Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation

PNP-08274; No of Pages 10 Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2012) xxx–xxx

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Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp

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Wencai Zhang a, Jianyou Guo a, Jianxin Zhang a,⁎, Jing Luo a, b,⁎⁎ a b

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Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences (CAS), 4A Datun Road, Chaoyang District, Beijing 100101, China Beijing Key Laboratory of Learning and Cognition, Department of Psychology, Capital Normal University Beijing 100048, China

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Article history: Received 21 August 2012 Received in revised form 16 October 2012 Accepted 21 October 2012 Available online xxxx

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The present study compared learning-based placebo effect and cognition-based reappraisal, to reveal the common and unique neural mechanisms between the two emotion regulations. First, the anxiety-relieving effect was tested by conducting a behavioral experiment. Next, the participants with the highest placebo or reappraisal effect were selected for the functional magnetic resonance imaging experiments. The results indicated that: (1) they both attenuated activity in the right amygdala and right insula, and (2) placebo effect activated the left subgenual cingulate whereas reappraisal activated the right dorsal prefrontal cortex (PFC) and the left inferior PFC. Our results show that learning-based placebo effect and cognition-based reappraisal have common anxiety-relieving effects. The placebo effect mainly depends on direct pathway subgenual cingulate–amygdala to regulate emotions, whereas the reappraisal may rely on both indirect pathways, such as the dorsal PFC– subgenual cingulate–amygdala, and direct pathways, such as the ventral lateral PFC–amygdala to regulate emotions. © 2012 Published by Elsevier Inc.

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Keywords: Placebo effect Reappraisal Emotion regulation Subgenual cingulate

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1. Introduction

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Different types of emotion regulation can be used to control the physiological, behavioral, and experiential components of our affective responses (Gross and Thompson, 2007). Therefore, understanding the differential impact of distinct types of emotion regulation may affect clinical practice and research (Goldin et al., 2008). Recently, some studies have conducted functional magnetic resonance imaging (fMRI)-based comparisons among different regulations such as reappraisal vs. distraction or reappraisal vs. suppression. They found reappraisal, distraction and suppression all increased activation in the medial and dorsolateral prefrontal cortex (PFC) (Goldin et al., 2008; Kanske et al., 2010; McRae et al., 2009a; Vrticka et al., 2011), while reappraisal selectively activated the orbitofrontal cortex (OFC)

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Abbreviations: PFC, prefrontal cortex; fMRI, functional magnetic resonance imaging; IAPS, International Affective Picture System; BOLD, blood oxygenation level-dependen; EPI, echo planar image; MNI, Montreal Neurological Institute; ANOVA, analysis of variance; CUR, viewing unpleasant pictures in the control condition; CNR, viewing neutral pictures in the control condition; RU, viewing unpleasant pictures in the reappraisal condition; RN, viewing neutral pictures in the reappraisal condition, for the placebo group; CUP, viewing unpleasant pictures in the control condition; CNP, viewing neutral pictures in the control condition; PU, viewing unpleasant pictures in the placebo condition; PN, viewing neutral pictures in the placebo condition. ⁎ Corresponding author. Tel.: +86 10 64855883; fax: +86 10 64872070. ⁎⁎ Correspondence to: J. Luo, Beijing Key Laboratory of Learning and Cognition, Department of Psychology, Capital Normal University, Beijing 100048, China. Tel.: +86 10 64836979; fax: +86 106487 2070. E-mail addresses: [email protected] (J. Zhang), [email protected], [email protected] (J. Luo).

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(Kanske et al., 2010), distraction selectively activated the parietal cortex (McRae et al., 2009a) and suppression was selectively activated the supplementary motor area (Vrticka et al., 2011). However, these studies didn't include the learning-base strategy which has been used widely in the psychotherapy. It is an important issue to study brain activation in the cognition-based and learning-base emotion regulation. Specifically, for the following considerations, the present study would determine the common and unique neural mechanisms in a laboratory setting between placebo effect, which is based on classical conditioning learning, and cognitive reappraisal, which is based on high-level cognition: (1) In the clinical psychotherapy behavioral and cognitive interventions have a significant position in treating emotion disorders such as depression, anxiety, and post-traumatic stress disorders (Frewen et al., 2008; Ritchey et al., 2010; Stewart and Chambless, 2009). (2) They two are often combined to increase clinical effectiveness. However, it is critical to keep cognition and learning intervention apart in a laboratory setting for identifying their separate and/or overlapped neural architectures. (3) Learning-based placebo effect and cognition-base cognitive reappraisal can be performed in an equivalent procedure and can apply a same set of standard affective pictures as experimental stimuli, so they two are well comparable. One previous study compared extinction and cognitive regulation for conditioned fear, and made the valuable finding that the lateral prefrontal cortices (PFC) engaged by cognitive regulation may influence the amygdala through similar ventral medial PFC connections that are thought to inhibit the amygdala during extinction (Delgado et al., 2008). However, this research applied conditioned fear stimuli (a color square which

0278-5846/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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All participants were free of medication and provided written informed consent in accordance with the Declaration of Helsinki. The ethics committee of the Institute of Psychology, Chinese Academy of Sciences approved this study, its participant-recruitment procedure and its methodology.

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2.2. Participants

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54 right-handed participants took part in this experiment and were randomly assigned to reappraisal (n= 27; age: 20.70 ± 1.21 yrs; 23 females) or placebo group (n= 27; age: 21.75± 1.27 yrs; 23 females). All participants were healthy and had normal or corrected-to-normal vision. We only selected right-handed participants to avoid the potential confusion from the different of brain structure correlated with the handedness (Dräger et al., 2000). None reported having a history of psychiatric or neurological disease, or of experiencing severe physical or emotional trauma. As per previous study shown (Wager et al., 2006; Zhang and Luo, 2009; Zhang et al., 2011), the effects associated with inter-individual variation can be minimized in the fMRI scanning part of the experiment by testing only the participants who showed a reliable placebo effect. So in this study, there were two separate parts for each group: behavioral experiment and fMRI scanning. We first tested all 54 participants' placebo or reappraisal effect in the behavioral experiment. Then 28 participants (14 in each group) selected from the behavioral experiment who showed higher placebo or reappraisal effect than others entered into fMRI experiment. Finally our analyses were based on 26 of these (12 females and one male in each group) because one in each group was ruled out for presenting incorrect stimuli or equipment fault.

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2.3. Pain and emotional stimuli

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Pain stimuli were delivered with a CO2 laser stimulator (DIMEI-300, China), with a spot diameter of 2.5 mm and a pulse duration of 100 ms. The output energy was kept below 300 mJ to avoid damaging the skin. Stimulation was applied to the dorsum of the right hand, with each stimulus applied to a different spot to avoid habituation. Emotional pictures for both the behavioral and fMRI parts of the experiment were selected from the International Affective Picture System (IAPS) (Lang et al., 2001). In the behavioral experiment, only emotionally unpleasant pictures were used (M± SE: valence and arousal were 2.62± 0.87 and 5.74 ±0.42, respectively). In the fMRI experiment, we used both high-arousal unpleasant (arousal: 5.84 ± 0.10; valence: 2.60± 0.10) and low-arousal neutral (arousal: 3.67 ±0.15; valence: 5.35± 0.11) pictures; these types of pictures differed significantly from each other in terms of both arousal [t (59)= 10.588, p b 0.001] and valence [t (59) =62.910, p b 0.001].

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2.4. Procedures

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There are two groups in this study, a placebo group and a reappraisal group. Here we should addressed two points: (1) In this study there were two sections for both placebo and reappraisal groups, a behavioral experiment was used to choose participants who showed greater unpleasantness reduction and a following fMRI experiment was used to test the neural bases of the placebo and reappraisal regulations (see Fig. 1). (2) Each group included both control condition and regulatory condition (such as placebo condition for placebo group or reappraisal condition for reappraisal group). We could observe the regulatory effect within the placebo and reappraisal groups by comparisons between the two conditions, and based on the within-group comparisons, we could continue to conduct comparisons between the placebo and reappraisal

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have paired with shock before) rather than standard affective pictures which were applied in most studies of cognitive reappraisal regulation. (4) fMRI study would provide potential imaging evidences for assessing curative effect of cognition-based or learning (behavior)-based emotion intervention. Placebo effect is viewed as a learning-based phenomenon. During experimental placebo anxiolysis or placebo analgesia, classical conditioning is commonly used to reinforce a placebo–outcome association (or Conditioned stimulus–Unconditioned Stimulus contingency) that informed by experimenter, to enhance the expectation of the placebo effectiveness (Davey, 1997; Mackintosh, 1983; Watson et al., 2009). It is suggested that even expectations acquired through simple verbal instructions might act as conditioning stimuli to reactivate previous stimulus-reinforcer associations (Klinger et al., 2007). Two recent placebo analgesia studies reported common or adjoining brain areas in the dorsal and medial PFC to be modulated throughout the placebo conditioning as well as the placebo analgesia periods (Lui et al., 2010; Watson et al., 2009). Placebo anxiolysis studies have also employed classical conditioning to enhance the placebo anxiolytic expectation. They found that the rostral anterior cingulated cortex, orbital PFC, ventral striatum (Petrovic et al., 2005), and subgenual anterior cingulate cortex (Zhang et al., 2011) were involved in placebo anxiolytic regulation. Some investigators further suggested that placebo responses are closely related to activation of the reward circuitry (de la Fuente-Fernandez et al., 2004; Sarah et al., 2005; Schweinhardt et al., 2009; Scott et al., 2007). The ventral striatum and subgenual anterior cingulate cortex (ventral medial PFC) are also involved in another learning-based form of emotion regulation—the extinction of fear conditioning (Phelps et al., 2004; Quirk and Mueller, 2008; Quirk et al., 2006; Rodriguez-Romaguera et al., 2012). Reappraisal refers to the reframing or recontextualization of a negative stimulus in less emotional terms, when used to down-regulate one's negative emotional response (McRae et al., 2008). Therefore, reappraisal is cognitively complex and should require processes necessary for generating, maintaining, and implementing a cognitive reframe, as well as processes that track changes in one's emotional states, such as working memory, attention, language, monitor, and long-term memory (Gross and Thompson, 2007; Ochsner and Gross, 2008). During reappraisal, activated regions include the dorsal lateral PFC and dorsal medial implicated in working memory and selective attention, the ventral lateral PFC that has been implicated in language or response inhibition, and the dorsal anterior cingulate cortex implicated in monitoring control processes (Campbell-Sills et al., 2010; Goldin et al., 2009; McRae et al., 2009b; Ochsner and Gross, 2005, 2007, 2008; Ochsner et al., 2002, 2004; Ohira et al., 2006; Phan et al., 2005; Urry et al., 2006). A previous study demonstrated that activity in the left amygdala co-varied with activity in the dorsal lateral PFC, the right dorsal medial PFC, the right subgenual region of the anterior cingulate cortex and the bilateral orbitofrontal cortices during a reappraisal-based strategy to down-regulate negative affect (Banks et al., 2007). Ochsner and Gross (Ochsner and Gross, 2008) proposed that high-level cognitive forms of emotion regulation like reappraisal may depend more upon dorsal frontal systems that are involved in working memory, language, and goal representation. In contrast, forms of regulation that depend on learning that the affective outcomes associated with stimuli or responses change over time may differentially depend upon ventral frontal systems that are essential for associative learning. In the present study, we try to examine these assumptions by comparing a cognitive-based reappraisal anxiolytic effect and a learning-based placebo anxiolytic effect in one study. We address two questions here: First, whether placebo effect and reappraisal have similar effects on the emotional experiences and on the typical emotion-responsive regions like the amygdala, and second, what commonalities and differences exist between the neural basis of these two emotion regulatory strategies.

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Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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2.4.1. Behavioral experiment The real aim of the behavioral experiment is to choose those people showing greater unpleasantness reduction in the placebo or reappraisal regulation. In the instruction stage we provided different guidance to the two groups. For the placebo group, all participants were informed that they would be participating in a study examining the alleviating effects of magnetic treatment (placebo) on pain and negative emotions. For the reappraisal group, all participants were

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informed that they would be participating in a study combining pain perception and the alleviating effects of cognitive reappraisal on negative emotions. In reality, pain perception experiment in the reappraisal group is a pretense to keep equivalence in experimental processes with placebo group. Thus, the participants of two groups underwent the behavioral experiment. Subsequently, the behavioral experiment was firstly administered. The behavioral experiment consisted of four phases (Fig. 2): a familiarization phase for the painful stimuli, a pain perception phase (simple perception for the reappraisal group but a expectation manipulation for the placebo group designed to induce an placebo expectation that

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group to observe the different and/or common regulatory effect between the two groups (Fig. 2).

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Fig. 1. Experimental procedure: There were two groups in this study, one group which used placebo regulation and the other group used reappraisal regulation, to alleviate the unpleasant emotion. A behavioral experiment was conducted to select participants showing greater unpleasantness reduction. A subsequent fMRI experiment was performed to test the neural basis of placebo and reappraisal regulations.

Fig. 2. The course of the experiment. (A) The behavioral and fMRI experiment both consisted of four phases: a familiarization phase for the painful stimuli, a pain perception phase, a practice phase for viewing the emotional image and a test phase to determine the presence of reappraisal effect in the reappraisal group or of placebo effect in placebo group on negative emotional arousal. (B) The test phase in fMRI experiment: fMRI scanning was consisted of 3 sessions, each session included a reappraisal block and a control block for reappraisal group, or a placebo block and a control block for placebo group. The order of presenting conditions was counterbalanced across all participants. Participants' unpleasantness ratings were obtained after each block. The behavioral experiment is similar to fMRI experiment in this phase except that it only included one session. Thus, each group included regulatory condition (such as placebo condition for placebo group or reappraisal condition for reappraisal group) and control condition. We could observe the regulatory effect within the placebo and reappraisal groups by the comparisons between the two conditions, and based on the within-group comparisons, we could continue to conduct comparisons between the placebo and reappraisal group to observe the different and/or common regulatory effect between the two groups (C) Timeline for events in each trial. Each picture was presented for 3 s at full-screen size with an interstimulus interval of 3 s, during which a fixation cross was presented.

Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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2.5. fMRI data acquisition and analysis

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The fMRI imaging was performed with a 3.0 Tesla MR scanner (Siemens, Magnetom Trio Germany), using the standard radio frequency headcoil. Each participant's head was fixed with foam pads throughout the experiment to minimize head movements. Thirty-two transversal slices of functional images that covered the whole brain were acquired with a T2*-weighted echo-planar imaging sequence based on blood oxygenation level-dependent (BOLD) contrast (repetition time (TR) = 2 s; echo time (TE) =30 ms; image matrix=64 ×64; slice thickness= 4 mm; gap=0.4 mm; FOV= 200×200 mm; flip angle (FA)=90°). For each participant, a high-resolution anatomical scan was acquired at the end of the experiment with a T1-weighted 3D magnetizationprepared rapid gradient-echo pulse sequence (TR=2530 ms, TE= 3.37 ms, FA=7°, FOV=256 ×256 mm, voxel size=1 ×1× 1.33 mm, 144 contiguous 1.33-mm thick sagittal slices, slice matrix size= 256× 256). The preprocessing and statistical analysis of images was performed using SPM5 software (http://www.fil.ion.ucl.ac.uk/spm). The first four functional echo planar image (EPI) volumes were discarded to allow for T1 equilibration. Preprocessing of the remaining functional EPI images included slice correction, motion correction, and normalization. Functional images were transformed into a standard anatomical space (3× 3 × 3 mm3 isotropic vexes) based on the Montreal Neurological Institute (MNI) template. Functional images were spatially smoothed using a Gaussian filter with 8-mm full width half maximum (FWHM). The data were statistically analyzed using general linear models and statistical parametric mapping. To assess the neural activity corresponding to the processing of the two different types of pictures under each of the experimental conditions in each group, four separate regressors were created for

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2.4.2. fMRI experiment After several days, the participants selected from the behavioral experiment in the two groups participated in an event-related fMRI experiment (Fig. 2). The fMRI experiment also included the first three phases that were similar to those of the behavioral experiment. But differently in the fourth phase we let participants view the unpleasant pictures in an fMRI scanning room to determine if placebo effect and reappraisal would have an anxiolytic effect on negative emotional arousal. This testing employed three runs of alternating reappraisal/placebo and control condition stimulus blocks of unpleasant pictures (Fig. 2). The runs began with a reappraisal/placebo condition block for half of the participants and with a control condition block for the other half. There are 60 emotional unpleasant pictures and 60 neutral pictures. Each block consisted of 10 unpleasant and 10 neutral pictures. The arousal and valance values of the pictures were equivalent across all blocks. Participants were instructed to view each picture during its 3-s presentation period. Unpleasant and neutral pictures were pseudo-randomly intermixed, and pictures from the same category were presented no more than three times in a row in order to avoid habituation effects. After each block, participants separately reported their unpleasantness ratings on an 11-point scale. Several days after the fMRI experiment had been concluded, these participants in each group were re-interviewed and debriefed about the true purpose of the study.

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unpleasant). These ratings were used to identify participants who showed a greater placebo or reappraisal effect on negative affectivity. Resultantly, fourteen participants in each group (seven participants beginning with reappraisal/placebo condition and seven participants beginning with control condition) showed more reduction of reported unpleasantness in the placebo or reappraisal condition than the mean group reduction, and were invited to return for the follow-up fMRI scanning. Several days after the experiment had been concluded, the remaining 13 participants were re-interviewed and debriefed about the true purpose of the study.

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the magnetic treatment would alleviate pain), a practice phase for viewing the emotional image (reappraisal training for reappraisal group but simple practice for placebo group) and a test phase to determine the presence of reappraisal effect in the reappraisal group or of placebo effect in placebo group on negative emotional arousal. In the first phase of familiarization all participants for the two groups were gradually familiarized with the laser pain stimuli via the administration of two sequences of six to seven increasingly intense stimuli. In terms of output energy, each sequence was 80 mJ, 120 mJ, 160 mJ, 200 mJ, 240 mJ, 280 mJ, and 300 mJ. In the second phase the same painful stimuli were administered in the two groups. There were four blocks of painful laser stimulation. The intensity of stimuli varied across the blocks, six low intensity stimuli were delivered in each of the second and fourth blocks and six high intensity stimuli were delivered in each of the second and fourth blocks. Participants in the reappraisal group were simply informed to report the perceived pain intensity of each stimulus. Participants in the placebo group were told that the intensity of the stimuli was always the same within and across each of these. In fact, stimulus intensity varied across the blocks as mentioned above. Low intensity stimuli block was delivered while the treatment equipment was connected to the electrode (a signal to the participants that the treatment equipment was being used). Conversely, high intensity stimuli block was delivered while the treatment equipment was disconnected (a signal to the participants that the treatment equipment was not being used). Given that the participants didn't realize that the intensity of painful stimuli was less in the placebo blocks, they were expected to believe that the reduced feelings of pain were an effect of magnetic treatment. After each block of stimuli, each participant in the two groups provided ratings of pain using an 11-point scale (from 0 = no pain to 10 = unbearable pain). This paradigm of inducing a placebo expectation in the placebo group was well established in our previous study (Zhang and Luo, 2009; Zhang et al., 2011). In the third phase of practice for viewing the emotional pictures, participants in the reappraisal group were instructed to use a cognitive reappraisal strategy by generating an interpretation of, or a story about, each picture that would explain apparently negative events in a less negative way (e.g., women depicted crying outside a church could be described as attending a wedding rather than a funeral) (Ochsner et al., 2002). Participants were trained and completed 10 practice trials to ensure that they were able to use their reappraisal strategies to reinterpret negative pictures. Differently, participants in the placebo group were informed that if the magnetic equipment was connected to an electrode at the Jiuwei acupoint on the upper abdomen, any negative emotional arousal would be reduced. They also were trained and completed 10 practice trials. In the fourth phase of test in the behavioral experiment, we used unpleasant pictures to determine if reappraisal or placebo has an anxiolytic effect on negative emotional arousal. Participants of the two groups were presented with two blocks of unpleasant pictures. The arousal and valence values of the pictures were equivalent between the two blocks. For the reappraisal group, participants passively viewed one block of the unpleasant pictures. In contrast, for the other block participants were asked to reappraise them. For the placebo group, participants passively viewed one block of the unpleasant pictures with the magnetic treatment equipment connected to the Jiuwei acupoint electrode (i.e. the placebo condition), and for the other block, participants viewed the pictures with the electrode disconnected from the equipment (i.e. the control condition).The order in which the two blocks were presented was counterbalanced across participants. Each block contained four high-arousal unpleasant pictures. Each picture was presented for 3 s, followed by a fixation cross (“+”) for 3 s. Blocks were separated by a one-minute rest period in order to avoid potential confounds of feelings. Immediately after each block, participants provided ratings of unpleasantness using an 11-point scale (from 0 = no unpleasantness to 10 = unbearably

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Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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In the behavioral experiment, we selected participants whose rating scores of actual unpleasantness decreased by more than the mean group reduction from both the groups. A similar approach has been used in previous studies (Wager et al., 2006; Zhang and Luo, 2009; Zhang et al., 2011). Next, a three-way mixed analysis of variance (ANOVA), with groups (placebo regulation group vs. reappraisal regulation group) and participant types (selected participants vs. rejected participants) as between-subject factors and conditions [control vs. regulation(placebo/reappraisal)] as a within-subject factor. (1) A significant main effect of condition [control vs. regulation (placebo/ reappraisal)], F (1, 50) = 94.279, p b 0.001 was revealed. It indicates that unpleasantness ratings were significantly lower in the emotion regulation condition (placebo and reappraisal) than in the control condition, providing evidence that a regulatory effect was indeed induced. (2) A significant interaction effects of conditions × participant types [F (1, 50) = 39.709, p b 0.001] in the behavioral experiment was revealed. Next, a simple effect test showed that in the regulatory (placebo/reappraisal) condition, the unpleasantness ratings in the selected participants were significantly lower than in rejected ones [t (52) = 3.131, p b 0.05] (Fig. 3, upper panel). These data indicate that the regulatory effect was significantly greater in selected participants than in rejected ones. The fMRI experiment revealed a significant main effect of condition (regulation vs. control) on the unpleasantness ratings [F (1, 24) = 89.742, p b 0.001] (Fig. 3 lower panel); No between–group main effect for two groups and no interaction effect was observed. These results indicate an anxiety-relieving regulatory effect was operating for these two groups during the scanning experiment.

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3.1. Unpleasantness ratings in the behavioral and fMRI experiments

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Fig. 3. Unpleasantness ratings. Upper panel: Unpleasantness ratings for selected (n=14) and rejected (n=13) participants under the regulation and control conditions in the behavioral experiment. Selected participants showed significantly decreased unpleasantness ratings in the regulation condition compared to the control condition. ***pb 0.001. Lower panel: Unpleasantness ratings (n=13) in the fMRI experiment were significantly reduced in the reappraisal/placebo condition compared to the control condition.

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each group (for the reappraisal group: CUR, viewing unpleasant pictures in the control condition; CNR, viewing neutral pictures in the control condition; RU, viewing unpleasant pictures in the reappraisal condition; RN, viewing neutral pictures in the reappraisal condition; for the placebo group: CUP, viewing unpleasant pictures in the control condition; CNP, viewing neutral pictures in the control condition; PU, viewing unpleasant pictures in the placebo condition; PN, viewing neutral pictures in the placebo condition); these were time-locked to the onset of picture presentation and then convolved with a canonical hemodynamic function. In addition, motion realignment parameters were modeled to account for variability related to head movements. A high-pass filter with a cut-off frequency of 1/128 Hz was used to correct for low-frequency components, and serial correlations were accounted for with an autoregressive AR (1) model. The relevant parameter contrasts generated on an individual level were submitted to a group analysis using a random effect model. A 2 × 2 × 2 full factorial analysis of variance was conducted with data from all participants; the factors were groups (reappraisal and placebo group), experimental condition (placebo vs. control) and emotional picture type (unpleasant vs. neutral). For the emotion responsive area, whole brain search results from the random effect analysis with a threshold at p b 0.001 (uncorrected) are reported (Worsley et al., 1996). For the emotion modulatory area, whole brain search results from the random effect analysis with a threshold at p b 0.005 (uncorrected) for strategy-specific brain area and p b 0.05(uncorrected) for strategy-common brain area are reported. Moreover, the activation patterns associated with the two experimental conditions in each group were characterized by extracting the signal changes from each region of interest using Marsbar (v0.41; http://marsbar.sourceforge. net), as recommended by Brett et al. (Brett et al., 2002). The MNI coordinates of the local maximum of each cluster were converted into Talairach coordinates, which are those reported here.

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3.2. Imaging results

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3.2.1. Common and different brain regions showing attenuated activity during the regulatory conditions (placebo and reappraisal) for these two groups To identify a common neural network associated with the anxiety-relieving effects in the 2 groups, we first contrasted the differences during unpleasant and neutral picture viewing between scans obtained in the control and placebo conditions [(CUP − PU) − (CNP − PN)] for the placebo group. We also contrasted the differences during unpleasant and neutral picture viewing between scans in the control and reappraisal conditions [(CUR − RU) − (CNR − RN)] for the reappraisal group. Then conjunction analyses were conducted in the 2 groups. We found several common activated regions in the right amygdala, right claustrum/insula, and left cingulate (Fig. 4). The results indicate that there was significantly attenuated activity in the amygdala and insula during unpleasant picture viewing when comparing the regulatory and control conditions for these two groups (Table 1). To identify the different neural networks associated with the anxiety-relieving effects in the 2 groups, we performed image subtraction for images obtained for the control and placebo conditions [CUP − PU] in the placebo group and for the control and reappraisal conditions [CUR − RU] in the reappraisal group during unpleasant picture viewing. We found the placebo group showed greater attenuation of activation in the bilateral parahippocampal regions, right insula, left temporal gyrus, and right fusiform in the placebo regulation than the reappraisal group did in the reappraisal regulation. Similarly, when we performed image subtracting for the contrast of [(CUP − PU) − (CNP − PN)] in the placebo group and for the contrast of [(CUR − RU) − (CNR − RN)] in the reappraisal group, we found the placebo group showed greater attenuation of activation in the bilateral insula, bilateral temporal gyrus, and right cingulate in the placebo regulation than the reappraisal group did in the reappraisal regulation (Fig. 5). These results indicate the compared to the

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Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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12 −24 27 −18 18 30 0 59 50 50

−3 −15 −1 −23 −5 −14 −1 −5 −8 −25

58 −4 −13 59 11 17 47 9 22 29

17 6 12 6 5 9 7 14 5 5

T

3.89 3.75 3.71 3.6 3.59 3.56 3.41 3.41 3.31 3.3

P(unc)

0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

4. Discussion

Notes: The threshold is set at ***pb 0.001 uncorrected.

447

reappraisal regulation, the placebo regulation produced greater attenuation of activation in a larger brain area (Table 2).

457 458

Q5 459 460 461

C

E

R

R

O

455 456

C

453 454

N

451 452

3.2.2. Common and different modulation networks showing enhanced activity during the regulatory conditions (placebo and reappraisal) for these two groups To identify common neural networks associated with the modulation effects in these two groups, we conducted a conjunction analysis with a loose threshold between the differences under the placebo and control conditions [PU − CUP] and under the reappraisal and control conditions [RU − CUR] during unpleasant picture viewing in the placebo and reappraisal groups, respectively. We found several commonly activated regions in the right subgenual cingulate and left inferior PFC (Fig. 6) (Table 3). To identify the unique neural networks associated with the modulation effects in these two groups, we performed image

463 464 465 466 467 468 469 470 471 Q6 472 473

4.1. Common and distinct influence of the placebo and reappraisal regulations on emotional responses

480

For the emotion-responsive areas, compared to the control conditions, both the reappraisal and placebo regulations produced decreased negative emotional experience as well as decreased activation in the right amygdala and right insula. The amygdala is implicated in the detection and encoding of affectively arousing stimuli, and the insula, which receives viscerosensory inputs, may play a general role in affective experience (Ochsner and Gross, 2008). Our finding is consistent with those of previous studies on the cognitive reappraisal and anxiolytic placebo effect (Goldin et al., 2008; Ochsner et al., 2002, 2004;

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To our knowledge, this is the first study to compare of the neural correlates of reappraisal and placebo effects. We observed partially overlapping effects for both strategies, along with important distinctions between them. As discussed below, these findings increase our understanding of the common and distinct neural architecture involved in the cognition-based and learning-based forms of emotion regulation.

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t1:15

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Regions of activation

subtraction for the differences under the placebo and control conditions [PU − CUP] in the placebo group and under the control and reappraisal conditions [RU − CUR] in the reappraisal group during unpleasant picture viewing. We observed specific activation in one region of the left subgenual cingulate and caudate (ventral striatum) for the contrast of [PU − CUP] but not for the contrast of [RU − CUR]. In contrast, we observed specific activation in the other nonoverlapping region of left subgenual cingulate, in the left inferior PFC, and in the dorsal medial PFC for the contrast of [RU − CUR] and not for the contrast of [PU − CUP] (Fig. 7) (Table 4).

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t1:3

Table 1 Brain regions activated in both (CUP − PU) −(CNP − PN) and (CUR − RU) −(CNR − RN).

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t1:1 t1:2

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Fig. 4. Common regions in attenuated activiation. Activity in the right amygdala (27, −1, −13), right insula (30, −14, 17), and left cingulate (0, −1, 47) was attenuated during the regulatory condition compared to the control condition for both types of emotion regulation.

Fig. 5. Different regions in attenuated activation. Activation in the left insula (−30, 24, 4), left middle temporal (−48, 5, −20), and right cingulate (15, 11, 35) was stronger in the [(CUP − PU) −(CNP −PN)] contrast than in the [(CUR − RU) − (CNR − RN)] contrast.

Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

474 475 476 477 478 479

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W. Zhang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2012) xxx–xxx

T

Y

Z

50 −18 27 33 −36 −36 39 18 −50 −18

−19 −13 −20 20 −20 −14 −8 −5 8 −6

11 12 18 7 3 3 7 1 2 2

5.26 4.27 4.21 4.19 4.18 4.01 3.9 3.76 3.71 3.49

0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

(CUP − PU) −(CNP − PN) > (CUR − RU) −(CNR − RN) Left insula 45 −30 24 Left middle temporal gyrus 38 −48 5 Left inferior frontal gyrus 47 −36 25 Left superior temporal gyrus 38 −45 19 Right superior temporal gyrus 38 39 19 Right cingulate gyrus 32 15 11 Left precentral gyrus 4 −24 −21 Right insula 13 33 −11

4 −20 −16 −19 −24 35 48 20

9 16 7

4.32 4.03 4 3.79 3.76 3.73 3.63 3.63

0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

t2:27

Notes: The threshold is set at ***pb 0.001 uncorrected.

P (unc)

t3:3 t3:4

Z

11 25

−9 15

43 14

−17 −16

3 10

2.33 2.24

0.05 0.05

t3:5 t3:6

34 39 34

−12 −59 −15

−1 −60 5

−18 28 −18

2 3 1

2.17 1.95 1.92

0.05 0.05 0.05

t3:7 t3:8 t3:9

Notes: The threshold is set at ***p b 0.05 uncorrected.

inferior PFC has been implicated in language processes (Stemmer and Whitaker, 2008), the dorsal anterior cingulate cortex is implicated in monitoring control processes (Pourtois et al., 2010), the parahippocampus is related to conscious appraisal of the emotional stimuli (Mechias et al., 2010), the superior and middle temporal gyri are implicated in feature detection of emotion stimuli (Kensinger and Schacter, 2006), and the fusiform gyrus is involved in the perception of visual emotion stimuli (Radua et al., 2009). Our data reveal that cognition-based reappraisal and learning-based placebo effect have common anxiety-relieving effects on the amygdala and insula, but the mobilization of cognitive resources such as attention, monitoring, language, and appraisal processes that are essential for the cognitive reappraisal to decrease emotional arousal, are unnecessary for the anxiety-relieving placebo effect.

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501 502

Petrovic et al., 2005; Zhang et al., 2011) and on the use of antidepressants and ataractics for major depression and panic disorder (Mayberg et al., 1999, 2002). Furthermore, we found neural networks uniquely associated with the placebo anxiety-relieving effects in placebo regulation. We observed greater attenuation of activation in a large area during the placebo regulation, including right cingulate, the bilateral inferior PFC, bilateral parahippocampal and superior and middle temporal regions, insula, right fusiform, and bilateral basal ganglia than during the reappraisal regulation, when they were compared to the control condition. As discussed in previous studies, these areas are associated with cognitive aspects of emotion processing. For example, the

R

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t3:10

503 504 505 506 507 508 509 510 511 512 513 514 515 516

4.2. Common and distinct control systems involved in reappraisal and 517 placebo effect 518 Regarding the emotion-regulatory areas, we observed partially overlapping PFC areas, including the right subgenual cingulate and left inferior PFC, in these two strategies, with a loose threshold for analysis. In addition, we observed placebo-specific activation in one region of the left subgenual cingulate (BA25) and reappraisalspecific activations in the another non-overlapping region of the left subgenual cingulate (BA34, close to BA25), in the right dorsal medial

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497 498

1 5 1 1

Left inferior frontal gyrus Right medial frontal gyrus/ subgenual cingulate Left parahippocampal gyrus Left superior temporal gyrus Left uncus

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Voxel

N C O

495 496

21

Talairach coordinate

U

493 494

13 38 47 47

BA

X

X

−21 2 −10 −11 −1 26 17 −3 −46 11

20 34

Regions of activation

P(unc)

t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25 t2:26

491 492

CU − PU > CU − RU Right fusiform gyrus Left parahippocampal gyrus Right parahippocampal gyrus Right insula Left superior temporal gyrus Left inferior frontal gyrus Right inferior frontal gyrus Right lateral globus pallidus Left middle temporal gyrus Left putamen

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t3:1 t3:2

Table 3 Brain regions activated in both PU–CU and RU–CU.

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Table 2 Brain regions uniquely activated in [(CUP − PU) −(CNP − PN)] or [(CUR − RU) − (CNR −RN)].

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t2:1 t2:2 t2:3

7

Fig. 6. Common regions in enhanced activation. Commonly activated regions were observed in the right subgenual cingulate (15, 14, −16) and left inferior PFC (−9, 43, −17) for both the contrast of [PU − CUP] and the contrast of [RU − CUR]. The pattern of activation in the two regions during contrasting the regulatory conditions (placebo and reappraisal) and control conditions was similar for the placebo and reappraisal groups.

Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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t4:3

Table 4 Brain regions uniquely activated in PU–CU or RU–CU.

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Fig. 7. Different regions in enhanced activation. Activation was specifically observed in one region of the left subgenual cingulated (−12, 17, −13) in the contrast of [PU − CUP] and not in the contrast of [RU − CUR], and in the another nonoverlapping region of the left subgenual cingulate (−15, 2, −10), left inferior PFC (−39, 26, −9), and dorsal medial PFC (24, 42, 17) in the contrast of [RU − CUR] and not in the contrast of [PU − CUP]. The pattern of activation in these regions during contrasting the regulatory conditions (placebo and reappraisal) and control conditions was different for the placebo and reappraisal groups.

Regions of activation

BA

t4:4 t4:5 t4:6 t4:7 t4:8 t4:9 t4:10 t4:11 t4:12 t4:13 t4:14 t4:15

Talairach coordinate X

PU–CU > RU–CU Left subgenual cingulate Left caudate RU–CU > PU–CU Left subcallosal gyrus Left inferior frontal gyrus Right medial frontal gyrus Left superior temporal gyrus Left medial globus pallidus

25

34 47 9 38

−12 −9

−15 −39 24 −39 −15

Y 17 20

2 26 42 16 −3

Voxel

T

P (unc)

Z −13 −6

−10 −9 17 −29 −5

Notes: The threshold is set at ***pb 0.005 uncorrected.

14

2 3 1 1 1

2.99 2.89

4.04 3.5 3.26 2.86 2.83

0.003 0.004

0.001 0.001 0.002 0.004 0.005

PFC and left inferior PFC. These differences may provide important insights into the key processes that uniquely underlie these two forms of emotion regulation. There is some knowledge about the anatomical connection between the PFC regions and the amygdala: (1) the subgenual cingulate (BA25) is notable in that it sends the densest projections to the amygdala. It also constitutes the structural foundation in which the subgenual cingulate directly influences amygdala processing (Ray and Zald, 2012), (2) the dorsal PFC from BA9 lacks direct projections to the amygdala. However, Vogt and Pandya (1987) reported that the subgenual cingulate receives projections from the dorsal PFC, providing an indirect route for the dorsal PFC to influence the amygdala (Ray and Zald, 2012), and (3) the ventral lateral PFC (lateral inferior PFC) provides moderately dense projections to the amygdala and is the only lateral PFC region with direct input to the amygdala (Ray

Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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Fig. 8. Learning-based placebo effect may rely on direct pathways including subgenual cingulate–amygdala route as well as ventral lateral PFC–amygdala route, to influence amygdala processing (left). In contrast, cognition-based reappraisal may rely on indirect pathways, such as the dorsal PFC–subgenual cingulate–amygdala route, and direct pathways, such as the ventral lateral PFC–amygdala route, to influence amygdala processing (right).

552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583

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relies on a phylogenetically shared ventral medial PFC–amygdala circuitry (Delgado et al., 2008; Hartley and Phelps, 2010). These evidences both increase our understanding of a common neural base between cognition-based and learning-based emotion regulations.

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4.3. Limitations

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551

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and Zald, 2012). The present study found some evidences for the three circuits raised by Ray and Zald. Learning-based placebo effect specifically activated the left subgenual cingulate and left ventral striatum and commonly activated the right subgenual cingulate and left lateral inferior PFC with cognition-based reappraisal. The subgenual cingulate and lateral inferior PFC both have direct routes to influence amygdala activity (Fig. 8). These areas are known to be correlated with learning-based placebo effect (Scott et al., 2007; Wager et al., 2007, 2008; Zhang et al., 2011) and other learning-based emotion regulation, such as the extinction of fear conditioning (Etkin et al., 2011; Hartley and Phelps, 2010; Quirk and Mueller, 2008) and reward responses (Bjork et al., 2008; Critchley and Rolls, 1996; Goldstein et al., 2007; Yang et al., 2009). In contrast, cognition-based reappraisal specifically activated the right dorsal PFC (BA9), the left subgenual cingulate (BA34) and left lateral inferior PFC, and commonly activated the right subgenual cingulate and left lateral inferior PFC with the learning-based placebo effect. The dorsal PFC lacks direct projections to the amygdala, whereas the subgenual cingulate and lateral inferior PFC do have direct amygdala projections. Therefore, cognition-based reappraisal may rely on indirect pathways, such as the dorsal PFC–subgenual cingulate–amygdala route, as well as direct pathways, such as the ventral lateral PFC–amygdala route, to influence amygdala processing (Fig. 8). Furthermore, previous studies have shown that activation in the dorsal PFC, subgenual cingulate, and inferior PFC is correlated with the emotion regulation by cognitive reappraisal (Banks et al., 2007; Campbell-Sills et al., 2010; Ochsner and Gross, 2007, 2008; Ochsner et al., 2002, 2004). We found that the learning-based placebo effect was uniquely associated with ventral PFC regions (subgenual cingulate) and the cognition-based reappraisal effect was uniquely associated with dorsal medial PFC regions. These findings provide important support for the model of emotion regulation suggested by Ochsner and Gross (2007). They proposed two different types of emotion regulation: the top-down outcome-based system consisting of orbital and ventral PFC that is important for learning associations such as extinction or stimulus-reinforcer reversal learning, and the top-down descriptionbased system consisting of the dorsal PFC that is important for generating mental descriptions of one's emotional states, such as controlled reappraisal. In addition, we found common activation in the right subgenual cingulate and left lateral inferior PFC. Consistent with this, other investigators found that the ventral medial PFC is activated in the cognitive regulation of fear and the extinction of fear and suggested that the inhibition of fear through cognitive regulation and extinction

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This study still has some limitations in sampling. Firstly, the sample size included 27 participants in each group in behavioral experiment, but the sample size in fMRI experiment (13 participants in each group who were selected from behavioral experiment) was relatively small. Secondly, we presented all the valid data, but the data set is less than perfect for the sample size was gender-mismatched (one male was included in each group). Although our major experimental observations were statistically sufficient, further experiment with larger and gender-matched sample size could be more informative.

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5. Conclusions

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Cognition-based reappraisal and learning-based placebo effect have a common anxiety-relieving effect that is correlated with attenuation of activity of the amygdala and insula. Additionally, there is decreased mobilization of cognitive resources for the learning-based placebo effect condition; this is correlated with a larger area of reduced activation, including the inferior PFC, cingulate, bilateral parahippocampus, and temporal gyrus. The learning-based placebo effect may depend on the direct pathway (subgenual cingulate–amygdala) to bring about the emotion regulation, whereas the cognition-based reappraisal may rely on both the indirect pathways, such as the dorsal PFC–subgenual cingulate–amygdala, and direct pathways, such as the ventral lateral PFC–amygdala, to regulate emotions.

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Acknowledgments

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This research was supported by the National Natural Science Foundation of China (grant nos. 30970890, 31100746, and 31170992), the Scientific Foundation of Institute of Psychology, Chinese Academy of Sciences (grant no. Y0CX451S01), the National Basic Research Program of China (grant no. 2010CB833904), the Knowledge Innovation Program of the Chinese Academy of Sciences (grant no. KSCX2-EW-J-8) and Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences. The funders had no role in study design, data

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Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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D

620 621

E

10

773

Please cite this article as: Zhang W., et al, Neural mechanism of placebo effects and cognitive reappraisal in emotion regulation, Progress in NeuroPsychopharmacology & Biological Psychiatry (2012), http://dx.doi.org/10.1016/j.pnpbp.2012.10.020

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