Action Of Spinal Cord Stimulation Research Articles

Spinal cord stimulation in severe pharmacoresistant restless legs syndrome—two case reports

Restless legs syndrome is a prevalent, sleep-related sensorimotor disorder with relevant impact on the patients’ quality of life. For patients suffering from severe, pharmacoresistant restless legs syndrome, few therapeutic options remain to alleviate symptoms. In this case series, two patients with severe, pharmacoresistant restless legs syndrome were treated with epidural spinal cord stimulation and repeatedly assessed with polysomnography, including sleep structure and periodic limb movements as objective biomarkers not subject to placebo effects, during a 6-month follow-up period. One of the patients experienced excellent short- and long-term efficacy on subjective symptom severity (International RLS Study group rating scale 1 vs. 34 points at 3 months) and objective sleep parameters such as sleep architecture and periodic limb movements during sleep, while the second patient only reported short-term benefits from spinal cord stimulation. Ultimately, both patients opted for removal of the device for inefficacy. Based on the complex pathophysiology of restless legs syndrome and presumed mechanism of action of spinal cord stimulation in chronic pain disorders, we provide a detailed hypothesis on the possible modulating effect of spinal cord stimulation on the key symptoms of restless legs syndrome. Apart from describing a new therapeutic option for pharmacoresistant restless legs syndrome, our findings might also provide further insights into the pathophysiology of the syndrome.

ID: 204572 Duty Cycling of Differential Target Multiplexed SCS for Analgesia in a Model of Neuropathic Pain

Our proteomics and transcriptomics work1-5 has provided evidence for the mechanism of action of spinal cord stimulation (SCS) using Differential Target Multiplexed Programming (DTMP) on the relief of pain-like behavior in an animal model of neuropathic pain. DTMP utilizes multiple electrical signals which provide better regulation of neuron-glial interactions. The utilization of multiple signals involves an increased recharge burden with rechargeable devices or early exhaustion of non-rechargeable systems. To mitigate this, duty cycling can be utilized to reduce energy consumption while maintaining significant relief of pain-like behavior. The effect of four duty cycled DTMPs on mechanical hypersensitivity and gene expression is presented.

Measures of Dosage for Spinal-Cord Electrical Stimulation: Review and Proposal.

This manuscript proposes an electrical definition of therapeutic dose for spinal-cord systems used for the treatment of chronic pain, analogous to the pharmacological definition. Dose-response relationships are fundamental to pharmacology, radio-therapy, and other treatments, but have never been properly established for neuromodulation. This manuscript offers a robust measure of dose, pre-requisite to establishing a reliable and repeatable dose-response relationship. The new definition, enabled by the system transresistance obtained from measurement of evoked action potentials, recognizes the mechanism of action of spinal cord stimulation (SCS), and should improve acceptance of the therapy as compared to pharmacological treatments which are currently used more frequently for the treatment of chronic pain. The new definition suggests methods for personalization and standardization of the dose in SCS, and is potentially generalizable to all neuromodulation therapies in which nervous tissue is excited including sacral nerve stimulation (SNS), vagal nerve stimulation (VNS) and deep-brain stimulation (DBS). Formulas are provided, and applied using patient data. Powerful conclusions are drawn from application of the new measure.

Differences in Gene Expression of Endogenous Opioid Peptide Precursor, Cannabinoid 1 and 2 Receptors and Interleukin Beta in Peripheral Blood Mononuclear Cells of Patients With Refractory Failed Back Surgery Syndrome Treated With Spinal Cord Stimulation: Markers of Therapeutic Outcomes?

The use of spinal cord stimulation for patients with failed back surgery syndrome (FBSS) is very common. In order to better understand the mechanisms of action of spinal cord stimulation (SCS), our aim was to determine potential changes in relative gene and protein expression in the peripheral blood mononuclear cells (PBMCs) of patients as potential biomarkers of disease outcomes and potential new targets for therapy. Twenty-four patients with diagnosis of FBSS refractory to conservative therapy for at least six months were included in the study. Clinical evaluation in this study included validated questionnaires. Blood samples (10 mL) were collected five times from baseline until two months after implant of the leads. Proenkephalin (PENK), cannabinoid receptors CB1 and CB2, and interleukin 1β (IL 1β) were analyzed. Each patient served as his/her own control by comparing the samples collected at different time points against the baseline sample collected at T0. A total of 16 patients met all relevant criteria during the whole study and were assessed. Only PENK showed significant changes over time (Friedman p = 0.000). A positive correlation was observed between changes in visual analog scale (VAS) scores and PENK and a negative correlation between changes in PENK and Short Form-12 (SF-12) mental component score (MCS) scores, as well as between changes in IL 1β and Pain Detect Questionnaire (PD-Q) scores. As PENK changes increased, so did pain (VAS). As changes in PENK increased, SF-12 MCS health worsened. As changes in IL 1β increased, PD-Q values decreased. No severe adverse events occurred. Previously unknown effects of SCS on levels of PBMCs biomarkers are demonstrated. The findings of our research suggest a potential for useful integration of genome analysis and lymphocyte expression in the daily practice of neurostimulation for pain management and represent a novel road map in the light of the important questions that remain unanswered.

Clinical Effectiveness and Mechanism of Action of Spinal Cord Stimulation for Treating Chronic Low Back and Lower Extremity Pain: a Systematic Review.

The purpose of the present systematic review is to provide a current understanding of the mechanism of action and the evidence available to support clinical decision-making. The focus is to summarize randomized controlled trials (RCTs) and nonrandomized or observational studies of spinal cord stimulation in chronic pain to understand clinical effectiveness and the mechanism of action. Several recent studies have demonstrated the benefit of spinal cord stimulation in managing chronic pain. Until recently, the mechanism of action was founded on a central paradigm derived from gate control theory, which is the need to stimulate the dorsal column of the spinal cord to generate paresthesia. The recent development of new therapies that do not rely on paresthesia has left the field without a clear mechanism of action that could serve as a strong foundation to further improve clinical outcomes. Consequently, multiple theories have emerged to explain how electrical pulse applied to the spinal cord could alleviate pain, including activation of specific supraspinal pathways, and segmental modulation of the neurological interaction. Recent systematic reviews also have shown the clinical effectiveness of spinal cord stimulation in managing chronic spinal pain, phantom limb pain, complex regional pain syndrome, and other chronic painful conditions. Spinal cord stimulation for the treatment of chronic pain is rapidly evolving with technology at its forefront. This comprehensive focused review evaluated 11 RCTs and 7 nonrandomized/observational studies which provided levels of evidence ranging from I to II.

Mechanisms of spinal cord stimulation for the treatment of pain: Still in the dark after 50 years.

Background and ObjectiveDespite the value of spinal cord stimulation (SCS) in treating some patients with focal neuropathic pain, technological advances in stimulator design and treatment protocols have not correlated with significant improvements in clinical outcomes. This may be because incomplete understanding of the mechanisms underlying SCS precludes improvement in clinical efficacy. In this brief review, we (a) review phenomenological effects of SCS, (b) review the literature on proposed spinal sites of action of SCS and (c) propose a novel hypothesis of mechanism of action.ResultsDorsal columns, dorsal roots and dorsal horns have each been proposed as spinal sites of action of SCS. We suggest that evidence in favour of the dorsal columns or dorsal roots as the primary mediators of SCS is weak and propose that the dorsal horn is the crucial site of action. Furthermore, we hypothesize that, based on their location, and neurochemical and morphological properties, dorsal horn islet cells may mediate the effects of SCS.ConclusionsThe precise spinal mechanisms of action of SCS are still unknown. Dorsal horn islet cells have properties that position them to play a key role in analgesic effects of electrical stimulation. Understanding the mechanisms responsible for positive SCS effects are needed for successful translation into clinical dividends.SignificanceWe review possible spinal mechanisms of action of spinal cord stimulation for neuropathic pain, proposing that direct modulation of dorsal horn neurons is crucial. We suggest that mechanistic insights are needed for translation into more favourable clinical outcomes.

Psychological Factors as Outcome Predictors for Spinal Cord Stimulation.

The mechanism of action of spinal cord stimulation (SCS) is poorly understood and the success of treatment can depend on factors beyond the technical aspects of implantation. The aim of this retrospective analysis is the identification of preimplantation psychological values that may predict outcome of SCS treatment. The retrospective analysis consisted of data from 83 patients who underwent SCS implantation from 2005 to 2013. Preimplantation evaluation included pain severity, sleep interference and distress each recorded with a numeric rating scale (NRS 0-10), depression and anxiety (Hospital Anxiety and Depression Score-HADS), catastrophizing (Pain Catastrophizing Scale-PCS), and patient's confidence in performing daily activity (Pain Self-Efficacy Questionnaire-PSEQ). A fall in pain score of greater than 50% at one year follow up was the criteria applied to divide patients into two groups. Group A consisted of 39 patients whose pain score fell more than 50% and group B consisted of 44 patients whose pain score fell less than 50% at one year follow up. The median preimplantation pain score was comparable between the two groups. However, the preimplantation scores for sleep interference, HADS-depression, PCS and PSEQ, were significantly worse in group B. Receiver operating characteristic (ROC) curve analysis and univariate regression show that HADS-depression >10 and PSEQ ≤18 are risk factors for failure of SCS treatment, but only sleep interference, assessed with NRS >7 out of 10 was found to be an independent predictor of a less optimal outcome in multiple logistic regression. Sleep interference appears to be an independent risk factor for unsuccessful SCS therapy.

Spinal autofluorescent flavoprotein imaging in a rat model of nerve injury-induced pain and the effect of spinal cord stimulation.

Nerve injury may cause neuropathic pain, which involves hyperexcitability of spinal dorsal horn neurons. The mechanisms of action of spinal cord stimulation (SCS), an established treatment for intractable neuropathic pain, are only partially understood. We used Autofluorescent Flavoprotein Imaging (AFI) to study changes in spinal dorsal horn metabolic activity. In the Seltzer model of nerve-injury induced pain, hypersensitivity was confirmed using the von Frey and hotplate test. 14 Days after nerve-injury, rats were anesthetized, a bipolar electrode was placed around the affected sciatic nerve and the spinal cord was exposed by a laminectomy at T13. AFI recordings were obtained in neuropathic rats and a control group of naïve rats following 10 seconds of electrical stimulation of the sciatic nerve at C-fiber strength, or following non-noxious palpation. Neuropathic rats were then treated with 30 minutes of SCS or sham stimulation and AFI recordings were obtained for up to 60 minutes after cessation of SCS/sham. Although AFI responses to noxious electrical stimulation were similar in neuropathic and naïve rats, only neuropathic rats demonstrated an AFI-response to palpation. Secondly, an immediate, short-lasting, but strong reduction in AFI intensity and area of excitation occurred following SCS, but not following sham stimulation. Our data confirm that AFI can be used to directly visualize changes in spinal metabolic activity following nerve injury and they imply that SCS acts through rapid modulation of nociceptive processing at the spinal level.

How Process Analysis Could Improve the Implementation of Spinal Cord Stimulation Treatment for Chronic Pain

SUMMARYSpinal cord stimulation has been in clinical use for the treatment of chronic pain for over four decades. Since the initial use by Norman Shealy, the indications for its use have increased steadily over the decades to include neuropathic pain owing to failed back surgery syndrome, complex regional pain syndrome and painful diabetic peripheral neuropathies. To date, the precise mechanism of action of spinal cord stimulation remains unclear, yet it is still one of the most expensive interventional treatment modalities available in pain medicine with increasing application across the world. Given the worldwide focus on cost-effective care, there is an opportunity to focus on process analysis as a mechanism for optimizing the operations within and between all specialties engaged in the provision of care in pain medicine. Here, we propose a process analysis approach to model, measure and improve the delivery of disease-based care to enhance effective treatment with a costly modality. Systems-based process analysis is not widely utilized in pain medicine, and there is a limited body of evidence for its application. The purpose of this article is to generate interest in the discipline of process analysis in pain medicine, as it has found value in other healthcare settings and industries. We mention the applicability across countries and specialties that we hope will increase the awareness of this concept and possibly generate interest in further examination by investigators that will lead to the development of highly efficient and effective healthcare delivery processes and systems across the globe.

Anesthesia Literature Review

Anesthesia Literature Review

Neurophysiological assessment of spinal cord stimulation in failed back surgery syndrome

Despite good clinical results, the mechanisms of action of spinal cord stimulation (SCS) for the treatment of chronic refractory neuropathic pain have not yet been elucidated. In the present study, the effects of SCS were assessed on various neurophysiological parameters in a series of 20 patients, successfully treated by SCS for mostly unilateral, drug-resistant lower limb pain due to failed back surgery syndrome. Plantar sympathetic skin response (SSR), F-wave and somatosensory-evoked potentials (P40-SEP) to tibial nerve stimulation, H-reflex of soleus muscle, and nociceptive flexion (RIII) reflex to sural nerve stimulation were recorded at the painful lower limb. The study included two recording sets while SCS was switched ‘ON’ or ‘OFF’ for 1 h. Significant changes in ‘ON’ condition were as follows: SSR amplitude, H-reflex threshold, and RIII-reflex threshold and latency were increased, whereas SSR latency, F-wave latency, H-reflex amplitude, P40-SEP amplitude, and RIII-reflex area were reduced. Analgesia induced by SCS mainly correlated with RIII attenuation, supporting a real analgesic efficacy of the procedure. This study showed that SCS is able to inhibit both nociceptive (RIII-reflex) and non-nociceptive (P40-SEP, H-reflex) myelinated sensory afferents at segmental spinal or supraspinal level, and to increase cholinergic sympathetic skin activities (SSR facilitation). Complex modulating effects can be produced by SCS on various neural circuits, including a broad inhibition of both noxious and innocuous sensory information processing.

Rare Adverse Effect of Spinal Cord Stimulation: Micturition Inhibition

In current medical literature, most of the reported complications of spinal cord stimulation concern technical problems, such as lead malfunction, migration, breakage, or internal pulse generator dysfunction, whereas reports about the side effects on internal organ function caused by spinal cord stimulation are rare. In this clinical report, we describe uncommon side effects owing to spinal cord stimulation in a patient with chronic neuropathic pain. Our patient developed unexpected urinary retention during electrical epidural stimulation. This case report highlights the incomplete knowledge about the mechanism of action of spinal cord stimulation and its influence on the interactions between the autonomic nervous system and voluntary control of urinary function. The complete recovery of bladder function after the interruption of stimulation suggests that electrical stimulation caused the adverse effects in this clinical case.

Mode of Action of Spinal Cord Stimulation in Neuropathic Pain

Spinal cord stimulation emerged as a spin-off from the classical gate-control theory, which, however, does not suffice to explain its clinical effects. Whether or not nociceptive forms of pain may be attenuated remains a controversial issue. Previous experimental studies aiming at elucidating the underlying mechanisms were performed on intact, anesthetized animals and were therefore of limited clinical relevance. Not until recent years have some data on the mode of action accumulated providing evidence that gamma-aminobutyric acid (GABA) ergic as well as adenosine-related mechanisms are involved in the pain amelioration. It appears that the effects are exerted mostly via segmental spinal levels, but recent evidence suggests that a supraspinal loop may also be of importance; this issue remains to be resolved. It should be emphasized that most experimental data pertaining to the mode of action are derived from so-called animal models of neuropathic pain. However, caution must be exercised in the translation of such data from bench to bedside, because some behavioral signs interpreted as “pain” in such models may be misleading. We still need animal studies to generate basic data but these findings should also be confirmed in humans.

Improved myocardial blood flow in patients with intractable angina pectoris through spinal cord stimulation

Introduction: Spinal cord electrical stimulation may be a treatment option for patients having angina pectoris CCS III-IV although being on optimal medical treatment (nitrate, β-blocker, aspirin, Ca++-antagonist, ACE-inhibitor, statin) and not suitable for conventional treatment strategies, e.g. CABG or PTCA. Although it has been shown to produce symptomatic relief, doubts remain about its effect on myocardial blood flow and cardiac ischemia. Study Design: A controlled prospective study was designed to investigate the effect and the mode of action of spinal cord stimulation (SCS) in patients with refractory angina pectoris. The primary end points of the study were the myocardial ischemia measured by MIBI scintigraphy (3 months and 12 months after the beginning of the stimulation) and the exercise capacity measured by treadmill exercise test and the 6-minute walk test. A further aim of the study was the quality of live of the patients (Seattle Angina Questionnaire [SAQ]). Results: 31 patients (65 ±12 years; 25 male, 6 female) were included into the study. All of the patients showed a clear symptomatic relief under neurostimulation. The average consumption of nitrogen decreased from 5 (±0.6 95% confidence interval [CI]) to 0.4 (±1.7 95% CI) per day (SAQ). The walking distance and the maximum workload increased from 143 (±33.4 95% CI) to 258 (± 35.5 95% CI) meters and 65 (±9.9) to 94 (±13.7) watts, respectively. The computer based analysis (Emory Cardiac Toolbox) of the MIBI scintigraphy after 3 months showed no significant decrease of myocardial ischemia (16 patients idem, 4 with increase and 10 with decrease of ischemia). Interestingly, after one year of neurostimulation 20 patients showed a clear decrease of myocardial ischemia and only one patient still had an increase of ischemia. Conclusion: Thus, spinal cord stimulation may not only improve symptoms, but may reduce myocardial ischemia as well. This might be a direct effect of neurostimulation or due to an increased exercise ability with improved cardiac blood flow because of better collateralisation.

Spinal Cord Stimulation

Spinal cord stimulation is the most common mode of neuromodulation used in managing chronic low back pain. It is minimally invasive and reversible as opposed to nerve ablation. The basic scientific background of the initial spinal cord stimulation trials was based on the gate control theory of Melzack and Wall. It has been demonstrated in multiple studies that dorsal horn neuronal activity caused by peripheral noxious stimuli could be inhibited by concomitant stimulation of the dorsal columns. Various other mechanisms, which may play a significant role in the mechanism of action of spinal cord stimulation, include the suppressive effect of spinal cord stimulation on tactile allodynia, increased dorsal horn inhibitory action of gamma-aminobutyric acid (GABA), prevention or abolition of peripheral ischemia, and effects on human brain activity. Spinal cord stimulation is indicated in low back pain with radiculopathy, failed back surgery syndrome, complex regional pain syndrome, peripheral vascular disease, and ischemic heart disease. There is substantial scientific evidence on the efficacy of spinal cord stimulation for treatment of low back and lower extremity pain of neuropathic nature. Clinical studies revealed a success rate of from 50% to 70% with spinal cord stimulation, with decreased pain intensity scores, functional improvement and decreased medication usage. This review discusses multiple aspects of spinal cord stimulation, including pathophysiology and mechanism of action, rationale, indications, technique, clinical effectiveness, and controversial aspects.

Mechanisms of spinal cord stimulation in neuropathic pain

The understanding of the mode of action of spinal cord stimulation (SCS) as treatment of neuropathic pain is still fragmentary. SCS evolved from the gate-control theory postulating a spinal modulation of noxious inflow, but there is little evidence that SCS influences nociceptive pain; pain relief in peripheral vascular disease and angina pectoris is presumably secondary to other SCS effects. In man, SCS may effectively abolish both continuous and evoked pain (tactile/thermal allodynia) whereas induced, acute nociceptive pain is unaffected. Recent SCS studies performed on rat models of mononeuropathy have demonstrated a preferential effect on AB fiber mediated functions, and the hyperexcitability of wide-dynamic-range dorsal horn neurons was attenuated. These effects were coupled to increased release of CABA and reduced glutamate and aspartate release in the dorsal horn. Intrathecal administration of GABA, baclofen and adenosine enhanced the SCS effect on tactile allodynia even in previously non-responsive rats. Preliminary results indicate that gabapentin may have a similar effect. GABAergic and adenosine-related mechanisms conceivably represent only examples of a number of putative receptor systems involved in SCS. Clinical trials have been initiated exploring the possibility to improve the efficacy of SCS by concomitant pharmacotherapy. [Neurol Res 2000; 22: 28S-292]

Spinal Cord Stimulation: Indications, Mechanism of Action, and Efficacy.

Unrelieved pain is costly to the economic fabric of our society; its direct costs to patients and their families is staggering. Spinal cord stimulation for the treatment of chronic pain is cost-effective when used in the context of a pain treatment continuum. Many theories on the mechanism of action of spinal cord stimulation have been suggested, including activation of gate control mechanisms, conductance blockade of the spinothalamic tracts, activation of supraspinal mechanisms, blockade of supraspinal sympathetic mechanisms, and activation or release of putative neuromodulators. Whatever theory or theories of mechanism are correct, spinal cord stimulation has efficacy in the treatment of failed back surgery syndrome, complex regional pain syndromes, intractable pain due to peripheral vascular disease, and intractable pain due to angina.

Adenosine receptor activation suppresses tactile hypersensitivity and potentiates spinal cord stimulation in mononeuropathic rats

The aim of the present study was to investigate the intrathecal (i.t.) action of a selective A 1-adenosine receptor agonist, R-phenylisopropyl adenosine (R-PIA), on tactile withdrawal thresholds in a rat model of mononeuropathy produced by sciatic chronic constriction injury (CCI). An additional aim was to examine whether adenosine receptor activation is involved in the effects of spinal cord stimulation (SCS), which activates low-threshold fibers and suppresses touch-evoked pain both in patients and in experimental animals with neuropathy. Animals presenting hindlimb withdrawal to von Frey filaments with a bending force of <7.5 g on the lesioned side (compared to ≥35 g in the normal limb), were considered as having tactile hypersensitivity (`allodynia'). R-PIA (1–10 nmol i.t.) induced a dose-dependent suppression of the tactile allodynia without producing impairment of motor function. The effect of R-PIA (3 nmol i.t.), a clearly submaximal dose, was abolished by concomitant treatment with the selective A 1-adenosine receptor antagonist cyclopentylxanthine (10 nmol i.t.). In animals where SCS failed to influence tactile allodynia, concomitant i.t. administration of R-PIA (3 nmol) and SCS induced a clear-cut and long-lasting suppression of the hypersensitivity to tactile stimulation. In conclusion, adenosine receptor stimulation antagonizes tactile hypersensitivity in a CCI model of mononeuropathy and potentiates the action of spinal cord stimulation.

Hypothetical role of long-loop reflex pathways.

It is nowadays well known that there are reflex loops starting in the spinal cord, relaying in various supraspinal structures and descending back to the cord. These long-loops regulate motor responses and work in cooperation with segmental mono- and polysynaptic reflexes. The role of certain well-documented long-loop reflexes is reviewed. The existence of additional long-loop reflexes is hypothesized and preliminary results supporting this view are presented. In discussing the mode of action of spinal cord stimulation, the various ascending and descending pathways involved in long-loop regulation of motricity are to be taken into account.

Underlying mechanisms of the effects of spinal cord stimulation in motor disorders. A review of the discussion.

Possible underlying neurophysiological mechanisms of spinal cord stimulation in the modification of motor disorders were discussed by scientists working in research on motor control mechanisms. Changes of motor unit properties in upper motoneuron lesions were reviewed, the role of proprioceptive input and long-loop reflexes in motor control was discussed, analysis of ramp and ballistic movements in motor control was presented, and some aspects of neural control of locomotion were reviewed. Some physiological considerations of the influence of electrical stimulation on various neural functions were given and the conclusion was reached that, at present, no definitive models of the action of spinal cord stimulation are available.