Effects of Positive and Negative Expectations on Human Pain Perception Engage Separate But Interrelated and Dependently Regulated Cerebral Mechanisms

Abstract

Expectations substantially influence pain perception, but the relationship between positive and negative expectations remains unclear. Recent evidence indicates that the integration between pain-related expectations and prediction errors is crucial for pain perception, which suggests that aversive prediction error-associated regions, such as the anterior insular cortex (aIC) and rostral anterior cingulate cortex (rACC), may play a pivotal role in expectation-induced pain modulation and help to delineate the relationship between positive and negative expectations. In a stimulus expectancy paradigm combining fMRI in healthy volunteers of both sexes, we found that, although positive and negative expectations respectively engaged the right aIC and right rACC to modulate pain, their associated activations and pain rating changes were significantly correlated. When positive and negative expectations modulated pain, the right aIC and rACC exhibited opposite coupling with periaqueductal gray (PAG) and the mismatch between actual and expected pain respectively modulated their coupling with PAG and thalamus across individuals. Participants' certainty about expectations predicted the extent of pain modulation, with positive expectations involving connectivity between aIC and hippocampus, a region regulating anxiety, and negative expectations engaging connectivity between rACC and lateral orbitofrontal cortex, a region reflecting outcome value and certainty. Interestingly, the strength of these certainty-related connectivities was also significantly associated between positive and negative expectations. These findings suggest that aversive prediction-error-related regions interact with pain-processing circuits to underlie stimulus expectancy effects on pain, with positive and negative expectations engaging dissociable but interrelated neural responses that are dependently regulated by individual certainty about expectations.

Mesocorticolimbic Pathways Encode Cue-Based Expectancy Effects on Pain

“…These studies have demonstrated that social observation can also elicit expectancy effects on pain (Egorova et al, 2015;Tu et al, 2019a). In parallel, studies using fMRI have demonstrated the cue-based expectancy effects on painevoked brain responses (Koyama et al, 2005;Atlas et al, 2010;Jensen et al, 2015;Shih et al, 2019). Consistent with these studies, our results showed that cue-based expectation modulated both perceived intensity and neurobiological responses of pain ( Fig.…”

“…These brain regions associated with cue-based expectancy effects on pain were largely overlapping with the neurological pain signature (Wager et al, 2013). To illustrate pain-evoked brain responses following different cues in the brain regions associated with cue-based effects on pain (Atlas et al, 2010;Jensen et al, 2015;Shih et al, 2019), dACC, SMA, bilateral insula, bilateral putamen, and bilateral thalamus were selected as ROIs. Pain-evoked brain responses in these ROIs were extracted and are shown in Figure 2E.…”

“…To investigate the relationship between expectation and pain, studies invoke conditioning to establish a link between a cue and increased or reduced pain that follows, thus creating predictive knowledge (i.e., expectation) that modulates future pain responses to the same cue (Wager et al, 2004;Jensen et al, 2012). Although the neural mechanisms underlying the interaction between expectation and pain are still under investigation, neuro-imaging studies using functional magnetic resonance imaging (fMRI) and positron emission tomography have offered insights into how predictive cues are processed by the coordination of complex brain circuits (e.g., brainstem, higher-order cortical and subcortical brain regions), and then modulate pain and painrelated brain responses (Wager et al, 2004(Wager et al, , 2007Koyama et al, 2005;Seymour et al, 2005;Atlas et al, 2010;Kong et al, 2013;Shih et al, 2019).…”

Managing rebound pain after regional anesthesia

“…Patient expectations can also significantly influence pain perception [40][41][42]. Cumulative evidence shows that subjects who have been primed to expect good pain relief subsequently exhibit decreased pain perception and associated cerebral activity in response to noxious stimulation -a phenomenon known as placebo analgesia [43][44][45][46][47].…”

Nitric oxide-mediated defensive and antinociceptive responses organised at the anterior hypothalamus of mice are modulated by glutamatergic inputs from area 24b of the cingulate cortex

“…In particular, the limbic cortex appears to modulate nociceptive transmission via either the activation or the inhibition of PAG efferent connections to brainstem neurons that project to laminae I and V of the dorsal horn of the spinal cord (Butler and Finn, 2009 for review; Nathan, 1977; Ohara et al, 2005). Although PAG neurons also play an important role in pain expectation in humans (Fairhurst et al, 2007; Shih et al, 2019; Tracey et al, 2002) and receive inputs from hypothalamic neurons (Falconi-Sobrinho et al, 2017a; Ullah et al, 2017), it remains unknown whether the cortical modulation of nociception is mediated by hypothalamic projections to the PAG. In fact, the AH is part of the medial hypothalamus defensive system that is activated in animals exposed to a natural predator (Canteras, 2002; Canteras et al, 1997; Paschoalin-Maurin et al, 2018).…”