMB‐SWIFT with 0.78 × 0.78 × 1.50 mm3 spatial resolution and 3‐s temporal resolution was used at 9.4 Tesla in rats undergoing epidural SCS at different frequencies. Its performance was compared with spin echo EPI. The origin of the functional contrast was also explored using suppression bands.ResultsMB‐SWIFT was tolerant to electrode‐induced artifacts and respiratory motion, leading to substantially higher fMRI sensitivity than spin echo fMRI. Clear stimulation frequency‐dependent responses to SCS were detected in the rat spinal cord close to the stimulation site. The origin of MB‐SWIFT fMRI signals was consistent with dominant inflow effects.ConclusionfMRI of the rat spinal cord during SCS can be consistently achieved with MB‐SWIFT, thus providing a valuable experimental framework for assessing the effects of SCS on the central nervous system.

Spinal Cord and Peripheral Nerve Stimulation Techniques for Neuropathic Pain

Spinal Cord Stimulation Attenuates Below-Level Mechanical Hypersensitivity in Rats After Thoracic Spinal Cord Injury

Low frequencies, but not high frequencies of bi-polar spinal cord stimulation reduce cutaneous and muscle hyperalgesia induced by nerve injury

Myocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known. In this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4-5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular in vivo and in situ spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS. ARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS. These results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons.

Decreased intracellular GABA levels contribute to spinal cord stimulation-induced analgesia in rats suffering from painful peripheral neuropathy: The role of KCC2 and GABA A receptor-mediated inhibition

ISSN 1758-1869 10.2217/PMT.10.13 © 2011 Future Medicine Ltd Pain Manage. (2011) 1(1), 7–10 The use of spinal cord stimulation (SCS) has become an essential part of the treatment armamentarium for neuropathic and visceral pain syndromes. In many cases, based on antiquated thought and a lack of an understanding of the literature, SCS is relegated to a treatment of desperation. The spine is not the only neuronal target to consider. In some clinical settings, such as postherpetic neuralgia, ilioingiunal nerve entrapment, transformed occipital (C2)-induced migraine and nerve trauma of the extremities, the use of devices to treat the peri pheral nerve fibers can be essential for a good outcome. Both of these advanced therapies can be helpful in reducing pain, improving function and reducing healthcare expenditures. It is important to use these treatment options earlier in the decision-making algorithm to assure the best possible outcome [1–3].

Responses of spinal progenitors to spinal cord stimulation (SCS) following spinal cord injury (SCI) in rats were assessed to reveal their potential contribution to SCS-induced analgesia. Spinal epidural electrodes were implanted in rats at T12 rostral to a quadrant dorsal horn injury at T13. Further groups additionally received either a microlesion to the dorsolateral funiculus (DLF) or gabapentin (10mg/kg). SCS was performed at 25Hz for 10minutes on day 4 (early SCS) and at 10Hz for 10minutes on day 8 (late SCS) after injury. Paw withdrawal threshold (PWT) was measured before injury, 30minutes before or after SCS, and before cull on day 14, followed by immunostaining assessment. Paw withdrawal thresholds in uninjured animals (51.0±4.0g) were markedly reduced after SCI (17.3±2.2g). This was significantly increased by early SCS (38.5±5.2g, P<0.01) and further enhanced by late SCS (50.9±1.9g, P<0.01) over 6days. Numbers of neural progenitors expressing nestin, Sox2, and doublecortin (DCX) in the spinal dorsal horn were increased 6days after SCS by 6-fold, 2-fold, and 2.5-fold, respectively (P<0.05 to 0.01). The elevated PWT evoked by SCS was abolished by DLF microlesions (48.9±2.6g vs. 19.0±3.9g, P<0.01) and the number of nestin-positive cells was reduced to the level without SCS (P<0.05). Gabapentin enhanced late SCS-induced analgesia from 37.0±3.9 g to 54.0±0.8g (P<0.01) and increased gamma-aminobutyric acid (GABA)-ergic neuronal marker vesicular GABA transporter-positive newborn cells 2-fold (P<0.01). Spinal progenitor cells appear to be activated by SCS via descending pathways, which may be enhanced by gabapentin and potentially contributes to relief of SCI-induced neuropathic pain.

Volitional movement requires descending input from the motor cortex and sensory feedback through the spinal cord. We previously developed a paired brain and spinal electrical stimulation approach in rats that relies on convergence of the descending motor and spinal sensory stimuli in the cervical cord. This approach strengthened sensorimotor circuits and improved volitional movement through associative plasticity. In humans, it is not known whether posterior epidural spinal cord stimulation targeted at the sensorimotor interface or anterior epidural spinal cord stimulation targeted within the motor system is effective at facilitating brain evoked responses. In 59 individuals undergoing elective cervical spine decompression surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord was stimulated with epidural electrodes, with muscle responses being recorded in arm and leg muscles. Spinal electrodes were placed either posteriorly or anteriorly, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and spinal sensory (posterior) but not spinal motor (anterior) stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred only when descending motor and spinal afferent stimuli were timed to converge in the spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, clinical signs suggest that facilitation was observed in both injured and uninjured segments of the spinal cord. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation. KEY POINTS: Pairs of stimuli designed to alter nervous system function typically target the motor system, or one targets the sensory system and the other targets the motor system for convergence in cortex. In humans undergoing clinically indicated surgery, we tested paired brain and spinal cord stimulation that we developed in rats aiming to target sensorimotor convergence in the cervical cord. Arm and hand muscle responses to paired sensorimotor stimulation were more than five times larger than brain or spinal cord stimulation alone when applied to the posterior but not anterior spinal cord. Arm and hand muscle responses to paired stimulation were more selective for targeted muscles than the brain- or spinal-only conditions, especially at latencies that produced the strongest effects of paired stimulation. Measures of clinical evidence of compression were only weakly related to the paired stimulation effect, suggesting that it could be applied as therapy in people affected by disorders of the central nervous system.

The successful use of spinal cord stimulation (SCS) in patients with stable angina pectoris refractory to medical management who are poor candidates for percutaneous or surgical angioplasty has been well described [1]. Janfaza et al. [2] recently described a critically ill patient with unstable angina pectoris who was treated with SCS. The patient's condition improved and stabilized, and the patient was discharged from the hospital and survived for at least 6 wk. To the best of our knowledge, there are no other reports of the use of SCS in such critically ill patients. We describe two similar patients treated with SCS but with different outcomes. Case Report 1 A 79-yr-old man was transferred to the cardiology service for treatment of intractable angina pectoris. He had experienced increasingly frequent and severe substernal chest pain, dyspnea, and diaphoresis worsened by mild exertion and mental stress for 8 days before this transfer. His electrocardiogram (EKG) showed new ST-segment depression in leads V3-V6. He was receiving IV heparin, nitroglycerin, and morphine in addition to oral metoprolol and nifedipine at the time of admission. An urgent cardiac catheterization showed severe three-vessel disease in addition to an 80% left main occlusion. The patient had suffered two previous myocardial infarctions and a cerebrovascular accident (CVA), and he had bilateral 100% carotid artery occlusions. He had a medical history of noninsulin-dependent diabetes mellitus, hypertension, severe peripheral vascular disease, and a 4.0-cm abdominal aortic aneurysm. Despite aggressive medical management, the patient continued to have severe and protracted episodes of chest pain at rest. His lesions were not amenable to percutaneous angioplasty, and he declined coronary artery bypass grafting because of the high risk of recurrent CVA. He decided not to be resuscitated or intubated in the event of a sudden decline in his status. On the 10th day after admission, the acute pain service was consulted. After a thorough discussion with the patient and his family regarding the risks, potential benefits, and uncertainty about the efficacy of the procedure under the current circumstances, the patient and his family agreed to a trial of SCS. The patient's heparin was stopped for 4 h, and coagulation variables were determined to be normal. The patient was taken to the operating room, monitored, lightly sedated by an anesthesiologist, and placed in the prone position. Anesthesia was accomplished by local anesthetic infiltration. A 15-gauge Tuohy needle was inserted at the T4-5 interspace. Position was identified and confirmed fluoroscopically throughout the procedure. The epidural space was identified using a loss-of-resistance to air technique. A Pisces Quad-Plus Electrode (Medtronic, Inc., Minneapolis, MN) was inserted into the epidural space and advanced under fluoroscopic guidance until the tip lay at the C7-T1 interspace and approximately 3 mm to the left of midline. A trial paresthesia was found to encompass the entire area of anginal pain. Electrode configuration was 0 = off; 1 = positive, 2 = negative, 3 = off. Pulse width was 300 ms and rate was 50 Hz. The threshold for paresthesia was 1.5 V, and the maximally tolerable paresthesia was 1.9 V. The procedure was well tolerated by the patient. Stimulation was kept constant at 1.6 V; if the patient had an episode of angina, the voltage was increased to 1.9 V until it resolved. The patient's IV medications were discontinued. Oral nitrates and morphine sulfate were used as needed. The patient had fewer and less severe episodes of angina. He was transferred out of the coronary care unit (CCU). Three days after placement of the trial electrode, the patient experienced worsening angina unrelieved by SCS, and he was transferred back to the CCU. IV heparin was resumed. His EKG indicated new ischemic changes, and he had signs and symptoms of congestive heart failure. His chest pain required SCS and IV morphine and nitroglycerin for control. On the fifth day after SCS implantation, the patient died quietly. Case Report 2 An 86-yr-old woman was admitted with a 1-wk history of uncontrolled left shoulder pressure radiating into her left arm and hand. At the time of admission, she was receiving metoprolol, amlodipine, and ticlopidine. She was treated with IV heparin, nitroglycerin, and morphine. The patient had a history of sinus node disease and had a dual-pacing, dual-sensing, dual-mode pacemaker. She had previously suffered a CVA and a myocardial infarction and had undergone percutaneous coronary angioplasty. She had a history of hypertension and peripheral vascular disease. An urgent cardiac catheterization and an attempt at revascularizaton via percutaneous angioplasty resulted in closure of the right coronary artery. The patient's creatinine phosphokinase level was increased, consistent with an acute myocardial infarction. She decided not to be resuscitated or intubated in the even her condition worsened. She was deemed to have a high risk of death and stroke with surgical bypass, and the acute pain service was consulted about the implantation of a SCS device. Informed consent was obtained, and the device was implanted as with the previous patient. Electrode configuration was 0 = off; 1 = positive, 2 = negative, 3 = off. Pulse width was 200 ms and rate was 80 Hz. The threshold was 2 V, and the patient's maximally tolerated voltage was 2.1 V. Paresthesia covered her entire painful area. IV medications were gradually discontinued. The patient had fewer episodes of angina, which were all easily aborted with SCS. Four days after her trial electrode was placed, the patient was returned to the operating room, and an Itrel 2 generator (Medtronic, Inc., Minneapolis, MN) was implanted into the right buttock area. She was transferred out of the CCU. The following evening, she developed palpitations while her SCS device was on at the threshold voltage, and an EKG showed ventricular tachycardia. The patient declined any treatment and subsequently developed left shoulder pain, which was incompletely but adequately relieved with her SCS device increased to 2.1 V. She became unconscious and died approximately 10 min later. Discussion Both of these patients had symptoms of ischemia when their cardiac status deteriorated. This supports the work of other investigators who have shown that SCS does not mask the symptoms of ischemia but improves the function of the heart [3,4]. There is a single report of interference between an unipolar pacemaker and unipolar SCS [5]. The safe use of a dual-pacing, dual-sensing, dual-mode pacemaker in conjunction with quadriploar SCS electrodes has been described [6]. It is unlikely that the arrhythmia observed in our second patient was the result of pacemaker interference, although it is possible. Janfaza et al. [2] reported the six-week survival of a single critically ill patient treated with SCS. Our cases suggest relief of pain but no, or minimal, survival advantage in this critically ill population. Although both patients experienced improvement of their anginal symptoms with SCS, the effect was not sufficient to overcome the severity of their ischemic disease. There is evidence demonstrating pain relief, low morbidity, and improved function of the heart in patients with stable angina treated with SCS [1]. Our patients had unstable angina and were considered terminally ill, with a life expectancy estimated in days to weeks. It may be that SCS is not indicated in endstage unstable angina because of its inability to prolong life, as demonstrated in the patients presented, but this remains undetermined. The precise niche for SCS in the treatment of angina is still being investigated.