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Amygdalar volumetric correlates of social anxiety in offspring of parents with bipolar disorder
Psychiatry Research: Neuroimaging 234 (2015) 252–258
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Amygdalar volumetric correlates of social anxiety in offspring of parents with bipolar disorder Min-Hyeon Park a, Amy Garrett b, Spencer Boucher b, Meghan Howe b, Erica Sanders b, Eunjoo Kim c, Manpreet Singh b, Kiki Chang b,n a
Department of Psychiatry, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA c Department of Psychiatry and Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea b
art ic l e i nf o Article history: Received 15 June 2014 Received in revised form 17 September 2015 Accepted 25 September 2015 Available online 28 September 2015 Keywords: Risk Affect Child Adolescence Family
a b s t r a c t The prevalence of social anxiety disorder is high in offspring of parents with bipolar disorder (BD) and anxiety may be a significant risk factor in these youth for developing BD. We compared social anxiety symptoms between BD offspring with mood symptoms (high-risk group for developing BD I or II: HR) and healthy controls (HC). We also explored the correlations between the amygdalar volumes and social anxiety symptoms in the HR group with high social anxiety scores (HRHSA) due to the potential involvement of the amygdala in the pathophysiology of both BD and social anxiety. Youth participating in the study included 29 h and 17 HC of comparable age and gender. To assess social anxiety symptoms, we used the Multidimensional Anxiety Scale for Children (MASC) social anxiety subscale. The HR group's MASC social anxiety score was significantly higher than that of the HC group. Among the 29 h, 17 subjects (58.6%) showed high social anxiety and they were classified as the HRHSA group. No significant difference was observed in amygdalar volume between the HRHSA and HC groups. However, there were significant negative correlations between amydalar volumes and MASC social anxiety score in the HRHSA group. These findings have implications for the link between amygdalar structure and both anxiety and mood control. This link may serve to implicate high social anxiety as a risk marker for future BD development. & 2015 Published by Elsevier Ireland Ltd.
1. Introduction Offspring of parents with bipolar disorder (BD) are at high risk for mood disorder, including BD, and also anxiety disorders (Birmaher et al., 2009). Among different anxiety disorders, the prevalence of social anxiety disorder is remarkably high, along with generalized anxiety disorder, in BD offspring (Birmaher et al., 2009; Duffy et al., 2013). Regardless of the high prevalence rate, social anxiety disorder itself is clinically important in that it may be a significant risk factor for developing mood disorders in BD offspring and for suicide in patients with BD (Duffy et al., 2013). Several functional magnetic resonance imaging (fMRI) studies of social anxiety disorder have suggested that abnormal brain activity in the amygdala might be involved in the pathophysiology n Correspondence to: Stanford University School of Medicine, Division of Child and Adolescent Psychiatry, 401 Quarry Road, Stanford, CA 94305-5719, USA. Fax: þ1 650 723 5531. E-mail address: [email protected] (K. Chang).
http://dx.doi.org/10.1016/j.pscychresns.2015.09.018 0925-4927/& 2015 Published by Elsevier Ireland Ltd.
of social anxiety disorder (Birbaumer et al., 1998; Blair et al., 2008; Campbell et al., 2007; Cooney et al., 2006; Gentili et al., 2008; Guyer et al., 2008; Marcinkiewcz et al., 2009; Phan et al., 2006; Schneider et al., 1999; Shah et al., 2009; Stein et al., 2002; Straube et al., 2004; Straube et al., 2005; Yoon et al., 2007). Although, social anxiety pathophysiology has a particularly close relationship with the amygdala (Rauch et al., 2003), to our knowledge only three studies, all in adults, have examined the correlation between amygdalar volume and the degree of social anxiety symptoms, and the results of those studies were inconsistent (Irle et al., 2010; Machado-de-Sousa et al., 2014; Syal et al., 2012). As BD youth have been shown to have decreased amygdalar volumes (Blumberg et al., 2003; Chang et al., 2005; DelBello et al., 2004; Dickstein et al., 2005; Pfeifer et al., 2008), and as social anxiety symptoms are a risk factor for BD offspring for developing BD (Duffy et al., 2013), we hypothesized that social anxiety could be correlated with the amygdalar volumetric alterations in BD offspring. Therefore, in this study we aimed to 1) compare social anxiety symptoms between BD offspring with subthreshold mood
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symptoms and who are thus at high risk for developing BD I or II (high-risk group: HR) and healthy controls (HCs), 2) compare amygdalar volume between the HR subjects with high social anxiety (HRHSA) and the HC group, and 3) explore the correlation between amygdalar volume and social anxiety symptoms in the HRHSA group.
2. Method 2.1. Subjects and assessment The protocol was approved by the Stanford University Panel of Medical Research in Human Subjects. Families were recruited from the Stanford Adult Bipolar Disorders Clinic, the Stanford Pediatric Bipolar Disorders Program, physician referrals, local adult bipolar support groups, and the surrounding community and this study was conducted at the Stanford University Department of Psychiatry. Thirty-five BD offspring and 20 HCs were recruited for the initial assessment. Written and oral informed consent was obtained from at least one parent, and written and oral assent was obtained from the youth. Parental diagnosis of BD I or II was confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) (First et al., 1995). When available, the other parent was also evaluated for psychopathology in this manner. Family history in all other relatives was obtained using the Family History–Research Diagnostic Criteria (FH-RDC) (Andreasen et al., 1977). Youth were assessed by the affective module of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-UKSADS) (Geller et al., 2001) and the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime (KSADS-PL). All subjects were evaluated either by a child psychiatrist (MS or KC) or trained masters-level research assistant (MH), who were aware of parental diagnosis. Inter-rater reliability was established by rating videotaped interviews, observing a trained rater, observing trained rater interviews, and performing interviews with observation by a trained rater (kappa40.9). Current and lifetime DSM-IV diagnoses were ultimately determined by a board certified child psychiatrist (KC) based on personal interview, discussion with the research assistant, and written notes of responses to individual questions. We assessed current manic symptom severity using the Young Mania Rating Scale (YMRS) (Young et al., 1978) and depression symptom severity using the Children's Depression Rating Scale– Revised (CDRS-R) (Poznanski et al., 1985). The inclusion criteria for the HR group were being 9–17 years of age, having a biological parent with bipolar I or II disorder and having subthreshold mood symptoms (YMRS412 or CDRS427). BD offspring with the following disorders or conditions were excluded from the HR group: BD I or II, pervasive developmental disorders, obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), Tourette's syndrome, substance use disorders, or neurological conditions (such as a seizure disorder).After applying the inclusion and exclusion criteria, 29 BD offspring were included in the HR group. Within the HR group, those who showed higher social anxiety than the upper limit of normal (MASC social anxiety T score455) were classified as the HRHSA group. Healthy controls (HC) were similarly interviewed, and determined to have no DSM-IV diagnoses, were not taking psychotropic medications, had both parents without any psychiatric diagnosis (determined by the SCID), did not have a first- or seconddegree relative with BD as determined by the FH-RDC, and were excluded with current YMRS scores greater than 8 or CDRS-R greater than 26. After applying these exclusion criteria, 17 youths were left for statistical analysis as the HC group.
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2.2. Multidimensional anxiety scale for children (MASC) social anxiety subscale To assess social anxiety symptoms, we used the MASC social anxiety scale (March et al., 1997). This scale is comprised of 9 items. A T-score of 45 to 55 is considered normal range. The MASC social anxiety subscale was found to be significantly predictive of the presence and severity of social anxiety disorder (Wei et al., 2014) and the validity of this scale is comparable to that of well-established measures of social anxiety disorder (Anderson et al., 2009). 2.3. MRI acquisition Subjects were scanned on a 3T GE Signa scanner using a custombuilt head coil. Functional MRI data were collected with thirty axial slices (4 mm thick,.5 mm skip), parallel to the axis of anterior and posterior commissures, covering the entire brain (FOV¼20 cm, 64 64 matrix, inplane spatial resolution¼3.43 mm). A spiral inout pulse sequence 35 (Glover and Lai, 1998) used the following parameters: TR¼2000 ms, TE¼30 ms, flip angle¼80° and one interleave. An individually calculated high-order shim was used to reduce B0 heterogeneity prior to acquiring the functional scans. To aid with normalization, a 3D high resolution T1-weighted image was acquired using a fast spoiled gradient recall (FSPGR) pulse sequence: TR/TI /TE¼5.9/1.5/300 ms, flip angle¼15°, field of view¼ 22 cm, 256 256 matrix, inplane resolution¼0.86 mm2, and slice thickness¼1.5 mm (Barnea-Goraly et al., 2014; Hoeft et al., 2014; Weems et al., 2013). 2.4. Image analysis Subcortical volumetric segmentation of the amygdalas was performed with the Freesurfer image analysis suite, a semi-automated volumetric analysis pipeline which is documented and freely available for download online (http://surfer.nmr.mgh.har vard.edu/). The technical details of these procedures are described in prior publications (Dale et al., 1999; Fischl et al., 2002). Before the Freesurfer analysis, we applied an image bias correction using SPM8 (http://www.fil.ion.ucl.ac.uk/spm), with a 30 mm full-width half-maximum Gaussian smoothing kernel and an extremely light regularization coefficient of.0001. Total tissue volume was also calculated using SPM8. All subcortical segmentations were visually inspected and manually edited for quality by one reviewer (SB). Four baseline subcortical segmentations required editing: 3 patients and 7 healthy controls. The analysis results in measures of total amygdala volume (left plus right hemispheres).These edits included removing non-brain voxels from the amygdala region of interest. ROI inspection and editing were performed blind to group. The final outputs of the FreeSurfer analysis are left and right amygdala volume. 2.5. Statistical analyses The χ 2 test and independent t test were conducted to compare the categorical and continuous variables to compare the demographic and clinical characteristics of both groups. Beta correlation coefficients, controlling for age, gender and total brain volume (TBV), YMRS score and CDRS-R score were calculated to examine the correlation between anxiety symptoms and the morphometric regions of interest (ROIs) by using linear regression. The statistical significance for all tests was set at p o 0.05. In cases in which it is assumed that statistical significance was not reached because the number of subjects was insufficient, we calculated effect sizes based on the difference in the means divided by the mean
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standard deviation (Cohen's d) (Cohen, 1977, 1988).
Table 1 Demographic and clinical characteristics of the participants.
3. Results Twenty-nine HR offspring (mean age: 13.9 years (S.D. 3.1) M¼ 18, F¼11) and 17 HC(mean age: 14.4 years (S.D. 2.4) M ¼8, F¼9) were included as subjects for statistical analysis. Table 1 shows demographic and clinical characteristics of the participants. The MASC social anxiety score of the HR group was significantly higher than that of the HC group (p o0.0001, Table 1). The YMRS and CDRS-R scores of the HR group were significantly higher than those of the HC group as well (p o0.0001, Table 1). No significant difference was observed in amygdalar volume between the HR and HC groups. Among the total of 29 h subjects, 17 (58.6%) showed high social anxiety and they were classified as HRHSA. No significant difference was observed in amygdalar volume between the HRHSA and HC groups (Table 2). However, when we calculated effect sizes for the amygdala volume differences between the HRHSA and HC groups, moderate effect sizes were observed (total amygdala:d ¼ 0.42, left amygdala:d ¼ 0.50, right amygdala: d ¼ 0.35) (Cohen, 1988). To avoid possible confound, we controlled for age, gender, TBV, YMRS score and CDRS-R score, and there was no significant correlation between amygdalar volume and MASC social anxiety scale in either the HR or HC group. However, after excluding the subjects who had MASC social anxiety scores in the normal range, when we examined the correlation between amydalar volumes and MASC social anxiety score in the HRHSA group, significant negative correlations were observed (controlling for age, gender, TBV, YMRS score and CDRS-R score: total amygdala: ß ¼ 0.742, p ¼0.004, left amygdala: ß ¼ 0.727, p ¼0.016, right amygdala: ß ¼ 0.672, p ¼0.002 )(Fig. 1, Table 3). Some of the HRHSA group (9 of 17, 52.9%) had been exposed to medication: 4 to lamotrigine, 3 to antidepressants, 2 to lithium, 1 to aripiprazole, 3 to methylphenidate, 1 to atomoxetine (These numbers include patients on multiple medications.). However, when we compared amygdalar volume of the HRHSA group with and without lithium or antipsychotic exposure, there was no difference observed.
4. Discussion We found that BD offspring with mood dysregulation have significantly higher levels of social anxiety than healthy controls. We also found significant negative correlations between amygdalar volumes and social anxiety symptoms in the BD offspring at high risk who had elevated symptoms of social anxiety. By excluding the subjects with PTSD, OCD, or panic disorder and by controlling for YMRS score and CDRS-R score, we minimized the effect of other anxiety and mood symptoms. By doing the aforementioned method, we tried to concentrate mainly on social anxiety symptoms. 4.1. The amygdala and anxiety, focusing on social anxiety Among the anxiety disorders, social anxiety pathophysiology has a particularly close relationship with the amygdala (Rauch et al., 2003). The amygdala is one of the crucial brain regions that play a role in social cognition (Adolphs, 2010), and previous fMRI studies have shown that the amygdala is the most hyper-activated brain area when subjects are exposed to threat-signaling faces (Sergerie et al., 2008). Interestingly, a meta-analysis showed that amygdalar hyper-activations were more noticeable in patients with social anxiety disorder than those with other anxiety
Age Gender Race MASC Social anxiety YMRS CDRS-R BD diagnosis
High-risk group (N ¼ 29)
Healthy controls (N ¼ 17)
p-value
mean (S.D.) male (%) Non-caucasian (%) T score (S.D.)
13.9 (3.1) 18 (62.1) 2 (7.0)
14.4 (2.4) 8 (47.1) 5 (29.4)
0.604 0.369 0.083
55.2 (11.8)
45.2 (7.0)
o0.00001
mean (S.D.) mean (S.D.)
11.1 (5.9) 34.4(8.5)
2.0 (2.9) 20.1 (7.0)
o0.00001 o0.00001
BD.NOS (%)
7 (24.1%)
0
Comorbidity ADHD (%) ODD (%) CD (%) GAD (%) Separation anxiety disorder (%)
13 4 1 5 1
(44.8%) (13.8%) (3.5) (17.2) (3.5)
MASC, Multidimensional Anxiety Scale for Children. YMRS, Young Mania Rating Scale. CDRS-R, Children's Depression Rating Scale-Revised. BD, Bipolar disorder. NOS, not otherwise specified. ADHD, attention-deficit/hyperactivity disorder. ODD, oppositional defiant disorder. CD, conduct disorder. GAD, generalized anxiety disorder.
disorders even including PTSD (Etkin and Wager, 2007). Considering that patients with social anxiety are particularly sensitive to threat-signaling faces, which can be interpreted as showing dislike or hostility (Arrais et al., 2009), there is the possibility that social anxiety disorder is more closely related to amygdalar abnormalities than are other anxiety disorders (Freitas-Ferrari et al., 2008). However, regarding brain structural studies, as far as we know, only three previous studies compared the amygdalar volumes of individuals with social anxiety disorder exclusively among anxiety disorders to those of controls. Results among these studies were inconsistent, with both increased (Machado-de-Sousa et al., 2014) and, decreased (Irle et al., 2010) volume in those with social anxiety disorder, as well as findings of no differences between groups (Syal et al., 2012). Limitations of these studies included the relatively small sample sizes (social anxiety patients vs healthy controls: 12 vs 12 (Machado-de-Sousa et al., 2014), 13 vs 13 (Syal et al., 2012), and 24 vs 24 (Irle et al., 2010) respectively). Interestingly, among these studies, the mean age of participants in the study by Irle et al. (2010), which reported a decreased amygdala volume in social anxiety patients, was approximately 10 years older than those of the other two studies, and the study found a correlation between the social anxiety symptom severity and the degree of volume reduction, whereas the other two studies did not examine this relationship. Furthermore, the study by Syal et al. (2012),which assessed cortical thickness and subcortical volumes, reported negative findings regarding amygdalar volume. However, when the data were examined at an uncorrected level, a decreased amygdalar volume was observed in the social anxiety patients. Taking together the results of previous studies with our result of the negative correlation between social anxiety symptoms and amygdala volume in this study, as well as and the fact that our participants were much younger than those of previous studies, it will be interesting to conduct more studies to assess whether the amygdala volume change progresses with prolonged social anxiety symptoms.
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Table 2 Mean (SD) brain regional raw volumes (in cubic centimeters) in high-risk group with high social anxiety and healthy controls. Brain region Volume (cm 3) Healthy controls (S.D.) (N¼ 26) High-risk group (S.D.) (N ¼ 17) p-valuea High-risk group with high social anxiety (S.D.) (N ¼ 17)
p-valueb
Total brain volume Total amygdalar volume Left amygdalar volume Right amygdalar volume
0.474 0.178 0.099 0.344
a b
1349.58 3.09 1.52 1.57
(93.19) (0.33) (0.12) (0.23)
1322.96 2.95 1.46 1.49
(111.59) (0.46) (0.26) (0.22)
0.412 0.282 0.355 0.264
1324.13 2.93 1.43 1.50
(110.70) (0.36) (0.20) (0.18)
High-risk group vs. Healthy control. High-risk group with high social anxiety vs. Healthy control.
4.2. Pediatric BD, BD offspring and the amygdala Previous fMRI studies in pediatric BD have demonstrated hyperactivity in the amygdala when performing affective tasks (Olsavsky et al., 2012; Rich et al., 2006). Also some fMRI studies on BD offspring have demonstrated amygdalar hyperactivity as well (Olsavsky et al., 2012). Even though amygdala volumetric findings in adults with BD are inconsistent (Altshuler et al., 1998; Blumberg et al., 2003; Pearlson et al., 1997; Strakowski et al., 1999; Swayze et al., 1992), amygdala findings in pediatric BD are more consistent and the majority found decreased amygdalar volume (Blumberg et al., 2003; Chang et al., 2005; DelBello et al., 2004; Dickstein
Table 3 Correlations between amygdalar volumes and the MASC social anxiety score. in the high-risk group with high social anxiety (n ¼17)
Total amygdalar volume Left amygdalar volume Right amygdalar volume
ß
P
0.742 0.727 0.672
0.004 0.016 0.002
corrected by age, gender,total brain volume, YMRS score and CDRS-R score.
Fig. 1. Correlations between amygdalar volumes and social anxiety symptoms. Total amygdala (a) (ß¼ .742, p¼ .004), (b) Left amygdala (ß¼ .727, p ¼ .016) and (c) Right amygdala (ß ¼ .672, p ¼ .002).
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et al., 2005; Pfeifer et al., 2008). However, previous volumetric studies on BD offspring have reported normal amygdalar volumes (Hajek et al., 2009; Karchemskiy et al., 2011; Ladouceur et al., 2008; Singh et al., 2008). In this study, we also did not find volumetric differences in the amygdala between the HR and HC groups. In addition, we were not able to predict any trend of decreased amygdalar volume in the portion of HR group without high social anxiety. On the other hand, when we examined the HRHSA group, decreased amygdalar volume trends compared to the HC group were observed and there were correlations between social anxiety symptoms and amygdalar volumes. There are two hypotheses regarding the causal relationship between BD development and amygdalar volumetric change. That is, it has been debated whether amygdalar volume abnormality predates the onset of mania, or the volumetric changes occur as a consequence of prolonged BD. The latter hypothesis has been viewed as more reliable (Karchemskiy et al., 2011) because while decreased amygdalar volume is observed in youth with BD, no such volumetric finding was observed in healthy or mood dysregulated BD offspring overall. However, the results of the present study of decreased volume trends in the HRHSA group compared with the HC group and the negative correlations between amygdalar volumes and MASC social anxiety scores in the HRHSA group may suggest the possibility that BD offspring with mood dysregulation who also have high levels of social anxiety might tend to already have smaller amygdalar volumes. However, we cannot confirm this due to the lack of a statistically significant volume difference between the HRHSA and HC groups and the small sample size. 4.3. BD offspring and social anxiety Masi et al. (2001) reported that social anxiety disorder is the second most common anxiety disorder comorbidity in child & adolescent BD after OCD. In the aforementioned study, social anxiety disorder showed the earliest onset age (except for separation anxiety disorder), which was 6.5 years earlier than that of BD. Previous studies on BD offspring have also suggested that anxiety symptoms, including social anxiety symptoms, in BD offspring may serve as a route for developing BD (Contreras et al., 2010). Taking the result of this study together with the results of previous studies (which revealed that pediatric BD patients have decreased amygdalar volume), one could conclude that high social anxiety in BD may be a risk marker for future BD development. In this study, only 4 subjects in the HRHSA group met the diagnostic criteria of BD NOS and no subject met BD I or II criteria yet. Additionally, it is not known whether the subjects who met the diagnostic criteria of BD NOS will eventually develop BD I or II, although previous studies indicated that a substantial number of youth with BD NOS progress to meet the full criteria for BD I or II (Adolphs, 2010). Therefore, the volumetric changes related to social anxiety symptoms may represent the start of the most subtle amygdalar volume changes in BD offspring. Even though we did not observe any significant difference in amygdalar volume between the HRHSA and HC groups, we discerned a trend for decreased amygdala volumes in the HRHSA group, and moderate effect sizes were observed in the differences of the amygdala volumes between the two groups. Therefore, this negative result could have arisen from the small size of the HRHSA group. This study's limitations are as follows. First, the number of subject in the HRHSA group was relatively small. Therefore, although we observed moderate effect sizes for the volume difference between the HRHSA and HC groups, and negative correlations between amygdalar volumes and the MASC social anxiety
score in the HRHSA group, we cannot completely exclude the chance that these results were falsely positive. Second, as a crosssectional study, we were not able to determine if these children with high social anxiety would indeed develop BD I or II. Third, although we tried to minimize the effects of anxiety symptoms other than social anxiety by excluding the subjects with PTSD, OCD, or panic disorder, as well as the effect of mood symptoms by controlling for YMRS score and CDRS-R score, other comorbid diagnoses may have influenced our findings. One met ODD, one met separation anxiety disorder, and five met GAD diagnoses among the high-risk group. Furthermore, not inconsiderable number of the HRHSA group (4 of 17, 23.5%) had attention-deficit/hyperactivity disorder (ADHD).The presence of ADHD may have had an effect on our findings. There are inconsistent results regarding amygdalar volume in ADHD patients: some studies reported smaller amygdalar volume (Perlov et al., 2008), whereas other studies did not find any difference compared to healthy control (Frodl et al., 2010). However, the amygdala is not considered a critical region in ADHD pathophysiology (Bush et al., 2005). Furthermore, regarding amygdalar volume, there were no significant findings in a recent meta-analytic study on ADHD subjects (Frodl and Skokauskas, 2012). Therefore, even if ADHD diagnosis had had an effect on our findings, the effect would be minimal. Fourth, some of the participants had been exposed to psychotropic medication. Although, previous studies on the psychotropic medication and amygdala volume have reported inconsistent findings, the possibility that psychotropic medication exposure might have affected the amygdala volume cannot be excluded (Foland et al., 2008; Joyal et al., 2003; Puri, 2011; Szeszko et al., 2004; Usher et al., 2010). Despite these limitations, this study supports the suggestion from previous studies that the presence of social anxiety symptoms in high-risk youth may increase the risk of developing BD. Future longitudinal studies may be able to confirm whether BD offspring with high social anxiety symptoms indeed develop BD I or II more frequently than those without high social anxiety symptoms, and whether amygdalar volumes in those youth do predict the development of mania.
Conflict of interest Dr. Chang is a consultant for GlaxoSmithKline, Eli Lilly, BristolMyers Squibb and Sunovion, and has received research support from GlaxoSmithKline and Merck in the last two years. The other authors have nothing to disclose.
Acknowledgments The authors gratefully acknowledge funding from the NIMH (R01 MH077047 and K23 MH064460 to KDC and K23 MH085919 to MKS). We thank the participants who gave their time for this study.
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Psychiatry Research: Neuroimaging journal homepage: www.elsevier.com/locate/psychresns
Amygdalar volumetric correlates of social anxiety in offspring of parents with bipolar disorder Min-Hyeon Park a, Amy Garrett b, Spencer Boucher b, Meghan Howe b, Erica Sanders b, Eunjoo Kim c, Manpreet Singh b, Kiki Chang b,n a
Department of Psychiatry, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA c Department of Psychiatry and Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, South Korea b
art ic l e i nf o Article history: Received 15 June 2014 Received in revised form 17 September 2015 Accepted 25 September 2015 Available online 28 September 2015 Keywords: Risk Affect Child Adolescence Family
a b s t r a c t The prevalence of social anxiety disorder is high in offspring of parents with bipolar disorder (BD) and anxiety may be a significant risk factor in these youth for developing BD. We compared social anxiety symptoms between BD offspring with mood symptoms (high-risk group for developing BD I or II: HR) and healthy controls (HC). We also explored the correlations between the amygdalar volumes and social anxiety symptoms in the HR group with high social anxiety scores (HRHSA) due to the potential involvement of the amygdala in the pathophysiology of both BD and social anxiety. Youth participating in the study included 29 h and 17 HC of comparable age and gender. To assess social anxiety symptoms, we used the Multidimensional Anxiety Scale for Children (MASC) social anxiety subscale. The HR group's MASC social anxiety score was significantly higher than that of the HC group. Among the 29 h, 17 subjects (58.6%) showed high social anxiety and they were classified as the HRHSA group. No significant difference was observed in amygdalar volume between the HRHSA and HC groups. However, there were significant negative correlations between amydalar volumes and MASC social anxiety score in the HRHSA group. These findings have implications for the link between amygdalar structure and both anxiety and mood control. This link may serve to implicate high social anxiety as a risk marker for future BD development. & 2015 Published by Elsevier Ireland Ltd.
1. Introduction Offspring of parents with bipolar disorder (BD) are at high risk for mood disorder, including BD, and also anxiety disorders (Birmaher et al., 2009). Among different anxiety disorders, the prevalence of social anxiety disorder is remarkably high, along with generalized anxiety disorder, in BD offspring (Birmaher et al., 2009; Duffy et al., 2013). Regardless of the high prevalence rate, social anxiety disorder itself is clinically important in that it may be a significant risk factor for developing mood disorders in BD offspring and for suicide in patients with BD (Duffy et al., 2013). Several functional magnetic resonance imaging (fMRI) studies of social anxiety disorder have suggested that abnormal brain activity in the amygdala might be involved in the pathophysiology n Correspondence to: Stanford University School of Medicine, Division of Child and Adolescent Psychiatry, 401 Quarry Road, Stanford, CA 94305-5719, USA. Fax: þ1 650 723 5531. E-mail address: [email protected] (K. Chang).
http://dx.doi.org/10.1016/j.pscychresns.2015.09.018 0925-4927/& 2015 Published by Elsevier Ireland Ltd.
of social anxiety disorder (Birbaumer et al., 1998; Blair et al., 2008; Campbell et al., 2007; Cooney et al., 2006; Gentili et al., 2008; Guyer et al., 2008; Marcinkiewcz et al., 2009; Phan et al., 2006; Schneider et al., 1999; Shah et al., 2009; Stein et al., 2002; Straube et al., 2004; Straube et al., 2005; Yoon et al., 2007). Although, social anxiety pathophysiology has a particularly close relationship with the amygdala (Rauch et al., 2003), to our knowledge only three studies, all in adults, have examined the correlation between amygdalar volume and the degree of social anxiety symptoms, and the results of those studies were inconsistent (Irle et al., 2010; Machado-de-Sousa et al., 2014; Syal et al., 2012). As BD youth have been shown to have decreased amygdalar volumes (Blumberg et al., 2003; Chang et al., 2005; DelBello et al., 2004; Dickstein et al., 2005; Pfeifer et al., 2008), and as social anxiety symptoms are a risk factor for BD offspring for developing BD (Duffy et al., 2013), we hypothesized that social anxiety could be correlated with the amygdalar volumetric alterations in BD offspring. Therefore, in this study we aimed to 1) compare social anxiety symptoms between BD offspring with subthreshold mood
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symptoms and who are thus at high risk for developing BD I or II (high-risk group: HR) and healthy controls (HCs), 2) compare amygdalar volume between the HR subjects with high social anxiety (HRHSA) and the HC group, and 3) explore the correlation between amygdalar volume and social anxiety symptoms in the HRHSA group.
2. Method 2.1. Subjects and assessment The protocol was approved by the Stanford University Panel of Medical Research in Human Subjects. Families were recruited from the Stanford Adult Bipolar Disorders Clinic, the Stanford Pediatric Bipolar Disorders Program, physician referrals, local adult bipolar support groups, and the surrounding community and this study was conducted at the Stanford University Department of Psychiatry. Thirty-five BD offspring and 20 HCs were recruited for the initial assessment. Written and oral informed consent was obtained from at least one parent, and written and oral assent was obtained from the youth. Parental diagnosis of BD I or II was confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) (First et al., 1995). When available, the other parent was also evaluated for psychopathology in this manner. Family history in all other relatives was obtained using the Family History–Research Diagnostic Criteria (FH-RDC) (Andreasen et al., 1977). Youth were assessed by the affective module of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-UKSADS) (Geller et al., 2001) and the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime (KSADS-PL). All subjects were evaluated either by a child psychiatrist (MS or KC) or trained masters-level research assistant (MH), who were aware of parental diagnosis. Inter-rater reliability was established by rating videotaped interviews, observing a trained rater, observing trained rater interviews, and performing interviews with observation by a trained rater (kappa40.9). Current and lifetime DSM-IV diagnoses were ultimately determined by a board certified child psychiatrist (KC) based on personal interview, discussion with the research assistant, and written notes of responses to individual questions. We assessed current manic symptom severity using the Young Mania Rating Scale (YMRS) (Young et al., 1978) and depression symptom severity using the Children's Depression Rating Scale– Revised (CDRS-R) (Poznanski et al., 1985). The inclusion criteria for the HR group were being 9–17 years of age, having a biological parent with bipolar I or II disorder and having subthreshold mood symptoms (YMRS412 or CDRS427). BD offspring with the following disorders or conditions were excluded from the HR group: BD I or II, pervasive developmental disorders, obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder (PTSD), Tourette's syndrome, substance use disorders, or neurological conditions (such as a seizure disorder).After applying the inclusion and exclusion criteria, 29 BD offspring were included in the HR group. Within the HR group, those who showed higher social anxiety than the upper limit of normal (MASC social anxiety T score455) were classified as the HRHSA group. Healthy controls (HC) were similarly interviewed, and determined to have no DSM-IV diagnoses, were not taking psychotropic medications, had both parents without any psychiatric diagnosis (determined by the SCID), did not have a first- or seconddegree relative with BD as determined by the FH-RDC, and were excluded with current YMRS scores greater than 8 or CDRS-R greater than 26. After applying these exclusion criteria, 17 youths were left for statistical analysis as the HC group.
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2.2. Multidimensional anxiety scale for children (MASC) social anxiety subscale To assess social anxiety symptoms, we used the MASC social anxiety scale (March et al., 1997). This scale is comprised of 9 items. A T-score of 45 to 55 is considered normal range. The MASC social anxiety subscale was found to be significantly predictive of the presence and severity of social anxiety disorder (Wei et al., 2014) and the validity of this scale is comparable to that of well-established measures of social anxiety disorder (Anderson et al., 2009). 2.3. MRI acquisition Subjects were scanned on a 3T GE Signa scanner using a custombuilt head coil. Functional MRI data were collected with thirty axial slices (4 mm thick,.5 mm skip), parallel to the axis of anterior and posterior commissures, covering the entire brain (FOV¼20 cm, 64 64 matrix, inplane spatial resolution¼3.43 mm). A spiral inout pulse sequence 35 (Glover and Lai, 1998) used the following parameters: TR¼2000 ms, TE¼30 ms, flip angle¼80° and one interleave. An individually calculated high-order shim was used to reduce B0 heterogeneity prior to acquiring the functional scans. To aid with normalization, a 3D high resolution T1-weighted image was acquired using a fast spoiled gradient recall (FSPGR) pulse sequence: TR/TI /TE¼5.9/1.5/300 ms, flip angle¼15°, field of view¼ 22 cm, 256 256 matrix, inplane resolution¼0.86 mm2, and slice thickness¼1.5 mm (Barnea-Goraly et al., 2014; Hoeft et al., 2014; Weems et al., 2013). 2.4. Image analysis Subcortical volumetric segmentation of the amygdalas was performed with the Freesurfer image analysis suite, a semi-automated volumetric analysis pipeline which is documented and freely available for download online (http://surfer.nmr.mgh.har vard.edu/). The technical details of these procedures are described in prior publications (Dale et al., 1999; Fischl et al., 2002). Before the Freesurfer analysis, we applied an image bias correction using SPM8 (http://www.fil.ion.ucl.ac.uk/spm), with a 30 mm full-width half-maximum Gaussian smoothing kernel and an extremely light regularization coefficient of.0001. Total tissue volume was also calculated using SPM8. All subcortical segmentations were visually inspected and manually edited for quality by one reviewer (SB). Four baseline subcortical segmentations required editing: 3 patients and 7 healthy controls. The analysis results in measures of total amygdala volume (left plus right hemispheres).These edits included removing non-brain voxels from the amygdala region of interest. ROI inspection and editing were performed blind to group. The final outputs of the FreeSurfer analysis are left and right amygdala volume. 2.5. Statistical analyses The χ 2 test and independent t test were conducted to compare the categorical and continuous variables to compare the demographic and clinical characteristics of both groups. Beta correlation coefficients, controlling for age, gender and total brain volume (TBV), YMRS score and CDRS-R score were calculated to examine the correlation between anxiety symptoms and the morphometric regions of interest (ROIs) by using linear regression. The statistical significance for all tests was set at p o 0.05. In cases in which it is assumed that statistical significance was not reached because the number of subjects was insufficient, we calculated effect sizes based on the difference in the means divided by the mean
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standard deviation (Cohen's d) (Cohen, 1977, 1988).
Table 1 Demographic and clinical characteristics of the participants.
3. Results Twenty-nine HR offspring (mean age: 13.9 years (S.D. 3.1) M¼ 18, F¼11) and 17 HC(mean age: 14.4 years (S.D. 2.4) M ¼8, F¼9) were included as subjects for statistical analysis. Table 1 shows demographic and clinical characteristics of the participants. The MASC social anxiety score of the HR group was significantly higher than that of the HC group (p o0.0001, Table 1). The YMRS and CDRS-R scores of the HR group were significantly higher than those of the HC group as well (p o0.0001, Table 1). No significant difference was observed in amygdalar volume between the HR and HC groups. Among the total of 29 h subjects, 17 (58.6%) showed high social anxiety and they were classified as HRHSA. No significant difference was observed in amygdalar volume between the HRHSA and HC groups (Table 2). However, when we calculated effect sizes for the amygdala volume differences between the HRHSA and HC groups, moderate effect sizes were observed (total amygdala:d ¼ 0.42, left amygdala:d ¼ 0.50, right amygdala: d ¼ 0.35) (Cohen, 1988). To avoid possible confound, we controlled for age, gender, TBV, YMRS score and CDRS-R score, and there was no significant correlation between amygdalar volume and MASC social anxiety scale in either the HR or HC group. However, after excluding the subjects who had MASC social anxiety scores in the normal range, when we examined the correlation between amydalar volumes and MASC social anxiety score in the HRHSA group, significant negative correlations were observed (controlling for age, gender, TBV, YMRS score and CDRS-R score: total amygdala: ß ¼ 0.742, p ¼0.004, left amygdala: ß ¼ 0.727, p ¼0.016, right amygdala: ß ¼ 0.672, p ¼0.002 )(Fig. 1, Table 3). Some of the HRHSA group (9 of 17, 52.9%) had been exposed to medication: 4 to lamotrigine, 3 to antidepressants, 2 to lithium, 1 to aripiprazole, 3 to methylphenidate, 1 to atomoxetine (These numbers include patients on multiple medications.). However, when we compared amygdalar volume of the HRHSA group with and without lithium or antipsychotic exposure, there was no difference observed.
4. Discussion We found that BD offspring with mood dysregulation have significantly higher levels of social anxiety than healthy controls. We also found significant negative correlations between amygdalar volumes and social anxiety symptoms in the BD offspring at high risk who had elevated symptoms of social anxiety. By excluding the subjects with PTSD, OCD, or panic disorder and by controlling for YMRS score and CDRS-R score, we minimized the effect of other anxiety and mood symptoms. By doing the aforementioned method, we tried to concentrate mainly on social anxiety symptoms. 4.1. The amygdala and anxiety, focusing on social anxiety Among the anxiety disorders, social anxiety pathophysiology has a particularly close relationship with the amygdala (Rauch et al., 2003). The amygdala is one of the crucial brain regions that play a role in social cognition (Adolphs, 2010), and previous fMRI studies have shown that the amygdala is the most hyper-activated brain area when subjects are exposed to threat-signaling faces (Sergerie et al., 2008). Interestingly, a meta-analysis showed that amygdalar hyper-activations were more noticeable in patients with social anxiety disorder than those with other anxiety
Age Gender Race MASC Social anxiety YMRS CDRS-R BD diagnosis
High-risk group (N ¼ 29)
Healthy controls (N ¼ 17)
p-value
mean (S.D.) male (%) Non-caucasian (%) T score (S.D.)
13.9 (3.1) 18 (62.1) 2 (7.0)
14.4 (2.4) 8 (47.1) 5 (29.4)
0.604 0.369 0.083
55.2 (11.8)
45.2 (7.0)
o0.00001
mean (S.D.) mean (S.D.)
11.1 (5.9) 34.4(8.5)
2.0 (2.9) 20.1 (7.0)
o0.00001 o0.00001
BD.NOS (%)
7 (24.1%)
0
Comorbidity ADHD (%) ODD (%) CD (%) GAD (%) Separation anxiety disorder (%)
13 4 1 5 1
(44.8%) (13.8%) (3.5) (17.2) (3.5)
MASC, Multidimensional Anxiety Scale for Children. YMRS, Young Mania Rating Scale. CDRS-R, Children's Depression Rating Scale-Revised. BD, Bipolar disorder. NOS, not otherwise specified. ADHD, attention-deficit/hyperactivity disorder. ODD, oppositional defiant disorder. CD, conduct disorder. GAD, generalized anxiety disorder.
disorders even including PTSD (Etkin and Wager, 2007). Considering that patients with social anxiety are particularly sensitive to threat-signaling faces, which can be interpreted as showing dislike or hostility (Arrais et al., 2009), there is the possibility that social anxiety disorder is more closely related to amygdalar abnormalities than are other anxiety disorders (Freitas-Ferrari et al., 2008). However, regarding brain structural studies, as far as we know, only three previous studies compared the amygdalar volumes of individuals with social anxiety disorder exclusively among anxiety disorders to those of controls. Results among these studies were inconsistent, with both increased (Machado-de-Sousa et al., 2014) and, decreased (Irle et al., 2010) volume in those with social anxiety disorder, as well as findings of no differences between groups (Syal et al., 2012). Limitations of these studies included the relatively small sample sizes (social anxiety patients vs healthy controls: 12 vs 12 (Machado-de-Sousa et al., 2014), 13 vs 13 (Syal et al., 2012), and 24 vs 24 (Irle et al., 2010) respectively). Interestingly, among these studies, the mean age of participants in the study by Irle et al. (2010), which reported a decreased amygdala volume in social anxiety patients, was approximately 10 years older than those of the other two studies, and the study found a correlation between the social anxiety symptom severity and the degree of volume reduction, whereas the other two studies did not examine this relationship. Furthermore, the study by Syal et al. (2012),which assessed cortical thickness and subcortical volumes, reported negative findings regarding amygdalar volume. However, when the data were examined at an uncorrected level, a decreased amygdalar volume was observed in the social anxiety patients. Taking together the results of previous studies with our result of the negative correlation between social anxiety symptoms and amygdala volume in this study, as well as and the fact that our participants were much younger than those of previous studies, it will be interesting to conduct more studies to assess whether the amygdala volume change progresses with prolonged social anxiety symptoms.
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Table 2 Mean (SD) brain regional raw volumes (in cubic centimeters) in high-risk group with high social anxiety and healthy controls. Brain region Volume (cm 3) Healthy controls (S.D.) (N¼ 26) High-risk group (S.D.) (N ¼ 17) p-valuea High-risk group with high social anxiety (S.D.) (N ¼ 17)
p-valueb
Total brain volume Total amygdalar volume Left amygdalar volume Right amygdalar volume
0.474 0.178 0.099 0.344
a b
1349.58 3.09 1.52 1.57
(93.19) (0.33) (0.12) (0.23)
1322.96 2.95 1.46 1.49
(111.59) (0.46) (0.26) (0.22)
0.412 0.282 0.355 0.264
1324.13 2.93 1.43 1.50
(110.70) (0.36) (0.20) (0.18)
High-risk group vs. Healthy control. High-risk group with high social anxiety vs. Healthy control.
4.2. Pediatric BD, BD offspring and the amygdala Previous fMRI studies in pediatric BD have demonstrated hyperactivity in the amygdala when performing affective tasks (Olsavsky et al., 2012; Rich et al., 2006). Also some fMRI studies on BD offspring have demonstrated amygdalar hyperactivity as well (Olsavsky et al., 2012). Even though amygdala volumetric findings in adults with BD are inconsistent (Altshuler et al., 1998; Blumberg et al., 2003; Pearlson et al., 1997; Strakowski et al., 1999; Swayze et al., 1992), amygdala findings in pediatric BD are more consistent and the majority found decreased amygdalar volume (Blumberg et al., 2003; Chang et al., 2005; DelBello et al., 2004; Dickstein
Table 3 Correlations between amygdalar volumes and the MASC social anxiety score. in the high-risk group with high social anxiety (n ¼17)
Total amygdalar volume Left amygdalar volume Right amygdalar volume
ß
P
0.742 0.727 0.672
0.004 0.016 0.002
corrected by age, gender,total brain volume, YMRS score and CDRS-R score.
Fig. 1. Correlations between amygdalar volumes and social anxiety symptoms. Total amygdala (a) (ß¼ .742, p¼ .004), (b) Left amygdala (ß¼ .727, p ¼ .016) and (c) Right amygdala (ß ¼ .672, p ¼ .002).
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et al., 2005; Pfeifer et al., 2008). However, previous volumetric studies on BD offspring have reported normal amygdalar volumes (Hajek et al., 2009; Karchemskiy et al., 2011; Ladouceur et al., 2008; Singh et al., 2008). In this study, we also did not find volumetric differences in the amygdala between the HR and HC groups. In addition, we were not able to predict any trend of decreased amygdalar volume in the portion of HR group without high social anxiety. On the other hand, when we examined the HRHSA group, decreased amygdalar volume trends compared to the HC group were observed and there were correlations between social anxiety symptoms and amygdalar volumes. There are two hypotheses regarding the causal relationship between BD development and amygdalar volumetric change. That is, it has been debated whether amygdalar volume abnormality predates the onset of mania, or the volumetric changes occur as a consequence of prolonged BD. The latter hypothesis has been viewed as more reliable (Karchemskiy et al., 2011) because while decreased amygdalar volume is observed in youth with BD, no such volumetric finding was observed in healthy or mood dysregulated BD offspring overall. However, the results of the present study of decreased volume trends in the HRHSA group compared with the HC group and the negative correlations between amygdalar volumes and MASC social anxiety scores in the HRHSA group may suggest the possibility that BD offspring with mood dysregulation who also have high levels of social anxiety might tend to already have smaller amygdalar volumes. However, we cannot confirm this due to the lack of a statistically significant volume difference between the HRHSA and HC groups and the small sample size. 4.3. BD offspring and social anxiety Masi et al. (2001) reported that social anxiety disorder is the second most common anxiety disorder comorbidity in child & adolescent BD after OCD. In the aforementioned study, social anxiety disorder showed the earliest onset age (except for separation anxiety disorder), which was 6.5 years earlier than that of BD. Previous studies on BD offspring have also suggested that anxiety symptoms, including social anxiety symptoms, in BD offspring may serve as a route for developing BD (Contreras et al., 2010). Taking the result of this study together with the results of previous studies (which revealed that pediatric BD patients have decreased amygdalar volume), one could conclude that high social anxiety in BD may be a risk marker for future BD development. In this study, only 4 subjects in the HRHSA group met the diagnostic criteria of BD NOS and no subject met BD I or II criteria yet. Additionally, it is not known whether the subjects who met the diagnostic criteria of BD NOS will eventually develop BD I or II, although previous studies indicated that a substantial number of youth with BD NOS progress to meet the full criteria for BD I or II (Adolphs, 2010). Therefore, the volumetric changes related to social anxiety symptoms may represent the start of the most subtle amygdalar volume changes in BD offspring. Even though we did not observe any significant difference in amygdalar volume between the HRHSA and HC groups, we discerned a trend for decreased amygdala volumes in the HRHSA group, and moderate effect sizes were observed in the differences of the amygdala volumes between the two groups. Therefore, this negative result could have arisen from the small size of the HRHSA group. This study's limitations are as follows. First, the number of subject in the HRHSA group was relatively small. Therefore, although we observed moderate effect sizes for the volume difference between the HRHSA and HC groups, and negative correlations between amygdalar volumes and the MASC social anxiety
score in the HRHSA group, we cannot completely exclude the chance that these results were falsely positive. Second, as a crosssectional study, we were not able to determine if these children with high social anxiety would indeed develop BD I or II. Third, although we tried to minimize the effects of anxiety symptoms other than social anxiety by excluding the subjects with PTSD, OCD, or panic disorder, as well as the effect of mood symptoms by controlling for YMRS score and CDRS-R score, other comorbid diagnoses may have influenced our findings. One met ODD, one met separation anxiety disorder, and five met GAD diagnoses among the high-risk group. Furthermore, not inconsiderable number of the HRHSA group (4 of 17, 23.5%) had attention-deficit/hyperactivity disorder (ADHD).The presence of ADHD may have had an effect on our findings. There are inconsistent results regarding amygdalar volume in ADHD patients: some studies reported smaller amygdalar volume (Perlov et al., 2008), whereas other studies did not find any difference compared to healthy control (Frodl et al., 2010). However, the amygdala is not considered a critical region in ADHD pathophysiology (Bush et al., 2005). Furthermore, regarding amygdalar volume, there were no significant findings in a recent meta-analytic study on ADHD subjects (Frodl and Skokauskas, 2012). Therefore, even if ADHD diagnosis had had an effect on our findings, the effect would be minimal. Fourth, some of the participants had been exposed to psychotropic medication. Although, previous studies on the psychotropic medication and amygdala volume have reported inconsistent findings, the possibility that psychotropic medication exposure might have affected the amygdala volume cannot be excluded (Foland et al., 2008; Joyal et al., 2003; Puri, 2011; Szeszko et al., 2004; Usher et al., 2010). Despite these limitations, this study supports the suggestion from previous studies that the presence of social anxiety symptoms in high-risk youth may increase the risk of developing BD. Future longitudinal studies may be able to confirm whether BD offspring with high social anxiety symptoms indeed develop BD I or II more frequently than those without high social anxiety symptoms, and whether amygdalar volumes in those youth do predict the development of mania.
Conflict of interest Dr. Chang is a consultant for GlaxoSmithKline, Eli Lilly, BristolMyers Squibb and Sunovion, and has received research support from GlaxoSmithKline and Merck in the last two years. The other authors have nothing to disclose.
Acknowledgments The authors gratefully acknowledge funding from the NIMH (R01 MH077047 and K23 MH064460 to KDC and K23 MH085919 to MKS). We thank the participants who gave their time for this study.
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