Volume reduction of ventromedial prefrontal cortex in bipolar II patients with rapid cycling: A voxel-based morphometric study Kosuke Narita a, ⁎, Masashi Suda a , Yuichi Takei a , Yoshiyuki Aoyama a , Takehiko Majima a , Masaki Kameyama a , Hirotaka Kosaka b , Makoto Amanuma c , Masato Fukuda a , Masahiko Mikuni a a Department of Psychiatry and Human Behavior, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan b Department of Neuropsychiatry, University of Fukui, Eiheiji-cho, Fukui 910-1193, Japan c Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan abstract article info Article history: Received 14 August 2010 Received in revised form 14 October 2010 Accepted 20 November 2010 Available online 27 November 2010 Keywords: Bipolar II disorder Medial prefrontal networks Rapid cycling Ventromedial prefrontal cortex Voxel-based morphometry Although rapid cycling (RC), a course specifier of bipolar I or II disorder, is particularly common among bipolar II patients compared with bipolar I patients, the pathophysiological lines of evidence regarding bipolar II with RC are still limited. In this preliminary study with a cross-sectional design, we examined the regional gray matter (GM) volume in 14 bipolar II patients with RC, 17 patients without RC and 84 healthy controls by whole-brain and region-of-interest (ROI) analysis methods, using magnetic resonance imaging with voxel- based morphometry. Whole-brain analysis in this study revealed that the bipolar II patients with RC showed GM volume reductions in the bilateral hemispheres of the medial orbital prefrontal cortex, ventromedial prefrontal cortex, anterior cingulate, insula and parahippocampus, in the left hemisphere of the inferior temporal cortex and cerebellum, and in the brainstem, compared with the healthy controls. Moreover, ROI analysis focusing on the ventral prefrontal cortex, i.e., Brodmann areas 10, 11 and 47, revealed that the bipolar II patients with RC showed GM volume reduction in the ventromedial prefrontal cortex, compared with the patients without RC. The findings of our pilot study suggest that the ventromedial prefrontal cortex is associated with the generation of RC in bipolar II disorder. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Rapid cycling (RC), a course specifier of bipolar I or II disorder, is associated with high rates of morbidity with potentially severe disability, an increase in suicide risk and an unsatisfactory response to lithium or valproate treatment (Bauer et al., 2008). Although the pathophysiological lines of evidence regarding RC are still limited, a previous region-of-interest (ROI) analytical study revealed that in young bipolar I patients, RC is associated with gray matter (GM) volume reduction in the ventral prefrontal cortex (Brodmann areas 10, 11 and 47), which includes the ventromedial to ventrolateral prefrontal cortexes, suggesting that the ventral prefrontal cortex is a key region for the generation of RC in bipolar I patients (Blumberg et al., 2006). The ventral prefrontal cortex subserves complex emotional, behavioral and cognitive processes (Phillips et al., 2008; Fuster, 2002). Furthermore, the medial and lateral areas of the ventral prefrontal cortex have been suggested to have different effects on mood disorders, i.e., the ventromedial prefrontal cortex is involved in mood regulation, whereas the ventrolateral prefrontal cortex is principally involved in higher executive function (Fuster, 2002). Recent epidemiological lines of evidence have revealed that RC is particularly common among bipolar II patients compared with bipolar I patients, and one study showed that its prevalence appears to be as high as 31% in bipolar II patients (Tondo and Baldessarini, 1998). However, brain volumetric studies on bipolar II patients with RC have been insufficient. Bipolar II disorder is not simply a milder form of bipolar I disorder, i.e., bipolar II patients have a chronic course with more frequent depressive episodes (Judd et al., 2003), higher suicide risk (Rihmer and Pestality, 1999), poorer quality of life (Maina et al., 2007) and higher morbidity of relatives of bipolar II patients (Heun and Maier, 1993) than bipolar I patients. Considering these clinical and genetic distinctions between the subtypes of bipolar disorder, brain volumetric investigation of bipolar II patients with RC, particularly focusing on the association of RC with the ventral prefrontal cortex, is expected to further our knowledge regarding the generation of RC. This preliminary study with a cross-sectional design is aimed at examining regional GM volume in bipolar II patients with and without RC (i.e., RC and non-RC groups, respectively) by magnetic resonance imaging (MRI) with voxel-based morphometry (VBM) (Ashburner and Friston, 2000). First, we conducted whole-brain comparisons Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 439–445 Abbreviations: RC, rapid cycling; ROI, region-of-interest; GM, gray matter; MRI, magnetic resonance imaging; VBM, voxel-based morphometry; WFU, the Wake Forest University Pickatlas; YMRS, the Young Mania Rating Scale; HAM-D, Hamilton Depression Rating Scale; RPV, the resel per voxel; MNI, Montreal Neurological Institute. ⁎ Corresponding author. Tel.: + 81 27 220 8185; fax: + 81 27 220 8187. E-mail address: knarita@med.gunma-u.ac.jp (K. Narita). 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.11.030 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp