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Aims: The posterior region of the orbitofrontal cortex (OFC), which forms its sulcogyral pattern during neurodevelopment, receives multisensory inputs. The purpose of the present study was to assess the relationship between posterior OFC sulcogyral pattern and OFC volume difference in patients with panic disorder.
Methods: The anatomical pattern of the posterior orbital sulcus (POS) was classified into three subtypes (absent POS, single POS, double POS) using 3-D high-spatial resolution magnetic resonance images obtained from 28 patients with panic disorder and 28 age- and gender-matched healthy controls. Optimized voxel-based morphometry (VBM) was performed to assess OFC volume differences between the two groups by subtype. Categorical regression analysis was applied to examine the association of POS subtypes with State–Trait Anxiety Inventory and Revised Neuroticism-Extraversion-Openness Personality Inventory scores.
Results: No significant difference was found in POS subtype distribution between control subjects and patients with panic disorder. VBM, however, indicated volume reduction in the right posterior–medial OFC region in panic disorder patients with absent POS and single POS. Single POS was positively associated with Trait-Anxiety (β = 0.446, F = 6.409, P = 0.020), and absent POS was negatively associated with Trait-Anxiety (β = −0.394, F = 5.341, P = 0.032) and Neuroticism trait (β = −0.492, F = 6.989, P = 0.017).
Conclusions: POS subtypes may be relevant to volume reduction in OFC and the anxiety trait in patients with panic disorder. These findings suggest that volume reduction in OFC in panic disorder may be associated with neurodevelopment.
THE ORBITOFRONTAL CORTEX (OFC) has direct reciprocal connections with the amygdala,1 which plays an important role in neuroanatomical pathways for panic disorder.2 The amygdala also has connections with a region of the anterior cingulate cortex known as the affective division.3 The OFC mediates anxiety behavior and perception in child and adolescent primates,4 and is involved in emotional processing in humans.5 Anxiety requires multiple sensory inputs, which enter the posterior region of the OFC from the primary sensory cortex.5 These findings suggest that anatomical differences may be related to OFC dysfunction.
The OFC sulcogyral pattern, which exhibits anatomical variability among individuals, is determined in early neurodevelopment,6 and develops during 16–44 weeks gestation.7 It has been reported that the OFC continues to mature longer than other ventral brain regions,5,8 although frontal gray matter volume decreases after the age of 10 years.9 The posterior region of the OFC develops before the anterior region.8,9 A recent volumetric study demonstrated that the OFC sulcogyral pattern was associated with brain volume in schizophrenia.10 These findings indicate a relationship between sulcogyral pattern and OFC gray matter volume. Few magnetic resonance imaging (MRI) volumetric studies of the OFC have involved patients with panic disorder, whereas several MRI volumetric studies of the amygdala11,12 and anterior cingulated cortex13 have been done.
Chiavaras and Petrides evaluated OFC sulcogyral patterns of 50 healthy volunteers, and reported considerable pattern differences among individuals.14 Based on these findings, the anatomical pattern of the posterior orbital sulcus (POS) was classified as absent POS, single POS, or double POS, according to the presence/absence and number of POS in the OFC.
In the present study we hypothesized that anatomical variability may be associated with dysfunction of the OFC in patients with panic disorder. This study focused on the structure of the OFC posterior region, which receives multiple sensory inputs and modulates the anxiety response. We investigated differences in the distribution of POS subtypes between patients with panic disorder and healthy control subjects. Additionally, we used optimized voxel-based morphometry (VBM) to investigate OFC volume differences between patients and control subjects of each POS subtype group. We also assessed the association of POS subtypes with clinical measures for anxiety and personality traits.
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In the present study we demonstrated that POS subtype is associated with posterior OFC volume reduction and anxiety in patients with panic disorder, although POS subtype distribution did not differ between the panic disorder and the control subjects. There have been inconsistent results for POS subtype distribution in panic disorder. No difference in POS subtype distribution was found in several studies.26,27 These studies suggested that acquired causes such as traumatic life events were also associated with the development of panic disorder symptoms. Studies in twins, however, have reported inherent different vulnerabilities to the same environmental factor among patients.28,29 OFC has been reported to be involved with guidance of reward-related behavior, expectation of reinforcements for goal-directed behavior, and decision making and motivation. These functions are processed primarily in the anterior OFC and require multisensory inputs from the posterior OFC.5 In addition, the central nucleus of the amygdala receives multisensory inputs and acts as the autonomic mediator for the brainstem nuclei related to panic attack.30 Our previous study showed that volume reduction in the right central nucleus may be associated with dysfunction in patients with panic disorder.12 Because the OFC has been reported to be interconnected with the amygdala,1 the OFC and amygdala may work together to mediate anxiety. The present study found significant gray matter volume reduction in the right posterior OFC in the absent-POS and single-POS groups of panic disorder patients, suggesting right posterior OFC dysfunction.
The OFC is connected to the anterior cingulate cortex, which is also connected to the amygdala.3 Our previous study indicated gray matter volume reduction of the right dorsal region of the anterior cingulate cortex, which is associated with cognitive function, whereas no reduction was found in the rostral ventral region, which is associated with emotion and affective processing.13 In the present study, however, VBM demonstrated that absent-POS and single-POS groups exhibited gray matter volume reduction in the right medial–posterior region of the OFC, which plays a role in the independent motivational system.5 This region is also located near the affective division of the anterior cingulate cortex. In the present study we found that single POS was positively associated with A Trait, and absent POS was negatively associated with A Trait. VBM also showed that single POS had more gray matter volume reduction than absent POS in OFC. A recent large cohort study found that premature infants had gray matter volume reduction.31 Additionally, adolescents with very low birthweight had increased anxiety.32 These previous findings may be relevant to the present findings. Given the anxiety-mediating role of the posterior OFC, these findings suggest that immaturity of the POS may be associated with anxiety in patients with panic disorder.
The present study has several limitations. Because comorbid depression may affect the anatomical and clinical features of panic disorder, it is necessary to investigate differences between patients with panic disorder and without major depression/dysthymia. Large studies are needed to perform VBM using statistically rigorous threshold Family-Wise Error (FWE)-correction.
In conclusion, we have demonstrated that the posterior OFC may play an important role in input of multisensory information to mediate anxiety. POS subtypes in the posterior OFC are associated with OFC volume reduction and anxiety in patients with panic disorder, but POS subtype distribution did not differ between patients and control subjects. These findings suggest that OFC volume reduction may be associated with neurodevelopment in patients with panic disorder.