Right-Sided Human Prefrontal Brain Activation During ... - APA PsycNET

Emotion 2002, Vol. 2, No. 3, 233–241

Copyright 2002 by the American Psychological Association, Inc. 1528-3542/02/$5.00 DOI: 10.1037//1528-3542.2.3.233

This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

Right-Sided Human Prefrontal Brain Activation During Acquisition of Conditioned Fear Håkan Fischer

Jesper L. R. Andersson

Karolinska Institute, Stockholm University, and Uppsala University

Uppsala University and Karolinska Institute and Hospital

Tomas Furmark

Gustav Wik

Uppsala University

Karolinska Institute and Hospital

Mats Fredrikson Uppsala University This H215O positron emission tomography (PET) study reports on relative regional cerebral blood flow (rCBF) alterations during fear conditioning in humans. In the PET scanner, subjects viewed a TV screen with either visual white noise or snake videotapes displayed alone, then with electric shocks, followed by final presentations of white noise and snakes. Autonomic nervous system responses confirmed fear conditioning only to snakes. To reveal neural activation during acquisition, while equating sensory stimulation, scans during snakes with shocks and white noise alone were contrasted against white noise with shocks and snakes alone. During acquisition, rCBF increased in the right medial frontal gyrus, supporting a role for the prefrontal cortex in fear conditioning to unmasked evolutionary fearrelevant stimuli.

Classical conditioning is at hand when a neutral stimulus (CS), through pairings with an uncondi-

tioned stimulus (US) that more or less reflexively elicits a given reaction, becomes a conditioned stimulus that in and of itself elicits a similar reaction (Pavlov, 1928). Classical conditioning with an aversive US is termed fear conditioning (cf. LeDoux, 1995) and may serve to alter stimulus valence experimentally (Pavlov, 1928). A number of recent brain imaging studies in humans have investigated brain correlates during the expression of the conditioned fear response using positron emission tomography (PET; Fischer, Andersson, Furmark, & Fredrikson, 2000; Fredrikson, Wik, Fischer, & Andersson, 1995; Furmark, Fischer, Wik, Larsson, & Fredrikson, 1997; Hugdahl et al., 1995; ¨ hman, & Morris, Friston, & Dolan, 1997; Morris, O Dolan, 1998, 1999), functional magnetic resonance imaging (fMRI; Bu¨chel, Dolan, Armony, & Friston, 1999; Bu¨ chel, Morris, Dolan, & Friston, 1998; Knight, Smith, Stein, & Helmstetter, 1999; LaBar, Gatenby, Gore, LeDoux, & Phelps, 1998; Morris, Bu¨chel, & Dolan, 2001), and magnetoencephalography (Wik, Elbert, Fredrikson, Hoke, & Ross, 1997). Two imaging studies in humans have investigated neural alterations specifically associated with acquisition of fear conditioning to masked (Morris et al., 2001) and unmasked CS (LaBar et al., 1998). Morris et al. (2001) studied fear conditioning acquisition

Håkan Fischer, Aging Research Center, Karolinska Institute and Stockholm University, Stockholm, Sweden, and Positron Emission Tomography (PET) Centre, University Hospital, Uppsala University, Uppsala, Sweden. Jesper L. R. Andersson, PET Centre, University Hospital, Uppsala University and Department of Clinical Neuroscience, Karolinska Institute and Hospital, Stockholm, Sweden. Tomas Furmark and Mats Fredrikson, Department of Psychology, Uppsala University. Gustav Wik, Department of Clinical Neuroscience, Karolinska Institute and Hospital. This article was supported by the Swedish Brain Foundation, the Wenner-Gren Foundation, and the Sasakawa Young Leaders’ Fellowship Fund, Faculty of Humanities and Social Sciences, Uppsala University, awarded to Håkan Fischer; the Swedish Council for Research in Humanities and Social Sciences; and the Bank of Sweden Tercentenary Foundation awarded to Mats Fredrikson. We thank Christopher I. Wright for valuable comments on an earlier version of this article. Correspondence concerning this article should be addressed to Håkan Fischer, Aging Research Center, Karolinska Institute, Box 6401, SE-113 82 Stockholm, Sweden. E-mail: [email protected]

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FISCHER, ANDERSSON, FURMARK, WIK, AND FREDRIKSON

while masked angry faces (CS) were associated with aversive auditory noise (US) and found blood oxygenation-level dependent (BOLD) signal increases in the medial geniculate nucleus, the auditory cortex, and the left amygdala. LaBar and colleagues (LaBar et al., 1998) used fMRI to study brain function during the association of unmasked visual geometric figures (CS) and aversive electric shocks (US). This study demonstrated BOLD signal increases during conditioning in the striatum, the paralimbic (i.e., the anterior cingulate gyrus), frontal (i.e., prefrontal-, supplementary motor- and premotor cortices), and temporal periamygdaloid cortices. When comparing these results (LaBar et al., 1998; Morris et al., 2001) with brain activity associated with the expression of learned fear, it seems that both acquisition and expression activate the amygdala, thalamus, anterior paralimbic, prefrontal, and sensory brain regions, while only acquisition seems to involve neural activation in the periamygdaloid cortex (LaBar et al., 1998). In contrast, expression, but not acquisition, seems associated with altered neural activity in the cerebellum (Fischer et al., 2000; Morris et al., 1999) and a more widely distributed subcortical network, including the central gray of the midbrain (Fischer et al., 2000; Fredrikson et al., 1995), brainstem (Morris et al., 1999), hypothalamus (Fischer et al., 2000; Fredrikson et al., 1995), posterior cingulate gyrus (Fredrikson et al., 1995), and the red nucleus (Bu¨ chel et al., 1998). This body of data suggests that acquisition and expression of conditioned fear in humans have partly overlapping and partly unique neural substrates.

A problem with the previous brain imaging study on conditioning with an unmasked CS (LaBar et al., 1998) was that behavioral measures, such as heart rate and skin conductance, were not recorded during scanning. Therefore, it is not possible to conclude whether or not the experimental manipulation resulted in a conditioned response. The primary aim of the PET study was to localize brain systems associated with acquisition of fear conditioning with unmasked CS using visual snake stimuli as CS and aversive electric shocks as US. A second aim was to compare results from this study with previous brain imaging investigations to determine whether acquisition with unmasked, biologically relevant (this study) and irrelevant CS (LaBar et al., 1998) engage similar or different neural networks. A third aim was to study rCBF differences between conditioning with unmasked (this study) and masked, biologically relevant CS (Morris et al. 2001). Finally, we wanted to compare rCBF distributions during acquisition (this study) and retrieval (previous studies) of conditioned responses with unmasked stimuli (e.g., Hugdahl et al., 1995; Fischer et al., 2000; Fredrikson et al., 1995; Furmark et al., 1997). To validate fear conditioning, recordings of electrodermal activity were collected during scanning. Subjects viewed a TV screen in the scanner displaying visual white noise or snake videotapes that were first presented alone, then paired with electric shocks, followed by a final presentation of snakes and visual noise (Figure 1). To reveal areas involved in acquisition of conditioned fear, PET scans during presentations of snakes paired with shocks

Figure 1. Schematic representation of the fear-conditioning acquisition paradigm and the contrast vector. Visual white noise (empty rectangle) was continuously displayed on the TV screen before, during, and after the administration of eight electric shocks (arrow symbol) for B, D, and F, respectively. Snake video clips (snake symbol) were presented before, during, and after pairing with unconditioned electric shocks for A, C, and E, respectively. Conditions were counterbalanced between subjects within all pairs of conditions (A–B, C–D, and E–F).

FEAR CONDITIONING AND BRAIN FUNCTION

were combined with scans of visual noise alone and then contrasted against scans of visual noise paired with shocks combined with scans of snakes alone. PET was used to enable exploration of neural activity in the whole brain, without risk of loosing data because of fMRI-related susceptibility artifacts in regions such as the orbitofrontal cortex and the amygdala.

Method This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

Subjects

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shocks and visual noise paired with shocks, respectively). Finally, the fifth and sixth conditions consisted of another presentation either of the snake video or of visual noise. Because of the study design, the order of all conditions could not be fully counterbalanced. However, the order of the snake video and the visual white noise was counterbalanced between subjects within all pairs of conditions (i.e., snake and white noise before, during, and after conditioning). Eight 0.5-s electric shock stimuli, individually determined to induce “discomfort but not pain,” were delivered during each shock condition through Beckman Offner Ag/AgCl 0.8-mm diameter electrodes applied to the second phalanx of the subject’s left third finger. The electric shocks were administered at predefined times during scanning, the first 4 with 8–12-s intervals and the last four with 18–22-s intervals. During scanning with visual snake stimulation, the shocks were associated with sudden movements of the snakes on the video.

Six right-handed women with a mean age (±SD) of 27.8 (± 7.28) years (range ⳱ 22–42 years) participated. Only young women were included in the present study to control for central nervous system (CNS)-conditioning differences that could occur as a function of gender and to ensure comparability with previous conditioning studies from our laboratory (Fischer et al., 2000; Fredrikson et al., 1995; Furmark et al., 1997). To be included, subjects could not meet any of the Diagnostic and Statistical Manual of Mental Disorders criteria for specific snake phobia (4th ed.; American Psychiatric Association, 1994). In addition, subjects with a previous or current psychiatric history or neurological deficit or who experienced somatic disease, chronic use of psychoactive medication, or abuse of alcohol or narcotics were excluded. This study was approved by Uppsala University Medical Faculty Ethics Review Board and the Uppsala University Isotope Committee. All subjects gave informed consent after the procedure had been fully explained.

Electrodermal activity was recorded with Ag/AgC1 electrodes, 8 mm in diameter, housed in plastic cups, through a Hagfors-type constant voltage circuit. Isotonic electrode paste (0.5% NaCl/100 ml H20) served as the electrolyte. The electrodes were fastened with adhesive collars to the second phalanx of the subject’s right second and third fingers, and electrodermal activity was recorded on paper with a Siemens–Elema Mingograph. Nonspecific skin conductance level fluctuations (NSF) that exceeded 0.05 ␮S were estimated and expressed in numbers per minute.

Procedure

PET Recordings

Subjects were scanned twice during five different conditions, while PET scanning was not performed during the sixth condition (because of radiation limitations; Figure 1). All visual stimuli were displayed during a 2-min period on an 11 × 8.5-cm screen approximately 0.5 m in front of the subject’s eyes. The snake videotape from our laboratory had been used in previous studies (e.g., Fischer et al., 2000; Fredrikson et al., 1995) and displays snakes indoors, moving on top of a table, and outdoors, moving in grass or in trees. The first and second conditions consisted of presentations either of a snake video (snakes alone) or of visual white noise (visual noise alone), respectively. The third and fourth conditions were identical to the first and second conditions, with the addition of the delivery of electric shocks to the subject’s left hand (hereafter referred to as snakes paired with

Scanning. Investigations were performed on a GEMS (General Electric Medical Systems, Uppsala, Sweden) PC2048-15B scanner (Holte, Erikson, & Dahlbom, 1989) with a 10-cm axial field of view. The scanner produces 15 slices, with 6.5-mm slice spacing and a 6-mm axial and transaxial resolution. A venous catheter was inserted in the left arm and the subjects were positioned in the scanner and fixated in a commercial head-holder using fast-hardening foam. The lights were dimmed and a 10-min transmission scan was performed with a rotating 68GE pin source. Before this, the subject was told that the first scan was to commence and she was then given a saline injection. Care was taken to mimic an actual emission scan during this injection, which was performed in order to attenuate novelty effects. Each emission scan was started by pressing a pedal while injecting 600–800

Autonomic Nervous System Recordings


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MBq of 15O water. Data were collected in fifteen10-s frames following injection. Each subject had 10 scans during five conditions. The order of conditions was partially counterbalanced (see Procedure section). After these 10 scans, an additional injection was administered during which the scanner couch was automatically translated back and forth between two positions 10 cm apart. Data were collected only when in one of these positions and not during the transfer. This additional scan was used during the image registration (described below). Image reconstruction. Data from the first 100 s after arrival of bolus to the brain were summed in a weighted fashion such that data from the initial uptake phase were given a higher weight (Andersson & Schneider, 1997). Images were reconstructed from the weighted summation data following correction for attenuation, dead time, and scatter (Bergstro¨ m, Eriksson, Bohm, Blomqvist, & Litton, 1983), and filtered with an 8-mm Hanning filter. The additional scan with couch translations was reconstructed to a 30slice image set with a 20-cm coverage in the axial direction, using controur finding for attenuation correction. Image registration. The scan with 20-cm axial coverage was automatically adapted (Andersson & Thurfjell, 1997) to a computerized brain atlas (CBA; Greitz, Bohm, Holte, & Erikson, 1991), and each of the other emission scans was registered to that scan. To facilitate communication of results, the Talairach brain (Talairach & Tournoux, 1988) was adapted to the CBA (Greitz et al., 1991). Statistical analysis. Image data were smoothed with a 20-mm FWHM Gaussian filter, normalized for global flow using linear scaling, and fitted to a statistical model described by the following: Yijk = u + ␶i + ␥j i = 1,2,…,5 共states兲 + ␧ijk j = 1,2,…,6 共subjects兲 k = 1,2 共scans for each subject and state兲,

再

using multiple linear regression (Friston et al., 1995). The areas of the brain exhibiting a change in perfusion resulting from the experimental design were excluded from the estimation of global flow (Andersson, 1998), thereby ensuring independence between local and global flow. The fear conditioning acquisition contrast (the contrast vector is given in Figure 1) was performed to evaluate rCBF during the association between the snake (CS) and the aversive electric shock stimuli (US). The significance of the z-score maps was assessed locally using the spatial extent of

connected clusters of voxels (Friston, Worsley, Frackowiak, Mazziotta, & Evans, 1994) with a z score above 1.96. This test takes into account multiple comparisons and has a cluster-localizing power (Friston, Holmes, Poline, Price, & Frith, 1996) meaning that the cluster taken as a whole is significantly activated. Consequently, no strong statements can be made concerning individual voxels within that cluster, especially not peripheral voxels located far from peak activations. Both rCBF and skin conductance data from one white-noise-plus-shocks scan in one subject was excluded from the analysis because of a panic attack (see Fischer, Andersson, Furmark, & Fredrikson, 1998).

Results A significant Stimuli (snakes vs. white noise) × Time (before vs. after pairing with shocks) interaction was observed in measures of electrodermal activity (NSF), F(1, 5) ⳱ 29.09, p < .005. Follow-up paired t tests showed a significant difference before versus after shock presentations only for snakes, t(5) ⳱ 2.9, p ⳱ .03, with more skin conductance fluctuations after (M ⳱ 6.0, SD ⳱ 2.6) than before electric shock presentations (M ⳱ 3.7, SD ⳱ 3.2) supporting fear conditioning. In addition, skin conductance fluctuations were more frequent during snake presentations than during visual white noise both before, t(5) ⳱ 2.9, p ⳱ .03, and after pairing with electric shocks, t(5) ⳱ 5.8, p ⳱ .002, supporting higher negative emotional valence for evolutionary fear-relevant snakes than for fear-irrelevant white noise. Significant alterations in rCBF during the acquisition phase of fear conditioning are displayed in Table 1. Increased rCBF during acquisition was observed in the right medial frontal gyrus (cluster size ⳱ 918 voxels; Figure 2). Decreased rCBF was evident in two clusters. The focus of the first cluster (size ⳱ 826 voxels) was located in the left hippocampal gyrus extending into the hippocampus, the entorhinal– perirhinal and anterior temporal cortices, as well as into the left occipitotemporal junction. The second cluster (size ⳱ 759 voxels) had a focus in the anterior temporal cortex extending into the right periamygdaloid and entorhinal–perirhinal cortices. To quantitatively assess differences between the right and left prefrontal cortex, mirror-image regions of interest were created by changing the sign of the x(i.e., L–R) Talairach coordinate for the voxel in the center of the cluster originally identified in the encoding contrast (Table 1, Figure 2). After rCBF values

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FEAR CONDITIONING AND BRAIN FUNCTION Table 1 Regional CBF During Fear Conditioning With Unmasked Visual Snake Stimuli as CS

Brain areas


Regions with increased rCBF Cluster R-frontal cortex Regions with decreased rCBF Cluster 1 L-temporal cortex Cluster 2 R-temporal cortex

Brodmann areas

x

y

z

Maximum voxel z value

10/46

35

50

15

3.98

27/28, 35–38 hippocampus

−14

−40

−02

.37

34,35,36,38

47

11

−16

Cluster p .001

.003

3.32

.004

Note. The coordinates in millimeters correspond to the stereotactic atlas of Talairach and Tournoux (1988). The x and z coordinates indicate the distance from a line between the anterior and posterior commissures, while the y coordinate indicates the position relative to the anterior commissure. Significance of clusters has been evaluated based on the spatial extent of suprathreshold clusters with z scores at 1.96 or above. Brain and Brodmann areas included in each cluster, Talairach coordinates for maximum voxel z value within each cluster, and cluster R values for significant increases and decreases in rCBF. CS ⳱ neutral stimulus; rCBF ⳱ regional cerebral blood flow; negative values indicate where the maximum voxel value is located when several brain–Brodmann areas are lumped together; R ⳱ right hemisphere; L ⳱ left hemisphere.

were extracted for each subject, they were analyzed with a factorial analysis of variance, with Stimuli (snakes paired with shocks vs. white noise paired with shocks) and Side (right vs. left hemisphere) as factors. A significant interaction, F(1, 10) ⳱ 7.9, p ⳱ .019, indicated a lateralization of brain blood flow during conditioning. Follow-up paired t tests showed a significant difference between snakes paired with shocks and white noise paired with shocks in the right, t(10) ⳱ 2.8, p ⳱ .02, but not in the left hemisphere, t(10) < 1, p ⳱ .89 (Figure 3).

Discussion Electrodermal activity supported conditioning only to snakes, and the functional neuroanatomy of acquisition of fear conditioned responses involved increased rCBF in the right medial frontal gyrus. Hence, the prefrontal cortex in humans seems to be involved not only in the expression and/or extinction of fear conditioning (Fischer et al., 2000; Hugdahl et al., 1995; LaBar et al., 1998; Morris et al., 1997), but also in the acquisition of learned fear. The increased neural activity in the prefrontal cortex indicates a right-sided lateralization of the acquisition of emotionally motivated associative memories. Prefrontal activation was also evident in a previous brain imaging study of fear conditioning acquisition (LaBar et al., 1998) with unmasked CS. However, that study showed left rather than right frontal cortex activation. This discrepancy

in prefrontal activation patterns between the present study and the LaBar et al. study (LaBar et al., 1998) could reflect differences in affective valence of the visual CS (snakes vs. geometric figures). If so, prefrontal data from the present study and from the LaBar et al. study (1998) support Seligman’s proposition (1970) that different CNS correlates underlie evolutionary prepared (the present study) and unprepared learning (LaBar et al., 1998). However, future functional brain imaging investigations should be designed to investigate this proposal in the same study to be able to make a strong argument about laterality and prepared learning. Differences in prefrontal activation between the present investigation and the one from LaBar et al. (1998) could also reflect differences in study paradigms (blocked vs. event related), imaging methodology (PET vs. fMRI), or the possibility that only this study actually investigated fear conditioning acquisition. One or more of these differences could potentially account for the diverging results between the studies. Morris and colleagues (Morris et al., 2001) did not demonstrate prefrontal involvement during acquisition with a masked evolutionary fearrelevant CS. This suggests that the prefrontal activation in our study could be related to the explicit knowledge of the visual CS. However, other studies have demonstrated activation of the right prefrontal cortex during dual- as compared with single-task conditions (D’Esposito et al., 1995). Because classical conditioning consists of two stimuli requiring pro-


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Figure 3. Lateralization of prefrontal regional cerebral blood flow during fear conditioning acquisition as indexed by number of radioactive counts. During conditioning, significantly (*) higher flow was evident during snakes paired with shocks than during visual white noise paired with shocks in the right, t(10) ⳱ 2.9, p ⳱ .03, but not in the left hemisphere, t(10) < 1, p ⳱ .89. Hatched bars indicate noise + shocks; solid bars indicate snake + shocks. Figure 2. Significant right medial frontal gyrus increases in regional cerebral blood flow (rCBF) as a function of fear conditioning acquisition (Talairach coordinates; Talairach & Tournoux, 1988) for the voxel with highest z value within this rCBF cluster are x ⳱ 35, y ⳱ 50, and z ⳱ 15. The CBF changes are displayed on a T1-weighted magnetic resonance image adapted to the stereotactic space. This figure is displayed according to radiological convention (i.e., left ⳱ right; right ⳱ left; top ⳱ anterior; bottom ⳱ posterior).

cessing of their timing, increased prefrontal activity might correspond to activity in the central executive of working memory (Baddeley, 1986; D’Esposito et al., 1995). Recently it was reported that the right frontal cortex was activated by face encoding (Kelley et al., 1998), supporting a distinction between verbal and nonverbal memory formation that may also apply to the present findings. Interestingly, in a previous study with unmasked CS (Fischer et al., 2000), we also found right prefrontal activation during the expression of fear conditioning in an area close to where we found activation during acquisition in this study. Because fear conditioning acquisition and expression with unmasked CS seem to activate similar parts of the prefrontal cortex, this might reflect an area where the conditioned emotional memory trace is formed and stored. Alternatively, storage is elsewhere, but memory processing, be it acquisition or retrieval, occurs in the prefrontal cortex consistent with working memory activity. The right lateralization of condi-

tioned prefrontal activation is in accordance with empirical findings (Davidson, Jackson, & Kalin, 2000) and theoretical notions (Davidson et al., 2000; Tucker, 1981) of greater right rather than left hemisphere involvement in negative emotions. No amygdala involvement, as indexed by rCBF activity, was evident during the acquisition phase. Animal studies have shown that nuclei, such as the central nucleus, are necessary for fear conditioning (Goosens & Maren, 2001; Kapp, Whalen, Supple, & Pascoe, 1992; Killcross, Robbins, & Everitt, 1997; Nader, Majidishad, Amorapanth, & LeDoux, 2001; Walker & Davis, 1997). Experiments in rats with lesions in the lateral–basolateral amygdala have demonstrated that these animals can still acquire a CS–US association (Cahill, Vazdarjanova, & Setlow, 2000; Killcross et al., 1997; Selden, Everitt, Jarrard, & Robbins, 1991). These data indicate that all parts of the animal amygdala are not necessary for conditioned learning. With the present spatial resolution and datasmoothing procedure, it is not possible to investigate whether or not neural activity in small nuclei, such as the central nucleus, is involved in human fear conditioning. Hence, we cannot exclude the possibility that specific amygdala nuclei in humans may be involved in acquisition of the conditioned fear response, although amygdala as a whole showed no activation. Although a recent neuroimaging study in humans has shown that associations between a US and a masked



CS activate the amygdala (Morris et al., 2001), acquisition with an unmasked CS in the present study did not. This discrepancy could reflect either a true difference between acquisition with masked and unmasked CS or be due to any of the other differences between the two studies, for example, the visual CS (snakes vs. angry faces), the US (electric shocks vs. auditory noise), study paradigms (blocked vs. event related), or imaging methodology (PET vs. fMRI). To exclude these alternative explanations, acquisition with both masked and unmasked CS has to be investigated in the same study. Recent neuroimaging experiments have demonstrated habituation of neural activity to repeatedly presented visual stimuli in both the hippocampus (Fischer, Furmark, Wik, & Fredrikson, 2000; Fischer et al., 2000) and the inferior temporal gyrus (Fischer et al., 2000; Fischer et al., 2000; Wright et al., 2001), including the periamygdaloid cortex (Fischer et al., 2000). Because the target “snakes paired with shocks” scans were always presented after the baseline “snakes or visual noise alone” scans, decreased neural activity in these medial temporal lobe regions possibly reflect habituation rather than fear conditioning. In conclusion, acquisition of conditioned fear with an unmasked biologically relevant CS is mainly associated with neural alterations in a right-sided prefrontal brain region involved in both cognitive (Cabeza & Nyberg, 2000) and affective processes (Davidson et al., 2000). The expression of fear conditioning has been associated with altered activity in a more widely distributed cortical and subcortical network involved in motor preparation as well as affective and attentive processes, possibly supporting the fight-and-flight response (Fischer et al., 2000; Fredrikson et al., 1995). This suggests that acquisition and expression of emotional associative learning involve partly overlapping and partly unique neural networks where the converging brain area is located within the right medial frontal gyrus (Brodmann Areas 10 and 46).

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Received June 26, 2001 Revision received March 1, 2002 Accepted March 25, 2002 ■