Background & Aims

High frequency repetitive transcranial magnetic stimulation (rTMS) to the posterosuperior insula (PSI) has been shown to have antinociceptive effects in animals and humans, and to significantly reduce pain in individuals with peripheral neuropathic pain. Despite these encouraging results, the brain mechanisms underpinning rTMS-induced analgesia in humans remain poorly understood. Recent work (Chowdhury et al, 2023; De Martino et al., 2023) has shown promise for the use of combined TMS-electroencephalography (EEG) to understand the brain processes underlying pain induced cortical neuroplasticity. The present study aimed to determine whether tonic experimental capsaicin-induced pain in humans and cortical inhibition (indexed using TMS-EEG) are modulated by PSI-rTMS.

Methods

Twenty healthy volunteers (10 females, 10 males) participated in a cross-over, sham-controlled trial and attended two sessions of either active or sham rTMS in a randomized sequence. Experimental pain was induced by application of a 4x4cm patch of 8% capsaicin to the volar forearm for 90 minutes, with numerical rating scale (NRS) pain ratings obtained every 5 minutes. Left PSI-rTMS (de Cunha et al., 2022) was delivered (10 Hz, 100 pulses per train, 15 trains) ~50 minutes after capsaicin administration. TMS-evoked potentials (TEPs) using combined TMS-EEG to the primary motor cortex and quantitative sensory testing (QST) were assessed at baseline (pre-pain), during capsaicin pain prior to rTMS (~30 minutes after capsaicin administration), and after rTMS (~60 minutes after capsaicin administration).

Results

Compared to the sham, active PSI-rTMS significantly reduced pain NRS to capsaicin (p<0.05) starting 10-15 minutes after rTMS completion, and an increase in the heat pain thresholds (p<0.001). Active PSI-rTMS also led to decrease in cortical inhibition, as indexed by the frontal negative peak ~45 ms (N45) on TMS-evoked responses (p<0.01).

Conclusions

PSI-rTMS reduces tonic experimental pain intensity and increases heat pain thresholds. These effects are accompanied by a decrease in cortical inhibition as indexed by the TEP N45 response. This study expands the knowledge on the effects of PSI stimulaiton in humans showing that not only pain thresholds but also experimental tonic pain is impacted by stimulating this target, and points to the N45 as a potential marker of the cortical plastic changes induced by this therapy.

References

Chowdhury, N. S., Chiang, A. K., Millard, S. K., Skippen, P., Chang, W. J., Seminowicz, D. A., & Schabrun, S. M. (2023). Combined transcranial magnetic stimulation and electroencephalography reveals alterations in cortical excitability during pain. Elife, 12, RP88567.

da Cunha, P. H. M., Tanaka, H., da Silva Lapa, J. D., Dongyang, L., Sorte, A. A. B., Pereira, T. M. R., … & de Andrade, D. C. (2022). The fast-posterior superior insula (Fast-PSI): A neuronavigation-free targeting method for non-invasive neuromodulation. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, 15(5), 1178-1180.

De Martino, E., Casali, A., Casarotto, S., Hassan, G., Rosanova, M., Graven-Nielsen, T., & Ciampi de Andrade, D. (2023). Acute pain drives different effects on local and global cortical excitability in motor and prefrontal areas: insights into interregional and interpersonal differences in pain processing. Cerebral Cortex, 33(18), 9986-9996.

Presenting Author

Nahian Chowdhury

Poster Authors

Nahian Chowdhury, PhD

PhD

University of Sydney

Lead Author

Samantha Millard (PhD)

Aalborg University

Lead Author

Enrico De Martino

Aalborg University

Lead Author

Dennis Boye Larsen (PhD)

Aalborg University

Lead Author

David Seminowicz (PhD)

University of Western Ontario

Lead Author

Siobhan Schabrun

University of Western Ontario

Lead Author

Daniel de Andrade

University of Aalborg

Lead Author

Thomas Graven-Nielsen

Thomas Graven-Nielsen

Lead Author

Topics

  • Mechanisms: Biological-Systems (Physiology/Anatomy)