Transcranial Direct Current Stimulation Principle of tDCS Safety Measures Behind tDCS Analgesic Effects of tDCS TDCS in central neuropathic pain TDCS in fibromyalgia TDCS in cancer pain TDCS in refractory pelvic pain TDCS in chronic pain of various origin TDCS in experimentally-induced acute pain References

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Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) was developed a decade ago as a non-invasive technique for modulation of cortical excitability (Nitsche and Paulus, 2000).

A rationale for using  modulation of cortical excitability in chronic pain is based on the evidence that patients with chronic pain (including CRPS/RSD) develop pathological changes in the excitability of the somatosensory and motor cortices, and that normalization of the cortical excitability has been paralleled by pain relief (Maihofner et al., 2003,2004; Pleger et al., 2005).

The nature of tDCS-induced changes of cortical excitability depends on the polarity of the current. It is well accepted that the anodal tDCS increases cortical excitability, while the cathodal tDCS decreases it (Nitsche and Paulus, 2001; Nitsche et al., 2003).

A significant analgesic effect has been observed from either the cathodal tDCS applied over the somatosensory cortex  (Antal et al., 2008; Knotkova et al., 2009), or the anodal tDCS applied over the primary motor cortex (Fregni et al., 2006a,b; Fenton et al., 2008; Kuhnl et al., 2008; Knotkova et al., 2008).

TDCS is non-invasive, painless, applied with two sponge-electrodes over the scalp, and does not elicit any substantial side effects. The most common reported side-effects (Poreisz et al., 2008) are mild tingling or mild burning under the electrodes during the stimulation.
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Principle of tDCS

The principle of tDCS is based on affecting neuronal excitability and modulating the firing rates of individual neurons by a low amplitude direct current which is delivered non-invasively, painlessly and safely through the scalp to the selected brain structures (Nitsche et al., 2005; Nitsche and Paulus, 2001). The nature of tDCS-induced changes of cortical excitability depends on the polarity of the current.

The anodal tDCS increases cortical excitability, while the cathodal tDCS decreases it (Nitsche and Paulus, 2001; Nitsche et al., 2003). Some of tDCS induced changes occurs immediately during the stimulation (so called intra-tDCS changes), while others occur later as short-lasting and long-lasting after-effects.

Intra-tDCS excitability changes: The intra-tDCS effects which elicit no after-effects can be induced by a short (seconds) single application of tDCS. As suggested by recent pharmacological studies (Liebetanz et al., 2002; Nitsche et al., 2004,2005), intra-effects depend on the activity of sodium and calcium channels but not on efficacy changes of NMDA and GABA receptors, and thus are probably generated solely by polarity specific shifts of resting membrane potential. The intra-tDCS effect of cathodal tDCS is reduction of intracortical facilitation, while anodal tDCS has no intra-effect on intracortical facilitation or inhibition; all effects of anodal stimulation occur later as after-effects.

After-effects: To obtain longer-lasting after-effects, at least 13 min of 1 mA tDCS is needed (Nitsche et al., 2000). As shown by Nitsche and colleagues (2003), the after-effects critically depend on membrane potential changes, but have been demonstrated to also involve modulations of NMDA receptors efficacy.
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Safety behind tDCS

There are several mechanisms of potential current-induced tissue damage (Agnew and McCreery, 1987) that need to be considered when using current-delivering procedures:

• Electrochemically produced toxic brain products and metallic electrode dissolution products caused by the electrode-tissue interface.
• Heat development under the electrodes.
• Current-induced neuronal hyper-excitability and brain tissue heating.

The tDCS technique has been shown not to conflict with any of the general mechanisms associated with potential current-induced tissue damage mentioned above (Nitsche and Paulus, 2000; Nitsche and Paulus, 2001; Nitsche et al. 2003). More specifically:

• In tDCS, electrodes and brain tissue do not come into direct contact. Further, to minimize chemical processes at the electrode-skin interface, sponge electrodes, instead of metallic ones, have been utilized in tDCS protocols.
• Heating under the electrodes has been shown not to occur during the tDCS protocol (Nitsche and Paulus, 2000). Damage from the heating of neuronal tissue can be also ruled out as a potential safety concern, since excessive heating directly on the skin under the electrodes was not experienced (Nitsche and Paulus, 2000).
• Potential damaging effects due to neuronal hyperactivity refer to high frequency of supra-threshold stimulation lasting for hours (Agnew et al. 1983). As pointed out by Nitsche et al. (2003), the effects of tDCS are sub-threshold in the means of eliciting action potentials in neurons at resting membrane potentials. Furthermore, tDCS induced only moderate changes in cortical excitability (Nitsche and Paulus, 2000; Nitsche and Paulus, 2001; Nitsche et al. 2003).

Thus, tDCS as a technique of non-invasive modulation of cortical excitability has been shown to comply with safety considerations in the means of above described current-induced tissue damage mechanisms.

However, besides the general safety parameters of the tDCS technique, safety parameters of stimulation within each particular tDCS protocol need to be strongly considered to ensure safety of subjects receiving tDCS stimulation. Sundaram et al. (2009), evaluated parameters of tDCS stimulation in existing tDCS protocols as published in 141 articles on tDCS in human subjects.

The table below shows parameters of stimulation separately for the cathodal and anodal stimulation in healthy subjects and patients with various diagnoses. As shown by McCreery et al (1990) and noted by Nitsche et al (2003), Current Densities below 25 mA/cm2 do not induce brain tissue damage even when applying high-frequency stimulation over several hours.

Thus, the Current Density of 0.02 mA/cm2 – 0.07 mA/cm2, as used in existing protocols (see the table below), is well within the safety limit. As for Total Charge, tissue damage after electrical stimulation has been detected at a charge of 216 C/cm2 (Yuen et al., 1981). Thus, the Total Charge per Session (0.002-0.096 C/cm2) and Total Charge per Block of Treatment (0.0206-0.686 C/cm2) in existing tDCS protocols is clearly well within safety limits.

Table: Range of Parameters “Current Density” and “Total Charge” in
tDCS Protocols Involving Human Subjects

	Current Density (mA/cm2)	Total Charge per session (C/cm2)	Total Charge per complete block of treatment (C/cm2)
Healthy subjects – cathodal tDCS	0.0204-0.08	0.00245-0.096	--
Healthy subjects – anodal tDCS	0.025-0.0667	0.0045-0.08	--
Patients – cathodal tDCS	0.0286-0.0571	0.00514-0.0686	0.0206-0.137
Patients –anodal tDCS	0.0286-0.0571	0.00514-0.0686	0.0206-0.686

Table 1, Legend:
Current Density (mA/cm2) = stimulation strength (mA)/electrode size (cm2)
Total Charge per Session (C/cm2) = stimulation strength (A)/electrode size (cm2) x total tDCS stimulation duration (s).
Total Charge per Block of Treatment (C/cm2) = stimulation strength (A)/electrode size (cm2) x total tDCS stimulation duration (s) x number of consecutive days of treatment.
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Analgesic Effects of tDCS

Research studies in samples of patients with chronic pain and healthy subjects with experimentally-induced pain, as well as clinical experience from tDCS in patients with various pain syndromes indicate analgesic efficacy of tDCS.

Evidence to date suggests that:

1) The analgesic effect can be elicited  either by tDCS of cathodal polarity applied over the somatosensory cortex  (Antal et al., 2008; Knotkova et al., 2009), or by tDCS of anodal polarity applied over the primary motor cortex (Fregni et al., 2006a,b; Fenton et al., 2008; Kuhnl et al., 2008; Knotkova et al., 2008).
As an example, a figure below shows the effect of anodal tDCS over the motor cortex (A), and cathodal tDCS over the somatosensory cortex (B) in a CRPS/RSD patient. The patient received one block of cathodal tDCS and one block of anodal tDCS. The period between the two blocks was 6 weeks. Each block of treatment consisted of 20 min of tDCS stimulation delivered on 5 consecutive days (Mon-Fri). A non-parametric permutation test was used to obtain the p-values for the correlation between level of pain and time.

 

3) Analgesic effects outlast the tDCS stimulation but are not permanent

Recent evidence (Fregni et al., 2006a,b; Roizenblatt et al., 2007; Knotkova et al., 2008; Kuhnl et al., 2008) indicates that the pain relieving effect of tDCS outlast the period of stimulation by either days, weeks, or several months. However, the effect is not permanent, and high inter-individual variability in the duration of pain relief has been observed.

For the long-term maintenance of chronic pain, the tDCS treatment needs to be repeated. However, some patients benefit from tDCS on a long-term basis, as their pain intensity after tDCS never fully returned to the initial pre-treatment level.

4) Multiple applications of tDCS did not result in “desensitization”

Preliminary observations (Knotkova et al., 2008) indicate that a repeated treatment with tDCS does not result in “desensitization” (the effect observed in certain types of analgesics, e.g. opioids, when the analgesic effect declines with repeated use), indicating the potential of tDCS for a long-term/repeated use in clinical settings.
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TDCS in central neuropathic pain

A controlled study by Fregni et al (2006a) was aimed to determine the effects of tDCS on pain control in patients with central pain due to a traumatic spinal cord injury. Seventeen patients were randomized to receive sham or active anodal tDCS over the motor cortex. The sham or real tDCS was delivered on 5 consecutive days for 20 min each day, using two saline-soaked sponge electrodes of size 35 cm2. The real tDCS delivered the direct current at the intensity of 2 mA for 20 min, while in the sham stimulation the current was turned off after several seconds.

Pain intensity was evaluated by the Visual Analogue Scale (VAS), Clinician Global Impression and Patient Global Assessment. Safety was assessed with a neuropsychological battery and confounders with the evaluation of depression and anxiety changes. The results have shown a significant pain improvement after active anodal stimulation of the motor cortex, but not after sham stimulation. The results were not confounded by depression or anxiety changes, and the subjects did not experience a decline in cognitive performance. Further, tDCS did not elicit any serious side effects. There was a low incidence of mild transient adverse events in both groups of treatment (active tDCS and sham stimulation), including mild headache and itching under the electrodes.

Fig. Pain scores as indexed by visual analogue scale (VAS) throughout the experiment: the VAS scores for each time point in the two groups of treatment (sham and active tDCS).
* Indicates statistically significant (p < 0.05). Each point represents mean VAS scores for pain ± SEM (standard error of mean).
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TDCS in fibromyalgia

Two controlled studies using an identical sample of 32 female patients with established diagnosis of fibromyalgia aimed to determine the effect of tDCS on pain (Fregni et al., 2006) and sleep pattern (Roizenblatt et al., 2007).

In the study by Fregni et at (2006,b), the participants were randomized to receive either sham or active anodal tDCS over the primary motor cortex or active anodal tDCS over the dorsolateral prefrontal cortex.  A sham or 2 mA current was delivered for 20 min on 5 consecutive days, using two saline-soaked electrodes (35 cm2). 

The results showed that the tDCS over the dorsolateral prefrontal cortex and sham stimulation did not induce any significant pain relief, while anodal tDCS of the primary motor cortex induced significant pain improvement (p= < 0.0001). Although the analgesic effect of the tDCS decreased after the end of tDCS treatment, it was still significant after 3 weeks of follow-up (p=0.004).  Few mild side effects (such as mild transient headache) were reported; the frequency of occurrence was similar in all the three treatment-groups.

The study by Roizenblatt and his colleagues (2007) evaluated the effect of tDCS on sleep structure in fibromyalgia. Thirty-two female patients with established diagnosis of fibromyalgia were randomized to receive sham or active anodal tDCS either over the motor cortex or over the dorsolateral prefrontal cortex at the current intensity of 2 mA for 20 min on 5 consecutive days. All-night polysomnography was performed before and after the 5-day block of tDCS treatment.

Interestingly, the tDCS over the primary motor cortex vs. dorsolateral prefrontal cortex induced opposite effects on sleep and pain.  The tDCS over the motor cortex had a positive effect on the sleep structure: it increased sleep efficiency (by 11.8%, p=0.004) and decreased arousals (by 35%, p=0.001), and the increase in sleep efficiency was associated with an improvement in fibromyalgia symptoms.  In opposite, tDCS over the dorsolateral prefrontal cortex resulted in a decrease of sleep efficiency (by 7.5%, p=0.02), causing increases in REM and sleep latency (by 47.7%, p=0.0002 and by 133%, p=0.02 respectively. The findings suggest that the positive effect of tDCS on sleep in fibromyalgia is specific to modulation of primary motor cortex activity. 
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TDCS in cancer pain

A case report by Silva et al. (2007) presented a sham-controlled use of tDCS to examine whether tDCS can produce clinically meaningful analgesia in a patient with pancreatic cancer pain.  The patient was a 65 year old woman who had a history of increasing upper abdominal pain for one year, and was subsequently diagnosed with pancreatic cancer. The biopsy confirmed an adenocarcinoma of the pancreas and surgical treatment was not considered due to local and metastatic invasion. She was started on chemotherapy with gemcitabine, and this helped with her pain to some extent.  After six months of treatment, her pain returned and she was started on 180 mg of codeine and up to 2 g of acetaminophen per day.

During the study, the patient received a session of active anodal tDCS over the motor cortex and a session of sham stimulation in a cross-over randomized order. The patient was blinded to the treatment condition and withheld from her medication.

The results showed that after active stimulation, not only did the patient’s pain score decrease significantly from four to zero, but it also lasted for several hours even though the patient did not take any medication during the study treatment. Prior to the study, the patient could not tolerate missing one dose of her medication for more than four hours. In contrast to active tDCS, sham stimulation did not result in pain relief. 

The findings from this case report indicate that tDCS can alleviate pain from metastatic pancreatic cancer. The findings also justify larger tDCS studies in patients with cancer pain.
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TDCS in refractory pelvic pain

The objective of the pilot sham-controlled trial by Fenton et al (2008) was to determine the efficacy of tDCS for the treatment of chronic pelvic pain. Seven patients underwent a cross-over sham controlled tDCS treatment.

Sham or real anodal tDCS at the current intensity of 1 mA was delivered for 20 minutes on 2 consecutive days with 2 weeks of follow up symptom recording.

Comparing sham with the real tDCS, results showed that ratings for overall pain as well as ratings for pelvic pain significantly decreased after the active tDCS (VASo: 5.86 > 4.97, p=0.04; VASpp: 5.86 > 5.06, p=0.03).  Significant decreases in pain scores occurred for 4/7 patients in VASpp and 3/7 patients for VASo.
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TDCS in chronic pain of various origin

In the sham controlled study by Kuhnl et al (2008), the researchers aimed to determine the length of pain relief induced by 5 days of tDCS, and to gather information on its potential side effects during and after stimulation.  Twenty two patients with pharmaco-therapy resistant chronic pain syndromes such as trigeminal neuralgia, post-stroke pain, back pain, and fibromyalgia participated in this trial, and received a 2 mA current or sham for 20 minutes for 5 consecutive days in a cross-over double-blind design. Pain intensity was assessed using VAS every day three times, 1 month before- and during and after the last session.

The results showed a significant decrease in pain during and after the real tDCS treatment, with pain relief lasting for about 2 weeks.

No serious adverse effects occurred; only minor side effects like headache and fatigue after stimulation were noted after both sham and the real tDCS treatment
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TDCS in experimentally-induced acute pain

The aim of the sham controlled study by Antal et al. (2008) was to investigate the effect of tDCS applied over the somatosensory cortex, on experimentally-induced (with Tm: YAG laser) acute pain perception in healthy subjects.

Ten healthy volunteers in the age range of 18 to 30 participated in the study. Subjective pain ratings and amplitude changes of laser-evoked potentials (LEPs) of the N1, N2, and P2 components were recorded and analyzed before and after 15 minutes of anodal, cathodal, and sham tDCS delivered over the somatosensory cortex. 

Using a numeric analog score, this figure illustrates the differences of reported subjective pain values in % reported by patients before and after cathodal, anodal, and sham tDCS for right (contralateral) and left (ipsilateral) laser hand stimulation.

The results showed that cathodal stimulation of the SI significantly reduced subjective pain perception (P<0.005) and the amplitude of N2 LEP component when stimulating the contralateral hand to the side of the tDCS with Tm:YAG laser, while anodal and sham had no effect.

The findings indicated that cathodal tDCS over the somatosensory cortex can reduce experimentally induced pain perception in healthy human participants.  Moreover, the study contributed to the understanding of the mechanisms underlying analgesic effects of tDCS.
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References

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Fenton B, Fanning J, Boggio P, Fregni F. A pilot efficacy trial of tDCS for the treatment of refractory chronic pelvic pain. Brain Stimulation 2008; 1(3): 260

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Fregni F, Gimenes R, Valle AC, Ferreira MJ, Rocha RR, et al. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum 2006;54(12):3988-98.

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