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

Abstract

Learning and negative outcome expectations can increase pain sensitivity, a phenomenon known as nocebo hyperalgesia. Here, we examined how a targeted pharmacological manipulation of learning would impact nocebo responses and their brain correlates. Participants received either a placebo (n = 27) or a single 80 mg dose of d-cycloserine (a partial NMDA receptor agonist; n = 23) and underwent fMRI. Behavioral conditioning and negative suggestions were used to induce nocebo responses. Participants underwent pre-conditioning outside the scanner. During scanning, we first delivered baseline pain stimulations, followed by nocebo acquisition and extinction phases. During acquisition, high intensity thermal pain was paired with supposed activation of sham electrical stimuli (nocebo trials), whereas moderate pain was administered with inactive electrical stimulation (control trials). Nocebo hyperalgesia was induced in both groups (p < 0.001). Nocebo magnitudes and brain activations did not show significant differences between d-cycloserine and placebo. In acquisition and extinction, there were significantly increased activations bilaterally in the amygdala, ACC, and insula, during nocebo compared to control trials. Nocebo acquisition trials also showed increased vlPFC activation. Increased opercular activation differentiated nocebo-augmented pain aggravation from baseline pain. These results support the involvement of integrative cognitive-emotional processes in nocebo hyperalgesia.

Placebo and nocebo in the treatment of migraine: How much does real world effectiveness depend on contextual effects?

“…Neuroimaging has also been essential for the study of nocebo effects, showing that the anticipation of pain and its intensity can activate several brain regions involved in nociceptive processing, including: the thalamus, prefrontal cortex, secondary somatosensory cortex, anterior cingulate cortex and insula (31,32). The hypothalamus-pituitary-adrenal axis and cholecystokinin systems are also directly involved in anticipatory anxiety and nocebo-induced hyperalgesia (33,34).…”