A Functional Magnetic Resonance Imaging Study on the Neural Mechanisms of Hyperalgesic Nocebo Effect

Abstract

Previous studies suggest that nocebo effects, sometimes termed "negative placebo effects," can contribute appreciably to a variety of medical symptoms and adverse events in clinical trials and medical care. In this study, using a within-subject design, we combined functional magnetic resonance imaging (fMRI) and an expectation/conditioning manipulation model to investigate the neural substrates of nocebo hyperalgesia using heat pain on the right forearm. Thirteen subjects completed the study. Results showed that, after administering inert treatment, subjective pain intensity ratings increased significantly more on nocebo regions compared with the control regions in which no expectancy/conditioning manipulation was performed. fMRI analysis of hyperalgesic nocebo responses to identical calibrated noxious stimuli showed signal increases in brain regions including bilateral dorsal anterior cingulate cortex (ACC), insula, superior temporal gyrus; left frontal and parietal operculum, medial frontal gyrus, orbital prefrontal cortex, superior parietal lobule, and hippocampus; right claustrum/putamen, lateral prefrontal gyrus, and middle temporal gyrus. Functional connectivity analysis of spontaneous resting-state fMRI data from the same cohort of subjects showed a correlation between two seed regions (left frontal operculum and hippocampus) and pain network including bilateral insula, operculum, ACC, and left S1/M1. In conclusion, we found evidence that nocebo hyperalgesia may be predominantly produced through an affective-cognitive pain pathway (medial pain system), and the left hippocampus may play an important role in this process.

Insular Cortex Activity Is Associated with Effects of Negative Expectation on Nociceptive Long-Term Habituation

“…Given that the functional imaging findings were primarily located in the affective-cognitive pain pathway, the authors concluded that their results underline the important role of anxiety in this process (Kong et al, 2008). This study was in part consistent with earlier studies (Sawamoto et al, 2000;Koyama et al, 2005;Keltner et al, 2006), namely that during nocebo hyperalgesia, brain activity in the ACC, insula, and operculum increases significantly during nocebo conditions.…”

“…Given that most groups found that the nocebo effect may be produced through a cortical network responsible for affective/ emotional and cognitive aspects of pain perception (Kong et al, 2008), we also obtained skin conductance levels of all participants on days 1, 8, and 90 to assess the arousal in response to painful stimulation. On days 1 and 90, there was no difference of skin conductance between groups.…”

“…Electrophysiological data in humans (Schlereth et al, 2003;Iannetti et al, 2005) and clinical observations in patients with cortical lesions (Greenspan et al, 1999) suggest the potential role of the parietal operculum as a nociceptive area that is activated very early after the onset of phasic noxious stimuli. More specifically, a recent functional imaging study by Kong et al (2008) suggested that the nocebo hyperalgesia is associated with an activation of the bilateral insula, operculum, ACC, and left S1/M1 as well as the left hippocampus. In our study, the only difference in brain imaging data between the context group and the control group was in the right parietal operculum.…”

Nocebo hyperalgesia and the startle response

“…Previous studies have shown that nocebo hyperalgesic manipulations heighten HPA activity (Benedetti et al 2006, Johansen et al 2003, cortical activity in pain-related regions (Kong et al 2008;Bingel et al 2011;Schmid et al 2015), pain-related activity in the spinal 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 cord (Geuter & Buchel 2013), blood pressure and reported negative emotions combined with increased pain reports. The findings from the present study further add that successful induction of nocebo expectations increase negative emotions significantly enough to engage physiological and motivational defense systems (Grillon et al 1991), that enhance cortical alertness measured by startle responses.…”

“…Cortical areas that are known to be involved in the processing of negative emotions, such as the amygdala (Schmid et al 2015) and the hippocampus (Kong et al 2008;Bingel et al 2011) were shown to be affected by nocebo manipulations. However, only one prior study has directly tested the assumption that nocebo hyperalgesic suggestions increase negative emotions that, in turn, predict increases in pain .…”