Individual Differences in Reward Responding Explain Placebo-Induced Expectations and Effects

Abstract

Expectations, positive or negative, are modulating factors influencing behavior. They are also thought to underlie placebo effects, impacting perceptions and biological processes. Using healthy human subjects, we examined the role of the nucleus accumbens (NAC), a region centrally involved in the encoding of reward expectation, in the formation of placebo responses. Employing functional molecular imaging, activation of NAC dopamine (DA) release was observed during placebo administration and related to its anticipated effects, perception-anticipation mismatches, and placebo effect development. In additional functional MRI studies, the expectation of monetary gain increased NAC synaptic activity in a manner proportional to placebo-induced DA release, anticipated effects, perception-anticipation differentials, and actual placebo effects. Individual variations in NAC response to reward expectation accounted for 28% of the variance in the formation of placebo analgesia.

Affective neuroscience of pleasure: reward in humans and animals

“…Each hotspot may be merely a cubic millimeter or so in volume in the rodent brain (and should be a cubic centimeter or so in humans, if proportional to whole brain volume) and is capable of generating enhancements of 'liking' reactions to a sensory pleasure such as sweetness, when opioid, endocannabinoid, or other neurochemical receptors within it are stimulated (Mahler et al 2007;Peciña and Berridge 2005;Peciña et al 2006;Smith and Berridge 2005;Smith et al 2008). Anatomical hotspot coding indicates a surprisingly high degree of localization of function for sufficient-cause pleasure mechanisms in the brain, and hotspot segregation within a limbic structure might provide a way for opioid or related brain signals to disambiguate pleasure versus pain via localization of function if the same neurochemical signal mediates both types of valence (Petrovic 2008;Reynolds and Berridge 2002;Scott et al 2007;Smith et al 2008;Wager et al 2004;Wightman et al 2007).…”

Placebo improves pleasure and pain through opposite modulation of sensory processing

“…A well-known feature of placebo treatment is individual variability in the magnitude of the placebo response. These behavioral differences are known to reflect differences in central placebo processing (15,23). We identified covariance with the behavioral placebo response within emotion appraisal circuitry by adding a regressor with each subject's average placebo improvement (placebo > control) for each stimulus type to the fMRI group analysis setup (placebo > control) for each stimulus.…”

“…Activity in these regions predicts individual placebo analgesia more accurately than regions involved in cognitive control or pain processing (21). This network is dependent on endogenous opioids (16,19,22) and interacts with the mesolimbic dopamine system (23)(24)(25) to reduce pain by inhibiting nociceptive signaling (15). Because these regions collectively are involved in valuation and reward-related processing more generally (26,27), and for reasons of clarity and brevity, we will refer to this set of regions as "emotion appraisal circuitry.…”

Expectancy-Induced Placebo Analgesia in Children and the Role of Magical Thinking

“…Dopaminergic activity has also been associated with personality traits such as reward susceptibility (18), which partially predicts the magnitude of PA (18,19). More recently, the personality dimension of magical thinking (MT), which is thought to be related to dopaminergic function (20), has been implicated in modulating expectation-related lateralized PA in healthy adults (21).…”