Temporal structure of brain oscillations predicts learned nocebo responses to pain

Abstract

This study aimed to identify electrophysiological correlates of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) has been found to impact how healthy and patient populations experience pain and is a phenomenon that could be better understood in terms of its neurophysiological underpinnings. In this study, nocebo hyperalgesia was induced in 36 healthy participants through classical conditioning and negative suggestions. Electroencephalography was recorded during rest (pre- and post-acquisition) and during pain stimulation (baseline, acquisition, evocation) First, participants received baseline high thermal pain stimulations. During nocebo acquisition, participants learned to associate an inert gel applied to their forearm with administered high pain stimuli, relative to moderate intensity control stimuli administered without gel. During evocation, all stimuli were accompanied by moderate pain, to measure nocebo responses to the inert gel. Pre- to post-acquisition beta-band alterations in long-range temporal correlations (LRTC) were negatively associated with nocebo magnitudes. Individuals with strong resting LRTC 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. These findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing.

A randomized pharmacological fMRI trial investigating d-cycloserine and brain plasticity mechanisms in learned pain responses

“…Neural circuits involving the vlPFC are thought to communicate through oscillations in gamma-band (60–160 Hz) frequency channels 83 . This relates to previous studies implicating gamma-band oscillations as a marker of learning in nocebo acquisition 16 , 84 , 85 . The vlPFC, as the present study also suggests, may be implicated in sensory stimuli whose properties are processed bottom-up 83 .…”

“…Negative suggestions are commonly used to enhance conditioning 9,10,14 . Concurrently, conditioned nocebo effects have been shown to effectively reduce using extinction paradigms in which learned associations are discontinued [14][15][16] . Such paradigms can be adapted for use in MRI settings, using thermal pain stimulations paired with sham electrodes to serve as the nocebo manipulation in conditioning paradigms.…”

Electrophysiological markers for anticipatory processing of nocebo-augmented pain

“…The CHEPS thermode ramps up from a baseline temperature (32˚C) to a target temperature at 70˚C/ PLOS ONE second, remains at target for 300ms, and returns to baseline at 40˚C/second. Using previously validated methods [28], warmth and pain perception threshold temperatures, and the temperatures needed to induce distinct moderate and high pain intensities as the control and nocebo pain stimuli, respectively, were determined. Participants rated a series of thermal stimuli on a 0-10 pain intensity scale, with 0 indicating no pain at all and 10 indicating the worst imaginable pain on their arm, to assess what temperatures were reliably rated as moderate and highly painful.…”

“…By focusing cognitive resources on a noceboassociated stimulus, fear may spur stronger associations between the stimulus and increased pain responses. However, findings for a relationship between fear of pain and the magnitude of the nocebo effect are mixed [27][28][29], despite the well-documented impacts of fear of pain in other contexts [30].…”

Implications of nocebo in anaesthesia care

“…Nocebo effects are also measurable through other neurobiological markers. For example, in an encephalographic study of the nocebo effects of an ‘inert’ gel in human volunteers, long‐range temporal correlations were lower during nocebo‐augmented pain, compared with baseline [28].…”