Editors' note: Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain

Abstract

In the article “Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain,” Dr. Galhardoni et al. compared the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep rTMS in 98 patients with central neuropathic pain (CNP) after stroke or spinal cord injury in a randomized, double-blinded, sham-controlled, 3-arm parallel study. They found that ACC- and PSI-rTMS were not different from sham-rTMS for pain relief despite a significant increase in heat thresholds after insular stimulation and anxiolytic effects after ACC-rTMS and concluded that different dimensions of pain can be modulated noninvasively by directly stimulating deeper structures without necessarily improving clinical pain. In response, Dr. Zugaib et al. point to their recent work suggesting that PSI-/ACC-rTMS involves more intense stimulation of superficial structures. They argue that the use of linear projection to estimate the stimulation targets—as was the case in the trial—does not correspond to the region of maximum-induced electrical field, which is more superficial, and therefore caution against interpreting the clinical findings as resulting from the stimulation of deep structures as opposed to a combination of stronger superficial and deeper stimulation. They suggest using electric field modeling to guide the coil positioning and adjustment of stimulation intensity. Responding to these comments, Dr. de Andrade et al. defend the precision of their approach, noting that in addition to linear projection-guided PSI stimulation providing antinociceptive effects in patients with CNP and healthy volunteers, direct cortical stimulation of the PSI during stereo-EEG in a previous study showed the same heat-pain changes as described by linear projection-target deep TMS. They also note that stimulation intensity was calculated using the tibialis anterior muscle as a parameter, represented medially in the primary motor cortex, suggesting that a measurable current was likely delivered to the PSI. They argue that computing electric fields would not solve the issue of stimulation intensity, and instead propose that future field models should account for the data from linear projection, validated against sham and active controls, in their algorithms. This exchange highlights the important points of debate in the field of rTMS regarding the most reliable means of targeting deeper structures in the brain, and conversely, identifying the responsible structural mediators of observed stimulation effects. In the article “Insular and anterior cingulate cortex deep stimulation for central neuropathic pain: Disassembling the percept of pain,” Dr. Galhardoni et al. compared the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep rTMS in 98 patients with central neuropathic pain (CNP) after stroke or spinal cord injury in a randomized, double-blinded, sham-controlled, 3-arm parallel study. They found that ACC- and PSI-rTMS were not different from sham-rTMS for pain relief despite a significant increase in heat thresholds after insular stimulation and anxiolytic effects after ACC-rTMS and concluded that different dimensions of pain can be modulated noninvasively by directly stimulating deeper structures without necessarily improving clinical pain. In response, Dr. Zugaib et al. point to their recent work suggesting that PSI-/ACC-rTMS involves more intense stimulation of superficial structures. They argue that the use of linear projection to estimate the stimulation targets—as was the case in the trial—does not correspond to the region of maximum-induced electrical field, which is more superficial, and therefore caution against interpreting the clinical findings as resulting from the stimulation of deep structures as opposed to a combination of stronger superficial and deeper stimulation. They suggest using electric field modeling to guide the coil positioning and adjustment of stimulation intensity. Responding to these comments, Dr. de Andrade et al. defend the precision of their approach, noting that in addition to linear projection-guided PSI stimulation providing antinociceptive effects in patients with CNP and healthy volunteers, direct cortical stimulation of the PSI during stereo-EEG in a previous study showed the same heat-pain changes as described by linear projection-target deep TMS. They also note that stimulation intensity was calculated using the tibialis anterior muscle as a parameter, represented medially in the primary motor cortex, suggesting that a measurable current was likely delivered to the PSI. They argue that computing electric fields would not solve the issue of stimulation intensity, and instead propose that future field models should account for the data from linear projection, validated against sham and active controls, in their algorithms. This exchange highlights the important points of debate in the field of rTMS regarding the most reliable means of targeting deeper structures in the brain, and conversely, identifying the responsible structural mediators of observed stimulation effects.