Background

Therapeutic effects of neuromodulation are based on the concept that selective excitation of large afferent fibers activates mechanisms that control pain. This fits well with the idea that pain may occur as a result of an imbalance between large and small fiber systems that transmit nociceptive information from the site of injury. Previous investigators have provided a long history of support for this concept. As early as 1906 Head and Thompson argued that fine discrimination such as touch normally exerts an inhibitory influence on impulses transmitted in fibers mediating nociception, which results in pain. This inhibition or facilitation of sensory impulses has been proposed to occur in the dorsal horn before nociceptive information is relayed onto secondary neurons. Furthermore, clinical trials performed in the early sixties using sensory thalamic stimulation were based on the notion that activation of fine discrimination receptors (touch) exerted an inhibitory influence over sensations such as pain, pressure, heat, or cold. It should also be noted that Noordenbos used the descriptive phrase “fast blocks slow” to stress the inhibitory influence of fast on slow fibers.

The concept of excitation of large afferent fibers activating pain control mechanisms advanced very rapidly with the publication of the article proposing the gate control theory; it is one of the most cited papers in modern pain literature. In this article the authors suggested that the therapeutic implication of their model would be to selectively activate large fibers to control pain. Thus even though the basic idea underlying the gate control theory was not completely unknown, it was built on a foundation of creative experiments using modern electrophysiological techniques. The results of these experiments were clearly synthesized and discussed in a form that postulated a new conceptualization of pain and pain control. Subsequently, numerous studies were conducted to criticize the theory, but nevertheless its simplicity has provided a useful frame of reference to explain mechanisms of pain generation and pain control. As Dickenson pointed out in his editorial about the ability of the gate control theory of pain to stand the test of time, the concepts of convergence and modulation changed the focus from destructing pathways for relief of pain to controlling pain by modulation in which excitation is reduced and inhibition is increased. The gate control theory accelerated the pursuit of modern pain research to explore how the pervasive plasticity of the nervous system plays a critical role in the generation, maintenance, and modulation of pain.

The gate control theory served as a critical catalyst in the clinical arena to spawn the development of various forms of neuromodulation that led to new therapies. The insights gained by Shealy and his colleagues and Shealy, Mortimer, and Reswick in animal experiments led them to conduct the first human trials with electrical spinal cord stimulation (SCS) as one form of neuromodulation. Their experimental studies in conscious cats revealed that stimulating the dorsal aspect of the spinal cord blocked responses to nociceptive peripheral stimuli. On the basis of this study and support of the gate control theory, it was assumed that neuromodulation could be used to treat all forms of nociceptive pain. However, several reports pointed out that SCS is ineffective for treating acute nociceptive conditions in contrast to what was predicted from the gate control theory; but eventually it has become the foremost treatment for neuropathic pain originating from the periphery. Nevertheless, numerous reports appeared during the eighties to convince clinicians that SCS could also be used to alleviate certain types of nociceptive pain, including selected ischemic pain states such as peripheral arterial occlusive disease (PAOD), vasospastic conditions, and therapy-resistant angina pectoris. The mechanisms of action for SCS are slowly emerging as more solid evidence has revealed some of the underlying physiological mechanisms. Clinical observations coupled with important experimental data clearly demonstrate that SCS applied to different segments of the spinal cord elicits fundamentally different results on various target organs or parts of the body ( Fig. 2-1 ).

Sites at different segments of the spinal cord where spinal cord stimulation induces functional changes in target organs.

The purpose of this chapter is to describe the organization of the spinal cord; explain the effects of electrical stimulation on the spinal cord; and discuss the underlying mechanisms activated by neuromodulation, specifically SCS, in ischemic pain, diseases of visceral organs, and neuropathic pain.

Organization and Electrical Properties of the Spinal Cord

The spinal cord is encased within the vertebral canal, which is made up of vertebrae that encircle the spinal cord but limit space for insertion of stimulating electrodes. The spinal cord in an adult human extends from the foramen magnum to the first or second lumbar vertebra and is divided into cervical, thoracic, lumbar, and sacral segments. The naming of the segments is based on the regions of the body innervated by the spinal cord. Examination of a cross section of the spinal cord shows that it is composed of gray matter and surrounded by white matter ( Fig. 2-2 ).

Model (A) and schematic diagram (B) of the spinal cord. The model is an actual cross section of the spinal cord; the diagram is provided because it will be used in subsequent figures to provide the space to more effectively illustrate neural connections.

The gray matter is comprised of cell bodies with their dendrites and initial segment of the axon, microglia, and astrocytes. It is divided into a posterior horn, intermediate zone, and the ventral horn. The gray matter is further divided into laminae I to X; these divisions are based on the size, shape, and distribution of neurons located in these laminae. The input received by these neurons and the trajectory of the axons from them also help to characterize laminae. Neurons of dorsal and intermediate laminae (I to VII, X) generally receive sensory information originating from peripheral sensory receptors. These neurons integrate this information with input arriving from descending pathways. Some of the cell bodies have short axons and serve as interneurons, whereas others are the cells of origin of ascending sensory pathways. The interneurons may also participate in local reflexes. The ventral laminae (VIII, IX) are generally composed of motoneurons that form the motor nuclei.

The white matter is divided into the posterior, lateral, and anterior funiculi. These funiculi are composed of individual tracts. The posterior funiculi are generally referred to as the dorsal columns. The lateral funiculi contain ascending and descending pathways that transmit information between the spinal cord and the brain. The descending pathways are generally located in the posterolateral region of the lateral funiculi, and the ascending pathways primarily composed of the anterolateral system reside in the anterolateral funiculi. The anterolateral system includes the spinothalamic, spinoreticular, spinomedullary, spinoparabrachial, spinomesencephalic, and spinohypothalamic fibers. The ventral funiculi contain part of the anterolateral system and also pathways that transmit axial muscle control information.

The electrical properties, more specifically the electrical conductivity, of white and gray matter of the spinal cord are not homogeneous. For SCS it is important to know that the electrical conductivity of the dorsal column is anisotropic; that is, current can travel in the direction parallel to the axons more easily than in the direction perpendicular to axons. The electrical properties within the gray matter also vary because neurons and glia have diverse orientations, ubiquitous dimensions, and different dendritic characteristics.

Neuromodulation using electrical stimulation of the spinal cord depends on the conductivity of the intraspinal elements relative to the position of the electrode. If an axon is depolarized or made more electrically positive, it produces an action potential that is transmitted orthodromically and antidromically within the axon. The cathode of an external electrode must be negatively charged to generate the action potential in the axon. In contrast, if an axon is hyperpolarized or made more negatively charged, its ability to generate an action potential is reduced because the threshold for depolarization is increased. A positively charged external electrode or anode produces this effect. Thus the active electrode for electrical stimulation serves as the cathode, whereas the anode or positive electrode may serve as a shield to prevent stimulation of neuronal structures such as dorsal roots that might interfere with effective neuromodulation. For SCS the electrode most commonly is placed on the surface of the dura mater. Activation of the electrode releases electric current that is transmitted through the dura mater and the highly conductive cerebrospinal fluid (CSF) before it reaches the dorsal part of the spinal cord. The dura mater has low conductivity, but it is so thin that the current generally is not impeded significantly as it passes through the dura to the CSF. Furthermore, the vertebral bone has the lowest conductivity so it insulates pelvic structures and visceral organs from the electric field generated by SCS. Once the electric current reaches the spinal cord, several factors may determine the neural structure being stimulated. Jan Holsheimer has used computerized models of the spinal cord to study the activation of axons by electrical current. In addition to the fiber diameter, the presence of myelination, and the depth of CSF layer surrounding the cord at the level of an electrode, the axon orientation has important implications for activation thresholds. In general, axons of the dorsal columns have higher activation thresholds than fibers such as the dorsal roots that are oriented laterally or angle as they enter the spinal cord.

The dorsal column is composed primarily of large-diameter afferent nerve fibers with relatively low thresholds for recruitment when cathodal electrical pulses are generated through the epidural electrode that is attached to a spinal cord stimulator. It is important to note that the electrode for SCS needs to be placed near midline to prevent the activation of dorsal root fibers. Stimulation amplitudes are then increased to intensities that recruit large fibers to produce action potentials and produce paresthesias. These action potentials are transmitted orthodromically and antidromically in these axons. The action potentials transmitted antidromically reach the collateral processes that penetrate the gray matter of the spinal cord. Their activation causes the release of transmitters, which activates the “gate.” Activation of the gate sets in motion neural mechanisms that reduce pain and improve organ function. The details of these mechanisms are discussed in subsequent paragraphs.

Neuromodulation Mechanisms in Ischemic Pain

Ischemic painful conditions of the limbs commonly results from PAOD, which is caused by obstruction of blood flow into an arterial tree. PAOD is a major cause of disability and loss of work and affects the quality of life. Morbidity and mortality are relatively high because effective treatments are very limited. Presently SCS is usually implemented only after vascular surgery and medications fail to slow or prevent the progression of PAOD. Surprisingly the success rate of SCS-treated PAOD is greater than 70%. Since ischemic pain is characterized generally as essentially nociceptive and several studies have indicated that SCS does not alleviate acute nociceptive pain, SCS-induced pain relief is most likely secondary to attenuation of tissue ischemia that occurs as a result of either increasing/redistributing blood flow to the ischemic area or decreasing tissue oxygen demand. Cook and associates were the first to report that SCS increased peripheral circulation of patients suffering from PAOD. Usually SCS is applied to the dorsal columns of lower thoracic (T10-T12) and higher lumbar spinal segments (L1-L2) to increase peripheral circulation in the legs of PAOD patients.

The mechanisms of SCS-induced vasodilation in the lower limbs and feet are not yet completely understood. Since no animal models of PAOD that generate ischemic pain have emerged, normal anesthetized animal models have been used to investigate the physiologic mechanisms of SCS-induced changes in peripheral blood flow (see for review). Cutaneous blood flow and calculated vascular resistance in the glabrous skin of ipsilateral and contralateral hindpaws have been determined most commonly by using laser Doppler flowmetry. A thermistor probe placed next to the laser Doppler probe on the plantar aspect of the foot has been used to measure skin temperature. Various interventions such as injections of hexamethonium, administration of adrenergic agonists and antagonists, sympathetic denervation, dorsal rhizotomies, calcitonin gene-related peptide (CGRP) antagonists, nitric oxide synthetase inhibitors, and local paw cooling have been used to explore the underlying mechanisms of peripheral microcirculation. Studies using Doppler flowmetry and interventions for more than 30 years of clinical and basic science studies have resulted in the evolution of two theories to explain the mechanisms of SCS-induced vasodilation. One theory is that SCS decreases sympathetic outflow and reduces the constriction of arterial vessels ; the alternative theory is that SCS antidromically activates sensory fibers, which causes the release of vasodilators ( Fig. 2-3 ). The theory for SCS-induced suppression of sympathetic activity was based on results from clinical observations showing that a sympathetic block or sympathectomy produced pain relief and vasodilation imitated effects of treatment with SCS. This theory was tested in animal models in which SCS-induced cutaneous vasodilation in the rat hindpaw at 66% of motor threshold was abolished by complete surgical sympathectomy. SCS-induced vasodilation was markedly attenuated after administrating the ganglionic blocker, hexamethonium, or the neuronal nicotinic ganglionic blocker, chlorisondamine. These results led to the suggestion that efferent sympathetic activity, including nicotinic transmission in the ganglia and the postganglionic α ₁ -adrenergic receptors are suppressed by SCS (see Fig. 2-3 ). The alternative theory of SCS-induced antidromic activation of sensory fibers was confirmed in studies showing that sensory afferent fibers are important for SCS-induced vasodilation and that at higher, but not painful, SCS intensities C-fibers may also contribute to the response (see Fig. 2-3 ). Thus SCS applied at the spinal L2-L5 segments excites dorsal column fibers that antidromically activate interneurons, which subsequently stimulate spinal terminals of transient receptor potential V1 (TRPV1) containing sensory fibers, which are primarily made up of C-fiber axons. These fibers transmit action potentials antidromically to nerve endings in the hindlimb. The action potentials evoke mechanisms that release vasodilators, including the most powerful vasodilator, CGRP, which binds to receptors on endothelial cells. The activation of these receptors leads to production and subsequent release of nitric oxide (NO), which results in relaxation of vascular smooth muscle cells (see for review). The overall result is that relaxation of vascular smooth muscle cells decreases vascular resistance and increases peripheral blood flow. It should be noted that SCS applied at 500 Hz significantly increased cutaneous blood flow and decreased vascular resistance when compared to the responses induced at 50 Hz and 200 Hz; the effects at all of these frequencies depend on the activation of TRPV1-containing fibers and release of CGRP. The clinical use of such findings remains to be determined.

Schematic diagram illustrating how spinal cord stimulation (SCS) (lightning bolt) of primary afferent fibers in the T1-T2 dorsal columns (DC) affects neuronal mechanisms that reduce pain and improves cardiac function resulting from ischemic heart disease. SCS activates interneurons (A) that may reduce activity of spinothalamic tract (STT) cells short term (B); modulate activity of sympathetic preganglionic (C) and postganglionic (D) neurons to stabilize the intrinsic cardiac nervous system (ICN), which reduces ischemia, decreases infarct size, and decreases arrhythmias. In addition, a protective effect associated with local release of catecholamines on ischemic cardiomyocytes has been demonstrated recently (see text). E, A-δ and C fibers transmit innocuous and nociceptive information from the heart to STT cells. A, Atria; V, ventricles; +, excitation; − , inhibition.

The level of sympathetic nervous system activity may shift the balance between the effects of sympathetic efferent suppression and antidromic activation of sensory afferent fibers. Cooler skin temperatures increase sympathetic activity. A notable observation is that SCS-induced vasodilation of a cooled hindpaw (<25° C) generated an early phase of vasodilation via sensory afferent fibers and a late phase via suppression of the sympathetic efferent activity. However, only sensory afferent activation occurred if SCS-induced vasodilation was performed in a warm paw (>28° C). Thus the balance of these two mechanisms most likely depends on the activity level of the sympathetic nervous system. Furthermore, another study showed that preemptive SCS increased the survival rate of skin flaps that were made ischemic by occluding the blood supply to the tissue for as long as 12 hours. Concomitant administration of the CGRP-1 receptor antagonist CGRP 8-37 markedly attenuated the cytoprotective effect ; whereas preoperative administration of antiadrenergic drugs such as guanethidine, reserpine, and 6-hydroxydopamine increased experimental flap survival. Thus the dual mechanisms of the release of vasodilators by antidromic activation of sensory fibers and suppression of sympathetic activity may all be involved in cytoprotection and prevention of vasospasm.

Neuromodulation Mechanisms of Visceral Organs

This section focuses on the heart and gastrointestinal tract because most of the basic research to determine mechanisms underlying the SCS-induced effects has been performed on these organs. Effects of SCS on spasms of bronchi in lungs were examined, but only an abstract was published. To the best of our knowledge the effects of SCS on other visceral organs of animals besides studies of the colon (see section on Gastrointestinal Tract that follows) have not been examined systematically. However, there is abundant evidence of SCS effects on the urinary bladder that were obtained mostly from multiple sclerosis patients.

Heart

Ischemic heart disease is often presented as shortness of breath and angina pectoris, which is described clinically as an extremely intense pain and severe discomfort that usually radiates to the chest, shoulder, and left arm and occasionally to the neck and jaw. This pain usually occurs during episodes of vasospasm or occlusion of the coronary vessels that result in decreased blood flow to the heart. The decreased blood flow generally causes an imbalance between the supply and the demand of oxygen in the heart. Ischemic episodes result in the release of prostaglandins, adenosine, bradykinin, and other substances that activate nociceptive spinal sensory afferent fibers innervating the heart. This nociceptive information is transmitted by these sensory afferent fibers, which enter the C7-T5 spinal segments and synapse on spinothalamic tract cells, and cells of other ascending pathways that are also receiving converging cutaneous and muscle input from the overlying somatic structures such as the chest and upper arm. Because of this convergent input, angina pectoris is felt as if it is originating from the chest and left arm. On occasion, angina is referred to the neck and jaw because the ischemic episodes can excite nociceptive vagal afferents that converge on spinothalamic tract cells in the upper cervical segments that also receive somatic convergent input from the neck and jaw.

It is important to note that a large population of patients suffering from chronic angina pectoris does not respond to conventional treatments. This group of patients led clinicians to develop alternative strategies such as neuromodulation to provide pain relief. Thus, following a period of using transcutaneous nerve stimulation for various types of visceral pain, including angina pectoris, SCS has been used to treat such therapy-resistant angina pectoris since the mid-eighties. Application of SCS at T1-T2 or higher spinal segments in patients provides pain relief by reducing both the frequency and to some extent the severity of angina attacks; the intake of short-acting nitrates is also reduced. Thus SCS improves the quality of life in these patients; however, the mechanisms producing pain relief and improved heart function still remain unclear. An early animal study showed that SCS produced antianginal effects by directly inhibiting spinothalamic tract cell activity resulting from cardiac nociception, but clinical and animal studies have proven that SCS does not solely relieve pain but also improves cardiac function. However, the primary factor appears to be the resolution of myocardial ischemia. Hautvast and colleagues have proposed an SCS-induced flow increase or redistribution of blood supply, whereas Eliasson, Augustinnson, and Mannheimer and Mannheimer and associates interpret the reduction of coronary ischemia (decreased ST changes; reversal of lactate production) as being mainly caused by decreased cardiomyocyte oxygen demand.

Studies have been conducted to determine if blood flow changes relieve angina pectoris with SCS. In a human experimental study, positron emission tomography (PET) was used to show that SCS appeared to redistribute blood. Blood flow and redistribution were also examined in an animal study by determining the distribution of isotope-labeled microspheres in hearts of anesthetized and artificially ventilated adult mongrel dogs. A comparison of occluding the left anterior descending coronary artery with and without SCS showed that local blood flow in the myocardium did not increase and no changes occurred in the pressure-volume relationships during SCS. However, this study was limited because it was performed using acute occlusions in animals with a normal heart. It would have been more appropriate to conduct such studies in canine hearts with previous infarctions and long-term ischemic episodes since patients have long-term coronary ischemic disease.

Clinical and animal studies have been done to determine if SCS produces anti-ischemic effects that contribute to improved cardiac function. In patients whose blood supply in the coronary arteries was reduced, SCS applied during standardized heart workloads, analogous to exercise and rapid cardiac pacing, significantly reduced the magnitude of ST segment changes of the electrocardiogram. These results support the idea that SCS may affect cardiac function by improving the working capacity of the heart. A canine animal model of myocardial ischemia was used to resemble the development of chronic ischemic heart disease by implanting an ameroid constrictor ring around the proximal left circumflex coronary artery. As the material inside the constrictor ring swells, it gradually reduces arterial blood flow and induces the development of collaterals. After 4 to 6 weeks the chest of anesthetized animals was opened, and the exposed heart was paced at a basal rate of 150 beats/min. A plaque containing 191 unipolar contacts was placed on the left ventricle distal to the left coronary artery occluded by the ameroid constrictor. Recordings were obtained from unipolar contact sites to determine changes in the ST segments. The heart was stressed by administering angiotensin II via the coronary artery blood supply to the right atrial ganglionated plexus. Hearts stressed with angiotensin II produced elevations of the ST segments; SCS markedly attenuated this ST segment elevation. These data indicate that SCS may counteract the deleterious effects caused by chemical activation of the intrinsic cardiac nervous system that stressors release in a myocardium with reduced coronary reserve. From these results it was concluded that SCS may produce anti-ischemic effects, which in turn contribute to improved cardiac function. In a more recent study Lopshire and associates demonstrated that SCS improved cardiac function in canine heart failure after an experimental myocardial infarction and further stressing the heart by using high-frequency cardiac pacing over 8 weeks.

Further evidence to support the anti-ischemic effects of SCS on the heart is the observation that SCS initiated before the onset of ischemic episodes (preemptive SCS) appears to activate mechanisms that reduce infarct size produced by coronary occlusions. This preemptive SCS treatment reduced infarct size produced by coronary occlusions. This reduction in infarct size depends on adrenergic receptors located in the membrane of cardiac myocytes. Thus preemptive SCS appears to provide protection to the heart during periods of critical ischemia. However, protective effects of SCS therapy are ineffective if SCS is initiated after (reactive SCS) the onset of the ischemic episode.

The intrinsic cardiac nervous system is powerfully activated during ischemic episodes. It is located in the cardiac ganglion plexi of epicardial fat pads adjacent to and within the myocardium. This system is composed of interconnecting local circuit neurons and sympathetic efferent, parasympathetic efferent, and sensory afferent fibers. Local circuit neurons have the capacity to produce local interactions and also to connect with neurons arising from other ganglia and higher centers. Thus the intrinsic cardiac nervous system is essential to coordinate regional cardiac function and provide rapid and timely reflex coordination of autonomic neuronal outflow to the heart. An important observation in animal studies is that SCS appears to stabilize activity of these intrinsic cardiac neurons during an ischemic challenge resulting from occlusion of a coronary artery. Thus SCS improves cardiac function to a considerable degree by regulating the intrinsic cardiac nervous system ( Fig. 2-4 ).

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