Pre-Exposure, But Not Overshadowing, Inhibits Nocebo Hyperalgesia.

Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies - overshadowing (Experiment 1) and pre-exposure (Experiment 2) - could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode 'activated', which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings. PERSPECTIVE: Nocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.

Motor Conflict: Revealing Involuntary Conditioned Motor Preparation Using Transcranial Magnetic Stimulation.

Preparing actions to achieve goals, overriding habitual responses, and substituting actions that are no longer relevant are aspects of motor control often assumed to be driven by deliberate top-down processes. In the present study, we investigated whether motor control could come under involuntary control of environmental cues that have been associated with specific actions in the past. We used transcranial magnetic stimulation (TMS) to probe corticospinal excitability as an index of motor preparation, while participants performed a Go/No-Go task (i.e., an action outcome or no action outcome task) and rated what trial was expected to appear next (Go or No-Go). We found that corticospinal excitability during a warning cue for the upcoming trial closely matched recent experience (i.e., cue-outcome pairings), despite conflicting with what participants expected would appear. The results reveal that in an action-outcome task, neurophysiological indices of motor preparation show changes that are consistent with participants learning to associate a preparatory warning cue with a specific action, and are not consistent with the action that participants explicitly anticipate making. This dissociation with conscious expectancy ratings reveals that conditioned responding and motor preparation can operate independently of conscious expectancies about having to act.

Latent Inhibition Reduces Nocebo Nausea, Even Without Deception.

BACKGROUND: Nocebo nausea is a debilitating and prevalent side effect that can develop after conditioning occurs between cues present in the treatment context and the experience of nausea. Interventions that retard conditioning may therefore be able to reduce nocebo nausea. PURPOSE: To test whether 'latent inhibition', where pre-exposing cues in the absence of an outcome retards subsequent learning about those cues, could reduce nocebo nausea in healthy adults. METHODS: We examined this possibility using a Galvanic Vestibular Stimulation (GVS) model of nausea in healthy participants, with pre-exposure to the treatment cues achieved using a placebo version of GVS. RESULTS: In Experiment 1 we found clear evidence of conditioned nocebo nausea that was eradicated by latent inhibition following pre-exposure to placebo stimulation. Experiment 2 tested whether deception, which may be unethical in clinical settings, was necessary to produce latent inhibition by including an open pre-exposure group informed they were pre-exposed to placebo stimulation. Experiment 2 replicated the latent inhibition effect on nocebo nausea following deceptive pre-exposure from Experiment 1 and found that open pre-exposure was just as effective for reducing nocebo nausea. In both experiments, there was an interesting discrepancy found in expectancy ratings whereby expectations appeared to drive the development of conditioned nocebo nausea, but were not responsible for its suppression through latent inhibition. CONCLUSIONS: These findings have significant clinical implications. Applying open pre-exposure in clinical settings may effectively and ethically reduce the development of nocebo effects for nausea and other conditions via latent inhibition.

Contextual cuing as a form of nonconscious learning: Theoretical and empirical analysis in large and very large samples.

Numerous studies have demonstrated that associative learning can affect visual cognition. In one such effect, search times for a target hidden among similar distractors are faster for repeated search configurations compared with novel configurations. This contextual cuing effect is particularly interesting, because researchers routinely have failed to find evidence of recognition of the repeated configurations, concluding that the effect is a form of nonconscious learning. Vadillo, Konstantinidis, and Shanks (2016) recently criticized this conclusion on a number of methodological and conceptual grounds that suggest the area suffers from a high probability of false-negative results on awareness tests and misinterpretation of weak or absent relationships between cuing and awareness measures. We developed further predictions from theoretical models assuming that single or independent memory sources drive learning and awareness and discuss how these predictions fare in three new contextual cuing experiments involving large (n > 60) and very large samples (n > 600). The data support the absence of a positive relationship between recognition and the cuing effect both at the participant and configuration level, the probability of which being a false negative is very low in a model assuming a single memory source drives learning and awareness. This was the case using both conventional and Bayesian analyses. The combination of this theoretical and empirical analysis suggests that contextual cuing is not dependent on cue recognition and provides evidence that it reflects a genuine form of nonconscious learning.

Discrimination and generalization along a simple dimension: peak shift and rule-governed responding.

In 2 experiments, participants learned to discriminate between a pair of simply related, but very similar, colors in a 2-choice categorization task. They were then tested over a wider range of isoluminant hues. Over these test values, both experiments yielded a postdiscrimination gradient that was initially peak-shifted but became monotonic through the course of testing. In Experiment 2, the presence of this early peak shift and subsequent change in gradient form were related to participants' inability to verbally characterize the difference between the training stimuli. This suggests a transition from generalization based on simple physical similarity to generalization based on a "verbalizable" rule, as a consequence of additional relevant information becoming available during test. An explanation appealing to both associative and strategically controlled verbal processes provides an accurate account of the results.