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Abnormal White Matter Structural Connectivity in Adults with Obsessive-Compulsive Disorder

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Abnormal White Matter Structural Connectivity in Adults with Obsessive-Compulsive Disorder OPEN Citation: Transl Psychiatry (2017) 7, e1062; doi:10.1038/tp.2017.22 www.nature.com/tp ORIGINAL ARTICLE Abnormal white matter structural connectivity in adults with obsessive-compulsive disorder J Gan1,2,7, M Zhong3,7,JFan1,2, W Liu1,2, C Niu1,2, S Cai4, L Zou5,6, Ya Wang5,6, Yi Wang5,6,CTan4, RCK Chan5,6 and X Zhu1,2 Obsessive-compulsive disorder (OCD) is a complex and severe psychiatric disorder whose pathogenesis is not fully understood. Recent studies have shown white matter (WM) alterations in adults with OCD, but the results have been inconsistent. The present study investigated WM structure in OCD patients with the hypothesis that large-scale brain networks may be disrupted in OCD. A total of 24 patients with OCD and 23 healthy controls (HCs) were scanned with diffusion tensor imaging. A tract-based spatial statistics (TBSS) approach was used to detect differences across the whole brain in patients with OCD vs HCs; post hoc fiber tractography was applied to characterize developmental differences between the two groups. Relative to HCs, patients with OCD had lower fractional anisotropy (FA) values in the corpus callosum (CC), left anterior corona radiata (ACR), left superior corona radiata (SCR) and left superior longitudinal fasciculus (SLF), and higher radial diffusivity in the genu and body of CC. Among the TBSS de-projected region of interest results, compared with HCs, patients with OCD showed lower of the mean FA values of fiber bundles passing though the SLF, and shorter lengths of ACR, SCR and CC. In conclusion, this study provides novel evidence of widespread microstructural alterations in OCD and suggests that OCD may involve abnormalities affecting a broader network of regions than commonly believed. Translational Psychiatry (2017) 7, e1062; doi:10.1038/tp.2017.22; published online 14 March 2017 INTRODUCTION white matter (WM) tracts, which can affect connectivity between 11 Obsessive-compulsive disorder (OCD) is a common mental disorder diverse brain regions. affecting 2 ~ 3% of the general population internationally.1 An increasing number of studies using diffusion tensor imaging (DTI) are suggesting that the OCD brain has WM alterations apart Recurrent, intrusive and distressing thoughts and/or repetitive 12 behaviors are regarded as the core difficulties for patients with from previously described alterations in gray matter regions. DTI is a noninvasive method that can be used to probe the intrinsic, OCD;2 impaired attention and spatial working memory abnorm- three-dimensional diffusion properties of water within tissues; it is alities are also common in OCD patients.3,4 These clinical features sensitive to the orientation and integrity of underlying WM fibers predispose patients to impairments of occupational and social in vivo.13 In the DTI paradigm, fractional anisotropy (FA) is an index functioning. of diffusion directionality in each voxel,14 which can reflect the Neurobiologically, the aforementioned core elements of OCD 5 structure of axonal cell membranes and myelin sheaths, with high have been linked to dysfunction of cortico-striatal circuits. The FA values being observed in heavily myelinated tracts.15 Mean cortico-striatal circuitry model of OCD suggests that the hallmark diffusivity (MD) is the magnitude of diffusion in each measured of OCD is a dysfunction of a neuronal loop running from the voxel, which varies with tissue density regardless of fiber orbitofrontal and cingulate cortices to the striatum (caudate orientation.16 Axial diffusivity (AD) is the tendency to diffuse nucleus and putamen), globus pallidus, thalamus and back to the along the principal direction of the fiber, and radial diffusivity (RD) frontal cortex.6 Among frontal regions, the dorsolateral prefrontal is the diffusivity perpendicular to axonal walls. Changes in RD cortex, oritofrontal cortex and anterior cingulate cortex seem to be appears to be associated with dys- or demyelination (cell of major psychopathological relevance to OCD.5,7,8 This concep- membrane and cytoskeleton) in WM, whereas variations in AD tualization of cortico-striatal dysfunction in OCD has spurred may be more specific to axonal degeneration (volume and 17 structural and functional imaging research, focusing mainly on the organization). orbitofrontal cortex, cingulate cortex, striatum and thalamus, and DTI based on voxel based morphometry (VBM) can be used to temporolimbic regions (that is, lateral and medial temporal investigate WM abnormalities within as well as beyond the cortico-striatal circuits classically associated with OCD.18 Studies of cortices, amygdala, hippocampus, parahippocampal cortex, 9 OCD using whole-brain and selected region of interest (ROI) hypothalamus and insular cortex). More recently, whole-brain analyses have revealed variable FA values in the anterior cingulate, analyses also have implicated additional parietal, insular and internal capsule, bilateral semioval center extending to medial 9,10 fi fl cerebellar regions. These ndings may re ect abnormalities in frontal WM, subinsular WM and corpus callosum (CC), as well as in 1Medical Psychological Center, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; 2Medical Psychological Institute of Central South University, Changsha, Hunan, China; 3Center for Studies of Psychological Application, School of Psychology, South China Normal University, Guangzhou, China; 4Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China; 5Neuropsychology and Applied Cognitive Neuroscience Laboratory, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China and 6University of Chinese Academy of Sciences, Beijing, China. Correspondence: Professor X Zhu, Medical Psychological Center, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China. E-mail: [email protected] 7These two authors contributed equally to this work. Received 18 July 2016; revised 22 December 2016; accepted 15 January 2017 Abnormal white matter structure in OCD patients J Gan et al 2 WM in parietal,18–20 left lingual gyrus and occipital lobe20 regions. Table 1. Demographic and clinical characteristics of the study However, these prior results are rather heterogeneous. For participants example, FA values in OCD brains have been reported to be both increased and decreased, in some cases in the same brain 4,11,18–26 Characteristic Group, mean ± s.d. or n% Group areas. The heterogeneous findings might be due to comparisons limitations of voxel-based morphometry methods, which do not 14 yield accurate inter-subject image registration. 2 OCD (N = 24) HC (N = 23) t/χ P Tract-based spatial statistics (TBSS) is an analytic method developed specifically for DTI data wherein analysis is restricted Age 22.58 ± 6.56 23.17 ± 2.12 − 0.419 0.679 to center areas of major white-brain volumes.27 This feature makes Females:males 9 (37.5%):15 11 (91.7%):12 0.512 0.474 TBSS highly sensitive to changes in microstructure within the (63.5%) (8.3%) major WM fiber pathways. The only three studies to have used IQ 129.64 ± 16.32 137.27 ± 20.60 1.405 0.168 TBSS to analyze DTI in OCD adults11,22,28 all found significantly BDI 21.00 ± 16.20 5.57 ± 5.82 − 4.308 o0.001 STAI-S 53.71 ± 11.48 36.23 ± 10.71 − 5.326 o0.001 reduced FA values, relative to controls, in the body of the CC. ± ± − o However, comprehensive MD, AD, and RD data reporting from STAI-T 56.46 9.87 39.91 10.69 5.516 0.001 YBOCS 32.45 ±5.98 ——— these studies was lacking. Importantly, TBSS analysis minimizes the potential misalign- Abbreviations: BDI, Beck Depression Inventory; HC, healthy control; IQ, ment problems of other voxel-based whole-brain analysis intelligence quotient; OCD, obsessive-compulsive disorder; STAI-S, State methods by producing a WM ‘skeleton’ restricted to the center Subscale of the State-Trait Anxiety Inventory; STAI-T, Trait Subscale of the of major WM tracts, and mapping diffusion values from each State-Trait Anxiety Inventory; YBOCS, Yale-Brown Obssesive individual participant directly onto this standard skeleton for Compulsive Scale. group comparisons. However, TBSS analysis fails to reveal commissural connections to lateral cerebral areas, probably fi A group of 23 age-, sex-, intelligence quotient- and handedness- because of massive projection and long association bers being matched HCs (Table 1) from the local community were recruited and situated lateral to the CC, beyond the reach of reconstruction screened for psychiatric and behavioral disorders by two experienced tracking. Previous DTI studies have focused exclusively on psychiatrists using the Structured Clinical Interview for Diagnostic and hypothesis-driven ROIs or broad exploratory TBSS analysis; both Statistical Manual of Mental Disorders, 4th edition Axis I. None were found approaches are important and the two are complementary. Only to have any neurological and psychiatric illnesses, major physical diseases two studies conducted post hoc tractography analysis based on or positive family history of major psychiatric disorders. Their general TBSS results by probabilistic tracking; they showed CC connections intelligence was also assessed with the Wechlser Abbreviated Scale of to the bilateral dorsal medial frontal cortex,14,22 dorsolateral Intelligence.30 prefrontal cortex22 and parietal regions as well as connections The study protocol was designed in accordance with the guidelines extending down to superior temporal regions,14 but neither outlined in the Declaration
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