Previous studies suggest that nocebo effects, sometimes termed "negative placebo effects," can contribute appreciably to a variety of medical symptoms and adverse events in clinical trials and medical care. In this study, using a within-subject design, we combined functional magnetic resonance imaging (fMRI) and an expectation/conditioning manipulation model to investigate the neural substrates of nocebo hyperalgesia using heat pain on the right forearm. Thirteen subjects completed the study. Results showed that, after administering inert treatment, subjective pain intensity ratings increased significantly more on nocebo regions compared with the control regions in which no expectancy/conditioning manipulation was performed. fMRI analysis of hyperalgesic nocebo responses to identical calibrated noxious stimuli showed signal increases in brain regions including bilateral dorsal anterior cingulate cortex (ACC), insula, superior temporal gyrus; left frontal and parietal operculum, medial frontal gyrus, orbital prefrontal cortex, superior parietal lobule, and hippocampus; right claustrum/putamen, lateral prefrontal gyrus, and middle temporal gyrus. Functional connectivity analysis of spontaneous resting-state fMRI data from the same cohort of subjects showed a correlation between two seed regions (left frontal operculum and hippocampus) and pain network including bilateral insula, operculum, ACC, and left S1/M1. In conclusion, we found evidence that nocebo hyperalgesia may be predominantly produced through an affective-cognitive pain pathway (medial pain system), and the left hippocampus may play an important role in this process.

Recent advances in placebo research have demonstrated the mind's power to alter physiology. In this study, we combined an expectancy manipulation model with both verum and sham acupuncture treatments to address: 1) how and to what extent treatment and expectancy effects - including both subjective pain intensity levels (pain sensory ratings) and objective physiological activations (fMRI)- interact; and 2) if the underlying mechanism of expectancy remains the same whether placebo treatment is given alone or in conjunction with active treatment. The results indicate that although verum acupuncture+high expectation and sham acupuncture+high expectation induced subjective reports of analgesia of equal magnitude, fMRI analysis showed that verum acupuncture produced greater fMRI signal decrease in pain related brain regions during application of calibrated heat pain stimuli on the right arm. We believe our study provides brain imaging evidence for the existence of different mechanisms underlying acupuncture analgesia and expectancy evoked placebo analgesia. Our results also suggest that the brain network involved in expectancy may vary under different treatment situations (verum and sham acupuncture treatment).

In this study, a well established expectancy manipulation model was combined with a novel placebo intervention, a validated sham acupuncture needle, to investigate the brain network involved in placebo analgesia. Sixteen subjects completed the experiment. We found that after placebo acupuncture treatment, subjective pain rating reduction (pre minus post) on the placebo-treated side was significantly greater than on the control side. When we calculated the contrast that subtracts the functional magnetic resonance imaging (fMRI) signal difference between post-treatment and pretreatment during pain application on placebo side from the same difference on control side [e.g., placebo (post - pre)- control (post - pre)], significant differences were observed in the bilateral rostral anterior cingulate cortex (rACC), lateral prefrontal cortex, right anterior insula, supramarginal gyrus, and left inferior parietal lobule. The simple regression (correlation) analysis between each subject's fMRI signal difference of post-treatment and pretreatment difference on placebo and control side and the corresponding subjective pain rating difference showed that significant negative correlation was observed in the bilateral lateral/orbital prefrontal cortex, rACC, cerebellum, right fusiform, parahippocampus, and pons. These results are different from a previous study that found decreased activity in pain-sensitive regions such as the thalamus, insula, and ACC when comparing the response to noxious stimuli applied to control and placebo cream-treated areas of the skin. Our results suggest that placebo analgesia may be configured through multiple brain pathways and mechanisms.

Comorbid psychopathology is a variable not explored in the acupuncture RCTs that could explain whether subgroups of patients with chronic low back pain have differential responses to acupuncture or placebo treatments. This was a controlled, blinded, crossover trial of verum acupuncture and validated sham acupuncture in 40 CLBP patients, with a Low or High level of psychiatric comorbidity. They completed a 0 to 10 rating scale for pain at the beginning and end of each treatment session, and rated their expectations for change in pain. Verum acupuncture was performed at Large Intestine 4 on the dorsal right hand for 30 minutes by a licensed acupuncturist. Data analysis used percent improvement in pain as the primary outcome for each of the treatment sessions. Both groups (21 Low and 19 High) reported significant analgesia with verum acupuncture needling, mean 33%, P =.9 for difference between groups; and with placebo, 26%, P =.09. In both groups, expectations were only a significant predictor of verum acupuncture response, P =.002, such that those with greater expectations had greater pain relief. Psychiatric comorbidity does not significantly impact acupuncture or placebo acupuncture analgesia in CLBP. It does not affect the positive impact of expectations on reported pain relief from real acupuncture. PERSPECTIVE: Psychiatric comorbidity may predict differences between acupuncture and placebo responses, not otherwise seen in the RCTs for low back pain. Using a blinded, crossover design, we report that it does not predict outcome, nor does it seem to modify the effect of expectancy (a known predictor) on acupuncture response.

De qi is an important traditional acupuncture term used to describe the connection between acupuncture needles and the energy pathways of the body. The concept is discussed in the earliest Chinese medical texts, but details of de qi phenomenon, which may include the acupuncturist's and/or the patient's experiences, were only fully described in the recent hundred years. In this paper, we will trace de qi historically as an evolving concept, and review the literature assessing acupuncture needle sensations, and the relationship between acupuncture-induced de qi and therapeutic effect. Thereafter, we will introduce the MGH Acupuncture Sensation Scale (MASS), a rubric designed to measure sensations evoked by acupuncture stimulation as perceived by the patient alone, and discuss some alternative statistical methods for analyzing the results of this questionnaire. We believe widespread use of this scale, or others like it, and investigations of the correlations between de qi and therapeutic effect will lead to greater precision in acupuncture research and enhance our understanding of acupuncture treatment.

The concept that specific acupuncture points have salubrious effects on distant target organ systems is a salient feature of Traditional Chinese Medicine (TCM). In this study, we used a multiple-session experiment to test whether electroacupuncture stimulation at two TCM vision-related acupoints, UB 60 and GB 37, located on the leg, could produce fMRI signal changes in the occipital regions of the brain, and the specificity of this effect when compared with stimulation at an adjacent non-acupoint (NAP). Six normal, acupuncture naïve subjects completed the study. Each subject participated in six identical scanning sessions. Voxelwise group analysis showed that electroacupuncture stimulation at both vision-related acupoints and the NAP produced modest, comparable fMRI signal decreases in the occipital cortex, including the bilateral cuneus, calcarine fissure and surrounding areas, lingual gyrus, and lateral occipital gyrus. Further analysis of fMRI signal changes in occipital cortex showed no significant difference among the three points, UB 60, GB 37, and NAP. Our results thus do not support the view that acupuncture stimulation at vision-related acupoints induces specific fMRI blood oxygen level dependent (BOLD) signal changes in the occipital cortex. We speculate that cross modal inhibition, produced by needling-evoked somatosensory stimulation, may account for our finding of BOLD signal decreases in the occipital cortex. Given the complexity of acupuncture systems and brain activity, additional work is required to determine whether functional neuroanatomical correlates of acupoint specificity can be validated by means of brain imaging tools. Hum Brain Mapp 2007.(c) 2007 Wiley-Liss, Inc.

The majority of neuroimaging studies on pain focuses on the study of BOLD activations, and more rarely on deactivations. In this study, in a relatively large cohort of subjects (N=61), we assess (a) the extent of brain activation and deactivation during the application of two different heat pain levels (HIGH and LOW) and (b) the relations between these two directions of fMRI signal change. Furthermore, in a subset of our subjects (N=12), we assess (c) the functional connectivity of pain-activated or -deactivated regions during resting states. As previously observed, we find that pain stimuli induce intensity dependent (HIGH pain>LOW pain) fMRI signal increases across the pain matrix. Simultaneously, the noxious stimuli induce activity decreases in several brain regions, including some of the 'core structures' of the default network (DMN). In contrast to what we observe with the signal increases, the extent of deactivations is greater for LOW than HIGH pain stimuli. The functional dissociation between activated and deactivated networks is further supported by correlational and functional connectivity analyses. Our results illustrate the absence of a linear relationship between pain activations and deactivations, and therefore suggest that these brain signal changes underlie different aspects of the pain experience.

Abstract The advent of scientific research on complementary and alternative medicine (CAM) has contributed to the current state of flux regarding the distinction between biomedicine and CAM. CAM research scientists play a unique role in reconfiguring this boundary by virtue of their training in biomedical sciences on the one hand and knowledge of CAM on the other. This study uses qualitative interviews to explore how CAM researchers perceive and negotiate challenges inherent in their work. Our analysis considers eight NIH-funded CAM researchers':(1) personal engagement with CAM,(2) social reactions towards perceived suspiciousness of research colleagues and (3) strategic methodological efforts to counteract perceived biases encountered during the peer review process. In response to peer suspicion, interviews showed CAM researchers adjusting their self-presentation style, highlighting their proximity to science, and carefully 'self-censoring' or reframing their unconventional beliefs. Because of what was experienced as peer reviewer bias, interviews showed CAM researchers making conciliatory efforts to adopt heightened methodological stringency. As CAM researchers navigate a broadening of biomedicine's boundaries, while still needing to maintain the identity and research methods of a biomedical scientist, this article explores the constant pressure on CAM researchers to appear and act a little more 'scientific'.

Objective: To determine whether placebo responses can be explained by characteristics of the patient, the practitioner, or their interpersonal interaction. Methods: We performed an analysis of videotape and psychometric data from a clinical trial of patients with irritable bowel syndrome who were treated with placebo acupuncture in either a warm empathic interaction (Augmented, n = 96), a neutral interaction (Limited, n = 97), or a waitlist control (Waitlist, n = 96). We examined the relationships between the placebo response and a) patient personality and demographics; b) treating practitioner; and c) the patient-practitioner interaction as captured on videotape and rated by the Psychotherapy Process Q-Set. Results: Patient extraversion, agreeableness, openness to experience, and female gender were associated with placebo response, but these effects held only in the augmented group. Regression analyses controlling for all other independent variables suggest that only extraversion is an independent predictor of placebo response. There were significant differences between practitioners in outcomes; this effect was twice as large as the effect attributable to treatment group assignment. Videotape analysis indicated that the augmented group fostered a treatment relationship similar to a prototype of an ideal healthcare interaction. Conclusions: Personality and gender influenced the placebo response, but only in the warm, empathic, augmented group. This suggests that, to the degree a placebo effect is evoked by the patient-practitioner relationship, personality characteristics of the patient will be associated with the placebo response. In addition, practitioners differed markedly in effectiveness, despite standardized interactions. We propose that the quality of the patient-practitioner interaction accounts for the significant difference between the groups in placebo response.

Functional neuroimaging studies suggest that a lateral network in the brain is associated with the sensory aspects of pain perception while a medial network is associated with affective aspects. The highest concentration of opioid receptors is in the medial network. There is significant evidence that endogenous opioids are central to the experience of pain and analgesia. We applied an integrative multimodal imaging approach during acupuncture. We found functional magnetic resonance imaging signal changes in the orbitofrontal cortex, insula, and pons and [11C]diprenorphine positron emission tomography signal changes in the orbitofrontal cortex, medial prefrontal cortex, insula, thalamus, and anterior cingulate cortex. These findings include brain regions within both the lateral and medial pain networks.

The placebo effect has been extensively studied in many disease states, some of the most notable being pain and depression. Utilizing a Medline search, studies were identified that reported on areas of the brain shown to be involved in either placebo analgesia or mood response. This paper presents a distillation of this research, in an effort to identify a common "placebo pathway" between mood and pain. Placebo-related responses to both analgesia and relief from depression were reported to be associated with an increase in activity in the frontal cortex and a decrease in activity in the thalamus.

Functional neuroimaging techniques have revealed the cerebral substrates of pain perception (pain matrix) in humans, which include the thalamus, as well as primary, secondary somatosensory, insular, anterior cingulate, and prefrontal cortices. Functional magnetic resonance imaging (fMRI) could be the most suitable candidate for routine clinical use in the evaluation of pain because of its relatively low cost and the absence of irradiation. Here the author summarizes the practical aspects of fMRI studies on pain, and proposes the "bottom-up/top-down theory" of cerebral pain processing that explains possible interaction among discrete parts of pain matrix. Long-term, plastic changes induced by such interaction could play a pivotal role in the exaggerated brain activity of chronic pain patients. The top-down component of pain matrix also explains basic neuroimaging findings on the anticipation, empathy, and placebo effects of pain, and on the cortical trigger of the descending pain inhibitory system. Finally, the author summarizes his recent research on the cerebral substrates of chronic low back pain, and shows a case study on neuropathic pain using fMRI, which hopefully should help in planning clinical fMRI studies for a longitudinal follow-up of chronic pain patients.

Expectations and beliefs modulate the experience of pain, which is particularly evident in placebo analgesia. The dorsolateral prefrontal cortex (DLPFC) has been associated with pain regulation and with the generation, maintenance and manipulation of cognitive representations, consistent with its role in expectation. In a heat-pain paradigm, we employed non-invasive low-frequency repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt left and right DLPFC function or used the TMS device itself as a placebo, before applying an expectation-induced placebo analgesia. The results demonstrated that placebo significantly increased pain threshold and pain tolerance. While rTMS did not affect pain experience, it completely blocked placebo analgesia. These findings suggest that expectation-induced placebo analgesia is mediated by symmetric prefrontal cortex function.

Placebo analgesia is a prime example of the impact that psychological factors have on pain perception. We used functional magnetic resonance imaging of the human spinal cord to test the hypothesis that placebo analgesia results in a reduction of nociceptive processing in the spinal cord. In line with behavioral data that show decreased pain responses under placebo, pain-related activity in the spinal cord is strongly reduced under placebo. These results provide direct evidence for spinal inhibition as one mechanism of placebo analgesia and highlight that psychological factors can act on the earliest stages of pain processing in the central nervous system.

Neuroimaging makes it possible to study pain processing beyond the peripheral nervous system, at the supraspinal level, in a safe, noninvasive way, without interfering with neurophysiological processes. In recent years, studies using brain imaging methods have contributed to our understanding of the mechanisms responsible for the development and maintenance of chronic pain. Moreover, neuroimaging shows promising results for analgesic drug development and in characterizing different types of pain, bringing us closer to development of mechanism-based diagnoses and treatments for the chronic pain patient.

Placebo has been reported to exert beneficial effects in patients regarding the treatment of pain. Human functional neuroimaging technology can study the intact human brain to elucidate its functional neuroanatomy and the neurobiological mechanism of the placebo effect. Blood flow measurement using functional magnetic resonance imaging and positron emission tomography (PET) has revealed that analgesia is related to decreased neural activities in pain-modulatory brain regions, such as the rostral anterior cingulate cortex (rACC), insula, thalamus, and brainstem including periaqueductal gray (PAG) and ventromedial medulla. The endogenous opioid system and its activation of mu-opioid receptors are thought to mediate the observed effects of placebo. The mu-opioid receptor-selective radiotracer-labeled PET studies show that the placebo effects are accompanied by reduction in activation of opioid neural transmission in pain-sensitive brain regions, including rACC, prefrontal cortex, insula, thalamus, amygdala, nucleus accumbens (NAC) and PAG. Further PET studies with dopamine D2/D3 receptor-labeling radiotracer demonstrate that basal ganglia including NAC are related to placebo analgesic responses. NAC dopamine release induced by placebo analgesia is related to expectation of analgesia. These data indicate that the aforementioned brain regions and neurotransmitters such as endogenous opioid and dopamine systems contribute to placebo analgesia.

The experience of a sensory event is extensively shaped by past experience and expectations. Placebo analgesia, one of the most studied models of expectation-mediated effects, can be induced by suggestion of analgesia and conditioning. The present study examined the possibility that sleep might contribute to the consolidation of new expectations and consequently influence the generation of expectation-mediated placebo effects. Strong expectations of analgesia were generated before sleep by conditioning manipulations wherein the intensity of thermal pain stimulation was surreptitiously reduced after the application of a topical placebo cream. Expectations and placebo analgesic effects were measured the following morning and compared with those of a control daytime group without sleep. Although placebo effects were observed in both groups, correlation analysis suggests that the mediating effect of expectations on placebo responses was strongest in the overnight group. Moreover, after exposure to a convincing analgesia experience, the relative duration of rapid eye movement (REM) sleep decreased in subjects showing higher analgesic expectations and placebo responses the next morning. In a third group exposed to less consistent analgesic experiences before sleep, expectations reported in the morning were comparable with other groups. However, expectations were positively correlated with REM sleep and did not emerge as a significant mediator of the analgesic effect. Together, these findings show that sleep-related processes may influence the association between expectations and placebo analgesia and that REM sleep can predict placebo-induced expectations of pain relief. However, equivocal previous experience with treatments may significantly alter the relationship between relief expectation, REM sleep, and placebo effects.