Research Article: Hypnotizability and Placebo Analgesia in Waking and Hypnosis as Modulators of Auditory Startle Responses in Healthy Women: An ERP Study

Date Published: August 3, 2016

Publisher: Public Library of Science

Author(s): Vilfredo De Pascalis, Paolo Scacchia, Alexandra Key.


We evaluated the influence of hypnotizability, pain expectation, placebo analgesia in waking and hypnosis on tonic pain relief. We also investigated how placebo analgesia affects somatic responses (eye blink) and N100 and P200 waves of event-related potentials (ERPs) elicited by auditory startle probes. Although expectation plays an important role in placebo and hypnotic analgesia, the neural mechanisms underlying these treatments are still poorly understood. We used the cold cup test (CCT) to induce tonic pain in 53 healthy women. Placebo analgesia was initially produced by manipulation, in which the intensity of pain induced by the CCT was surreptitiously reduced after the administration of a sham analgesic cream. Participants were then tested in waking and hypnosis under three treatments: (1) resting (Baseline); (2) CCT-alone (Pain); and (3) CCT plus placebo cream for pain relief (Placebo). For each painful treatment, we assessed pain and distress ratings, eye blink responses, N100 and P200 amplitudes. We used LORETA analysis of N100 and P200 waves, as elicited by auditory startle, to identify cortical regions sensitive to pain reduction through placebo and hypnotic analgesia. Higher pain expectation was associated with higher pain reductions. In highly hypnotizable participants placebo treatment produced significant reductions of pain and distress perception in both waking and hypnosis condition. P200 wave, during placebo analgesia, was larger in the frontal left hemisphere while placebo analgesia, during hypnosis, involved the activity of the left hemisphere including the occipital region. These findings demonstrate that hypnosis and placebo analgesia are different processes of top-down regulation. Pain reduction was associated with larger EMG startle amplitudes, N100 and P200 responses, and enhanced activity within the frontal, parietal, and anterior and posterior cingulate gyres. LORETA results showed that placebo analgesia modulated pain-responsive areas known to reflect the ongoing pain experience.

Partial Text

Human pain is a potent stressor with immediate relevance to survival and is believed to be a multi-faceted protective experience involving the activity of sensory-discriminative, affective-emotional, attentional-cognitive, behavioral and social learning systems [1–3]. Multiple psychological factors have been suggested to modulate the magnitude of pain, i.e., past experience [4, 5], classical conditioning [6–13], suggestibility [14, 15], expectancy [16], and ritualistic therapeutic acts [14, 17, 18]. This type of modulation is believed to happen through a top-down neurophysiological process that, when activated by one or more of the above mentioned factors, may produce neurophysiological changes that affect pain perception. The use of placebos and hypnosis represents two ways of how the top-down control can modulate pain perception, but the research of placebo and hypnosis often follows two separate tracks and their neurobiological similarities and differences are yet not fully understood. We have known, for a long time, that hypnotic analgesia is not a variant on placebo analgesia since highly hypnotizable individuals report feeling less pain during hypnosis than during placebo condition [19], suggesting that the effects of placebo and hypnosis analgesia are at least in part separate processes. A recent literature review on brain activity changes to placebo and hypnotic analgesia has highlighted similarities and differences between these two treatments [20]. First, these treatments produce similar changes in the activity of a number of brain regions labeled as pain network (i.e., somatosensory cortex, ACC, insula, thalamus, and prefrontal cortex). The activation of prefrontal cortex is necessary for cognitive evaluation and plays a leading role during both placebo and hypnotic analgesia treatments [21–24]. Pain relief elicited through these treatments are mediated by dopaminergic activity in the prefrontal cortex [25–28] and caused by changes in expectation [29, 30]. Second, the major differences between these two treatments lie in the fact that placebo analgesia produces functional changes in several parts of the limbic system (i.e., amygdala, hypothalamus and hippocampus, periaqueductal gray, nucleus accumbens). In contrast, hypnosis causes changes of activity in the occipital areas which are elicited by mental imagery [31–33] and basal ganglia which operate in the voluntary movement regulation [32, 34, 35].

In the current study we found that higher pain expectation, rated before participants had experienced experimental pain for the first time (Fig 1A), was associated with higher levels of pain reduction through placebo treatment in waking condition (Table 1, and Fig 2A). Although we have not found another study reporting this relation, this effect is sometimes observed in a clinical context and can be reasonably understood if we assume that an inhibitory conservative mechanism is operating in order to fit with the expected painful event. In contrast, during hypnotic placebo analgesia the association of pain expectation with pain or distress reduction was weakened and not significant (Table 1). We conceived this result assuming that hypnosis disrupted the upper-mentioned significant associations found in waking condition. This result supports previous findings suggesting that placebo and hypnosis involve, at least to some extent, different processes of top-down regulation [19]. This observation also corroborates our previously reported pain-hypnosis ERP findings [31]

The present findings are in line with prior reports that the placebo treatment in both waking and hypnosis condition can reduce pain and distress perception. Moreover, they show that hypnosis is not equal to common placebo in terms of brain activity, thus questioning the hypothesis that the pain reducing properties of hypnosis are just one form of placebo effect.