ABSTRACT Pain-related depression of motor cortico-spinal excitability has been explored using transcranial magnetic stimulation (TMS)-based motor evoked potentials. Recently, TMS combined with concomitant high-density electroencephalography (TMS-EEG) enabled cortical excitability (CE) assessments in non-motor areas, offering novel insights into CE changes during pain states. Here, pain-related CE changes were explored in the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC). CE was recorded in 24 healthy participants before (Baseline), during painful heat (Acute Pain), and non-painful warm (Non-noxious warm) stimulation for eight minutes at the right forearm in a randomized sequence, followed by a pain-free stimulation measurement. Local CE was measured as peak-to-peak amplitude of the early latencies of the TMS-evoked potential (&lt;120 ms) on each target. Furthermore, global-mean field power (GMFP) was used to measure global excitability. Relative to the Baseline, Acute Pain induced a decrease of −9.9±8.8% in the peak-to-peak amplitude in M1 and −10.2±7.4% in DFPFC, while no significant differences were found for Non-noxious warm (+0.6±8.0% in M1 and +3.4±7.2% in DLPFC; both P&lt;0.05). A reduced GMFP of - 9.1±9.0% was only found in M1 during Acute Pain compared with Non-noxious warm (P=0.003). Participants with the largest reduction in local CE under Acute Pain showed a negative correlation between DLPFC and M1 local CE (r=-0.769; P=0.006). Acute experimental pain drove differential pain-related effects on local and global CE changes in motor and non-motor areas at a group level while also revealing different interindividual patterns of CE changes, which can be explored when designing personalized treatment plans. SUMMARY Cortical motor and prefrontal areas present reduced excitability during acute pain, but they occur in different patterns across individuals and present distinct impacts on global connectivity.

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