Instructions and experiential learning have similar impacts on pain and pain-related brain responses but produce dissociations in value-based reversal learning

Abstract

Recent data suggest that interactions between systems involved in higher order knowledge and associative learning drive responses during value-based learning. However, it is unknown how these systems impact subjective responses, such as pain. We tested how instructions and reversal learning influence pain and pain-evoked brain activation. Healthy volunteers (n = 40) were either instructed about contingencies between cues and aversive outcomes or learned through experience in a paradigm where contingencies reversed three times. We measured predictive cue effects on pain and heat-evoked brain responses using functional magnetic resonance imaging. Predictive cues dynamically modulated pain perception as contingencies changed, regardless of whether participants received contingency instructions. Heat-evoked responses in the insula, anterior cingulate, and other regions updated as contingencies changed, and responses in the prefrontal cortex mediated dynamic cue effects on pain, whereas responses in the brainstem's rostroventral medulla (RVM) were shaped by initial contingencies throughout the task. Quantitative modeling revealed that expected value was shaped purely by instructions in the Instructed Group, whereas expected value updated dynamically in the Uninstructed Group as a function of error-based learning. These differences were accompanied by dissociations in the neural correlates of value-based learning in the rostral anterior cingulate, thalamus, and posterior insula, among other regions. These results show how predictions dynamically impact subjective pain. Moreover, imaging data delineate three types of networks involved in pain generation and value-based learning: those that respond to initial contingencies, those that update dynamically during feedback-driven learning as contingencies change, and those that are sensitive to instruction. Together, these findings provide multiple points of entry for therapies designs to impact pain.

Towards a Real-Life Understanding of the Altered Functional Behaviour of the Default Mode and Salience Network in Chronic Pain: Are People with Chronic Pain Overthinking the Meaning of Their Pain?

“…Contradictory to what might be expected given the frequently reported increased activity in the dorsal vmPFC in people with chronic pain [ 52 , 53 , 54 , 55 , 56 ], the vast majority of endogenous pain modulation trials in which healthy individuals exhibit increased activity in the dorsal vmPFC also report an associated reduction in subjective pain intensity and/or unpleasantness. This includes, for instance, relative pain relief (i.e., the pain relief experienced when a moderate-intensity stimulus is presented following a stimulus of high intensity) [ 95 , 96 ], positive reappraisal of pain [ 97 , 98 ], distraction analgesia [ 99 , 100 ], and when pain intensity is expected to be low [ 101 , 102 ] or reduced [ 103 , 104 ]. Increased activity in the dorsal vmPFC has also been found to encode pain-specific, positive reinforcement learning [ 105 , 106 ], and there is even an increased pain-evoked activation of the dorsal vmPFC if a painful stimulus has been accepted on behalf of one’s romantic partner [ 107 ].…”

“…There are, however, critical exceptions to this trend [ 102 , 108 , 109 , 110 , 111 , 112 , 113 ], with one of the main examples being the recent results of Zunhammer et al concerning placebo analgesia [ 114 ]. In accordance with the common trend, early meta-analyses of placebo analgesia report increased pain-evoked activity in the dorsal vmPFC [ 103 , 104 ].…”

“…Conversely, experimental pain-evoked activation of the pgACC has been more closely related to the expected value of pain rather than the factual stimulus-evoked pain experience itself [ 101 , 102 , 103 , 105 , 106 , 110 , 122 ]. Expectations are well-known to be able to shape the experience of pain [ 123 ], as well as other sensory perceptions [ 124 ], and expectations resemble one of the most well-established contributors to the placebo analgesic effect [ 123 , 125 , 126 , 127 ].…”

“…Expectations are well-known to be able to shape the experience of pain [ 123 ], as well as other sensory perceptions [ 124 ], and expectations resemble one of the most well-established contributors to the placebo analgesic effect [ 123 , 125 , 126 , 127 ]. However, recent results by Atlas et al showed that expectations of pain intensity were associated with different pain-evoked activity responses in the pgACC depending on how the cue that caused the expectations had been learned [ 102 ]. If the meaning of an auditory cue preceding a painful stimulus had been learned via uninstructed learning (i.e., learning by experience), expectations of high pain were associated with a significant pain-evoked deactivation of the pgACC.…”

“…If the meaning of an auditory cue preceding a painful stimulus had been learned via uninstructed learning (i.e., learning by experience), expectations of high pain were associated with a significant pain-evoked deactivation of the pgACC. In contrast, if the meaning of the cues had been learned through explicit verbal instructions, expectations of high pain were rather associated with increased pain-evoked activation of the pgACC [ 102 ]. These results suggest that the altered behaviour of the pgACC observed in people with chronic pain may not be related to the expectations of pain per se.…”