Mechanisms Of Spinal Cord Stimulation Research Articles

Model-based analysis of subthreshold mechanisms of spinal cord stimulation for pain

Objective. Spinal cord stimulation (SCS) is a common treatment for chronic pain. For decades, SCS maximized overlap between stimulation-induced paresthesias and the patient’s painful areas. Recently developed SCS paradigms relieve pain at sub-perceptible amplitudes, yet little is known about the neural response to these new waveforms or their analgesic mechanisms of action. Therefore, in this study, we investigated the neural response to multiple forms of paresthesia-free SCS. Approach. We used computational modeling to investigate the neurophysiological effects and the plausibility of commonly proposed mechanisms of three paresthesia-free SCS paradigms: burst, 1 kHz, and 10 kHz SCS. Specifically, in C- and Aβ-fibers, we investigated the effects of different SCS waveforms on spike timing and activation thresholds, as well as how stochastic ion channel gating affects the response of dorsal column axons. Finally, we characterized membrane polarization of superficial dorsal horn neurons. Main results. We found that none of the SCS waveforms activate nor modulate spike timing in C-fibers. Spike timing was modulated in Aβ-fibers only at suprathreshold amplitudes. Ion channel stochasticity had little effect on Aβ-fiber activation thresholds but produced heterogeneous spike timings at suprathreshold amplitudes. Finally, local cells were preferentially polarized in their axon terminals, and the magnitude of this polarization was dependent on cellular morphology and position relative to the stimulation electrodes. Significance. Overall, the mechanisms of action of subparesthetic SCS remain unclear. Our results suggest that no SCS waveforms directly activate C-fibers, and modulation of spike timing is unlikely at subthreshold amplitudes. We conclude that potential subthreshold neuromodulatory effects of SCS on local cells are likely to be presynaptic in nature, as axons are preferentially depolarized during SCS.

Progress in the efficacy and mechanism of spinal cord stimulation in neuropathological pain.

Neuropathic pain (NP) is a long-term recurrent disease caused by somatosensory nervous system injury, with spontaneous pain, hyperalgesia, ectopic pain, and paresthesia as the main clinical manifestations. It adversely affects patients' quality of life. NP treatments often include medication, physical therapy, and invasive therapy; the first two therapies are generally ineffective for some NP patients. These patients sometimes rely on invasive therapy to alleviate pain. Spinal cord stimulation (SCS) is a very effective therapeutic method. SCS is a neuroregulatory method that involves placing the electrodes on the corresponding painful spinal cords. Pain is greatly alleviated after SCS. SCS has been proven to be an effective therapeutic method for the treatment of neurological pain. Furthermore, SCS provides a feasible approach for patients with unsuccessful drug treatment. This paper reviews the relevant literature of spinal cord electrical stimulation, focusing on the mechanism of action, clinical application, clinical efficacy and technical progress of spinal cord electrical stimulation. SCS is widely used in the treatment of NP diseases such as postherpetic neuralgia, back surgery failure syndrome, and phantom limb pain. With advancements in science and technology, tremendous progress has also been made in the spinal cord electrical stimulation method and good momentum has been maintained.

The Neuroprotective Mechanism of Spinal Cord Stimulation in Spinal Cord Ischemia/Reperfusion Injury

Spinal cord ischemia/reperfusion (I/R) injury following thoracoabdominal aneurysm surgery can lead to severe lower limb neurologic defect. The preliminary result of our study suggested that spinal cord stimulation (SCS) postconditioning effectively protected spinal cord from I/R injury on rabbits. But the mechanism is unknown. In this study, we further investigated the mechanism of SCS postconditioning. New Zealand white rabbits were randomly divided into sham, I/R, I/R + 2 Hz SCS, and I/R + 50 Hz SCS group (n = 24/group). Transient spinal cord ischemia was induced by infrarenal aortic balloon occlusion and performed on all rabbits except rabbits of sham group. Rabbits of I/R group received no further intervention. Rabbits of I/R + 2 Hz SCS and I/R + 50 Hz SCS group received 2 Hz or 50 Hz SCS for 30 min at the onset of reperfusion and then daily. The expression of Akt (serine-threonine kinase)/p-Akt, STAT3 (signal transducer and activator of transcription 3)/p-STAT3 and GSK-3β (glycogen synthase kinase)/p-GSK-3β of spinal cord were measured by Western blot analysis at 8 h, 1 day, 3 day, and 7 day of reperfusion. The Akt expressions of sham, I/R, I/R + 2 Hz SCS, and I/R + 50 Hz SCS group were not significantly different at all prescribed time points, while the p-Akt expression of I/R + 2 Hz SCS group was significantly higher than that of I/R group and sham group at all prescribed time points; The STAT3 and p-STAT3 expression of I/R, I/R + 2 Hz SCS, and I/R + 50 Hz SCS group were not significantly different at all prescribed time points except that at 1day of reperfusion the p-STAT3 expression of I/R + 50 Hz SCS group was significantly lower than I/R group. The GSK-3β and p-GSK-3β expressions of I/R, I/R + 2 Hz SCS and I/R + 50 Hz SCS group were not significantly different at all prescribed time points. The neuroprotective effect of 2 Hz SCS postconditioning in spinal cord I/R injury is related to Akt activation but not regulation of STAT3 and GSK-3β phosphorylation.

Possible Mechanisms of Spinal Cord Stimulation: Disinhibition of the Dorsal Horn Circuits and Ascending Nociceptive Control

Neuromodulation: Technology at the Neural InterfaceVolume 23, Issue 3 p. 407-408 Letter to the Editor Possible Mechanisms of Spinal Cord Stimulation: Disinhibition of the Dorsal Horn Circuits and Ascending Nociceptive Control Takeshi Uno MD, PhD, Corresponding Author t.uno@junwakai.com Pain Clinic, Junwakai Memorial Hospital, Miyazaki, Japan Address correspondence to: Takeshi Uno MD, PhD, Pain Clinic, Junwakai Memorial Hospital, 1119 Komatsu, Miyazaki, Japan. Email: t.uno@junwakai.comSearch for more papers by this author Takeshi Uno MD, PhD, Corresponding Author t.uno@junwakai.com Pain Clinic, Junwakai Memorial Hospital, Miyazaki, Japan Address correspondence to: Takeshi Uno MD, PhD, Pain Clinic, Junwakai Memorial Hospital, 1119 Komatsu, Miyazaki, Japan. Email: t.uno@junwakai.comSearch for more papers by this author First published: 03 March 2020 https://doi.org/10.1111/ner.13135Citations: 3 Conflict of Interest: Dr. Uno has received speaker's fees and travel fees from Abbott Medical Japan. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue3April 2020Pages 407-408 RelatedInformation

Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain: Five Decades of Research and Prospects for the Future.

The field of spinal cord stimulation is expanding rapidly, with new waveform paradigms asserting supraspinal sites of action. The scope of treatment applications is also broadening from chronic pain to include cerebral ischemia, dystonia, tremor, multiple sclerosis, Parkinson disease, neuropsychiatric disorders, memory, addiction, cognitive function, and other neurologic diseases. The role of neurostimulation as an alternative strategy to opioids for chronic pain treatment is under robust discussion in both scientific and public forums. An understanding of the supraspinal mechanisms underlying the beneficial effects of spinal cord stimulation will aid in the appropriate application and development of optimal stimulation strategies for modulating pain signaling pathways. In this review, the authors focus on clinical and preclinical studies that indicate the role of supraspinal mechanisms in spinal cord stimulation-induced pain inhibition, and explore directions for future investigations.

Neuroprotective mechanism involved in spinal cord stimulation postconditioning

ObjectivesDelayed paraplegia developed postoperatively after thoracoabdominal aneurysm surgery is primarily associated with spinal cord ischemia/reperfusion injury. Our previous study suggested that spinal cord stimulation postconditioning protected the spinal cord from ischemia/reperfusion injury through microglia inhibition. In this study, we further investigated whether α7 nicotinic acetylcholine receptors were involved in the neuroprotective mechanism of spinal cord stimulation. MethodsRabbits were randomly assigned to sham, control, 2 Hz, α-bungarotoxin, and 2 Hz-α-bungarotoxin groups (n = 24/group). Transient spinal cord ischemia was performed on all rabbits except rabbits in the sham group. Rabbits in the control group received no further intervention, rabbits in the 2 Hz group were given 2 Hz spinal cord stimulation, rabbits in the α-bungarotoxin group received prescribed intrathecal α-bungarotoxin (α-bungarotoxin, a specific α7 nicotinic acetylcholine receptor antagonist) injections, and rabbits in the 2 Hz-α-bungarotoxin group received both α-bungarotoxin injections and 2 Hz spinal cord stimulation. Hind-limb neurologic function was assessed, and spinal cord histologic examination, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, and microglia staining were performed at 8 hours, 1 day, 3 days, and 7 days of reperfusion. ResultsRabbits in the 2 Hz group had significantly better neurologic functions, more α-motor neurons, and lower terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling–positive neuron rates and microglia area/anterior horn area ratios (microglia area ratios) than the control group. The neurologic functions of the α-bungarotoxin group were significantly worse than those of the control group, whereas other results were not significantly different from the control group. The results of the 2 Hz-α-bungarotoxin group were insignificant to the control group except for the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling–positive neuron rates, which were significantly lower than in the control group. ConclusionsThe neuroprotective effects of spinal cord stimulation postconditioning against spinal cord ischemia/reperfusion injury were partially mediated by activating α7 nicotinic acetylcholine receptors.

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.

Spinal cord stimulation postconditioning reduces microglial activation through down-regulation of ERK1/2 phosphorylation during spinal cord ischemic reperfusion in rabbits.

Microglial activation plays a critical role in spinal cord ischemic reperfusion injury. Spinal cord stimulation preconditioning and postconditioning has shown spinal cord protection in ischemic reperfusion injury in animal studies. However, whether spinal cord stimulation could reduce microglial activation is still unclear. In this study, rabbits experienced 28-min infrarenal aorta occlusion and reperfusion for 8 h, 1, 3, and 7 days correspondingly. Immediately after reperfusion, rabbits received spinal cord stimulation of 2 or 50 Hz for 30 min and daily for a week. The results showed that spinal cord stimulation of 2 Hz reduced microglial activation. Microglial activation was accompanied with up-regulated p-ERK1/2, and microglial inhibition by 2 Hz spinal cord stimulation was associated with down-regulated p-ERK1/2. Spinal cord stimulation increased the expression of IL-1β. Our results revealed, for the first time, that spinal cord stimulation postconditioning suppresses microglial activation during spinal cord ischemic reperfusion by down-regulation of p-ERK1/2, which may be the protective mechanism of spinal cord stimulation.

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

BackgroundIt is becoming increasingly important to understand the mechanisms of spinal cord stimulation (SCS) in alleviating neuropathic pain as novel stimulation paradigms arise.PurposeAdditionally, the small anatomic scale of current SCS animal models is a barrier to more translational research.MethodsUsing chronic constriction injury (CCI) of the common peroneal nerve (CPN) in sheep (ovine), we have created a chronic model of neuropathic pain that avoids motor deficits present in prior large animal models. This large animal model has allowed us to implant clinical grade SCS hardware, which enables both acute and chronic testing using von Frey filament thresholds and gait analysis. Furthermore, the larger anatomic scale of the sheep allows for simultaneous single-unit recordings from the dorsal horn and SCS with minimal electrical artifact.ResultsDetectable tactile hypersensitivity occurred 21 days after nerve injury, with preliminary indications that chronic SCS may reverse it in the painful limb. Gait analysis revealed no hoof drop in the CCI model. Single neurons were identified and discriminated in the dorsal horn, and their activity was modulated via SCS. Unlike previous large animal models that employed a complete transection of the nerve, no motor deficit was observed in the sheep with CCI.ConclusionTo our knowledge, this is the first reported large animal model of chronic neuropathic pain which facilitates the study of both acute and chronic SCS using complementary behavioral and electrophysiologic measures. As demonstrated by our successful establishment of these techniques, an ovine model of neuropathic pain is suitable for testing the mechanisms of SCS.

Comparison of a Simple Model of Dorsal Column Axons with the Electrically Evoked Compound Action Potential

Computational modeling has provided insights into the electrophysiological mechanisms of spinal cord stimulation. The models are complex and conclusions drawn from them are only as valid as their assumptions and choice of parameters. Model validation has proved difficult due to lack of direct electrophysiological evidence for comparison. Here, we compare an axon model with measurement of the compound action potential response of dorsal columns axons of the sheep spinal cord. The extracellular potential is calculated from a simple single axon and rather than repeating this calculation for multiple fibers of different sizes and positions, we instead estimate the single fiber response from the ECAP measurements. The single fiber potential is derived from ECAP by reversing the effect of propagation from the stimulation site. We used literature values for the ion channel properties for sensory neurons and the axon model predicts the shape of the ECAP-derived single fiber action potential remarkably well.

Spinal cord anatomy, pain, and spinal cord stimulation mechanisms

ABSTRACT The effectiveness and mechanisms of spinal cord stimulation described in literature rely on a proper understanding of spinal cord anatomy and pain theory. In this article we provide an overview of relevant spinal cord anatomy, pain mechanisms, and theories of pain perception. This includes the gate control theory that is the foundation for spinal cord stimulation as a treatment for chronic pain. Thereafter, we describe the different mechanisms of spinal cord stimulation. Specifically, there are considerations in anatomy, electrophysiology, neurochemistry, and neurophysiology of the central nervous system that play a role in how spinal cord stimulation modulates the pain “gate” system.

New players in the mechanism of spinal cord stimulation for neuropathic pain

Abstract Aims The aim of this study was to uncover possible proteins involved in the mechanism for neuropathic spinal cord stimulation (SCS) pain relief in humans. Methods Using two different proteomic protocols we compared the protein concentration in cerebrospinal fluid (CSF) from 14 SCS responsive neuropathic pain patients using a shotgun proteomic approach. The comparison was made between samples from the same individual taken when the stimulator had been off for 48 h, and after the stimulator had been used as normal for three weeks. Mass spectrometry raw files from both experimental setups were analysed using MS Quant and DeCyder softwares and proteins were identified using MASCOT search against Swissprot database. After median normalization moderate paired t-test statistics were used in R limma package to find up-and down regulated proteins. Results In total, 255 and 216 proteins could be identified by the dimethyl and label free methods respectively and relatively quantified. Of these several were significantly up- and down regulated. Conclusions These novel proteins add to the SCS mechanism in patients with neuropathic pain. These results strengthen the evidence for SCS as altering extracellular matrix components and affecting central nervous system plasticity.

Proteomic analysis of cerebrospinal fluid gives insight into the pain relief of spinal cord stimulation

Abstract Aims Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system affecting approximately 2% of the population. Current pharmacological treatments are ineffective for more than 50% of the patients and often give much adverse effects. Spinal cord stimulation (SCS) is an alternative cost-effective treatment with high efficacy, prolonged pain relief, few side effects. We have compared the cerebrospinal fluid (CSF) proteomes from neuropathic pain patients during pain relief induced by SCS and during pain sensation without SCS, to gain further insights into the mechanisms behind the obtained analgesia. Methods Paired CSF samples were taken from SCS-responsive neuropathic pain patients after the SCS had been turned off for 48 h and when the SCS had been used normally for three weeks. Thus, each patient acted as their own control. The corresponding proteomes for each patient were relatively quantified using a mass spectrometry based shotgun approach. Results In total, 419 unique proteins were simultaneously identified and relatively quantified. A panel consisting of seven proteins, 5 up-regulated and 2 down, were found to be significantly regulated by SCS in two complementary statistical tests (P ≤ 0.01). The most up-regulated protein in the SCS linked panel is a known modulator of nicotinic acetylcholine (ACh) receptor activity. Interestingly, it has a striking tertiary structural similarity and biological functionality as pain modulating prototoxins found in snake venoms. Conclusions Our findings reveal possible insights into the mechanism of spinal cord stimulation and the obtained pain relief.

Exploration of supraspinal mechanisms in effects of spinal cord stimulation: Role of the locus coeruleus

The neurobiological mechanisms of spinal cord stimulation (SCS) when applied for neuropathic pain are still incompletely known. Previous research indicates that brainstem circuitry is pivotal for the SCS effect. The present study aims at exploring the possible contribution to the SCS effects of the pain controlling system emanating from the locus coeruleus (LC) in the brain stem. Experiments were performed on the rat-spared nerve injury pain model. After evaluation of the attenuation of mechanical hypersensitivity induced by SCS, the effects of SCS on neuronal activity in the LC and on the noradrenaline (NA) content in the dorsal spinal cord were analyzed. SCS produced a significant increase in the discharge rate of LC neurons only in rats behaviorally responding to SCS as compared to non-responding and control animals. The NA content in the dorsal quadrant of the spinal cord ipsilateral to the nerve injury was analyzed using enzyme-linked immunosorbent assay in responding, non-responding and intact control rats both immediately following SCS and without SCS. No differences were found between these groups. In awake animals, lidocaine silencing of the ipsilateral LC or blocking of spinal noradrenergic system by intrathecal administration of α1,2 adrenoceptor antagonists failed to influence the antihypersensitivity effect of SCS. The present results indicate that the SCS-induced control of hypersensitivity in an experimental animal model of peripheral neuropathic pain may not be explained by the activation of direct spinal projections of noradrenergic LC neurons, while supraspinal projections of LC neurons still may play a role in the SCS effect.

Electrically Evoked Compound Action Potentials Recorded From the Sheep Spinal Cord

The study aims to characterize the electrical response of dorsal column axons to depolarizing stimuli to help understand the mechanisms of spinal cord stimulation (SCS) for the relief of chronic pain. We recorded electrically evoked compound action potentials (ECAPs) during SCS in 10 anesthetized sheep using stimulating and recording electrodes on the same epidural SCS leads. A novel stimulating and recording system allowed artifact contamination of the ECAP to be minimized. The ECAP in the sheep spinal cord demonstrates a triphasic morphology, with P1, N1, and P2 peaks. The amplitude of the ECAP varies along the length of the spinal cord, with minimum amplitudes recorded from electrodes positioned over each intervertebral disc, and maximum amplitudes recorded in the midvertebral positions. This anatomically correlated depression of ECAP also correlates with the areas of the spinal cord with the highest thresholds for stimulation; thus regions of weakest response invariably had least sensitivity to stimulation by as much as a factor of two. The choice of stimulating electrode location can therefore have a profound effect on the power consumption for an implanted stimulator for SCS. There may be optimal positions for stimulation in the sheep, and this observation may translate to humans. Almost no change in conduction velocity (∼100 ms) was observed with increasing currents from threshold to twice threshold, despite increased Aβ fiber recruitment. Amplitude of sheep Aβ fiber potentials during SCS exhibit dependence on electrode location, highlighting potential optimization of Aβ recruitment and power consumption in SCS devices.

Neurophysiological Responses for Better Understanding the Antalgic Mechanisms of Spinal Cord Stimulation

Spinal cord stimulation (SCS) is a physical invasive therapy largely used to treat patients with neuropathic pain refractory to pharmacologic treatments. Its mechanisms of action are not completely understood and, so far, patients continue to be enrolled with a trial and error approach. SCS is based on the electrical stimulation of dorsal columns, which evokes a typical electrical paresthesia, similar to that experienced by any person when an electrical stimulation is applied over the skin. This electrical sensation is not physiological because it is the result of an ectopic, direct activation of nerve fibers with a by-pass of the receptor’s activation. The electrical stimulation of dorsal columns induces action potentials in the lemniscal pathway, a “system” made by fibers with large diameter and high conduction velocity. As any other electrical stimulation of nerve fibers, SCS creates potentials which travel in opposite direction: cranially and caudally. Afferent, orthodromic propagation of action potentials during SCS is mandatory for any supposed antalgic mechanism occurring in brainstem or brain, while antidromic propagation is considered the basis for the antalgic, segmental effect of SCS. Studies on neurophysiological effects of SCS are rare and further investigations are warranted in order to achieve a better understanding of the antalgic effects of SCS, and consequently improve therapeutic targeting and patient selection.

Compound action potentials recorded in the human spinal cord during neurostimulation for pain relief

Electrical stimulation of the spinal cord provides effective pain relief to hundreds of thousands of chronic neuropathic pain sufferers. The therapy involves implantation of an electrode array into the epidural space of the subject and then stimulation of the dorsal column with electrical pulses. The stimulation depolarises axons and generates propagating action potentials that interfere with the perception of pain. Despite the long-term clinical experience with spinal cord stimulation, the mechanism of action is not understood, and no direct evidence of the properties of neurons being stimulated has been presented. Here we report novel measurements of evoked compound action potentials from the spinal cords of patients undergoing stimulation for pain relief. The results reveal that Aβ sensory nerve fibres are recruited at therapeutic stimulation levels and the Aβ potential amplitude correlates with the degree of coverage of the painful area. Aβ-evoked responses are not measurable below a threshold stimulation level, and their amplitude increases with increasing stimulation current. At high currents, additional late responses are observed. Our results contribute towards efforts to define the mechanism of spinal cord stimulation. The minimally invasive recording technique we have developed provides data previously obtained only through microelectrode techniques in spinal cords of animals. Our observations also allow the development of systems that use neuronal recording in a feedback loop to control neurostimulation on a continuous basis and deliver more effective pain relief. This is one of numerous benefits that in vivo electrophysiological recording can bring to a broad range of neuromodulation therapies.

A model combining in vivo electrophysiological and behavioral approaches to study mechanisms of spinal cord stimulation induced analgesia in spinal nerve injured rats

The mechanisms for the beneficial effects of spinal cord stimulation (SCS) in the treatment of chronic pain remain unclear. In electrophysiological studies, SCS-like bi-polar conditioning electrical stimulation (CS, 50 Hz, 5 min) of the dorsal column attenuated the spontaneous activity and evoked responses of spinal wide-dynamic-range (WDR) neurons to mechanical stimuli at 0-15 min post-CS in rats at day 14-16 and 45-75 post-L5 spinal nerve injury. The lowest intensity that evoked a peak antidromic sciatic Aα/β-compound action potential (CAP) without inducing an Aδ-CAP to graded electrical stimulation from the test site was used for CS.

Mechanisms of Spinal Cord Stimulation in Painful Syndromes: Role of Animal Models

ABSTRACT Spinal cord stimulation (SCS) came into clinical practice as a direct spin-off from the gate control theory. This therapy has been used to treat neuropathic pain of peripheral origin as well as ischemic pain states, vasospastic conditions, and therapy-resistant angina pectoris. The physiological mech- anisms of action for SCS are slowly emerging but still are only fragmentarily understood. This chapter will describe the research methods and basic studies used to explore these mech- anisms in normal healthy animals, as well as the use of animal models exhibiting different neuro- pathic, vasculopathic, and other pathological conditions. Brief discussions will address human experimental and clinical studies. The results show that SCS is effective in some pain syndromes otherwise resistant to treatment. The mechanisms of SCS differ between the pathologies treated; in neuropathic pain, stimula- tion-induced suppression of central hyperexcitability seems pivotal, while in ischemic pain, inhibi- tion of sympathetic outflow and in particular antodromic vasodilation are important mechanisms. Depending on where along the neuro-axis SCS is applied, stimulation can be used to control autonomic and viscero-somatic reflex activity involved in a certain syndrome, thereby alleviating the disease symptoms. Additionally, SCS may have its primary effect on improving organ function and could also reduce pain associated with the disease. SCS is a therapy that is safe, minimally invasive, reversible, and has few side effects compared with chronic pharmacotherapy. We firmly believe that SCS at present is an underused treatment modality. Furthermore, our society demands evidence-based and mechanism-based therapies. This demand amplifies the need to expand our knowledge through research projects aimed at further exploration of physiological mechanisms that are activated using neurostimulation. The results of these studies will lead to improvement and expansion of future neuromodulation therapies that will be of benefit to patients.

Spinal cord stimulation: mechanisms of action.

A literature review and synthesis were performed. To present the current understanding of the mechanisms of spinal cord stimulation in relation to the physiology of pain. Spinal cord stimulation has been used for more than 30 years in the armamentarium of the interventional pain specialist to treat a variety of pain syndromes. Traditionally used for persisting leg pain after lumbar spinal surgery, it has been applied successfully in the treatment of angina pectoris, ischemic pain in the extremity, complex regional pain syndrome Types 1 and 2, and a variety of other pain states. This review presents the current status of what is known concerning how electrical stimulation of the spinal cord may achieve pain relief. A literature review was conducted. The literature supports the theory that the mechanism of spinal cord stimulation cannot be completely explained by one model. It is likely that multiple mechanisms operate sequentially or simultaneously. Some clinical or experimental support can be found in the literature for 10 specific mechanisms or proposed mechanisms of spinal cord stimulation.