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Aims: Anxiety a core feature of panic disorder, is linked to function of the amygdala. Volume alterations in the brain of patients with panic disorder have previously been reported, but there has been no report of amygdala volume association with anxiety.
Methods: Volumes of hippocampus and amygdala were manually measured using magnetic resonance imaging obtained from 27 patients with panic disorder and 30 healthy comparison subjects. In addition the amygdala was focused on, applying small volume correction to optimized voxel-based morphometry (VBM). State–Trait Anxiety Inventory and the NEO Personality Inventory Revised were also used to evaluate anxiety.
Results: Amygdala volumes in both hemispheres were significantly smaller in patients with panic disorder compared with control subjects (left: t = −2.248, d.f. = 55, P = 0.029; right: t = −2.892, d.f. = 55, P = 0.005). VBM showed that structural alteration in the panic disorder group occurred on the corticomedial nuclear group within the right amygdala (coordinates [x,y,z (mm)]: [26,−6,−16], Z score = 3.92, family-wise error-corrected P = 0.002). The state anxiety was negatively correlated with the left amygdala volume in patients with panic disorder (r = −0.545, P = 0.016).
Conclusions: These findings suggested that the smaller volume of the amygdala may be associated with anxiety in panic disorder. Of note, the smaller subregion in the amygdala estimated on VBM could correspond to the corticomedial nuclear group including the central nucleus, which may play a crucial role in panic attack.
PANIC DISORDER (PD) is a complex anxiety disorder characterized by recurrent episodes of sudden and uncontrollable fear (panic attack) and autonomic imbalance such as palpitation, perspiration, trembling, shortness of breath, a sense of suffocation, chest pain or discomfort, nausea or gastrointestinal discomfort, and dizziness.
The amygdala, a major target in the present study, is divided phylogenetically into two groups: the corticomedial nuclear group and basolateral nuclear group.1,2 The corticomedial nuclear group includes the cortical nucleus (CO), medial nucleus (ME) and central nucleus (CE). The basolateral nuclear group includes the lateral nucleus (LA), basal nucleus (BA), and accessory basal nucleus (ABA). The corticomedial nuclear group occupies the dorsal medial area in amygdala.3 The CE is located near the tail of the caudate nucleus and putamen, mamillary body, and hippocampal head.4
The neurobiological pathway of PD has been considered to act along a circuit mainly involving the amygdala according to previous animal studies.5–7 Viscerosensory information is conveyed to the CE via LA and BA in the amygdala. When the CE recognizes input information as ‘fear’, it activates the autonomic nervous system.7 Thus these studies suggest that the CE plays a very important role in PD pathophysiology.
Recently human brain regions including the medial temporal lobe, amygdala, and hippocampus have been linked to anxiety and depression.8–10 Regional gray matter (GM) volume reduction in the brain of patients with PD compared with healthy controls has been reported on magnetic resonance imaging (MRI). Manual tracing studies for PD showed smaller GM volumes in right temporal lobe,11 bilateral temporal lobes,12 and bilateral amygdala.13 Previous voxel-based morphometry (VBM) studies for PD demonstrated volume reduction in the left parahippocampal gyrus;14 volume increase in the midbrain, rostral pons and the left hippocampus with a prefrontal cortex volumes decrease;15 increased GM volume in the left insula, the left superior temporal gyrus, the midbrain and the pons, and volume reduction in right anterior cingulate cortex.16 Asami et al. previously reported the volume reduction of the right anterior cingulate cortex (ACC) in PD17 although no relationship was detected between ACC volumes and anxiety.
The basic conception of PD is fear of panic attack and anticipatory anxiety, ‘Panic attack may happen to me’. Fear and anxiety are inseparably connected the function of the amygdala, and the sense of fear is stored in the hippocampus area. The amygdala and hippocampus may play an important role in PD but there have been few MRI structural studies, or studies on the association of structure with function, in those regions.
The combination of region of interest (ROI) and optimized VBM was used in the present study. It has been suggested that the manually traced ROI is superior in anatomical accuracy to the atlas-based ROI in optimized VBM, although it may be potentially influenced by rater bias. In contrast, optimized VBM may be unbiased, and reproducible. Therefore, it has been suggested that the manually traced ROI and optimized VBM provide different aspects of information and should thus be used in tandem.18
The aim of the present study was to investigate structural alterations in the hippocampus and amygdala of PD patients compared with healthy comparison (HC) subjects. Subsequent VBM with small volume correction was applied to investigate which subregion in the medial temporal region might be more affected in PD patients. Furthermore, we investigated whether any structural alteration in the medial temporal region may be associated with anxiety in the PD population. As far as we know, this is the first paper to report a structure–function association between amygdala volume and anxiety in PD.
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Table 1 lists demographic and clinical characteristics of the two study groups. The two groups did not differ significantly in age, gender, handedness, subject's own and parental SES, or IQ score. GAF scores, however, were significantly lower in PD patients than in HC subjects (t = −8.67, d.f. = 55, P < 0.001). Also, education (years of schooling) was significantly shorter in PD patients than in HC subjects (t = −2.48, d.f. = 55, P = 0.02). STAI-T and STAI-S scores were significantly higher in PD patients than in HC subjects (STAI-T: t = 4.54, d.f. = 45, P = 0.00004; STAI-S: t = 4.26, d.f. = 45, P = 0.0001). Neuroticism score on the NEO-PI-R was also significantly different (t = 3.27, d.f. = 45, P = 0.002).
Table 1. Subject details
|Variable||Panic disorder patients (n = 27)||Healthy comparison subjects (n = 30)|| t-test|
|Mean||SD||Mean||SD|| t (d.f. = 55)|| P |
|Gender(male/female)||10/17|| ||9/21|| || || |
|Socioeconomic status§|| || || || || || |
|WAIS-R IQ score¶||105.1||13.4||110.1||14.2||1.20||0.23|
|Age first medicated (years)||33.1||10.0|| || || || |
|Duration of illness (years)||5.4||6.4|| || || || |
|PDSS||8.8||4.8|| || || || |
Three-way ANOVA indicated a significant group × hemisphere interaction (F = 7.957, d.f. = 1, 55, P = 0.007) without main effect of group (F = 0.115, d.f. = 1,55, P = 0.736). The two-way ANOVA in amygdala volume showed no significant group × hemisphere interaction (F = 0.184, d.f. = 1,55, P = 0.669) and a significant main effect of group (F = 9.110, d.f. = 1,55, P = 0.004). The two-way anova in hippocampus volume indicated a significant group × hemisphere interaction (F = 10.609, d.f. = 1,55, P = 0.002) without main effect of group (F = 0.335, d.f. = 1,55, P = 0.565). Post-hoc t-tests indicated that right amygdala volume was significantly different (t = −2.892, d.f. = 55, P = 0.005) and left amygdala volume also was significantly different (t = −2.248, d.f. = 55, P = 0.029). t-Tests were performed in each hemisphere because there was a group × hemisphere interaction in the hippocampus. The hippocampal volumes, however, did not indicate a significant group difference (right: t = −0.244, d.f. = 55, P = 0.808; left: t = 1.467, d.f. = 55, P = 0.148). The effect sizes of Cohen's d were medium–large for amygdala (left, 0.67; right, 0.70) but small–medium for hippocampus (left, 0.39; right, 0.04). These results suggest that the volumes of the bilateral amygdala but not hippocampus were decreased in the PD patients compared with the HC subjects (Fig. 1).
Figure 1. Relative volumes of the amygdala and hippocampus in panic disorder (PD) patients (blue; n = 27) and healthy comparison (HC) subjects (pink, n = 30). Horizontal bar, mean normalized volumes (absolute amygdalar and hippocampal volume/intracranial content volume) × 100 in (a) left and (b) right amygdala and (c) left and (d) right hippocampal volume. PD patients had smaller amygdala (left, P = 0.029; right, P = 0.005), compared with HC subjects. There were no group difference for bilateral hippocampus (left, P = 0.148; right, P = 0.806).
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Whole brain analysis of optimized VBM showed that PD patients had significant GM volume reductions in multiple sites including right amygdala.37 To investigate which subregion was more affected within the amygdala, an ROI analysis was performed using small volume correction with threshold at FWE-corrected P (P < 0.05). A significant volume reduction was seen within the right amygdala (coordinate [x,y,z (mm)]: [26,−6,−16], Z score = 3.92, FWE-corrected P = 0.002; Fig. 2), which could correspond to the corticomedial nuclear group.
Figure 2. Voxels with a significant decrease in region of amygdala area among panic disorder (PD) patients compared with healthy control (HC) subjects. (a) statistical parametric map showing significantly smaller subregion within the amygdala. (b) The same statistical parametric map overlayed on a structural volume.
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Correlation with volume
We computed Pearson's correlation between manually traced volumes of the bilateral amygdala and hippocampus and psychological evaluation. There was a significant negative correlation between the volume of the left amygdala and STAI-S score for PD patients (r = −0.545, P = 0.016). Right amygdala volume was associated with neuroticism scores of NEO-PI-R for PD patients (r = −0.483, P = 0.036; Fig. 3), although it was a trend-level difference after Bonferroni correction. There was no significant correlation between the volume of the left amygdala and STAI-S score in HC subjects (r = 0.072, P = 0.715), or between the volume of the right amygdala and neuroticism score of NEO-PI-R for HC subjects (r = 0.017, P = 0.931).
Figure 3. Scatter plots of the correlation between left amygdala volume and STAI-S scores for (a) PD patients (r = −0.545, P = 0.016*) and (b) HC subjects (r = 0.072, P = 0.715) and right amygdala volumes and neuroticism scores of NEO-PI-R for (c) PD patients (r = −0.483, P = 0.036) and (d) HC subjects (r = 0.017, P = 0.931). Blue, panic disorder (PD) patients; pink, healthy comparison (HC) subjects. *P < 0.025 (0.05/2).
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In addition, we examined small-volume corrections for the bilateral amygdala using SPM2. We did not find a correlation between the bilateral amygdala volumes and STAI score or NEO-PI-R score for PD patients and HC subjects.
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Our previous study found volume reduction of the amygdala when we estimated regional GM volume using optimized VBM for the PD patients.37 The present study showed volume reduction of amygdala in PD patients, confirmed on both manual tracing and optimized VBM with small-volume correction. Furthermore, smaller amygdala was associated with anxiety, suggesting that the amygdala, especially the corticomedial nuclear group, is a crucial area of the neurobiological pathway underlying PD.
The amygdala is a heterogeneous collection of nuclear groups located in the temporal lobe.38 A variety of different functions has been attributed to the amygdaloid complex, including memory, attention, interpretation of emotional significance of sensory stimuli, perception of body movements and generation of emotional aspects of dreams.39–41 The amygdala consists of anterior nucleus (AN), LA, BA, CE, ME, CO and ABA. Notably, LA, BA and CE are candidate nuclei related to PD pathophysiology.42,43 The LA and BA receive information from the stimulation of various senses.44,45 When fear is recognized in BA, the signal is transmitted to CE.46 The fiber pathway from CE is connected with fear action and physiological changes. Efferent fibers from CE reach the parabrachial nucleus, which influences respiratory rate,47 the hypothalamic lateral nucleus, which induces autonomic arousal and sympathetic discharge,48 the hypothalamic paraventricular nucleus, which induces an increase in the release of adrenocorticoids,49 the locus ceruleus, which increases norepinephrine release resulting in increases in blood pressure, heart rate, and behavioral fear response,50 and the periaqueductal gray region, which is related to defensive behaviors and postural freezing.51 All these responses develop as autonomic failure in the case of panic attack.
Using VBM we observed significant reduction in the corticomedial nuclear group of the right amygdala in the PD group in comparison with the HC group. Because CE in the corticomedial nuclear group is an area possibly related to autonomic failure during a panic attack, it seems that the volume reduction of this area could affect CE function.
We confirmed no impact of demographic and clinical factors on ROI volume, indicating statistical validity of group comparison. Structure–personality association was examined by calculating correlations between VBM and NEO-PI-R scores. As shown by the Omura et al. study, there was a negative correlation between right amygdala volume and neuroticism score of NEO-PI-R.52 The present study found similar associations in the PD group: a negative correlation between left amygdala volume and the state anxiety of STAI and a trend-level negative correlation between right amygdala volume and neuroticism of NEO-PI-R. The relationship between amygdala volume and anxiety was reflected in volume correlations with STAI and NEO, supporting a prior hypothesis of neurobehavioral association between amygdala and anxiety.
In the present study hippocampus volumes did not differ between the study groups. According to a recent report it is suggested that antidepressant treatment may inhibit or reverse the atrophy or damage of hippocampus by upregulation of adult neurogenesis.53,54 Furthermore, in another study hippocampus but not amygdala had volume increase on antidepressants.55 In the present study the hippocampus volume in the PD group was slightly larger as compared with the HC group (effect size: left, 0.39; right, 0.04), possibly reflecting adult neurogenesis in dentate gyrus induced by antidepressants.
There were methodological limitations in the present study. First, the sample size for subjects in both groups was not large enough. Second, the present study included three subjects with a past history of major depression, therefore this might have affected measurement of the volume. A previous study has reported that there were no significant differences for the volume of whole brain and temporal lobe between PD patients with any current comorbidity and those without comorbidity,12 but it might have affected measurement of the volume of amygdala and hippocampus. We note here that structural differences between PD patients with and without any comorbidity (current and past), between those with and without agoraphobia should be investigated in future studies with large sample.
In the present study the reduction of amygdala volume in PD was shown on both manual tracing and optimized VBM. Furthermore, the smaller volume of the right amygdala was associated with anxiety. The present results suggest that the smaller volume of the amygdala could reflect a dysfunctional aspect of the region in PD subjects.