Temporal Structure of Brain Oscillations Is A Biomarker of Pain and Predicts Learned Nocebo Responses.

Abstract This study aimed to identify electrophysiological biomarkers of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) was induced in 36 healthy participants through classical conditioning and negative suggestions. In a baseline phase, participants received high thermal pain stimulations. During acquisition, participants learned to associate an inert gel applied to their forearm with high pain, relative to a moderate intensity control stimulus administered without gel. During evocation, nocebo and control stimuli were both accompanied by moderate pain to measure nocebo responses. Electroencephalography was recorded during rest (pre and post nocebo acquisition) and during pain stimulation (baseline, nocebo acquisition and evocation). Nocebo hyperalgesia led to pre- to post-acquisition increases in long-range temporal correlations (LRTC), with beta-band alterations being negatively associated with nocebo magnitudes. Moreover, individuals with strong LRTC at rest showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. By involving LRTC, these findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing. This study provides novel insights into neural underpinnings of nocebo hyperalgesia, a phenomenon that greatly impacts the experience of pain.