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- MATERIALS AND METHODS
Aim: Recent neuroimaging studies have suggested that the anterior cingulate cortex (ACC) has an important role in the pathology of panic disorder. Despite numerous functional neuroimaging studies that have elucidated the strong relationship between functional abnormalities of the ACC and panic disorder and its symptoms and response to emotional tasks associated with panic disorder, there has been no study showing volumetric changes of the ACC or its subregions.
Methods: To clarify the structural abnormalities of ACC and its subregions, the combination of region of interest (ROI) and optimized voxel-based morphometry (VBM) methods were performed on 26 patients with panic disorder, and 26 age and sex-matched healthy subjects. In the ROI study, ACC was divided into four subregions: dorsal, rostral, subcallosal and subgenual ACC.
Results: The results of the manually traced ROI volume comparison showed significant volume reduction in the right dorsal ACC. VBM also showed a volume reduction in the right dorsal as well as a part of the rostral ACC as a compound mass.
Conclusions: Both manual ROI tracing and optimized VBM suggest a subregion-specific pattern of ACC volume deficit in panic disorder. In addition to functional abnormalities, these results suggest that structural abnormalities of the ACC contribute to the pathophysiology of panic disorder.
RECENT STUDIES HAVE suggested that brain abnormalities contribute to the occurrence of panic disorder, and many functional neuroimaging studies have shown that the functional abnormalities of the anterior cingulate cortex (ACC)–amygdala connection play an important role.1–5 While some structural neuroimaging studies have shown abnormalities in the amygdala,6,7 there has been no report about structural change of ACC in patients with panic disorder.
ACC is a well studied region, with known anatomical and functional heterogeneities in its subdivisions. Bush et al. have suggested that the ACC is divided into two major subdivisions according to separate processing of cognitive and emotional information.8 One subdivision is the dorsal cognitive division (Brodmann's area [BA] 24b′-c′ and 32′) and the other is the rostral–ventral affective division (rostral area: BA 24a-c and 32; ventral area: BA 25 and 32). The dorsal cognitive subdivision has strong reciprocal interconnections with the lateral prefrontal cortex and parietal cortex,9 and governs various functions such as the modulation of attention and anticipation during cognitively demanding tasks.9–12 On the other hand, the rostral–ventral affective subdivision is connected with the amygdala, anterior insula and orbitofrontal cortex,9 and has the role of regulating emotional responses.11,12 Moreover, recent structural and functional imaging studies have focused on the subgenual region (BA 25). Abnormalities of this region have been shown in affective disorder,13,14 which is a common comorbidity with panic disorder, as well as the brain response to fear15 and sadness.16
Many functional neuroimaging studies have indicated a strong relationship between functional abnormalities of the ACC and panic disorder symptoms and responses to emotional tasks related to panic disorder. For example, Pillay et al. reported that the significant activation of the ACC (bilateral rostral and subgenual regions) was found in control subjects but was not found in patients with panic disorder when they were exposed to the fearful facial affects.4 Another study showed that injections of cholecystokinin tetrapeptide (CCK-4) for occurring panic attacks in healthy subjects activated ACC (BA 24, 32: rostral region).17 Furthermore, Fischer et al. showed that regional cerebral blood flow (rCBF) was decreased in right ACC (area 32) when a patient unexpectedly experienced a panic attack.18 These findings suggest that the functional abnormalities in the ACC, especially the rostral–ventral affective subdivision, is certainly related with panic disorder and its symptoms.
Previous structural neuroimaging studies have also shown a relationship between ACC and anxiety-related disorders. Yamasue et al. reported volume reduction of the left dorsal ACC in patients with post-traumatic stress disorder (PTSD).19 Several other PTSD studies have also shown volume reduction of various ACC subregions (Kitayama et al. right dorsal region;20 Woodward et al., left dorsal and rostral regions;21 Chen et al., left rostral region22). One structural study about pediatric obsessive–compulsive disorder has also revealed that the volume of the bilateral dorsal ACC was significantly smaller in the patients compared with control subjects.23
Although there have been many reports that show functional abnormalities of the ACC in patients with panic disorder, and structural abnormalities of ACC in patients with anxiety-related disorders, to our knowledge, there has been no report showing structural changes of the ACC and its subregions in patients with panic disorder. The purpose of the present study was to clarify the structural change of the ACC and its subregions in patients with panic disorder. The combination of region of interest (ROI) and optimized voxel-based morphometry (VBM) methods were employed in this study. It has been suggested that the manually traced ROI is superior in anatomical accuracy to the atlas-based ROI in VBM, however, it could be potentially influenced by the rater's biases and anatomical varieties such as sulcogyral patterns.24 On the other hand, in VBM the volume is assessed beyond anatomical varieties through the spatial normalization process. At the same time, a disadvantage of VBM is that it can reduce information about individual differences in brain structure. So, it has been suggested that the manually traced ROIs and VBM provide different aspects of information and therefore should be used in tandem.25 In the manually traced ROI method of this study, the ACC was divided into four subregions (dorsal, rostral, subcallosal and subgenual ACC) and the atlas-based ACC ROI in VBM was applied as a single region.
- Top of page
- MATERIALS AND METHODS
The present volumetric study compared ACC volume in patients with panic disorder and control subjects using two methods: ROI volume comparison and optimized VBM. The result of the ROI volume comparison showed significant volume reduction in the right dorsal ACC in panic disorder patients compared to healthy controls. The finding from optimized VBM showed significant volume reduction in the right dorsal ACC partially extending to rostral ACC in patients compared to control subjects (Table 2, Figs 2, 3). Of particular note, manual ROI tracing and automated optimized VBM showed volume deficit in the largely overlapped ACC region despite their totally different methodologies. To our knowledge, this is the first report of a subregion-specific ACC volume deficit in patients with panic disorder.
The current study did not find any correlation between the right rostral/dorsal ACC and antidepressants or benzodiazepines. This might suggest that the psychotropic medication did not affect the group difference in ACC volume.
Previous reports have suggested that functional abnormalities in ACC–amygdala interaction play an important role in panic disorder,1–5 and that neural activation in ACC, amygdala, or both are altered when subjects are exposed to an emotional task, especially a fear-related task. The rostral–ventral affective division of the ACC has strong neuronal connectivity with the amygdala,9 and has a role of regulating emotional responses.11,12 Functional neuroimaging studies have shown a relationship between abnormalities of these regions and panic disorder and its symptoms.
Concerning the rostral ACC region, Bystritsky et al. demonstrated increased activity in the right rostral ACC during panic anticipation exposure.1 Boshuisen et al. also showed activation in the bilateral rostral ACC during anticipatory anxiety as a result of pentagastrin injections in patients with panic disorder.46 A CCK-4 trial study for occurring panic attacks showed that rostral ACC was activated when CCK-4 was injected in healthy subjects.17 Further more, Sakai et al. showed that the glucose utilization in left rostral ACC was decreased after cognitive-behavioral therapy was successful in patients with panic disorder.47 Give that these findings show a functional relationship between rostral ACC and panic disorder, it seems reasonable that the current study showed the structural abnormalities in this region.
The present study also showed a volume reduction of the right dorsal ACC in patients with panic disorder compared with control subjects. Dorsal ACC is suggested to be a cognitive subdivision, governing various functions such as modulation of attention and anticipation of cognitively demanding tasks.9–11 Some structural neuroimaging studies of anxiety-related disorders such as PTSD have shown volume reduction in dorsal ACC.19–21 According to the recent reviews about ACC, the anterior part of the dorsal ACC was related to neural activations of not only the cognitive tasks but also the emotional tasks.8 Vogt also reported that the anterior part of dorsal ACC received input from the amygdala, and fear was mainly associated with activity in this region.16
Here we address methodological considerations. Our study included subjects who had a history of depressive disorders (four subjects, past history of major depression; one subject, current history of dysthymia). Since previous studies have reported brain structural changes in patients with depressive disorders, the effect of comorbid depression on the current results cannot totally be ruled out. When the examination was performed without these five subjects and age-, sex-matched five healthy subjects, the results of ROI showed the volume reduction in the right dorsal ACC at a less significant level (t = 2.23, P = 0.031), and VBM showed volume reduction in dorsal and rostral ACC but as smaller regions. We note here that structural differences between panic disorder patients with and without comorbid depression should be investigated in future studies with larger sample.
In conclusion, the present study demonstrated the first evidence of a subregion-specific volume deficit in the right dorsal ACC partially extending to rostral ACC in the patients with panic disorder. This subregion-specific pattern of ACC volume deficit in panic disorder was confirmed by both manual ROI tracing and optimized VBM methods. These findings may provide further evidence that not only functional but also structural abnormalities of ACC contribute to the pathophysiology of panic disorder.