Distinct neural representations of placebo and nocebo effects

Abstract

Expectations shape the way we experience the world. In this study, we used fMRI to investigate how positive and negative expectation can changes pain experiences in the same cohort of subjects. We first manipulated subjects’ treatment expectation of the effectiveness of three inert creams, with one cream labeled “Lidocaine” (positive expectancy), one labeled “Capsaicin” (negative expectancy) and one labeled “Neutral” by surreptitiously decreasing, increasing, or not changing respectively, the intensity of the noxious stimuli administered following cream application. We then used fMRI to investigate the signal changes associated with administration of identical pain stimuli before and after the treatment and control creams. Twenty-four healthy adults completed the study. Results showed expectancy significantly modulated subjective pain ratings. After controlling for changes in the neutral condition, the subjective pain rating changes evoked by positive and negative expectancy were significantly associated. fMRI results showed that the expectation of an increase in pain induced significant fMRI signal changes in the insula, orbitofrontal cortex, and periaqueductal gray, whereas the expectation of pain relief evoked significant fMRI signal changes in the striatum. No brain regions were identified as common to both “Capsaicin” and “Lidocaine” conditioning. There was also no significant association between the brain response to identical noxious stimuli in the pain matrix evoked by positive and negative expectancy. Our findings suggest that positive and negative expectancy engage different brain networks to modulate our pain experiences, but, overall, these distinct patterns of neural activation result in a correlated placebo and nocebo behavioral response.

The imagined itch: brain circuitry supporting nocebo-induced itch in atopic dermatitis patients

“…While some pain studies suggest that the brain circuitry supporting nocebo involves limbic (e.g. hippocampus) brain activity and is distinct from the circuitry associated with placebo effects (10, 12, 41), other studies have shown that nocebo/placebo effects occur via opposite responses of the same neurochemical systems (13). Similarly, a recent study found that placebo manipulations produce analgesia and hyperhedonia via shared affective neurocircuitry, which targets early sensory processing (42), a finding that may relate to our observation that nocebo itch was engaged through cortico-striatal activity during an early increasing itch phase.…”

Learning by experience? Visceral pain‐related neural and behavioral responses in a classical conditioning paradigm

“…Negative expectations or previous experience are demonstrably capable of triggering processes of pain modulation, which are central to nocebo effects . Brain imaging studies addressing neural mechanisms underlying nocebo effects support an involvement of brain regions associated with sensory, cognitive, and emotional pain modulation . Some studies noted nocebo‐induced changes in neural activation also during mere pain anticipation, in keeping with the role of conditioned pain‐related fear .…”

“…Although the clinical relevance of nocebo effects in the context of pain is indisputable, studies addressing the underlying neural mechanisms have almost exclusively focused on negative expectations induced by verbal suggestions in experimental thermal and visceral pain . The neural correlates of nocebo effects induced by classical conditioning remain essentially unknown.…”

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

“…However, considering the broad range of potential physiologic systems and drugs' side effects, various exchanges between placebo and nocebo mechanisms may be occurring for each symptom and physiologic system (Enck et al, 2008). A recent study reported distinct patterns of neural activation induced by positive or negative expectancies, however, that resulted in a correlated placebo and nocebo behavioral response (Freeman et al, 2015).…”