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).”

“[16,47,48]), with increases occurring also during nocebo hyperalgesia [49].”

“[21,22].”

“Benedetti et al. (2006) showed that (as summarized in Manchikanti et al., 2011): (1) oral administration of an inert substance, together with the verbal suggestions of hyperalgesia, induced hyperalgesia as well as increased adrenocorticotropic hormone (ACTH) and cortisol-2 plasma concentrations,…”

“First, administering a placebo with the suggestion of an adverse outcome can cause participants to experience that outcome, often referred to as the nocebo effect (Ikemi and Nakagawa, 1962; Luparello et al., 1968; McFadden et al., 1969; Schweiger and Parducci, 1981; Bayer et al., 1991; Benedetti et al., 1997, 2006; Co…”

“Neuroimaging studies of nocebo effects in pain found elevated activation in hippocampus, MCC and the amygdala (Kong et al., 2008; Bingel et al., 2011; Schmid et al., 2015), which were also involved in the present study.”

“4B(d)), the right IFG (Fig.”

“hypoalgesia, activation patterns involve regions such as the PAG and prefrontal cortex (Freeman et al., 2015; Kong et al., 2008; Tinnermann et al., 2017).”

“contrast, nocebo hyperalgesia is associated with increased painrelated brain activation.(28) Importantly, the efficacy of expectations of shaping afferent nociceptive processing and the experience of pain may likely be”

“For example, this is evident when looking at the placebo/ nocebo effect that influences pain related brain activation (Bingel 2010; Kong et al. 2008; Lidstone and Stoessl 2007).”

“…imagery and contagiousness (Holle et al., 2012; Mochizuki et al., 2013) were reported for some brain regions (insula and prefrontal areas), which are also involved in hyperalgesic nocebo and nocebo-related responses (Kong et al., 2008; Freeman et al., 2015; for review see: Benedetti et al., 2007).”

“Statistical Analysis To assess the magnitude of placebo effects, we calculated the changes of subjective pain intensity and unpleasantness by subtracting the ratings in the post-treatment session from those in the pre-treatment session in Test phase (49).”

“Anterior cingulate cortex, insula, left orbital frontal cortex, right lateral prefrontal cortex Experimental noxious thermal stimuluswith nocebowords fMRI showed activation in the anterior cingulate cortex, insula, left orbital frontal cortex and right lateral prefrontal cortex during nocebo hyperalgesia [73]”

“For instance, it has been suggested that the hyperalgesic effect of pain expectancy is facilitated through the central activation of the pain matrix.(39) Relatedly, previous findings suggest that when individuals anticipate pain, a number of neural substrates associated with affective and cognitive processing are acti…”

“Another meaningful study (Kong et al., 2008) showed that activity in the dorsal anterior cingulate cortex was significantly enhanced under a pain nocebo condition, indicating that this region played an important role in negative arousal.”

“the spinal cord [3] and in brain regions involved in pain processing, like the thalamus, the insula, the prefrontal cortex, the anterior cingulate cortex [4, 5].”

“Because the ACC has been implicated in descending facilitation [54], these findings suggest that OA patients have hyperactive descending facilitatory pathways.”

“, cholecystokinin for nocebo effects) [62, 63].”

“A potential explanation for this finding could be that brain areas involved in expectation and anticipation, like the dorsolateral prefrontal cortex (Kong et al., 2008; Wager et al., 2004; Krummenacher, Candia, Folkers, Schedlowski, & Schonbachler, 2010), may exert a top‐down influence on the inhibitory circuits of th…”

“In addition, given that an administration of placebos may not be only lead to placebo effect but also result in nocebo effect [16, 17], a negative response to the treatment [4, 17, 18], the examinations on how expectation interventions influence the nocebo effect were also included to provide insights into the avoidan…”

“The areas of the brain and rostral portions of the brainstem that play a key role in pain/sensation perception and descending modulation have been observed in humans by means of fMRI and positron emission tomography and by microstimulation during surgical procedures [8,9,26–29].”

“A large number of studies have investigated the neural mechanisms of placebo analgesia and nocebo hyperalgesia using neuroimaging techniques, but few have directly compared them (Amanzio et al., 2013; Atlas and Wager, 2014; Kong et al., 2008; Reicherts et al., 2017; Schmid et al., 2015a; Schmid et al., 2013; Scott et…”

“Kong and colleagues [33] found that an expectation/conditioning manipulation model can produce a nocebo effect (expectationinduced pain enhancement, opposite of the placebo effect) correlated with activation of the medial pain system.”

“This phenomenon is called “ disinhibition, ” which means neurons in an area are no longer inhibited with no original input or output (Kong et al., 2008).”

“2008), and also in situations that induce negative expectations not resulting from drug-related information but rather disease-related information as well as from learning or conditioning (Colloca et al. 2008, 2010; Jensen et al. 2012; Kong et al. 2008).”

“At the neural level, it has been shown that negative expectancies and subsequent pain enhancement are associated with an increase in brain activity observed in cortical regions such as insula and anterior cingulate cortex (ACC) [18].”

“Moreover, the level of rACC deactivation predicted the strength of reported nocebo hyperalgesia and the spinal cord and rACC revealed coupling with the PAG that correlated with the nocebo magnitude.”

“In a functional resonance imaging study Kong et al. (2008) [USA] found that nocebo hyperalgesia may be produced through a cognitive pain pathway (medial pain system) and that the hippocampus may play an important role in this process.”

“In addition, most acupuncture neuroimaging studies have characterized brain response to acupuncture in healthy adults as opposed to the responses in patient populations.(3,5,6) Acupuncture and Traditional Chinese Medicine are usually not clinically applied to healthy adults but have been widely applied as alternative…”

“Cortical areas that are known to be involved in the processing of negative emotions, such as the amygdala (Schmid et al 2015) and the hippocampus (Kong et al 2008; Bingel et al 2011) were shown to be affected by nocebo manipulations.”

“This finding concurs with previous reports of heightened hippocampal activity during nocebo hyperalgesia (Jensen et al., 2015; Kong et al., 2008).”

“Nocebo effects might be produced through the medial pain system (54), with the hippocampus, the dopaminergic system, and the release of endorphins and endogenic opioids as key players.”

“The majority of previous nocebo neuroimaging studies have investigated nocebo effects in the context of pain (e.g., Kong et al. 2008).”

“For example, in experimental nocebo research, some nocebo conditioning paradigms include as few as four associative learning trials (5), whereas others use much longer paradigms (6,8,31).”

“In addition, the FC of the aIC and OFC was increased prior to or during the stimulus.(4,7,31,32) During anticipation of dental treatment and hyperventila-”

“nocebo hyperalgesic effects as measured by higher pain levels in a nocebo-treated than a no-treated group.(24,49,69,79) Laboratory”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript and (iii) been previously used to assess subjective pain ratings in fMRI studies of treatment expectancy in chronic pain patients (Gollub et al., 2018; Kong et al., 2018) and healthy adults (Kong et al., 2008).”

“The results in the nocebo acupuncture manipulation study (N = 13) (Kong et al., 2008) showed a significant correlation between the pre-post control and pre-post nocebo effects, r = 0.”

“All human beings experience nocebo behaviors which vary by person, and they are controlled by identified brain mechanisms located in labelled brain areas [12,35,36].”

“Subjects were trained to use the Sensory Gracely Scale (0 – 20) (Gracely et al., 1978a, 1978b) to rate pain experiences using the same method as in our previous studies (Freeman et al., 2015; Kong et al., 2008, 2006).”

“Bidirectional influences on pain are well known as placebo attenuation and nocebo enhancement of pain sensitivity following overt suggestions which influence central mechanisms for pain coding andmodulation (Enck et al., 2008; Kong et al., 2008; Scott et al., 2008).”

“…altered in psychotic states (Adams et al. 2013; Fletcher & Frith 2009) due to aberrant (or hyper) salience of incoming information (Kapur 2003) - possibly linked to a hypersensitive dopamine system (Kuepper et al. 2012) - and weakened or imprecise priors (Adams et al. 2013; Fletcher & Frith 2009).”

“26, 32, 47, 66 A limitation of this study is the unequal gender representation, despite the known influence of sex on pain anticipation and perception, with female individuals often experiencing greater psychological distress from pain.”

“Feelings like anxiety are known to be associated with nocebo effects [68], which can diminish therapeutic outcomes, whereas feelings of reward often have the opposite effect [69].”

“For instance, in clinical, the physician usually compares several medical images of the same patient at different times to evaluate the effect of the treatment [8].”

“Moreover, studies of nocebo procedures have shown altered activity in the endogenous pain modulatory system (Bingel et al., 2011; Scott et al., 2008), and increased activity of the affective–cognitive (medial) pain system (Kong et al., 2008).”

“These were the orbitofrontal cortex (OFC 9,28 ; Schiene et al. 2018), ACC 29 ), NAc, and PVH 9 .”

“…meta-regression, nocebo response Nocebo response has been mostly studied in the field of Neurology: neurological pain syndromes—nocebo hyperalgesia (Kong et al., 2008), headaches (Mitsikostas et al., 2011), neuropathic pain (Papadopoulos & Mitsikostas, 2012)—, neuromuscular disorders—chronic…”

“In another study, other researchers investigated the effect of negative expectancy and found that it can produce a painrating increase after placebo acupuncture (hyperalgesic nocebo effect), as well as an fMRI-signal increase in brain regions associated with anxiety about pain (such as the hippocampus) and the brain r…”

“20,25,35 Furthermore, in a recent ultra-high field fMRI study, we demonstrated that nocebo hyperalgesia is associated with signal changes in the well-described brainstem pain modulatory circuit: the lPAG–rostral ventromedial medulla (RVM)axis.”

“Especially the left hippocampus, as affected in our study, is responsible for the development of hyperalgesia and the emergence of persistent pain 42,43 .”