Pain Anticipation and Nocebo-Related Responses: A Descriptive Mini-Review of Functional Neuroimaging Studies in Normal Subjects and Precious Hints on Pain Processing in the Context of Neurodegenerative Disorders

Abstract

The exacerbation of a clinical condition or the occurrence of negative symptoms after an inert substance dispensation or a sham treatment is known as "nocebo effect." Nocebo is the psychobiological effect due to the negative psychosocial context that accompanies a therapy, and it is a direct consequence of negative expectations by the patients and their own personal characteristics. Although the clinical relevance of the phenomenon is now recognized, a small number of studies have tried to ascertain its neural underpinnings (that it means nocebo responses). Moreover, there is no consensus on the brain networks involved in nocebo processes in humans. In particular, nocebo hyperalgesia has attracted almost no research attention. We conducted a mini-review on the few experimental pain functional magnetic resonance imaging (fMRI) studies of nocebo responses to discuss how negative expectancies and conditioning effects engage brain networks to modulate pain experiences. Moreover, we present possible clinical implications considering Alzheimer's disease and behavioral frontotemporal dementia, in which the existence of a hypothetically disrupted neurocognitive anticipatory network-secondary to an endogenous pain modulatory system damage-may be responsible for pain processing alterations.

Keywords: anterior cingulate cortex; anterior insular cortex; fMRI; negative expectation; nocebo responses; pain anticipation; prefrontal dorsolateral cortex.

Figure 1

Red panel: Activations were projected onto a 3D rendering model of the brain. Blue panel: Deactivations were projected onto a 3D rendering model of the brain. ALE maps were computed using GingerALE 2.3.1 at a false discovery rate (FDR)-corrected threshold of P < 0.05, with a minimum cluster size of K > 50 mm³ and visualized using MRIcron.

Figure 2

A suggested stepwise theoretical algorithm to study pain anticipation and nocebo-related responses.