A Functional Magnetic Resonance Imaging Study on the Neural Mechanisms of Hyperalgesic Nocebo Effect

“In an early study, Biswal et al. (1995) found that, while subjects were at rest, spontaneous fMRI blood oxygen leveldependent signal fluctuations observed in left sensory motor areas showed a high degree of temporal correlation with right sensory motor-related brain areas and medial motor areas.”

“Methods for functional connectivity analysis were adopted from previous studies (Fox et al., 2005; AndrewsHanna et al., 2007; Vincent et al., 2007).”

“At the very beginning of fMRI scanning session, we also collected a 6 min spontaneous fMRI data set to investigate functional connectivity (Raichle and Mintun, 2006; Buckner and Vincent, 2007; Fox and Raichle, 2007) among the brain regions observed to be activated in the subsequent analysis of the nocebo scans.”

“…Neuroscience 0270-6474/08/2813354-09$15.00/0 Previous studies have suggested that the central pain matrix consists of approximately two parallel subsystems, the lateral (sensory– discriminatory) and medial (affective– cognitive evaluation) system (Apkarian et al., 2005; Tracey and Mantyh, 2007).”

“In this experiment, we found a significant fMRI signal increase to pain in bilateral ACC, a key region involved in processing the affective components of pain (Rainville et al., 1997; Price, 2000; Rainville, 2002).”

“Previous studies implicate operculum/insula as the most reliable region in brain imaging studies on pain (Peyron et al., 2000) and report its direct association with S1, SII, prefrontal areas, superior temporal gyrus, amygdaloid, and perirhinal cortex, which is an important source of hippocampal…”

“In this experiment, we found a significant fMRI signal increase to pain in bilateral ACC, a key region involved in processing the affective components of pain (Rainville et al., 1997; Price, 2000; Rainville, 2002).”

“…2001); (3) has not been reported in the substantial placebo analgesia neuroimaging literature base (Petrovic et al., 2002; Lieberman et al., 2004; Wager et al., 2004, 2007); Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006a; Craggs et al., 2007; Price et al., 2007; Scott et al.,…”

“Previous studies have suggested that the central pain matrix consists of approximately two parallel subsystems, the lateral (sensory– discriminatory) and medial (affective– cognitive evaluation) system (Apkarian et al., 2005; Tracey and Mantyh, 2007).”

“The medial system projects through the medial thalamic nuclei to the cortex and includes the anterior cingulate cortex (ACC), insula, and prefrontal cortices (Price, 2000; Rainville, 2002; Vogt, 2005).”

“Methods for functional connectivity analysis were adopted from previous studies (Fox et al., 2005; AndrewsHanna et al., 2007; Vincent et al., 2007).”

“…region in brain imaging studies on pain (Peyron et al., 2000) and report its direct association with S1, SII, prefrontal areas, superior temporal gyrus, amygdaloid, and perirhinal cortex, which is an important source of hippocampal and ACC afferents (Augustine, 1996; Cipolloni and Pandya, 1999).”

“At the very beginning of fMRI scanning session, we also collected a 6 min spontaneous fMRI data set to investigate functional connectivity (Raichle and Mintun, 2006; Buckner and Vincent, 2007; Fox and Raichle, 2007) among the brain regions observed to be activated in the subsequent analysis of the nocebo scans.”

“Interestingly, although the brain-imaging literature for placebo analgesia is quite robust (Petrovic et al., 2002; Lieberman et al., 2004; Wager et al., 2004, 2007; Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006a; Craggs et al., 2007; Price et al., 2007; Scott et al., 2007, 2008), no placebo analgesia st…”

“Sham electro-acupuncture was then performed at two acupoints on the right hand (LI 4 and LI 3) using the validated, nonpenetrating Streitberger sham acupuncture device (Streitberger and Kleinhenz, 1998; Kleinhenz et al., 1999; Kong et al., 2006a; McManus et al., 2007).”

“) We selected the left hippocampus as a seed region because it (1) showed significant differences in group analysis; (2) played an important role in the correlation between anxiety and pain intensity ratings, as indicated by a previous study (Ploghaus et al., 2001); (3) has not been reported in the substantial placebo…”

“Placebo effects have received much attention in recent decades, and with the advent of brain imaging tools, our understanding of their neurobiology has greatly expanded (Benedetti et al., 2005; Colloca and Benedetti, 2005; Kong et al., 2007; Benedetti, 2008).”

“Previous studies suggest that nocebo effects, sometimes termed “negative placebo effects,” contribute appreciably to a variety of medical symptoms (Barsky and Borus, 1999; Barsky et al., 2002), adverse events in clinical trials and medical care (Myers et al.”

“…the brain-imaging literature for placebo analgesia is quite robust (Petrovic et al., 2002; Lieberman et al., 2004; Wager et al., 2004, 2007; Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006a; Craggs et al., 2007; Price et al., 2007; Scott et al., 2007, 2008), no placebo…”

“Previous brain imaging studies have indicated that expectation can significantly modulate subsequent noxious stimuli perception (Sawamoto et al., 2000; Koyama et al., 2005; Keltner et al., 2006).”

“In a recent Positron Emission Tomography study, Scott and colleagues (Scott et al., 2008) asked subjects to undergo a 20 minute pain challenge and found placebo-enhanced opioid Kong et al.”

“In this experiment, we found a significant fMRI signal increase to pain in bilateral ACC, a key region involved in processing the affective components of pain (Rainville et al., 1997; Price, 2000; Rainville, 2002).”

“Our study also showed nocebo-induced fMRI signal changes in left hippocampus, a region known to play an important role in encoding relations between various learning context cues (Olsson and Phelps, 2007) and mediating aversive drive and the affective characteristics of pain (Melzack and Casey, 1968).”

“Session 2—We used Session 2 to manipulate subjects’ expectancy to sham acupuncture treatment using a method modified from our previous work (Montgomery and Kirsch, 1997; Price et al., 1999; Wager et al., 2004; Kong et al., 2006b).”

“…placebo analgesia neuroimaging literature base (Petrovic et al., 2002; Lieberman et al., 2004; Wager et al., 2004, 2007); Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006a; Craggs et al., 2007; Price et al., 2007; Scott et al., 2007, 2008) and may thus be uniquely involved in…”

“, 2001) ; 3) has not been reported in the substantial placebo analgesia neuroimaging literature base (Petrovic et al., 2002; Lieberman et al., 2004; Wagner et al., 2005; Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006b; Craggs et al., 2007; Price et al., 2007; Scott et al., 2007; Wager et al., 2007; Scott…”

“, 2002), adverse events in clinical trials and medical care (Myers et al., 1987; Roscoe et al., 2000; Reuter et al., 2003; Kaptchuk et al., 2006), and public health “mass psychogenic illness” outbreaks (Jones et al.”

“At the very beginning of fMRI scanning session, we also collected a 6 min spontaneous fMRI data set to investigate functional connectivity (Raichle and Mintun, 2006; Buckner and Vincent, 2007; Fox and Raichle, 2007) among the brain regions observed to be activated in the subsequent analysis of the nocebo scans.”

“Previous brain imaging studies have indicated that expectation can significantly modulate subsequent noxious stimuli perception (Sawamoto et al., 2000; Koyama et al., 2005; Keltner et al., 2006).”

“In this current experiment, we used functional magnetic resonance imaging (fMRI) and a modified expectancy/conditioning manipulation model (Montgomery and Kirsch, 1997; Price et al., 1999; Wager et al., 2004; Kong et al., 2006a) to investigate the neural substrates of hyperalgesic nocebo.”

“, 2001) ; 3) has not been reported in the substantial placebo analgesia neuroimaging literature base (Petrovic et al., 2002; Lieberman et al., 2004; Wagner et al., 2005; Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006b; Craggs et al., 2007; Price et al., 2007; Scott et al., 2007; Wager et al., 2007; Scott…”

“Previous studies have characterized the behavioral response to nocebo hyperalgesia and described the important role of anxiety in this process (Benedetti et al., 2006).”

“Placebo effects have received much attention in recent decades, and with the advent of brain imaging tools, our understanding of their neurobiology has greatly expanded (Benedetti et al., 2005; Colloca and Benedetti, 2005; Kong et al., 2007; Benedetti, 2008).”

“…later use to test for nocebo effects, we conducted an initial group comparison of all pretreatment high and low pain sequences (Wager et al., 2004; Kong et al., 2006a), constructing a mask for subsequent group analysis (with threshold set at voxelwise p 0.005, uncorrected with 20 contiguous…”

“Previous brain imaging studies have indicated that expectation can significantly modulate subsequent noxious stimuli perception (Sawamoto et al., 2000; Koyama et al., 2005; Keltner et al., 2006).”

“The lateral orbital prefrontal cortex and dACC are known to play key roles in cognitively modulating the emotional components of pain (Petrovic and Ingvar, 2002) and processing affective aspects of pain (Price, 2000), respectively.”

“Sham electro-acupuncture was then performed at two acupoints on the right hand (LI 4 and LI 3) using the validated, nonpenetrating Streitberger sham acupuncture device (Streitberger and Kleinhenz, 1998; Kleinhenz et al., 1999; Kong et al., 2006a; McManus et al., 2007).”

“Interestingly, although the brain-imaging literature for placebo analgesia is quite robust (Petrovic et al., 2002; Lieberman et al., 2004; Wager et al., 2004, 2007; Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006a; Craggs et al., 2007; Price et al., 2007; Scott et al., 2007, 2008), no…”

“Interestingly, although the brain-imaging literature for placebo analgesia is quite robust (Petrovic et al., 2002; Lieberman et al., 2004; Wager et al., 2004, 2007; Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006a; Craggs et al., 2007; Price et al., 2007; Scott et al., 2007, 2008), no placebo analgesia st…”

“In one of the few nocebo mechanism studies to date, Benedetti and colleagues (Benedetti et al., 1997) reported that while proglumide, a nonspecific cholecystokinin (CCK) antagonist, could counteract nocebo-induced hyperalgesia, the opioid antagonist naloxone had no effect on nocebo responses.”

“, 2002), adverse events in clinical trials and medical care (Myers et al., 1987; Roscoe et al., 2000; Reuter et al., 2003; Kaptchuk et al., 2006), and public health “mass psychogenic illness” outbreaks (Jones et al.”

“Because we wanted our intervention to be novel for patients, we used a validated sham acupuncture device and allowed only ing methods used in our previous studies (Kong et al., 2005, 2006a,b).”

“…robust (Petrovic et al., 2002; Lieberman et al., 2004; Wager et al., 2004, 2007; Zubieta et al., 2005; Bingel et al., 2006; Kong et al., 2006a; Craggs et al., 2007; Price et al., 2007; Scott et al., 2007, 2008), no placebo analgesia study to date has ever reported involvement of the…”

“An animal study (Andre et al., 2005) further documented the ability of CCK-B receptor antagonist CI-988 (4-[[2-[[3-(1H-indol-3-yl)-2methyl - 1- oxo - 2[[(tricyclo[3 .”

“Placebo effects have received much attention in recent decades, and with the advent of brain imaging tools, our understanding of their neurobiology has greatly expanded (Benedetti et al., 2005; Colloca and Benedetti, 2005; Kong et al., 2007; Benedetti, 2008).”

“, 2002), adverse events in clinical trials and medical care (Myers et al., 1987; Roscoe et al., 2000; Reuter et al., 2003; Kaptchuk et al., 2006), and public health “mass psychogenic illness” outbreaks (Jones et al.”

“Sham electro-acupuncture was then performed at two acupoints on the right hand (LI 4 and LI 3) using the validated, nonpenetrating Streitberger sham acupuncture device (Streitberger and Kleinhenz, 1998; Kleinhenz et al., 1999; Kong et al., 2006a; McManus et al., 2007).”

“, 2002), adverse events in clinical trials and medical care (Myers et al., 1987; Roscoe et al., 2000; Reuter et al., 2003; Kaptchuk et al., 2006), and public health “mass psychogenic illness” outbreaks (Jones et al.”

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“ACC and insula responses vary not simply as a function of noxious input but rather as a function of subjectively felt pain intensity (Kong et al. 2008).”

“Activity in medial frontal areas and hippocampus has also been observed in a recent study on the nocebo hyperalgesic effects during sham acupuncture (29).”

“In a recent fMRI study activation in the anterior insula was not simply driven by the noxious input but was more pronounced when participants were instructed to rate their subjective intensity of pain (Kong et al., 2008).”

“A recent neuroimaging study has shown that nocebo effects are mediated by the hippocampus and regions involved with anticipatory anxiety and, as such, are distinct from placebo effects at a neural leve”