Intracortical modulation, and not spinal inhibition, mediates placebo analgesia

Suppression of spinal responses to noxious stimulation has been detected using spinal fMRI
(sfMRI) during placebo analgesia, which is increasingly considered a phenomenon caused by
descending inhibition. However, the sfMRI is technically challenging and prone to falsepositive
results. We employed EEG and recorded laser‐evoked potentials (LEPs), which allows
neural activity to be measured directly and with high enough temporal resolution to capture
the ensemble of cortical areas that are activated by nociceptive stimuli. The hypothesis is that
inhibition at the spinal level during placebo analgesia should be evidenced by a general
suppression of LEPs, rather than by a selective reduction of late LEP components. LEPs and
subjective ratings of pain were obtained in two groups of healthy volunteers: one was
conditioned for placebo analgesia, while the other served as unconditioned control. Three
different supra‐threshold laser stimulus energies (3, 3.5 and 4 Joules) were delivered to the
right hand dorsum. Placebo analgesia was associated with a selective reduction of late
components of LEPs (P2 wave). In contrast, early component (N1 wave) reflecting the arrival
of the nociceptive input to the primary somatosensory cortex (SI) were affected by the
magnitude of laser stimulus energies only. The selective suppression of late LEPs during
placebo analgesia suggests an underlying mechanism of direct intra‐cortical modulation,
rather than inhibition at the spinal level of afferent nociceptive input. Furthermore, cortical
modulation occurs after the responses elicited by the nociceptive stimulus in the SI, suggesting
that higher order sensory processes are modulated during placebo analgesia.