Uncertainty increases pain: evidence for a novel mechanism of pain modulation involving the periaqueductal gray.

Predictions about sensory input exert a dominant effect on what we perceive, and this is particularly true for the experience of pain. However, it remains unclear what component of prediction, from an information-theoretic perspective, controls this effect. We used a vicarious pain observation paradigm to study how the underlying statistics of predictive information modulate experience. Subjects observed judgments that a group of people made to a painful thermal stimulus, before receiving the same stimulus themselves. We show that the mean observed rating exerted a strong assimilative effect on subjective pain. In addition, we show that observed uncertainty had a specific and potent hyperalgesic effect. Using computational functional magnetic resonance imaging, we found that this effect correlated with activity in the periaqueductal gray. Our results provide evidence for a novel form of cognitive hyperalgesia relating to perceptual uncertainty, induced here by vicarious observation, with control mediated by the brainstem pain modulatory system.

The price of pain and the value of suffering.

Estimating the financial value of pain informs issues as diverse as the market price of analgesics, the cost-effectiveness of clinical treatments, compensation for injury, and the response to public hazards. Such valuations are assumed to reflect a stable trade-off between relief of discomfort and money. Here, using an auction-based health-market experiment, we show that the price people pay for relief of pain is strongly determined by the local context of the market, that is, by recent intensities of pain or immediately disposable income (but not overall wealth). The absence of a stable valuation metric suggests that the dynamic behavior of health markets is not predictable from the static behavior of individuals. We conclude that the results follow the dynamics of habit-formation models of economic theory, and thus, this study provides the first scientific basis for this type of preference modeling.

Modulation of pain ratings by expectation and uncertainty: Behavioral characteristics and anticipatory neural correlates.

Expectations about the magnitude of impending pain exert a substantial effect on subsequent perception. However, the neural mechanisms that underlie the predictive processes that modulate pain are poorly understood. In a combined behavioral and high-density electrophysiological study we measured anticipatory neural responses to heat stimuli to determine how predictions of pain intensity, and certainty about those predictions, modulate brain activity and subjective pain ratings. Prior to receiving randomized laser heat stimuli at different intensities (low, medium or high) subjects (n=15) viewed cues that either accurately informed them of forthcoming intensity (certain expectation) or not (uncertain expectation). Pain ratings were biased towards prior expectations of either high or low intensity. Anticipatory neural responses increased with expectations of painful vs. non-painful heat intensity, suggesting the presence of neural responses that represent predicted heat stimulus intensity. These anticipatory responses also correlated with the amplitude of the Laser-Evoked Potential (LEP) response to painful stimuli when the intensity was predictable. Source analysis (LORETA) revealed that uncertainty about expected heat intensity involves an anticipatory cortical network commonly associated with attention (left dorsolateral prefrontal, posterior cingulate and bilateral inferior parietal cortices). Relative certainty, however, involves cortical areas previously associated with semantic and prospective memory (left inferior frontal and inferior temporal cortex, and right anterior prefrontal cortex). This suggests that biasing of pain reports and LEPs by expectation involves temporally precise activity in specific cortical networks.

Opponent appetitive-aversive neural processes underlie predictive learning of pain relief.

Termination of a painful or unpleasant event can be rewarding. However, whether the brain treats relief in a similar way as it treats natural reward is unclear, and the neural processes that underlie its representation as a motivational goal remain poorly understood. We used fMRI (functional magnetic resonance imaging) to investigate how humans learn to generate expectations of pain relief. Using a pavlovian conditioning procedure, we show that subjects experiencing prolonged experimentally induced pain can be conditioned to predict pain relief. This proceeds in a manner consistent with contemporary reward-learning theory (average reward/loss reinforcement learning), reflected by neural activity in the amygdala and midbrain. Furthermore, these reward-like learning signals are mirrored by opposite aversion-like signals in lateral orbitofrontal cortex and anterior cingulate cortex. This dual coding has parallels to 'opponent process' theories in psychology and promotes a formal account of prediction and expectation during pain.

Modulation of pain processing in hyperalgesia by cognitive demand.

The relationship between pain and cognitive function is of theoretical and clinical interest, exemplified by observations that attention-demanding activities reduce pain in chronically afflicted patients. Previous studies have concentrated on phasic pain, which bears little correspondence to clinical pain conditions. Indeed, phasic pain is often associated with differential or opposing effects to tonic pain in behavioral, lesion, and pharmacological studies. To address how cognitive engagement interacts with tonic pain, we assessed the influence of an attention-demanding cognitive task on pain-evoked neural responses in an experimental model of chronic pain, the capsaicin-induced heat hyperalgesia model. Using functional magnetic resonance imaging (fMRI), we show that activity in the orbitofrontal and medial prefrontal cortices, insula, and cerebellum correlates with the intensity of tonic pain. This pain-related activity in medial prefrontal cortex and cerebellum was modulated by the demand level of the cognitive task. Our findings highlight a role for these structures in the integration of motivational and cognitive functions associated with a physiological state of injury. Within the limitations of an experimental model of pain, we suggest that the findings are relevant to understanding both the neurobiology and pathophysiology of chronic pain and its amelioration by cognitive strategies.

Empathy for pain involves the affective but not sensory components of pain.

Our ability to have an experience of another's pain is characteristic of empathy. Using functional imaging, we assessed brain activity while volunteers experienced a painful stimulus and compared it to that elicited when they observed a signal indicating that their loved one--present in the same room--was receiving a similar pain stimulus. Bilateral anterior insula (AI), rostral anterior cingulate cortex (ACC), brainstem, and cerebellum were activated when subjects received pain and also by a signal that a loved one experienced pain. AI and ACC activation correlated with individual empathy scores. Activity in the posterior insula/secondary somatosensory cortex, the sensorimotor cortex (SI/MI), and the caudal ACC was specific to receiving pain. Thus, a neural response in AI and rostral ACC, activated in common for "self" and "other" conditions, suggests that the neural substrate for empathic experience does not involve the entire "pain matrix." We conclude that only that part of the pain network associated with its affective qualities, but not its sensory qualities, mediates empathy.

Dread and the disvalue of future pain.

Standard theories of decision-making involving delayed outcomes predict that people should defer a punishment, whilst advancing a reward. In some cases, such as pain, people seem to prefer to expedite punishment, implying that its anticipation carries a cost, often conceptualized as 'dread'. Despite empirical support for the existence of dread, whether and how it depends on prospective delay is unknown. Furthermore, it is unclear whether dread represents a stable component of value, or is modulated by biases such as framing effects. Here, we examine choices made between different numbers of painful shocks to be delivered faithfully at different time points up to 15 minutes in the future, as well as choices between hypothetical painful dental appointments at time points of up to approximately eight months in the future, to test alternative models for how future pain is disvalued. We show that future pain initially becomes increasingly aversive with increasing delay, but does so at a decreasing rate. This is consistent with a value model in which moment-by-moment dread increases up to the time of expected pain, such that dread becomes equivalent to the discounted expectation of pain. For a minority of individuals pain has maximum negative value at intermediate delay, suggesting that the dread function may itself be prospectively discounted in time. Framing an outcome as relief reduces the overall preference to expedite pain, which can be parameterized by reducing the rate of the dread-discounting function. Our data support an account of disvaluation for primary punishments such as pain, which differs fundamentally from existing models applied to financial punishments, in which dread exerts a powerful but time-dependent influence over choice.