The effect of prolonged elbow pain and rTMS on TMS-evoked potentials: A TMS-EEG study

Recent studies using combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) have shown that pain leads to an increase in the N45 peak of the TMS-evoked potential (TEP), potentially linked to changes in GABAergic activity. Conversely, 10 Hz repetitive TMS (10 Hz-rTMS), which provides pain relief, reduces the N45 peak. However, these studies used brief pain stimuli (lasting minutes), limiting their clinical relevance. The present study determined the effect of pain and 10 Hz-rTMS on the N45 peak in a prolonged pain model (lasting several days) induced by nerve growth factor (NGF) injection to the elbow muscle. In Experiment 1, TEPs were measured in 22 healthy participants on Day 0 (pre-NGF), Day 2 (peak pain), and Day 7 (pain recovery). In Experiment 2, we examined the effect of 5 days of active (n = 16) or sham (n = 16) rTMS to the left primary motor cortex (M1) on the N45 peak during prolonged NGF-induced pain, with TEPs measured on Day 0 and Day 4 (post-rTMS). Peak pain and muscle soreness was mild to moderate across experiments. In Experiment 1, there was no evidence for an increase in the N45 peak during prolonged pain. Exploratory analyses revealed evidence for a reduction in the N45 peak from Day 2 to 7, and a correlation between higher pain severity on Day 2 and a larger increase in the N45 peak. In Experiment 2, active rTMS reduced the N45 peak on Day 4 versus Day 0, with no effect in the sham group. Overall, our study showed that during prolonged pain, 5 days of 10 Hz rTMS induces a reduction in the TEP N45 peak. However, contrary to previous studies, prolonged pain itself did not increase the N45 peak. Taken together, this study provides weaker evidence for a link between the N45 peak and pain perception compared to previous research. Nonetheless, exploratory findings-such as a reduction in the N45 peak during the pain recovery phase and an individual-level relationship between increases in N45 and pain severity-suggest that further studies with larger sample sizes and more robust pain models are needed to clarify this connection.