Intensity-dependent modulation of cortical somatosensory processing during external, low-frequency peripheral nerve stimulation in humans

External low-frequency peripheral nerve stimulation (LFS) has been proposed as a novel method for neuropathic pain relief. Previous studies have reported that LFS elicits long-term depression-like effects on human pain perception when delivered at noxious intensities, whereas lower intensities are ineffective. To shed light on cortical regions mediating the effects of LFS, we investigated changes in somatosensory-evoked potentials (SEPs) during four LFS intensities. LFS was applied to the radial nerve (600 pulses, 1 Hz) of 24 healthy participants at perception (1 times), low (5 times), medium (10 times), and high intensities (15 times detection threshold). SEPs were recorded during LFS, and averaged SEPs in 10 consecutive 1-min epochs of LFS were analyzed using source dipole modeling. Changes in resting electroencephalography (EEG) were investigated after each LFS block. Source activity in the midcingulate cortex (MCC) decreased linearly during LFS, with greater attenuation at stronger LFS intensities, and in the ipsilateral operculo-insular cortex during the two lowest LFS stimulus intensities. Increased LFS intensities resulted in greater augmentation of contralateral primary sensorimotor cortex (SI/MI) activity. Stronger LFS intensities were followed by increased α (alpha, 9–11 Hz) band power in SI/MI and decreased θ (theta, 3–5 Hz) band power in MCC. Intensity-dependent attenuation of MCC activity with LFS is consistent with a state of long-term depression. Sustained increases in contralateral SI/MI activity suggests that effects of LFS on somatosensory processing may also be dependent on satiation of SI/MI. Further research could clarify if the activation of SI/MI during LFS competes with nociceptive processing in neuropathic pain. NEW & NOTEWORTHY Somatosensory-evoked potentials during low-frequency stimulation of peripheral nerves were examined at graded stimulus intensities. Low-frequency stimulation was associated with decreased responsiveness in the midcingulate cortex and increased responsiveness in primary sensorimotor cortex. Greater intensities were associated with increased midcingulate cortex θ band power and decreased sensorimotor cortex α band power. Results further previous evidence of an inhibition of somatosensory processing during and after low-frequency stimulation and point toward a potential augmentation of activity in somatosensory processing regions.