Diminished medial prefrontal cortex activity in blood-injection-injury phobia

Biological Psychology 75 (2007) 124–130 www.elsevier.com/locate/biopsycho

Diminished medial prefrontal cortex activity in blood-injection-injury phobia Andrea Hermann a,*, Axel Scha¨fer b, Bertram Walter a, Rudolf Stark a, Dieter Vaitl a, Anne Schienle a,b b

a Bender Institute of Neuroimaging, University of Giessen, Otto-Behaghel-Str. 10 H, 35394 Giessen, Germany Department of Clinical Psychology and Health Psychology, University of Graz, Universita¨tsplatz 2/III, 8010 Graz, Austria

Received 16 January 2007; accepted 16 January 2007 Available online 19 January 2007

Abstract We examined the effects of symptom induction on neural activation in blood-injection-injury (BII) phobia. Nine phobic and 10 non-phobic subjects participated in an fMRI study in which they were presented with disorder-relevant, generally disgust-inducing, generally fear-evoking and neutral pictures. We observed diminished medial prefrontal cortex (MPFC) activity in patients compared to controls for phobia-relevant and disgust-inducing pictures. The MPFC has been shown to be critically involved in the automatic and effortful cognitive regulation of emotions. Therefore, the results might reflect reduced cognitive control of emotions in BII phobics during the experience of phobic symptoms as well as during states of disgust. The latter response component might be a result of the elevated disgust sensitivity of BII phobics. # 2007 Elsevier B.V. All rights reserved. Keywords: Blood phobia; Fear; Disgust; Medial prefrontal cortex, MPFC; Cognitive control; Emotion regulation

1. Introduction Blood-injection-injury (BII) phobia is an atypical specific phobia that strongly affects patients’ daily lives. The sufferers often experience emotional fainting (vasovagal syncope) when exposed to phobic stimuli such as blood, injections or injuries (APA, 1994). This physiological response is at first sympathetically dominated, as seen in other specific phobias (e.g. spider phobia), but is then followed by a pronounced parasympathetic component (Page, 1994). The phobics display excessive fear reactions and avoidance behavior. Moreover, it has been shown that not only fear, but the emotion disgust, plays a major role in this disorder as well. Questionnaire studies and picture perception experiments have shown positive associations between blood-related fears and disgust reactivity (e.g. Tolin et al., 1997; deJong and Merkelbach, 1998; Schienle et al., 2003). To our knowledge there is only one published fMRI study on BII phobia (Schienle et al., 2003). This investigation addressed the elevated disgust sensitivity of this patient group by analyzing

* Corresponding author. Tel.: +49 641 99 26338; fax: +49 641 99 26099. E-mail address: [email protected] (A. Hermann). 0301-0511/$ – see front matter # 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.biopsycho.2007.01.002

neural responses to generally disgust-inducing pictures. The only ascertainable difference between BII phobics and healthy controls was a heightened activity in the visual association cortex. A shortcoming of this study was the lack of a phobiarelevant condition. The goal of another fMRI investigation (Wright et al., 2004) was to determine if two types of disgustrelevant stimuli, pictures depicting mutilation or contamination, were able to provoke similar or differential hemodynamic responses in healthy subjects. The findings indicated that the insula was crucial for the processing of both disgust stimuli, whereas pictures of mutilation specifically activated the superior parietal cortex. The results could not be replicated in a similar experiment (Schienle et al., 2006). In this case, a comparable activation pattern including the occipitotemporal cortex, the amygdala and the orbitofrontal cortex occurred in both disgust conditions. Mutilation scenes triggered greater activity in inferior parietal cortex regions as compared to contamination scenes. Neuroimaging studies focusing on other anxiety disorders besides BII phobia have often found increased activity in regions involved in the automatic processing of fear stimuli such as the amygdala, the hippocampus, the thalamus, the insula, the anterior cingulate cortex (ACC) and motor-related regions, e.g. the supplementary motor area (Lorberbaum et al.,

A. Hermann et al. / Biological Psychology 75 (2007) 124–130

2004; Schienle et al., 2005; Kim and Gorman, 2005). Also, a decreased activation in prefrontal cortex regions has frequently been observed (Kim and Gorman, 2005). The latter component might reflect a deficit in cognitive control during excessive states of anxiety. This could possibly lead to reduced inhibitory regulation of limbic regions such as the amygdala. Especially, the medial prefrontal cortex (MPFC) and the ACC are assumed to have specific functions in cognitive and self-referential processing as well as in emotion modulation (Phan et al., 2004). Taking this into account, it is likely that abnormal activity in MPFC areas might be an important characteristic of anxiety disorders (LeDoux, 2002). Furthermore, neuroimaging studies on cognitive regulation of emotions in healthy subjects have shown that these prefrontal areas are involved in different kinds of cognitive control of emotions, for instance reappraisal, anticipation and attention distraction (Ochsner and Gross, 2005). The main goal of the present study was to identify the neural correlates of phobic states in BII phobics. We hypothesized that the presentation of blood-related pictures would activate regions important for the automatic processing of emotions (e.g. the amygdala). This should apply to both patients and non-phobic control subjects due to the overall emotional relevance of this stimulus type. The activation, however, should be greater in patients than controls. Further, the smaller capacity of phobics to cognitively regulate affective responses during the exposure should be mirrored in a reduced activation of prefrontal cortex regions relative to controls. Moreover, we hypothesized that phobic compared to healthy subjects would show an elevated disgust sensitivity and stronger hemodynamic responses towards disgust-inducing disorder-irrelevant pictures (e.g. in the amygdala). A fear condition with threatening, but non-phobic pictures served as a further emotional control condition. 2. Materials and methods The participants of this study consisted of 9 female patients with a DSM-IV diagnosis of BII phobia (mean age = 22.9 years; S.D. = 4.7) and 10 non-phobic female control subjects (mean age = 27.6 years; S.D. = 10.7), who gave written informed consent for the study after the experiment had been explained to them. All participants denied taking any medication. The control subjects received 20 Euros for their participation. The patients underwent an exposure therapy after the experiment. This study was approved by the Ethics Committee of the German Society for Psychology. The study consisted of two separate sessions. In the first session the participants were interviewed with the short form of the clinical interview for DSM-IV (Margraf et al., 1991) to ensure the diagnosis and exclude individuals with comorbidities. A behavior test was conducted, where the subjects were asked to undergo a blood draw. All control subjects and none of the patients were able to perform this test. Afterwards, the participants completed the Mutilation Questionnaire (MQ, Klorman et al., 1974), the Blood Injection Symptom Scale (BISS, Page et al., 1997), the Questionnaire for the Assessment of Disgust Sensitivity (QADS, Schienle et al., 2002b), the trait scale of the State Trait Anxiety Inventory (STAI, Laux et al., 1981) and the Beck Depression Inventory (BDI, Hautzinger et al., 1993). The fMRI study was conducted in the second session (approximately 1 week later). After the scanning, the subjects gave disgust, fear, valence and arousal ratings for each picture category (possible range: 1–9; ‘9’ indicated that the subject felt disgusted, anxious, pleasant and aroused). The Self-Assessment Manikin (SAM; Bradley and Lang, 1994) was used for the valence and arousal ratings. The intensity of experienced disgust and fear was rated on 9-point Likert scales (1 = ‘not at all’; 9 = ‘very strong’), which had been developed by the authors.

125

The stimulus material consisted of four categories with 160 pictures in total: 40 phobic, 40 disgust, 40 fear and 40 neutral pictures. These stimuli were selected from the IAPS (Lang et al., 1997) and another picture set (Schienle et al., 2002a). The phobia-relevant scenes depicted, e.g. blood draws and wounds. The disgust-evoking pictures represented the domains poor hygiene (e.g. garbage piles, dirty toilets), animals (e.g. maggots, snails), body products (e.g. excrements, vomit) and unusual food (e.g. a man eating a grasshopper). Pictures showing attacks by humans (e.g. with pistols or knives) and animals (e.g. lions, sharks) formed the fear category, whereas the affectively neutral scenes consisted of, e.g. geometric figures and household articles. The pictures were presented for 1.5 s in blocks of 40 pictures of the same category. The pictures sequence in each block was randomized and each block was shown six times during the experiment. Two categories of the same type were not allowed to follow each other. Participants viewed the pictures by a mirror fixed on the head coil (visual field = 188). The complete experiment took 24 min. A total of 492 volumes (T2*-weighted gradient echo-planar imaging sequence with 30 slices covering the whole brain, slice thickness = 5 mm, no gap, interleaved, TA = 100 ms, TE = 60 ms, TR = 3000 ms, flip angle = 908, field of view = 192 mm  192 mm, matrix size = 64  64) were acquired with a 1.5 T whole-body tomograph (Siemens Symphony, Erlangen, Germany; standard head coil). The axial slices were oriented parallel to the AC-PC line. To control for saturation effects the first six volumes were discarded. The statistical parametric mapping software package (SPM2, Wellcome Department of Cognitive Neurology, London) implemented in Matlab (Mathworks, Inc., Natick, MA, USA, release 12) was used for the preprocessing and statistical analyses. Slice time correction, realignment and normalization to the standard space of the Montreal Neurological Institute brain and the smoothing procedure (isotropic three-dimensional Gaussian filter with a full width at half maximum of 9 mm) were carried out. Each experimental condition was modeled by a boxcar function convolved with a hemodynamic response function in the GLM. The six movement parameters of the rigid body transformation were introduced in the model as covariates. Serial correlations were controlled by an AR(1) process and the high pass filter was set at 512 s. In the first level analyses the following contrasts were calculated for each subject: Phobia > Neutral, Disgust > Neutral, Fear > Neutral, Fear > Disgust, Disgust > Fear, Phobia > Fear, Fear > PhoPhobia, Phobia > Disgust and Disgust > Phobia. Then, the contrast images were used in second level random effects analyses. We conducted one-sample t-tests for each group and two-sample t-tests to explore differences between the phobic and the control group. We computed voxel intensity tests (intensity threshold: p = 0.01 uncorrected) for the whole brain volume (exploratory analyses) and for regions of interest (ROI). Error probabilities ( p) were corrected for multiple comparisons using the random field theory. When exploratory analyses were conducted, p was corrected for the whole brain volume, when a ROI test was used p was corrected for the specific volume of interest according to the tested hypothesis. The significance level was always set to alpha = 0.05. The following ROIs had been selected on the basis of previous findings on anxiety disorders and the neural processing of mutilation stimuli: anterior cingulate cortex (ACC), amygdala, dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), hippocampus, insula, lateral orbital prefrontal cortex (LOFC), supplementary motor area (SMA), inferior parietal cortex, superior parietal cortex, thalamus, ventromedial prefrontal cortex (VMPFC). The ROIs had been defined by the anatomical parcellation of the normalized brain (single-subject high-resolution T1 volume of the Montreal Neurological Institute). We created masks based on this assignment between anatomical structures and voxel coordinates (Tzourio-Mazoyer et al., 2002).

3. Results 3.1. Self-report-data Phobic subjects scored significantly higher on the Mutilation Questionnaire, the Blood Injection Symptom Scale and the Questionnaire for the Assessment of Disgust Sensitivity

126

A. Hermann et al. / Biological Psychology 75 (2007) 124–130

Table 1 Questionnaire scores for the phobic and non-phobic group

**

MQ BISS ** QADS * STAI-Trait BDI

3.2. FMRI-data

Phobics M(S.D.)

Controls M(S.D.)

19.9 (6.03) 9.00 (3.61) 2.31 (0.53) 35.00 (8.17) 5.00 (5.07)

6.30 2.90 1.63 35.50 3.50

(4.03) (2.51) (0.53) (6.77) (5.19)

t-tests (phobics vs. controls); M, mean; S.D., standard deviation; MQ, Mutilation Questionnaire; BISS, Blood-injection-symptom scale; QADS, Questionnaire for the assessment of disgust sensitivity; STAI-Trait, Trait-Scale of the State-trait-anxiety inventory; BDI, Beck Depression Inventory. * p < 0.05; ** p < 0.001.

than control subjects (MQ: t(17) = 5.83, p < 0.001; BISS: t(17) = 4.32, p < 0.001; QADS-total: t(17) = 2.76, p = 0.013; see Table 1). Both groups were comparable in their trait anxiety and depressive symptoms. The affective ratings differed significantly between the two groups for the phobic stimuli (one-tailed t-tests; Table 2). Phobic compared to control participants rated disorder-relevant pictures higher on the dimensions fear (t(17) = 4.8, p < 0.001), disgust (t(17) = 2.2, p = 0.023) and arousal (t(14.2) = 4.5, p < 0.001) and lower on the dimension valence (t(17) = 3.0, p = 0.005). Disgust pictures received higher ratings of fear (t(8.9) = 2.8, p = 0.01), disgust (t(17) = 2.6, p = 0.01) and arousal (t(17) = 2.6, p = 0.01) from the phobic compared to the control group. Ratings for the fear and neutral pictures did not differ between the two groups. Within the phobic group phobic pictures received comparable disgust- and fear-ratings, whereas control subjects reported stronger feelings of disgust than fear in response to these pictures (two-tailed t-tests; t(9) = 3.8; p = 0.004). Table 2 Affective ratings by phobic and non-phobic subjects for the four picture categories Category Phobic

Rating *

Disgust Fear** Valence* Arousal** *

Phobics M(S.D.)

Controls M(S.D.)

6.44 6.22 2.11 7.78

(2.40) (2.33) (1.36) (1.39)

3.90 1.80 4.80 3.60

(2.69) (1.62) (2.39) (2.55)

Disgust

Disgust Fear* Valence Arousal*

6.56 3.11 3.67 5.67

(2.30) (1.90) (2.40) (1.66)

4.00 1.30 5.40 3.50

(2.06) (0.48) (2.01) (1.96)

Fear

Disgust Fear Valence Arousal

1.89 3.33 5.11 4.11

(0.93) (2.06) (1.83) (1.90)

1.70 3.30 5.20 3.70

(1.34) (2.21) (2.15) (2.26)

Neutral

Disgust Fear Valence Arousal

1.00 1.22 8.56 1.56

(0.00) (0.44) (1.33) (0.88)

1.00 1.00 7.40 1.50

(0.00) (0.00) (2.59) (1.27)

M, mean; S.D., standard deviation. * p < 0.05; ** p < 0.001.

3.2.1. Phobics The ROI analyses for Phobia > Neutral revealed significant activation in the left hippocampus and in the bilateral thalamus (see Table 3a). The effect in the left amygdala (MNI: 21, 3, 21; k = 14; t = 4.24; p = 0.053) was marginally significant. The exploratory analysis showed no significant results. Disgust > Neutral evoked significant activity in the left fusiform gyrus (exploratory analysis). ROI analyses revealed significant activation in the right superior parietal cortex. Fear > Neutral was associated with activation in the right amygdala (ROI analysis). Activation for Fear > Disgust occurred in the left VMPFC (ROI analysis). Disgust > Fear showed significant activity in the bilateral superior parietal cortex. In order to explore disorder-specific activity, the phobic condition was compared with the other emotional conditions. ROI analyses for Phobia > Fear showed activation in the bilateral thalamus. Fear > Phobia was associated with significant activity in the left VMPFC. Analyses of the contrasts Phobia > Disgust and Disgust > Phobia did not show any significant results. 3.2.2. Controls The control subjects activated the right inferior temporal gyrus in response to Phobia > Neutral (exploratory analyses; see Table 3b). The ROI analyses revealed activity in the right superior parietal cortex, the left inferior parietal cortex, the right thalamus and the bilateral LOFC. Marginally significant activation occurred in the left amygdala (MNI: 24, 3, 18; k = 14; t = 3.60; p = 0.073). The disgust pictures (Disgust > Neutral) evoked significant activity in the calcarine fissure (exploratory analysis). In the ROI analyses significant activity was observed in the right LOFC and the left DMPFC. Exploratory analysis for Fear > Neutral detected marginally significant activity in the right middle temporal gyrus (MNI: 57, 69, 3; k = 1154; t = 10.97; p = 0.059). Left amygdala and bilateral thalamus activation (ROI analyses) were observed for Phobia > Fear. Analyses of Fear > Phobia, Disgust > Fear, Fear > Disgust, Disgust > Phobia and Phobia > Disgust did not show any significant results. 3.2.3. Group comparisons The comparison of the two groups by means of ROI analyses showed more pronounced activation in the left SMA for Phobia > Neutral in patients relative to controls (Table 3c). Disgust > Neutral was associated with enhanced left DLPFC activation in patients. Analyses of the other contrasts (Fear > Neutral, Phobia > Fear, Phobia > Disgust) did not reveal significant results. The control subjects responded with greater bilateral DMPFC and left VMPFC activation for the contrast Phobia > Neutral (ROI analyses; see Table 3d; Fig. 1a). The effect for the right VMPFC (MNI: 12, 48, 15; k = 105; t = 4.13; p = 0.060) was marginally significant. Contrast estimates for these regions (bilateral DMPFC and VMPFC) are displayed in Fig. 1b. The control subjects displayed enhanced right VMPFC activation for

A. Hermann et al. / Biological Psychology 75 (2007) 124–130

127

Table 3 FMRI results for (a) phobics, (b) controls, (c) phobics > controls and (d) controls > phobics Region

H

X

y

z

k

t

p

(a) Phobics Phobia > Neutral Hippocampus Thalamus Thalamus

L L R

15 0 3

30 21 21

6 6 6

32 184 37

6.05 8.25 6.76

0.043 0.006 0.024

Disgust > Neutral Fusiform gyrus (BA 19) Superior parietal gyrus (BA 7)

L R

S36 27

S69 63

S12 54

4461 70

14.88 9.75

0.014 0.003

Fear > Neutral Amygdala

R

18

0

18

5

4.70

0.039

Phobia > Fear Thalamus Thalamus

L R

6 12

21 21

6 18

83 13

7.78 6.04

0.009 0.048

Fear > Phobia VMPFC (BA 10/11)

L

6

48

15

180

6.91

0.020

Fear > Disgust VMPFC (BA 10/11)

L

9

45

21

84

6.17

0.044

Disgust > Fear Superior parietal gyrus (BA 7) Superior parietal gyrus (BA 7)

L R

21 27

63 63

54 54

87 99

9.14 7.47

0.005 0.020

(b) Controls Phobia > Neutral Inferior temporal gyrus (BA 37) Inferior parietal gyrus (BA 3) Superior parietal gyrus (BA 7) Thalamus LOFC (BA 11/47) LOFC (BA 11/47)

R L R R L R

57 57 18 18 27 51

S69 24 81 12 39 36

S12 42 54 3 21 18

5083 94 110 65 33 30

19.28 6.11 7.46 5.60 6.79 7.29

<0.001 0.033 0.011 0.043 0.035 0.021

Disgust > Neutral Calcarine fissure (BA 18) LOFC (BA 11/47) DMPFC (BA8/9/10/32)

L R L

S12 30 3

S96 33 63

S6 15 24

3290 12 39

17.36 7.10 6.68

0.001 0.025 0.039

Phobia > Fear Amygdala Thalamus Thalamus

L L R

24 15 6

0 30 24

15 0 12

33 132 151

5.47 7.80 5.58

0.013 0.005 0.049

(c) Phobics > Controls Phobia > Neutral SMA (BA 6)

L

9

3

63

16

4.51

0.042

Disgust > Neutral DLPFC (BA 9/46)

L

12

15

42

7

4.87

0.045

(d) Controls > Phobics Phobia > Neutral DMPFC (BA 8/9/10/32) DMPFC (BA 8/9/10/32) VMPFC (BA 10/11)

L R L

3 6 3

57 57 36

30 30 21

61 133 111

4.79 6.56 4.29

0.038 0.001 0.045

Disgust > Neutral VMPFC (BA 10/11)

R

12

48

9

34

4.44

0.028

Phobia > Disgust DMPFC (BA 8/9/10/32)

R

9

54

24

53

4.63

0.032

ROI analyses: p < 0.05; bold: exploratory analyses: p < 0.05; H, hemisphere; L, left; R, right; x, y, z: MNI-coordinates; BA, Brodmann areas; k, number of voxels; t, tvalue (max.).

128

A. Hermann et al. / Biological Psychology 75 (2007) 124–130

Fig. 1. (a) Greater bilateral DMPFC (1, 2), left VMPFC (3) and marginally significant right VMPFC (4) activity in control subjects relative to BII phobics (y = 47; x = 7); (b) mean contrast estimates for left DMPFC (MNI: 3, 57, 30), right DMPFC (6, 57, 30), left VMPFC (MNI: 3, 36, 21) and right VMPFC (12, 48, 15) in the phobic and control group.

the contrast Disgust > Neutral, and enhanced left DMPFC activation for Phobia > Disgust relative to phobics. Furthermore, controls showed marginally greater activation than phobics in the right DMPFC (MNI: 9, 57, 27; k = 45; t = 4.30; p = 0.058) and in the left VMPFC (MNI: 6, 48, 12; k = 141; t = 3.97; p = 0.071) for Phobia > Fear. Both groups were characterized by comparable activation for Fear > Neutral. 4. Discussion This is the first study to investigate the neural correlates of phobic states in patients suffering from BII phobia. As expected, the viewing of disorder-specific relative to affectively neutral scenes provoked increased activity in emotionrelevant brain structures in the patient group (i.e. thalamus and hippocampus; Kim and Gorman, 2005; Phillips et al., 2003). The phobics were further characterized by marginally significant amygdala activation ( p = 0.054), which was also present in the control subjects ( p = 0.073). Interestingly, phobics and controls did not differ in their amygdala responses, which points to the overall emotional significance of stimuli involving blood and injury, as well as to the central role of the amygdala for the decoding of threat (LeDoux, 2002). The control subjects showed activity in the visual association cortex, the thalamus and the LOFC when looking at blood relative to neutral pictures. The LOFC has been conceptualized as being important for the evaluation of the punishment value of emotional stimuli and the alteration of ongoing behavior (Kringelbach and Rolls, 2004). The controls also displayed significant activation of the parietal cortex, which might reflect

a detailed visual inspection of the pictures as these parietal areas are involved in attention processes (Behrmann et al., 2004). More activity in phobics than controls was seen in the SMA, which is an important region for the preparation of movement. This response might be linked to intended avoidance behavior in BII-phobic subjects. However, diminished dorso- and ventromedial prefrontal cortex activity seems to be the main characteristic that distinguishes the hemodynamic responses towards phobic versus neutral pictures of BII phobics from those of non-phobic control subjects. These regions have been shown to be critically involved in the cognitive regulation of emotions (Ochsner and Gross, 2005). It can be assumed that this mechanism is impaired in patients suffering from BII phobia. Therefore, those individuals might experience significantly stronger feelings of fear, disgust, arousal and unpleasantness in response to phobic objects as seen in their subjective stimulus ratings. There were two distinct clusters of diminished activity in the PFC that are possibly related to different processes of cognitive emotion regulation. The ventral parts belong to a system that is important for the identification of the emotional significance of stimuli, the production of affective states and the automatic regulation of autonomic responses (Phillips et al., 2003). A more dorsal system including the DMPFC and the DLPFC is found to be concerned with effortful regulation of affective states (Phillips et al., 2003; Ochsner and Gross, 2005). Together with the ventral system, the dorsal PFC is activated by processes such as reappraisal and anticipation (Ochsner and Gross, 2005). This goes along with the inhibition of limbic regions such as the amygdala, which is important for the processing of emotional stimuli and the production of affective states (Phelps, 2006). Disturbances of both mechanisms (automatic and controlled regulation of emotions) might be related to the maladaptive emotional responses in BII phobics during exposure. Diminished activity in the VMPFC was also observed for the contrast Phobia > Fear in the patient group. Furthermore, between-group comparison for Phobia > Fear revealed marginally significant stronger activity in the DMPFC and VMPFC in controls than phobics. This finding points to the relevance of altered MPFC responses to phobic stimuli even when being compared with other threatening stimuli. Beyond this, there is evidence for altered MPFC reactivity in other anxiety disorders. Diminished neuronal activation has been shown in patients afflicted with post-traumatic stress disorder (Shin et al., 2005) and generalized social phobia (Lorberbaum et al., 2004). Moreover, there are PET studies on spider phobia which indicated reduced activity in prefrontal areas in response to phobic objects (Fredrikson et al., 1995; Johanson et al., 1998), especially when the patients experienced panic symptoms and had no effective coping strategies on hand (Johanson et al., 1998). Even in depressed relative to healthy subjects decreased activity in the VMPFC towards sad facial expressions in combination with congruent autobiographical memory has been observed (Keedwell et al., 2005). The reduced activity in ventromedial PFC regions in BII phobics relative to controls was not restricted to disorder-relevant

A. Hermann et al. / Biological Psychology 75 (2007) 124–130

stimuli, but was also present in the disgust condition (Disgust > Neutral). Here, phobics further exhibited enhanced DLPFC activation; however, they did not deviate in the DMPFC involvement from controls. This response pattern might be due to a deficit in the automatic, as opposed to the effortful regulation of disgust experiences in phobics. Their elevated disgust sensitivity could be associated with their reduced automatic control over disgust reactions leading to stronger feelings of disgust, fear and arousal towards these stimuli. It is important to note that phobic compared to healthy individuals did not generally show reduced activity in the VMPFC in response to emotional material. These two groups were characterized by comparable brain activation for the contrast Fear > Neutral. Also, both groups had comparable trait anxiety scores and gave similar affective ratings for the fear stimuli. All in all, this finding seems to imply that the blood-phobic patients did not have a general fear disposition. Yet, they displayed significant amygdala activation for the contrast Fear > Neutral, which was not present in control subjects. Thus, there might be a small group difference in the reactivity of the central fear network, which could not be detected due to the small sample sizes limiting statistical power. There are two further limitations that need to be acknowledged and addressed regarding the present study. The first of which is the concern that the majority of neutral scenes depicted objects, whereas the affective pictures mainly showed human beings and animals. The fact that the picture type and the inclusion of living versus non-living-stimuli were not independent from each other could have contributed to the observed neural activation pattern as pointed out by one reviewer. It seems however unlikely that the most important finding, the MPFC deactivation, was due to this confound, since it was also present when comparing the phobic with the fear category, which both included human beings. A further limitation of our study is that only female subjects were measured. This had been done in order to control for genderrelated differences in disgust sensitivity. Nevertheless, it remains open if the described fMRI responses would also be detectable in male phobics. In summary, BII phobics relative to controls were characterized by an elevated overall disgust but not fear sensitivity in addition to their phobic symptoms. On the neural level this was mirrored by reduced activation of the VMPFC in response to phobic and disgust but not to fear pictures. Finally, phobics displayed diminished VMPFC activity for the contrasts Phobia > Fear and Disgust > Fear but not for Phobia > Disgust. This provides further support for the role of this region in the enhancement of emotional reactions due to reduced cognitive control. 5. Conclusions This is the first fMRI study on symptom provocation in BII phobia. We observed decreased activation in medial prefrontal cortex areas towards phobic pictures in phobic compared to control subjects. Since this brain region is critically involved in the cognitive regulation of emotions, we assume that BII phobia

129

is characterized by a disturbance of this mechanism during exposure. Furthermore, BII phobics showed reduced activity in the VMPFC in response to generally disgust-inducing pictures, which might be related to their elevated disgust sensitivity. Future studies on BII phobia in particular and anxiety disorders in general should focus on a more detailed analysis of possible deficits in the cognitive regulation of emotions. References American Psychiatric Association (APA), 1994. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Press, Washington, DC. Behrmann, M., Geng, J.J., Shomstein, S., 2004. Parietal cortex and attention. Current Opinion in Neurobiology 14, 212–217. Bradley, M.M., Lang, P.J., 1994. Measuring emotion: the self-assessment manikin and the semantic differential. Journal of Behavioral Therapy and Experimental Psychiatry 25, 49–59. deJong, P.J., Merkelbach, H., 1998. Blood-injection-injury phobia and fear of spiders: domain specific individual differences in disgust sensitivity. Personality and Individual Differences 24, 153–158. Fredrikson, M., Wik, G., Annas, P., Ericson, K., Stone-Elander, S., 1995. Functional neuroanatomy of visually elicited simple phobic fear: additional data and theoretical analysis. Psychophysiology 32, 43–48. Hautzinger, M., Bailer, M., Worall, H., Keller, F., 1993. Beck-DepressionsInventar (BDI). Huber, Bern. Johanson, A., Gustafson, L., Passant, U., Risberg, J., Smith, G., Warkentin, S., Tucker, D., 1998. Brain function in spider phobia. Psychiatry Research Neuroimaging 84, 101–111. Keedwell, P.A., Andrew, C., Williams, S.C.R., Brammer, M.J., Phillips, M.L., 2005. A double dissociation of ventromedial prefrontal cortical responses to sad and happy stimuli in depressed and healthy individuals. Biological Psychiatry 58, 495–503. Kim, J., Gorman, J., 2005. The psychobiology of anxiety. Clinical Neuroscience Research 4, 335–347. Klorman, R., Weerts, T., Hastings, J., Melamed, B., Lang, P., 1974. Psychometric description of some fear-specific questionnaires. Behaviour Research 5, 401–409. Kringelbach, M.L., Rolls, E.T., 2004. The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology. Progress in Neurobiology 72, 341–372. Lang, P.J., Bradley, M.M., Cuthbert, B., 1997. International Affective Picture System Gainsville. Center for Research in Psychophysiology, University of Florida, Florida. Laux, L., Glanzmann, P., Schaffner, P., Spielberger, L., 1981. Das State-TraitAngstinventar. Beltz Testgesellschaft, Weinheim. LeDoux, J.E., 2002. Synaptic Self: How Our Brains Become Who We Are. Penguin Books, New York. Lorberbaum, J.P., Kose, S., Johnson, M.R., Arana, G.W., Sullivan, L.K., Hamner, M.B., Ballenger, J.C., Lydiard, R.B., Brodrick, P.S., Bohning, D.E., George, M.S., 2004. Neural correlates of speech anticipatory anxiety in generalized social phobia. NeuroReport 15, 2701–2705. Margraf, J., Schneider, S., Ehlers, A., 1991. Diagnostisches Interview bei Psychischen Sto¨rungen (DIPS). Springer, Berlin. Ochsner, K.N., Gross, J.J., 2005. The cognitive control of emotion. Trends in Cognitive Sciences 9, 242–249. Page, A.C., 1994. Blood-injury phobia. Clinical Psychology Review 14, 443– 461. Page, A.C., Bennet, K.S., Carter, O., Smith, J., Woodmore, K., 1997. The Blood-Injection Symptom Scale (BISS): assessing a structure of phobic symptoms elicited by blood and injections. Behaviour Research and Therapy 5, 457–464. Phan, K.L., Wager, T.D., Taylor, S.F., Liberzon, I., 2004. Functional neuroimaging studies of human emotions. CNS Spectrums 9, 258–266. Phelps, E.A., 2006. Emotion and cognition: insights from studies of the human amygdala. Annual Review of Psychology 57, 27–53.

130

A. Hermann et al. / Biological Psychology 75 (2007) 124–130

Phillips, M.L., Drevets, W.C., Rauch, S.L., Lane, R., 2003. Neurobiology of emotion perception i: the neural basis of normal emotion perception. Biological Psychiatry 54, 504–514. Schienle, A., Stark, R., Walter, B., Blecker, C., Ott, U., Kirsch, P., Sammer, G., Vaitl, D., 2002a. The insula is not specifically involved in disgust processing: an fMRI study. NeuroReport 13, 2023–2026. Schienle, A., Walter, B., Stark, R., Vaitl, D., 2002b. A questionnaire for the assessment of disgust sensitivity. Zeitschrift fu¨r Klinische Psychologie und Psychotherapie 31, 110–120. Schienle, A., Scha¨fer, A., Stark, R., Walter, B., Vaitl, D., 2003. Disgust processing in phobia of blood-injection injury. Journal of Psychophysiology 17, 87–93. Schienle, A., Scha¨fer, A., Walter, B., Stark, R., Vaitl, D., 2005. Brain activation of spider phobics towards disorder-relevant, generally disgust- and fearinducing pictures. Neuroscience Letters 388, 1–6. Schienle, A., Scha¨fer, A., Hermann, A., Walter, B., Stark, R., Vaitl, D., 2006. FMRI responses to pictures of mutilation and contamination. Neuroscience Letters 393, 174–178.

Shin, L.M., Wright, C.I., Cannistraro, P.A., Wedig, M.M., McMullin, K., Martis, B., Macklin, M.L., Lasko, N.B., Cavanagh, S.R., Krangel, T.S., Orr, S.P., Pitman, R.K., Whalen, P.J., Rauch, S.L., 2005. A Functional Magnetic Resonance Imaging Study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Archives of General Psychiatry 62, 273–281. Tolin, D.F., Lohr, J.M., Sawchuk, C.N., Lee, T.C., 1997. Disgust and disgust sensitivity in blood-injection-injury and spider phobia. Behaviour Research and Therapy 35, 949–953. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., Mazoyer, B., Joliot, M., 2002. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neurolmage 15, 273–289. Wright, P., He, G., Shapira, N.A., Goodman, W.K., Liu, Y., 2004. Disgust and the insula: fMRI responses to pictures of mutilation and contamination. NeuroReport 15, 2347–2351.