**5. Noninvasive brain stimulation: Investigative and therapeutic uses**

frequency, and baseline corticospinal excitability of the targeted brain area is a critical param-

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Given the known efficacy of MCS for pain relief, the primary motor cortex was an obvious initial choice of target for NIBS interventions. Further given the corticospinal tract is known to have non-motor functions, that include a role in nociception, the stimulation could have an

High-frequency rTMS of the motor cortex has been shown to be efficacious in the treatment of pain [35, 43, 46, 47]. Significant reductions in pain ratings occur following high-frequency stimulation and these stimulation effects lasting from several minutes up to 8 days and even longer after multiple rTMS sessions. Stimulation of the motor cortex with high-frequency rTMS showed significantly increased pain thresholds with regard to cold thermal stimuli, meaning rTMS reduced the temperature at which the cold sensation became painful [40]. This demonstrates that

Evidence for M1 rTMS for pain relief is mounting, but there is still a shortage of large studies, and the duration of the neuromodulatory effect is not well established. Technical considerations with coil positioning may alter the effectiveness of rTMS as an intervention for pain relief which may not be completely controlled for in different studies. In rTMS, the coil is typically placed over M1 in an anteroposterior orientation which is associated with transsynaptic activation of pyramidal neurons, and this placement is believed to be optimal for analgesic effects compared with the placement of the coil in a lateromedial orientation, similar to findings with MCS [27]. Further, there is evidence that when the electrodes are placed over the somatotopic M1 region of the painful area, that optimal analgesic effect can be obtained [27]. The mechanisms behind M1 rTMS-facilitated analgesia are still not established. Previous research on implanted MCS has suggested that the modulation of pain is related to the inhibition of thalamic activity. M1 rTMS could modulate the pathways from the insula and orbitofrontal cortex to the posterior thalamus in order to upregulate these pain thresholds [48]. The modulation of pathways from the insula could be particularly significant, given recent research suggesting that the insula act as the cortical generator of pain perception, integrating

The neurochemical mediation of the neuromodulation is still uncertain. There is evidence that the endogenous opioid system may be responsible. Additionally, the activation of GABA (*gamma*-Aminobutyric acid)-ergic and glutamatergic pathways may be critical. For instance, high-frequency rTMS is believed to restore defective intracortical inhibition, a measure associated with impairments in GABAergic neurotransmission in patients with chronic pain [47]. Glutamate N-methyl-D-aspartate (NMDA)-receptors are also thought to be involved in rTMS neuromodulatory effects, in that there was observed a decrease in analgesic effects after the administration of the NMDA antagonist, ketamine [49]. This supports the ability of rTMS to induce synaptic plasticity via long-term potentiation (LTP) and long-term depression (LTD) like mechanisms.

rTMS not only can modulate chronic pain, but also experimentally induced acute pain.

**5.2. Pain modulation through repetitive transcranial magnetic stimulation of** 

eter in determining the consequence of rTMS [44].

sensory and affective components of pain [2].

**motor cortex**

effect on this pathway [45].

NIBS is well established as a tool to study the physiology of the CNS, elucidate functional anatomy of specific brain regions and explore brain network organization and plasticity [34]. However, currently the application of NIBS to pain research is much more recent, although this is a rapidly expanding field [35]. The most commonly used forms of NIBS that aim to modulate neuronal plasticity are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), with the techniques rapidly expanding to variations on these methods. Transcranial alternating current stimulation (tACS) is a particularly exciting new method where an alternating current is applied with the aim of enhancing network oscillations at frequencies close to the stimulation frequency [36]. Therefore, the rationale behind the tACS technique is that it may lead to pain modulation via the alteration of specific rhythmic activity known to be associated with pain processing [37], but currently, there are only a few experimental studies applying this technique to experimental or clinical pain. For all of these methodologies, the noninvasive nature, relatively low cost, and well-established safety and tolerability make these neuromodulatory techniques potentially important tools both for neurophysiological studies and to aid the development of long-term therapeutic interventions [38].

#### **5.1. Transcranial magnetic stimulation**

Transcranial magnetic stimulation (TMS) has both neuromodulatory and neurostimulatory properties. The technique, first introduced in 1985, has subsequently been widely used as a tool to study cortical brain areas, particularly motor cortex. The technique involves a stimulating coil of wire positioned over the desired brain target area, with a brief pulse of current passed through the coil, so generating a magnetic field which penetrates through the skull with negligible attenuation. The rapidly changing magnetic field induces a secondary current in the subject's brain, thus stimulating neural tissue via the depolarization of neurons [34]. Thus the technique overcame many of the problems associated with electrical stimulation, where the skull provides a barrier. With an appropriate figure of eight coil [39], TMS can be used to stimulate precise regions, such as the hand area of the motor cortex (C3). The motor cortex is a particularly good target for TMS usage in the absence of neuronavigation software packages that guide coil positioning over the appropriate brain target area as single-pulse TMS eliciting motor evoked potentials (MEPs) that can be recorded using electromyography (EMG), which enable the determination that the correct cortical area has been stimulated. MEPs are further used to determine the stimulation intensity required in an experimental protocol via the measurement of motor threshold and the quantification of changes in corticospinal excitability [34, 40, 41].

Repetitive transcranial magnetic stimulation (rTMS) refers to the application of a train of pulses and dependent on the frequency acts to suppress or facilitate the activity in an underlying brain area. The stimulation of the motor cortex with low frequencies (1 Hz or less) is associated with a decrease in corticospinal excitability, whereas higher frequencies (20–50 Hz) have been associated with an increase in excitability [42]. It has been noted that these effects are somewhat inconsistent, thereby limiting its therapeutic applications [43]. A possible reason behind this is that rTMS is dependent on stimulation parameters other than frequency, and baseline corticospinal excitability of the targeted brain area is a critical parameter in determining the consequence of rTMS [44].

### **5.2. Pain modulation through repetitive transcranial magnetic stimulation of motor cortex**

**5. Noninvasive brain stimulation: Investigative and therapeutic uses**

development of long-term therapeutic interventions [38].

tion of changes in corticospinal excitability [34, 40, 41].

**5.1. Transcranial magnetic stimulation**

108 Transcranial Magnetic Stimulation in Neuropsychiatry

NIBS is well established as a tool to study the physiology of the CNS, elucidate functional anatomy of specific brain regions and explore brain network organization and plasticity [34]. However, currently the application of NIBS to pain research is much more recent, although this is a rapidly expanding field [35]. The most commonly used forms of NIBS that aim to modulate neuronal plasticity are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), with the techniques rapidly expanding to variations on these methods. Transcranial alternating current stimulation (tACS) is a particularly exciting new method where an alternating current is applied with the aim of enhancing network oscillations at frequencies close to the stimulation frequency [36]. Therefore, the rationale behind the tACS technique is that it may lead to pain modulation via the alteration of specific rhythmic activity known to be associated with pain processing [37], but currently, there are only a few experimental studies applying this technique to experimental or clinical pain. For all of these methodologies, the noninvasive nature, relatively low cost, and well-established safety and tolerability make these neuromodulatory techniques potentially important tools both for neurophysiological studies and to aid the

Transcranial magnetic stimulation (TMS) has both neuromodulatory and neurostimulatory properties. The technique, first introduced in 1985, has subsequently been widely used as a tool to study cortical brain areas, particularly motor cortex. The technique involves a stimulating coil of wire positioned over the desired brain target area, with a brief pulse of current passed through the coil, so generating a magnetic field which penetrates through the skull with negligible attenuation. The rapidly changing magnetic field induces a secondary current in the subject's brain, thus stimulating neural tissue via the depolarization of neurons [34]. Thus the technique overcame many of the problems associated with electrical stimulation, where the skull provides a barrier. With an appropriate figure of eight coil [39], TMS can be used to stimulate precise regions, such as the hand area of the motor cortex (C3). The motor cortex is a particularly good target for TMS usage in the absence of neuronavigation software packages that guide coil positioning over the appropriate brain target area as single-pulse TMS eliciting motor evoked potentials (MEPs) that can be recorded using electromyography (EMG), which enable the determination that the correct cortical area has been stimulated. MEPs are further used to determine the stimulation intensity required in an experimental protocol via the measurement of motor threshold and the quantifica-

Repetitive transcranial magnetic stimulation (rTMS) refers to the application of a train of pulses and dependent on the frequency acts to suppress or facilitate the activity in an underlying brain area. The stimulation of the motor cortex with low frequencies (1 Hz or less) is associated with a decrease in corticospinal excitability, whereas higher frequencies (20–50 Hz) have been associated with an increase in excitability [42]. It has been noted that these effects are somewhat inconsistent, thereby limiting its therapeutic applications [43]. A possible reason behind this is that rTMS is dependent on stimulation parameters other than Given the known efficacy of MCS for pain relief, the primary motor cortex was an obvious initial choice of target for NIBS interventions. Further given the corticospinal tract is known to have non-motor functions, that include a role in nociception, the stimulation could have an effect on this pathway [45].

High-frequency rTMS of the motor cortex has been shown to be efficacious in the treatment of pain [35, 43, 46, 47]. Significant reductions in pain ratings occur following high-frequency stimulation and these stimulation effects lasting from several minutes up to 8 days and even longer after multiple rTMS sessions. Stimulation of the motor cortex with high-frequency rTMS showed significantly increased pain thresholds with regard to cold thermal stimuli, meaning rTMS reduced the temperature at which the cold sensation became painful [40]. This demonstrates that rTMS not only can modulate chronic pain, but also experimentally induced acute pain.

Evidence for M1 rTMS for pain relief is mounting, but there is still a shortage of large studies, and the duration of the neuromodulatory effect is not well established. Technical considerations with coil positioning may alter the effectiveness of rTMS as an intervention for pain relief which may not be completely controlled for in different studies. In rTMS, the coil is typically placed over M1 in an anteroposterior orientation which is associated with transsynaptic activation of pyramidal neurons, and this placement is believed to be optimal for analgesic effects compared with the placement of the coil in a lateromedial orientation, similar to findings with MCS [27]. Further, there is evidence that when the electrodes are placed over the somatotopic M1 region of the painful area, that optimal analgesic effect can be obtained [27].

The mechanisms behind M1 rTMS-facilitated analgesia are still not established. Previous research on implanted MCS has suggested that the modulation of pain is related to the inhibition of thalamic activity. M1 rTMS could modulate the pathways from the insula and orbitofrontal cortex to the posterior thalamus in order to upregulate these pain thresholds [48]. The modulation of pathways from the insula could be particularly significant, given recent research suggesting that the insula act as the cortical generator of pain perception, integrating sensory and affective components of pain [2].

The neurochemical mediation of the neuromodulation is still uncertain. There is evidence that the endogenous opioid system may be responsible. Additionally, the activation of GABA (*gamma*-Aminobutyric acid)-ergic and glutamatergic pathways may be critical. For instance, high-frequency rTMS is believed to restore defective intracortical inhibition, a measure associated with impairments in GABAergic neurotransmission in patients with chronic pain [47]. Glutamate N-methyl-D-aspartate (NMDA)-receptors are also thought to be involved in rTMS neuromodulatory effects, in that there was observed a decrease in analgesic effects after the administration of the NMDA antagonist, ketamine [49]. This supports the ability of rTMS to induce synaptic plasticity via long-term potentiation (LTP) and long-term depression (LTD) like mechanisms.

#### **5.3. The dorsolateral prefrontal cortex**

A second cortical target that has been investigated by NIBS is the DLPFC [50] The DLPFC is connected to the orbitofrontal cortex and to other areas of the pain "neuromatrix," in particular the thalamus and dorsal caudate nucleus. Evidence from multimodal studies, including neuroimaging, TMS, and tDCS, suggests that DLPFC is important in the affective modulation of pain [51–55]. The DLPFC has shared connectivity with regions associated with sensorimotor processing and monitoring of motor performance. This connectivity highlights the potential importance of the DLPFC as a target for neurostimulation for the modulation of pain [56]. Further, in addition to its possible ability to modulate the sensory-discriminative aspects of pain perception and experience, DLPFC has reciprocal networks within the ventromedial prefrontal cortex supporting the integration of memory and stimulus characteristics. Additionally, it has been found that increased activity in the DLPFC is associated with decreased pain intensity and unpleasantness.

that anodal stimulation inhibits neurotransmission by the inhibitory neurotransmitter GABA [66], whereas cathodal stimulation inhibits neurotransmission by the excitatory neurotransmitter glutamate [67, 68]. While the precise mechanisms remain elusive, recent research in animal models suggest that weak electrical stimulation acts as a modulator, rather than an inducer of synaptic plasticity with its effects highly dependent on endogenous synaptic activity [69].

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High-definition transcranial direct current stimulation *(*HD-tDCS) is a technique used to increase the spatial focality of tDCS by using <12 mm diameter ring electrodes [70]. As an investigative tool, HD-tDCS holds several advantages over conventional tDCS. Neuroimaging and modeling studies have demonstrated that conventional parameters induced neuromodulation extends outside the area covered by the target electrode [2, 71]. In addition, the largest current densities for conventional tDCS may not be produced directly under the target electrodes [70]. In comparison to the diffuse effects of conventional tDCS, HD-tDCS enables a more targeted approach to neurostimulation, potentially avoiding modulation of confound-

The predominant montage for HD-tDCS is a 4x1 array configuration consisting of five ring electrodes: 1 "active electrode" placed over the target area surrounded by a ring of 4 "return" electrodes placed equidistant from the central electrode [71]. This 4x1 montage increases intensity and focality of the stimulation, with peak stimulation situated under the central electrode. Further, the montage also allows for depth, focality, and intensity of stimulation to be titrated depending on the ring diameter [73]. In addition to improved focality, HD-tDCS has lower observed adverse effects, including less itching and scalp discomfort and with the further advantage of a longer duration of neuromodulatory effects [3]. Recent multidimensional electrode arrays are now available but, thus far, very little research has been conducted.

Multiple types of experimental pain have been used to study the effects of NIBS on nociceptive signaling in healthy human subjects [74]. tDCS of M1 produces sustained analgesia in chronic migraine, fibromyalgia, and orofacial pain [38]. Currently, the level of evidence for the use of tDCS in neuropathic pain is currently lower than that for rTMS [17, 75]. Similar to the effect of rTMS on DLPFC, there is also evidence that tDCS of the DLPFC modulates pain. For instance, anodal tDCS of the left DLPFC has been shown to increase electrical pain thresholds [76]. There are currently fewer studies targeting DLPFC, but future work on this area is of clear interest.

The mechanisms by which tDCS modulates pain processing have not yet been fully elucidated and likely differs between target brain regions. Anodal M1 tDCS increases cortical excitability [62] that may result in disinhibition of glutamatergic M1 neurons that activate sensory gating mechanisms in the thalamus via corticothalamic projections, reducing incoming nociceptive information to somatosensory cortex [77]. Alternatively, stimulation of M1 may stimulate GABAergic neurons to restore functional intracortical inhibition in chronic neuropathic pain

ing brain regions and permitting isolation of certain pain processing pathways [72].

**5.6. Pain modulation using transcranial direct current stimulation**

[47]. In addition, tDCS of M1 may directly increase opioid release [46, 78].

**5.5. High-definition transcranial direct current stimulation**

High-frequency rTMS of the DLPFC has been shown to alleviate neuropathic pain in patient groups [57]. Experimentally, the effects of low-frequency rTMS on both left and right DLPFC have also been reported where it was found that stimulation inhibited placebo analgesia, and so increased heat pain ratings [51]. This finding related to placebo analgesia highlights some of the difficulties involved in assessing the efficacy of NIBS interventions.

Differing mechanisms have been proposed for the alleviation of pain through increased activity in the DLPFC, one is that it is able to activate descending modulatory pathways through the periacqueductal gray, whereas an alternative mechanism was via modulation of thalamic activity as has been proposed by fMRI studies [58]. There is also a proposed role for the DLPFC in terms of the anticipation of pain, which could provide some explanation for placebo-related alternations in pain thresholds. One of the difficulties that arises in the comparison of active treatments to placebo is the possibility of an analgesic response to the placebo itself, which may be mediated by endogenous opioids [59, 60]. With this in mind, the ability of NIBS to modulate the placebo effect is in itself interesting.

#### **5.4. Neurophysiology of tDCS**

tDCS is a non-invasive technique, where weak direct current (<2 mA) is applied on the scalp for 10–20 mins using large saline-soaked sponge electrodes. In contrast to TMS, tDCS is neuromodulatory rather than neurostimulatory and as such influences spontaneous neuronal activity by modulating resting membrane potentials [61]. Animal studies have demonstrated that anodal tDCS depolarizes membrane potentials and increases neuronal firing rates and excitability, whereas cathodal stimulation hyperpolarizes membrane potentials, leading to decreased excitability [62]. Modeling techniques suggest that these short-term effects may be mediated by glia, with tDCS modulating glial transmembrane potential that may in turn alter glial regulation of potassium or glutamate homeostasis [63]. Due to technical difficulties, experimental evidence to examine the precise effect on glia is limited. Both anodal and cathodal long-term effects have been attributed to N-methyl-D-aspartate (NMDA)-receptor activation; the NMDA-receptor antagonist dextromethorphan has been reported to suppress the aftereffects of anodal and cathodal tDCS [64, 65]. Further, studies using magnetic resonance spectroscopy have reported that anodal stimulation inhibits neurotransmission by the inhibitory neurotransmitter GABA [66], whereas cathodal stimulation inhibits neurotransmission by the excitatory neurotransmitter glutamate [67, 68]. While the precise mechanisms remain elusive, recent research in animal models suggest that weak electrical stimulation acts as a modulator, rather than an inducer of synaptic plasticity with its effects highly dependent on endogenous synaptic activity [69].

#### **5.5. High-definition transcranial direct current stimulation**

**5.3. The dorsolateral prefrontal cortex**

110 Transcranial Magnetic Stimulation in Neuropsychiatry

decreased pain intensity and unpleasantness.

modulate the placebo effect is in itself interesting.

**5.4. Neurophysiology of tDCS**

A second cortical target that has been investigated by NIBS is the DLPFC [50] The DLPFC is connected to the orbitofrontal cortex and to other areas of the pain "neuromatrix," in particular the thalamus and dorsal caudate nucleus. Evidence from multimodal studies, including neuroimaging, TMS, and tDCS, suggests that DLPFC is important in the affective modulation of pain [51–55]. The DLPFC has shared connectivity with regions associated with sensorimotor processing and monitoring of motor performance. This connectivity highlights the potential importance of the DLPFC as a target for neurostimulation for the modulation of pain [56]. Further, in addition to its possible ability to modulate the sensory-discriminative aspects of pain perception and experience, DLPFC has reciprocal networks within the ventromedial prefrontal cortex supporting the integration of memory and stimulus characteristics. Additionally, it has been found that increased activity in the DLPFC is associated with

High-frequency rTMS of the DLPFC has been shown to alleviate neuropathic pain in patient groups [57]. Experimentally, the effects of low-frequency rTMS on both left and right DLPFC have also been reported where it was found that stimulation inhibited placebo analgesia, and so increased heat pain ratings [51]. This finding related to placebo analgesia highlights some

Differing mechanisms have been proposed for the alleviation of pain through increased activity in the DLPFC, one is that it is able to activate descending modulatory pathways through the periacqueductal gray, whereas an alternative mechanism was via modulation of thalamic activity as has been proposed by fMRI studies [58]. There is also a proposed role for the DLPFC in terms of the anticipation of pain, which could provide some explanation for placebo-related alternations in pain thresholds. One of the difficulties that arises in the comparison of active treatments to placebo is the possibility of an analgesic response to the placebo itself, which may be mediated by endogenous opioids [59, 60]. With this in mind, the ability of NIBS to

tDCS is a non-invasive technique, where weak direct current (<2 mA) is applied on the scalp for 10–20 mins using large saline-soaked sponge electrodes. In contrast to TMS, tDCS is neuromodulatory rather than neurostimulatory and as such influences spontaneous neuronal activity by modulating resting membrane potentials [61]. Animal studies have demonstrated that anodal tDCS depolarizes membrane potentials and increases neuronal firing rates and excitability, whereas cathodal stimulation hyperpolarizes membrane potentials, leading to decreased excitability [62]. Modeling techniques suggest that these short-term effects may be mediated by glia, with tDCS modulating glial transmembrane potential that may in turn alter glial regulation of potassium or glutamate homeostasis [63]. Due to technical difficulties, experimental evidence to examine the precise effect on glia is limited. Both anodal and cathodal long-term effects have been attributed to N-methyl-D-aspartate (NMDA)-receptor activation; the NMDA-receptor antagonist dextromethorphan has been reported to suppress the aftereffects of anodal and cathodal tDCS [64, 65]. Further, studies using magnetic resonance spectroscopy have reported

of the difficulties involved in assessing the efficacy of NIBS interventions.

High-definition transcranial direct current stimulation *(*HD-tDCS) is a technique used to increase the spatial focality of tDCS by using <12 mm diameter ring electrodes [70]. As an investigative tool, HD-tDCS holds several advantages over conventional tDCS. Neuroimaging and modeling studies have demonstrated that conventional parameters induced neuromodulation extends outside the area covered by the target electrode [2, 71]. In addition, the largest current densities for conventional tDCS may not be produced directly under the target electrodes [70]. In comparison to the diffuse effects of conventional tDCS, HD-tDCS enables a more targeted approach to neurostimulation, potentially avoiding modulation of confounding brain regions and permitting isolation of certain pain processing pathways [72].

The predominant montage for HD-tDCS is a 4x1 array configuration consisting of five ring electrodes: 1 "active electrode" placed over the target area surrounded by a ring of 4 "return" electrodes placed equidistant from the central electrode [71]. This 4x1 montage increases intensity and focality of the stimulation, with peak stimulation situated under the central electrode. Further, the montage also allows for depth, focality, and intensity of stimulation to be titrated depending on the ring diameter [73]. In addition to improved focality, HD-tDCS has lower observed adverse effects, including less itching and scalp discomfort and with the further advantage of a longer duration of neuromodulatory effects [3]. Recent multidimensional electrode arrays are now available but, thus far, very little research has been conducted.

#### **5.6. Pain modulation using transcranial direct current stimulation**

Multiple types of experimental pain have been used to study the effects of NIBS on nociceptive signaling in healthy human subjects [74]. tDCS of M1 produces sustained analgesia in chronic migraine, fibromyalgia, and orofacial pain [38]. Currently, the level of evidence for the use of tDCS in neuropathic pain is currently lower than that for rTMS [17, 75]. Similar to the effect of rTMS on DLPFC, there is also evidence that tDCS of the DLPFC modulates pain. For instance, anodal tDCS of the left DLPFC has been shown to increase electrical pain thresholds [76]. There are currently fewer studies targeting DLPFC, but future work on this area is of clear interest.

The mechanisms by which tDCS modulates pain processing have not yet been fully elucidated and likely differs between target brain regions. Anodal M1 tDCS increases cortical excitability [62] that may result in disinhibition of glutamatergic M1 neurons that activate sensory gating mechanisms in the thalamus via corticothalamic projections, reducing incoming nociceptive information to somatosensory cortex [77]. Alternatively, stimulation of M1 may stimulate GABAergic neurons to restore functional intracortical inhibition in chronic neuropathic pain [47]. In addition, tDCS of M1 may directly increase opioid release [46, 78].

### **5.7. Transcranial direct current stimulation priming of repetitive transcranial magnetic stimulation**

The physiological connectivity and neuronal plasticity of the M1 are two important factors that have been overlooked in the development of NIBS pain modulation protocols in the past. The use of tDCS-primed/preconditioned rTMS stimulation has been suggested as a more robust form of intervention [79, 80]. When tDCS was used to augment background motor corticospinal excitability, the cortical plastic changes induced by subsequent rTMSs were standardized. It has been demonstrated that weak 1 mA tDCS reversed the usual effects of rTMS on corticospinal excitability [81]. That is, preconditioning using a session of cathodal tDCS modified the expected suppressive effect of low-frequency rTMS and led to an overall cortical excitation, whereas anodal tDCS resulted in an overall motor cortical inhibition. This manipulation of effects is based on the conceptual form of brain plasticity, "homeostatic plasticity" [82]. This protocol has been applied to the modulation of pain, and weak tDCS (1 mA) was used to "precondition" the brain to enhance the effects of subsequent stimulation via low-frequency rTMS (1 Hz) on the modulation of thermal sensation, thermal pain thresholds, and pressure pain thresholds, thereby producing a form of analgesia [83, 84].

controllable TMS (c-TMS) [87]. These devices may be critical in optimizing TMS to maximize

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In addition to independent efficacy, it may be that NIBS can work in a synergistic fashion with pharamacological interventions for pain relief. This question has been examined with regard to stroke recovery in large randomized control trials in an extensive research network. A number of recent studies have combined drug interventions with rTMS in rehabilitation in patients after stroke [88]. Interesting questions can be raised as to whether drug action can prime the brain and enhance the effect of TMS or vice versa. The same approach should be

NIBS is rapidly emerging as an intervention proposed for wide-ranging neurological and psychiatric disorders. However, tDCS studies have recently been scrutinized due to reported high degree of variability in effectiveness in published studies to date [89]. Evidence on the therapeutic use of both tDCS and newer methodologies like tACS are currently very limited, and the optimal parameters for use have yet to be fully elucidated. Many have suggested that there is a currently a general lack of understanding of the mechanisms by which these interventions are effective. However, tDCS has several advantages compared to the better investigated rTMS including ease of use, portability, and reduced expense [90], which sup-

Despite this, there is increasing evidence that NIBS are effective in the modulation of experimentally induced pain [91] as well as chronic pain conditions although the caveat to this is that there is reported variability in responsiveness across studies and individuals in both experimental and clinical studies. This efficacy of NIBS for experimental pain challenges the previously held understanding that neurostimulation devices act solely by interfering with the long-term maladaptive plasticity associated with chronic pain. Instead, it points toward a general lack of sufficient mechanistic understanding as to how NIBS modulates pain and how this modulation differs across individuals [92]. Moves toward characterizing differing individual "pain phenotypes," based on a battery of quantitative sensory testing, may provide insights into why some individuals respond to NIBS [7]. The use of protocols designed to give insights into an individual's endogenous descending modulation such as conditioned pain modulation (CPM) [93] may also be useful in conjunction with NIBS, in the same way that these protocols have been used when differentiating groups that respond to pharmacological treatment interventions. Another possible reason for the variability of the effects of rTMS on acute pain could be differential effects on each pain modality. For example, it is possible that rTMS may influence A- δ –fiber-mediated and C-fiber-mediated

**5.9. Combining neuromodulation with pharmacological interventions**

systematically carried out in patients with chronic pain conditions (27).

port further investigation into the potential of tDCS in the treatment of pain.

**6. Challenging issues and inconsistencies in NIBS**

analgesic effects.

pain differently [94].

#### **5.8. Dose effects of neuromodulatory interventions**

The physiological mechanism underlying the effects of tDCS remains controversial. Unlike pharmacological interventions for pain relief, where the appropriate dosage is carefully considered, the issue of "dosage" of neurostimulation has been somewhat neglected in the literature [85, 86]. Recent research has been working toward establishing factors responsible for variability in tDCS effects; such as the positioning of the electrodes on the scalp as well as the intensity and duration of the stimulation. This is best demonstrated in studies regarding application to the human motor cortex, where they attempt to direct the current to strictly follow the orientation of axons and/or dendrites in the induced electrical field [61]. Recent studies employ current flow models with defined montages [86] and use improved electrode positioning through the use of caps based on the international 10–20 positioning system [84].

Interestingly, there is evidence that when the electrodes are placed over the somatotopic M1 region of the painful area, optimal analgesic effect can be obtained [27]. This could potentially explain some of the differences in treatment efficacy reported in rTMS studies in pain patients where the exact target of the stimulation in relation to the painful area is not controlled for or appropriately selected. A further complication to this is the variation in chronic pain conditions as to the extent of spatial localization of the perceived pain.

TMS has a much longer history of research than other NIBS techniques. However, there has been only slow development in stimulator design. An interesting recent development has recently occurred in TMS that may improve future therapeutic interventions. Until recently, there has been a complete lack of complete experimental control over the stimulation pulse shape in TMS. It will be interesting to see the emerging literature as new devices develop that examine the differential impact of altering stimulation pulse widths and waveforms via controllable TMS (c-TMS) [87]. These devices may be critical in optimizing TMS to maximize analgesic effects.

#### **5.9. Combining neuromodulation with pharmacological interventions**

**5.7. Transcranial direct current stimulation priming of repetitive transcranial** 

and pressure pain thresholds, thereby producing a form of analgesia [83, 84].

**5.8. Dose effects of neuromodulatory interventions**

tions as to the extent of spatial localization of the perceived pain.

The physiological connectivity and neuronal plasticity of the M1 are two important factors that have been overlooked in the development of NIBS pain modulation protocols in the past. The use of tDCS-primed/preconditioned rTMS stimulation has been suggested as a more robust form of intervention [79, 80]. When tDCS was used to augment background motor corticospinal excitability, the cortical plastic changes induced by subsequent rTMSs were standardized. It has been demonstrated that weak 1 mA tDCS reversed the usual effects of rTMS on corticospinal excitability [81]. That is, preconditioning using a session of cathodal tDCS modified the expected suppressive effect of low-frequency rTMS and led to an overall cortical excitation, whereas anodal tDCS resulted in an overall motor cortical inhibition. This manipulation of effects is based on the conceptual form of brain plasticity, "homeostatic plasticity" [82]. This protocol has been applied to the modulation of pain, and weak tDCS (1 mA) was used to "precondition" the brain to enhance the effects of subsequent stimulation via low-frequency rTMS (1 Hz) on the modulation of thermal sensation, thermal pain thresholds,

The physiological mechanism underlying the effects of tDCS remains controversial. Unlike pharmacological interventions for pain relief, where the appropriate dosage is carefully considered, the issue of "dosage" of neurostimulation has been somewhat neglected in the literature [85, 86]. Recent research has been working toward establishing factors responsible for variability in tDCS effects; such as the positioning of the electrodes on the scalp as well as the intensity and duration of the stimulation. This is best demonstrated in studies regarding application to the human motor cortex, where they attempt to direct the current to strictly follow the orientation of axons and/or dendrites in the induced electrical field [61]. Recent studies employ current flow models with defined montages [86] and use improved electrode positioning through the use of caps based on the international 10–20 positioning system [84]. Interestingly, there is evidence that when the electrodes are placed over the somatotopic M1 region of the painful area, optimal analgesic effect can be obtained [27]. This could potentially explain some of the differences in treatment efficacy reported in rTMS studies in pain patients where the exact target of the stimulation in relation to the painful area is not controlled for or appropriately selected. A further complication to this is the variation in chronic pain condi-

TMS has a much longer history of research than other NIBS techniques. However, there has been only slow development in stimulator design. An interesting recent development has recently occurred in TMS that may improve future therapeutic interventions. Until recently, there has been a complete lack of complete experimental control over the stimulation pulse shape in TMS. It will be interesting to see the emerging literature as new devices develop that examine the differential impact of altering stimulation pulse widths and waveforms via

**magnetic stimulation**

112 Transcranial Magnetic Stimulation in Neuropsychiatry

In addition to independent efficacy, it may be that NIBS can work in a synergistic fashion with pharamacological interventions for pain relief. This question has been examined with regard to stroke recovery in large randomized control trials in an extensive research network. A number of recent studies have combined drug interventions with rTMS in rehabilitation in patients after stroke [88]. Interesting questions can be raised as to whether drug action can prime the brain and enhance the effect of TMS or vice versa. The same approach should be systematically carried out in patients with chronic pain conditions (27).
