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9 Articles in Volume 15, Issue #3
Abuse-Deterrent Formulations
Ask The Expert: False-Positive Screen for Benzodiazepines
Clinical Diagnosis of Centralized Pain in the Age of ICD 10
Editor's Memo: The WHO Pain Treatment 3-Step Ladder
Letters to the Editor: Hormone Dosing, Adhesive Arachnoiditis
Pain in Women
PROMIS Pain-Related Measures: An Overview
Selective Interventional Spinal Techniques: Injections and Ablations
Transcranial Direct Current Stimulation (tDCS): What Pain Practitioners Need to Know

Transcranial Direct Current Stimulation (tDCS): What Pain Practitioners Need to Know

Non-invasive brain stimulation with tDCS is an emerging tool for adjunctive treatment of pain syndromes. Its long-lasting analgesic effects are probably caused by alterations of activity in cerebral pain-processing networks.

Transcranial direct current stimulation (tDCS) is a non-invasive, painless brain stimulation technique that is showing promise in the treatment of depression and chronic pain.1 tDCS is delivered through a battery-operated device that transfers electrical current of low intensity (1-2 mA) to the surface of the head, typically with 2 large (20-35 cm2) saline-soaked sponge-electrodes (Figure 1).

 

The primary mechanism of tDCS is a subthreshold modulation of neuronal resting membrane potential. In other words, the electrodes provide stimulation to specific areas of the brain for a few minutes, which results in neuroplasticity of glutamatergic synapses, and, thus, alterations of cortical excitability that last for 1 hour or more.2-4 There are 2 types of stimulation with tDCS: anodal and cathodal stimulation. The effects of tDCS on cortical excitability are polarity-dependent—anodal tDCS enhances activity, whereas cathodal tDCS diminishes excitability, if delivered within certain parameters.5,6

In addition, recent evidence suggests that tDCS interacts with various neurotransmitters in the brain, such as dopamine, acetylcholine, serotonin, and g-aminobutryic acid (GABA), and also can trigger changes in brain-derived neurotrophic factor (BDNF) that are associated with pain processing.7-12 Furthermore, research findings show that tDCS can upregulate and downregulate functional connectivity within brain networks, such as those that are important for cognitive, motor, and pain processing (Figure 2, page 60).13

These data, together with findings from other studies,14,15 have demonstrated that the neurophysiologic effects of tDCS are not limited to the area under the electrodes, providing evidence of activity alterations in distant interconnected cortical and subcortical areas.

These features make tDCS a promising tool for modulation of pain syndromes, which include pathological alterations of neural activity, excitability, and connectivity at multiple levels and sites of cerebral pain processing.16,17 Since reversal of maladaptive plasticity in the pain processing cerebral system has been shown to be associated with pain relief,18-20 the potential use of tDCS to prevent or reverse such maladaptive changes, or to enhance adaptive neuroplastic changes in the pain processing network is of high relevance for pain management.

However, the effects and functional outcomes of tDCS depend on a multitude of factors such as:

  • The parameters of tDCS, (ie, delivered dose,21 including polarity of the current and position of the electrodes)
  • Patient population and disease etiology
  • Adjunct therapies and interventions

As neurophysiologic studies indicate, the brain state determined by chronic illness, and transient adjunct therapy, such as pharmacological intervention, profoundly influence outcomes.22,23 It is likely that other factors, many of them still unknown, contribute to shaping the effects of tDCS and defining patient responsiveness to this intervention.

Exploration in Pain Management

tDCS has been explored in a variety of pain populations with various conditions, including difficult-to-treat pain syndromes such as multiple sclerosis (MS)-related pain, fibromyalgia, complex regional pain syndrome, central pain due to spinal cord injury or stroke; as well as headaches, and acute post-
operative pain.24-32 The level of evidence for tDCS ranges from case reports to small-sample Phase II, randomized controlled trials in adult populations.

Critical reviews as well as meta-analyses of randomized controlled trials of tDCS in chronic pain reveal high variability of tDCS stimulation protocols.33,34 This is not unexpected given the diversity of tDCS dose, patient populations, disease etiology, and adjunct therapies. The most common electrode montages and stimulation parameters that yielded promising findings with respect to the analgesic effects of tDCS are described below.

tDCS Protocols

Pain processing in the brain is not limited to one area or one sensory system. Therefore, the variety of electrode placements used in pain studies derives from the complexity of the cerebral pain processing neural network, which mediates vegetative, sensory-discriminative, affective, and cognitive aspects of pain. The vegetative and neuroendocrine effects of pain perception are linked, for the most part, to various subcortical regions, such as the amygdala or hypothalamus. The sensory-discriminative aspects of pain are covered by the spino-thalamic tract, the lateral thalamus, somatosensory areas, and the posterior insula, with the input from descending cortico-thalamic pathways originating in the motor cortex. Lastly, affective/cognitive processing of pain is related to the anterior insular and cingulate cortices, as well as the prefrontal areas of the brain.35-37

The pattern of current flow through the brain during tDCS (hence, which brain regions are targeted during stimulation) is determined by the configuration of the electrodes and the underlying brain anatomy. The operator can control the number of electrodes (typically ≥2), electrode assembly shape and size (typically 5 x 7 or 5 x 5 cm sponges), and the position of the electrodes on the body. Brain regions that are near the anode electrode are expected to increase their excitability, whereas regions near the cathode are expected to have decreased excitability. However, these relationships will vary with dose and brain state. In general, if the goal is increasing or decreasing brain function in a specific region, the anode or cathode, respectively, will be placed over that brain target and the other “return” electrode usually will be placed over the contralateral supra-orbital region.

Systems used to determine the electrode positioning vary; the most common is the International 10-20 EEG positioning system, but sophisticated electronic neuronavigational systems also are available. Reflecting the major components of the pain processing network, the main tDCS paradigms and electrode montages probed for analgesic effects include:

  • Excitability-enhancing tDCS over the primary motor cortex. The anode is placed over the primary motor cortex and the cathode is placed over the supraorbital region (Figure 3A). This corresponds with regions SO/C3 or SO/C4 of the 10-20 EEG system.24-26, 29
  • Excitability-diminishing tDCS over the somatosensory cortex. The cathode is placed over S1, the anode over the contralateral supraorbital region (SO/C3’ or SO/C4’; Figure 3B).27,30
  • Stimulation over the dorsolateral prefrontal cortex (DLPFC). The anode is placed over the left DLPFC, the cathode over the contralateral supraorbital region or over the right DLPFC (F3/F4 or F3/SO).31,32

The most frequently used intensity of tDCS that yielded positive results in pain ranges from 1 to 2 mA, delivered for 15 to 20 minutes, with electrodes between 25 and 35 cm2 in size. Treatment is repeated on several days (consecutive or with breaks) over 1 or more weeks. There is extensive evidence for the safety and tolerability of tDCS within these dose limits.38

Although some studies explored higher stimulation intensities or longer stimulation duration, this might not enhance efficacy in each case. In studies of the model for the primary motor cortex, it has been shown that prolonged stimulation at higher intensities might lead to reversed effects on neural excitability.5,6

Furthermore, a range of pharmacologic agents can inhibit or enhance the effects of tDCS and, thus, patient medication should be taken into account when planning tDCS. For example, serotonergic enhancement via serotonin reuptake inhibitors increases excitability enhancement accomplished by anodal tDCS, but it converts cathodal tDCS-generated excitability diminution into facilitation. A similar effect is obtained with amphetamine, and the N-methyl-D-aspartate receptor agonist D-cycloserine. In contrast, agents that block dopaminergic receptors, such as neuroleptics, abolish tDCS effects, and dopaminergic enhancement has a non-linear impact on tDCS-induced excitability alterations, including prolongation of excitability diminution. These effects can be useful to improve the efficacy of tDCS, but they also might counteract the intended effect. In addition, it might be relevant that tDCS effects are reduced in smokers (nicotine-dependents) under nicotine withdrawal.39

Moreover, studies using computerized modeling of tDCS-induced current flow in the human brain indicate that adjustment of tDCS protocols should be considered in specific vulnerable populations, such as children (Figure 4), or in patients with specific conditions such as skull defects or after stroke.40

Because the delivery of current flow to the brain depends on both the tDCS dose (electrode placement, current) and the head anatomy, general features as well as pathologic variations in anatomy should be considered when planning tDCS application. For example, the smaller head size of children relative to adults results in a higher brain current intensity with the same applied scalp current,41 although there is no evidence of increased risk in children using conventional tDCS protocols.42,43 In cases with skull injury or surgery, the delivery of the current may be altered. Current flow patterns in the brain also will be altered by the presence of a cerebral lesion, for example following stroke,44 although there is no evidence that this decreases tolerability using conventional protocols.45

 

tDCS Analgesic Effects

The existing evidence of tDCS analgesic effects in pain populations is mixed, although it builds on the results of more than 30 randomized sham-controlled Phase II trials, as well as open-label studies and case reports. The most frequently examined primary outcome measure was pain intensity, but other outcomes relevant to chronic pain have been measured, including pain quality, pain medication intake, symptom burden, changes in mood and sleep, and overall quality of life. Examples of tDCS outcomes and findings relevant to pain management are described below. A complete overview and meta-analysis of the findings from tDCS clinical trials in pain populations can be found in O’Connell et al.34

In a sham-controlled 2 parallel arm study of 19 patients with chronic MS-related pain, the patients who received tDCS delivered over the motor cortex (M1) at 2 mA with electrodes of 35 cm2 for 20 min on 5 consecutive days had a significant decrease in pain intensity and overall pain experience compared with patients who had the sham treatment.29 Moreover, pain relief was accompanied by improvements in quality-of-life that persisted at the end of the follow-up period 3 weeks after the last tDCS session (Figure 5).

Similar protocols yielded significant pain relief in patients with central pain due to spinal cord injury24 and in patients with chronic neuropathic pain of various etiologies.28,46 Another study involving a 2-day tDCS protocol (M1, 1 mA) significantly relieved chronic pelvic pain.26

In a sham-controlled study in migraine patients, tDCS over the motor cortex ( 2 mA, 20 min, electrodes 35cm2) or a sham procedure was delivered in 10 sessions spread over 4 weeks, on alternated working days Mon-Wed-Fri, and Tue-Thur.15 The rationale for this strategy was to be able to provide the procedure for the entire month without excessive burden to the patients. The stimulation resulted in gradual decrease of pain intensity and length of the chronic migraine episodes; the decrease continued in the post-tDCS follow-up period and reached statistical significance at the follow-up end point at 4 months. Although many factors could contribute to the observed trend, it is possible that the stimulation on alternate days might have reduced the initial efficacy of tDCS compared to daily tDCS sessions, and the cumulative effect built up more gradually. A replication of this finding in future studies is warranted.

In a randomized, 3 parallel-arm study in patients with chronic medically refractory fibromyalgia, Valle et al examined differences in analgesic effects of tDCS over the M1 and DLPFC respectively, (delivered for 20 min at 2 mA with electrodes 35 cm2 at 10 sessions over 2 weeks) versus a sham procedure.32 Patients were followed immediately after the last tDCS application, and then 30 and 60 days later. Although both M1 and DLPFC stimulation (but not sham) resulted in a significant decrease in pain intensity, with a positive impact on quality-of-life measures immediately after the last tDCS session, only the M1 stimulation yielded longer-lasting pain relief thorough the 60-day follow up. The analgesic effects of the DLPFC stimulation did not last to the 30-day follow up point.

Notably, Fregni et al found no significant effect of DLPFC stimulation on pain-intensity measures in patients with fibromyalgia.25 Considering that the prefrontal areas are involved in the affective/cognitive processing of pain, it is possible that tDCS delivered over DLPFC is more relevant for modulation of the emotional experience of pain than for the somatosensory aspect, operationalized as pain intensity. However, further studies are needed to clarify this point.

Another finding of high clinical interest came from a sham-controlled study of 40 patients undergoing total knee arthroplasty.47 Here, tDCS was delivered twice a day on 2 consecutive days (2 mA, 20 min, electrodes 35cm2; the anode placed over the M1 somatotopic representation of knee and cathode over the right DLPFC). The investigators reported a significant decrease in opioid consumption in the postoperative period (48-h) among those treated tDCS compared with patients who received the sham procedure. Despite using less opioid medication, participants in the tDCS group reported no pain exacerbation or worse mood as compared to the sham group. Although another study of tDCS for the management of postoperative pain in patients undergoing lumbar spine surgery could not replicate these positive findings,48 the potential of tDCS for management of postoperative pain deserves to be further explored.

Future Directions

Non-invasive brain stimulation with tDCS is an emerging tool for adjunctive treatment of pain syndromes. Its long-lasting effects suggest that it works, at least partially, via neuroplastic modulation of the pain matrix.

The results obtained with available tDCS techniques, although promising, suffer from some variability. To enhance the efficacy of this new therapeutic agent, we need to enhance our knowledge of the neuroplasticity of the brain in pain patients, and its specific modulation by tDCS, develop more efficient tDCS protocols to obtain more targeted stimulation, and shape the effects of tDCS to enhance its analgesic efficacy, reduce individual variability, and increase inter-individual and intra-individual replicability of outcomes. Moreover, therapeutic approaches combining stimulation with pharmacologic agents, or behavioral interventions, which have been shown to be successful in patients with stroke and depression, might also be an attractive way to improve tDCS efficacy in pain treatment in future.

Formal comprehensive training in the application of tDCS is necessary to ensure that tDCS is delivered to pain patients using an effective, consistent, and replicable approach. Thus, enthusiasm for application of this apparently “simple” technique must be tempered by respect for patient safety and careful development and mastery of proper tDCS-administration techniques.

Overall, tDCS seems attractive from clinical perspective, because it is portable and user friendly, with low maintenance costs. Regardless of limitations noted above, existing evidence indicate a clinical potential of tDCS for pain management and warrants further research toward tDCS transition to clinical settings.

Acknowledgement: The authors would like to thank Ms. Alexa Riggs for technical assistance with the manuscript preparation.

 

Last updated on: June 12, 2017
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