《认知神经科学》课程教学资源（参考文献）[Phan, K. L., Wager, T., Taylor, S. F., & Liberzon, I.（2002）]Functional neuroanatomy of emotion_A meta-analysis of emotion activation studies in PET and fMRI

Aoioegnigza3l8s0galabeonlneatmtpzAiheabrayeomnlnE大le REVIEW Functional Neuroanatomy of Emotion:A Meta-Analysis of Emotion Activation Studies in PET and fMRI1 K.Luan Phan.Tor Wager,t Stephan F.Taylor.and Israel Liberzon Received November 2.2001 studies with ositron to olved in brain regions are ography PE ic re Sclence (USA) ging (IMK to d va in task dir INTRODUCTION e(s)o and are I It has long been proposed that emotion involves the ht to determin (Pa pez,1937:Mac exis acro ntly.thi en t vielding 761 emission tomography PE nd functional magnetic which in stigated in healthy cts resonance imaging (fMRD).These studies have re Peak acti trans】 ported emot on-relat increase in cerebral blo s h d each r gion that specific brain regions have specialized functions by disgust),to 0 ar-r different induction methods(visual, d tha and In 10 amygdala activations o ond to dis affec the foll (L)The me tive style(Irwin and Davidson 1999) had corte prefronta al role dala:()sad ed with act ty in the and e .2000.wh the orbital prefrontal cortex is considered important emoti nd action by for the related rein ement e o pital he 19989tio retrosplenial rte ited the anterior ate ar sula tasks with ally salient stimuli,particularly in the interaction be cogn Ive de ved th tween emotion and episodic memory (Maddock,1999). critical ce gener greer ab some or thes sing different induction This arch ed in e APIRE/Ja methods and imaging techniques. Severe part b aken separately,individual im ence rd( al I naging studies ca on due to lou arch fel hip T.W.) nd her ity in task design.ima P

REVIEW Functional Neuroanatomy of Emotion: A Meta-Analysis of Emotion Activation Studies in PET and fMRI1 K. Luan Phan,*,2 Tor Wager,† Stephan F. Taylor,* and Israel Liberzon*, ‡ *Department of Psychiatry and †Department of Psychology, University of Michigan, Ann Arbor, Michigan 48109; and ‡Psychiatry Service, Ann Arbor VAMC, Ann Arbor, Michigan 48105 Received November 2, 2001 Neuroimaging studies with positron emission to￾mography (PET) and functional magnetic resonance imaging (fMRI) have begun to describe the func￾tional neuroanatomy of emotion. Taken separately, specific studies vary in task dimensions and in type(s) of emotion studied and are limited by statis￾tical power and sensitivity. By examining findings across studies, we sought to determine if common or segregated patterns of activations exist across vari￾ous emotional tasks. We reviewed 55 PET and fMRI activation studies (yielding 761 individual peaks) which investigated emotion in healthy subjects. Peak activation coordinates were transformed into a standard space and plotted onto canonical 3-D brain renderings. We divided the brain into 20 non￾overlapping regions, and characterized each region by its responsiveness across individual emotions (positive, negative, happiness, fear, anger, sadness, disgust), to different induction methods (visual, au￾ditory, recall/imagery), and in emotional tasks with and without cognitive demand. Our review yielded the following summary observations: (1) The medial prefrontal cortex had a general role in emotional processing; (2) fear specifically engaged the amyg￾dala; (3) sadness was associated with activity in the subcallosal cingulate; (4) emotional induction by vi￾sual stimuli activated the occipital cortex and the amygdala; (5) induction by emotional recall/imagery recruited the anterior cingulate and insula; (6) emo￾tional tasks with cognitive demand also involved the anterior cingulate and insula. This review provides a critical comparison of findings across individual studies and suggests that separate brain regions are involved in different aspects of emotion. © 2002 Elsevier Science (USA) INTRODUCTION It has long been proposed that emotion involves the limbic system (Papez, 1937; MacLean, 1952; LeDoux, 1996). Recently, this assumption has been tested with functional neuroimaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These studies have re￾ported emotion-related increases in cerebral blood flow or BOLD signal (activations) in cortical, limbic, and paralimbic regions. Many authors have hypothesized that specific brain regions have specialized functions for emotional operations. For example, while some pos￾tulated that the amygdala is critical to fear-related processing (LeDoux, 2000), others have suggested that amygdala activations correspond to dispositional affec￾tive style (Irwin and Davidson, 1999). The medial pre￾frontal cortex has been hypothesized to have specific roles for emotional decision making (Damasio, 1996) and emotional self-regulation (Davidson, 2000), while the orbital prefrontal cortex is considered important for the evaluation of emotion-related reinforcement contingencies (Rolls, 1999). The retrosplenial cortex has been proposed as important in processing emotion￾ally salient stimuli, particularly in the interaction be￾tween emotion and episodic memory (Maddock, 1999). In spite of general agreement about some of these specialized emotional regions, conflicting findings are often produced by studies using different induction methods and imaging techniques. Taken separately, individual imaging studies cannot fully characterize which brain regions are responsible for emotion due to low statistical power and heteroge￾neity in task design, imaging methods, and analysis. These variations have made it difficult to interpret the 1 This research was supported in part by the APIRE/Janssen Re￾search on Severe Mental Illness Award (K.L.P.), the Rachel Upjohn Clinical Neuroscience Scholars Award (K.L.P.), the Mental Illness Research Association (K.L.P.), and the National Science Foundation Graduate Research Fellowship (T.W.). 2 To whom correspondence and reprint requests should be ad￾dressed. Fax: (734) 647-8514. E-mail: luan@umich.edu. NeuroImage 16, 331–348 (2002) doi:10.1006/nimg.2002.1087, available online at http://www.idealibrary.com on 331 1053-8119/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved

332 PHAN ET AL. s found.Unde this et al.1998b:LaBar et al.1998:Buchel et al.1999 s I ve udies one a 21100g B iti n and ex across studies patterns of activa nde them ine hle to the tions can be evaluated across similar and dissimilar tional tasks in our database.Furthermore.ths fe emotional tasks.This meta-analysis examines findings conditioning related activations were discussed in a recent review by Buchel and Dolan (2000).0n ific activation peaks were examined in this md if there are meta-analysis.The reporting of deactivation or de with emotional activation tasks that had a comitive creases in din acti alty was en component (e.g.. emotional ni tod mined activations remain undetermine and their spe in regions w ere to ifferent tio s re ain inconclusive or unclear (Hutchinson a em 1999:Raichle et al 2001) ditio cer tain brain regions were for different emotional responses Organization of Results (reflected by the frequency of activation in a s Fifty-five publications/studies (43 PET and 12 fMRI) region ith tas ning from May.1993.to December.2000.that met T ehtfanteria.yalding19subtractiornscoatst atterns and the and 761 individual activation peaks,were included for stion of laterality in activation patterns are major topics in neuroimagi meta-analysis(Table 1).Because the studies adopted dif ng of emotion and thus require an extensive and separate discussion. all foci the Therefore,we have as sig ficant by hosen to report these results sep- ia d lual stu arately (Wager et nanner:(1)Res ith Indivdual Emotion METHODS Socated with Induction Method (visual auditpry.auto happiness):(2)regions as Scope of Review plographical recall/imagery): and (3)regions associated with preser e and abs ence of Cognitive Demand.Table sof activa on uy,an a large for English-language manuscripts of PET and fMRI he af rate but emotionindction5udespubihedbetwenpdaotm2a nent of Induction Method.for a variety of reaso 1990,and Decemb To allow us to pertorm literature often distinguishes between er,200 11T Ireports otional tasks contain varous degrees of cognitive de. s②Th mand.Furthermore,there is a clear interaction between tal processes of emotion (thus.studies of lower -order lon and cog onon a eve To exa sensory or motor processes,such as gustatory/olfactory we ti a were excluded)see reviews er al.1999 vation b s in which an emotional task was co pled with a concurren nitive task (e.g en BOLD-MRD der/emotional expression discrimination.emotional rat- across the entire brain (i.e..excl studi tha ing,picture/face recognition/encoding.naming,counting focused on limited regions of the brain):(4)They all autobiographical recall/imagery.etc.)as Emotion- Cog used the image subtraction methodology to determine or eman provided ta dard a irach n the em rnou Montreal pa (MNI ith nitive Demand This classification allo ws us to examing laboratories.We chose not to include studies on aver the effect of a "nonemotional" ognitive component on sive and trace conditioning (Buchel et al,1998:Morris emotional tasks

differences in activation patterns found. Under this circumstance, a broader-based meta-analysis of multi￾ple studies may be one solution (Fox et al., 1998). By examining findings across studies, patterns of activa￾tions can be evaluated across similar and dissimilar emotional tasks. This meta-analysis examines findings across imaging studies in search of specific regions associated with emotional activation in general, with specific emotions and different induction methods. We also examined if there are brain regions associated with emotional activation tasks that had a cognitive component (e.g., emotional expression recognition, gender discrimination, etc.). Particularly, we examined how “sensitive” specific brain regions were to different emotional tasks (reflected by the percentage of studies reporting activation in a region according to a condition of interest). We also examined how “specific” certain brain regions were for different emotional responses (reflected by the frequency of activation in a specific region with a given task in comparison to other re￾gions). The effect of gender and valence (the extent to which emotion is unpleasant or pleasant) on activation patterns, and the question of laterality in activation patterns are major topics in neuroimaging of emotion, and thus require an extensive and separate discussion. Therefore, we have chosen to report these results sep￾arately (Wager et al., in preparation). METHODS Scope of Review In order to illuminate both general and specific pat￾terns of activation associated with different emotional tasks, we searched peer-reviewed journals (indexed in large databases [MEDLINE, PsychInfo, BrainMap]) for English-language manuscripts of PET and fMRI emotion induction studies published between January, 1990, and December, 2000. To allow us to performed planned meta-analysis, all reports included met the following criteria: (1) They involved unmedicated healthy adults; (2) They focused on higher-order men￾tal processes of emotion (thus, studies of lower-order sensory or motor processes, such as gustatory/olfactory or pain induction, were excluded) [see reviews by by Small et al., 1999; Casey et al., 1994, respectively]; (3) They all measured regional cerebral blood flow (e.g., O15H2O-PET) or blood oxygenation (e.g., BOLD-fMRI) across the entire brain (i.e., excluding studies that focused on limited regions of the brain); (4) They all used the image subtraction methodology to determine activation foci; (5) They provided standard Talairach (Talairach and Tournoux, 1988) or Montreal Neuro￾logic Institute (MNI) coordinates, allowing for compar￾ison of findings across different studies and different laboratories. We chose not to include studies on aver￾sive and trace conditioning (Bu¨ chel et al., 1998; Morris et al., 1998b; LaBar et al., 1998; Bu¨ chel et al., 1999) because those tasks involve associative learning and behavioral conditioning (including acquisition and ex￾tinction), rendering them incomparable to the emo￾tional tasks in our database. Furthermore, these fear￾conditioning related activations were extensively discussed in a recent review by Bu¨ chel and Dolan (2000). Only activation peaks were examined in this meta-analysis. The reporting of deactivation or de￾creases in brain activity was not consistent across studies which did not allow meaningful generalization. Also, the neural mechanisms underlying reported de￾activations remain undetermined and their interpreta￾tions remain inconclusive or unclear (Hutchinson et al., 1999; Raichle et al., 2001). Organization of Results Fifty-five publications/studies (43 PET and 12 fMRI) spanning from May, 1993, to December, 2000, that met our database criteria, yielding 119 subtractions/contrasts and 761 individual activation peaks, were included for meta-analysis (Table 1). Because the studies adopted dif￾ferent analysis methods and significance criteria, all foci were accepted when reported as significant by the crite￾ria designated in the individual studies. The activation results are grouped in the following manner: (1) Regions associated with Individual Emotion (fear, sadness, disgust, anger, happiness); (2) regions as￾sociated with Induction Method (visual, auditory, auto￾biographical recall/imagery); and (3) regions associated with presence and absence of Cognitive Demand. Table 1 lists all studies included in the review, arranged alpha￾betically, and identifies the Individual Emotion exam￾ined and the Induction Method employed. We examined the effect of Cognitive Demand, as a separate but related component of Induction Method, for a variety of reasons. Neuroimaging literature often distinguishes between cognitive and emotional tasks, but the majority of the emotional tasks contain various degrees of cognitive de￾mand. Furthermore, there is a clear interaction between emotion and cognition on a functional level. To examine the neuroanatomic basis of this interaction, we examined the effect of these cognitive components in emotion acti￾vation by grouping conditions in which an emotional task was coupled with a concurrent cognitive task (e.g., gen￾der/emotional expression discrimination, emotional rat￾ing, picture/face recognition/encoding, naming, counting, autobiographical recall/imagery, etc.) as Emotion
Cog￾nition or with Cognitive Demand. Conversely, we grouped conditions in which the emotional task did not explicitly have a cognitive component (i.e., passive view￾ing, passive listening) as Emotion alone or without Cog￾nitive Demand. This classification allows us to examine the effect of a “nonemotional” cognitive component on emotional tasks. 332 PHAN ET AL

FUNCTIONAL NEUROANATOMY OF EMOTION 333 TABLE 1 List of Emotion Activation Studies Included in the Meta-Analysis Induction Methoc Type of Emotio Study No. Reference Visual Auditory Recall Happy Fear Anger Sad Disgust 9 d97 ard 9 d99 nli 98 y99 199 111213145677809001223450667896006123456008890426456469505268 Har 19 L 99 is neye ”98 55 Whalen 98b The stand coor tes of activation peaks re- 96.Wellcome Department of Cognitive Neurology,Lon and medial i onto I SPM IA-IC show the es va

The standard coordinates of activation peaks re￾ported by individual studies were plotted onto lateral and medial views of a 3-D canonical brain image (SPM 96, Wellcome Department of Cognitive Neurology, Lon￾don; derived from the MNI brain template). Figures 1A–1C show the result of grouping plotted activa￾TABLE 1 List of Emotion Activation Studies Included in the Meta-Analysis Study No. Reference Induction Method Type of Emotion Visual Auditory Recall Happy Fear Anger Sad Disgust 1 Baker 97 X X X 2 Beauregard 97 X 3 Beauregard 98 X X 4 Blair 99 X X X 5 Blood 99 X 6 Breiter 96 X X X 7 Canli 98 X 8 Crosson 99 X 9 Damasio 00 X X X X X 10 Dolan 00 X 11 Dougherty 99 X X 12 Frey 00 X 13 Gemar 96 X X 14 George 93 X 15 George 94 X X 16 George 95 X X X 17 George 96a X 18 George 96b X X X 19 Hamann 99 X 20 Hariri 00 X 21 Isenberg 99 X X 22 Kimbrell 99 X X X 23 Kosslyn 96 X 24 Lane 97a X 25 Lane 97b X 26 Lane 97c X X X X X 27 Lane 98 X X 28 Lane 99 X 29 Liberzon 00 X 30 Liotti 00 X X X 31 Maddock 97 X X 32 Mayberg 99 X X 33 Morris 96 X X X 34 Morris 98a X X X 35 Morris 99 X X 36 Nakamura 99 X 37 Paradiso 97 X X X X 38 Paradiso 99 X 39 Pardo 93 X X 40 Partiot 95 X X 41 Phillips 97 X X X 42 Phillips 98a X X X X 43 Phillips 98b X X X 44 Pietrini 00 X 45 Rauch 99 X 46 Redoute 00 X 47 Reiman 97 X X 48 Royet 00 X X 49 Shin 00 X 50 Simpson 00 X 51 Sprengelmeyer 98 X X X X 52 Taylor 98 X 53 Taylor 00 X 54 Teasdale 99 X 55 Whalen 98b X FUNCTIONAL NEUROANATOMY OF EMOTION 333

334 PHAN ET AL. Visual Auditory Recall

FIG. 1A. Activation foci: Individual emotion. FIG. 1B. Activation foci: Induction method. 334 PHAN ET AL

FUNCTIONAL NEUROANATOMY OF EMOTION 36 ☐Emotion+cognition Emotion alone FIG.IC. Activ n foci:Cognitive demand tage of studies that reported an acti- specific tion in se to each rect con parisons across studies.we translated re- Indivumoton.Indun Methd.no (alarachand e nttp: .cam.ac can lead to D os that we chose not to include spatial extent of activation compared the number of studies that found activation peaks when plotting onto the 3-D canonical brain. in a particular region to those that did not using chi- For a semiquantitative analysis,we divided the atl square (X)analysis.The results of the X?analysis are into an presented in Fig.2. egowaoas0atedy udy included in this review RESULTS AND DISCUSSION tomical structure/gyrus and/or Brodmann area. We 1.Regions Involved Across Individual Emotions on to l lize the activation pea s in rCereral emgtionali and the medial 0 tudy's cho hr shold d sidered a re that no single brain egion is commonly activated bya more over 50%of all stuc media proach was choser to counterba ency fo cortex (MPFC)was commonly activated natiionmnetiod2tepig 2A and 2B)

tion foci according to Individual Emotion, Induction Method, and Cognitive Demand. In order to make di￾rect comparisons across studies, we translated re￾ported Talairach coordinates (Talairach and Tournoux, 1998) into MNI coordinates (transformation developed by Matthew Brett, http://www.mrc.cbu.cam.ac.uk/Im￾aging). Because differences in image smoothing tech￾niques can lead to different numbers of activation foci, we chose not to include spatial extent of activation peaks when plotting onto the 3-D canonical brain. For a semiquantitative analysis, we divided the atlas brain into 20 general regions, and examined whether activations in each specific region was associated with different Individual Emotion, Induction Method, and Cognitive Demand. Each study included in this review identified the location of the activation peak as ana￾tomical structure/gyrus and/or Brodmann area. We used this information to localize the activation peaks in the 20 brain regions used in this review. The number of activation peaks reported for a single region differed according to each study’s chosen statistical threshold and analysis methods. Therefore, we considered a re￾gion as activated for a particular study if one or more activation peak in this region was reported. This ap￾proach was chosen to counterbalance the tendency for overestimating activations based on variable thresh￾olds used in different studies, and allowed us to esti￾mate the percentage of studies that reported an acti￾vation foci in a specific region in response to each Individual Emotion, Induction Method, and Cognitive Demand (Figs. 2A–2C). Additionally, we examined how specific the reported regional activations were to Individual Emotion, In￾duction Method, and Cognitive Demand. For all stud￾ies that employed similar contrasts and methods, we compared the number of studies that found activation in a particular region to those that did not using chi￾square (X2 ) analysis. The results of the X2 analysis are presented in Fig. 2. RESULTS AND DISCUSSION 1. Regions Involved Across Individual Emotions 1.1. General emotional processing and the medial prefrontal cortex. No specific brain region was consis￾tently activated in the majority of studies, across indi￾vidual emotions and induction methods, suggesting that no single brain region is commonly activated by all emotional tasks. Although no region was activated in over 50% of all studies, we did find that the medial prefrontal cortex (MPFC) was commonly activated, and that its activation was not specific to a specific emotion or induction method (see Figs. 2A and 2B). FIG. 1C. Activation foci: Cognitive demand. FUNCTIONAL NEUROANATOMY OF EMOTION 335

336 PHAN ET AL. While th e may not be a particular brain both emotion without Cognitive De ation of th flect that ntral MPEC 1 nd 2C).Inte tain a ects may be shared across differ nt emotional vious meta-analyse sof cognition revealed that the tasks.Figure 2A shows that the MPFC was activated rostral-ventral and orbital regions of the MPFC are across multiple individual emotions (four of five spe argely insensitive to cognitive tasks (Duncan and cific emoti ons in at 40%oI stu Owen,2000:Cabeza and Nyberg.2000). he MPEC a to st that the MPFC 2.Regions Associated with Individual Emotions may have a general role in emotional processing.as 2.1 Fear and the amygdala.Specifically,fear induc suggested by Lane. Reiman and colleagues,whe tion had a strong association with the amygdala.Sixty ported that emotional films,pictures and recall percen ed t em y9 12 nd the of these th he is res ponsible for detecting. generating.and maintain- Lane et al 1997c:Re an et al1gg7刀This is co tent with the notion that a number of processes are potentially various emotional tasks (e.g. s(Adolphs et al. der et al. 1996 appraisa n吧 ter et a (D 100 (1997)did find the 005. aubiects inter allv-atte nded to their nal state al 1998b)and in evocation of fearful emotional re not when they externally atte nded to nonaffective sponses from direct stimulation (Halgren et al.,1978). cha acter of a picture stimulus.Furthermore,ac The amygdala al Iso appears importan t in the detection tivity to co elate with envronment threa Scott 1997 Isenberg e emo a 0 an recal et a as ir ate th (Kluber Bucy 193 :Weiskra 1g56 et al 1998)One n ossibility therefore is that the King.1992).Strikingly,of the eight studies that exam- MPFC may be involved in the cognitive aspects (e.g. ned cerebral responses to fearful faces,six pointed to attention to emotion,appraisal emo tical involvement of the a amygd a orris et a of emotional processing (Drevets and 199 en the tivation als tion into other modalities such as words (Ise nbera et al vided into affective and cognitive regions,which has 1999)and vocalizations (Phillips 1998a).Morris et al been observed in the ante rio cingulate cortex (ACC) 1996)found that the amy ygdalar response to fearful (Bush e 2000 ACC is nown to b olved in aces ant raction with th form n that serves emo sing with incre th ta.2000 d to th of facial as subie MPEC (Petrides and Pandya.1999:Devinsky et al. were instructed to classify en notional faces by ender 1995).Figures 1A and 1B show that activatic ns re- not by emotion.Such an interpretation is further ported in the prefrontal cortex in response to different n from studies ng masked are ces wh amygo of e the ate cortex (Accad)(BA rostral 24 anterior/ven erience ubjectively (Morris et al..1998b: tral 32,33).While the activations located in the area of Whalen et al..1998a) the MPFC are more ventral and less dorsal,we did not Given that f ar is the most salient of the individual nnd any e or an alternative interpretation for the amyg. e s a mo. gen tha eaks fell into dor sal MPEC (se Fig 10) L 20011 son to studies with tasks that involved Emotion and Whalen et al.(1998b)observed that the amygdala re- Cognition.Thus.MPFC appears equally sensitive to sponds to fearful faces despite the lack of explicit rec-

While there may not be a particular brain region that is absolutely necessary for all emotional functions, the common activation of the MPFC may reflect that cer￾tain aspects may be shared across different emotional tasks. Figure 2A shows that the MPFC was activated across multiple individual emotions (four of five spe￾cific emotions in at least 40% of studies). Accordingly, X2 analysis revealed no specific association between the MPFC and Individual Emotion as compared to other regions. These findings suggest that the MPFC may have a general role in emotional processing, as suggested by Lane, Reiman, and colleagues, who re￾ported that emotional films, pictures, and recall as wells as positive and negative emotion, happiness, sad￾ness, disgust, and the mixture of these emotions all separately engaged the MPFC (Lane et al., 1997a; Lane et al., 1997c; Reiman et al., 1997). This is consis￾tent with the notion that a number of processes are potentially common to various emotional tasks (e.g., appraisal/evaluation of emotion, emotional regulation, and emotion-driven decision-making). Lane et al. (1997b) did find that the MPFC (BA9) activated when subjects internally-attended to their emotional state, but not when they externally attended to nonaffective characteristics of a picture stimulus. Furthermore, ac￾tivity in the MPFC has been shown to correlate with emotional awareness to both film and recall-generated emotion, suggesting its role in detecting emotional sig￾nals from both exteroceptive and interoceptive cues (Lane et al., 1998). One possibility therefore is that the MPFC may be involved in the cognitive aspects (e.g., attention to emotion, appraisal/identification of emo￾tion) of emotional processing (Drevets and Raichle, 1998). Given the putative importance of cognition in emo￾tion, we questioned whether the MPFC can be subdi￾vided into affective and cognitive regions, which has been observed in the anterior cingulate cortex (ACC) (Bush et al., 2000). The ACC is known to be involved in a form of attention that serves to regulate both cogni￾tive and emotional processing (Whalen et al., 1998a; Bush et al., 2000), and is closely interconnected to the MPFC (Petrides and Pandya, 1999; Devinsky et al., 1995). Figures 1A and 1B show that activations re￾ported in the prefrontal cortex in response to different Individual Emotions and Induction Methods are lo￾cated within ventral-rostral BA 9 and 10 of MPFC, and extend into the affective division of rostral anterior cingulate cortex (ACCad) (BA rostral 24, anterior/ven￾tral 32, 33). While the activations located in the area of the MPFC are more ventral and less dorsal, we did not find any evidence for a functional affective-cognitive division of the MPFC. Our Cognitive Demand analysis revealed that relatively much fewer Emotion alone peaks fell into dorsal MPFC (see Fig. 1C), in compari￾son to studies with tasks that involved Emotion and Cognition. Thus, MPFC appears equally sensitive to both emotional tasks with and without Cognitive De￾mand, as activations from both conditions cluster in ventral MPFC (see Figs. 1C and 2C). Interestingly, previous meta-analyses of cognition revealed that the rostral-ventral and orbital regions of the MPFC are largely insensitive to cognitive tasks (Duncan and Owen, 2000; Cabeza and Nyberg, 2000). 2. Regions Associated with Individual Emotions 2.1 Fear and the amygdala. Specifically, fear induc￾tion had a strong association with the amygdala. Sixty percent of studies that examined fear activated the amygdala (X2 12.57, P 0.01) (Fig. 2A). Several lines of evidence support the notion that the amygdala is responsible for detecting, generating, and maintain￾ing fear-related emotions. Particularly, the amygdala has been implicated in the recognition of fearful facial expressions (Adolphs et al., 1995; Calder et al., 1996), feelings of fear after procaine induction (Ketter et al., 1996), fear conditioning (LeDoux, 1993; Bechara et al., 1995; LaBar et al., 1995; Morris et al., 1998b; Whalen et al., 1998b), and in evocation of fearful emotional re￾sponses from direct stimulation (Halgren et al., 1978). The amygdala also appears important in the detection of environment threat (Scott et al., 1997; Isenberg et al., 1999; Phillips et al., 1998a), as well as in the coordination of appropriate responses to threat and danger (Kluber and Bucy, 1939; Weiskrantz, 1956; King, 1992). Strikingly, of the eight studies that exam￾ined cerebral responses to fearful faces, six pointed to the critical involvement of the amygdala (Morris et al., 1996; Breiter et al., 1996; Phillips et al., 1997; Phillips et al., 1998a; Morris et al., 1998a; Whalen et al., 1998a). Fear-associated amygdalar activations also extended into other modalities such as words (Isenberg et al., 1999) and vocalizations (Phillips 1998a). Morris et al. (1996) found that the amygdalar response to fearful faces showed a significant interaction with the inten￾sity of emotion (increasing with increasing fearfulness) and that the activation was not contingent upon the explicit processing of facial expression, as subjects were instructed to classify emotional faces by gender not by emotion. Such an interpretation is further strengthened by findings from studies using masked fearful faces which found that the amygdalar response occurred even when the fearful expression was not consciously perceived or even when subjects did not experience fear subjectively (Morris et al., 1998b; Whalen et al., 1998a). Given that fear is the most salient of the individual emotions, an alternative interpretation for the amyg￾dala’s involvement is that it has a more general role for vigilance or for processing salience, or attributes that make stimuli meaningful (Davis and Whalen, 2001). Whalen et al. (1998b) observed that the amygdala re￾sponds to fearful faces despite the lack of explicit rec- 336 PHAN ET AL.

FUNCTIONAL NEUROANATOMY OF EMOTION 337 ognition of the expression and that fearful faces are Though this review found that many of the SCC acti- more likely to signify a signal for threat than to induce vations arose from studies in which sadness was tran- fear given that subjects often do not report being ntly induced by autobiographical scripts (George e Hence.th amygdalar ctivati ons may be pri 00 n Derg et al. 9:Liott for proces he ocati ding toother inducti fear faces (Morris et al.1996:Breiter et al.1996 ods The inco istent findings in earlier activation Phillips et al.,1997).aversive pictures (Irwin et al. studies on transient sadness in healthy subjects,par 1996:Taylor et al,1998:Simpson et al,2000),as well ticularly in the subgenual ACC(Gemar et al,1996; as sac et al 1999)and happy faces (Breiter e Pardo et 93:George et al.. 1995,may attrib to the in prov on meth A positi on the fuly all of the with additio task uch as re activated to both pleasant and unpl visualizing emotional memories.Liotti et al.(2000)and Thus,the amygdala may not exclusively respond to Mayberg et al.(1999)attempted to address these per- affectively laden stimuli,but may respond to meaning- ceptua or cogn itive confounds by scanning subjects ul stim general.Ou own findings also concu er they ha eved a de nd. ral amyg the activations in subgenua al.2000e avers BA25). and the arly 70% studies f the Happines structure's role in mediating conditioned r nglia (BG)(F 2A)The cthat this a which enhance information processing to nonaversive may be ir ortant in sitive e otions,such as happi stimuli(Everitt,1991).These findings suggest that the gains support from multiple in vivo investiga- amy ala respond mportanc or stimu tions of addictive substances and behaviors (Breiter et alience egar ence (v e co ent 1997:Stein et al..1998 992:Roch et co 996),rew 999,a with id se(SCR)to affective pictur which der aying a vi n the es (Kocpp to salient arousing stimuli. nd n ive been obs regardless of emotional valence (Lang et al.1993). faces (Whalen et al. 1998a Morris et al 2.2 Sadness and the subcallosal cir ulate Sad oleasant pictures induction was significantly associated with subcallosal et al.,1997a;Lane et al,1999:Davidson and cingulate cortex (SCC)activation. About 46% of sad win,1999), ed recall (George ness in duc lized studies reported nd the Dam region ante P000 a Ci requ any 00 Int olimbic don the basal g or hy has be fou d in ventral striatum is well positioned to res ond to the SCC in resting state studies of patients with clin incentive reward motivation and to pregoal attainment ical depression,a mood disorder with relatively more of positive affect arising from progre on toward a sustained sadness (Baxter et al., 1985:Mayberg,1994 re goal (Dav and 1999 cons Drevets et al As expected,activ ity in he sub gula B 25 nc when o1s8tuali 1999. and th a211005 ulated that d in the BG:60%of s this area may lead those susceptible towards a com- nent of the BG(Fig.2A).Contrary to happ pensatory pattern of hypometabolism. disgust has been theoretically conceptuali as a Reiman and colleagues(1997)found anterior cingulate withdrawal emotion (Davidson et al.1990).The re- activity to rec -genera dD t no -ind ce viewed stu facial y mt rpr ps et taoge he d 07 9 its s (1998)hvp

ognition of the expression and that fearful faces are more likely to signify a signal for threat than to induce fear given that subjects often do not report being afraid. Hence, the amygdalar activations may be pri￾marily for processing affective information in service of imparting danger warnings. Amygdala activations oc￾cur throughout various evocative stimuli, including fear faces (Morris et al., 1996; Breiter et al., 1996; Phillips et al., 1997), aversive pictures (Irwin et al., 1996; Taylor et al., 1998; Simpson et al., 2000), as well as sad (Blair et al., 1999) and happy faces (Breiter et al., 1996), and positive pictures (Hamann et al., 1999). A positive correlation of blood flow in the amygdala was found with subsequent recall of pleasant pictures (Hamann et al., 1999): in that study, the amygdala activated to both pleasant and unpleasant pictures. Thus, the amygdala may not exclusively respond to affectively laden stimuli, but may respond to meaning￾ful stimuli in general. Our own findings also concur this interpretation since we have observed that amyg￾dala also responds to nonaversive/neutral (Taylor et al., 2000) and positive (Liberzon et al., submitted) pic￾tures, supporting evidence from animal studies of the structure’s role in mediating conditioned responses which enhance information processing to nonaversive stimuli (Everitt, 1991). These findings suggest that the amygdala responds to emotional importance or stimu￾lus salience, regardless of valence (whether the content is pleasant or aversive/unpleasant). This is also consis￾tent with psychophysiologic evidence of skin conduc￾tance response (SCR) to affective pictures which dem￾onstrate a response to salient, arousing stimuli, regardless of emotional valence (Lang et al., 1993). 2.2 Sadness and the subcallosal cingulate. Sadness induction was significantly associated with subcallosal cingulate cortex (SCC) activation. About 46% of sad￾ness induction studies reported activation of the SCC, region localized to the ventral/subgenual anterior cin￾gulate (BA 25), over twice as frequently as any other specific emotion (X2 9.24, P 0.05). Interestingly, hypometabolism or hypoperfusion has been found in the SCC in resting state studies of patients with clin￾ical depression, a mood disorder with relatively more sustained sadness (Baxter et al., 1985; Mayberg, 1994; Drevets et al., 1997). As expected, activity in the sub￾genual cingulate (BA 25) increased when depressed subjects respond to pharmacologic treatment (Brody et al., 1999; Mayberg et al., 2000). George et al. (1995) speculated that dysphoria-induced hyperactivity in this area may lead those susceptible towards a com￾pensatory pattern of hypometabolism. Because Reiman and colleagues (1997) found anterior cingulate activity to recall-generated but not film-induced sad￾ness, they interpreted that the SCC activations may result more from the cognitive process of internally generating emotion, and less from sadness itself. Though this review found that many of the SCC acti￾vations arose from studies in which sadness was tran￾siently induced by autobiographical scripts (George et al., 1995; Lane et al., 1997c; Mayberg et al., 1999; Liotti et al., 2000), the X2 analysis did not support the notion that SCC activation was specifically associated with recall induction, as compared to other induction meth￾ods. The inconsistent findings in earlier activation studies on transient sadness in healthy subjects, par￾ticularly in the subgenual ACC (Gemar et al., 1996; Pardo et al., 1993; George et al., 1995), may be attrib￾uted to the differences in provocation method. Partic￾ularly, subjects were partly or fully scanned while they were actively generating the targeted emotional state with additional cognitive tasks such as recalling or visualizing emotional memories. Liotti et al. (2000) and Mayberg et al. (1999) attempted to address these per￾ceptual or cognitive confounds by scanning subjects after they had achieved a desired intensity of sadness, and confirmed the activations in subgenual ACC (BA 25). 2.3 Happiness and the basal ganglia. Nearly 70% happiness induction studies reported activation in the basal ganglia (BG) (Fig. 2A). The notion that this area may be important in positive emotions, such as happi￾ness, gains support from multiple in vivo investiga￾tions of addictive substances and behaviors (Breiter et al., 1997; Stein et al., 1998; Koob, 1992; Koch et al., 1996), reward processing (Rolls, 1999), and enjoyable (playing a video game) activities (Koepp et al., 1998). Activations in the basal ganglia, including the ventral striatum and putamen, have been observed in response to happy faces (Whalen et al., 1998a; Morris et al., 1996, 1998a; Phillips et al., 1998b), pleasant pictures (Lane et al., 1997a; Lane et al., 1999; Davidson and Irwin, 1999), happiness-induced recall (George et al., 1996b; Damasio et al., 2000), pleasant sexual and suc￾cessful competitive arousal (Rauch et al., 1999; Red￾oute et al., 2000). Given its rich innervation of me￾solimbic dopaminergic neurons, the basal ganglia/ ventral striatum is well positioned to respond to incentive reward motivation and to pregoal attainment of positive affect arising from progression toward a desired goal (Davidson and Irwin, 1999), consistent with the notion that happiness can be conceptualized as an approach emotion (Davidson et al., 1990). 2.4 Disgust and the basal ganglia. Interesting, we also found that disgust induction frequently activated the BG; 60% of studies evoking disgust reported en￾gagement of the BG (Fig. 2A). Contrary to happiness, disgust has been theoretically conceptualized as a withdrawal emotion (Davidson et al., 1990). The re￾viewed studies suggest that, particularly, facial ex￾pressions of disgust activated the BG (Phillips et al., 1997, 1998a; Sprengelmeyer et al., 1998). Sprengel￾meyer and colleagues (1998) hypothesized a specific FUNCTIONAL NEUROANATOMY OF EMOTION 337

338 PHAN ET AL. amy hipp ☐Happiness Fear Anger Sadness Disqust ee ac 10 20 30 40 Percentage of studies FIG.2A.Regional activations:Individual emotion

FIG. 2A. Regional activations: Individual emotions. 338 PHAN ET AL

FUNCTIONAL NEUROANATOMY OF EMOTION 339 ■a ■ ■Real 00 10 30405060 Per加dies *1=12.93,p=.002,Cramer'sV=0.47 4X=8.23,p=.02,Cramer''sV=0.38 FIG.2B.Regional activations:Induction method

FIG. 2B. Regional activations: Induction method. FUNCTIONAL NEUROANATOMY OF EMOTION 339

340 PHAN ET AL. functional rol for the basal gangli th MPFC.whileco y-bound mot ona s specif wit y en in der who have neuronathology y in their basal ganglia which r its this fr have impairments in recognizing facial expressions of fewer than 30%and 20%res F1g.2B). disgust compared to other emotions.The activations Instead,fear studies engage the amygdala robustly seen in the b respor to sgust may (over 60%frequency:d ussed earlier) Additionallv represent a state prepar by aw passive emotional co nditions witho e.g.,Emo et al 1998)With its know a functions.the basal ganglia may also serv to coordi. pu d nate appropriate action responses to stimuli that un- nections to s ubcortical limbic structur the MPEC oleasant (inducing disgusting).or pleasing (promoting and Acc could serve as ton-dowr modulators of in. nappiness),in at and gui e org towa hdraw)(Pank tense emotional responses,especially those generated by the amygdala.Several lines of evidence support sepp such an interpretation. al studies to be in fea condi 3.Regions Associated with Induction Methoo 1994.H ti 3.1 Regions involved in with and MPFC (Mor etal.1993). s in the hu an rostral MPFC also lead to socially inappropriate ex l tasks with ically engaged the AcC as compared to passive pressions of emotions and impairments in making ad- emo tageous personally relevant decisions (Damasio tional conditions (36 vs 12%.respectively:X 3.52. 994 ve proces ng of emo P=0.06) Earlier,when discussing the sugge nndings of the MPFC act with b ion and h s,we hypo ith tho dala in the of the bercrombie er al.1996).Our group has found that al task ct by cog nitive Demand).and interpreted that the MPFC may activity is the amygdaloid region is attenuated while have a general role in emotional proce the MPFC and cingulate sulcus are activated during a g.We spe ulated that the MPFC may respond to cognitive cognitive appraisal condition of aversive as versus pas ve view ylor et a ubmitted).A pects that are pot ng)(T ti y,de sLs th he am motional tasks and therefore are ent both in the nd Raichle 1008)one alterna studies with Cognitive Demand and in the studies with tive hynoth sis of thes e reciprocal findings is that lim- bic structures,like the amygdala,are more likely to Emotion alone.However,based on this analysis,when respond to stimuli that are more emotive at a sen cognitive comp ents explicit to an e emot ona sory/pe eptua recogniti level,and are ess likely to be engaged (e.g.,gen 1 cogni or to cogn motion rendering these task in the with Cognitive d emotions 31 Demand e1999 1997 it a ars that the ACC is re cruted.Therefore.the ACCad may interactwith the 32 Recall an th MPFC to regulate terconnected cog gnitive and emo- conditi ng on v it ly laden ev the A MDE ired e plicit intensive nitive effort Accordin xtensive co tions to subcortical limbic structures the recollection/recall induction of emotion specifically constitute both the heteromodal ass iation cortex and activated the anterior cingulate; 50%of recall in- and therefore comprise dies reporte AC activat ns,versus a pla rar sition and interaction zone between a studie oe C08 pect 05 also have additional of th A motional mo this tively der anding er onal tasks.and therefore this emotion interaction.As noted above.conditions with association suggests that recalled emotions are cogni- and without Cognitive Demand equally activate the tively elicited.as noted by Reiman et a/(1997)and

functional role for the basal ganglia in processing dis￾gust, consistent with observations that patients with Huntington’s disease and obsessive-compulsive disor￾der, who have neuropathology in their basal ganglia, have impairments in recognizing facial expressions of disgust compared to other emotions. The activations seen in the basal ganglia in response to disgust may represent a state of preparedness triggered by a warn￾ing stimulus to process emotionally salient information (Sprengelmeyer et al., 1998). With its known motor functions, the basal ganglia may also serve to coordi￾nate appropriate action responses to stimuli that un￾pleasant (inducing disgusting), or pleasing (promoting happiness), in nature, and guide the organism towards a desired goal (e.g., to approach or withdraw) (Pank￾sepp, 1998). 3. Regions Associated with Induction Method 3.1 Regions involved in emotion induction with and without cognitive demand. This meta-analysis found that emotional tasks with cognitive components specif￾ically engaged the ACC as compared to passive emo￾tional conditions (36 vs 12%, respectively; X2 3.52, P 0.06). Earlier, when discussing the findings of the MPFC activation with both Emotion
Cognition and Emotion alone tasks, we hypothesized that activations seen in the MPFC are driven by the general component of the emotional task (e.g., with little impact by Cog￾nitive Demand), and interpreted that the MPFC may have a general role in emotional processing. We spec￾ulated that the MPFC may respond to cognitive as￾pects that are potentially common across various emo￾tional responses (e.g., attention to emotion, appraisal or interpretation of emotion), which are implicit to the emotional tasks and therefore are present both in the studies with Cognitive Demand and in the studies with Emotion alone. However, based on this analysis, when the cognitive components are explicit to an emotional task (e.g., gender identification, recognition/encoding or rating of emotional stimuli, biographical recall of emotion) rendering these task in the “with Cognitive Demand” category, it appears that the ACC is re￾cruited. Therefore, the ACCad may interact with the MPFC to regulate interconnected cognitive and emo￾tional tasks, depending on whether the cognitive com￾ponent is implicit or explicit to that emotional re￾sponse. Together, the rostral ACC and MPFC, with extensive connections to subcortical limbic structures, constitute both the heteromodal association cortex and paralimbic cortex respectively, and therefore comprise a plausible transition and interaction zone between affective and cognitive processing. The MPFC and ACCad may also have additional emotional modulatory functions from this cognitive￾emotion interaction. As noted above, conditions with and without Cognitive Demand equally activate the MPFC, while cognitively-bound emotional tasks specif￾ically engaged ACC. While most Individual Emotions activate both the MPFC and ACC, one exception in￾volves fear, which recruits this region at frequencies fewer than 30% and 20% respectively (see Fig. 2B). Instead, fear studies engage the amygdala robustly (over 60% frequency; discussed earlier). Additionally, passive emotional conditions without Cognitive De￾mand (e.g., Emotion alone) activate the amygdala more often than cognitive emotional tasks. Given their pu￾tative affective-cognitive functions and reciprocal con￾nections to subcortical limbic structures, the MPFC and ACC could serve as top-down modulators of in￾tense emotional responses, especially those generated by the amygdala. Several lines of evidence support such an interpretation. From animal studies, the amygdala has been shown to be critical in fear condi￾tioning (LeDoux, 1994). However, one can prolong the extinction of this conditioned fear by ablation of the MPFC (Morgan et al., 1993). Lesions in the human rostral MPFC also lead to socially inappropriate ex￾pressions of emotions and impairments in making ad￾vantageous personally relevant decisions (Damasio, 1994), suggesting a lack of cognitive processing of emo￾tionally “loaded” situations. Furthermore, glucose me￾tabolism in the MPFC is strongly inversely associated with the glucose metabolic rate of the amygdala (Am￾bercrombie et al., 1996). Our group has found that activity is the amygdaloid region is attenuated while the MPFC and cingulate sulcus are activated during a cognitive appraisal condition of aversive visual stimuli (versus passive viewing) (Taylor et al., submitted). Ad￾ditionally, deactivation of the amygdala has been ob￾served in several tasks that involve higher cognitive processing (Drevets and Raichle, 1998). One alterna￾tive hypothesis of these reciprocal findings is that lim￾bic structures, like the amygdala, are more likely to respond to stimuli that are more “emotive” at a sen￾sory/perceptual level, and are less likely to be engaged by cognitively demanding emotional tasks, or to cogni￾tively elicited emotions (Reiman et al., 1997; Teasdale et al., 1999). 3.2 Recall induction and the anterior cingulate. Similar to conditions with Cognitive Demand, those which induced emotions by evoking memories or imag￾ery of personally relevant affectively laden events re￾quired explicit intensive cognitive effort. Accordingly, the recollection/recall induction of emotion specifically activated the anterior cingulate; 50% of recall in￾duction studies reported ACC activations, versus 31% and 0% of visual and auditory induction studies, respectively (X2 5.96, P 0.05). As described above, recruitment of the ACC was specific to cogni￾tively demanding emotional tasks, and therefore, this association suggests that recalled emotions are cogni￾tively elicited, as noted by Reiman et al. (1997) and 340 PHAN ET AL.