Effectiveness of tonic and burst motor cortex stimulation in chronic neuropathic pain

Introduction

Motor cortex stimulation (MCS) and deep brain stimulation (DBS) are established intracranial methods for treatment of chronic, neuropathic pain. Main indications for MCS are central post stroke pain, neuropathic facial pain, phantom limb pain, brachial plexus injury pain or spinal cord injury pain.^1–7 In our previous study good response on tonic MCS in chronic neuropathic pain has been observed in over 50% with postoperative follow-up of 1 year.⁸ These findings were consistent with the results of other reports.^9–11 Cortical stimulation has also been used in such conditions as Parkinson’s disease and tinnitus.^12,13 Mechanisms underlying the analgesic effect of MCS has not yet been elucidated, but may be due to stimulation of cortico-subcortical fibers, which inhibits hyperactive sensory units in the thalamus. MCS hypothetically modulates thalamic nuclei, cortical somatosensory areas, striatum, cerebellum and inhibits spinothalamic tracts.^2,14–16 MCS can also control intracortical horizontal fibers instead of direct stimulation of the pyramidal tract.¹⁷ Tonic stimulation with low frequency in MCS has been applied for years.^{1,4,8–10,18} A new generation of stimulators with the burst waveform are available in spinal cord stimulation (SCS).^19–21 Necessity of replacement of depleted batteries, which used to provide tonic mode only, gave us an opportunity to use these new generation of cortical stimulators applying other modes including burst stimulation. The burst firing is able to overdrive ongoing tonic firing.²² Burst auditory cortex stimulation has been applied in tinnitus patients with better effect on noise-like tinnitus than with tonic stimulation.²³ In the literature there is one case report on the effects of burst MCS in chronic pain.²⁴ SCS with burst waveform has been more effective than tonic in neuropathic pain.²⁵ The main feature of commonly used tonic stimulation was low frequency not exceeding 100 Hz.^26,27 Frequency and pulse can influence the number of recruited neurons. The burst stimulation in contrast to tonic SCS correlates with the amount of neurons and different neurotransmitter mechanisms of action.²⁵ The pattern of SCS burst stimulation is such that 500 Hz stimulation is delivered in groups of five pulses with 1-ms pulse width and it is repeated 40 times per second in stimulators of spinal cord.²⁵ The objective of the pilot study was to evaluate the effects of burst stimulation applied on motor cortex in patients with central neurogenic pain as well as comparison to tonic stimulation.

Figure 4 Results of tonic and burst cortical stimulation in VAS score in mm. Notes: Statistical analysis was performed with software package Statistica Version 10.0. Data were expressed as means ±SD. Comparisons between groups were performed with analysis of nonparametric repeated measures test ANOVA chi square. (N=6, df=2)=1156522 P=0,.00308. A value of P<0.05 was considered statistically significant. Coefficient of concordance =09638, average rank r=095653.

Materials and methods

We evaluated 6 patients (females N=3, males N=3) belonging to the group of 14 cases (females N=5, males N=9) who had undergone surgical procedure of MCS in our institution in years 2005–2017 Table 1.

Table 1 Characteristics of patients.

Approval was obtained from the Ethics Committee at the Military Medical Chamber in Warsaw, Poland (138/16) in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient. Replacement of a new, implantable pulse generator (IPG) was performed under local anaesthesia with sedation, unlike surgeries of implantation of cranial electrodes and primary IPGs. They had been conducted under general anaesthesia without myorelaxation with the use of MRI based neuronavigation. Craniotomy over the dura covering the motor strip had been performed, motor evoked potentials had been used to confirm proper localization and then four paddle type 4-contact electrodes were placed perpendicular to precentral gyrus Figures 1 and 2 or one 16-contact electrode along this gyrus Figure 3.⁸

Figure 1 Four-paddle type electrodes placed on motor cortex in a patient 1 with thalamic pain predominantly in left upper extremity. 62 years old male with thalamic pain and MCS for 4 years had VAS=90 mm on tonic and VAS=70 mm on burst mode. Abbreviations: MCS, motor cortex stimulation; VAS, visual analogue scale.

Figure 2 Electrodes placed on motor cortex in a patient 3. 60 years old female with atypical facial pain and with tonic MCS for 10 years had VAS=70mm on five tonic programs and VAS=40mm on burst mode. Abbreviations: MCS, motor cortex stimulation; VAS, visual analogue scale.

Figure 3 Electrode 2×8 contact placed on dura along motor strip in patient 2, 48 year old female with anaesthesia dolorosa on face with MCS for 2 years; VAS=70mm on tonic and 50 on burst mode. Abbreviations: MCS, motor cortex stimulation; VAS, visual analogue scale.

Half of the selected subjects for the study were patients with thalamic pain N=3, and other half with atypical facial pain N=3 (anaesthesia dolorosa and neuropathic trigeminal neuralgia). Unfortunately all of them had to wait on replacement of IPG for at least 3 months on a waiting list and meanwhile they were complaining about pain exacerbation. These patients received stimulators capable of inducing both tonic or burst stimulation and were given an opportunity to choose the most efficient program of neuromodulation using their own patients’ programmer. Patients could change program after 5–7 days of stimulation between tonic and burst. Outcome was based after at least 4 weeks during a control visit basing on personal choice of patients who were selecting the most frequently applied program causing the most efficient pain relief. Pain intensity was assessed with the visual analogue scale (VAS) after the stimulation with both tonic and burst mode. VAS is a continuous line scale, which begins with 0, no pain and ends with 100 mm describing as pain “as bad as it could be”.²⁸ Baseline VAS score was defined as score attained before surgical replacement of IPG when there was no effective stimulation due to depleted battery of tonic stimulator.

Results

In the study 5 out of 6 patients found burst mode of motor cortex stimulation more effective than tonic. Baseline VAS score without stimulation due to depletion of battery in patients who had been treated previously with tonic MCS  was 95 mm. Mean VAS score after tonic stimulation was 72 mm and improvement after burst stimulation was 53 mm on average Figure 4. Intensity of pain after subsequent periods of tonic and burst stimulation is presented in Table 2.

Table 2 Level of pain assessed with VAS in mm before application of MCS, on tonic MCS and on burst MCS, with parameters of burst MCS.

Discussion

MCS is supposed to be last resort of treatment for chronic, neuropathic pain of central and peripheral origin; pain that is refractory to pharmacological treatment and that cannot be treated with other stimulation techniques such as SCS and peripheral nerve stimulation. Frequently after long-term MCS the analgesic effects of neuromodulation are diminished due to habituation on stimulation.⁸ In our series we examined patients with central neurogenic, ie thalamic syndrome after stroke or traumatic brain injury, and neuropathic facial pain. Out of 14 patients who received MCS, 6 were subjected to burst stimulation of the cerebral cortex. Patients with refractory pain lasting for a long period approximately 16 years (mean value) treated with tonic MCS for approximately 6 years (mean value) posed a challenge for achieving a satisfactory pain reduction. Primary waveform of MCS was tonic stimulation with frequency of 10–50 Hz with amplitudes from 1–10 mA. Although tonic MCS in the majority of patients with all types of central pain after long-term of stimulation had provided moderate effects, patients demanded reimplantation of IPG, when the battery had been depleted. After the implantation of the new IPG, patients were able to choose between tonic and burst stimulations. The most preferred option was burst stimulation. Due to exacerbation of pain in the period before replacement, patients were receiving analgesics such as tramadol. After surgery they were asked to reduce doses or withdraw it. The majority of them were taking 1 or 2 tramadol daily but no one noticed significant improvement after it. Gabapentin was the medicine administered permanently in unchanged doses to patient 2 before and during both tonic and burst stimulation.

The efficacy of MCS is dependent on proper selection of patients, accurate localization of electrodes and optimal adjusting of parameters.^1,3,4,7 Suitable location of electrodes nearby central sulcus provide more expressed analgesia than over precentral gyrus.²⁹ In tonic MCS—efficacy of pain treatment can be attained by titration of amplitude of current intensity, diversification of contacts or cyclization.³⁰ Cycling stimulation was initially recommended by Nguyien, recent Vancouver group presented programming algorithm in which cyclization 15 minutes on and 15 minutes off was the most preferred setting.^4,31,32 According to Fontaine et al chronic stimulation with parameters 40 Hz, PW 210 can, not only reduce the pain, but also improve sensory discrimination.³³ Thermal sensory restoration induced by MCS have been noticed also after repetitive transcranial magnetic stimulation (rTMS). Thus sensory changes are the result of reorganization of the sensory cortex. Both MCS and rTMS can have influence on neural plasticity of somatosensory cortex.³⁴ rTMS have a positive predicitive value on the effects of MCS.³⁵ Transcranial magnetic stimulation with paradigm of theta burst stimulation can modulate cognitive and neurologic function in chronic neurologic, psychiatric disorders and pain syndromes.^36,37 TMS with burst mode has been successfully applied in tinnitus.²³ Initially burst stimulation has been applied on auditory cortex to suppress tinnitus more effectively than tonic stimulation.^22,38 De Ridder was the first who reported improvement in trigeminal anesthesia dolorosa after somatosensory cortex stimulation with burst mode, but also to the anterior cingulate cortex and dorsolateral, prefrontal cortex.²⁴ Finally, burst stimulation has been developed for spinal cord stimulation.³⁹ Burst spinal cord stimulation is hypothesized to react, not only on lateral spinoreticular and spinothalamic ascending pathways and descending inhibitory pathway, but also on medial ascending pathway, which is responsible for affective component of pain. Burst stimulation with 500 Hz spike mode 40 times per second has been designed in a way that mimics burst firing in the thalamus engaged in generation of tinnitus and pain.^40,41 This phenomenon can explain better improvement after burst stimulation in MCS in our series (mean VAS=72 after tonic and mean VAS=48 after burst). While the burst stimulation and high frequency stimulation in SCS are supposed to be paraesthesia-free methods, MCS both with tonic and burst generally do not induce paraesthesias. This phenomenon may confuse patients in assessment of effects of MCS. The confusion might be associated with the lack of perception of active brain stimulation, which is in general devoid of paraesthesia in both waveforms. In patients’ opinion one of the greatest advantages of burst mode was the lack of paraesthesia and reduction of pain.

Contemporary neurostimulation systems allow patients to participate actively in the therapeutic process. Based on reports of patients engaged in the study they acknowledged the possibility to change programs by themselves. This kind of a patient—controlled, neuromodulatory analgesia helps them become more independent. The limitation of the study is a small sample of participants, lack of randomization and lack of double-blind control, which can affect the reliability of this report. Nevertheless, this study has shown that some patients may benefit from the burst stimulation, which mimics the function of the central nervous system.

Conclusions

Reduction of pain after burst MCS has been clinically meaningful in comparison to tonic stimulation in chronic, neuropathic pain. According to results of this study—burst cortex stimulation is a promising modality in refractory pain in patients habituated to tonic stimulation. New generation stimulators enable improved efficiency of MCS. Further studies with larger cohorts are needed to confirm these preliminary results.