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REVIEW

Imaging the placebo response:A neurofunctional reviewVanda Faria ⁎, Mats Fredrikson, Tomas Furmark

Department of Psychology, Uppsala University, Uppsala, Sweden

Received 20 November 2007; received in revised form 4 March 2008; accepted 12 March 2008

Abstract

An emerging literature has started to document the neuronal changes associatedwith the placebophenomenon. This has altered placebo from being considered a nuisance factor in clinicalresearch to a target of scientific investigation per se. This paper reviews the neuroimagingliterature on the placebo effect, and illustrates how imaging tools can improve current under-standing of brain mechanisms underlying the placebo response. Imaging studies provide evidenceof specific, predictable and replicable patterns of neural changes associated with placeboadministration. In general, placebo responses seem mediated by “top-down” processes depen-dent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergicreward pathways may underlie these expectancies. Placebo-induced clinical benefits also involvedisorder-specific neuronal responses, yielding neurofunctional or neurochemical alterationssimilar to those produced by pharmacological treatments.© 2008 Elsevier B.V. and ECNP. All rights reserved.

KEYWORDSPlacebo effect;Neuroimaging;Positron emissiontomography;Functional magneticresonance imaging;Review

1. Introduction

Neuroimaging research on the placebo effect is an emergingfield that may ultimately provide a key to one of the oldestquestions in the history of medicine, namely how mind–bodyprocesses affect healing. Historically, placebos have had animportant role in the development of medicine (Wolf, 1959).Interestingly the term placebo was first introduced into amedical dictionary in 1785 as “a commonplace method ormedicine” (cited in Shapiro and Shapiro, 1997 p.30). Nowadays,despite not having an unequivocal definition (see Macedo et al.,2003), it usually refers to the beneficial outcome of a treatment

known tohaveno specific effect for the conditionbeing treated,but in which the patient believes in its efficacy. Placebo effectshave been reported in several ailments (see Beecher, 1955) inthousandsof randomizedcontrolled trials.Hence, it has becomeobvious that the placebo effect is not restricted to one type oftherapy or condition (Benedetti et al., 2005).

Expectancies and conditioning have traditionally beenused to explain the placebo responses (see Wolf, 1950). Areview of this theoretical framework can be found in Stewart-Williams and Podd (2004), Haour (2005) or Koshi and Short(2007). Recent studies searching for the psychological basis ofthe placebo effect have demonstrated that expectation and

⁎ Corresponding author. Department of Psychology, Uppsala University, Box 1225, SE-751 42 Uppsala, Sweden. Tel.: +46 18 4712202; fax: +4618 4712123.

E-mail address: vanda.faria@psyk.uu.se (V. Faria).

0924-977X/$ - see front matter © 2008 Elsevier B.V. and ECNP. All rights reserved.doi:10.1016/j.euroneuro.2008.03.002

www.e l sev i e r. com/ loca te /eu roneu ro

European Neuropsychopharmacology (2008) 18, 473–485

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conditioning mechanisms are involved in eliciting differentplacebo responses (Benedetti et al., 2003). Moreover,psychobiological research have showed that placebos notonly influence behavior, but also disorder-specific brain ac-tivity (Benedetti et al., 2004; de la Fuente-Fernández et al.,2001; Mayberg et al., 2002). This supports that placeboresponses should be defined in terms of active mechanisms(Price, 2000) rather than confounding factors (Hrobjartssonand Gotzsche, 2001, 2004; Kienle and Kiene, 1996, 1997).

In 1978, a pioneering study on placebo-induced endoge-nous opioid release introduced a neurobiological approach tothe investigation of the placebo effect (Levine et al., 1978).However, present day neuroimaging techniques, such as pos-itron emission tomography (PET) and functional magneticresonance imaging (fMRI) enable a more extensive descriptionof how successful placebos affect the central nervous system.

The aim of this paper was to provide a comprehensivereview of the available literature describing the effects ofplacebo treatment on brain activation as measured by neuro-imaging techniques. By examining findings across conditionsand studies, we sought to determine if common or segregatedplacebo brain activity patterns exist.

2. Literature search

The literature obtained was derived from a systematic searchwithin the MEDLINE and PsychInfo databases. The key wordsused were: [“placebo effect”, OR “placebo response”], AND[“imaging”, “PET”, “fMRI”, “single photon emission computedtomography (SPECT)” “regional cerebral blood flow (rCBF)”,“blood oxygen level dependence (BOLD)”, OR “brain”]. Toenhance comparability of cortical and subcortical patternsacross conditions and studies, articles using other techniquessuch as electroencephalography (Benedetti et al., 2006;Hunter et al., 2006; Leuchter et al., 2002; Radin and Lobach,2007; Wager et al., 2006; Watson et al., 2007), or deep brainstimulation (Benedetti et al., 2004; de la Fuente-Fernández,2004; Mercado et al., 2006; Pollo et al., 2002) were notincluded.

A total of 24 imaging studies published up to October2007 were identified and reviewed, six of which measuredBOLD changes using fMRI, whereas 18 used PET to measurerCBF, µ-opioid receptor availability, synaptic availability ofdopamine, or regional cerebral glucose metabolism. Table 1lists the imaging studies using hemodynamic measures of

Table 1 Hemodynamic imaging studies: placebo main findings

Condition/task Participants Method Main findings Reference

Pain/placebo analgesia1. Thermal stimulation Healthy participants PET (rCBF) ↑ rACC and OBFC Petrovic et al. (2002)

↑ rACC covaried with ↑ PAG andpons

2. Intestinal stimulation Irritable bowelsyndrome

PET (rCBF) ↑ VLPFC was associated with ↓dACC

Lieberman et al.(2004)

3. Shock and thermalstimulation

Healthy participants fMRI (BOLD) Anticipation: ↑ DLPFC, OBFC,PAG and rACC

Wager et al. (2004)

Pain: ↓ rACC, thalamus and insula4. Laser stimulation Healthy participants fMRI (BOLD) ↑ rACC covaried with ↑

amygdalae, PAG and the ponsBingel et al. (2006)

5. Intestinal stimulation Irritable bowelsyndrome

fMRI (BOLD) ↓ dACC, thalamus and insula Price et al. (2007)

6. Laser stimulation Healthy participants PET (rCBF) ↑ Medial PFC, posterior parietalcortex and inferior parietal lobe

Nemoto et al. (2007)

↓ ACC, supplementary motorarea and inferior temporal lobe

7. Single case report Chronic lumbar pain PET (rCBF) ↓ Thalamus, rACC and NAc Kupers et al. (2007)8. Monetary incentivedelay task

Healthy participants fMRI (BOLD) Anticipation: ↑ NAc Scott et al. (2007)

Pain/placebo acupuncture analgesia9. Placebo acupuncture Osteoarthritis pain PET (rCBF) ↑ DLPFC, rACC and midbrain Pariente et al. (2005)10. Thermal stimulation Healthy participants fMRI (BOLD) ↑ rACC, LPFC, AI, supramarginal

gyrus and inferior parietal lobuleKong et al. (2006)

Emotional processing/placebo anxiolysis11. Unpleasant pictures Healthy participants fMRI (BOLD) ↑ rACC, OBFC, DLPFC and VLPFC Petrovic et al. (2005)

↓ Fusiform gyrus and inferioroccipital gyrus

Abbreviations: (↑) increases; (↓) decreases; positron emission tomography (PET); regional cerebral blood flow (rCBF); functionalmagnetic resonance imaging (fMRI); blood oxygenation level dependence (BOLD); rostral anterior cingulate cortex (rACC); orbitofrontalcortex (OBFC); periaqueductal gray (PAG); ventrolateral prefrontal cortex (VLPFC); dorsal anterior cingulate cortex (dACC); dorsolateralprefrontal cortex (DLPFC); prefrontal cortex (PFC); nucleus accumbens (NAc); lateral prefrontal cortex (LPFC); anterior insula (AI).

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rCBF and BOLD, and Table 2 lists the neurochemical imagingstudies.

3. Outcome of the literature search

3.1. Hemodynamic imaging studies

3.1.1. Placebo analgesiaThe experience of pain is shaped by personal beliefs andexpectations, which according to some explains how placebotreatments may produce analgesia, despite not having in-trinsic pharmacological effects (Price, 1999).

In a pioneering study, Petrovic et al. (2002) measured rCBFwith PET to investigate the neural circuitry in placebo an-algesia. While exposed to painful and non-painful conditions,healthy participants received either no treatment or an in-

jection either of saline (placebo) or the analgesic remifenta-nil, both paired with instructions of pain relief. Brain areasengaged in opioid as compared to placebo-induced analge-sia were evaluated. Both conditions were associated withincreased activity in the rostral anterior cingulate cortex(rACC) and the orbitofrontal cortex (OBFC), suggestingthat placebo activates the same opioid receptors to whichremifentanil binds (Petrovic et al., 2002). Moreover, covaria-tions between the activity in rACC and the periaqueductalgray (PAG) and pons were also observed in both conditions,possibly reflecting activation of a descendent pain modulat-ing circuitry. These results indicate that placebo and opioidanalgesia share a common neuronal network. Only placebohowever, led to increased activity in the right ventrolateralprefrontal cortex (RVLPFC), suggesting that cognitive pro-cesses may have a role in placebo mediated analgesia.

Table 2 Neurochemical imaging studies: placebo main findings

Condition/task Participants Method Main findings Reference

Opioid release1–2. Sustainedmusclestimulation

Healthyparticipants

[11C-CAR] PET ↑ pgACC, DLPFC, AI and NAc Zubieta et al. (2005, 2006)

3. Thermalstimulation

Healthyparticipants

[11C-CAR] PET Anticipation: ↓ LPFC, AI, pgACC,left amygdala, dorsal PAG, caudate,PFC and inferior frontal junction

Wager et al. (2007)

Pain: ↑ OBFC, right amygdala,thalamus, rACC, PAG and NAc

Dopamine release4–5. Parkinson'sdisease

Parkinson'sdisease

[11C-RAC] PET Striatal (caudate and putamen)release of dopamine

de la Fuente-Fernándezet al. (2001, 2002)

6. Parkinson'sdisease

Parkinson'sdisease

[11C-RAC] PET Striatal (dorsal and ventral)release of dopamine

Strafella et al. (2006)

7. Psychostimulantexpectation

Habitualcaffeine users

[11C-RAC] PET Thalamic release of dopamine Kaasinen et al. (2004b)

8. Thermalstimulation

Healthyparticipants

[11C-RAC] PET No correlations observed between theplacebo-induced analgesia and baselinestriatal dopamine receptor binding potential

Martikainen et al. (2005)

9. Psychostimulantconditioning

Healthyparticipants

[11C-RAC] PET Ventral striatal release of dopamine Boileau et al. (2007)

10. Sustainedmusclestimulation

Healthyparticipants

[11C-RAC] PET Dopamine release in the NAc duringanalgesic anticipation

Scott et al. (2007)

Glucose metabolism11. Depression Unipolar

depression[18FDG] PET ↑ Prefrontal, anterior cingulate, premotor,

parietal, posterior insula and posteriorcingulate

Mayberg et al. (2002)

↓ Subgenual cingulate,parahippocampus and thalamus

12. Psychostimulantexpectation

Cocaineabusers

[18FDG] PET Expectation effectswere negligible when placebowas administered

Volkow et al. (2003)

13. Psychostimulantexpectation

Healthyparticipants

[18FDG] PET ↑ Ventral cingulate gyrus and NAc Volkow et al. (2006)

Abbreviations: (↑) increases; (↓) decreases; carbon 11-carfentanil positron emission tomography ([11C-CAR] PET); carbon11-raclopride[11C-RAC]; fluorodeoxyglucose [18 FDG]; pregenual ACC (pgACC); dorsolateral prefrontal cortex (DLPFC); anterior insula (AI); nucleusaccumbens (NAc); lateral prefrontal cortex (LPFC); periaqueductal gray (PAG); prefrontal cortex (PFC); orbitofrontal cortex (OBFC);rostral anterior cingulate cortex (rACC).

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In order to specifically investigate the functional contribu-tion of the RVLPFC in placebo analgesia, Lieberman et al.(2004) reanalyzed the PET placebo data of a previouslypublished drug trial (Berman et al., 2002), in patients withirritable bowel syndrome (IBS). In this study, visceral painwas induced, both before and after a three week placeboor active drug regimen. As predicted by disruption theory(Lieberman, 2003), enhanced activity in RVLPFC was asso-ciated with attenuated activity in dorsal ACC (dACC), which inturn was predictive of symptom improvement. Having thedisruptionmodel as the theoretical rationale, and arguing thatRVLPFC effects on symptom improvement were mediated bydACC changes, Lieberman et al. (2004) proposed a route bywhich the placebo effects may be achieved through expec-tancy. However, due to the fact that the patients' expectanciesof relief were not assessed, itwas not possible to conclude thatthe observed RVLPFC activity was related to expectancies ofanalgesic effects. Lieberman et al. (2004) suggested that theRVLPFC is an important initiator of the cognitive regulation ofpain. Accordingly, in a recent study with Alzheimer patients, aloss of communication between the prefrontal lobes and therest of the brain was reported to result in the disruption ofexpectancy-related mechanisms ultimately reducing placeboanalgesia efficacy (Benedetti et al., 2006). Hence, imagingstudies can widen our understanding of how higher corticalfunctions contribute to the placebo response.

In two fMRI trials, using different pain modalities (i.e.shock or thermal pain), Wager et al. (2004) sought to discrimi-nate the activity induced by placebo analgesia in anticipationof pain from changes registered during pain experience. Re-ductions in pain evoked brain activity in areas encompassingthe rACC, thalamus and insula, predicted decreased painreports during placebo analgesia both during shock andthermal pain, suggesting that placebos reduce nociceptivepain transmission. During pain anticipation, enhanced activ-ity observed in the dorsolateral prefrontal cortex (DLPFC),OBFC, midbrain/PAG, and rACC was associated with attenu-ated subjective pain ratings. Additionally, negative correla-tions between prefrontal activity during anticipation andbrain activity in the pain matrix were also observed, indica-ting that cognitive processes during anticipation of pain maybe crucial for downregulating activity in the pain circuitry.

Overall, the Wager et al. (2004) study not only confirm theinvolvement of rACC and OBFC previously reported by Petrovicet al. (2002), but also provide additional evidence sustainingLieberman et al.'s (2004) hypothesis that a cognitive evalua-tive network is activated before placebo analgesia occurs.While Petrovic et al. (2002) reported rACC activation duringpain placebo analgesia, Wager et al. (2004) only observedrACC increases in the anticipatory phase. During heat placeboanalgesia, decreased activation was found in the rACC (Wageret al., 2004). These findings suggest that, when it comes toplacebo analgesia, ACC is not only involved in pain responsesbut also serve as a crucial regulatory area for pain. A recentstudy reported activation in this same area both during painfulstimulation and when observing another individual in pain(Singer et al., 2004). This suggests that neurons that areactivated by empathy are also activated by pain anticipation,or that pain mirror neuron systems exist.

The results provided by Wager's et al. (2004) thermal paintrial indicate that most of the registered deactivationsoccurred late in the pain response time course, after the

stimulation had ceased. According to the authors (Wageret al., 2004), this could imply involvement of cognitive re-appraisal of pain rather than just expectations of pain relief.

Consistentwith thedata presentedabove, another studyalsoreported that the rACCnot only is implicated in pain experience,but also plays an importantmodulatory role in placebo analgesia(Bingel et al., 2006). Using event-related fMRI, Bingel et al.(2006) assessed BOLD responses to painful laser stimulationinduced during placebo and non-placebo conditions in healthyparticipants. After placebo-related activity in the rACC hadbeen identified, connectivity analyses were performed in orderto test placebo dependent influences of other brain areas.During placebo analgesia, rACC activity covaried positively withactivity in a subcortical modulatory opioid-dependent painnetwork, including the amygdala and PAG. Rostral ACC covaria-tion with amygdala and PAG activity indicates that this corticalarea plays an important role in modulating pain experience.Thus, during placebo analgesia, rACC may exert its effectsthrough a subcortical system, implicated in endogenous opioid-dependent antinociception (Bingel et al., 2006).

Using a fMRI-paradigm in IBS patients, Price et al. (2007)investigated whether the placebo response was accompaniedby deactivation of pain-related brain regions during painfulstimulation. To induce intestinal pain, visceral stimulation wasused by applying 200 mg of saline jelly in a rectal balloon. Inthe placebo condition, a suggestion of pain relief accompaniedthe saline, whereas at baseline no treatment expectationswere induced. The placebo analgesic response was assessedby contrasting baseline with the placebo condition. Placeboanalgesia lowered neuronal responses in the thalamus, insulaand the dACC (Price et al., 2007). As in the Lieberman et al.(2004) study, symptom improvement was accompanied bydACCdecreases. However, in contrast tomost of the registereddeactivations observed by Wager et al. (2004), the neuralreductions reportedbyPriceet al. (2007)wereobtained duringthe actual stimulation, suggesting that placebo analgesia ac-tually alters afferent input to the brain.

Recently, Nemoto et al. (2007) used PET to analyze rCBFchanges associatedwith placebo analgesia during hot, painfuland resting conditions in healthy volunteers. Participantswere classified as responders or non-responders based onsubjective reports of reactions to painful stimuli after sevendays of pill placebo administration. As compared to beforeadministration, placebo responders showed increased rCBF inthe medial prefrontal cortex, posterior parietal cortex, andinferior parietal lobe both during pain and rest. During thepainful condition, decreased rCBF was observed in the ACC,supplementary motor area and inferior temporal lobe. TheACC along with inferior temporal lobe was deactivated duringrest. Curiously, rCBF-increases in the inferior parietal lobule,posterior parietal cortex and decreases in ACC were alsoobtained in the non-responders group during the painfulstimulation. However, there were no rCBF changes reportedat rest in non-responders, leading the investigators to suggestthat placebo analgesia showed its effects under the restingcondition as a result of the anticipation of pain reduction(Nemoto et al., 2007). These results converge with the notionthat anticipation is a critical factor in placebo analgesia.

As shown in Table 1, imaging studies of placebo analgesiareport similar prefrontal cortical activations, and also co-activations of these prefrontal cortical structures withthe brainstem and midbrain. Prefrontal activity during pain

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anticipation may represent activation of a cognitive evalua-tive network tied to downregulation of pain via “top-down”processes. Top-down control in placebo analgesia is alsosupported by the well known anatomical connections be-tween the PFC and the thalamus (Fuster, 2001), as well asthe midbrain/PAG area (Fuster, 2001; Miller and D'Esposito,2005). Thus, subcortical brain regions that are targets foractive pharmacological treatments that presumably actthrough “bottom-up” processes (Price, 2002), may be regu-lated upstream in placebo analgesia.

The early involvement of the midbrain/PAG region (seeWager et al., 2004), which is known to contain endogenousopioids and to be involved in modulating spinal nociceptivetransmission (Fields, 2004), suggests that the opioid system istriggered by expectations of analgesia. Moreover, the factthat placebo-induced decreases are reported in pain respon-sive regions such as the thalamus, insula and ACC reinforcesthe idea that placebos are notmerely the result of alterationsin reported behavior, but that they do influence nocicep-tive processes. By looking at the overall placebo analgesiafindings, there is reasonable consistency with respect tostructures involved. However, the directions of the observedchanges in ACC seem somewhat conflicting. We return tothese cingulate inconsistencies below (see Section 3.1.4).

It is noteworthy that, although the hemodynamicimaging techniques in the reviewed studies did not directlyexamine the neurochemical mechanisms underlying pla-cebo analgesia, the implicated regions have high concen-trations of µ-opioid receptors (see Sprenger et al., 2005).Thus, neuroimaging data appears to be consistent with thenotion that the expectancy-induced placebo effect in pain-related states is at least in part mediated by endogenousopioids (Amanzio and Benedetti, 1999; Benedetti et al.,1999). On the other hand, a recently reported clinical casestudy of a patient with severe chronic lumbar pain indicatedthat verbal suggestions of pain relief, resulting in placeboanalgesia, were not opioid dependent (Kupers et al., 2007).According to this case report (Kupers et al., 2007),expectancy-induced analgesia was accompanied bydecreased rCBF in the thalamus, rACC and nucleus accum-bens (NAc). Interestingly, naloxone did not abolish neitherbehavioral nor neuronal analgesic responses, but with anocebo suggestion (i.e. expecting an opioid antagonist) bothanalgesic responses were blocked. Consistently, Vase et al.(2005) reported that expectancy-induced analgesia was alsonot naloxone reversible in IBS patients. Taken together,these results suggest that non-opioid mechanisms are alsoinvolved in expectancy-induced placebo analgesia, at leastin clinical conditions (i.e. hyperalgesic states).

Studies have shown that dopaminergic pathways are alsoimplicated in pain processing (see Tracey and Mantyh, 2007,for review) and pain control (see Wood, 2006, for review).Therefore, dopamine might also contribute to placebo-induced pain relief. Accordingly, pain studies demonstratethat analgesic effects can be blocked by antagonizing NAcdopamine receptors (Altier and Stewart, 1999). Evidencesupporting the contribution of dopamine in mediating theplacebo responses is further discussed on Section 3.2.

3.1.2. Placebo acupuncture analgesiaAs implied above, feelings of pain seemmediated by activity ina complex matrix that in part overlaps with brain areas

involved in pain expectancy. Even though some neuroimagingdata point to specific brain responses to acupuncture treat-ments (Wu et al., 2002), in western cultures acupuncture canstill be considered as a complementary or alternativemedicineassociated with specific beliefs (Kaptchuk, 2002). Therefore,further understanding of the mechanisms of action in placeboanalgesia may be gained by imaging studies that have eval-uated placebo acupuncture.

Using PET, Pariente et al. (2005) explored the effects ofacupuncture expectation on rCBF in patients with chronicpainful osteoarthritis. Different patterns of activation wereidentified in response to skin prick (i.e. control conditionwithout expectancy) and acupuncture expectation, bothduring placebo acupuncture (i.e. Streitberger needle) andreal acupuncture. Despite the fact that no analgesic effectwasobtained from either treatment, activations were found in theDLPFC, rACC and in the midbrain when expecting active treat-ment, as compared to the no expectation condition. Activity inthe observedareas overlapswithpatterns described in placeboanalgesia further supporting their relevance to expectation.Although the reported brain alterations do not seem to besufficient, they may be necessary to induce pain relief.

In a recent fMRI study, Kong et al. (2006) explored theneuralmechanisms involved in placebo acupuncture analgesia duringpainful thermal stimulation induced in the rightmedial forearmof healthy participants. Placebo acupuncture treatment (i.e.Streitberger needle) was accompaniedwith analgesic expecta-tions that were manipulated by lowering the temperature inthe placebo side of the arm but not in the control side, givingthe participants an obvious experience of analgesia. Altera-tions in pain-induced BOLD signals from pre- to post-treatmentwere evaluated on placebo and control stimulation sides at theoriginal stimulus temperature in a subsequent session. Pre-viously experienced placebo acupuncture analgesia wasassociated with increased activity in several brain regionsincluding the rACC, lateral PFC, anterior insula, supramarginalgyrus and inferior parietal lobule. Significant negative correla-tions between each subject's fMRI signal change and thecorresponding difference in pain ratings were observed in theDLPFC, rACC, cerebellum, fusiform gyrus, parahippocampusand pons, again supporting a mediating or modulatory role forthese brain regions in pain experiences.

Kong et al. (2006) could, however, not demonstrate de-creased neural activity in pain-related regions like the thal-amus, insula, or ACC as a function of placebo analgesiapreviously reported by Price et al. (2007) and Wager et al.(2004). Inconsistencies between the findings by Kong et al.(2006) and Wager et al. (2004) were attributed to the pos-sible measurement of different aspects of pain and also tothe possibility of having induced different components ofplacebo analgesia. Kong et al. (2006) suggested that placeboanalgesia mechanisms vary depending on the circumstances,which is in concordance with studies suggesting that bothopioid and non-opioid processes may underlie the placeboanalgesic effect under different circumstances like expec-tancy and conditioning (Amanzio and Benedetti, 1999). Col-lectively, studies support the existence of several placebopathways possibly responsible for some of the reported pla-cebo analgesia inconsistencies. The variability in the placeboresponses found within conditions and between placeboneurofunctional imaging studies could also be explained, atleast with respect to pain, by differences in experimental

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designs or more specifically the degree of certainty asso-ciated with pain relief expectations (Ploghaus et al., 2003).

3.1.3. Placebo anxiolysisIt has been suggested that the opioid system is directlyinvolved in the processing and regulation of emotion (Zubietaet al., 2003) and also that brain mechanisms involved indealing with reward signals should be set in motion duringplacebo responses (de la Fuente-Fernández and Stoessl,2002). Just as placebos have been shown to alleviate pain,Petrovic et al. (2005) demonstrated that placebos also canhave an effect when processing emotionally unpleasantvisual stimuli. In order to increase the likelihood of placebomodulating emotional processing, expectancies were ma-nipulated by administering both a benzodiazepine and abenzodiazepine receptor antagonist which gave the subjectsunequivocal experiences used to induce treatment expecta-tion on a subsequent day. Participants were informed thatthe same drugs used previously would be administered, butplacebo was actually given. In this event-related fMRI study(Petrovic et al., 2005), the observed neuronal influence ofplacebo on emotional processing shared several key regionswith the networks described in studies of pain analgesia(Petrovic et al., 2002; Wager et al., 2004), includingactivation of rACC and OBFC.

Frontal areas such as the cingulate and the orbitofrontalcortices, known to respond to reward expectations (O'Dohertyet al., 2002), have been constantly activated in the majorityof the placebo studies regardless of conditions. Thus, placebomay involve a general process of modulation induced by ex-pectations. Increases in the VLPFC and rACC, as well as de-creases in the amygdala, correlated with the reportedemotional ratings (Petrovic et al., 2005). Participants expect-ing the largest effect also showed the largest changes inemotional modulatory areas. Furthermore, placebo-inducedactivations in the ventral striatum were also reported to becorrelated with the previously induced treatment expectation(Petrovic et al., 2005). All together these findings point to arelation between the placebo effect and reward expectancy.

3.1.4. The role of the cingulate in placeboAs illustrated in Fig. 1a and b, placebo induced both cingulateactivations and deactivations. Fig. 1a displays increases in 29activation spots reported by six studies, i.e. three on pain(Bingel et al., 2006; Petrovic et al., 2002; Wager et al., 2004),two on pain with acupuncture (Kong et al., 2006; Parienteet al., 2005) and one on emotional processing (Petrovic et al.,2005), whereas Fig. 1b illustrates 11 deactivations reported infive pain studies (Kupers et al., 2007; Lieberman et al., 2004;Nemoto et al., 2007; Price et al., 2007; Wager et al., 2004).

The cingulate cortex has been related to cognitive pro-cesses including attention (Bush et al., 1999), emotion (Allmanet al., 2001), visuospatial functions and nociception (Vogtet al., 1992). The anterior cingulate can be subdivided basedon it's distinct connections, cytoarchitecture and functionsinto a dorsal cognitive section and a rostral ventral affectivesection (Bush et al., 2000; Devinsky et al., 1995; Vogt et al.,1992). Even though the anatomical description varies betweenstudies, Fig. 1a shows that the cognitive section was active inthe overall placebo response, whereas the affective divisionwas mostly active in placebo anxiolysis. This appears to beconsistent with the expectancy theory in which placebo

responses are held to be mediated by explicit, conscious,accessible cognitive factors like expectancies (see Stewart-Williams and Podd, 2004). Accordingly, pain studies suggestthat mid-cingulate activation is associated with cognitiveprocesses (Vogt et al., 1996). Because activity in the affectivesection of the cingulate was altered by placebo anxiolysis(Petrovic et al., 2005), but also by placebo acupuncture an-algesia (Kong et al., 2006), the pregenual cingulate may mod-ulate negative affect more generally.

As mentioned previously, decreases in the ACC have alsobeen noted. Fig. 1b shows that placebo analgesia alsoinduced suppression of the dorsal cognitive division of the

Figure 1 Sagital view of cingulate increases (a) and decreases(b) during placebo administration in hemodynamic imagingstudies. Legend: pain/placebo analgesia; pain/placeboacupuncture analgesia; emotional processing/placebo anxioly-sis. Upper panel (1a): Reported peaks of activations across sixstudies. Lower panel (1b): Reported peaks of deactivations acrossfive pain studies. Reported stereotaxic coordinates of hemody-namic changes were projected in two sagital normalizedmagneticresonance templates (Montreal Neurologic Institute) that illus-trate both correlations and main effects provided by tenhemodynamic reviewed studies. Note that these are the peakactivation voxels and that although some of these hot spots areclearly not in the cingulate, the extension of the activated anddeactivated clusters may encompass broader regions of thecingulate.

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ACC. Given that expectancy-mediated cognitive control isassociated with increased ACC activity, this suppression mayindicate that the placebo response was not mediatedby expectancies in these studies. On the other hand, themid-cingulate is the most commonly reported area in painstudies (Peyron et al., 2000), and a decrease might simplyillustrate a reduction of the affective pain component (Foltzand White, 1962; Rainville et al., 1997). Accordingly, in theWager et al. (2004) pain study, decreased activity in thecingulate was reported in previously defined pain codingareas. The involvement of the cingulate in placebo anal-gesia studies support the ACC role, together with severalother brain structures, in mediating the conscious percep-tion of pain (deCharms et al., 2005; Peyron et al., 2000).

The fact that placebo-induced analgesia resulted incingulate increases as well as decreases in one study (Wageret al., 2004) during anticipation and pain experience, re-spectively, could mean that inconsistencies in the cingulatebetween pain studies are due to differences in experimentaldesigns. According to Peyron et al. (2000), the cingulate mayboth react to pain and contribute to pain control. Congruently,the administration of opioids activates the cingulate at similarsites that have been reported to be suppressed in chronic painconditions. While trying to explain cingulate inconsistenciesone should also keep in mind that, even at a neural level,subpopulations of the anterior cingulate neurons might reactin a analogous manner to different experimental protocols(Koyama et al., 1998). Consistently, the ACC was reported asbeing involved both during anticipation and during the actualexperience of pain (Fairhurst et al., 2007).

The cingulate has been shown to be involved in expectationof reward which is thought to activate midbrain dopaminergicneurotransmission (Ernst et al., 2004). Activity observed in thisarea is consistent with the proposed relation between rewardexpectancy and placebo response (de la Fuente-Fernándezand Stoessl, 2002; Petrovic et al., 2005). This relation will befurther discussed below (see. Section 3.2.2). Recent experi-ments suggest that the cingulate plays an important rolein guiding behavior based on previous rewarded outcomes(Kennerley et al., 2006). With its privileged connections toprefrontal and limbic structures, projections to the spinal cord(He et al., 1995) andmidbrain dopamine neurons (Holroyd andColes, 2002), the ACC may therefore be a key anatomical sitein the modulation of placebo responses.

3.2. Neurochemical imaging studies

3.2.1. Endogenous opioid releaseIn a study of in vivo availability of synaptic µ-opioid receptors,Zubieta et al. (2005) found evidence consolidating thesuggested key role of endogenous opioids in placebo analgesia.PET and the radiolabeled tracer carfentanil were used toexamine whether the administration of placebo with expecta-tion of analgesia alters pain suppressive endogenous opioidneurotransmission. Placebo administration during the sus-tained pain challenge was associated with significantly higherµ-opioid neurotransmission in the pregenual rACC and DLPFC,as well as the anterior insula and nucleus accumbens. Con-sistent with other findings (Wager et al., 2004), endogenousopioid activity in the DLPFCwas associatedwith themagnitudeof the expected analgesic effect determined before theplacebo administration (Zubieta et al., 2005). These findings

support a key role of expectations underlying the observedplacebo response.

Enhanced pain suppressive neurotransmission was asso-ciated with lower pain ratings and less negative affect(Zubieta et al., 2005). However, when examining individualdifferences, the authors found some variations in individualneurotransmitter activation patterns, indicating that thedegree of opioid activation induced by placebowas regionallyspecific for individual subjects (Zubieta et al., 2005). In asubsequent study, Zubieta et al. (2006) found that thevariance in the regional neurochemistry of placebo analgesiawas related both to the individual experience of pain, and theaffective state of the individual. Nevertheless, as in thestudies by Petrovic et al. (2002) and Nemoto et al. (2007) acontroversial criterion of 10–20% improvement in pain ratingswas used by Zubieta et al. (2005) to classify subjects asresponders. Therefore, this small improvement could reflecthabituation effects rather than placebo effects (see Rainvilleand Duncan, 2006).

Most recently, Wager et al. (2007) examined µ-opioidneurotransmission during thermal warm and pain conditionsinduced in the participants forearms treated either with pla-cebo (i.e. expecting analgesia) or control (i.e. no expectationsof analgesia) creams. During noxious pain stimulation, pla-cebo resulted in µ-opioid increases in the anterior, medial andlateral OBFC, right amygdala, thalamus, rACC, midventralregions of PAG and NAc. However, unexpected negative cor-relations were reported between activity in medial and la-teral OBFC, right amygdala and reported behavioral effects,suggesting that greater opioid release is associated with apoorer response.

During warm stimulation (i.e. anticipation phase) placeboseemed to reduce opioid activity in LPFC, anterior insula,pregenual ACC, left amygdala, dorsal PAG, caudate nucleus,PFC and inferior frontal junction (Wager et al., 2007). Ac-cording to Wager et al. (2007) this suppression could meanthat, while pain anticipation triggers the opioid system,placebo-induced expectations of analgesia may block therelease of opioids. However, seemingly contrasting findingswere reported in a previous hemodynamic study of placeboanalgesia by the same group (Wager et al., 2004), in whichthe observed anticipatory PAG activation indirectly supportsan early involvement of the opioid system triggered by ex-pectations of pain relief. During anticipation, left anteriorinsula was found to be positively correlated with reportedanalgesic effects and also a negative correlation was re-ported between right DLPFC and behavioral analgesic effects(Wager et al., 2007). Connectivity analyses support theexistence of distinct subsystems activated during anticipa-tion and pain. Similar to the results reported by Bingel et al.(2006), correlations between activity in the PAG and rACCwere stronger in the placebo than in the control condition(Wager et al., 2007), supporting the cingulate region tobe the interface between a cognitive evaluative networkand endogenous opioid release. Interestingly, increasedfunctional connectivity was observed between limbic andprefrontal regions (Wager et al., 2007) supporting the asso-ciation between expectancies with activity in a fronto-limbicnetwork.

Overall, these results support previous hemodynamic find-ings suggesting that expectancy-induced placebo analgesia isin part mediated by activity in the opioid neurotransmitter

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system, even though seemingly contradictory results regardingthe early phase of the opioid involvement have been reported(Wager et al., 2004; Wager et al., 2007).

3.2.2. Endogenous dopamine releaseThe release of endogenous substances as a result of placeboadministration is not limited to pain states. Increased endog-enous dopamine release has been demonstrated in motordisorders such as Parkinson's disease (PD) when patients aregiven a placebo coupled with verbal suggestions of improvedmotor performance (de la Fuente-Fernández et al., 2001).

Byusing PETand the carbon-11 labeled raclopride [11C-RAC]tracer, which competes with dopamine for D2/3 receptors, dela Fuente-Fernández et al. (2001) showed that the adminis-tration of placebo with an apomorphine expectation induceddopamine release in the caudate nuclei and putamen whencompared to a no treatment baseline condition. Patients whoreported clinical benefits after placebo administration hadhigher release of dopamine in the motor striatum as comparedto those who did not perceive a clinical effect, suggesting thatthe release of endogenous dopamine in the dorsal striatumwasrelated to the symptomatic benefit of the treatment. Theplaceboeffect in PDappears tobemediatedby thenigrostriataldopaminergic system even though it is in part damaged in thisdisorder (de la Fuente-Fernández et al., 2001). Later, de laFuente-Fernández et al. (2002) proposed that the release ofdopamine previously observed in the ventral striatum wasrelated to reward expectancy rather than reward experienceitself.

Dopaminergic involvement in placebo have been corro-borated by a [11C-RAC] PET study of PD patients undergoingsham (i.e. placebo) repetitive transcranial magnetic stimu-lation (rTMS) (Strafella et al., 2006). Patients were told thatthey had a 50% chance of receiving either real or sham rTMS,but were not aware that only sham treatment was used.Enhanced release of dopamine in the dorsal and ventralstriatum was observed in the placebo condition as comparedto baseline. Nevertheless, only four of the seven patientsperceived a clinical benefit at the behavioral level. Eventhough the patients who perceived clinical benefits hadhigher release of dopamine in the striatum, the reporteddifference did not reach statistical significance. The dis-crepancy between behavioral and biochemical responses inthe ventral striatum of the PD patients was also noted by dela Fuente-Fernández et al. (2002).

Kaasinen et al. (2004b) provided support for dopaminergicinvolvement in the placebo response in a placebo caffeinestudy. Using PETand [11C-RAC], dopaminergic functioning wasinvestigated in habitual caffeine users when they expectedcaffeine arousing effects from a pill placebo. Placebo ad-ministration was associated with increased endogenousdopamine concentrations in the thalamus, a structure involvedin arousal (Portas et al., 1998) and reward (Komura et al.,2001). Alterations in the striatum failed to reach statisticalsignificance, but a positive relation between placebo caffeine-induced arousal and dopaminergic activity in the putamenwasobserved. As in the study by de la Fuente-Fernández et al.(2002) and Strafella et al. (2006), no behavioral effects wereobserved in the group as a whole. The observed correlation(Kaasinen et al., 2004b) mirrors a previously described asso-ciation using actual caffeine administration (Kaasinen et al.,2004a) indicating that the dopamine neurons in the putamen

modulate arousal, both when pharmacologically and psycho-logically induced.

Using [11C-RAC] PET, Martikainen et al. (2005) investigatedwhether striatal dopamine D2/3 receptor binding determinedsix years earlier predicted the magnitude of placeboanalgesia in eight healthy participants. Heat pain thresholdswere measured before and after the administration of oralplacebo tablets coupled with analgesic instructions. Placebo-induced analgesia was assessed by measuring increases inthe heat pain threshold but dopamine D2/3 receptor bindingpotential was not associated with any threshold change in anystriatal region.

Striatal dopamine release was also observed in a [11C-RAC]PETstudywith non drug abusing subjects (Boileau et al., 2007).After consecutive pairing of amphetamine with a PETcontext,re-experiencing this context with administration of an“amphetamine” pill placebo resulted in dopamine release inthe ventral striatum. Neurochemical alterations in the placebocondition were significantly different from the control scanwithout pill administration, but not from the amphetamineadministration.

Conditioning has been shown to play an important role ineliciting hormone secretion as a function of placebo response,indicating that unconscious physiological functions mayrespondmore to conditioning than to expectancies (Benedettiet al., 2003). On the other hand, expectancies seem to pre-vail over conditioning when conscious functions are involved(Benedetti et al., 2003). Boileau et al. (2007) suggested thatthe release of dopamine in the ventral striatum resultedfrom conditioning. However, in that study it is not possibleto determine whether the changes observed were driven byconditioning or by the participants' amphetamine-expecta-tions. Actually, most of the placebo studies assume that verbalsuggestions, accompanying the placebo intake, were success-ful in inducing treatment expectations, nevertheless themajority of the studies do not use explicit measures of ex-pectancy. Classical conditioning is one of the vehicles throughwhich expectancies, that mediate placebo effects, areacquired (Montgomery and Kirsch, 1997). Thus, collectively,these results support the association previously suggestedbetween the placebo effects and reward mechanisms.

Two recent studies further support the relationship be-tween reward expectation mechanisms and placebo response(Scott et al., 2007). First, using [11C-RAC] PET, Scott et al.(2007), reported that the magnitude of DA release in the NAcduring analgesic anticipation was positively correlated withthe anticipated analgesic effect. High as compared to lowplacebo responders (i.e. above or below the median averagedchange in pain intensity ratings) demonstrated greatermagnitude of right NAc DA responses during anticipation ofanalgesia. According to these findings, the amount of DAneurotransmission in NAc increases as function of the effec-tiveness of the anticipated effects.

Second, Scott et al. (2007) carried another experimentwith fMRI to verify whether inter-individual differences ob-served in pain placebo responses were associated withdifferences in the BOLD response to reward anticipation ina monetary incentive delay task. It was found that partici-pants showing the greatest NAc BOLD activations during thereward anticipation task also showed the most profoundanalgesic placebo responses such as higher positive affectscores during analgesia expectation and a more profound

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analgesic reaction during the pain trials. Moreover, the groupof participants reporting placebo asmore or equally effectivethan anticipated, showed augmented responses in the rightNAc to rising levels of expected reward, as compared to thosewho judged placebo to be less effective than anticipated.NAc BOLD activation during reward anticipation was alsopositively correlated with the placebo analgesic effectsobtained during the pain trials, accounting for 28% of thevariance in placebo analgesia. Furthermore, when examiningdata of subjects that participated in both PETand fMRI trials,positive correlations were found between the extent of rightNAc BOLD activity during reward anticipation and DA releasein NAc during analgesia anticipation.

Thus, these trials (Scott et al., 2007) indicate that placeboinvolves reward anticipation and that individual variations inresponse to placebo may reflect individual differences inmesolimbic dopaminergic pathways.

3.2.3. Glucose metabolismMayberg et al. (2002) assessed brain glucose metabolismwith PET, to identify brain regions associated with placebotreatment of depression. After treatment, the placeboresponders had higher resting glucose metabolism in theprefrontal, anterior cingulate, premotor, parietal, posteriorinsula, and posterior cingulate cortices, and lower glucosemetabolism in the subgenual cingulate cortex, parahippocam-pus and the thalamus. In response to placebo treatmentalterations in cortical and limbic-paralimbic regions weresimilar to those produced by the selective serotonin reuptakeinhibitor fluoxetine. This supports that placebo treatment canproduce alterations in brain activity similar to those resultingfrom pharmacological treatment and that altered serotoninmay mediate the placebo response in depression. However,because there was no control group without placebo or med-ication, it is not possible to exclude that spontaneous re-mission over time or repeated assessment might have biasedthe results.

Recently, Volkow et al. (2006) studied brain glucose me-tabolism in order to evaluate the effects of expectancy inresponse to the central nervous system stimulant methylphe-nidate and placebo in healthy volunteers (i.e. non drug abusingsubjects). They reported that intravenous administrationof methylphenidate, when expected to be received, inducedgreater reductions in the striatum, as compared to when ad-ministration was not expected. However, in a previous study,Volkow et al. (2003) reported that when cocaine abusersexpected to receive the drug, glucose brain metabolism in thethalamus and cerebellum increased. The failure to replicatethe effects of the preceding study (Volkow et al., 2003)indicate that enhanced thalamic and cerebellar metabolism incocaine abusers reflect conditioned responses (Volkow et al.,2006). Hence, findings in healthy volunteers suggest thatexpectations affect brain responses to drugs also in subjectswho have no prior drug experiences (Volkow et al., 2006).When expecting to receive methylphenidate but given pla-cebo, increases in the ventral cingulate gyrus and nucleusaccumbens were observed. This effect was larger in naïvemethylphenidate participants than in participants who hadpreviously experienced methylphenidate, supporting the roleof expectations over conditioning. Moreover, because subjectswere uncertain about the drug effects, the activated regionswere proposed to be involved in expectations of an uncertain

experience. Since DA is implicated in response to uncertaintyand reward prediction (Schultz, 1998), these findings indir-ectly support a dopaminergic contribution, induced by ex-pectation of reward, that seems to affect the NAc glucosemetabolism responses in placebo.

4. Key points

The results from the 24 identified neuroimaging studies ofplacebo response lead to the following tentative conclusions:

• Expectancy-induced placebo analgesia involves both opioidand non-opioid networks.

• Expectancy-induced placebo analgesia and placeboanxiolysis seem to share a similar modulatory network.

• Placebo and pharmacological treatments yield similarneuronal changes, as supported by studies of pain, motordisorders and depression.

• Neural changes in the anterior cingulate cortex, inducedthrough conscious cognitive factors like expectancies, playan important cognitive control role that may modulate theplacebo responses regardless of conditions.

• Overall, placebo responses seem mediated by top-downprocesses initiated in frontal cortical areas that generateand maintain cognitive expectancies.

• Since dopamine mediates the placebo response in motordisorders, psychostimulant expectation and analgesia,dopaminergic reward pathways may underlie expectancy-induced placebo effects.

5. Overall discussion

Investigations of the placebo response with functional brainimaging techniques have opened new avenues to exploremind–body interactions. Although much of our current knowl-edge about the neurofunctional mechanisms behind the pla-cebo phenomenon stems from studies in the field of pain(Colloca and Benedetti, 2005; Hoffman et al., 2005), it is clearthat other conditions are also susceptible to placebo treat-ments and associated with distinct neural outcomes (de laFuente-Fernández et al., 2001; Mayberg et al., 2002).

Findings from hemodynamic imaging studies indicate thatbrain areas involved in cognitive regulation of placebo-inducedanalgesia are implicated also when placebos regulate emo-tional processing. Collectively, the observed brain patternssupport that a similar modulatory network, generally engagedby expectations, may drive the placebo response regardlessthe conditions.

With regard to the neurochemical imaging studies, there isevidence of placebo-related endogenous dopamine release inthe ventral striatum in PD (de la Fuente-Fernández et al.,2002; Strafella et al., 2006), as an effect of psychostimulantexpectation (Boileau et al., 2007), and in anticipation of an-algesia (Scott et al., 2007). de la Fuente-Fernández and Stoessl(2004) proposed that expecting a clinical benefit (i.e. reward),triggers the placebo responses through the activation of thereward circuitry. The proposed placebo-reward model sug-gests the involvement of dopamine neurons in mediatingexpectancy-induced placebo responses regardless of condi-tions (de la Fuente-Fernández et al., 2006). In addition, thismodel holds that other neurotransmitters involved in the

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reward circuitry, operate in a disease-specific manner (de laFuente-Fernandez and Stoessl, 2004) thus, accounting fordifferent neurological responses in the placebo effect, forexample, opioids in pain, dopamine in PD and serotonin indepression. Nevertheless, there is a lack of placebo imagingstudies on neuroreceptor or transmitter functioning in affec-tive conditions and in disorders other than Parkinson's.

Overall, the neuroimaging literature supports the hypoth-esis that effective placebo treatments exert their effects byengaging neural systems mediating reward expectancy (i.e.mesolimbic dopaminergic pathway). The literature also in-dicates that clinical benefits caused by placebo, involve dis-order-specific neuronal responses engaging similar anatomicalstructures and neurochemical processes as those usuallyrecruited by pharmacologically active drugs. This is indicativeof distinct neural mechanisms underlying the placebo re-sponses that on the other hand share a modulatory cognitivefactor (i.e. reward expectancy), which seems to play a cru-cial role in the development of the different therapeutic re-sponses. Nonetheless, both more automated conditioningprocesses and cognitions like expectancy of improvementseem to be placebo-linked mechanisms. Mesolimbic dopami-nergic activity, for instance, seem enhanced by both.

6. Concluding remarks and future directions

Even though imaging techniques have been increasinglyused in the field of placebo, it is clear that the neurobiologyof placebo is still an understudied topic. This review high-lights some convergent data and promising results that,with continuing advances in the field, will contribute tobetter understanding of the neural mechanisms underlyingthe placebo response. However, because studies are stillfew and methodologies to investigate the placebo effectvary, the field has not reached enough maturity to allowmore specific conclusions to be drawn regarding the neuro-biological underpinnings.

Further research addressing reward mechanisms and re-lease of endogenous neurotransmitters other than dopamineand opioids is needed. Moreover, if placebo effects involvesimilar modulatory mechanisms, why can they improve someconditions but not others? Are there biological mechanismsunderlying individual differences in the placebo response,for example, genetic predispositions or endophenotypes in-fluencing the magnitude of the response?

Because the clinical relevance of experimental data, onwhich most of the placebos findings are now based is notalways obvious, it is also important to focus the attention onthe biological basis and correlates of the placebo phenom-enon within the context of randomized controlled clinicaltrials. Furthermore, since expectancy seems to play such animportant role in treatment outcome (Bausell et al., 2005;Benedetti, 2005; McRae et al., 2004), and given that inclinical conditions expectancy-induced placebo effects maybe considerably larger than in experimental studies withhealthy subjects (e.g. Kupers et al., 2007; e.g. Vase et al.,2003), the open-hidden paradigm (see Finniss and Benedetti,2005) might be an alternative way to overcome the ethicalconstrains within the use of placebos in clinical trials (“WorldMedical Association Declaration of Helsinki: Ethical princi-ples for medical research involving human subjects”, 2000).

The continuing advances in brain imaging and neuroge-netics will allow us to pose and answer novel and also morespecific questions about the placebo effect. This couldprovide fundamental insights into the body's own naturalhealing capability.

Role of the funding source

This work was supported by the Swedish Research Council and theFundação para a Ciência e Tecnologia that had no further role in thedecision of writing and submitting this paper for publication.

Contributors

MF and TF were responsible for initiation and direction of the review.VF managed the literature search and wrote the first draft of themanuscript, which was discussed and changes were implemented byall authors. All authors have approved the final manuscript.

Conflict of interest

Authors declare that they have no conflicts of interest.

Acknowledgments

Supported by the Swedish Research Council and the Fundação para aCiência e Tecnologia.

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485Imaging the placebo response: A neurofunctional review