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NeuroImage 29 (2006) 125 – 135

Effects of cognitive-behavioral therapy on brain activation in

specific phobia

Thomas Straube,a,* Madlen Glauer,a Stefan Dilger,a

Hans-Joachim Mentzel,b and Wolfgang H.R. Miltnera

aDepartment of Biological and Clinical Psychology, Friedrich-Schiller-University, Am Steiger 3,1, D-07743 Jena, GermanybInstitute of Diagnostic and Interventional Radiology, Friedrich-Schiller-University, Jena, Germany

Received 9 February 2005; revised 3 June 2005; accepted 5 July 2005

Available online 8 August 2005

Little is known about the effects of successful psychotherapy on brain

function in subjects with anxiety disorders. The present study aimed to

identify changes in brain activation following cognitive-behavioral

therapy (CBT) in subjects suffering from specific phobia. Using

functional magnetic resonance imaging (fMRI), brain activation to

spider videos was measured in 28 spider phobic and 14 healthy control

subjects. Phobics were randomly assigned to a therapy-group (TG) and

a waiting-list control group (WG). Both groups of phobics were

scanned twice. Between scanning sessions, CBT was given to the TG.

Before therapy, brain activation did not differ between both groups of

phobics. As compared to control subjects, phobics showed greater

responses to spider vs. control videos in the insula and anterior

cingulate cortex (ACC). CBT strongly reduced phobic symptoms in the

TG while the WG remained behaviorally unchanged. In the second

scanning session, a significant reduction of hyperactivity in the insula

and ACC was found in the TG compared to the WG. These results

propose that increased activation in the insula and ACC is associated

with specific phobia, whereas an attenuation of these brain responses

correlates with successful therapeutic intervention.

D 2005 Elsevier Inc. All rights reserved.

Keywords: ACC; Insula; Phobia; Therapy; Amygdala; Threat

Introduction

The most common forms of specific phobia, an anxiety disorder

with a high prevalence of approximately 10% in the general

population, are related to small animals such as spiders, snakes, or

rodents (Fyer, 1998). The functional neuroanatomy associated with

symptoms of animal or other kinds of specific phobia is not yet

clear. Neuroimaging studies investigating neuronal correlates of the

processing of threat in specific phobia have provided mixed results.

1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.neuroimage.2005.07.007

* Corresponding author. Fax: +49 3641 9 45 142.

E-mail address: straube@biopsy.uni-jena.de (T. Straube).

Available online on ScienceDirect (www.sciencedirect.com).

Several previous positron-emission tomography (PET) studies

found increased regional cerebral blood flow (rCBF) in extrastriate

visual cortex but not in other brain regions during visual

phobogenic stimulation in animal phobics (Fredrikson et al.,

1993, 1995; Wik et al., 1993). A PET-study with animal phobics

by Rauch et al. (1995) demonstrated activation of the anterior

cingulate cortex (ACC), somatosensory cortex, thalamus, and a

fronto-temporal region including the anterior insula during

symptom provocation induced by tactile imagery of the feared

stimulus. Similar results were also reported by other PET studies,

which showed increased responses in anterior insula, ACC/ medial

frontal cortex, and in the thalamus or midbrain to real feared

animals or pictures of these animals (Carlsson et al., 2004; Reiman,

1997). Furthermore, recent functional resonance magnetic imaging

(fMRI) studies from our group found significant activation of the

insula, ACC, and prefrontal cortex in response to visually

presented phobia-related stimuli in animal phobics (Dilger et al.,

2003; Straube et al., 2004b, in press).

Especially, the findings regarding activation of the insula and

ACC are in accordance with brain activation patterns observed

during threat processing and symptom provocation in other anxiety

disorders. For example, insula activation was shown in social

phobia (Straube et al., 2004a, but see Stein et al., 2002; Tillfors et

al., 2002), panic disorder (Reiman, 1997), or posttraumatic stress

disorder (Osuch et al., 2001; Rauch et al., 1997). Significantly

increased activation of the insula associated with provocation of

clinically relevant anxiety symptoms was also reported by Rauch et

al. (1997), who used pooled data across different anxiety disorders

(obsessive–compulsive disorder, specific phobia, posttraumatic

stress disorder). In all studies included in the analysis of Rauch et

al., activation of the ACC was observed as well. ACC responses

during clinically relevant anxiety were also described by other

authors (Aouizerate et al., 2004; Boshuisen et al., 2002; Osuch et

al., 2001; Pissiota et al., 2002). Furthermore, an involvement of

ACC and insula was found during the provocation of anxiety and

during evaluation of visual threat signals such as fear conditioned

fear stimuli and fearful facial expressions in healthy subjects (for

T. Straube et al. / NeuroImage 29 (2006) 125–135126

reviews see Critchley, 2003; Phan et al., 2002; Reiman, 1997). It

has been suggested that areas such as the ACC and anterior insula,

but also the thalamus and prefrontal cortex might be part of a core

anxiety system relevant for sustained evaluation of (potential)

danger and the subjective experience of fear (Critchley, 2003;

Rauch et al., 1997; Reiman, 1997).

Remarkably, numerous functional imaging studies with patients

suffering from specific phobia failed to show amygdala activation

when subjects were exposed to phobia-relevant stimulation

(Fredrikson et al., 1993, 1995; Mountz et al., 1989; Paquette et

al., 2003; Pissiota et al., 2003; Rauch et al., 1995; Reiman, 1997;

Wik et al., 1993, 1997). This is in contrast to the widely

demonstrated role of the amygdala in the processing of fear-related

stimuli and the mediation of fear responses in healthy subjects

(e.g., Anderson et al., 2003; Breiter et al., 1996; Buchel et al.,

1998; Critchley et al., 2002; Morris et al., 1998) and patients with

other anxiety disorders (e.g., Birbaumer et al., 1998; Gilboa et al.,

2004; Liberzon et al., 1999; Rauch et al., 2000; Shin et al.,

1997a,b, 2004; Stein et al., 2002; Straube et al., 2004a; Tillfors et

al., 2001, 2002). Previously, we suggested (Dilger et al., 2003;

Straube et al., in press) that the absence of amygdala activation in

several studies on specific phobia might be due to sustained

periods of symptom provocation, leading to an attenuation of rapid

amygdalar responses (see also Breiter et al., 1996; Buchel et al.,

1998; Keightley et al., 2003; Taylor et al., 2003; Veltman et al.,

2004; Wright et al., 2001). By means of event-related fMRI, we

were able to show increased amygdala activation in spider phobics

during the processing of briefly presented phobia-related pictures

(Dilger et al., 2003; Straube et al., in press; see also Carlsson et al.,

2004). These findings strongly suggest a crucial function of the

amygdala in the initial processing of phobia-related threat and in

the induction of fear, while sustained processing of threat-related

stimuli, such as confrontation with real, imagined, or filmed

feared objects, does not seem to be based on amygdalar activity

(see also Rauch et al., 1997; Walker et al., 2003).

Although the most conclusive indices regarding the functional

neuroanatomy of specific phobia may arise from studies inves-

tigating the neuronal effects of successful therapeutic intervention,

only one such study has been performed so far (Paquette et al.,

2003). In this fMRI study, spider phobics showed a therapy-

induced attenuation of hyperactivity, which had been observed

pretreatment in the parahippocampal gyrus and dorsolateral

prefrontal cortex (DLPFC) in response to spider vs. control videos.

Results were interpreted to reflect a reduction in coping strategies

(DLPFC) and in stimulus-related mnemonic processes (para-

hippocampal gyrus). Remarkably, no phobia-related activation of

the insula, ACC, or other areas was detected. This outcome was

attributed to the fact that threatening visual stimuli might not be

suited to induce activation in these areas. However, this inter-

pretation is not justified by results of several functional imaging

studies (see above), which showed that the (anxious) evaluation of

visual fear-relevant stimuli is associated with activation in the

insula and ACC in phobics and healthy subjects. Although of high

impact for the research regarding neurobiological correlates of

psychotherapy, the study of Paquette and colleagues had the

important limitation that no untreated phobic control group was

included. Since repeated scanning sessions may be associated with

confounding variables such as habituation, anticipation, and

novelty effects (e.g., Johansen-Berg et al., 2002; McGonigle et

al., 2000; Stark et al., 2004), a phobic waiting-list control group

offers the possibility to properly control for these influences.

Furthermore, the videos, which were used in the pre- and

posttreatment scanning sessions, were also presented extensively

between scanning sessions as part of the therapy. Therefore, no

clear conclusion was possible whether the modification of brain

activation was due to effects of the psychotherapy applied, or to

other factors such as stimuli-specific habituation.

The present study aimed at the investigation of brain activation

to phobogenic videos in spider phobics and the effects of

successful therapeutic intervention on these brain responses. The

study included a healthy control group as well as a phobic waiting-

list group. As therapeutic intervention, we administered CBT,

which has been consistently shown to be highly effective in the

reduction of phobic symptoms (e.g., Ost, 1989, 1996; Paquette et

al., 2003). Data analysis was focused on those brain regions that

have been suggested to play a critical role in the processing of

visual threatening stimuli in specific phobia and/or in the mediation

of phobic fear (DLPFC, anterior insula, ACC, thalamus, amygdala,

parahippocampal gyrus, extrastriate cortex).

Methods

Subjects

Twenty-eight female spider phobic subjects and 14 healthy

female control subjects (mean age: 22.07, SD: 1.98) participated in

the study. The participants were recruited by public advertisements.

Subjects were diagnosed as spider phobics prior to the experiment

according to the criteria of the diagnostic and statistic manual of

mental disorders for spider phobia (DSM-IV, American Psychiatric

Association, 1994) as assessed by a structured clinical interview

(Wittchen et al., 1997). In addition, spider phobics had to show

high scores on a spider phobia questionnaire [SPQ (Klorman et al.,

1974); TG (finally analyzed subjects): mean = 22.69, SD = 2.95;

WG (finally analyzed subjects): mean = 22.33, SD = 2.84]. Control

subjects had to be free of any kind of phobia and to show low

scores in the SPQ (mean = 1.57, SD = 1.60). Furthermore,

according to the outcome of the structured clinical interview for

DSM-IV, all subjects were free from additional psychopathological

and neurological disorders. Subjects with spider phobia were

randomly assigned to a therapy-group (TG) and a waiting-list

control group (WG). The groups did not differ in phobia severity

(based on SPQ scores), age, or level of education (all participants

were university students). One subject of the TG did not participate

in the second scanning session leaving a sample of 13 subjects in

this group (mean age: 21.92, SD: 2.02). In the WG, two subjects

had to be excluded due to a missing second scanning session and a

panic attack during scanning, leaving a sample of 12 subjects for

this group (mean age: 21.33, SD: 2.46). Subjects of the healthy

control group (CG) received 6 Euro per hour for participation. The

study was approved by the ethics committee of the University of

Jena and written informed consent was obtained from each

participant prior to the experiment.

Stimuli and tasks

Subjects were exposed to video clips depicting a moving

spider on a grey background or—as baseline condition—a

moving black small synthetic cylinder of comparable size. To

assure high ecological relevance of spider stimuli, a German

house spider (species Tegenaria atrica) most commonly occur-

Table 1

Ratings: descriptive data

Variable CG TG WG

First First Second First Second

Valence

Spider 3.64 (0.39) 8.15 (0.25) 5.46 (0.24) 8.17 (0.27) 8.10 (0.25)

Baseline 3.86 (0.40) 3.93 (0.37) 4.31 (0.38) 4.0 (0.48) 4.10 (0.55)

Arousal

Spider 2.14 (0.39) 7.70 (0.33) 3.15 (0.50) 7.42 (0.36) 7.45 (0.28)

Baseline 1.64 (0.20) 2.08 (0.31) 1.54 (0.31) 2.67 (0.47) 3.10 (0.62)

Fear

Spider 1.07 (0.07) 6.30 (0.65) 2.77 (0.51) 6.25 (0.65) 6.27 (0.62)

Baseline 1.00 (0.00) 1.38 (0.24) 1.15 (0.10) 1.58 (0.26) 2.27 (0.68)

Data are given as mean (standard error of the mean).

T. Straube et al. / NeuroImage 29 (2006) 125–135 127

ring in houses and cellars was used. The baseline control object

had a metallic bottom and was moved by a magnet on the same

grey background the spider had previously been filmed on. Both

objects were filmed from a distance of 1 m. The range and speed

of movements of the cylinder were matched as far as possible to

the movements of the spider. In the scanner, the stimuli were

presented via a back-projection screen on an overhead mirror

(screen size: 11.8 � 11.0 cm). Moving radius of both objects did

not exceed 2 cm. Subjects saw a continuous stream of 5 different

baseline clip sequences alternating with 4 different spider clip

sequences. Each sequence lasted 24 s. The videos showed always

the same spider or control object. Each sequence, however,

displayed different unpredictable movement patterns. During the

second scanning session (after therapy or waiting time), phobics

were also presented with a stream of 5 control and 4 spider

videos displaying the same spider and control object as during the

first scanning session, but movement of both objects were

different as compared to the presentations during the first

scanning session. All subjects were tested before the experiment

proper whether they were able to pay continuous attention to the

videos (using an example of the videos), which was confirmed

for all subjects After the scanning sessions, participants rated the

fear-induction, valence, and arousal during the presentation of the

spider and baseline clips using a 9 point Likert scale (fear: 1 = no

fear to 9 = strongest fear; valence: 1 = most pleasant to 9 = most

unpleasant; arousal: 1 = not arousing to 9 = most arousing). From

one subject of the waiting-list group, ratings after the second

scanning session could not be obtained due to technical problems.

Behavioral data were analyzed by means of repeated measures

analysis of variance (ANOVA) using SPSS (Version 10; SPSS,

INC., Chicago). For post-hoc comparisons, Bonferroni correction

was applied. A probability level of P < 0.05 was considered

statistically significant. All data are expressed as means T SEM

(standard error of mean).

Therapy and therapy outcome measurements

The cognitive-behavioral therapy was based mainly on the rapid

gradual exposure to the feared animals according to Ost (1989,

1996) during two sessions with a duration of 4–5 h each. In the

therapy group, the two sessions were conducted on succeeding days

to the first scanning session, while the waiting group received

therapy after the second scanning session. The CBT started with a

problem analysis and general education of the types and role of

misbeliefs about the dangerousness and properties of spiders and

the major psychological reasons for the maintenance of fear

reactions. Thereafter, the following therapeutic aims were stipu-

lated: (1) to hold a living tarantula for about 10 min; (2) to catch

moving and non-moving spiders at least 10 times with a glass at

different locations within the therapy room; (3) to catch any species

of spiders at least 3 times in the basement of the institute; (4) to

touch a rapid moving house spider. Furthermore, all four treatment

goals had to be fulfilled by subjects without strong feelings of

anxiety. At the end of each exposure, anxiety ratings had to be

below 50 on a scale that ranged from 0 (no fear at all) to 100

(strongest fear). Therapy was given in groups of 2 to 3 subjects by

advanced students of psychotherapy under supervision of experi-

enced psychologists (TS., SD., WHRM.). Gradual exposure started

with the presentation of spider pictures. Then, subjects were

exposed to the skin of a tarantula, followed by exposure to a real

tarantula, which, at the end, had to be touched and to be taken into

the hand. Thereafter, subjects were exposed to rapid moving spiders

whose size increased across succeeding exposures. This procedure

was continued until all therapeutic aims were reached. Participants

were encouraged to catch as many spiders as possible outside the

therapeutic setting and to ‘‘avoid’’ avoidance behavior. All subjects

of the therapy group responded successfully to the therapy and

reached the therapeutic aims. Additional outcome measurements

included ratings of the video presentations (see Results) and

posttherapy scores of the SPQ. For SPQ scores, the ANOVA

showed a significant main effects of scanning session [F(1,23) =

106.8, P < 0.0001] and group [F(1,23) = 27.7, P < 0.0001], and an

interaction of group by session [F(1,23) = 109.2, P < 0.0001]. Post-

hoc tests revealed that posttherapy scores of the TG (mean = 7.69,

SD = 5.38) were significantly reduced compared to pretherapy

scores (t = 19.52, P < 0.0001) and to postwaiting time scores of the

WG (mean = 22.42, SD = 3.6; t = 14.36, P < 0.0001).

fMRI

In the 1.5 T magnetic resonance scanner (‘‘Magnetom Vision

plus’’, Siemens, Medical Systems), one run of 65 volumes was

acquired per session using a T2*-weighted echo-planar sequence

(TE = 50 ms, flip angle = 90-, matrix = 64 � 64, FOV = 192 mm,

TR = 3.9 s). Phobics underwent two sessions separated by an

interval of 2 weeks, except of one TG subject, who had to be

measured with a 3 week interval due to illness. Control subjects

were examined only once. Each volume comprised 38 axial slices

(thickness = 2 mm, no gap, in plane resolution = 3 � 3 mm), which

were acquired using a tilted angel to reduce susceptibility artifacts

in inferior brain areas (Deichmann et al., 2003). The slices covered

the whole brain except for the most superior part of the parietal

cortex. Additionally, a high-resolution T1-weighted anatomical

volume was recorded. Preprocessing and analysis of the functional

data were performed using the software Brain Voyager 2000

(Version 4.9; Brain Innovation, Maastricht, The Netherlands). The

first four volumes of each run were discarded from the analysis to

ensure that steady state tissue magnetization was reached.

The volumes were realigned to the first volume in order to

minimize the effects of head movements on data analysis.

Succeeding data preprocessing comprised spatial (8 mm full-

width half-maximum isotropic Gaussian kernel) as well as

temporal (high pass filter: 3 cycles per run) smoothing.

Anatomical and functional images were coregistered and

T. Straube et al. / NeuroImage 29 (2006) 125–135128

normalized to the Talairach space (Talairach and Tournoux,

1988). Statistical analysis was performed by multiple linear

regression of the signal time course at each voxel. The expected

blood oxygen level-dependent (BOLD) signal change for the

spider videos (=predictor) relative to the baseline videos was

modeled by a canonical hemodynamic response function

(modified gamma function; delta = 2.5, tau = 1.25). Within-

and between-group statistical comparisons were conducted using

a mixed effect analysis, which considers inter-subject variance

and permits population-level inferences. In the first step,

voxelwise statistical maps were generated and the relevant,

planned contrasts of predictor estimates (beta-weights) were

computed for each individual. In the second step, a random

effect group analysis of these individual contrasts was

performed. The results of the analysis were considered statisti-

cally significant for t values with P < 0.005 within the a priori

defined ROIs (see Straube et al., 2004a,b). A cluster threshold

of 5 contiguously activated voxels was used to minimize false

positive results. Only activated voxels (according to the

Table 2

Significant activation to spider vs. control videos in all groups during the first sc

Region WG TG

x y z t value x

ROI

DLPFC R 51 27 20 7.30 51

L �31 40 35 7.02

ACC 3 2 43 7.74 6

Insula R 39 13 3 5.86 35

L �36 19 12 5.1 �36

Amygdala R

L

Parahippocampal g R 36 �47 �7 9.75 33

L �39

Fusiform gyrus R 21 �82 �15 16.83 39

L �33 �83 �14 5.63 �42

Thalamus R 20 �20 7 5.63 22

L �15

Exploratory

DLFC R 3 5 48 5.22 37

L �21 �14 62 8.61 �52

VLPFC R 45 34 13 7.65 54

L �54 32 10 5.59 �39

Precentral gyrus R 39 �9 43 11.57 56

L �41 11 6 7.81 �53

Postcentral gyrus R

Temporal gyri R 50 �62 �2 13.65 50

L �46 �62 �2 7.70 �46

Parietal gyri R 57 �34 28 10.78 24

L �35 �60 47 6.43

Cuneus R 26 �82 13 11.61 27

L �24 �93 0 11.98 �22

Precuneus R 15 �79 38 9.47 24

L �16 �82 38 6.44 �22

Lingual gyrus R 27 �86 �6 15.10 27

L �25 �91 �5 9.67 �22

Occipital gyri R 32 �82 0 16.96 29

L �36 �83 �11 10.44 �42

Basal ganglia R 30 �16 �5 6.76 30

L �30 �11 �3 7.19

DLFC, dorsolateral frontal cortex; DLPFC, dorsolateral prefrontal cortex; g, gyrus

coordinates of maximally activated voxel [Activation threshold: P < 0.005, unco

statistical and cluster thresholds) within the ROIs were used

for further analysis. The following ROIs were defined a priori:

DLPFC, anterior insula, ACC, amygdala, parahippocampal

gyrus, thalamus, and as extrastriate region the fusiform gyrus

(Dilger et al., 2003; Straube et al., in press). The ROIs were

defined using Talairach daemon software (http://www.ric.uthscsa.

edu/projects/talairachdaemon.html). For exploratory analysis out-

side of the ROIs (without cerebellum), thresholds were set at

P < 0.0005 (of at least 5 contiguous voxels).

Results

Behavioral data

First scanning session

Descriptive data for the ratings of valence, arousal, and fear

associated with the stimuli are given in Table 1. Valence and

arousal ratings of the videos showed a significant main effect of

anning session

Controls

y z t value x y z t value

37 20 6.18 57 28 18 3.43

5 46 5.37

�2 �3 6.37

19 12 5.10

24 �9 �11 3.90

�21 �5 �17 5.70

�51 �7 7.11 36 �28 �20 5.50

�35 �23 7.86 �39 �35 �20 9.08

�55 �19 15.49 24 �85 �14 13.24

�80 �14 17.08 �42 �59 �19 16.69

�23 11 6.57

�17 11 4.89 �18 �29 4 5.14

�8 46 6.25

1 39 7.25 �4 43 47 5.05

44 10 5.41 44 25 �4 5.64

25 10 5.35

1 40 5.35 54 �14 34 8.18

1 39 7.25 �45 �8 34 7.41

55 �16 38 7.12

�55 �11 14.45 44 �67 6 18.69

�67 6 16.43 �45 �74 �1 16.60

�57 43 8.23 38 �35 42 6.80

�30 �49 46 8.42

�77 11 8.24 28 �92 �1 7.70

�80 19 6.61 �25 �94 2 10.52

�66 39 10.68 21 �56 43 6.72

�74 25 5.85 �28 �49 48 8.42

�80 �5 22.65 27 �83 �4 20.11

�89 �5 11.36 �22 �84 �10 10.32

�81 �5 22.65 27 �88 �11 20.59

�79 �10 19.88 �43 �74 �3 28.36

�1 0 8.46

; L, left; R, right; VLPFC, ventrolateral prefrontal cortex; (x,y,z), Talairach

rr. (ROI), P < 0.0005, uncorr. (Exploratory), cluster �135 mm3].

Table 3

Significant differences between control subjects and phobicsa in brain

activation to spider vs. control videos during the first scanning session

Region of interest Controls > phobics Phobics > controls

x y z t value x y z t value

ROI

ACC 3 2 43 4.51

Insula R 38 4 0 4.03

L �36 19 12 3.39

Amygdala R

L �28 �8 �19 3.71

Parahippocampal g R 16 �12 �20 4.08

L �30 �11 �17 3.91

Exploratory

Precentral gyrus R 52 �16 35 5.03

Postcentral gyrus R 65 �11 18 4.48

Lingual gyrus L �19 �71 1 4.97

DLFC, dorsolateral frontal cortex; DLPFC, dorsolateral prefrontal cortex;

g, gyrus; L, left; R, right; VLPFC, ventrolateral prefrontal cortex; (x, y, z),

Talairach coordinates of maximally activated voxel [Activation threshold:

P < 0.005, uncorr. (ROI), P < 0.0005, uncorr. (Exploratory), cluster �135

mm3].a There was no significant difference in activation between the TG and

WG.

T. Straube et al. / NeuroImage 29 (2006) 125–135 129

group [valence: F(2,36) = 19.37, P < 0.0001; arousal: F(2,36) =

46.73, P < 0.0001] and object [valence: F(1,36) = 136.31, P <

0.0001; arousal: F(1,36) = 251.89, P < 0.0001] and a significant

interaction of group by object [valence: F(2,36) = 41.24, P <

0.0001; arousal: F(2,36) = 50.15, P < 0.0001]. Post-hoc analysis

revealed that both groups of phobics rated spider videos as

significantly more unpleasant and arousing than control subjects

(TG vs. CG: valence: t = 9.85, P < 0.0001; arousal: t = 12.64,

P < 0.0001; WG vs. CG: valence: t = 9.59, P < 0.0001;

arousal: t = 11.50, P < 0.0001), while no significant differences

between groups were found for the control videos. There was

also no significant difference in the valence and arousal ratings

Fig. 1. Increased activation of ACC (A, x,y,z = 2,8,41) and insula (B, x,y,z = 40,11

subjects (CS) during the first scanning session. Statistical parametric maps ( P < 0

plots show the contrasts of parameter estimates (spider vs. baseline; mean T SEM

of spider videos between both groups of phobics (valence: t =

0.035, P > 0.5; arousal: t = 0.57, P > 0.5).

For fear ratings, only phobics were included in the ANOVA,

because controls did not show any variance or only marginal

variance in their fear ratings of the control objects and spiders,

which were rated as not fear-inducing at all (see Table 1). In

phobics, the ANOVA showed a significant main effect of object

[F(1,23) = 125.0, P < 0.0001], which was based on increased

ratings for spider videos as compared to control videos (t = 11.40,

P < 0.0001).

Second scanning session

Descriptive data for the ratings of valence, arousal, and fear

in response to the stimuli are given in Table 1. Ratings of the

clips indicated a significant main effect of group [valence:

F(1,22) = 19.10, P < 0.0001; arousal: F(1,22) = 34.67, P <

0.0001; fear: F(1,22) = 16.32, P < 0.005], object [valence:

F(1,22) = 33.58, P < 0.0001; arousal: F(1,22) = 58.84, P <

0.0001; fear: F(1,22) = 42.58, P < 0.0001], and a significant

interaction of group by object [valence: F(1,22) = 10.24, P <

0.004; arousal: F(1,22) = 12.43, P < 0.005; fear: F(1,22) =

7.68, P < 0.05]. Post-hoc analysis revealed that the WG

compared to the TG rated spiders as significantly more

unpleasant (t = 7.49, P < 0.0001), arousing (t = 7.23, P <

0.0001), and fear-inducing (t = 4.41, P < 0.0001), while no

significant group difference was found for the control object

(valence: t = �0.33, P > 0.5; arousal: t = 2.23, P > 0.05; fear:

t = 1.63, P > 0.1).

fMRI data

First scanning session

The ROI analysis for the contrast spider > baseline revealed

increased brain responses in several areas in control subjects

and phobics (see Table 2). However, only phobics showed

activation in the insula and ACC, while amygdala activation

was restricted to control subjects (see Table 2). For all other

ROIs, increased activation to spider videos was found in all

,3) to spider vs. control videos in phobic subjects (PS) compared to control

.005) are overlaid on a T1 scan (radiological convention: left = right). The

for maximally activated voxel in the ROI).

T. Straube et al. / NeuroImage 29 (2006) 125–135130

groups (see Table 2). Between-group comparisons did not reveal

any significant differences in activation of the ROIs between

both groups of phobic subjects. When activation in a combined

group of phobics was compared with the non-phobic control

subjects, greater responses in the left and right anterior insula

(Table 3; Fig. 1), and in the ACC (Table 3; Fig. 1) were

detected in phobics, while controls showed increased activation

in the left amygdala and bilaterally in the parahippocampal

gyrus (Table 3). Exploratory analysis revealed activation in

several areas in all groups, above all in primary and secondary

visual cortex (Table 2). Between-group comparisons did not

reveal significant differences between both groups of phobic

subjects in these regions. Phobics as compared to non-phobic

control subjects exhibited greater responses in the left extras-

triate visual cortex (lingual gyrus; see Table 3), while control

subjects showed increased activation in the pre- and postcentral

gyri (see Table 3).

Table 4

Significant activation to spider vs. control videos in phobics during the second s

Region WG TG

x y z t value x

ROI

DLPFC R 51 31 20 6.00 43

L �32 45 43 5.94 �51

ACC �6 11 37 4.84

Insula R 39 10 7 5.24 38

L �40 18 7 5.02

Parahippocampal g R 35 �35 �23 10.89 35

L �40 �35 �20 5.19

Fusiform gyrus R 30 �42 �19 12.29 19

L �36 �73 �14 7.89 �36

Thalamus R 14 �17 7 7.48

L �15 �20 10 5.53 �24

Exploratory

DMPFC R

L �11 47 37 4.11

DLFC R 42

L �16 �9 65 5.92 �48

VLPFC R 51 27 15 4.94 41

L �52 45 13 6.33

Precentral gyrus R 47 �5 34 8.92 26

L �36 9 36 7.11 �46

Postcentral gyrus R 45 �26 35 6.34

L �57 �23 36 6.28

Temporal gyri R 38 �72 0 10.18 44

L �52 �65 3 8.40 �48

Parietal gyri R 30 �67 46 16.25 35

L �38 �55 55 7.45 �33

Cuneus R 26 �82 13 8.33 21

L �19

Precuneus R 27 �58 50 10.63 21

L �21

Lingual gyrus R 30 �78 �5 8.66 18

L �25 �88 �6 9.38 �22

Occipital gyri R 38 �73 0 10.18 31

L �25 �88 �7 9.38 �36

Basal ganglia R 14 1 16 7.73

L �27 1 1 6.08 �21

DLFC, dorsolateral frontal cortex; DLPFC, dorsolateral prefrontal cortex; g, gyrus

coordinates of maximally activated voxel [Activation threshold: P < 0.005, uncoa There was no significant result for the contrast TG > WG, except for the cun

Second scanning session

In contrast to the first scanning session, where no differences

between the TG and WG were detected in the ROI analysis,

pronounced differences in brain activation emerged between both

groups at the second scanning time point. The TG showed an

absence of activation to spider videos in the ACC and only a small

cluster of activation in the ventral anterior insula, while the WG

exhibited pronounced responses bilaterally in the insula and in the

ACC (Table 4; Fig. 2). Between-group comparisons demonstrated

stronger activation bilaterally in the insula, thalamus, and in the

ACC in the WG compared to the TG (Table 2; Fig. 2), while the TG

did not exhibit higher activation than the WG in any ROI. In

exploratory analysis, increased activation in the WG compared to

the TG was detected in the left dorsomedial prefrontal cortex

(DMPFC, see Table 4) and left precuneus (Table 4). The TG as

compared to the WG showed greater responses in the right cuneus

(see Table 4).

canning session

WG > TGa

y z t value x y z t value

19 24 5.61

31 24 6.33

�3 11 37 3.66

19 12 5.33 38 4 �2 3.57

�31 5 �14 4.36

�35 �20 6.55

�82 �14 18.85

�82 �14 14.46

17 �14 11 4.48

�26 6 5.28 �9 �13 11 3.71

�16 43 34 4.14

2 40 5.98

0 39 6.91

21 13 5.11

�12 52 6.30

1 37 6.91

�71 2 13.27

�68 �2 11.51

�39 39 9.03

�47 46 6.73

�84 6 9.92

�81 28 8.53

�63 46 8.39

�80 29 8.53 �18 �68 7 4.44

�81 �14 18.85

�84 �9 10.57

�78 �3 17.82

�85 �11 15.58

�3 �3 7.11

; L, left; R, right; VLPFC, ventrolateral prefrontal cortex; (x,y,z), Talairach

rr. (ROI), P < 0.0005, uncorr. (Exploratory), cluster �135 mm3].

eus (x,y,z = 29, �80, 30; t = 5.07).

Fig. 2. Increased activation of ACC (A, x,y,z = 0,13,40) and insula (B, x,y,z = 40,8,�4) to spider vs. control videos in the waiting-list group (WG) compared to

the therapy group (TG) during the second but not the first scanning session. Statistical parametric maps ( P < 0.005) for the second scanning session (WG >

TG) are overlaid on a T1 scan (radiological convention: left = right). The plots show the contrasts of parameter estimates for both scanning sessions (spider vs.

baseline; mean T SEM for maximally activated voxel in the ROI).

T. Straube et al. / NeuroImage 29 (2006) 125–135 131

For those ROIs where decreased activation was found in the TG

compared to the WG, we compared the second with the first

scanning session in the TG using one-tailed t tests. These

comparisons confirmed significant reductions of activation in the

ACC [Talairach coordinates (x,y,z) and statistical values of peak

activation: �3, 8, 34, t = 4.20, P < 0.005], left insula [Talairach

coordinates (x,y,z) and statistical values of peak activation: �39,

22, 7, t = 3.31, P < 0.005], and left thalamus [Talairach coordinates

(x,y,z) and statistical values of peak activation: �9, �17, 11, t =

3.90, P < 0.005]. For the ROIs with differential activation between

the TG and WG, we also contrasted BOLD responses of each

phobic group with BOLD responses of the control subjects from

the first scanning session. These comparisons showed no signifi-

cant differences between control subjects and the TG, while the

WG exhibited increased activation in the right insula [Talairach

coordinates (x,y,z) and statistical values of peak activation: 38, 4,

0, t = 3.59, P < 0.005] and the ACC [Talairach coordinates (x,y,z)

and statistical values of peak activation: 15, 23, 31, t = 4.13, P <

0.005], suggesting a normalization of brain activation in the TG but

not in the WG.

Discussion

The present study revealed that the processing of phobogenic

threat is associated with increased activation in the insula and ACC

in subjects suffering from specific phobia. Most importantly,

successful cognitive-behavioral therapy led to a reduction of

hyperactivity within these brain regions. Thus, in comparison to

subjects of the untreated WG, subjects of the treated TG showed a

marked attenuation of phobic symptomatology and of responses in

the insula and ACC during the second scanning session.

The activation pattern observed in the insula fits theoretical

accounts and increasing empirical evidence that this brain region is

important for pathological but also non-pathological emotional

experiences (for reviews see Critchley, 2003; Phan et al., 2002;

Reiman, 1997). For example, involvement of the insula has been

described in spider phobics in response to real or imagined feared

animals (Rauch et al., 1995; Reiman, 1997), spider pictures (Dilger

et al., 2003; Carlsson et al., 2004; Straube et al., in press), and

spider-related words (Straube et al., 2004b). Significant insula

activation was also demonstrated in social phobics and healthy

subjects during the processing of angry faces (Straube et al.,

2004a), and during symptom provocation in other anxiety

disorders (Osuch et al., 2001; Rauch et al., 1997; Reiman, 1997).

Significantly increased responses of the insula associated with

provocation of clinically relevant anxiety symptoms were reported

by Rauch et al. (1997) when using pooled data across different

anxiety disorders. Furthermore, in healthy subjects, the insular

cortex has been shown to be involved in the recognition and

experience of aversive states such as disgust, fear, or pain (e.g.,

Critchley et al., 2002; Peyron et al., 2002; Phillips et al., 1997;

Reiman, 1997). The insular cortex is also activated by interocep-

tive stimulation and correlates with autonomic activity (Aziz et al.,

2002; Critchley et al., 2003). Above all, the work of Critchley et al.

(2001, 2002) provided strong evidence that the insula might

support the interaction of perceived threat signals and bodily states

of arousal leading to subjective emotional experiences such as the

feeling of fear.

However, although a growing number of studies strongly

implicate a critical involvement of the insula in the processing of

phobia-related threat, several studies failed to find support for this

assumption (e.g., Fredrikson et al., 1993, 1995; Tillfors et al.,

2002; Wik et al., 1993, 1997). Such discrepancies between studies

require further research, in which experimental conditions should

be systematically varied. As suggested elsewhere (Straube et al.,

2004a, in press), an important aspect might be the amount of

subjects’ attentional resources while threatening stimuli are

present. For example, attentional distraction by concurring

cognitive tasks reduces insula responses to threat (e.g., Anderson

et al., 2003; Critchley et al., 2002; Gorno-Tempini et al., 2001;

Straube et al., 2004a). Recently, we showed that activation of the

insula and ACC was even blocked when spider phobics were

requested to solve a demanding cognitive task that was displayed

T. Straube et al. / NeuroImage 29 (2006) 125–135132

in the foreground of phobia-relevant pictures (Straube et al., in

press). Similarly, high processing demand associated with the

coordination of ongoing active behavior (e.g., Tillfors et al., 2002)

could also attenuate or suppress activation of the insula. Finally,

attentional distraction that is self-induced as a kind of avoidance or

coping behavior might lead to an attenuation of insula responses

(see also Paquette et al., 2003).

Even more clearly as for the insula, responses in the ACC were

normalized in the TG at the second scanning time point, whereas

the waiting-list group did not show such an effect. Activation of the

ACC during threat processing has been shown in specific phobia

and in other anxiety disorders (Rauch et al., 1995, 1997; Osuch et

al., 2001; Boshuisen et al., 2002; Pissiota et al., 2002; Aouizerate

et al., 2004; Carlsson et al., 2004). Remarkably, direct stimulation

of the ACC evokes anxiety in humans (Laitinen, 1979) suggesting

a functional relevance of ACC activity in anxiety provocation

studies. In healthy subjects, involvement of the ACC, especially of

its rostral part, has been repeatedly described during the emotional

evaluation of threatening and other salient emotional stimuli (for

reviews see Bush et al., 2000; Phan et al., 2002). Several studies

reported also emotion-related activation of dorsal ACC (for review

see Phan et al., 2002), which has been implicated in cognitive

operations such as attentional control or response selection (for

review see Bush et al., 2000). Recently, Carlsson et al. (2004)

demonstrated augmented rCBF in dorsal ACC to phobogenic vs.

other fear-related pictures in spider phobics during passive view-

ing, suggesting a stimuli-specific, phobia-related increase of

activation in this area. In the present study, ACC activation was

also found rather in the dorsal part of the ACC. Furthermore, the

dorsal ACC has been implicated in the elicitation and control of

sympathetic autonomic arousal (Critchley et al., 2003). Thus, the

ACC activation observed in the present study might be associated

with the sympathetic hyperarousal that has been repeatedly

described to be a main physiological feature during the processing

of phobogenic stimuli in animal phobics (e.g., Hamm et al., 1997;

Globisch et al., 1999; Cuthbert et al., 2003). Successful therapy

strongly reduces these responses (e.g., Antony et al., 2001; Bracht

et al., 1999; Gutberlet and Miltner, 1999, 2001; Hellstrom and Ost,

1995, 1996; Ost, 1996; Ost et al., 2001), which suggests that the

therapy-induced elimination of ACC activation might be coupled

to attenuated fear-associated arousal.

Besides for the insula and ACC, we found stronger activation in

extrastriate visual cortex in phobics than in controls during the first

scanning session. This finding is in accordance with several reports

showing that the processing of threatening visual stimuli is

associated with increased activation in extrastriate visual areas in

phobics (Dilger et al., 2003; Fredrikson et al., 1993, 1995; Straube

et al., 2004a; Wik et al., 1993; but see Paquette et al., 2003) and

healthy controls (e.g., Keightley et al., 2003; Vuilleumier et al.,

2001). However, we found no clear therapy-effect in visual areas.

This suggests that increased activation in these regions is not

necessarily coupled to the fear-relevance of the visual stimulus

during sustained stimulus presentation. Thus, the role of other

factors, such as novelty, attention, and general salience of stimuli,

or an interaction of fear with these factors has to be taken into

account (see also Stark et al., 2004; Ishai et al., 2004).

In the DMPFC and thalamus, the WG showed stronger

activation than the TG at the second scanning time point, whereas

no differences of activation were observed in the first scanning

session. Increased responses in DMPFC has been shown in phobics

during the evaluation of threat-relevant stimulation (Carlsson et al.,

2004; Rauch et al., 1995; Stein et al., 2002; Straube et al., 2004a).

This region has been implicated in anxiety and the general

assessment of the emotional significance of stimuli (Phan et al.,

2002; Simpson et al., 2001). Evidence for a significantly increased

activation of the thalamus during threat is less consistent (for

review see Phan et al., 2002) and seems to be more strongly

associated with the internal induction of emotion during recall or

imagery (e.g., Rauch et al., 1997). The assumed role of the

DMPFC and thalamus in threat processing is partially supported by

the therapy effects found in these areas in the present study.

However, the data for the first scanning session do not confirm this

hypothesis. At least, the observed differences between treated and

untreated phobics indicate that augmented responses of the

DMPFC and thalamus correlate with the maintenance of anxiety

during a repeated confrontation with phobia-related stimuli (see

also Furmark et al., 2002).

In contrast to the study by Paquette et al. (2003), we did not

find activation in DLPFC or parahippocampal gyrus in phobics as

compared with healthy subjects. In parahippocampal gyrus, rather

less activation was detected in phobics. Furthermore, we found no

evidence of a therapy effect in these areas. Activation of the

DLPFC during anxiety provocation paradigms was proposed to

reflect coping strategies and inhibitory control but also anticipatory

anxiety or worrying (e.g., Johanson et al., 1998; Paquette et al.,

2003; Reiman, 1997). Interestingly, a study by Johanson et al.

(1998) suggested that rCBF in prefrontal areas in phobics might

depend on the amount of panic during phobogenic stimulation. In

this study, an increase of prefrontal rCBF was associated with a

higher level of control of anxiety responses, while a decrease was

observed when subjects experienced panic. Therefore, it seems

reasonable that studies with inhomogeneous groups of phobic

subjects in respect to the individual coping or phobic behavior

should not obtain consistent results for the DLPFC.

The other region for which Paquette et al. found a therapy-

induced reduction of hyperactivity was the parahippocampal gyrus.

This area has been strongly associated with memory functions

(Brewer et al., 1998; Wagner et al., 1998), particularly during

processing of emotional stimuli (Kilpatrick and Cahill, 2003).

Although there is evidence for increased parahippocampal activa-

tion in phobics during threat processing (Paquette et al., 2003; Stein

et al., 2002, Straube et al., 2004a), several studies with animal

phobics did not report activation or even deactivation in this region

(e.g., Dilger et al., 2003; Fredrikson et al., 1995; Rauch et al., 1995;

Wik et al., 1993). Eventually, the discrepant findings could be

explained by assuming an inverted U-function of activation

depending on the amount of stress (see Diamond et al., 1992;

Pavlides et al., 1993). Strongest activation would then occur during

an optimal level of emotional arousal (see also Straube et al., 2003),

while high levels of stress or anxiety would decrease neuronal

activity. However, this idea remains to be tested in future studies by

using samples with high variance in emotional reactions or by using

parametric designs allowing the induction of different levels of

anxiety.

The absence of activation in animal phobics in the other ROI in

the medial temporal lobe, the amygdala, is in line with previous

symptom provocation studies that used stimulation paradigms such

as imagery (Rauch et al., 1995), video presentation (Mountz et al.,

1989; Fredrikson et al., 1993, 1995; Wik et al., 1993, 1997;

Paquette et al., 2003), prolonged picture presentation in blocked

designs (Pissiota et al., 2003), or in vivo confrontation (Reiman,

1997). These consistent outcomes, therefore, indicate that sus-

T. Straube et al. / NeuroImage 29 (2006) 125–135 133

tained phobia-related stimulation in specific phobia (in contrast to

social phobia, see Furmark et al., 2002; Tillfors et al., 2001, 2002)

does not seem to be associated with amygdalar activity. The

amygdala, however, has been implicated in the initial processing of

threat and the induction of rapid fear responses (Dilger et al., 2003;

Carlsson et al., 2004; Ohman and Mineka, 2001). In recent event-

related fMRI studies, we showed activation of the amygdala in

spider phobics during brief presentations of spider as compared to

phobia-unrelated pictures (Dilger et al., 2003; Straube et al., in

press). Most importantly, we also demonstrated that amygdala

activation is more pronounced during attentional distraction than

during the attended processing of the phobic stimuli (Straube et al.,

in press). Similar effects of amygdala inhibition during explicit or

direct as compared to implicit processing of threat-related stimuli

were also described by other studies that investigated anxiety

patients and healthy subjects (Keightley et al., 2003; Lange et al.,

2003; Straube et al., 2004a). Furthermore, several studies have

reported an inverse correlation between activation in ACC/medial

prefrontal cortex and amygdala (e.g., Keightley et al., 2003;

Ochsner et al., 2004; Shin et al., 2004; Taylor et al., 2003),

suggesting that the medial frontal cortex might exert inhibitory

control over the amygdala (see also Quirk et al., 2003). Somewhat

unexpectedly, amygdala activation was observed in controls in the

present study. We interpret this effect as normal response to more

interesting/relevant and also perceptually different (especially in

respect to the movements of the spider extremities) stimuli in

contrast to the baseline videos. These factors together with novelty

aspects may lead to amygdala activation in controls (see also

Schwartz et al., 2003; Wright et al., 2003). The amygdala of

phobics might have been inhibited for example by influences of the

ACC during the first scanning (see above). However, if this was

the case, there should be amygdala activation due to the absence of

ACC activity in the therapy group during the second scanning (at

least compared to the WG). On the other hand, this expectation is

based on the assumption that the ‘‘normal’’ activation in healthy

controls is stable over time. A limitation of our study is that we

cannot answer this question since healthy controls were measured

only once. Thus, further studies are needed to reveal the

mechanisms by which amygdala activation is modulated during

sustained symptom provocation in specific phobia.

In conclusion, the observed pattern of phobia-associated brain

activation and therapy-related decrease of hyperactivation suggests

an important role of the ACC and insula in the effective treatment

of specific phobia. Furthermore, successful cognitive-behavioral

therapy led also to reduced activation in thalamus and DMPFC in

the treated as compared to the untreated phobic subjects,

indicating that the reduction of fear is associated with decreased

activity in these areas. In accordance with previous studies, we

found no evidence of amygdala involvement in sustained

processing of phobia-related stimuli. Future studies should

investigate whether initial and rather automatic brain responses

to phobogenic stimuli, for example in the amygdala, will be also

modified by psychotherapy.

Acknowledgments

The study was supported by the Deutsche-Forschungsgemein-

schaft (DFG project number: Mi 265/6-1; Mi 265/6-2). We are

thankful to Mike Hammer for expert technical assistance and help

during acquisition and analysis of the data.

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