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Clinical brain imaging
Whole-brain gray matter volume abnormalities in patients with generalized anxiety disorder: voxel-based morphometry Chung-Man Moona, Gwang-Won Kimb and Gwang-Woo Jeonga,c Patients with generalized anxiety disorder (GAD) experience psychological distress because of excessive and uncontrollable anxiety in everyday life. Only a few morphological studies have so far focused on specific brain regions of interest as well as the gray matter volume changes in GAD patients. This study evaluated gray matter volume alterations in whole-brain areas between GAD patients and healthy controls, and sex differences between the specific brain areas with significant volume changes in GAD patients using voxel-based morphometry. Twenty-two patients with GAD (13 men and nine women), who were diagnosed using the DSM-IV-TR, and 22 age-matched healthy controls (13 men and nine women) participated in this study. The high-resolution MRI data were processed using voxel-based morphometry analysis on the basis of diffeomorphic anatomical registration through an exponentiated Lie algebra algorithm in Statistical Parametric Mapping 8. There was no significant difference in the total intracranial volume between GAD patients and controls, but a significant difference was observed between sexes (P < 0.05). Patients with GAD showed significant volume reductions in the hippocampus, midbrain, thalamus, insula, and superior temporal gyrus compared with the controls. As for the sex comparison,
Introduction Patients with generalized anxiety disorder (GAD) diagnosed by DSM-IV-TR criteria are characterized by psychological distress because of excessive and uncontrollable anxiety [1]. The European Study on the Epidemiology of Mental Disorders reported that patients with GAD have a higher frequency of suicidal ideation and attempts than patients with other anxiety disorders [2]. Moreover, the diagnosis of GAD is difficult because of a high rate of comorbidity, frequently occurring depression, and panic disorder [2]. The diagnosis of GAD has been commonly compromised by its dependence on sensual evaluation methods based on clinical questionnaires [3]. Therefore, an advanced study is needed to determine the neuroanatomical mechanisms associated with GAD using quantitative indicators for the diagnostic accuracy of GAD. Recently, functional MRI studies [4,5] have shown the association of cerebral centers with major symptoms of GAD. Patients with GAD showed differential activation patterns in the regions of the amygdala (Amg), ventrolateral prefrontal cortex, and anterior cingulate cortex in response to anxiety-inducing negative images compared c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4965
female patients showed a significant increase in the volume of the dorsolateral prefrontal cortex relative to male patients. Also, the volume of the dorsolateral prefrontal cortex in female patients was correlated positively with the Hamilton Anxiety Rating Scale score (c = 0.68, P = 0.04). The specific morphological variations in patient with GAD will be helpful to understand the neural mechanism associated with a symptom of GAD. Furthermore, the findings would be valuable for the diagnostic accuracy of GAD using c morphometric MRI analysis. NeuroReport 25:184–189 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. NeuroReport 2014, 25:184–189 Keywords: generalized anxiety disorder, sex, voxel-based morphometry a Interdisciplinary Program of Biomedical Engineering, Chonnam National University, bResearch Institute for Medical Imaging, Chonnam National University Medical School and cDepartment of Radiology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
Correspondence to Gwang-Woo Jeong, MPh, PhD, Department of Radiology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju 501 757, Republic of Korea Tel: + 82 62 220 5881; fax: + 82 62 226 4280; e-mail: [email protected] Received 29 October 2013 accepted 5 November 2013
with healthy controls. These differential activation areas could be considered the brain centers that are associated closely with the major symptoms of GAD. In particular, a neuroimaging study investigated the association between specific brain activation pattern and volumetric alteration in GAD patients with an average duration of illness of 3 years. The Amg volume increased in patients with GAD relative to healthy controls, and was correlated positively with specific activation induced by anxiety or worry [6]. Therefore, both the brain function and the brain morphology in patients with GAD could be altered by the anxiety symptoms. With the help of volumetry using MRI, a couple of studies [6,7] investigated the morphological changes in patients with GAD using region of interest measurements and voxel-based morphometry (VBM). The VBM findings indicated that patients with GAD showed a significant increase in gray matter (GM) volumes of the Amg and dorsomedial prefrontal cortex (PFC) compared with healthy controls [6]. Also, compared with healthy controls, adolescents with GAD showed increased volumes in the regions of the precuneus and precentral gyrus, but decreased volumes in the orbital and posterior cingulate DOI: 10.1097/WNR.0000000000000100
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Regional volume changes Moon et al. 185
gyrus [7]. Volumetric changes in these regions were consistent with differential activation areas in patients with GAD during excessive anxiety.
Statistical Parametric Mapping 8 (SPM8) program (Wellcome Department of Imaging Neuroscience, London, UK).
These findings support the view that hyperactivation in specific brain areas associated with major symptoms of GAD could lead to volumetric alterations. However, few morphological studies have been carried out and have focused only on specific brain regions of interest; the volume changes in patients with GAD were inconsistent between the studies. Therefore, one of the major purposes of the current study was to assess the wholebrain areas related to major symptoms of GAD.
The T1-weighted images of each of the 44 participants were aligned with the plane of the anterior and posterior commissure. Field bias correction was performed to correct nonuniformity field on images. GM, white matter, and cerebrospinal fluid of each tissue image were segmented using tissue probability maps on the basis of the International Consortium of Brain Mapping space template type of East Asian Brains provided by SPM8. The mean template in each group was created using individual GM images and these images were spatially normalized to the mean template with Jacobian determinants. The images were spatially normalized to the Montreal Neurological Institute template, modulated in terms of GM volume, and smoothed with an 8-mm fullwidth at half-maximum Gaussian kernel to increase the signal-to-noise ratio.
The major feature of prevalence rate in patients with GAD is the sex difference. In the National Comorbidity Survey [8], which included 8098 participants, the morbidity rate of GAD was twice in women than in men (6.6 vs. 3.6%). Another study [9] reported that the anxiety sensitivity in female patients was higher than that in male patients, suggesting sex-related difference in the prevalence of GAD. This study compared the GM-based structural volume alterations between patients with GAD and healthy controls, and further to determine the sex differences between the specific brain areas with significant volume changes in patients with GAD.
Participants and methods Participants
A total of 44 individuals were studied: 22 patients with GAD (mean age, 37.0±10.7 years; 13 men and nine women) who were diagnosed using the DSM-IV-TR by a psychiatrist and 22 age-matched sex-matched healthy controls (mean age, 33.4±9.7 years). The duration of illness of the patients was 4.5±6.6 years (Table 1). The anxiety level of the participants was assessed by the Hamilton Anxiety Rating Scale (HAMA; 14 items with a five-level scale, cutoff score > 14). All participants provided informed written consent before participation in this study. The study protocol was approved by the Chonbuk National University Hospital Institutional Review Board. Magnetic resonance imaging
Participants were examined using a 3 T Magnetom Verio MR Scanner (Siemens Medical Solutions, Erlangen, Germany) with a birdcage head coil. The high-resolution T1-weighted images [repetition time (TR)/echo time (TE) = 1900/2.35, field of view = 22 22 cm2, matrix size = 256 256, number of excitations = 1, and slice thickness = 5 mm] were acquired using a three-dimensional magnetization-prepared rapid acquisition gradient-echo sequence. Postprocessing and statistical analysis of magnetic resonance images
High-resolution MRI data processing and statistical analysis were carried out using VBM analysis with the
After postprocessing, GM volume alterations in patients with GAD and healthy controls, as well as in male and female patients, were assessed using an independent twosample t-test. To correct the difference in the total volume between male and female patients, total intracranial volume (TICV) obtained by summing the GM, white matter, and cerebrospinal fluid volumes (ml) in each participant was used as a covariate for analysis of covariance. Then, the anatomical labeling for specific areas with volume changes between patients with GAD and healthy controls, as well as between sexes in patients with GAD was implemented using FALBA [10], which is useful to identify and quantify the volumetric changes. The x, y, and z coordinates of the maximum t-value were based on the MNI brain space. The correlation between volume and anxiety level (the rating score of HAMA) in male and female patients was analyzed by a simple correlation test. Also, the difference in anxiety level in both groups was analyzed by an independent two-sample t-test using SPSS 19.0 (SPSS Inc., Chicago, Illinois, USA).
Results Assessment of anxiety level
Compared with healthy controls, patients with GAD scored significantly higher on the HAMA (P < 0.001). The score of female patients (mean±SD, 18.3±6.3) compared with male patients (mean±SD, 17.5±2.7) was not significantly different (Table 1). Total intracranial volume
The TICV was 1570.9±176.6 ml for patients with GAD and 1609.6±147.6 ml for healthy controls. There was no significant difference in TICV between both groups. In addition, TICV was 1659.0±161.3 ml for male patients and 1443.7±109.6 ml for female patients. There was a significant difference between sexes (P < 0.05).
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Table 1
Characteristics of patients with generalized anxiety disorder and healthy controls Patients with GAD (n = 22)
a
Age (years) Education (years)a Duration of illness (years) Hamilton Anxiety Rating Scale (HAMA)**
Healthy controls (n = 22)
Male (n = 13)
Female (n = 9)
Mean±SD
Male (n = 13)
Female (n = 9)
Mean±SD
35.6±13.4 13.9±2.2 4.9±8.2 17.5±2.7
38.9±5.0 13.9±2.7 4.0±3.6 18.3±6.3
37.0±10.7 13.9±2.3 4.5±6.6 17.9±4.5
29.4±8.8 14.6±2.6 – 0.6±0.9
39.1±8.2 15.1±1.8 – 1.0±1.4
33.4±9.7 14.8±2.3 – 0.8±1.1
GAD, generalized anxiety disorder. a No significant differences between patients with GAD and healthy controls (Mann–Whitney U-test). **Significant differences between patients with GAD and healthy controls (Mann–Whitney U-test, P < 0.001).
Table 2
Total intracranial volume estimates in milliliters
Men (n = 13) Women (n = 9) Total (n = 22)
GAD (n = 22)
Healthy controls (n = 22)
1659.0±161.3 1443.7±109.6 1570.9±176.6*
1683.1±130.5 1503.4±101.0 1609.6±147.6*
GAD, generalized anxiety disorder. *Significantly greater total intracranial volume in men relative to women (two-sample t-test, P < 0.05).
Therefore, TICV was used as the covariance in the statistical analysis between male and female patients (Table 2). Regional volume changes
Figure 1a shows the group differences in GM volume between patients with GAD and healthy controls, and regional volume alterations between the two groups are summarized in Table 3. Patients with GAD showed a significant reduction in volumes, especially in the regions of the hippocampus (Hip), midbrain, thalamus, insula, and superior temporal gyrus (STG) (uncorrected, P < 0.001). Hip, midbrain, thalamus, insula, and STG volumes in patients with GAD were significantly reduced compared with healthy controls. The specific volume changes between both sexes of patients with GAD are summarized in Fig. 1b. Women with GAD showed a significant increase in the volume of the dorsolateral prefrontal cortex (DLPFC) (family-wise error, P < 0.05) (Fig. 1b). Therefore, the sex-related difference in the prevalence rate of GAD could be associated with volume change in the DLPFC. The reversed contrast (GAD > controls, men with GAD > women with GAD) showed no localized increases in volume. Correlation of volume with anxiety level
Figure 2 shows the correlation between the volume and anxiety level in both groups, as well as in the sex of patients with GAD. The volume of the DLPFC in female patients was correlated positively with the HAMA score (g = 0.68, P = 0.04). However, there was no correlation in both groups and male patients.
Discussion Volume deformation related to the pathogenesis and status of disease in the brain can be diagnosed using
morphometric MRI analysis [11]. In the present study, the specific volume alterations in patients with GAD and healthy controls, as well as in male and female patients, were assessed by qualitative and quantitative analyses using the diffeomorphic anatomical registration through the exponentiated Lie algebra (DARTEL) algorithm in VBM-based SPM8. An interesting feature of this study is the reduced volume in the Hip in patients with GAD. Hip innervates various types of hormone receptors and plays an important role in neuroendocrine system associated with the hypothalamic– pituitary–adrenal (HPA) axis [12]. In particular, it was reported that Hip in patients with psychiatric disorders is hypersensitive in response to emotional experiences such as stress and anxiety [13]. In other words, emotional and stressful responses under the normal status without any disorders in the Hip are regulated by appropriate secretion of glucocorticoid hormone during anxiety-induced or stress-induced activation of the HPA axis, whereas such responses under the symptoms of psychiatric disorders are regulated by glucocorticoid hypersecretion during psychiatric symptoms-induced hyperactivation of the HPA axis. Consequently, an increase in glucocorticoid concentration leads to neurotoxicity and volume reduction in Hip. An animal study [14] reported that glucocorticoid hypersecretion during anxiety or depression caused neuronal damage, reduction, and neurogenesis deficits in the Hip. In addition, a recent study [15] showed that major symptoms of patients with GAD were closely related to abnormalities of HPA axis and an increase in glucocorticoid concentration. These neuroscientific findings support the views that the Hip is associated with hypersensitive responses in anxiety or stress induced by psychiatric disorders including GAD, and that glucocorticoid hypersecretion in this area could lead to neuronal damage and volume alterations. However, in patients with GAD, the volumetric change in the Hip has not been clearly identified. In a 1H-MR spectroscopy study [16], the level of N-acetylaspartate, which is a biochemical marker of cellular dysfunction and/or neuronal loss, decreased in the Hip of patients with GAD compared with healthy controls. Furthermore, the neuronal loss, deformation, and/or volume change in the Hip were closely related to the GAD symptoms and abnormalities
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Regional volume changes Moon et al. 187
Fig. 1
(a)
(b)
R
L
S L DLPFC
DLPFC P A MB Th
R
Hip
I
x = −4
y = −32
x = −21
DLPFC
STG Ins DLPFC STG
z=9 z = −19
x = −42
y = 52
z = 21
Brain areas with significant alterations in gray matter volume in healthy controls over patients with generalized anxiety disorder (a) and female patients over male patients (b), which were obtained from a two-sample t-test. Hip, hippocampus; MB, midbrain; Th, thalamus; STG, superior temporal gyrus; Ins, insula; DLPFC, dorsolateral prefrontal cortex.
Brain regions with significant alterations in gray matter volume between patients with generalized anxiety disorder and healthy controls (a), and generalized anxiety disorder men and generalized anxiety disorder women (b) (two-sample t-test)
Table 3
Brain areas (a) Group comparison GAD (n = 22) < controls (n = 22) Midbrain (MB) Thalamus (Th) Hippocampus (Hip) Insula (Ins) Superior temporal gyrus (STG) GAD (n = 22) > controls (n = 22) None (b) Sex comparison GAD men (n = 13) < GAD women (n = 9) DLPFC (SFG) GAD men (n = 13) > GAD women (n = 9) None
t-value
MNI coordinates (x, y, z)
Voxels in cluster
P-value
5.09 4.53 3.84 3.78 3.64
(– 5, – 9, – 13) (– 7, – 17, 13) (– 29, – 32, – 8) (– 39, – 9, 9) (– 42, 19, – 19)
281 648 51 55 64
Uncorrected, P < 0.001
–
–
–
–
8.64
(– 21, 52, 12)
–
–
68 –
FWE, P < 0.05 –
DLPFC (SFG), dorsolateral prefrontal cortex (superior frontal gyrus); FEW, family-wise error; GAD, generalized anxiety disorder.
of emotional response to anxiety. Therefore, the volume alteration of the Hip can be considered as an important morphological feature in patients with GAD. Patients with GAD showed a significant reduction in the insula and STG relative to controls. The insula and STG play an important role in regulating the interoception, which is the sense of the physiological condition from the internal organs such as temperature, pain, and movement induced by anxiety response [17,18]. Although the insula is a stable and invariant structure, and the ratio of the insular volume to the total cortical volume remains almost constant in healthy controls [19], in psychiatric patients experiencing anxiety disorder, depression, bipolar disorder,
and psychosis, a volume reduction has been reported compared with controls [17]. Also, the STG in patients with anxiety disorders such as GAD, panic disorder, and social anxiety disorder are atrophied relative to controls [18]. These findings suggest that the volume reductions in the insula and STG are associated with difficulties in emotional response and lower function of interoceptive sense by anxiety-inducing situations. Therefore, the morphological alterations in the insula and STG could be considered the feature reflecting psychopathological and/or GAD symptoms. The midbrain and thalamus, significant areas in this study, showed a decrease in volume of patients with GAD
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Fig. 2
0.5
DLPFC volumes
0.4
0.3
0.2
0.1
0.0 5
10
20 15 HAMA scores
25
30
Correlation between the dorsolateral prefrontal cortex (DLPFC) volumes and Hamilton Anxiety Rating Scale (HAMA) scores in female patients with generalized anxiety disorder (P < 0.04, Spearman’s correlation coefficient = 0.68), in which the band with dotted lines shows 95% confidence interval.
compared with controls. Recently, a combined restingstate functional MRI and VBM study [20] reported that the midbrain, thalamus, and Amg in patients with GAD are functionally connected. In particular, the functional connectivity in patients with GAD was altered by emotional responses of anxiety or fear. Also, a previous study [21] showed that the neuronal loss or deformation in the midbrain and thalamus, which features the wide distribution of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) and serotonin transporter (5-HTT), is closely related to symptoms including anxiety, depression, and hysteria. Especially, Maron et al. [22] reported lower levels of serotonin transporter in the midbrain of women with GAD relative to healthy controls, and a negative correlation with anxiety level using a visual analogue scale. Reimold et al. [23] reported that serotonin transporter in the thalamus was correlated negatively with the State-Trait Anxiety Inventory score in psychiatric patients with depression and obsessive compulsive disorder with anxiety symptoms. These findings could reflect the increase in anxiety level in patients with anxiety disorders, with a heightened decrease in the serotonin transporter in the midbrain and thalamus. Therefore, this study suggests that the anxiety symptoms of GAD could be related to neuronal dysfunction and volume alterations in the midbrain and thalamus. This current study investigated for the first time the sex difference in the cortical volumes in patients with GAD. Female patients showed significantly larger volume than male patients in the DLPFC. Although the levels of anxiety or worry in male and female patients with GAD are sex dependent in terms of the prevalence rate [9], few morphometric or functional studies have been reported to date. Recently, a morphologic study [6] has
reported a positive correlation between volume variation and brain activity in patients with GAD. The activation of the DLPFC in patients with GAD increased in response to emotional stimuli [24]. The DLPFC has an executive function in working memory and regulation of emotional responses [25]. From these findings, the significant changes in the volume of the DLPFC would be related to specific brain activation induced by major symptoms of GAD. Especially, Schienle et al. [6] showed a correlation between the level of major symptom (Penn State Worry Questionnaire) and volume of the PFC in patients with GAD. The questionnaire score was correlated positively with its volume. Together with the previous findings, the volume change of the PFC in patients with GAD could be associated with the level of major symptoms. In this study, the anxiety level (HAMA) in female patients was higher than that in male patients, and also the level was correlated positively with the volume of the DLPFC (g = 0.68, P < 0.04). This finding supports the view that the DLPFC volume increases with an increase in anxiety level. Therefore, this study assumed that the significant volume difference in the DLPFC between male and female patients could be related to the difference in anxiety sensitivity by sex. The current study has several limitations. First, this study included small sample sizes in each group: 13 men and nine women. Second, patients with GAD took medicines, such as anxioytics and/or antidepressants. However, there was no consideration of the effects of the drugs on brain morphology.
Conclusion This study showed the localized GM volumetric differences between patients with GAD and healthy controls using VBM analysis, and further showed sex differences in the DLPFC volumes in patients with GAD. The findings on the specific morphological variations associated with a symptom of GAD will be useful for understanding the neuroanatomical mechanisms.
Acknowledgements This work was supported by the National Research Foundation of Korea (No. 2011-0016291). Conflicts of interest
There are no conflicts of interest.
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Clinical brain imaging
Whole-brain gray matter volume abnormalities in patients with generalized anxiety disorder: voxel-based morphometry Chung-Man Moona, Gwang-Won Kimb and Gwang-Woo Jeonga,c Patients with generalized anxiety disorder (GAD) experience psychological distress because of excessive and uncontrollable anxiety in everyday life. Only a few morphological studies have so far focused on specific brain regions of interest as well as the gray matter volume changes in GAD patients. This study evaluated gray matter volume alterations in whole-brain areas between GAD patients and healthy controls, and sex differences between the specific brain areas with significant volume changes in GAD patients using voxel-based morphometry. Twenty-two patients with GAD (13 men and nine women), who were diagnosed using the DSM-IV-TR, and 22 age-matched healthy controls (13 men and nine women) participated in this study. The high-resolution MRI data were processed using voxel-based morphometry analysis on the basis of diffeomorphic anatomical registration through an exponentiated Lie algebra algorithm in Statistical Parametric Mapping 8. There was no significant difference in the total intracranial volume between GAD patients and controls, but a significant difference was observed between sexes (P < 0.05). Patients with GAD showed significant volume reductions in the hippocampus, midbrain, thalamus, insula, and superior temporal gyrus compared with the controls. As for the sex comparison,
Introduction Patients with generalized anxiety disorder (GAD) diagnosed by DSM-IV-TR criteria are characterized by psychological distress because of excessive and uncontrollable anxiety [1]. The European Study on the Epidemiology of Mental Disorders reported that patients with GAD have a higher frequency of suicidal ideation and attempts than patients with other anxiety disorders [2]. Moreover, the diagnosis of GAD is difficult because of a high rate of comorbidity, frequently occurring depression, and panic disorder [2]. The diagnosis of GAD has been commonly compromised by its dependence on sensual evaluation methods based on clinical questionnaires [3]. Therefore, an advanced study is needed to determine the neuroanatomical mechanisms associated with GAD using quantitative indicators for the diagnostic accuracy of GAD. Recently, functional MRI studies [4,5] have shown the association of cerebral centers with major symptoms of GAD. Patients with GAD showed differential activation patterns in the regions of the amygdala (Amg), ventrolateral prefrontal cortex, and anterior cingulate cortex in response to anxiety-inducing negative images compared c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4965
female patients showed a significant increase in the volume of the dorsolateral prefrontal cortex relative to male patients. Also, the volume of the dorsolateral prefrontal cortex in female patients was correlated positively with the Hamilton Anxiety Rating Scale score (c = 0.68, P = 0.04). The specific morphological variations in patient with GAD will be helpful to understand the neural mechanism associated with a symptom of GAD. Furthermore, the findings would be valuable for the diagnostic accuracy of GAD using c morphometric MRI analysis. NeuroReport 25:184–189 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. NeuroReport 2014, 25:184–189 Keywords: generalized anxiety disorder, sex, voxel-based morphometry a Interdisciplinary Program of Biomedical Engineering, Chonnam National University, bResearch Institute for Medical Imaging, Chonnam National University Medical School and cDepartment of Radiology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea
Correspondence to Gwang-Woo Jeong, MPh, PhD, Department of Radiology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju 501 757, Republic of Korea Tel: + 82 62 220 5881; fax: + 82 62 226 4280; e-mail: [email protected] Received 29 October 2013 accepted 5 November 2013
with healthy controls. These differential activation areas could be considered the brain centers that are associated closely with the major symptoms of GAD. In particular, a neuroimaging study investigated the association between specific brain activation pattern and volumetric alteration in GAD patients with an average duration of illness of 3 years. The Amg volume increased in patients with GAD relative to healthy controls, and was correlated positively with specific activation induced by anxiety or worry [6]. Therefore, both the brain function and the brain morphology in patients with GAD could be altered by the anxiety symptoms. With the help of volumetry using MRI, a couple of studies [6,7] investigated the morphological changes in patients with GAD using region of interest measurements and voxel-based morphometry (VBM). The VBM findings indicated that patients with GAD showed a significant increase in gray matter (GM) volumes of the Amg and dorsomedial prefrontal cortex (PFC) compared with healthy controls [6]. Also, compared with healthy controls, adolescents with GAD showed increased volumes in the regions of the precuneus and precentral gyrus, but decreased volumes in the orbital and posterior cingulate DOI: 10.1097/WNR.0000000000000100
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Regional volume changes Moon et al. 185
gyrus [7]. Volumetric changes in these regions were consistent with differential activation areas in patients with GAD during excessive anxiety.
Statistical Parametric Mapping 8 (SPM8) program (Wellcome Department of Imaging Neuroscience, London, UK).
These findings support the view that hyperactivation in specific brain areas associated with major symptoms of GAD could lead to volumetric alterations. However, few morphological studies have been carried out and have focused only on specific brain regions of interest; the volume changes in patients with GAD were inconsistent between the studies. Therefore, one of the major purposes of the current study was to assess the wholebrain areas related to major symptoms of GAD.
The T1-weighted images of each of the 44 participants were aligned with the plane of the anterior and posterior commissure. Field bias correction was performed to correct nonuniformity field on images. GM, white matter, and cerebrospinal fluid of each tissue image were segmented using tissue probability maps on the basis of the International Consortium of Brain Mapping space template type of East Asian Brains provided by SPM8. The mean template in each group was created using individual GM images and these images were spatially normalized to the mean template with Jacobian determinants. The images were spatially normalized to the Montreal Neurological Institute template, modulated in terms of GM volume, and smoothed with an 8-mm fullwidth at half-maximum Gaussian kernel to increase the signal-to-noise ratio.
The major feature of prevalence rate in patients with GAD is the sex difference. In the National Comorbidity Survey [8], which included 8098 participants, the morbidity rate of GAD was twice in women than in men (6.6 vs. 3.6%). Another study [9] reported that the anxiety sensitivity in female patients was higher than that in male patients, suggesting sex-related difference in the prevalence of GAD. This study compared the GM-based structural volume alterations between patients with GAD and healthy controls, and further to determine the sex differences between the specific brain areas with significant volume changes in patients with GAD.
Participants and methods Participants
A total of 44 individuals were studied: 22 patients with GAD (mean age, 37.0±10.7 years; 13 men and nine women) who were diagnosed using the DSM-IV-TR by a psychiatrist and 22 age-matched sex-matched healthy controls (mean age, 33.4±9.7 years). The duration of illness of the patients was 4.5±6.6 years (Table 1). The anxiety level of the participants was assessed by the Hamilton Anxiety Rating Scale (HAMA; 14 items with a five-level scale, cutoff score > 14). All participants provided informed written consent before participation in this study. The study protocol was approved by the Chonbuk National University Hospital Institutional Review Board. Magnetic resonance imaging
Participants were examined using a 3 T Magnetom Verio MR Scanner (Siemens Medical Solutions, Erlangen, Germany) with a birdcage head coil. The high-resolution T1-weighted images [repetition time (TR)/echo time (TE) = 1900/2.35, field of view = 22 22 cm2, matrix size = 256 256, number of excitations = 1, and slice thickness = 5 mm] were acquired using a three-dimensional magnetization-prepared rapid acquisition gradient-echo sequence. Postprocessing and statistical analysis of magnetic resonance images
High-resolution MRI data processing and statistical analysis were carried out using VBM analysis with the
After postprocessing, GM volume alterations in patients with GAD and healthy controls, as well as in male and female patients, were assessed using an independent twosample t-test. To correct the difference in the total volume between male and female patients, total intracranial volume (TICV) obtained by summing the GM, white matter, and cerebrospinal fluid volumes (ml) in each participant was used as a covariate for analysis of covariance. Then, the anatomical labeling for specific areas with volume changes between patients with GAD and healthy controls, as well as between sexes in patients with GAD was implemented using FALBA [10], which is useful to identify and quantify the volumetric changes. The x, y, and z coordinates of the maximum t-value were based on the MNI brain space. The correlation between volume and anxiety level (the rating score of HAMA) in male and female patients was analyzed by a simple correlation test. Also, the difference in anxiety level in both groups was analyzed by an independent two-sample t-test using SPSS 19.0 (SPSS Inc., Chicago, Illinois, USA).
Results Assessment of anxiety level
Compared with healthy controls, patients with GAD scored significantly higher on the HAMA (P < 0.001). The score of female patients (mean±SD, 18.3±6.3) compared with male patients (mean±SD, 17.5±2.7) was not significantly different (Table 1). Total intracranial volume
The TICV was 1570.9±176.6 ml for patients with GAD and 1609.6±147.6 ml for healthy controls. There was no significant difference in TICV between both groups. In addition, TICV was 1659.0±161.3 ml for male patients and 1443.7±109.6 ml for female patients. There was a significant difference between sexes (P < 0.05).
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Table 1
Characteristics of patients with generalized anxiety disorder and healthy controls Patients with GAD (n = 22)
a
Age (years) Education (years)a Duration of illness (years) Hamilton Anxiety Rating Scale (HAMA)**
Healthy controls (n = 22)
Male (n = 13)
Female (n = 9)
Mean±SD
Male (n = 13)
Female (n = 9)
Mean±SD
35.6±13.4 13.9±2.2 4.9±8.2 17.5±2.7
38.9±5.0 13.9±2.7 4.0±3.6 18.3±6.3
37.0±10.7 13.9±2.3 4.5±6.6 17.9±4.5
29.4±8.8 14.6±2.6 – 0.6±0.9
39.1±8.2 15.1±1.8 – 1.0±1.4
33.4±9.7 14.8±2.3 – 0.8±1.1
GAD, generalized anxiety disorder. a No significant differences between patients with GAD and healthy controls (Mann–Whitney U-test). **Significant differences between patients with GAD and healthy controls (Mann–Whitney U-test, P < 0.001).
Table 2
Total intracranial volume estimates in milliliters
Men (n = 13) Women (n = 9) Total (n = 22)
GAD (n = 22)
Healthy controls (n = 22)
1659.0±161.3 1443.7±109.6 1570.9±176.6*
1683.1±130.5 1503.4±101.0 1609.6±147.6*
GAD, generalized anxiety disorder. *Significantly greater total intracranial volume in men relative to women (two-sample t-test, P < 0.05).
Therefore, TICV was used as the covariance in the statistical analysis between male and female patients (Table 2). Regional volume changes
Figure 1a shows the group differences in GM volume between patients with GAD and healthy controls, and regional volume alterations between the two groups are summarized in Table 3. Patients with GAD showed a significant reduction in volumes, especially in the regions of the hippocampus (Hip), midbrain, thalamus, insula, and superior temporal gyrus (STG) (uncorrected, P < 0.001). Hip, midbrain, thalamus, insula, and STG volumes in patients with GAD were significantly reduced compared with healthy controls. The specific volume changes between both sexes of patients with GAD are summarized in Fig. 1b. Women with GAD showed a significant increase in the volume of the dorsolateral prefrontal cortex (DLPFC) (family-wise error, P < 0.05) (Fig. 1b). Therefore, the sex-related difference in the prevalence rate of GAD could be associated with volume change in the DLPFC. The reversed contrast (GAD > controls, men with GAD > women with GAD) showed no localized increases in volume. Correlation of volume with anxiety level
Figure 2 shows the correlation between the volume and anxiety level in both groups, as well as in the sex of patients with GAD. The volume of the DLPFC in female patients was correlated positively with the HAMA score (g = 0.68, P = 0.04). However, there was no correlation in both groups and male patients.
Discussion Volume deformation related to the pathogenesis and status of disease in the brain can be diagnosed using
morphometric MRI analysis [11]. In the present study, the specific volume alterations in patients with GAD and healthy controls, as well as in male and female patients, were assessed by qualitative and quantitative analyses using the diffeomorphic anatomical registration through the exponentiated Lie algebra (DARTEL) algorithm in VBM-based SPM8. An interesting feature of this study is the reduced volume in the Hip in patients with GAD. Hip innervates various types of hormone receptors and plays an important role in neuroendocrine system associated with the hypothalamic– pituitary–adrenal (HPA) axis [12]. In particular, it was reported that Hip in patients with psychiatric disorders is hypersensitive in response to emotional experiences such as stress and anxiety [13]. In other words, emotional and stressful responses under the normal status without any disorders in the Hip are regulated by appropriate secretion of glucocorticoid hormone during anxiety-induced or stress-induced activation of the HPA axis, whereas such responses under the symptoms of psychiatric disorders are regulated by glucocorticoid hypersecretion during psychiatric symptoms-induced hyperactivation of the HPA axis. Consequently, an increase in glucocorticoid concentration leads to neurotoxicity and volume reduction in Hip. An animal study [14] reported that glucocorticoid hypersecretion during anxiety or depression caused neuronal damage, reduction, and neurogenesis deficits in the Hip. In addition, a recent study [15] showed that major symptoms of patients with GAD were closely related to abnormalities of HPA axis and an increase in glucocorticoid concentration. These neuroscientific findings support the views that the Hip is associated with hypersensitive responses in anxiety or stress induced by psychiatric disorders including GAD, and that glucocorticoid hypersecretion in this area could lead to neuronal damage and volume alterations. However, in patients with GAD, the volumetric change in the Hip has not been clearly identified. In a 1H-MR spectroscopy study [16], the level of N-acetylaspartate, which is a biochemical marker of cellular dysfunction and/or neuronal loss, decreased in the Hip of patients with GAD compared with healthy controls. Furthermore, the neuronal loss, deformation, and/or volume change in the Hip were closely related to the GAD symptoms and abnormalities
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Regional volume changes Moon et al. 187
Fig. 1
(a)
(b)
R
L
S L DLPFC
DLPFC P A MB Th
R
Hip
I
x = −4
y = −32
x = −21
DLPFC
STG Ins DLPFC STG
z=9 z = −19
x = −42
y = 52
z = 21
Brain areas with significant alterations in gray matter volume in healthy controls over patients with generalized anxiety disorder (a) and female patients over male patients (b), which were obtained from a two-sample t-test. Hip, hippocampus; MB, midbrain; Th, thalamus; STG, superior temporal gyrus; Ins, insula; DLPFC, dorsolateral prefrontal cortex.
Brain regions with significant alterations in gray matter volume between patients with generalized anxiety disorder and healthy controls (a), and generalized anxiety disorder men and generalized anxiety disorder women (b) (two-sample t-test)
Table 3
Brain areas (a) Group comparison GAD (n = 22) < controls (n = 22) Midbrain (MB) Thalamus (Th) Hippocampus (Hip) Insula (Ins) Superior temporal gyrus (STG) GAD (n = 22) > controls (n = 22) None (b) Sex comparison GAD men (n = 13) < GAD women (n = 9) DLPFC (SFG) GAD men (n = 13) > GAD women (n = 9) None
t-value
MNI coordinates (x, y, z)
Voxels in cluster
P-value
5.09 4.53 3.84 3.78 3.64
(– 5, – 9, – 13) (– 7, – 17, 13) (– 29, – 32, – 8) (– 39, – 9, 9) (– 42, 19, – 19)
281 648 51 55 64
Uncorrected, P < 0.001
–
–
–
–
8.64
(– 21, 52, 12)
–
–
68 –
FWE, P < 0.05 –
DLPFC (SFG), dorsolateral prefrontal cortex (superior frontal gyrus); FEW, family-wise error; GAD, generalized anxiety disorder.
of emotional response to anxiety. Therefore, the volume alteration of the Hip can be considered as an important morphological feature in patients with GAD. Patients with GAD showed a significant reduction in the insula and STG relative to controls. The insula and STG play an important role in regulating the interoception, which is the sense of the physiological condition from the internal organs such as temperature, pain, and movement induced by anxiety response [17,18]. Although the insula is a stable and invariant structure, and the ratio of the insular volume to the total cortical volume remains almost constant in healthy controls [19], in psychiatric patients experiencing anxiety disorder, depression, bipolar disorder,
and psychosis, a volume reduction has been reported compared with controls [17]. Also, the STG in patients with anxiety disorders such as GAD, panic disorder, and social anxiety disorder are atrophied relative to controls [18]. These findings suggest that the volume reductions in the insula and STG are associated with difficulties in emotional response and lower function of interoceptive sense by anxiety-inducing situations. Therefore, the morphological alterations in the insula and STG could be considered the feature reflecting psychopathological and/or GAD symptoms. The midbrain and thalamus, significant areas in this study, showed a decrease in volume of patients with GAD
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Fig. 2
0.5
DLPFC volumes
0.4
0.3
0.2
0.1
0.0 5
10
20 15 HAMA scores
25
30
Correlation between the dorsolateral prefrontal cortex (DLPFC) volumes and Hamilton Anxiety Rating Scale (HAMA) scores in female patients with generalized anxiety disorder (P < 0.04, Spearman’s correlation coefficient = 0.68), in which the band with dotted lines shows 95% confidence interval.
compared with controls. Recently, a combined restingstate functional MRI and VBM study [20] reported that the midbrain, thalamus, and Amg in patients with GAD are functionally connected. In particular, the functional connectivity in patients with GAD was altered by emotional responses of anxiety or fear. Also, a previous study [21] showed that the neuronal loss or deformation in the midbrain and thalamus, which features the wide distribution of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) and serotonin transporter (5-HTT), is closely related to symptoms including anxiety, depression, and hysteria. Especially, Maron et al. [22] reported lower levels of serotonin transporter in the midbrain of women with GAD relative to healthy controls, and a negative correlation with anxiety level using a visual analogue scale. Reimold et al. [23] reported that serotonin transporter in the thalamus was correlated negatively with the State-Trait Anxiety Inventory score in psychiatric patients with depression and obsessive compulsive disorder with anxiety symptoms. These findings could reflect the increase in anxiety level in patients with anxiety disorders, with a heightened decrease in the serotonin transporter in the midbrain and thalamus. Therefore, this study suggests that the anxiety symptoms of GAD could be related to neuronal dysfunction and volume alterations in the midbrain and thalamus. This current study investigated for the first time the sex difference in the cortical volumes in patients with GAD. Female patients showed significantly larger volume than male patients in the DLPFC. Although the levels of anxiety or worry in male and female patients with GAD are sex dependent in terms of the prevalence rate [9], few morphometric or functional studies have been reported to date. Recently, a morphologic study [6] has
reported a positive correlation between volume variation and brain activity in patients with GAD. The activation of the DLPFC in patients with GAD increased in response to emotional stimuli [24]. The DLPFC has an executive function in working memory and regulation of emotional responses [25]. From these findings, the significant changes in the volume of the DLPFC would be related to specific brain activation induced by major symptoms of GAD. Especially, Schienle et al. [6] showed a correlation between the level of major symptom (Penn State Worry Questionnaire) and volume of the PFC in patients with GAD. The questionnaire score was correlated positively with its volume. Together with the previous findings, the volume change of the PFC in patients with GAD could be associated with the level of major symptoms. In this study, the anxiety level (HAMA) in female patients was higher than that in male patients, and also the level was correlated positively with the volume of the DLPFC (g = 0.68, P < 0.04). This finding supports the view that the DLPFC volume increases with an increase in anxiety level. Therefore, this study assumed that the significant volume difference in the DLPFC between male and female patients could be related to the difference in anxiety sensitivity by sex. The current study has several limitations. First, this study included small sample sizes in each group: 13 men and nine women. Second, patients with GAD took medicines, such as anxioytics and/or antidepressants. However, there was no consideration of the effects of the drugs on brain morphology.
Conclusion This study showed the localized GM volumetric differences between patients with GAD and healthy controls using VBM analysis, and further showed sex differences in the DLPFC volumes in patients with GAD. The findings on the specific morphological variations associated with a symptom of GAD will be useful for understanding the neuroanatomical mechanisms.
Acknowledgements This work was supported by the National Research Foundation of Korea (No. 2011-0016291). Conflicts of interest
There are no conflicts of interest.
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