**5. Methodology for translation of electric current stimulation to the clinic**

Evidence for the efficacy of non-invasive application of electric currents in humans for neuromodulatory effects has been rapidly increasing, with many proposed applications, including pain. The potential applications explored have been extensive as the technique is easy to implement, cheap and well tolerated by participants. Additionally an interesting potential development of non-invasive neuromodulation interventions suggests the method is a viable technique for patients to use in their homes with remote monitoring [68]. However there is not currently a consensus on the optimal protocols and variability in effects across individuals have been widely reported. For translation to the clinic, systematic study into the effect of altering the amplitude and duration of the applied electrical current is essential. These parameters include; electrode montage when targeting a given area; size of the electrodes; magnitude of stimulation and duration of stimulation [69]. As with many therapeutic interventions key questions are; how can neurostimulation dose be determined?; how can treatment fidelity be ensured?; how can individual variability be controlled when determining dose?

### **5.1 Electrode montage in tDCS**

In tDCS the stimulation electrodes are typically two saline soaked sponge electrodes; an anode and a cathode; that range from 25 to 35 cm2 placed above the region of interest and the reference electrode is positioned at another cortical region [70]. Early studies with tDCS used a very simple electrode montage, with two electrodes of the same size often with the assumption that the effect of the active electrode would be independent of the placement and size of the second, reference electrode. For motor cortex stimulation the typical electrode montage is to have the reference electrode placed over the contralateral orbit. It has been suggested that anodal stimulation protocols can be optimized by having the cathodal reference electrode as a larger size, thus rendering it functionally inert [71]. Another montage option has been the selection of an extracephalic reference electrode; typically the deltoid or buccinator muscles. Regardless of site used the montage of the two electrodes will inevitably impact on the regions where brain modulation will occur due to stimulation. Further the different forms of electrodes now available will also influence the applied stimulation as it is known that the electrode-skin interface has variable impedance that will be dependent on a number of factors that lead to variability in the delivered current. Modern

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

but there are currently only a few studies.

perceptual threshold using sequential testing protocols.

**3.3 Vagal nerve stimulation**

explored the use of cerebellar tDCS as a target for modulating pain thresholds [51],

The vagus nerve is a large tract originating at the brainstem and is known for its widespread innervation, targeting every major thoracic and abdominal organ [52, 53]. Vagal nerve stimulation (VNS) has similarly been shown to provide multi-systems effects, and thus useful for a wide range of disease interventions. The recent development of non-invasive vagal nerve stimulation; via transcutaneous auricular vagus nerve stimulation (ta-VNS); rather than the traditional cervical implantation; increases therapeutic potential of the intervention as it removes the need for surgery [54]. Due to the novelty of ta-VNS there is currently a lack of consensus over the optimal stimulation protocol [55]. Stimulation is typically of low amplitude current (~5 mA) with pulses of 250–500 μs with a frequency of between 10 and 25 Hz [54]. Recently a number of studies have made efforts to individualize the stimulation level based on

There is increasing evidence that VNS has anti-nociceptive effects [56, 57]. Analgesia is thought to occur through both the inhibition of spinal nociceptive reflexes and ascending transmission. There is evidence VNS and ta-VNS also modulates ascending inputs in the brain by altered activity in pain processing regions as observed via fMRI [55, 58]. Further a recent study examined the brainstem fMRI response to a respiratory gated ta-VNS protocol (known as RAVANS). Interestingly this study found that stimulation led to greater blood oxygen level dependent (BOLD) responses in the PAG [59]. Further this study explored the use of different stimulation frequencies, with a frequency of 100 Hz showing increased responsiveness of PAG. This alteration to a key site for endogenous pain modulation provides additional support for the potential of VNS for pain relief. Opioid receptor antagonists are found to reduce the efficacy of VNS, indicating that there is an opioid based mechanism for analgesia. Further VNS is also widely thought to have anti-inflammatory effects [56]. These anti-inflammatory effects are proposed to be due to neural-immune interaction at the peripheral nerves [60], with electric stimulation of the vagus nerve triggering a neural-immune reflex via cholinergic anti-inflammatory pathways that dampen the inflammatory response to infection

or tissue injury and suppress the release of pro-inflammatory cytokines.

Early studies using tDCS in patient studies have had variable success and lack strong evidence of treatment efficacy [61]. Initial randomized controlled trials of anodal tDCS to primary motor cortex (M1) as an intervention for neuropathic pain found the intervention to be ineffective [62]. However, recent studies provide support for tDCS of M1 as a treatment intervention for knee osteoarthritis [63], fibromyalgia [64] and inflammatory bowel disease [29]. There have also been randomized clinical trials using prefrontal tDCS demonstrating tDCS to be effective in pain reduction in patients with multiple sclerosis [65] and fibromyalgia [49] and also reduce post-surgical opioid use [66]. A recent meta-analysis of selected randomized controlled trials of tDCS for non-cancer pain included predominantly M1 tDCS but also left dorsolateral prefrontal tDCS [48]. The meta-analysis showed active stimulation was consistently better than sham stimulation with stronger evidence for the efficacy of anodal M1 tDCS [48]. However, overall there remain shortcomings in the current literature on tDCS in patient groups; the study numbers are

**4. Translation for patient pain relief ?**

**196**

stimulators are current controlled, but some earlier studies are voltage controlled leading to the current that reaches the scalp being dependent on differences in impedance thus leading to greater variability and difficulty in making comparisons across studies.

## **5.2 Modeling current flow in tDCS**

One limitation of tDCS is that the sites of stimulation are typically identified based on the cranial landmarks of the 10-20 system for EEG electrode placement. However individual differences in brain anatomy will result in electrode placement that may not correspond exactly to the intended target site of stimulation. M1 stimulation can be improved by identifying the individual's motor hotspot via transcranial magnetic stimulation (TMS) before electrode placement, but currently this is not typically included in the protocols for tDCS studies for pain relief. Recently current flow diagrams have been developed and are regarded as critical to the optimal administration of tDCS [72]. Ideally these predictions of the current flow are adapted to the specific anatomy as recorded via magnetic resonance imaging (MRI). Implementing tDCS in this way may help to control for some of the observed inconsistency in the effects of tDCS across populations [73]. This may be particularly important in some patient populations; recent work has further suggested that brain atrophy may also impact of the flow of current [74]. Given the observation of structural changes in the brain of chronic pain patients this may be problematic [22]. This may to some extent be ameliorated by individualized electric field models that can optimize tDCS dosage for patients [75, 76]. Current flow modeling also enables tailoring the dose to electrodes of different sizes, including high-definition transcranial direct stimulation protocols with smaller electrodes arranged in more complex montages to facilitate more focused effects [77, 78]. Additionally the current flow modeling may be able to facilitate the use of noninvasive neurostimulation techniques to deeper brain structures [77], so that novel targets in the pain neuromatrix could be stimulated.

### **5.3 What is the optimum magnitude of the applied electric current?**

The effects of electric stimulation of the brain have long been studied in animal models [79, 80]. When applied to the brain, the current is thought to alter underlying neuronal excitability but is also thought to affect functionally connected distant cortical and sub-cortical regions. However many animal studies apply direct current stimulation onto the cortical area (DCS). Therefore the current reaching the cortex is typically much greater than with transcranial application. The magnitude of electric current may be critical for the observed effects so the two methodologies could differ substantially. Similarly the trans-cutaneous application of electric currents to nerves is also emerging as a useful non-invasive intervention, and again the existing animal and human studies are often based on observations from invasive methods.

tDCS and tACS studies typically apply low currents (typically 1–3 mA) with 1.5–2 mA being the most usual stimulation levels. Recent studies have experimented with the use of higher currents (up to 4 mA) [81]. Studies have varied substantially in the protocols used, but all would lead to charge densities that would be far lower than that required to elicit an action potential. The charge density used in a study varies dependent on the size of the electrodes used, and is calculated by the size of the electrical current applied divided by the electrode area. The duration of the applied electrical stimulation has also been variable across studies but is typically within the range of 10–30 minutes. To enhance intervention comparisons studies could compare the total charge administered over stimulation period, so taking into account the duration electrical stimulation is applied in the intervention period.

**199**

**5.5 Mechanisms of tDCS**

*From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain…*

Future work exploring the appropriate current, as well as how this can be adjusted for different individuals is essential. It already known that lower currents are sufficient to lead to membrane polarization and have potential therapeutic benefits. Indeed the lower stimulation levels applied to primary motor cortex were in fact more effective in increasing motor cortical excitability [82], and may avoid the problematic finding of non-linear tDCS effects that have recently been reported when increasing current, with a reversal of effects observed in the mid-range of applied current (2 mA) [83]. This observation has been paralleled in animal models but pharmacological studies are required to discern the effect of the current on specific ion channels. Since it has been reported that there is non-linear effect in the stimulation magnitude, individual differences in cortical excitability; determined by differences in motor evoked potentials when primary motor cortex is the target;

A further tDCS effect that has not undergone much investigation and yet is important for implementation in a patient population is the duration of any tDCS therapeutic effects, and the impact of protocols involving repetitive stimulation is applied. Recent research has explored the short and long stimulation durations and compared these with those where short duration protocols are repeated with intervals. There is some evidence that repeated stimulation is more efficacious than

There are multiple parameters that can be altered in the administration of tDCS stimulation [48]. There will also be alterations of the effect of tDCS due to differing characteristics of the patient. There will be environmental factors that will impact on tDCS effects that could include the patient's current cognitive state and fatigue levels. Increasingly studies have explored the interaction between tDCS and pharmacological interventions, but it must also be considered that other medications taken by the participant could impact on the effect of neurostimulation. Many of the conditions that tDCS has been proposed to treat would mean that the patient would be taking medication [85]. This is particularly critical when considering the use of tDCS for pain relief, as chronic pain is a frequent comorbidity. Hormonal influences have been suggested to impact both on the perception of pain but also on the effects of tDCS. The effect of the interaction of tDCS with estrogen has only recently been explored [86]. This is particularly important when considering pain interventions as many conditions

associated with chronic pain have a higher prevalence in women than men.

inhibiting calcium channels and voltage-dependent sodium channels [90].

The effect of tDCS has been shown to be polarity-dependent [87]. Application of the anodal electrode (a-tDCS) over the target area increases neuronal excitability whereas a cathodal electrode (c-tDCS) decreases neuronal excitability [70, 88]. The underlying mechanisms of tDCS effects are unclear but tDCS is thought to alter neuronal membrane potential and so impact on the action potential threshold [89]. These studies suggest that anodal stimulation induced neuronal excitability results from neuronal membrane subthreshold depolarization and cathodal inhibitory effects are produced by membrane hyperpolarization. It was originally proposed that the polarization was from the somatic membrane where there is a higher density of sodium channels. Following from this, the short term effect of tDCS have been suggested to be related to increasing permeability to sodium. Additionally the neuronal excitability that occurs during anodal tDCS can be removed by pharmacologically

could become critical for appropriately setting therapeutic dose.

continual longer duration stimulation protocols [84].

**5.4 Interaction with individual patient characteristics**

*DOI: http://dx.doi.org/10.5772/intechopen.93277*

*From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain… DOI: http://dx.doi.org/10.5772/intechopen.93277*

Future work exploring the appropriate current, as well as how this can be adjusted for different individuals is essential. It already known that lower currents are sufficient to lead to membrane polarization and have potential therapeutic benefits. Indeed the lower stimulation levels applied to primary motor cortex were in fact more effective in increasing motor cortical excitability [82], and may avoid the problematic finding of non-linear tDCS effects that have recently been reported when increasing current, with a reversal of effects observed in the mid-range of applied current (2 mA) [83]. This observation has been paralleled in animal models but pharmacological studies are required to discern the effect of the current on specific ion channels. Since it has been reported that there is non-linear effect in the stimulation magnitude, individual differences in cortical excitability; determined by differences in motor evoked potentials when primary motor cortex is the target; could become critical for appropriately setting therapeutic dose.

A further tDCS effect that has not undergone much investigation and yet is important for implementation in a patient population is the duration of any tDCS therapeutic effects, and the impact of protocols involving repetitive stimulation is applied. Recent research has explored the short and long stimulation durations and compared these with those where short duration protocols are repeated with intervals. There is some evidence that repeated stimulation is more efficacious than continual longer duration stimulation protocols [84].

### **5.4 Interaction with individual patient characteristics**

There are multiple parameters that can be altered in the administration of tDCS stimulation [48]. There will also be alterations of the effect of tDCS due to differing characteristics of the patient. There will be environmental factors that will impact on tDCS effects that could include the patient's current cognitive state and fatigue levels. Increasingly studies have explored the interaction between tDCS and pharmacological interventions, but it must also be considered that other medications taken by the participant could impact on the effect of neurostimulation. Many of the conditions that tDCS has been proposed to treat would mean that the patient would be taking medication [85]. This is particularly critical when considering the use of tDCS for pain relief, as chronic pain is a frequent comorbidity. Hormonal influences have been suggested to impact both on the perception of pain but also on the effects of tDCS. The effect of the interaction of tDCS with estrogen has only recently been explored [86]. This is particularly important when considering pain interventions as many conditions associated with chronic pain have a higher prevalence in women than men.

### **5.5 Mechanisms of tDCS**

The effect of tDCS has been shown to be polarity-dependent [87]. Application of the anodal electrode (a-tDCS) over the target area increases neuronal excitability whereas a cathodal electrode (c-tDCS) decreases neuronal excitability [70, 88]. The underlying mechanisms of tDCS effects are unclear but tDCS is thought to alter neuronal membrane potential and so impact on the action potential threshold [89]. These studies suggest that anodal stimulation induced neuronal excitability results from neuronal membrane subthreshold depolarization and cathodal inhibitory effects are produced by membrane hyperpolarization. It was originally proposed that the polarization was from the somatic membrane where there is a higher density of sodium channels. Following from this, the short term effect of tDCS have been suggested to be related to increasing permeability to sodium. Additionally the neuronal excitability that occurs during anodal tDCS can be removed by pharmacologically inhibiting calcium channels and voltage-dependent sodium channels [90].

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

**5.2 Modeling current flow in tDCS**

targets in the pain neuromatrix could be stimulated.

**5.3 What is the optimum magnitude of the applied electric current?**

The effects of electric stimulation of the brain have long been studied in animal models [79, 80]. When applied to the brain, the current is thought to alter underlying neuronal excitability but is also thought to affect functionally connected distant cortical and sub-cortical regions. However many animal studies apply direct current stimulation onto the cortical area (DCS). Therefore the current reaching the cortex is typically much greater than with transcranial application. The magnitude of electric current may be critical for the observed effects so the two methodologies could differ substantially. Similarly the trans-cutaneous application of electric currents to nerves is also emerging as a useful non-invasive intervention, and again the existing animal and human studies are often based on observations from invasive methods. tDCS and tACS studies typically apply low currents (typically 1–3 mA) with 1.5–2 mA being the most usual stimulation levels. Recent studies have experimented with the use of higher currents (up to 4 mA) [81]. Studies have varied substantially in the protocols used, but all would lead to charge densities that would be far lower than that required to elicit an action potential. The charge density used in a study varies dependent on the size of the electrodes used, and is calculated by the size of the electrical current applied divided by the electrode area. The duration of the applied electrical stimulation has also been variable across studies but is typically within the range of 10–30 minutes. To enhance intervention comparisons studies could compare the total charge administered over stimulation period, so taking into account the duration electrical stimulation is applied in the intervention period.

stimulators are current controlled, but some earlier studies are voltage controlled leading to the current that reaches the scalp being dependent on differences in impedance thus leading to greater variability and difficulty in making comparisons across studies.

One limitation of tDCS is that the sites of stimulation are typically identified based on the cranial landmarks of the 10-20 system for EEG electrode placement. However individual differences in brain anatomy will result in electrode placement that may not correspond exactly to the intended target site of stimulation. M1 stimulation can be improved by identifying the individual's motor hotspot via transcranial magnetic stimulation (TMS) before electrode placement, but currently this is not typically included in the protocols for tDCS studies for pain relief. Recently current flow diagrams have been developed and are regarded as critical to the optimal administration of tDCS [72]. Ideally these predictions of the current flow are adapted to the specific anatomy as recorded via magnetic resonance imaging (MRI). Implementing tDCS in this way may help to control for some of the observed inconsistency in the effects of tDCS across populations [73]. This may be particularly important in some patient populations; recent work has further suggested that brain atrophy may also impact of the flow of current [74]. Given the observation of structural changes in the brain of chronic pain patients this may be problematic [22]. This may to some extent be ameliorated by individualized electric field models that can optimize tDCS dosage for patients [75, 76]. Current flow modeling also enables tailoring the dose to electrodes of different sizes, including high-definition transcranial direct stimulation protocols with smaller electrodes arranged in more complex montages to facilitate more focused effects [77, 78]. Additionally the current flow modeling may be able to facilitate the use of noninvasive neurostimulation techniques to deeper brain structures [77], so that novel

**198**

Human spectroscopy studies have demonstrated that anodal tDCS causes a local gamma aminobutyric acid (GABA) reduction [91] whereas cathodal stimulation leads to decreased glutamatergic neuronal activity. Currently the suggested mechanism of tDCS is thought to include presynaptic modulation of neurons, with the stimulation effects related to synaptic inputs rather than solely action potential generation [92, 93]. Evidence from animal studies of DCS also suggests presynaptic effects, with cathodal stimulation reducing the probability of glutamate release and anodal stimulation increasing glutamate release probability.

To explain the longer term effects of tDCS, anodal tDCS had been initially assumed to induce long term potentiation (LTP)-like effects whereas cathodal tDCS thought to induce long term depression (LDP)-like effects. However this is now thought to be overly simplistic. Some of the variability in effects of anodal and cathodal stimulation has been explained by mechanisms of homeostatic plasticity [94] formalized in the Bienenstock-Cooper-Munro (BCM) rule of bidirectional synaptic plasticity [95]. These mechanisms are proposed to occur within neural networks to prevent hyperactivity or hypoactivity [95].

Importantly recently it has also been highlighted that polarization of the cell membrane must be dependent on the orientation of the neuron to the extracellular current vector [96]. Further evidence of the importance of axonal orientation has been provided by animal studies with evidence from rat hippocampus suggests that effects of electrical current vary dependent on the orientation of axons [97]. The significance of axonal orientation in the effects of DCS could have wider implications as to how develop tDCS methods. Diffusion magnetic resonance imaging (dMRI) enables an assessment of the structural connectivity and integrity of tracts. It has been suggested that tractography achieved from dMRI may be beneficial for optimal electrode positioning in clinical instances where there has been disruption in fibre tracts due to disease [98] or that dMRI may aid understanding of the effects of neuromodulation at a cellular level [99]. Imaging techniques may also offer a means of individualizing interventions, but they would have the disadvantage of a substantial cost increase for an otherwise cheap intervention.

### **5.6 tACS**

Transcranial alternating current (tACS) of the primary motor cortex (M1) has been shown in the past to be effective in modulating sensory thresholds for tactile sensation and visual phenomena [100] and offers potential for pain modulation [101]. tACS involves weak alternating currents being applied through the skull via electrodes on the scalp with montages similar to those used with tDCS. tACS can be applied in a wide frequency range, with the effect of each frequency range still to be explored. There is evidence of gamma and alpha oscillations being associated with pain processing and perception. Despite its potential only a limited number of studies have used tACS although alpha range stimulation has been found beneficial for pain relief [102]. Studies combining tACS with fMRI, neurophysiology or QST may help address the optimum tACS frequency for pain relief. The mechanistic effects of tACS are less well understood than tDCS and interestingly there has been the suggestion that tACS effects could be a result of stimulation of peripheral nerves trans-cutaneously rather than effects on cortical neurons [103].

### **5.7 Less explored effects of electric currents and future research avenues**

Imposed electric fields may have a wider biological effects. For instance tDCS could influence glia [89, 104]. Future work should consider these largely unexplored effects so as to provide a more comprehensive mechanistic basis for weak

**201**

**Author details**

**6. Conclusion**

Alice G. Witney

Department of Physiology, Trinity Centre for Biomedical Engineering,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Trinity College Institute of Neurosciences, Dublin, Ireland

and tailored to individuals and different disease groups.

\*Address all correspondence to: awitney@tcd.ie

provided the original work is properly cited.

*From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain…*

electric currents dependent on targeted pain processing region. Further some consequences of weak electric currents are not widely monitored. Recent studies have begun to explore the possible consequences of tDCS on immune responses, which is particularly relevant when considering tDCS and ta-VNS for analgesia. However, thus far this has been in animal models [105, 106]. Imaging techniques such as proton magnetic resonance spectroscopy (H-MRS) could provide a useful methodology for monitoring changes in metabolites in response to patient tDCS or ta-VNS interventions. For instance, choline and myo-inositol are thought to be altered in chronic pain patients and are associated with neuroinflammation [21].

Pain is a complex sensation associated with the activity of multiple cortical and sub-cortical regions in the brain. The overall pain percept must result from the interplay between multiple ascending pathways that convey nociceptive input from the peripheral with descending pathways that act to modulate nociceptive input. The mechanisms for the formation of chronic pain are uncertain; though it is known that there are both peripheral, spinal cord and central mechanisms underlying the formation of chronic pain. Non-invasive neuromodulation through tDCS presents a particularly interesting treatment intervention for pain as recent evidence also suggests that its mechanism of action is not only the modulation of neuronal activity but that the technique also influences the neuro-immune response. However, for appropriate translation of tDCS to a clinical setting there remains the need for research for both increased mechanistic understanding as well as studies how the level of electric stimulation applied can be accurately targeted

*DOI: http://dx.doi.org/10.5772/intechopen.93277*

*From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain… DOI: http://dx.doi.org/10.5772/intechopen.93277*

electric currents dependent on targeted pain processing region. Further some consequences of weak electric currents are not widely monitored. Recent studies have begun to explore the possible consequences of tDCS on immune responses, which is particularly relevant when considering tDCS and ta-VNS for analgesia. However, thus far this has been in animal models [105, 106]. Imaging techniques such as proton magnetic resonance spectroscopy (H-MRS) could provide a useful methodology for monitoring changes in metabolites in response to patient tDCS or ta-VNS interventions. For instance, choline and myo-inositol are thought to be altered in chronic pain patients and are associated with neuroinflammation [21].
