Elsevier

NeuroImage

Volume 38, Issue 4, December 2007, Pages 720-729
NeuroImage

Functional brain interactions that serve cognitive–affective processing during pain and placebo analgesia

https://doi.org/10.1016/j.neuroimage.2007.07.057Get rights and content

Abstract

Pain requires the integration of sensory, cognitive, and affective information. The use of placebo is a common methodological ploy in many fields, including pain. Neuroimaging studies of pain and placebo analgesia (PA) have yet to identify a mechanism of action. Because PA must result from higher order processes, it is likely influenced by cognitive and affective dimensions of the pain experience. A network of brain regions involved in these processes includes the anterior and posterior insula (A-Ins, P-Ins), dorsal anterior cingulate cortex (DACC), dorsolateral prefrontal cortex (DLPFC), and the supplementary motor area (SMA). We used connectivity analyses to investigate the underlying mechanisms associated with Placebo analgesia in a group of chronic pain patients. Structural equation models (SEM) of fMRI data evaluated the inter-regional connectivity of these regions across three conditions: (1) initial Baseline (B1), (2) placebo (PA), and (3) Placebo Match (PM). SEM results of B1 data in the left hemisphere confirmed hypothesized regional relationships. However, inter-regional relationships were dynamic and the network models varied across hemispheres and conditions. Deviations from the B1 model in the PA and PM conditions correspond to our manipulation of expectation for pain. The dynamic changes in inter-regional influence across conditions are interpreted in the context of a self-reinforcing feedback loop involved in the induction and maintenance of PA. Although it is likely that placebo analgesia results partly from afferent inhibition of a nociceptive signal, the mechanisms likely involve the interaction of a cognitive–affective network with input from both hemispheres.

Introduction

Neuroimaging studies have identified large reductions in pain ratings and neural activation that accompany placebo analgesia (PA) during visceral stimulation and in proximity to when subjects rated pain (Price et al., 2007, Wager, 2005a). Research suggests that placebo-induced analgesia is a complex phenomenon brought about by the interaction of multiple functional processes (e.g., sensory, cognitive, and affective) (Amanzio and Benedetti, 1999, Colloca and Benedetti, 2005).

The manner in which cortico-subcortical and cortico-cortical connections respond to and process nociceptive information may be modulated by previous experience and expectation. Work in neurophysiology, and more recently in neuroimaging, frequently identify several brain regions including the dorsolateral prefrontal cortex (DLPFC), dorsal anterior cingulate cortex (DACC), anterior insula (A-Ins), and posterior insula (P-Ins) as being involved with the functional processing of painful stimuli (Brooks et al., 2005, Kong et al., 2006a, Kong et al., 2006b). It follows then that the interaction of these regions plays an important role in processing nociceptive information, ascribing valence and determining the level of pain experienced. Consequently, these regions may reflect a crucial cortico-cortical network for nociceptive processing whose role in pain modulation is not well defined.

Neuroimaging studies have identified distinct but overlapping networks involved in processing sensory and affective aspects of nociceptive stimuli (Kong et al., 2006b). Questions about the manner in which these networks function with respect to context continue to emerge. It has been reasonably argued that nociceptive information may be differentially processed across pain-related affective networks under different conditions (Ohara et al., 2006). Thus, information is needed to help clarify the implications of changes to the functional processing of nociceptive information brought about by placebo.

The present fMRI study analyzed the consistency with which a cognitive–affective network of brain regions processed pain-related information across several conditions using structural equation modeling (SEM). Based on research and theory from the fields of neurophysiology, psychology, and neuroimaging, we hypothesized a specific set of interactions for processing pain-related information (Kim et al., 2006, Solodkin et al., 2004). These interactions were first estimated in an initial Baseline (B1) condition to validate the model and establish a baseline characterization of the model during nociception. Data from two additional conditions, Placebo Analgesia (PA) and one with decreased stimulation (to match the placebo response), referred to as Placebo Match (PM) were then fitted to the established B1 model. The pain ratings of the latter two conditions were significantly lower than those of the B1 condition, indicating a substantial change in the processing related to the cognitive evaluation and affect. The inter-regional associations were carefully examined, compared, and contrasted across the three conditions in order to identify the corresponding manifest changes in the way the information was processed. This method of identifying the resultant changes in processing nociceptive information due to a placebo suggestion represents an important preliminary step in understanding the implications of how manipulating expectation, a cognitive process, may alter how sensory information is processed.

Section snippets

Materials and methods

The work presented here extends that of a previously published study. In that study, relative to a Baseline condition, reductions in response pain ratings were accompanied by less activation in pain-related brain regions as a result of a placebo (Price et al., 2007). Repeated here is an information related to subjects, experimental design, and procedures to give the reader sufficient background to evaluate the analysis in the present report.

Pain rating results

Compared to the Baseline condition, the pain ratings for the placebo condition were significantly lower and confirmed the presence of a placebo analgesic effect. Specifically, a repeated measures ANOVA for pain ratings and condition identified a significant main effect for condition (F(2,18) = 10.88, p < .001, partial η2 = .547; mean B1 = 52, PA = 36, and PM = 31), and trial (F(6,54) = p < .036, η2 = .214). As noted previously, there was an increase in the placebo analgesic effect following the first two

Placebo manipulation decreases pain ratings and brain activation

In our previous work, examination of the BOLD signal revealed that the placebo response was active and identifiable within a few seconds of stimulus onset. This supported our hypothesis that reductions in pain-related brain activation resulted from the placebo manipulation rather than a response or report bias as others have suggested (Hrobjartsson and Gotzsche, 2001, Wager et al., 2004).

The observed placebo analgesic effect of that study was larger than in previous fMRI experiments and was

Acknowledgments

Support for this research was provided from Grant RO1 (AT001424) to Dr. Michael Robinson, from the National Institutes of Health, National Center for Complementary and Alternative Medicine, a Merit Review Award (PI: G.N. Verne) from the Medical Research Service of the Department of Veteran Affairs, and Grant 1-R01-NS053090-01 from the National Institutes of Health (PI: G.N. Verne). The authors would also like to thank Adam Hirsh, Erin O’Brien, Karen Chung, Xeve Silver and Trish Stamm for their

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