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Aim: Although recent studies suggest abnormalities of the cerebral cortex, limbic structures, and brain stem regions in panic disorder (PD), the extent to which the midbrain is associated with PD pathophysiology is unclear. The aim of this study was to investigate structural abnormalities of the midbrain using magnetic resonance imaging and to determine if there is a clinical correlation between midbrain volume and clinical measurements in patients with PD.
Methods: Thirty-eight patients with PD (PD group) and 38 healthy controls (HC group) participated in this study. The midbrain was measured with a manual tracing method with high spatial resolution magnetic resonance imaging. The Panic Disorder Severity Scale and Global Assessment of Functioning were used to examine the correlation between volume abnormality and clinical symptoms and functioning in the PD group.
Results: Relative midbrain volume was larger in the PD group than in the HC group. The relative volume of the dorsal midbrain was larger in the PD group, while the volume of the ventral midbrain was not. We found a significant positive correlation between relative dorsal midbrain volume and total Panic Disorder Severity Scale score, and a significant negative correlation between relative dorsal midbrain volume and Global Assessment of Functioning score in the PD group.
Conclusions: Our findings suggest that the dorsal midbrain is associated with PD pathophysiology. The midbrain volume increase may reflect PD severity.
AN ESSENTIAL FEATURE of panic disorder (PD), a type of anxiety disorder, is the recurrence of spontaneous and incapacitating panic attacks that are not due to any specific situation or environmental factor. A panic attack is characterized by a discrete period of intense fear or discomfort that develops abruptly and reaches a peak within 10 minutes. The symptoms of a panic attack include a fear of losing control or dying, and various physical symptoms, such as heart palpitations, a smothering sensation, dizziness, nausea, or sweating.
Gorman et al. proposed a neuroanatomical model specific to PD, in which unexpected panic attacks involve brain stem nuclei. They hypothesized that selective serotonin reuptake inhibitors (SSRI) work through stabilization of brain stem nuclei.1 Viscerosensory information is conveyed to the amygdala, which coordinates autonomic and behavioral responses.2 Efferent pathways of the amygdala include the parabrachial nucleus,3 the lateral4 and paraventricular5 nucleus of the hypothalamus, and the locus ceruleus.6 A projection to the periaqueductal gray (PAG) region is responsible for defensive behaviors and postural freezing, which may be the animal equivalent of phobic avoidance.7 Coplan and Lydiard reviewed fear circuitries and modulation of neurotransmitter systems in PD. They concluded that the serotonin (5-hydroxytryptamine [5-HT]) system, which includes the dorsal (DRN) and median raphe nuclei (MRN) in the brainstem, is relevant to panic neurocircuits.8 Electrical or chemical stimulation of the PAG evokes escape, a defensive behavior that has been related to panic attacks. Evidence in the literature suggests that changes in 5-HT-mediated neurotransmission at the level of the PAG are involved in the pathophysiology of panic disorder and in the mode of action of panicolytic drugs. Anxiety in PD may result from either enhanced or diminished 5-HT neurotransmission.9,10
Several functional magnetic resonance imaging (fMRI) studies have reported abnormal function in the brainstem of patients with PD. Boshuisen et al. reported hyperactivity in the midbrain of patients with PD compared to control participants,11 and Reiman et al. showed that lactate-induced panic attacks activate the midbrain.12 In a positron emission tomography (PET) study, Sakai et al. reported that glucose metabolism increases in the midbrain of untreated patients with PD.13 Previous structural neuroimaging studies in PD patients have shown abnormalities in the amygdala,14 parahippocampus,15 anterior cingulate cortex,16 and frontal regions.17 These previous findings support Coplan's and Gorman's hypotheses on PD. In the brainstem, only two structural imaging studies in patients with PD have reported midbrain volume changes by voxel-based morphometry (VBM).18,19 No study has quantitatively examined midbrain volume abnormalities in patients with PD using manual tracing of the region of interest (ROI). We hypothesize that the structure in the dorsal section of the midbrain has changed in PD. The aim of this study was to investigate structural midbrain abnormalities, mainly the dorsal section containing PAG, in patients with PD using a manual method and to determine the clinical correlation between midbrain volume and clinical PD measurements.
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The present study demonstrated dorsal midbrain volume increases in patients with PD compared to healthy controls, regardless of sex, using manual tracing of ROI. This result is consistent with previous findings of VBM studies that also showed midbrain volume increases.18,19 There was a significant difference between the groups, and significant correlation between the volume and psychological evaluation score only in the dorsal section. The correlation was also significant on partial correlation analysis covariated with dose of medications. These findings suggest that the dorsal section of the midbrain may be more strongly involved with PD pathophysiology, and suggest that a midbrain volume increase may reflect the global severity of clinical symptoms in patients with PD. Moreover, we show that the ventral midbrain volume is larger in the symptomatic group than in the non-symptomatic group in female PD patients only. These findings might reflect sex difference of pathophysiology of PD in the structure of the midbrain.
Anatomically, the PAG, which is a cell-dense region, surrounds the midbrain aqueduct in the dorsal midbrain. In this study, the PAG was included in the dorsal section of the midbrain. The PAG consists of longitudinal columns of afferent inputs and output neurons, and intrinsic interneurons. The PAG contains many neurons that project to the brainstem, hypothalamus, thalamus, and amygdala, regions that also input to the PAG.27
Animal studies using electrical stimulation28 and intracerebral drug injection29 into the PAG indicate a role for 5-HT in the regulation of defense. 5-HT enhanced in the PAG inhibits unconditioned defense reactions to proximal threats.30 This 5-HT system in PAG is essential to the pathophysiology of PD.31 Ascending tracts of the neural network in PD include 5-HT neurons in the DRN and MRN.32 The DRN have been shown to receive input from many nuclei in the limbic system and elsewhere,8 while these neurites project into the PAG, hypothalamus, and amygdala.2 Descending tracts of the neural network in PD projecting from the amygdala into parabrachial nuclei,4 hypothalamus,5,7 locus coeruleus,6 and PAG,33 control fear behavior and relate physiological changes of the body. These studies suggest the probability of more important involvement of the midbrain, including the DRN, MRN, and PAG.31,32 Electrical stimulation in or near the dorsal PAG in humans had also induced intense states of fear and/or terror and autonomic outflow suggestive of the ‘fight or flight’ response.34
In fMRI study, distal threat elicits activity in the prefrontal cortices in humans. Whereas threat becomes proximal and immediate, brain activity shifted from the prefrontal cortex to the PAG.35 These results indicate the PAG involvement in the process of reflexive responding (e.g. fight or flight) to the aversive stimuli and threat. Furthermore, higher cortical systems control behavior when the degree of threat is appraised as non-life-endangering and guides the organism to choose the most effective and resourceful strategy for instrumental avoidance. This defense system for threat can conduct the important role of PAG in the neurobiology of panic disorder. This study showed volume changes in the dorsal midbrain in which the PAG is included. The correlation between dorsal midbrain volume and psychological evaluation score in patients with PD indicates the possibility of PAG participation in PD symptom severity.
There were methodological limitations in this study. First, the sample size of participants in both groups was not large. Second, we do not distinguish PD from other anxiety disorders with situation-dependent panic attacks. No previous reports have examined midbrain volume in patients with other anxiety disorders. While there was a positive correlation between midbrain volume and PDSS score for patients with PD, we have not evaluated midbrain volume and clinical symptoms in other anxiety disorders. Therefore, we cannot conclude whether midbrain volume increase is specific to PD. Third, we have shown volume increase of dorsal midbrain volume in PD only with manual tracing volumetry, not the automatic measuring method. Findings shown by several studies with ROI manual tracing are different from those with automatic volumetry, which could be accounted for the influence of the rater's proficiency of measuring ROI. Although ROI are manually traced with high intra-class correlation coefficients (more than 0.90 for each ROI) in this study, further studies using atlas-based automatic volumetry are needed to clarify the involvement of the dorsal midbrain including PAG in the pathophysiology of PD.
In conclusion, this study used a manual tracing method on MRI to demonstrate dorsal midbrain volume increases in patients with PD. The volume change of the ROI is associated with the clinical severity of PD symptoms and GAF score. These findings suggest that dorsal midbrain volume increases may be associated with PD pathophysiology.