Journal of Anxiety Disorders 28 (2014) 276–279

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Journal of Anxiety Disorders

Effects of cognitive behavior therapy on regional brain volume in spider-phobic patients: Preliminary results Anne Schienle ∗ , Albert Wabnegger, Wilfried Scharmüller Department of Clinical Psychology, University of Graz, Universitätsplatz 2/III, A-8010 Graz, Austria

a r t i c l e

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Article history: Received 12 November 2013 Received in revised form 9 January 2014 Accepted 10 January 2014 Keywords: Voxel-based morphometry Spider phobia Cognitive behavior therapy Amygdala

a b s t r a c t Successful cognitive behavior therapy (CBT) for spider phobia is able to change patients’ brain activation during visual symptom provocation. The present voxel-based morphometry study investigated whether this therapy approach can additionally affect brain structure. We analyzed gray matter volume of 12 spider-phobic patients prior to CBT and in a six-month follow-up investigation, and contrasted the results with data from 13 non-phobic controls. CBT provoked a dramatic decrease in syndrome severity in the clinical group as indexed by self-report and by a behavioral approach test. This was accompanied by a reduction of left supplementary motor area volume, which was correlated with the reduction of symptom severity. The therapy-related decrease of left amygdala volume was marginally significant. Nevertheless, in both sessions the patients were characterized by increased amygdala volume relative to controls. Our findings have to be considered preliminary and need replication in a bigger sample. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction Cognitive behavior therapy (CBT), including graduate exposure and cognitive restructuring, is the most effective intervention method for individuals suffering from spider phobia. Primary goals of this type of treatment are to reduce phobic anxiety, to eliminate avoidance and to alter negative automatic thoughts about the animal (Choy, Fyer, & Lipsitz, 2007). Successful CBT is able to change brain activation during visual symptom provocation in spider-phobic patients. A first waiting-list controlled neuroimaging investigation on short-term effects of CBT observed reduced activation of the anterior cingulate cortex (ACC) and the insula (Straube, Glauer, Dilger, Mentzel, & Miltner, 2006). This therapy-related activation decrease was interpreted to reflect normalization of somatic arousal. Schienle, Schäfer, Hermann, Rohrmann, and Vaitl (2007) conducted one-session CBT and taught spider-phobic patients to hold a living spider in their hands, which was associated with increased medial orbitofrontal cortex (OFC) activation directly after the therapy. The enhanced medial OFC activation during the viewing of spider pictures continued to be present in a 6-month follow-up investigation in the patients who were still able to show the learned approach behavior. Considering that the OFC is central for the relearning of stimulus-reinforcement

∗ Corresponding author at: Department of Psychology, University of Graz, Universitätsplatz 2/III, A-8010 Graz, Austria. Tel.: +43 316 380 5086; fax: +43 316 380 9808. E-mail address: [email protected] (A. Schienle). 0887-6185/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.janxdis.2014.01.002

associations (Kringelbach & Rolls, 2004), the main therapy effect was understood as cognitive restructuring with a new valence assignment to the phobic stimulus. Interestingly, only one study observed a reduction of phobia-related amygdala hyperactivation directly after exposure therapy (Goossens, Sunaert, Peeters, Griez, & Schruers, 2007). The mentioned brain imaging studies demonstrate that CBT is able to change brain activation of the afflicted patients in disorderrelevant situations. Whether this psychotherapy approach can also affect brain structure has not been studied thus far. We analyzed data acquired in two previously published magnetic resonance imaging studies on CBT effects in spider phobia (Schienle et al., 2007; Schienle, Schäfer, Stark, & Vaitl, 2009). We investigated whether those brain structures that have shown functional changes due to CBT (ACC, insula, amygdala, medial OFC) would also undergo structural changes. 2. Methods 2.1. Subjects We analyzed data from 12 successfully treated spider-phobic females (M = 27.17 years, SD = 10.13), who had participated in an fMRI study on short-term and long-term CBT effects (Schienle et al., 2007, 2009). Prior to CBT the females had suffered from spider phobia according to DSM-IV (APA, 1994) since their childhood (and did not suffer from any other mental disorder). Thirteen non-phobic women with a comparable mean age (M = 26.38 years, SD = 5.75; t(23) = −.24, p = .81) also agreed to participate in the investigation.

A. Schienle et al. / Journal of Anxiety Disorders 28 (2014) 276–279

All subjects were medication-naive and right-handed. They gave written informed consent after the nature of the experiment had been explained to them. The ethics committee of the German Society of Psychology had approved this study.

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insula and medial OFC. The ROI masks for the present analysis were created using the WFU Pickatlas (WFU Pickatlas v2.4; Wake Forest University School of Medicine) and are based on the automated anatomical labeling (AAL) template (Tzourio-Mazoyer et al., 2002). Voxel intensity peaks were considered significant when p < .05 and marginally significant when p < .10 (corrected for family-wise error (FWE); small volume correction).

2.2. Procedure The course of the investigation has been previously described in detail (Schienle et al., 2007, 2009). We analyzed brain-structural data that had been acquired directly before CBT (one-session exposure therapy according to Öst (1989)), and during a six-month follow-up investigation. We studied those patients, who were successfully treated and had continued to practice their approach behavior toward spiders over the half-year interval. The controls also underwent two MRI sessions separated by six months. All participants had answered the spider phobia questionnaire (SPQ; Klorman, Weerts, Hastings, Melamed, & Lang, 1974) and had performed a behavioral approach test (BAT) before CBT and in the follow-up session. For the BAT, a spider was put in a transparent box and placed 5 m in front of the participants, who were then instructed to approach the box. The subjects received points (range: 1–12) based on their approach behavior (1 point = no movement, 12 points = removing the spider from the box and holding it in their hands for 20 s).

3. Results 3.1. Self-report and behavioral approach test The patients had an average SPQ score of M = 21.91 (SD = 1.76) prior to CBT. This score was significantly reduced in the follow-up investigation (M = 4.36, SD = 2.06; t(11) = 20.48, p < .001). The SPQ score of the controls did not change from the first (M = 2.41, SD = 1.68) to the second assessment (M = 1.83, SD = 1.33, t(12) = 1.54, p = .15). The patients showed a significant increase in approach behavior over time (before CBT: M = 4.5 (SD = 1.8); follow-up session: M = 12 (0.0), t(12) = 12.1, p < .001), whereas the control subjects obtained a BAT score of 12 in both sessions. 3.2. VBM data The group comparison indicated that the patients were characterized by a greater GMV of the bilateral amygdala prior to CBT as well as in the 6-month follow-up investigation. The reversed contrast (controls > patients) revealed no statistically significant results. The within-group analyses for the selected ROIs detected a marginally significant reduction of left amygdala volume in the patient group (Table 1 and Fig. 1). Additional exploratory analyses with further ROIs that are usually activated during visual symptom provocation in spider phobia (supplementary motor area (SMA), lateral OFC) showed that in the patient sample the SMA volume decreased over time (Table 1). The volume reduction of this ROI was correlated with the degree of symptom reduction (spider phobia questionnaire (SPQ) score prior CBT minus follow-up) as determined by means of simple regression (MNI coordinates: −3,30,64, t = 6.59, p(FWE) = .021). The group contrasts (patients < > controls) for SMA and OFC were nonsignificant prior as well as post CBT.

2.3. VBM analysis Brain imaging data were analyzed using SPM8 (Wellcome Trust Centre for Neuroimaging) including the VBM8 toolbox (revision 343, http://dbm.neuro.uni-jena.de/vbm) for voxel-based morphometry in order to gain voxel-wise comparisons of gray matter volume (GMV). Anatomical scans were segmented into gray matter, white matter, and cerebrospinal fluid partitions. An optimized blockwise non-local means de-noising filter, a Hidden Markov Random Field approach, partial volume estimates, and normalization to MNI space by high-dimensional warping (DARTEL) with a standard template included in the VBM8-toolbox were used for pre-processing (final resolution: 1.5 mm × 1.5 mm × 1.5 mm). A Jacobian modulation for non-linear normalization was applied to correct for differences in head sizes and to obtain brain volume. Smoothing was executed with a Gaussian kernel with a full width at half maximum (FWHM) of 10 mm. Statistical analyses were carried out using random effects models. To test for differences in GMV between patients and controls a two sample t-test was conducted. To test for GMV changes over time (GMV prior therapy vs. GMV in the 6-month follow-up investigation) we computed one-sample t-tests separately for each group. The preprocessed gray matter images were thresholded with an explicit mask (threshold >0.2) to restrict analysis to gray matter. The following regions of interest (ROIs) were selected based on previous fMRI studies on CBT effects in spider phobia (Goossens et al., 2007; Schienle et al., 2007; Straube et al., 2006): ACC, amygdala,

4. Discussion This study revealed increased bilateral amygdala volume in spider-phobic patients relative to non-phobic controls prior to cognitive behavior therapy (CBT). The amygdala is a key brain structure implicated in normal fear processing as well as in phobic responses (e.g., Goossens et al., 2007). Previous MRI studies observed a positive association between gray matter volume (GMV) of the amygdala and anxiety proneness (e.g., Van der Plas,

Table 1 Gray matter volume differences between patients and controls and changes over time. Region

x

y

z

Before CBT: Patients > Controls L Amygdala R Amygdala

H

−16 22

−3 2

−14 −17

Six-month after CBT: Patients > Controls L Amygdala R Amygdala

−16 22

−4 −1

Before CBT > Six-month after CBT: Patients L SMA L Amygdala

−3 −16

−3 −3

Cluster size (voxel)

T

p(FWE)

492 468

3.96 3.46

.007 .020

−15 −12

485 579

3.73 5.37

.015 .001

57 −12

100 62

5.66 3.07

.022 .088

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A. Schienle et al. / Journal of Anxiety Disorders 28 (2014) 276–279

Fig. 1. Difference in amygdala volume between patients and controls (upper panel) and supplementary motor area volume in patients before and after cognitive behavior therapy (CBT).

Boes, Wemmie, Tranel, & Nopoulos, 2010). However, Fisler et al. (2013) identified reduced left amygdala GMV in spider-phobic women. It is possible that factors such as symptom duration and comorbidity contributed to the observed variance of amygdala structure. In the present study, only those patients were included, who suffered from spider phobia and no other mental disorder. The functional MRI part of the present investigation on visual symptom provocation had demonstrated increased amygdala activation in the patients relative to the controls prior to treatment. Following successful exposure therapy, amygdala activation did not show statistically significant changes (Schienle et al., 2007). This also applied to amygdala structure. However, we observed a marginally significant reduction of left amygdala volume due to CBT. This change did not affect observed group differences. The patients showed an increased bilateral amygdala volume directly before the therapy and also six months later relative to non-phobic controls. As a short-coming of the study we have to mention the small sample size limiting statistical power. Moreover, the use of a longer follow-up interval seems to be desirable as the spider-phobic

behavior prior to CBT had been shown by the afflicted patients for many years since childhood. Thus, only extended practice of approach behavior toward spiders might lead to structural changes of the amygdala. Interestingly, we observed one exploratory effect, which consisted of a CBT-related decrease in SMA volume. The SMA is involved in the preparation of motor responses in general and specifically in flight tendencies in spider phobia (e.g. Schienle et al., 2007). The elimination of avoidance and the acquisition of controlled approach behavior taught in the therapy program (holding a spider in the hands) might be the basis of this structural SMA change. This interpretation is supported by the conducted regression analysis. In the clinical group SMA volume reduction correlated with symptom reduction (as indexed by the spider phobia questionnaire). Previous MRI studies already demonstrated that behavioral trainings can alter brain areas involved in motor activity (e.g. Draganski, Gaser, Busch, Schuierer, & Bogdahn, 2004). In conclusion, this VBM study indicated that successful cognitive behavior therapy is able to change regional brain volume. The results are preliminary and need replication in a bigger patient sample.

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Conflict of interest The authors declare no conflict of interest. References Choy, Y., Fyer, A. J., & Lipsitz, J. (2007). Treatment of specific phobia in adults. Clinical Psychology Review, 27, 266–286. Draganski, B., Gaser, C., Busch, V., Schuierer, G., & Bogdahn, U. (2004). Neuroplasticity: changes in grey matter induced by training. Nature, 427(6972), 311–312. Fisler, M. S., Federspiel, A., Horn, H., Dierks, T., Schmitt, W., Wiest, R., et al. (2013). Spider phobia is associated with decreased left amygdala volume: a cross-sectional study BMC. Psychiatry, 13, 70. Goossens, L., Sunaert, S., Peeters, R., Griez, E. J. L., & Schruers, K. R. J. (2007). Amygdala hyperfunction in phobic fear normalizes after exposure. Biological Psychiatry, 62, 1119–1125. Klorman, R., Weerts, T. C., Hastings, J. Y., Melamed, B. G., & Lang, P. J. (1974). Psychometric description of some specific-fear questionnaires. Behavior Therapy, 5, 401–409.

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