Placebo effects in laser-evoked pain potentials

Abstract

Placebo treatment may affect multiple components of pain, including inhibition of nociceptive input, automatic or deliberative appraisal of pain, or cognitive judgments involved in pain reporting. If placebo analgesia is due in part to an attenuation of early nociceptive processing, then pain-evoked event-related potentials (ERPs) should be reduced with placebo. In this study, we tested for placebo effects in P2 laser-evoked potentials at midline scalp electrodes. We found that placebo treatment produced significant decreases in P2 amplitude, and that P2 placebo responses were large enough to reflect a meaningful difference in nociceptive processing. However, we also found evidence that the very robust placebo-induced decreases in reported pain are not solely explained by early reductions in P2. N2 amplitude was affected by neither placebo nor reduction of laser intensity. These results suggest that placebo treatment affects early nociceptive processing, but that another component of placebo effects in reported pain occurs later, either in evaluation of pain or cognitive judgments about pain reports.

Introduction

A major theme in contemporary neuroscientific research is that subjective experience is not a direct reflection of events in the world, but rather is constructed within the brain. According to this view, sensory signals are only one component of an experience, whether that experience is the perception of an object or the feeling of pain (Bruner et al., 1951). These “bottom-up” signals are integrated with “top-down” information about the context of the experience (Miller and Cohen, 2001), including memories of relevant past experiences, expectations for the future, and the significance of the experience for the self. Recent research suggests that placebo effects emerge from such interactions, as cognitive expectations interact with ongoing processes in the brain and body. Placebo effects and other context effects are particularly powerful in pain, a multifaceted experience that is closely tied to physical and mental well-being (Koyama et al., 2005, Lorenz et al., 2005, Melzack and Casey, 1968, Price, 2000, Sawamoto et al., 2000, Wager et al., 2004).

A question with major implications for understanding the neurobiology of expectation and brain–body interactions is the question of how deep into the body placebo effects reach. Though a number of studies have reported reliable placebo effects in reported pain (e.g., Benedetti et al., 1999, De Pascalis et al., 2002, Pollo et al., 2001, Price and Barrell, 2000, Vase et al., 2002), reports are based on cognitively constructed representations of experience. Judgment of pain is an active neurobiological process that appears to engage affective and decision circuits in the brain (Moulton et al., 2005). Like other forms of judgment (e.g., Ericsson and Simon, 1980, Manis et al., 1991), pain reports may be highly susceptible to expectancy-induced biases in a variety of settings (Kirsch, 1985, Moerman, 2000).

Two primary issues that bear on the physiological ‘depth’ of placebo effects are whether placebo treatments have active psychobiological effects (Wager, 2005a, Wager, 2005b), as opposed to resulting from demand characteristics or statistical artifacts (Hrobjartsson and Gotzsche, 2001, Hrobjartsson and Gotzsche, 2004, Kienle and Kiene, 1997); and if placebo effects are active, whether they affect biological processes related to physical health and mental well-being. A recent fMRI study provided evidence that placebo treatment involves active recruitment of cortical regions involved in the regulation of attention and pain (Wager et al., 2004), suggesting that the placebo response is an active psychobiological process. The study also found that placebo treatment suppressed pain-induced activity in the insula, thalamus, and anterior cingulate cortex, suggesting that it alters ongoing processing of pain. Zubieta et al. (2005), using PET, found evidence that placebo treatment both reduces pain and elicits increases in endogenous opioid activity (cf. Benedetti et al., 1999).

However, these neuroimaging studies are limited in their ability to address a critical question about the physiological ‘depth’ of placebo: whether placebo treatments can alter nociceptive processing, rather than or in addition to pain affect, evaluation, and judgments about pain. The fMRI study of Wager et al. found decreases in pain regions only late during pain, after the stimulus had been turned off, though strong responders also showed evidence for greater decreases in anterior cingulate activity during the first several seconds of painful stimulation. Either effect could be related to the evaluation of pain, rather than to the suppression of nociceptive processing, particularly since a key area showing decreases—the insula—is also involved in cognitive judgments of pain (Moulton et al., 2005). The Zubieta et al. study provides converging, but also indirect, evidence: opioid systems are involved in pain, but also in affect, reward, and motivation, and so the evidence that placebo effects inhibit nociceptive processing remains indirect.

In the present study, we recorded brain potentials evoked by painful laser stimuli to test for placebo effects on early nociceptive responses. Laser-evoked potentials (LEPs) are a reliable, objective marker of pain processing (Bromm and Treede, 1984), and they are considered by many to be the best tool for probing the function of nociceptive pathways (Cruccu et al., 2004). Laser stimuli selectively activate A-delta and C nociceptive fibers, and so activate the nociceptive system without activating touch and vibration pathways (Bromm and Treede, 1984). LEPs are influenced by arousal and attention (Kakigi et al., 2000), as is pain-induced fMRI activity (Petrovic and Ingvar, 2002), consistent with the idea that pain processing is sensitive to behavioral context. However, unlike measures of fMRI or PET activity, which may reflect the process of making subjective cognitive judgments about pain, LEPs arise from nociceptive processes that occur before most evaluation and decision processes begin. Some studies have suggested that strategic response processes do not affect stimulus processing until relatively late (at least 450 ms; Ratcliff and McKoon, 1981), and that strategic control is unlikely to affect responses faster than 700 ms (Seymour et al., 2000). Thus, the cognitive biases known to affect decisions about sensory experience and other types of self-report are unlikely to affect LEPs.

A demonstration that placebo treatment affects LEPs would provide converging evidence that placebo treatment can affect early (pre-evaluative) nociceptive processing, with implications for the relationship between cognitive expectations and the function of one of the body’s most basic systems for avoiding harm. There are both theoretical and empirical reasons to expect such effects. The theory is that cognitive expectations maintained in prefrontal cortex may activate the PAG, which has the capability to inhibit pain signals at the level of the spinal cord (e.g., Fields, 2004). The evidence comes from two recent studies, in addition to the fMRI and opioid placebo studies discussed above. Matre et al. (2006) induced secondary hyperalgesia by heating the skin to 46 °C for 5 min. Sensitization of the skin area surrounding the stimulation site is thought to result from sensitization in the spinal dorsal horn. Expectation of pain relief reduced the size of the secondary hyperalgesic area, compared to a control session where pain relief was not expected, implicating a spinal mechanism in the placebo effect. Converging electrophysiological evidence comes from a study by Lorenz et al. (2005), who found that expectations about the intensity of a laser stimulus produced systematic changes in laser-evoked magneto-encephalogram (MEG) potentials. They delivered laser stimuli of high and low intensities, and crossed intensity with a manipulation of whether the expected intensity was high or low. They found that MEG potentials localized approximately to SII—a cortical area critical for nociceptive processing—were reduced in the low-expectation condition and increased in the high-expectation condition.

There are several components of LEPs that may be affected by placebo expectancies, with different implications for the cognitive control of nociception. The major components of LEPs are a lateralized mid-latency negativity (N160) likely to be localized in the parietal operculum (SII) and the late N2/P2 complex (200–300 ms; Lorenz and Garcia-Larrea, 2003). The N2/P2 complex arises from the activation of Aδ fibers and is sometimes followed by an ultralate component (400–600 ms) thought to arise from C-fiber activation (Bromm and Treede, 1984, Bromm et al., 1984). The P2 increases as a function of both laser intensity and reported pain (Iannetti et al., 2004). It is likely to be separable from the P3, but it may overlap with the P3a and reflect cognitive appraisal or attention to pain (Lorenz and Garcia-Larrea, 2003). This is consistent with a view of P2 LEPs as markers of early brain processing of pain, which may involve attention and appraisal of behavioral context as integral components (Garcia-Larrea et al., 1997, Garcia-Larrea et al., 2003, Legrain et al., 2005).

A likely source of the P2 is the anterior cingulate gyrus (Garcia-Larrea et al., 2003, Lenz et al., 1998), which plays a central role in both attention and pain, and also appears to be modulated by placebo in studies of pain and emotion (Petrovic et al., 2002, Petrovic et al., 2005, Wager et al., 2004, Zubieta et al., 2005). Though the cingulate may show both increases and decreases in different subregions during different phases of pain anticipation and regulation (Porro et al., 2003), the analyses in this study are sensitive to changes occurring within several hundred milliseconds of laser stimulus onset. Slower changes in anterior cingulate activity (i.e., sustained changes beginning in anticipation) will neither influence nor be detected by the measures employed here. The N160 is also of interest because it is a marker for early nociceptive processing, but the midline electrode configuration used in this study was not suitable for examining that component.

One account of placebo effects is that they induce an affective/motivational state that permits reduced attention to pain. The motivational state that regulates the allocation of attention appears to be only partly under voluntary control (e.g., it is very difficult to willfully ignore a rattlesnake next to one’s foot), and the effects of placebo serve as a safety signal and permit attention to be directed away from pain. Placebo effects on the mid-frontal P2 would be consistent with this view. Notably, behavioral context (i.e., factors that affect motivated attention) also affects sensory pathways in the dorsal spinal horn (Duncan et al., 1987), which suggests that attentional set can have far-reaching physiological effects.

Understanding the psychobiological mechanisms of placebo will likely be an enduring research question. The immediate goal of assessing whether placebo treatment affects early nociceptive processing is a preliminary step towards this understanding. Thus, in this study, we sought to test three specific hypotheses: (a) that placebo treatment would reduce P2 LEP amplitude; (b) that placebo reductions in LEP would correlate with reductions in reported pain; and (c) that the placebo P2 reduction would be comparable in magnitude to an equivalent reduction in the intensity of the laser.