Preliminary communicationLack of gender effects on gray matter volumes in adolescent generalized anxiety disorder
Introduction
Generalized anxiety disorder (GAD) is a common anxiety disorder with an estimated lifetime prevalence of 5.7% in the general population (Kessler et al., 2005) and characterized by uncontrollable and excessive worry about everyday things. GAD often co-occurs with other psychiatric disorders and causes significant personal, societal, and economical burden (Grant et al., 2005). Gender differences in prevalence and clinical features of GAD have been reported in a series of epidemiological and clinical studies (Rodriguez et al., 2006, Steiner et al., 2005, Vesga-Lopez et al., 2008). The lifetime or 12-month prevalence of GAD in female is about two times higher than that in male (Vesga-Lopez et al., 2008). Women with GAD have an earlier age of onset (Steiner et al., 2005), more somatic symptoms (Steiner et al., 2005), and lower rates of remission and relapse (Rodriguez et al., 2006). Women with GAD have significantly higher rates of comorbid mood disorders and anxiety disorders, while men with GAD have significantly higher rates of comorbid substance abuse or dependence and antisocial personality (Vesga-Lopez et al., 2008).
Such gender differences in clinical phenomenology suggest that the underlying neural circuitry of GAD could also be different in males and females. There have been a large number of studies investigating gender differences of brain structure in healthy participants (Chen et al., 2007, Cosgrove et al., 2007, Goldstein et al., 2001, Lenroot and Giedd, 2010, Luders et al., 2009, Raz et al., 2004). The most consistent result is that men have greater brain volumes than women (Chen et al., 2007, Cosgrove et al., 2007, Goldstein et al., 2001, Lenroot and Giedd, 2010, Luders et al., 2009, Raz et al., 2004). Yet, when controlling for total intracranial volumes, women have a higher percentage of gray matter, and men a higher percentage of white matter (Chen et al., 2007, Cosgrove et al., 2007, Goldstein et al., 2001). Regional brain volumes differences are inconsistent (Chen et al., 2007, Cosgrove et al., 2007, Goldstein et al., 2001, Lenroot and Giedd, 2010, Luders et al., 2009, Raz et al., 2004). Some studies have suggested that men have more gray matter volumes in the amygdala (Cosgrove et al., 2007, Goldstein et al., 2001, Lenroot and Giedd, 2010), occipital lingual gyrus (Chen et al., 2007), temporal lobe (Chen et al., 2007, Raz et al., 2004), and hypothalamus (Cosgrove et al., 2007, Goldstein et al., 2001) while women have larger gray matter volumes in the basal ganglia (Cosgrove et al., 2007, Lenroot and Giedd, 2010, Luders et al., 2009), cingulate gyrus (Chen et al., 2007), orbitofrontal cortex (Lenroot and Giedd, 2010, Luders et al., 2009), and hippocampus (Cosgrove et al., 2007, Lenroot and Giedd, 2010). Other studies have shown different findings, including larger gray matter volumes in the frontomedial cortex (Goldstein et al., 2001, Raz et al., 2004), cingulate cortex (Raz et al., 2004), and hippocampus (Raz et al., 2004) in men and larger gray matter volumes in the temporal gyrus (Luders et al., 2009) in women or no gender differences in the basal ganglia (Chen et al., 2007), amygdala (Gur et al., 2002) and hippocampus (Gur et al., 2002). One study (Yamasue et al., 2008) investigated the gender-related neuroanatomical basis of human anxiety-related personality traits and found a correlation between smaller regional brain volume in the left anterior prefrontal cortex and higher anxiety-related personality traits only in female group. The brain regions with gender differences, such as the amygdala, hippocampus, cingulate gyrus and prefrontal cortex, have been suggested to be involved in anxiety circuitry (Shin and Liberzon, 2010). The question arises as to whether gender might interact with the development of GAD.
In the limited studies exploring the alterations of gray matter volumes in GAD patients, three studies (Etkin et al., 2009, Milham et al., 2005, Mohlman et al., 2009) did not examine the gender effect on the gray matter volumes, two studies (Hettema et al., 2012, Schienle et al., 2011) only investigated female population, one study (Terlevic et al., 2013) considered gender as a covariant to control, and only one study (De Bellis et al., 2000) examined the gender effect but found no gender-by-diagnosis interaction effects on gray matter volumes. In this study, we employed high-resolution structural magnetic resonance imaging techniques and a voxel-based morphometry (VMB) analysis approach to assess the gender-by-diagnosis interaction effects in gray matter volumes. Given the existence of gender-related differences in brain structure and gender differences of clinical phenomenology in GAD, we hypothesized that the gender-related brain structural differences might be associated with GAD. For lack of evidence on gender related differences in brain structure in GAD, we conducted a whole brain analysis to explore the possible brain regions that might mediate gender effect and the development of GAD.
Section snippets
Subjects
Twenty-six adolescents with GAD (13 female and 13 male) and 25 healthy controls (12 female and 13 male) were recruited in the present study. All subjects were recruited from local high schools in Hunan Province via advertisements and school notice, as described in our previous study (Liao et al., 2013). First, 1885 subjects finished the 41-item self-report questionnaire, the Screen for Child Anxiety Related Emotional Disorders (SCARED) (Birmaher et al., 1999, Su et al., 2008). The SCARED is a
Results
The demographic and clinical measures between GAD patients and healthy controls were listed in Table 1. There were no significant differences between the two groups in gender and age. Across the gender, there were no significant differences in age. No significant gender differences were found in BDI and PSWQ scores in adolescent GAD patients.
A significant diagnosis main effect was found in the right putamen (x=27, y=11, z=10, F1,46=34.21, pFWE-corrected=0.012; cluster size k=361), with larger
Discussion
High-resolution structural magnetic resonance imaging and voxel-based morphometry approaches were employed in the current study to explore the gender effect on gray matter volumes in GAD patients. We found a significant diagnosis main effect in the right putamen. We also found significant gender main effect on the left precuneus/posterior cingulate cortex and marginally significant gender effects on the bilateral caudate and the right orbitofrontal cortex. No gender-by-diagnosis interaction
Role of funding source
This study was supported by the National Natural Science Foundation of China (30830046, 81171286 and 91232714 to Lingjiang Li, 81171291 to Linyan Su, and 81101004 to Yan Zhang), the National 973 Program of China (2009CB918303 to Lingjiang Li) and Program of Chinese Ministry of Education (20090162110011 to Lingjiang Li).
Conflict of interest
No conflict declared.
Acknowledgments
We thank all subjects that participated in this study.
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2021, Journal of Affective DisordersCitation Excerpt :Of note, the GAD patients are all treatment-naïve and first episode, which rules out the confounding effects of medication, psychotherapeutic interventions and cumulative disease load (Madonna et al., 2019). This dataset has been used to study gray matter volumes (Liao et al., 2014b), temporal features of dynamic and frequency-specific FC density (Zhang et al., 2017), functional connectivity (Yang et al., 2019), and white matter structural connectivity (Yang et al., 2020). Using multimodal approach, the current study thus goes beyond the previous works using the same dataset to incorporate both the functional and structural alterations and assess the functional and structural couplings in relation to GAD.
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2021, Journal of Affective DisordersCitation Excerpt :The current study found qualitatively and quantitatively negative effects of demographic and clinical variables, such as psychiatric comorbidity and concomitant medication use, on regional GMV alterations in PD patients, together with qualitatively mixed effects in SAD patients. The sex differences in cerebral volume were evenly distributed, with all four equally smaller lobes (Nopoulos et al., 2000) and a smaller cingulate cortex (Liao et al., 2014) being found in females compared to males, in line with our finding of the negative correlation between a higher percentage of female PD patients and a smaller right ACC volume quantitatively. Similarly, other studies also reported that PD patients with more severe anxiety-related clinical symptoms tended to have more GMV deficits in the prefrontal and temporal-parietal cortices and subcortical regions (Lai, 2011; Lai and Hsu, 2011).
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Shared genetic etiology between anxiety disorders and psychiatric and related intermediate phenotypes
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Mei Liao and Fan Yang are first co-authors.