Background
Several studies showed that transcranial direct current stimulation (tDCS) modulates the cortical excitability of the motor cortex depending on the direction of the electric current (e.g. anodal or cathodal) and that its neuroplastic effects sustain after stimulation[
1]. The primary effect of tDCS is a modulation of the membrane potential of neurons in the stimulated cortical area[
2,
3], mediated by N-methyl-D-aspartate receptors (NMDA-R)[
4]. Nonetheless, the effects of tDCS on cortical excitability can spread to distant cortical areas possibly along interconnections between the stimulated area and adjacent regions[
5]. It was suggested, that anodal tDCS modulates pain perception by shifts of the resting membrane potential and consequent alteration of the corticospinal excitability at the stimulation site. tDCS was demonstrated to improve pain symptoms in patients with different types of chronic pain[
6] but with conflicting results. While in painful diabetic neuropathy anodal tDCS produces pain relief, in chronic lower back pain and postoperative pain the results were conflicting, while cathodal nor anodal tDCS was ineffective[
7‐
9], recently a combination of tDCS and peripheral electrical stimulation has been shown to improve low back pain symptoms more effectively than either applied alone or a sham control[
10]. In chronic headaches, anodal tDCS was demonstrated to be an effective non-invasive treatment, but for classical trigeminal neuralgia (TN) and orofacial pain data is rare[
11].
TN is a rare facial pain disorder with a prevalence of 0.1 – 0.2/1000 that leads to paroxysms of short lasting but very severe pain[
12]. In most cases the third and second branch of the trigeminal nerve are affected[
13]. Pain can occur spontaneously but also triggered attacks due to e.g. eating, talking or brushing the teeth occur frequently[
13]. Between the attacks the patient is usually asymptomatic, but a constant dull background pain in the affected trigeminal facial area may persist[
13], which has been suggested to be a sign of central sensitization and chronification of pain[
14]. Carbamazepine is currently the drug of first choice in the treatment of TN. It is effective in 70-80% of patients but often associated with severe adverse effects such as drowsiness, confusion, nausea and ataxia, which may require discontinuation of medication[
15]. TN often begins with higher age, which lowers the tolerability of side effects and interactions due to medication[
16]. Surgical interventions, like the microvascular decompression, stereotactic radiotherapy or the percutaneous may not be suitable for all patients and waiting for the procedure can be agonizing. Therefore, different non-invasive treatment options are indispensable. This study aims to investigate the efficacy of anodal tDCS of the motor cortex in the treatment of TN with and without concomitant permanent pain using a randomized, cross-over design. Pain evoked potentials and the nociceptive blink reflex were used as objective measure of the tDCS effect on human trigeminal pain processing.
Discussion
Our results provide evidence that anodal tDCS of the primary motor cortex (M1 area) contralateral to the symptomatic side moderately ameliorates pain in patients with classical TN with purely paroxysmal pain by modulation of trigeminal nociceptive processing. Patients with concomitant permanent pain do not seem to benefit from tDCS[
18‐
21].
To our knowledge, the effects of anodal tDCS on facial pain were investigated in only one study, including 22 patients with different pain syndromes. Three patients suffered from TN and one patient from persistent idiopathic facial pain. However, the efficacy of pain relief in these patients was not analyzed separately, so that a clear effect on TN specifically cannot be derived from these data[
6]. Comparing our data with previous studies that used anodal tDCS for the treatment of pain we found a slightly attenuated analgesic effect with a reduction of VRS by 29% compared to a maximum of 50% that was previously described[
6,
22]. This increases to 38% when we remove those patients with concomitant permanent pain from the analysis that did not respond to tDCS, but remains in a rather moderate nevertheless realistic range.
TDCS has been used more and more frequently over the past decade as a non-invasive neuromodulation for targeted alteration of cortical excitability for the treatment of different diseases like depression, reorganization after stroke and pain[
23‐
25]. Effects of tDCS depend on several factors including polarity, stimulated area, intensity and duration. The improvement of pain by anodal tDCS was convincingly demonstrated in several studies[
6,
22,
11]. Although the exact mechanism behind the efficacy of tDCS on chronic pain is not known, probable mechanisms are the changes of the resting membrane potential under the active electrode and remote effects in other parts of the pain processing network by functional interconnections between motor-cortex driven inhibition of the somatosensory cortex and changes in thalamic activity. In addition, long-term effects are mediated by modulation of i.e. NMDA and nicotinic receptor activity inducing neuroplastic effects[
5]. Furthermore, anodal stimulation was shown to induce an increase of endogenous opioid release[
26] which was located in parts of the pain processing network after tDCS over the M1 area.
When pain becomes chronic tDCS modulation might be less prominent[
14]. This could explain why TN patients with concomitant permanent pain in our study did not respond. Moreover, it was demonstrated that the analgesic effect of tDCS critically depends on the electrode montage. An optimized cortical target supported by high-resolution computational models including CNS structures of the pain processing network markedly improved tDCS efficacy[
27] and utilization of smaller, more focal electrodes led to significant pain reduction in fibromyalgia[
28]. Differences in electrode montage might explain some of the contradictory results in different studies.
Central facilitation and hyperexcitability of the trigeminal system was recently demonstrated in TN patients using PREP and nBR[
19]. Other reports presented an increased fMRI activation and grey matter changes of cortical pain processing networks to further support an involvement of cortical structures[
29,
21]. It was shown that tDCS affects human trigeminal pain processing[
30]. Recordings of PREP and nBR before and after anodal tDCS resulted in decreased peak-to-peak amplitudes of PREP suggesting an inhibition of trigeminal pain processing which provides evidence that tDCS is a potential therapeutic option in disorders associated with central facilitation. Anodal tDCS modulates pain processing by inhibition of corticothalamic epicritic and nociceptive sensations at the thalamic nuclei[
31] and induces changes in brain synchronization in the stimulated area[
32]. Moreover, changes were observed in the anterior cingulate cortex which was suggested to be the generator of PREP in humans[
33]. These observations reconfirm tDCS to interfere with TN pathophysiology. The results in the anodal group of our study showed an inhibition of trigeminal pain processing after tDCS in PREP similar to what was observed previously in healthy patients[
30] even though these changes did not reach the level of significance due to the small sample size.
Supposing that the intensity of TN pain depends on combined peripheral and central mechanisms, the attack frequency may be more dependent on peripheral mechanisms e.g. nerve-vessel contact as trigger and, therefore, may not be equally well modulated by cortical stimulation. This might explain why the tDCS effect on attack frequency was insignificant.
The limitations of this study have to be considered. The relatively high drop out rate with more female than male patients shows that self-tDCS application at home may pose a huge problem for the mostly elderly TN target population, even though side effects were not reported and tolerability of participating patients was high. The stimulation with tDCS appears to be more difficult for the patients than previously suspected and probably requires a considerable education effort before it can be used sufficiently. Stimulation frequency (every day for 14 days) may not be optimal as a shorter duration may be just as effective or longer duration may be even more effective, but that will have to be tested in future studies. Due to the enormous interindividual variability in regard to tDCS treatment response it might be difficult to find the optimal stimulation parameters that suits all patients.
All patients received therapy with different anti-epileptic medications that may have influenced clinical and electrophysiological data. We tried to minimize this impact by requiring a stable dose for six months prior to study inclusion. Carry-over effects due to the cross over trial design must be considered despite the 30-day interval between treatment conditions. There is evidence that patients with a special polymorphism in the BDNF receptor gene showed a pronounced facilitation after anodal and inhibition after cathodal tDCS[
34]. This may also have affected our patients, but due to the low patient numbers we did not want to exclude anybody and, therefore, did not control for this. Long term effects of tDCS have to be considered. The duration of tDCS effects depend on several factors including the stimulation protocol, remote effects of other cortical areas and modulation of neuronal receptor activity beside NMDA-R effects. These factors are highly individual and underline the complexity of tDCS effects. It has been shown that brain plasticity depends also on the modulation of nicotinic receptors, BDNF polymorphisms and sex hormonal variations[
35,
36]. Therefore, the differences in efficacy of the acute and long-term effects of tDCS may depend on factors that are hard to control in studies with rare diseases and low patient numbers.
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Competing interests
Tim Hagenacker has received research support from Astellas and CSL Behring.
Vera Bude, Steffen Naegel have nothing to disclose.
Dagny Holle has received research support from Grünental and Allergan.
Mark Obermann has received scientific support and/or honoraria from Biogen Idec, Novartis, Sanofi-Aventis, Genzyme, Pfizer, Teva. He received research grants from Allergan, Electrocore, and the German Ministry for Education and Research (BMBF).
Hans-Christoph Diener has received honoraria for participation in clinical trials, contribution to advisory boards or lectures from Addex Pharma, Allergan, Almirall, AstraZeneca, Bayer Vital, Berlin Chemie, Coherex Medical, CoLucid, Böhringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Grünenthal, Janssen-Cilag, Lilly, La Roche, 3M Medica , Minster, MSD, Novartis, Johnson & Johnson, Pierre Fabre, Pfizer, Schaper and Brümmer, SanofiAventis, and Weber & Weber; received research support from Allergan, Almirall, AstraZeneca, Bayer, Galaxo-Smith-Kline, Janssen-Cilag, and Pfizer. Headache research at the Department of Neurology in Essen is supported by the German Research Council (DFG), the German Ministry of Education and Research (BMBF), and the European Union.
Authors’ contributions
MO and ZK conceptualized the experimental design. MO and TH organized the study. TH and VB acquired the data. TH, VB, SN and DH were responsible for the clinical supervision of the test persons. TH, DH, HD and MO analyzed the data. MO conducted the statistical analysis. TH wrote the first draft of the manuscript and interpreted the findings. All authors gave input to the manuscript. All authors read and approved the final manuscript.