We have read with great interest the meta-analysis by Shen et al. The authors examined the effect of non-invasive brain stimulation as a potential treatment for neuropathic pain in patients with spinal cord injury (SCI). Neurophatic pain is a clinically relevant complication in this population and conventional treatments often do not achieve sufficient pain control. Therefore, approaches such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) are of great interest as alternative methods to control or mitigate persistent neuropathic pain.
However, reading the work of Shen and coworkers, we noted two major points, which in our opinion hamper quality and information content of the present meta-analysis:
Shen at al. included in their analysis 127 patients originating from six randomized trials (RCT) assessing the effectiveness of rTMS. Although the authors of these original trials clearly stated and declared patients with mixed aetiology of neuropathic pain, Shen et al. failed to only include the subset of patients suffering from SCI.
For example, Lefaucheur et al. assessed 12 patients with trigeminal nerve lesion, 12 patients with brain stem stroke, 12 patients with brachial plexus lesion, 12 patients with thalamic stroke, and only 12 patients with SCI.
In addition, Saitoh et al. assessed only 3 patients suffering from SCI (1 with spinal cord infarction, 1 with ruptured spinal arteriovenous malformation, 1 with cauda equina lesion), the other 10 patients suffered from neuropathic pain due to a cerebral or peripheral lesion.
Despite this, Shen and coworkers included all 98 patients in their analysis, of which more than half of the sample, did not suffer from SCI (namely 58 patients). In our opinion, inclusion of such a strongly heterogenic population is not only a methodological shortcoming but also completely neglects the fact, that the underlying neurologic pathology may significantly influence treatment effect: Transsynaptic descending modulation of rTMS within the motor cortex, corticospinal tract, and corticothalamic tracts are believed to play an important role in pain control. Hence, integrity of the thalamocortical tracts is required to treat neuropathic pain, and it was shown that stroke regions lead to highly variable outcomes of rTMS. Based on this observation, one could expect different efficacy of rTMS in Patients with SCI, having intact supraspinal tracts, compared to patients with neuropathic pain and disrupted descending tracts.
Therefore, we feel that the analysis of Shen et al. will not yield any meaningful conclusions in estimating the effect of rTMS in patients with neuropathic pain due to SCI. We recently criticized such practice in another meta-analysis of rTMS as treatment for neuropathic pain.
The second, in the search strategy section, Shen et al. reported that electronic databases were used to search for articles until November 2019. The search strategy using (“transcranial magnetic stimulation" OR “TMS" OR “transcranial direct current stimulation" OR “tDCS") AND (“spinal injury") AND (“pain") seemed to us overly simplistic and not at all exhaustive. Missing published original trials could significantly impair the statistical power of a meta-analysis, especially in scarcely researched field as the present.
We would have wanted for example the inclusion or at least the discussion of the studies by Nardone et al., Gharooni et al.,Sun et al., Zhao et al. , and Choi et al. all published by November 2019 or earlier:
Nardone and co-worker conducted a preliminary study in 12 patients with SCI which suggested that rTMS of the premotor cortex/dorsolateral prefrontal cortex might be effective in relieving neuropathic pain. It has been discussed that stimulation of the dorsolateral prefrontal cortex might be an under-investigated in neuropathic pain conditions, as it has to be taken into account that these locations might elicit other analgesic responses and might include top-down modulation of the medial spinal thalamic system with a preferential effect in the affective and evaluative aspects of pain.
Gharooni et al. conducted a single-blind, sham-controlled, crossover randomized study in 10 patients with incomplete SCI. They used a theta burst stimulation protocol over the primary motor cortex.
They did not find any intervention effects and no significant pain reduction. It has to mentioned that in this study pain was a secondary outcome.
In Sun et al.'s preliminary study with a full data set of 17 patients with SCI pain intensity gradually decreased in both the active rTMS and the sham group.
Finally, published on 13.11.2019, Zhao et al. conducted a RCT in 21 patients with neuropathic pain after SCI which indicated that 10 Hz rTMS over the hand area of the motor cortex could alleviate acute neuropathic pain in the early phase of SCI.
Choi et al. published a single-blind crossover study which evaluated neuropathic pain in patients with SCI after the application of a single transcutaneous spinal DCS. which did not have a significant analgesic effect in individuals with chronic cervical SCI.
In conclusion, we feel that meta-analysing published trials is an elegant and powerful way to push our knowledge further, even in areas, where statistically significant sample sizes are hard to collect. However, mechanistic understanding of the underlying pathology or mechanism of action is mandatory during the process of data collection and data selection in order to yield meaningful results. Moreover, great effort should be put in transparently communicating why studies are included or not, as the selection process can strongly bias outcome.
By accounting for the latter, we are confident that more high quality meta-analyses will be published on this highly interesting topic and ultimately lead to new treatment methods for patients suffering from neuropathic pain in SCI.
Anna Walter, MD, REHAB, Clinic for Neurorehabilitation and Paraplegiology, Basel, Switzerland
Email: [email protected]
Claudia Suenderhauf, Merian Iselin Clinic, Basel, Switzerland
 Shen Z, Li Z, Ke J, et al. Effect of non-invasive brain stimulation on neuropathic pain following spinal cord injury: A systematic review and meta-analysis. Medicine. 2020;99(34):e21507. doi:10.1097/MD.0000000000021507
 Lefaucheur JP, Drouot X, Menard-Lefaucheur I, et al. Neurogenic pain relief by repetitive transcranial magnetic cortical stimulation depends on the origin and the site of pain. Journal of Neurology, Neurosurgery and Psychiatry. 2004;75(4):612-616. doi:10.1136/jnnp.2003.022236
 Saitoh Y, Hirayama A, Kishima H, et al. Reduction of intractable deafferentation pain due to spinal cord or peripheral lesion by high-frequency repetitive transcranial magnetic stimulation of the primary motor cortex. Journal of Neurosurgery. 2007;107(3):555-559. doi:10.3171/JNS-07/09/0555
 Ohn SH, Chang WH, Park CH, et al. Neural correlates of the antinociceptive effects of repetitive transcranial magnetic stimulation on central pain after stroke. Neurorehabilitation and Neural Repair. 2012;26(4):344-352. doi:10.1177/1545968311423110
 O'Brien AT, Amorim R, Rushmore RJ, et al. Motor Cortex Neurostimulation Technologies for Chronic Post-stroke Pain: Implications of Tissue Damage on Stimulation Currents. Frontiers in Human Neuroscience. Published online 2016. doi:10.3389/fnhum.2016.00545
 Walter A, Denier N, Hund M, Suenderhauf C. Repetitive transcranial magnetic stimulation as treatment for neuropathic pain in patients with spinal cord injury. Journal of Neurosurgical Sciences. 2020;64(4):404-405. doi:10.23736/S0390-5616.19.04716-7
 Nardone R, Höller Y, Langthaler PB, et al. RTMS of the prefrontal cortex has analgesic effects on neuropathic pain in subjects with spinal cord injury. Spinal Cord. 2017;55(1):20-25. doi:10.1038/sc.2016.87
 Gharooni AA, Nair KPS, Hawkins D, Scivill I, Hind D, Hariharan R. Intermittent theta-burst stimulation for upper-limb dysfunction and spasticity in spinal cord injury: a single-blind randomized feasibility study. Spinal Cord. 2018;56(8):762-768. doi:10.1038/s41393-018-0152-5
 Sun X, Long H, Zhao C, et al. Analgesia-enhancing effects of repetitive transcranial magnetic stimulation on neuropathic pain after spinal cord injury:An fNIRS study. Restorative Neurology and Neuroscience. 2019;37(5):497-507. doi:10.3233/RNN-190934
 Zhao CG, Sun W, Ju F, et al. Analgesic Effects of Directed Repetitive Transcranial Magnetic Stimulation in Acute Neuropathic Pain after Spinal Cord Injury. Pain Medicine (United States). 2020;21(6):1216-1223. doi:10.1093/pm/pnz290
 Choi YA, Kim Y, Shin HI. Pilot study of feasibility and effect of anodal transcutaneous spinal direct current stimulation on chronic neuropathic pain after spinal cord injury. Spinal Cord. 2019;57(6):461-470. doi:10.1038/s41393-019-0244-x