The surgical treatment of neuropathic pain with ESCC has been evolving over last decades, starting from the first implantation, reported by Tsubokawa and colleagues 8. Most of the centres currently using image guidance with MRI to localize the region of the pain, i.e. in case of facial pain – anterior to the central sulcus at the level of the inferior frontal sulcus 8. This information then loaded into a neuronavigation workstation to direct the most appropriate location for the incision and craniotomy. Typically, the specific region of motor cortex is identified through intraoperative somato-sensory evoked potentials (SSEP) and confirmed by trial intraoperative stimulation 8,10. In addition, TMS can be useful for non-invasive trial stimulation and might potentially be considered as an assessment tool for cortical stimulation efficiency 24. The surgical technique, however, varies significantly between institutions, with most centers placing electrodes in the epidural space. Epidural placement has several advantages including lower operative risk and shorter operative time, however, epidural electrode placement often leads to a scarring around the electrodes, resulting in higher electrode impedance and consequent declines in stimulation efficacy over time 25,26. Epidural stimulation can also lead to less localized stimulation and may require a higher stimulus intensity, which usually results in shorter battery life. Epidural stimulation may also induce pain by direct activation of the dural pain fibers, limiting therapeutic effect of stimulation 4,14,27. In a computer simulation study, Kim et al. compared the efficacy of both epidural and subdural placement and reported that the effective volume and depth of pulse penetration is significantly higher with subdural stimulation compared to epidural 28,29. Placing stimulating electrodes in the subdural space routinely over last ten years we have shown consistent results with minimal surgical complication 14,30.
Regardless of the long history of ESCC, the mechanisms responsible for alleviating of chronic pain are largely unknown. In animal studies it has been demonstrated that after deafferentation of reticular thalamic nucleus and ventral posterior lateral thalamus, normal thalamocortical circuitry activity shifts from high-threshold tonic firing to low-threshold theta-range oscillatory bursts 31. This transformation further leads to a decrease in the excitatory input to the reticular thalamus and their subsequent hyperpolarization and low-frequency bursting that induces rhythmic discoordination of the thalamocortical loops in theta frequency band 32. Based on these observations it was proposed that cortical stimulation may inhibit the hyperactivity of the thalamus and particularly the sensory nuclei of the thalamus that exhibit chronic pain-induced hyperactivity with increased spike density 8. In fact, outcomes of multiple trials suggest that the mechanisms of neuropathic pain that respond to the cortical stimulation may have a final common pathway of deafferentation at the different levels of the sensory system. Later, it was shown that cortical stimulation may initially activate the axons that run horizontally in the precentral gyrus, parallel to the surface of the cortex. These cortico-cortical projections directed from primary motor to primary sensory cortex, and travel in Layer I, making them easily accessible for stimulation 14. These results altogether support the commonly accepted hypothesis that during neuropathic pain, most of the cortical inputs tend to balance pathological thalamocortical oscillations and may also facilitate following reorganization in these areas, while cortical stimulation targeting the same mechanisms could further compensate pathological oscillations and related neuropathic pain. The brain areas with relatively higher degree of functional connectivity and plasticity, like premotor and motor cortical areas, could be particularly effective in compensation of central deafferentation. Multiple studies suggest that cortical stimulation can lead to reinforcement of intracortical GABAergic inhibition, increased secretion of endogenous opioids in various structures and more specifically, the cingulate cortex and periaqueductal gray matter (PAG) 33,34. It was also found that the density of opioid receptors binding in the brain is correlated with postoperative pain relief with cortical stimulation in patients with chronic pain 34. Another mechanism of ESCC could be related with activation of cortical and mesencephalic areas involved in the emotional appraisal of pain, particularly insula, cingulate, and orbitofrontal cortex 35,36.
Only few studies have explored the effect of cortical stimulation on various pain syndromes (Supplementary table 1) with total of over few hundreds participants evaluated. Most of reports with MCS are focusing on trigeminal neuralgia and post stroke pain treatment. Trigeminal neuralgia generally showed a good response to cortical stimulation with more than a half of the patients receiving significant pain relief 10,31,37. Several recent reviews indicate that 75-85% of patients have at least 50% reduction of trigeminal pain with motor cortex stimulation 9,29. Results however, vary between the centers 4,38. In contrast with trigeminal neuralgia, there is a lack of clinical trials on cortical stimulation for phantom limb pain with only few case-reports and mixed trials with small number of patients. Recently we reported an improvement of phantom limb syndrome with cortical stimulation in two subjects along with other studies demonstrating effect of cortical stimulation on phantom limb pain 30,39,40. Currently, the implantable neuromodulation systems for MCS in patients with chronic pain are considered “off label” which significantly limits further exploration of this technique 41. MCS can lead to several complications, typical for most craniotomies, such as infection and hemorrhage (Supplementary table 1). In several trials cortical stimulation has been associated with focal seizures during stimulation, although, it disappeared when stimulation was stopped. The seizure threshold does appear to respond to standard anticonvulsants (e.g. levetiracetam or fosphenytoin) that were used in this study 35,39,42,43. Henderson et al. reported that seizures were associated primarily with stimulus rates between 70 and 90Hz and patients who experience seizures did not develop chronic epilepsy.47 In this retrospective study we report several surgical complications, which did not affect the outcome, except one subject with hematoma, which led to the brain shift and electrode misplacement.
Summarizing these results, we can outline two key outcomes of this study. The first outcome indicates on specific role of electrode location in the efficacy of cortical stimulation to control chronic neuropathic pain, and particularly the effect of pre-motor cortex stimulation. Most of the previous studies were focused on neuromodulation of the motor cortex, after initially negative experience with S1 stimulation 8,10,28. The effect of premotor cortex stimulation was not studied and remained largely unknown. In contrast to a somatotopic organization (motor homunculus), premotor cortex is likely organized in a functional manner, where overlapped regions represent different motor patterns 44–46. This organization has been supported by several studies in animals, and indicates that the areas of cerebral cortex controlling specific part of the body in pre-motor cortex may have more diffuse and overlapped representations compared to M1, i.e. related to complex sensorimotor functions with involvement of multiple body parts and may have higher cortical plasticity 47,48. This specific organization was primarily suggested by animal studies and still needs to be confirmed in humans. Recent works suggest that premotor cortex along with primary motor cortex, primary sensory cortex, and prefrontal cortex are organized in a neuronal network responsible for complex control of movements and sensorimotor integration (Fig 6) 47–50. Specific mechanisms of this organization and functioning of this network still need to be investigated and may further facilitate development of new strategies for treatment of neuropathic pain.
The first outcome of this study indicates on importance of trial stimulation for target optimization. According to these results, initial reduction in pain, observed during trial stimulation, was consistent during chronic stimulation for most of the tested subjects. Those who did not respond to trial stimulation, in fact, did not improve, even after multiple adjustments. These findings suggest that trial stimulation provides important information for positioning of permanent electrodes and helps to assess individual response to initial stimulation settings. Trial stimulation started after the ’honeymoon period‘, when the pain is returning to the baseline, can help to avoid misinterpretation of results of trial stimulation. The main disadvantage of trial stimulation with temporary grids is surgical side effects, i.e. increased risk of hematoma and loss of CSF. In combination, this leads to the shifting from initially planned position and may result in displacement of the permanent grid that we observed in one subject. To our knowledge this is the first study with cortical stimulation for neuropathic pain that describes the effect of trial stimulation. Retrospective analysis of DBS implantations has been performed previously for evaluation of the electrode shift and did not find significant displacement with postoperative intracranial air volume up to 35 cm3, although, DBS electrodes are less affected by the brain shift due to their deeper locations 51.
In conclusion, the results of this study suggest that modulation of neural networks with subdural ESCC is beneficial and provides control of neuropathic pain when located on motor and particularly on pre-motor areas. The most important and novel finding of this study is that pre-motor cortex stimulation is at least as beneficial as motor cortex stimulation and can be considered for future therapy with ESCC. In cases of complex pain syndromes, i.e. thalamic pain, regional pain syndrome, or spinal cord injury-associated pain, pre-motor cortex stimulation could provide additional benefits through the coverage the wider functional area. Another important finding of this study is that trial stimulation for target optimization can significantly improve the outcome of ESCC. Future differentiation of specific mechanisms related to effect of ESCC could improve pain control in cases when access to the motor cortex is limited or the effect of stimulation is insufficient.