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Spinal Cord Stimulation in Chronic Pain

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Vallejo, Ricardo MD, PhD∗,†; Bradley, Kerry MSEE; Kapural, Leonardo MD, PhD§

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doi: 10.1097/BRS.0000000000002179
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Abstract

Modulation of nociceptive transmission by activity in large diameter mechanoreceptive afferent fibers (e.g., involved in fine discrimination) was first described in by Head and Thompson.1 Later, Melzack and Wall's gate control theory attempted to unify previous decades of similar research into spinal pain processing.2–4 Spinal cord stimulation (SCS) was developed following the pioneering work by Shealy et al5,6 under the assumption that electrical stimulation of Aβ fiber projections in the dorsal column (DC) will modulate painful signals conducted by small Aδ and C fibers.

Fundamental to the success of SCS has been the concept that paresthesia (i.e., abnormal sensation caused by Aβ fiber activation; including what is often perceived by patients as tingling, buzzing, pins and needles, pressure, etc.)7–9 must be experienced as overlapping the patient's painful areas to provide pain relief. This notion, derived from the gate control theory, was demonstrated to be the single statistically significant technical predictor of therapeutic outcome by North et al,10 although perfect coverage with paresthesia did not assure a successful outcome. The advent of therapies such as HF10, which do not emphasize on paresthesia, have challenged the conventional paradigm, and sparked attention to the mechanism of action.

Despite advances in our understanding about the molecular mechanisms involved in the development and maintenance of chronic pain,11 further efforts are needed to clarify the reasons behind the observed effects with SCS. Our goal is to review what is presently known of mechanisms involved in SCS for pain relief.

COMPUTATIONAL MODELS OF SPINAL CORD STIMULATION

For decades, the mechanistic understanding of SCS was based on activation of the dorsal structures in the spinal cord. Early finite-element mathematical models provided insight into neurons affected by SCS. From these, it was inferred that large axons have lower thresholds than small fibers; cell bodies were unlikely to be stimulated; transverse dorsal root (DR) fibers have lower thresholds than longitudinal DC fibers; and that the presence of well-conducting CSF shunts current away from the spinal cord and promotes activation of DR fibers over DC fibers.12–14 Clinical observations confirmed that paresthesia generated by monopolar SCS at the mid- to low-thoracic vertebral location were first experienced in the abdomen, whereas further increases in amplitude caused DC activation and paresthesia perceived in the lower extremity.15

Holsheimer's group16–18 confirmed that DR fibers would be predominantly activated in monopolar stimulation and emphasized the importance of the contribution of the highly conductive CSF, the curvature of the root fiber, the abrupt change in the conductive environment at the DR entry zone, and collateral branching to low DR thresholds. Evolving SCS technology and clinical programming practices demonstrated that bipolar and especially guarded cathode or “tripolar” stimulation on a multicontact array could more selectively activate DC fibers, as the rostrocaudal orientation of the current flow of these contact combinations was along the most excitable orientation for DC fibers.19–22

Studies into the thickness of the cerebrospinal fluid generated further insight into clinical observations and corroborated computational models23–25 predicting that a thinner CSF layer would result in a lower activation threshold. Accordingly, cervical stimulation thresholds are lower than midthoracic thresholds.26 In addition, an extensive clinical programming study with wide-contact paddles showed that unilateral paresthesia was generated predominantly for contacts that were only slightly off-midline.27 Computational modeling confirmed that an off-midline cathode would have a lower threshold (due to DR activation) and would activate DC fibers unilaterally.25 Finally, models incorporated realistic human fiber diameters and distributions predicted that the penetration depth of the electrical field was no greater than 1 mm and that small axons (<10 μm diameter) were unlikely to be activated by typical SCS.28

Next-generation computational models explored how the stimulation pulse width (PW) altered selectively different fiber diameters: short PW settings activated only large diameter fibers, whereas longer PW recruited both large and smaller diameter midline fibers.29 A companion clinical study confirmed these predictions, showing that wider PW settings tended to generate more overall paresthesia coverage, primarily by “adding” more lower extremity dermatomes as PW was increased.30

Computational models have been developed to explore the effect of stimulation frequency. Their primary focus has been on determining whether kHz frequency stimulation can create depolarization blockade in DC or DR fibers, as has been observed in peripheral nerve stimulation.31–33 These models predict that DC block can occur only at amplitudes much higher than activation threshold. This implies that fiber blockade would only occur after a paresthesia is experienced.34 Another computational model suggests that kHz frequency stimulation may indeed block large (e.g., 12–14 μm) diameter fibers while activating slightly smaller fibers (7–10 μm) in the DC.35 This model assumes that the dura and CSF, interposed between the electrode and the DC axons, alter the stimulation waveform to a quasimonophasic shape, which lowers the relative block threshold. These models, however, have not been clinically validated.

ELECTROPHYSIOLOGY STUDIES: BIOELECTRICAL MECHANISMS AND STIMULATION TARGETS

Bioelectrical Mechanisms of Neurostimulation

Much of the studies on electrical neurostimulation has focused on axons. An electrical field applied to a neuron causes changes in the transmembrane potential, which may, particularly in the axon, lead to the generation of an action potential (AP) as a result of a flux of ions into the cell in response to the stimulating field.36 The AP is initiated if the stimulus provides enough charge to depolarize the membrane by a nominal amount (e.g., typically ∼15 mV).37 The particular current required to depolarize the membrane and initiate an AP is called the stimulation threshold.

Certain anatomic characteristics of axons influence their stimulation threshold providing the basis for bioelectrical mechanisms. The thickness of the myelin sheath correlates to the distance between nodes of Ranvier; thus, greater diameter means larger spatial difference between adjacent nodes. Larger nodal spatial differences translate into greater individual nodal potential changes for a given stimulation current, and lower stimulation thresholds.38–40 Therefore, neurons with large diameter axons, such as the ones in Aβ-fibers have lower stimulation thresholds than smaller ones; thus, these are recruited preferentially, although the design of the stimulation waveform can be customized to reverse this.41,42

Stimulation Targets of Spinal Cord Stimulation

Although focus in SCS has been on axonal activation leading to the perception of paresthesia, and the activation of neurons causing neurotransmitter release, it is important to consider that electrical stimulation may affect other cells and processes in neural tissue.43 Indeed, the majority of cells in the central nervous system are glia44,45; thus, it is therefore interesting to contemplate the potential effects of SCS on neuroglia.

Glial cells play an important role in the development and maintenance of neuropathic pain.46–49 Following a noxious stimulus, glial cells surrounding the synapse cleft in the dorsal horn will modulate neurotransmitters and cytokine concentrations. Under specific conditions, an unbalance of these molecules at synapses may lead to chronic pain.47 It is notable that the concentration of the main inhibitory and excitatory neurotransmitters, gamma-amino-butyric acid (GABA), and glutamate, respectively, requires glutamine for their synthesis in the neurons and glutamine can only be synthesized by astrocytes.50 In addition, glial cells and neurons communicate via release of glutamate and glutamine mediated by calcium regulation in the synapse.51

From an electrical standpoint, the membrane potential of glial cells is different from neurons (e.g., −80 mV).52In vivo and in vitro studies have shown that electrical stimulation can cause glial depolarization and glutamate release, which is amplitude and frequency dependent.52,53In vitro studies showed that extracellular electrical stimulation increased astrocytic intracellular calcium concentrations leading to glutamate release. This effect was blocked by ziconotide, a calcium channel blocker. Interestingly, blockade of both, ionotropic and metabotropic glutamate receptors was required to observe similar results, while 4-aminopyridine, a potassium antagonist, enhanced glutamate release.54 In order to determine whether neurons or glial cells were responsible for post-stimulation glutamate release, Tawfik et al53 evaluated blockade of spontaneous wave oscillations created by a 100 Hz, 100 μs, 0.3 mA pulse train. Application of tetrodotoxin, a sodium channel antagonist, eliminated the spontaneous oscillations, whereas glutamate release remained unchanged, confirming the role of glial cells in this process.

Furthermore, glial cells seem capable of discerning the pattern of stimulation. In a neuromuscular ex vivo model, perisynaptic Schwann cells were exposed to burst or tetanic stimulation.55 Burst stimulation caused oscillatory calcium activity and a reduced amount of glial-derived ATP that is degraded to adenosine. Low adenosine concentrations led to synaptic depression through activation of the adenosine A1 receptor and a decrease in presynaptic calcium entry through a P/Q-type calcium channel. In contrast, continuous presynaptic activity from tetanic stimulation caused calcium elevation and the release of larger amounts of glial-derived ATP. Once degraded into adenosine, there was activation of A2A receptors leading to activation of L-type calcium channels and synaptic potentiation. Finally, astrocytic release of glutamate observed after monophasic cathodic pulses was prevented by biphasic stimulation, suggesting differential glial sensitivity to pulse shape.56

SEGMENTAL EFFECTS: CENTRAL AND PERIPHERAL

Central Segmental Effects of Spinal Cord Stimulation

Central sensitization is the abnormal amplification of information in the central nervous system, particularly to afferent activity.57–60 Central sensitization is believed responsible for allodynia and hyperalgesia in chronic pain.60 It is characterized by increased synaptic strength in the spinal cord and brain regions due to intensification of excitatory synaptic transmission mediated by the effect of the excitatory neurotransmitter glutamate on metabotropic and ionotropic receptors and/or decrease in GABA inhibitory synaptic transmission.58,59

SCS activates the projection collaterals of large myelinated innocuous afferents in the DC and DR fibers. APs generated in these fiber types appear to directly or indirectly result in the release of a wide variety of pain-relevant neurotransmitter systems. The use of SCS in neuropathic pain rodent models led to a reduction and shortening of long-term potentiation and modulation of hyperexcitability of wide dynamic range neurons in the dorsal horn, likely related to reduction in extracellular glutamate concentration and GABA release.61–65 The GABA-B receptor plays a critical role in suppressing glutamate release.66 Interestingly, in animal and human studies, the use of intrathecal subtherapeutic doses of baclofen, a GABA-B receptor agonist, enhances the response to SCS even for long periods of time.64,67,68 Similarly, low-dose intrathecal injection of clonidine, an alpha-2 adrenergic agonist with inhibitory nicotinic effects, transformed animals, and humans implanted with SCS from nonresponders to responders, suggesting the involvement of the cholinergic system in SCS.69–71 Intrathecal application of subeffective doses of oxotremorine, a muscarinic receptor agonist, improved the response in animals previously unresponsive to SCS.72 These effects are related to acetylcholine release in the dorsal horn after SCS leading to activation of muscarinic (M4) receptor.73

Peripheral Segmental Effects of Spinal Cord Stimulation

Although the understanding of SCS mechanisms has predominantly focused on the activity of central spinal neurons, peripheral segmental effects have also been studied. Cook et al74 first observed that subjects receiving SCS demonstrated increased blood flow in their extremities in dermatomes matching the segmental level of the implanted electrodes. These observations led to the eventual success of SCS to treat ischemic conditions such as peripheral vascular disease.75,76 Linderoth and Meyerson77–80 showed that modulations in extremity blood flow with DC stimulation involved both antidromic activation of small diameter afferent fibers (similar to a DR reflex) and inhibition of efferent sympathetic outflow Further investigations suggested that these effects were related to the intensity of the applied stimulation: at lower SCS intensities, activation of DC Aβ fibers generates antidromic APs, which monosynaptically trigger dorsal horn interneurons containing extracellular-signal related kinase, protein kinase B (AKT), and GABA.81 These interneurons, via a presynaptic mechanism, then activate unmyelinated afferents, creating antidromic activity that yields release of calcitonin gene related protein (CGRP), a powerful vasodilator, at these neurons’ peripheral terminals, leading to increased blood flow in the affected limb. The activation of endothelial receptors to CGRP, leads to synthesis and later release of nitric oxide that produces relaxation of vascular smooth muscle cells.82

Recent clinical trials have shown significant pain relief in patients using high frequency SCS (10 kHz) at amplitudes significantly below the sensory threshold. This peculiarity raises questions regarding the mode of action 10 kHz SCS. Although membrane integration and desynchronization could explain the effects of high-frequency stimulation in different models, generation of APs at clinically used amplitudes is questionable. McMahon and colleagues83 recently offered a plausible explanation in an in vivo model. In their experiments, 10 kHz stimulation pulses at low amplitudes had no observable effect on DC axon performance but reduced the excitability of lamina I pain projection neurons compared to sham.

At significantly higher intensities of SCS, Tanaka et al82 demonstrated that increased blood flow from SCS in the cooled limb of anesthetized rats was reduced by administration of a CGRP antagonist and ganglionic blocker demonstrating reduced sympathetic efferent activity.

Suprathreshold SCS generates segmental effects in large fibers including motor efferents. In subjects with implanted low-thoracic SCS systems, Hunter and Ashby15 measured antidromic-evoked potentials in sural, peroneal, and medial gastrocnemius at paresthesia-generating intensities of SCS. While frank motor activity was observed only for high-amplitude SCS, even at lower intensities, orthodromic APs were observed in peripheral motor nerves at lower SCS amplitudes, suggesting that some muscle activity occurs in clinical use of paresthesia-generating SCS.15 Work by DiMarco et al suggests that motor activation is due to Aβ monosynaptic facilitation of spinal motor reflexes strong enough to reach threshold and create efferent motor traffic.84 Other studies have confirmed that antidromic activity is observed during paresthesia-based SCS.85,86

The contribution of these segmental effects to pain relief, however, is not known. Clinical and preclinical studies have shown that strong activation of peripheral afferents and DC fibers can reduce the size of evoked compound APs, suggesting that the axons become less efficient at generating APs; this effect was seen most profoundly in Aδ fibers86–90 with a corresponding report in patients of increased pain relief.

SUPRASPINAL EFFECTS

It is well-established that chronic pain affects certain supraspinal pathways in the medulla and specific regions in the brain.91 SCS induces the release of serotonin and norepinephrine at the spinal dorsal horns, via descending pathways that originate at the brain stem.92 Experiments demonstrate that the release of neurotransmitters from a descending path exert an inhibitory effect via GABA-B receptors in the spinal cord, implying that segmental and supraspinal effects are complementary.93–98

Studies have demonstrated that electrical stimulation of DCs influences the activity of neurons in the thalamus and somatosensory cortices.99 Functional magnetic resonance imaging and positron emission tomography imaging provided evidence that SCS modulates the activity of regions within the brain.100–103 One positron emission tomography study traced cerebral blood flow before and after SCS in nine patients with chronic neuropathic leg pain.104 Significant increases in blood flow were identified in the thalamus contralateral to the painful leg, the bilateral parietal association area, the anterior cingulate cortex (ACC) and prefrontal areas. These changes indicate that SCS regulates pain threshold at the thalamus and parietal association, whereas the ACC and prefrontal areas are involved in the emotional aspects of pain. Another study using functional magnetic resonance imaging evaluated the effect of conventional SCS on cortical and subcortical regions of the brain of 10 patients with chronic pain.101 The study concluded that SCS reduces the affective component of pain and modulates the activity of somatosensory cortices decreasing their connectivity to associated limbic areas when SCS therapy was applied.

NEW STIMULATION STRATEGIES

Pulse Patterns

Most stimulation pulse patterns in SCS have been essentially tonic/continuous in nature. North studied interleaved waveforms in SCS and found that frequency doubling resulted in greater paresthesia coverage.105 De Ridder et al introduced a 40 Hz, 5 pulses of 1 ms burst pattern for SCS,106 which was shown at 1 year in a crossover RCT to yield 43% relief of baseline overall pain versus 36% relief for traditional low frequency tonic stimulation, which was statistically significant.107 In cervical neuropathic model rodent in vivo studies, both tonic low-frequency and burst-patterned stimulation similarly reduced dorsal horn activity and tactile allodynia, although the effect with burst-patterned stimulation was not associated with increased GABA release whereas low-frequency tonic SCS was.108 A recent study based on electroencephalogram recordings from five fail back syndrome patients inferred that both conventional paresthesia-based SCS and burst-patterned SCS modulate the perceptive lateral ascending pain pathway and the inhibitory descending pathway. The authors, however, imply that the burst-patterned SCS differs in the way it modulates the affective medial pain pathway with the involvement of the dorsal ACC.109

High Frequency

Most of the work reported in previous sections relate to the effects of low frequency (e.g., 2–100 Hz), high-amplitude (e.g., paresthesia-generating) SCS, predominantly because those parameter ranges have been used clinically since inception of the therapy. Historically, the effect of frequency on paresthesia was believed to be qualitative, affecting primarily the character of the sensation rather than expansion of coverage, and therefore not critical to pain relief. The use of 10 kHz paresthesia-free SCS was, however, recently demonstrated to provide clinically and statistically superior long-term outcomes of more than 65% relief in back and leg pain compared to low-frequency SCS.110,111

An analysis of low-frequency paresthesia generated from 10 kHz−optimized spinal targets in patients responsive to paresthesia-free SCS suggested that paresthesia overlap of pain regions was not correlated to relief, as would be expected of low-frequency SCS.112,113 This raises the question of whether 10 kHz and traditional low frequency stimulation share similar mechanism(s) of action or whether the modification of specific stimulation parameters (frequency, PW, and/or amplitude) may affect different cell populations and improve clinical results. Recent in vivo work suggests that 10 kHz low intensity (i.e., non-DC stimulating) SCS significantly reduced wind-up in pain model rodents.114 In addition, in vitro work of superficial dorsal horn cells from neuropathic pain model rats demonstrated suppression of spontaneous activity in dorsal horn cells.115Figure 1 summarizes segmental and supraspinal effects of SCS.

Figure 1
Figure 1:
Differential effects of conventional and high frequency stimulation on spinal cell population. 5-HT indicates 5-hydroxytryptamine; NE, norepinephrine; SCS, spinal cord stimulation; STT, spinothalamic tract.

CONCLUSION

The mechanisms of SCS have been extensively studied over the last 30 years, and several consistent phenomena have emerged. First, the activation of Aβcollaterals in the DC for low-frequency suprathreshold SCS has been repeatedly shown to involve central neurotransmitter release, predominantly GABA, in the dorsal horn via segmental and supraspinal pathways. In addition, antidromic effects in the periphery have been shown to contribute to segmental peripheral effects. Nonetheless, much remains to be understood: What is the role of neuroglia? How do electric fields affect nonaxonal spinal structures? Does the predominant mechanism of pain relief occur in the spinal cord or at higher centers? Why do some patients not respond to SCS? Continuing investigations of SCS mechanisms will hopefully shed light on these questions in the coming years.

Key Points

  • SCS is an effective therapy for intractable chronic pain.
  • Current understanding of SCS mechanism of action has been focused on stimulation parameters that activate A-beta fibers to induce paresthesia on the painful dermatome.
  • Expanding mechanisms have emerged in which neurotransmitter release, particularly GABA, is induced by the stimulating electrical field involving segmental and supraspinal pathways.
  • New stimulation strategies driven by paresthesia-free paradigms have emerged, which are promoting new research in the field.
  • There are still many opportunities to explore unanswered questions involving the role of neuroglia, the role of other neurotransmitters and receptors, and improving clinical outcomes in nonresponders.

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Keywords:

bioelectrical mechanism; computational models; mode of action; potential role of neuroglia; segmental mechanisms; spinal cord stimulation; structural targets; supraspinal mechanisms

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