Activity In Spinal Cord Research Articles

ID: 212917 Closed-Loop Spinal Cord Stimulation for Chronic Low Back-/Leg Pain – A Single-Center Follow-Up Study

Since the first use of spinal cord stimulation (SCS), there have been tremendous software and hardware improvements. The closed-loop technology (CLT) maintains the spinal cord activation (SC) within a therapeutic window for each patient. SC activation is measured through the evoked compound action potential generated by each stimulus pulse. The scope of this work is to present our one-year experience with this novel CLT.

PO127 / #657 CLOSED-LOOP SPINAL CORD STIMULATION FOR CHRONIC LOW BACK & LEG PAIN – A 12-MONTH SINGLE-CENTER FOLLOW-UP STUDY: E-POSTER VIEWING

Since the first use of spinal cord stimulation (SCS), there have been tremendous software and hardware improvements. The closed-loop technology (CLT) maintains the spinal cord activation (SC) within a therapeutic window for each patient. SC activation is measured through the evoked compound action potential generated by each stimulus pulse.1 The scope of this work is to present our one-year experience with this novel CLT.

122 ECAP-Controlled Closed-Loop Spinal Cord Stimulation (CL SCS): Double-Blind, Randomized Trial for the Treatment of Chronic Pain – 24-Month Outcomes

INTRODUCTION: Evoked compound action potential (ECAP) recording provides an objective measure of spinal cord (SC) activation during SCS and can assist in programing of the SCS system. ECAP-controlled CL SCS, in which the stimulation output is automatically adjusted to maintain a desired ECAP amplitude, has been shown to provide effective pain relief in an open-label study (ACTRN12615000713594). METHODS: 134 subjects were enrolled and randomized after trial leads were implanted. The primary endpoint evaluated =50% reduction in overall back and leg pain measured by the Visual Analog Scale (VAS). Opioid usage and other patient-reported outcomes (PROs) including emotional/physical functioning, sleep quality, and quality of life were also collected. Additionally, objective neurophysiological data, including SC activation and time spent in the therapeutic range, were collected. RESULTS: Herein the Evoke Study Group reports the 24-month outcomes from this ongoing RCT. The proportion of implanted subjects with =50% overall back and leg pain reduction at 24 months was statistically superior in the CL vs. OL group (84.0% vs. 65.9% subjects, respectively; p = 0.040). Long-term improvements in all other PROs, including POMS, ODI, PSQI, EQ-5D-5L, and SF-12, were also demonstrated. Opioids were reduced or eliminated in 66.7% (CL) and 60.9% (OL), respectively. The most frequent level of SC activation was three times greater for CL (median ECAP Amplitude: 22.5 µV CL vs. 7.5 µV OL). SC activation was better maintained within the therapeutic range with CL (median: 93.9% CL vs. 46.1% OL). There were no differences in the safety profiles between treatment groups, and the type, nature, and severity of adverse events were similar to other SCS studies. CONCLUSION: In this ongoing study, ECAP-controlled CL SCS provided statistically superior pain relief and greater improvement in other PROs compared with OL SCS at 24 months. CL delivered greater levels of SC activation and better maintained SC activation in the subject’s therapeutic range.

Low-dose cannabinoid receptor 2 agonist induces microglial activation in a cancer pain-morphine tolerance rat model

AimsCancer pain seriously affects the life quality of patients. Morphine is commonly used for cancer pain, but tolerance development limits its clinical administration. Central immune signaling is important in the development of cancer pain and morphine tolerance. Cannabinoid receptor 2 (CB2) inhibits cancer pain and morphine tolerance by regulating central immune signaling. In the present study, we investigated the mechanisms of central immune signaling involved in morphine tolerance inhibition by the CB2 agonist AM1241 in cancer pain treatment. Main methodsRats were implanted with tumor cells and divided into 4 groups: Vehicle (PBS), 0.07 μg AM1241, 0.03 μg AM1241, and AM630 (10 μg) + AM1241 (0.07 μg). All groups received morphine (20 μg/day, i.t.) for 8 days. AM630 (CB2 antagonist) was intrathecally injected 30 min before AM1241, and AM1241 was intrathecally injected 30 min before morphine. The spinal cord (SC) and dorsal root ganglion (DRG) were collected to determine the expression of Toll-like receptor 4 (TLR4), the p38 mitogen-activated protein kinase (MAPK), microglial markers, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α. Key findingsThe expression of TLR4, p38 MAPK, microglial markers, IL-1β, and TNF-α was significantly higher in AM1241-pretreated groups than in the vehicle group (P < 0.05). No difference in microglial markers, IL-1β, and TNF-α expression was detected in the AM630 + AM1241 group compared with the vehicle group. SignificanceOur results suggest that in a cancer pain-morphine tolerance model, an i.t. non-analgesic dose of AM1241 induces microglial activation and IL-1β TNF-α upregulation in SC and DRG via the CB2 receptor pathway.

Sustained Long-Term Outcomes With Closed-Loop Spinal Cord Stimulation: 12-Month Results of the Prospective, Multicenter, Open-Label Avalon Study.

BACKGROUNDSpinal cord stimulation (SCS) activates the dorsal column fibers using electrical stimuli. Current SCS systems function in fixed-output mode, delivering the same stimulus regardless of spinal cord (SC) activation.OBJECTIVETo present long-term outcomes of a novel closed-loop SCS system that aims to maintain the SC activation near a set target level and within a therapeutic window for each patient. SC activation is measured through the evoked compound action potential (ECAP) generated by each stimulus pulse.METHODSFifty patients with lower back and/or leg pain who were successfully trialed received a permanent system (Evoke; Saluda Medical, Sydney, Australia). Ratings of pain (visual analog scale), quality of life, function, sleep, and medication use were collected at baseline and at each visit. SC activation levels were reported in summary statistics. The therapeutic window for each individual patient was defined as the range of ECAP amplitudes between sensation threshold and uncomfortably strong stimulation.RESULTSAt 12 mo, the proportion of patients with ≥50% relief was 76.9% (back), 79.3% (leg), and 81.4% (overall), and the proportion with ≥80% pain relief was 56.4% (back), 58.6% (leg), and 53.5% (overall). Patients spent a median of 84.9% of their time with stimulation in their therapeutic window, and 68.8% (22/32) eliminated or reduced their opioid intake. Statistically significant improvements in secondary outcomes were observed.CONCLUSIONThe majority of patients experienced more than 80% pain relief with stable SC activation, as measured by ECAP amplitude at 12 mo, providing evidence for the long-term effectiveness of the Evoke closed-loop SCS system.

Defining the Therapeutic Window (TW) for Spinal Cord Stimulation (SCS) Using Evoked Compound Action Potential (ECAP) Recordings: Results From the Evoke Study

Abstract INTRODUCTION Spinal cord stimulation (SCS) is an established treatment for chronic pain; however, long-term success remains suboptimal. Current SCS therapies are fixed-output and do not account for large variation in electrical field strength due to changes in distance between the electrode and spinal cord (SC). METHODS In Avalon, 50 subjects were implanted and programmed in closed-loop; in Evoke, 134 subjects were randomized into open-loop (OL-SCS) or closed-loop (CL-SCS). ECAPs, a measure of SC activation, are recorded following each stimulation pulse in both groups. Each subject's therapeutic window (TW) is determined individually as the ECAP amplitude range between sensation perception threshold and discomfort. Without a measure of SC activation (eg, ECAPs), TW can only be based on perception of intensity; however, stimulation can produce variable SC activation (ECAP amplitude) as the electrode to SC distance varies with movement. RESULTS In the Evoke Study, each subjects' TW was determined in the clinic, along with the clinician prescribed level. There was no statistical difference between the 2 groups' TWs; however, CL-SCS subjects spent significantly more time in the TW despite having equivalent therapeutic ranges. Long-term data showed a similar percentage of stimuli in the TW (83%-97%). CONCLUSION TW can be individually defined by ECAP amplitudes (measure of SC activation), removing the need to rely on subjective reports of intensity, which can vary over time and with movement.

Randomized, Double-Blind Trial of Evoked Compound Action Potential (ECAP)-Controlled Closed-Loop Spinal Cord Stimulation for Patients With Chronic Trunk and/or Limb Pain

Abstract INTRODUCTION Spinal cord stimulation (SCS) is a well-established treatment for chronic pain. Advancements in SCS systems have focused on eliminating paresthesias, but long-term success rates remain suboptimal. Variability in spinal cord (SC) activation with open-loop systems results in unpredictable inhibition of pain processing pathways, and may limit the efficacy of SCS. We report the first randomized, double-blind, pivotal study of SCS and the first therapy to measure real-time in Vivo SC neurophysiology using evoked compound action potentials (ECAPs). This study provides comparative efficacy and safety of ECAP-controlled closed-loop (CL) feedback stimulation compared to open-loop (OL) stimulation, and objective evidence of the mechanism of action of SCS. METHODS A total of 134 subjects were randomized into OL or CL. Subjects and the clinical staff were blinded to the treatment assignment. Both groups received the same device. Programming was equivalent with the only difference being that the closed-loop feedback feature was enabled in the Investigational group. A pain assessment and other patient reported outcome measures per IMMPACT were collected. ECAPs were also collected in both groups to compare the magnitude of SC activation and the percentage of time within the therapeutic window. RESULTS The primary composite endpoint demonstrated superior results in overall pain responders (P = .005) for CL-SCS (82.3%) compared to OL-SCS (60.3%). In addition, all prespecified hierarchical endpoints demonstrated better outcomes in the CL group, with both back pain reduction (P = .015) and back pain responders (P = .003) demonstrating superiority. The magnitude of SC activation was 7 times greater for CL-SCS and CL subjects spend 50% more time within the therapeutic window. In both groups, subjects showed improvements across disability, psychological, sleep, quality of life, and satisfaction. CONCLUSION ECAP-controlled closed-loop SCS has demonstrated superior overall pain relief compared to open-loop SCS. The study has just completed the primary outcome data analysis.

Multicenter, Randomized, Double-Blind Study Protocol Using Human Spinal Cord Recording Comparing Safety, Efficacy, and Neurophysiological Responses Between Patients Being Treated With Evoked Compound Action Potential–Controlled Closed-Loop Spinal Cord Stimulation or Open-Loop Spinal Cord Stimulation (the Evoke Study)

The spinal cord (SC) response to stimulation has yet to be studied in a pivotal clinical study. We report the study design of an ongoing multicenter, randomized, double-blind, controlled, parallel-arm study of an evoked compound action potential (ECAP) controlled closed-loop spinal cord stimulation (SCS) system, which aims to gain U.S. Food and Drug Administration approval. This study will enroll 134 SCS candidates with chronic trunk and limb pain from up to 20 United States sites. Subjects are randomized 1:1 to receive ECAP-controlled closed-loop or open-loop, conventional SCS. The primary objective is noninferiority of closed-loop stimulation determined by the proportion of subjects with ≥50% reduction in overall trunk and limb pain and no increase in pain medications at the three-month visit. If noninferiority is met, superiority is tested. In addition, measures recommended by IMMPACT (e.g., pain intensity, functional disability, emotional functioning, quality of life, impression of change, and sleep), neurophysiological properties (e.g., SC activation, conduction velocity, chronaxie, and rheobase), and safety are analyzed. All approved SCS therapies, regardless of the presence or absence of stimulation induced paresthesias, produce fixed-output stimuli; that is, the energy delivered from the electrode array has a defined output irrespective of the neural response of SC fibers. An SCS system has been developed that directly measures the neurophysiologic activation of the SC to stimulation (i.e., ECAP amplitude) and uses this information in a feedback mechanism to produce closed-loop SCS to maintain optimal and stable activation of the SC. This study represents the first randomized, double-blind, pivotal study in the field of neuromodulation to measure SC activation in ECAP-controlled closed-loop versus open-loop stimulation and is expected to yield important information regarding differences in safety, efficacy, and neurophysiological properties. The potential clinical utility of these objective measurements of SC activation and other neurophysiological properties promises to improve outcomes of SCS for chronic pain patients.

Toward the monitoring of the spinal cord: A feasibility study

The usual imaging techniques providing only limited information, there is an unmet need for methods, firstly, to monitor in real time the functional status of the Spinal Cord (SC) and, secondly, to assess the functional consequences of the SC Injuries (SCI) and the effect of therapeutic interventions. To meet these needs, our project aims to investigate a new imaging approach, through the realization of a device for measuring the SC activity. This approach will establish locally and specifically the functional state of the SC in real time, which will provide a breakthrough in surgery, as well as in the care and therapeutic trials for SCI.This paper presents the first results of this research project on pig subjects, focusing on the opto-electrical part, based on Near-InfraRed Spectroscopy (NIRS). Firstly, the pig SC optical characterization was performed in different conditions, using a portable spectrophotometer in order to define the wavelengths of interest and their corresponding optical attenuation. In transmission mode, the Optical Density (OD) was evaluated between 3.5 and 6.5 in the [500; 950] nm range. In reflection mode, a figure between 11% and 33% is obtained in the same wavelength range. We find that wavelengths between 600 nm and 940 nm are good candidates to monitor the SC functional activity. Secondly, thanks to these results, a specific opto-electrical system has been designed for the transmission mode only, with adapted light sources and custom probes with its front-end to observe the autonomic functions in the SC. Results on the measured haemodynamic variations, at rest and under stimulation, show in real time the impact of a global stimulus on a local section of the SC. However, with a low AC-to-DC ratio (around 1%), the SC Photo PlethysmoGram (PPG) acquisition isn't simple and the best trade-off between power consumption and Signal-to-Noise Ratio (SNR) must be found in the perspective of the Embedded System (ES) development.This study demonstrates, for the first time, the feasibility of the SC activity monitoring using NIRS in transmission mode in a big animal model, where the perfect alignment of the light emitter and receptor isn't necessary due to the diffusive property of the biological media. It contributes to heading towards the use of the Internet of Things (IoT) for medical applications, through the monitoring of the SC during highly invasive processes, such as the stabilization of the spine, in the form of implants and other surgeries, such as that of the aorta, with the use of specific minimally invasive catheters.

Acetylcholine controls GABA-, glutamate-, and glycine-dependent giant depolarizing potentials that govern spontaneous motoneuron activity at the onset of synaptogenesis in the mouse embryonic spinal cord.

A remarkable feature of early neuronal networks is their endogenous ability to generate spontaneous rhythmic electrical activity independently of any external stimuli. In the mouse embryonic SC, this activity starts at an embryonic age of ∼ 12 d and is characterized by bursts of action potentials recurring every 2-3 min. Although these bursts have been extensively studied using extracellular recordings and are known to play an important role in motoneuron (MN) maturation, the mechanisms driving MN activity at the onset of synaptogenesis are still poorly understood. Because only cholinergic antagonists are known to abolish early spontaneous activity, it has long been assumed that spinal cord (SC) activity relies on a core network of MNs synchronized via direct cholinergic collaterals. Using a combination of whole-cell patch-clamp recordings and extracellular recordings in E12.5 isolated mouse SC preparations, we found that spontaneous MN activity is driven by recurrent giant depolarizing potentials. Our analysis reveals that these giant depolarizing potentials are mediated by the activation of GABA, glutamate, and glycine receptors. We did not detect direct nAChR activation evoked by ACh application on MNs, indicating that cholinergic inputs between MNs are not functional at this age. However, we obtained evidence that the cholinergic dependency of early SC activity reflects a presynaptic facilitation of GABA and glutamate synaptic release via nicotinic AChRs. Our study demonstrates that, even in its earliest form, the activity of spinal MNs relies on a refined poly-synaptic network and involves a tight presynaptic cholinergic regulation of both GABAergic and glutamatergic inputs.

Postnatal growth hormone deficiency in growing rats causes marked decline in the activity of spinal cord acetylcholinesterase but not butyrylcholinesterase

The effects of growth hormone (GH) deficiency on the developmental changes in the abundance and activity of cholinesterase enzymes were studied in the developing spinal cord (SC) of postnatal rats by measuring the specific activity of acetylcholinesterase (AChE), a marker for cholinergic neurons and their synaptic compartments, and butyrylcholinesterase (BuChE), a marker for glial cells and neurovascular cells. Specific activities of these two enzymes were measured in SC tissue of 21- and 90 day-old (P21, weaning age; P90, young adulthood) GH deficient spontaneous dwarf (SpDwf) mutant rats which lack anterior pituitary and circulating plasma GH, and were compared with SC tissue of normal age-matched control animals. Assays were carried out for AChE and BuChE activity in the presence of their specific chemical inhibitors, BW284C51 and iso-OMPA, respectively. Results revealed that mean AChE activity was markedly and significantly reduced [28% at P21, 49% at P90, (p<0.01)] in the SC of GH deficient rats compared to age-matched controls. GH deficiency had a higher and more significant effect on AChE activity of the older (P90) rats than the younger ones (P21) ones. In contrast, BuChE activity in SC showed no significant changes in GH deficient rats at either of the two ages studied. Results imply that, in the absence of pituitary GH, the postnatal proliferation of cholinergic synapses in the rat SC, a CNS structure, where AChE activity is abundant, is markedly reduced during both the pre- and postweaning periods; more so in the postweaning than preweaning ages. In contrast, the absence of any effects on BuChE activity implies that GH does not affect the development of non-neuronal elements, e.g., glia, as much as the neuronal and synaptic compartments of the developing rat SC.

Differential effects of developmental hypo- and hyperthyroidism on acetylcholinesterase and butyrylcholinesterase activity in the spinal cord of developing postnatal rat pups

The plasticity and vulnerability of the rat spinal cord (SC) during postnatal development has been less investigated compared to other CNS structures. In this study, we determined the effects of thyroid hormonal (TH) deficiency and excess on postnatal growth and neurochemical development of the rat SC. The growth as well as the specific and total activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes of the SC were determined in hypo- and hyperthyroid rat pups at postnatal (P) days P1, P5, P10 and P21 (weaning), and were compared to age-matched untreated normal controls. AChE is a cholinergic synaptic enzyme while BuChE is a metabolic enzyme mainly found in glial cells and neurovascular cells. The SC is rich in somatic motor, autonomic cholinergic neurons and associated interneurons. Daily subcutaneous injection of pups with thyroxine (T4) and administration of antithyroid goitrogen propylthiouracil (PTU) in the litter's drinking water were used to induce hyper- and hypothyroidism, respectively. Enzyme assays were carried out spectrophotometrically at the above-mentioned ages, using SC homogenates with acetylthiocholine-chloride as the substrate, together with specific cholinesterase inhibitors, which specifically target AChE and BuChE. SC weights were significantly lower at P10 and P21 in hypothyroid pups but unchanged in the hyperthyroid ones. Hypothyroidism significantly reduced both specific and total AChE activity in SC of P10 and P21 rat pups, while having no effects on the BuChE activity, although total BuChE activity was decreased due to reduced total tissue weight. In contrast both specific and total AChE activities were markedly and significantly increased (>100%) in the P10 and P21 hyperthyroid pups. However, BuChE specific activity was unaffected by this treatment. The results indicate that hypothyroid condition significantly reduces, while hyperthyroidism increases, the postnatal development of cholinergic synapses, thereby influencing the functional development of this major sensory and motor structure. However, the neurochemical development of glia and other non-neuronal cells, where BuChE is mainly localized, is comparatively unaffected in these abnormal developmental conditions.

Steroids, spinal cord and pain sensation.

During the whole life, the nervous system is continuously submitted to the actions of different categories of hormones, including steroids. Therefore, the interactions between hormonal compounds and neural tissues are subjected to intense investigations. While a majority of studies focus on the brain, the spinal cord (SC) has received little attention, although this structure is also an important part of the central nervous system, controlling motor and sensory functions. To point out the importance of interactions between hormones and the SC in the regulation of neurobiological activities, we recapitulated and discussed herein various key data, revealing that the pivotal role played by the SC in nociception and pain modulation, directly depends on the SC ability to metabolize and synthesize steroidal molecules. The paper suggests that future investigations aiming to develop effective strategies against chronic pain, must integrate regulatory effects exerted by hormonal steroids on the SC activity, as well as the actions of endogenous neurosteroids locally synthesized in spinal neural networks.

The biological activity of 3α-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury

Identification of cellular targets pertinent for the development of effective therapies against pathological pain constitutes a difficult challenge. We combined several approaches to show that 3α-hydroxysteroid oxido-reductase (3α-HSOR), abundantly expressed in the spinal cord (SC), is a key target, the modulation of which markedly affects nociception. 3α-HSOR catalyzes the biosynthesis and oxidation of 3α,5α-reduced neurosteroids as allopregnanolone (3α,5α-THP), which stimulates GABA A receptors. Intrathecal injection of Provera (pharmacological inhibitor of 3α-HSOR activity) in naive rat SC decreased thermal and mechanical nociceptive thresholds assessed with behavioral methods. In contrast, pain thresholds were dose-dependently increased by 3α,5α-THP. In animals subjected to sciatic nerve injury-evoked neuropathic pain, molecular and biochemical experiments revealed an up-regulation of 3α-HSOR reductive activity in the SC. Enhancement of 3α,5α-THP concentration in the SC induced analgesia in neuropathic rats while Provera exacerbated their pathological state. Possibilities are opened for chronic pain control with drugs modulating 3α-HSOR activity in nerve cells.

Alterations in the neutral proteinase activities of central and peripheral nervous systems of acrylamide-, carbon disulfide-, or 2,5-hexanedione-treated rats.

Proteinases are widespread in neuronal or nonneuronal eukaryotic cells. They are suggested to play an important role in the turnover of proteins in neuronal perikaryon and axon, and digestion of the transported cytoskeletal proteins in synaptic terminals. We examined the effect of acrylamide (50 mg/kg, ip), carbon disulfide (700 ppm, 9 h, 7 d a week), and 2,5-hexanedione (2,5-HD) (1% in drinking water) treatment of rats on mCANP (2 mM Ca2+), microCANP (0.1 mM Ca2+), and CINP (Ca(2+)-independent) activity in telencephalon + diencephalon (FB), rhombencephalon + mesencephalon (LB), spinal cord (SC), and sciatic nerve (SN). The proteinase activity was determined in the 30,000g supernatant fraction of tissues using 14C-methylated casein as the substrate. mCANP activity in FB, LB, and SC was inhibited only by acrylamide. Acrylamide or 2,5-HD treatment had no effect on microCANP and CINP activities of SN, whereas carbon disulfide enhanced microCANP after 15 d and CINP activity after 10 d. It is suggested that alteration in in vitro calpain activity shown by these chemicals may not be directly related to their neurotoxic effect. However, calpain may still be playing a role in this polyneuropathy by alteration in activity through inflow of Ca2+, release of Ca2+ from intracellular organelles, or other factors. Modification of cytoskeletal proteins making them more susceptible to proteases and the role of some other proteinase is also possible.