DEPRESSION AND ANXIETY 31:1007–1017 (2014)
Research Article MICROSTRUCTURAL BRAIN ABNORMALITIES AND SYMPTOM DIMENSIONS IN CHILD AND ADOLESCENT PATIENTS WITH OBSESSIVE-COMPULSIVE DISORDER: A DIFFUSION TENSOR IMAGING STUDY Luisa L´azaro, Ph.D.,1,2,3,4 ∗ Anna Calvo, Sc.M.,5 Ana G. Ortiz, Sc.M.,1 Ana E. Ortiz, M.D.,1 Astrid Morer, Ph.D.,1,2,4 Elena Moreno, Sc.M.,1 Rosa Calvo, Ph.D.,1,4 and Nuria ´ Bargallo, Ph.D.4,5,6
Background: The aims of this study were to determine white matter (WM) microstructure abnormalities in obsessive-compulsive disorder (OCD) using diffusion tensor imaging, and to investigate whether these abnormalities differ according to OCD symptom dimensions. Methods: Sixty-three child and adolescent OCD patients (11–18 years old) and 37 healthy subjects matched for gender, age, and estimated intelligence quotient were assessed by means of psychopathology scales and diffusion tensor magnetic resonance imaging. Results: Compared with healthy controls OCD patients showed a significant decrease (t = 3.79, P = .049 FDR-corrected) in fractional anisotropy (FA) in the anterior region of the corpus callosum (CC). In addition, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values were significantly increased in OCD compared with controls in the CC and in several WM regions of the cingulate, frontal and occipital lobes, basal ganglia, cerebellum, and pons. Compared with healthy controls, OCD patients presenting the harm/checking dimension showed decreased FA in the CC and in the left anterior cingulate gyrus and caudate nucleus, whereas patients with a predominant contamination/washing symptom dimension presented significantly decreased FA in the left midbrain, lentiform nucleus, insula, and thalamus, and increased MD, AD, and RD in both the anterior lobes of cerebellum and in the pons. Conclusions: The findings suggest WM abnormalities at the microstructural level in the pathogenesis of OCD. Moreover, WM abnormalities in OCD may vary according to the specific OCD symptom dimensions, thus indicating the clinical heterogeneity of the condition. C 2014 Wiley Periodicals, Inc. Depression and Anxiety 31:1007–1017, 2014. Key words: diffusion tensor imaging; obsessive-compulsive disorder; symptom dimensions; children and adolescents
of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Cl´ınic Universitari, Barcelona, Spain 2 Institut d’Investigacions Biomediques ` August Pi i Sunyer (IDIBAPS), Barcelona, Spain 3 Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Barcelona, Spain 4 Centro de Investigacion ´ Biomedica ´ en red de Salud Mental (CIBERSAM), Spain 5 Magnetic Resonance Image Core Facility, IDIBAPS (Institut ` d’Investigacions Biomediques August Pi i Sunyer), Barcelona, Spain
C 2014 Wiley Periodicals, Inc.
Diagnostic Center, Hospital Cl´ınic, Barcelona, Spain
to: Luisa Lazaro Garc´ıa, Department of Child ´ and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Cl´ınic Universitari, C/Villaroel 170, Barcelona 08036, Spain. E-mail: [email protected]
Received for publication 15 July 2014; Revised 29 September 2014; Accepted 4 October 2014 DOI 10.1002/da.22330 Published online 28 November 2014 in Wiley Online Library (wileyonlinelibrary.com).
´ Lazaro et al.
bsessive-compulsive disorder (OCD) is a common neuropsychiatric illness characterized by recurrent intrusive thoughts and repetitive ritualistic behaviors that cause severe distress. OCD usually has an early onset, with an estimated prevalence between 1 and 3% in different samples of young adults around the world. Over the last decade, considerable attention has been paid to the symptomatic heterogeneity of OCD in an attempt to ﬁnd biological markers, genetic transmission mechanisms, or ways of predicting treatment response. Brain-imaging and genetic studies[3, 4] have provided evidence for the biological validity of OCD dimensions (aggressive, sexual, and religious obsessions and checking compulsions; symmetry obsessions and repeating, counting, and ordering compulsions; contamination obsessions and cleaning compulsions; and hoarding obsessions and compulsions). In addition, another promising approach in relation to reducing phenotypic heterogeneity involves the identiﬁcation of homogeneous subtypes of OCD based on clinical characteristics such as age at onset. Neuroimaging studies have identiﬁed the involvement of several brain regions in OCD symptomatology. Although neuroanatomical models of OCD have focused on the cortico–striato–thalamic circuits (CSTCs),[5, 6] other structures such as the anterior cingulate and parietal and limbic areas have recently been included in the circuits of interest. Furthermore, ﬁndings from functional imaging reveal hyperactivation in regions of the orbitofrontal and anterior cingulate loops.[4, 8] More recently, and consistent with this model of OCD pathophysiology, several studies have shown altered functional connectivity among gray matter (GM) nodes of the CSTC circuitry, middle frontal gyrus and anterior cingulate cortex, and temporal regions. Diffusion tensor imaging (DTI) is a structural MRI technique that can be used to examine white matter (WM) microstructure in humans by quantifying the directionality and coherence of water self-diffusion. A systematic review of DTI studies involving mostly adult OCD patients concluded that, in addition to the frontostriatal model, other WM regions are also involved in OCD pathophysiology. Notably, altered WM microstructure has been repeatedly described in the cingulum and in the anterior and posterior limb of the internal capsule.[12, 13] Other structures that have been reported in several studies as showing microstructural WM abnormalities are the corpus callosum (CC); prefrontal regions; and parietal, temporal, and occipital areas. On the other hand, pharmacological treatment at the time of the scan may be a confounding factor. A recent meta-regression analysis showed that the decrease in fractional anisotropy (FA) in the midline structures was most prominent in the samples with higher percentages of medicated patients. Four studies have been conducted in pediatric patients with OCD. Zarei et al. reported higher FA values in Depression and Anxiety
various WM tracts, including both inferior and superior longitudinal fasciculus bilaterally, the corticospinal tracts, CC, left cingulum, right uncinate fasciculum, and cerebellar and brainstem WM. Gruner et al. reported similar ﬁndings, with greater FA corresponding to the left cingulum, CC, right corticospinal tract, and left inferior longitudinal fasciculus. Finally, two studies in small OCD samples reported greater axial diffusivity (AD) in regions within the parietal cortex, lateral prefrontal cortex, and limbic system, and lower AD in both the genu and splenium of the CC. Heterogeneous ﬁndings are frequent in psychiatric neuroimaging studies, mainly due to technical differences in MRI acquisitions and analysis, modest sample sizes that might cause mixed or inconsistent results, and clinical features such as differential exposure to pharmacological treatment. Although there was signiﬁcant phenotypic overlap across the different obsessive-compulsive (OC) symptom dimensions, speciﬁc genetic and particularly nonshared environmental factors are important in their etiology. So, there is a growing body of literature that indicates that a dimensional approach to OC symptoms may be of value in genetic, neurobiological, and treatment response studies. Thus, it is thought that the major symptom dimensions are mediated by least partially distinct neural substrates. To date, different neuroimaging studies have investigated brain structure and function related to OCD symptom dimensions.[21, 22] Recent functional MRI studies have found aggression symptoms to have a speciﬁc inﬂuence on ventromedial frontal cortex and amygdala connectivity, whereas sexual/religious symptoms affected ventral striatal–insular connectivity. Moreover, the severity of aggressive/checking and sexual/religious symptom dimensions was signiﬁcantly associated with heightened amygdala activation in patients with OCD when responding to fearful faces. Finally, two studies have investigated the microstructure of WM related to OCD symptom dimensions. Ha et al. compared 25 male OCD adult patients with 25 normal controls and found that patients with a predominant aggressive/checking symptom dimension had lower FA in the left anterior cingulate WM compared with controls, whereas patients with a predominant contamination/washing symptom dimension showed higher FA in the bilateral prefrontal WM. In a more recent study of 33 adult patients, Koch et al. reported a negative correlation between FA in the right inferior fronto-occipital fasciculus and the right optic radiation and severity on the ordering and symmetry dimension. Both investigations suggest that different patterns of WM abnormalities are associated with different symptom dimensions. There is, therefore, growing evidence that OCD symptoms may be at least partly underpinned by abnormal WM microstructure. Consequently, we sought here to identify brain regions with abnormal FA in OCD patients and to analyze the underlying diffusion changes in terms of mean diffusivity (MD, AD and radial diffusivity (RD)). Speciﬁcally, the aim of this study was to
Research Article: Microstructural Brain Abnormalities in OCD
TABLE 1. Demographic and clinical data of OCD patients and control subjects
OCD patients (N = 63) Mean SD
Healthy control subjects (N = 37) Mean SD
Gender (boys/girls) Age Vocabulary OCI-CV CDI SCARED
36/27 15.6 11.4 13.8 13.8 27.7
2.1 2.2 8.1 9.6 14.2
19/18 15.8 11.9 4.3 3.3 9.4
2.6 24.1 (3–112)
N 13 38 12
% 20.6 60.3 19
13 6 5 5 2 2 1 1 1 1 1
20.6 9.5 7.9 7.9 3.2 3.2 1.6 1.6 1.6 1.6 1.6
Clinical data OCD Age of onset Duration of illness (months) CY-BOCS At time of MRI scan Maximum illness severity Main dimension Contamination/washing Harm/checking Order/symmetry Comorbid conditionsa Generalized anxiety disorder ADHD Anorexia nervosa Tic disorder Hypomania Major depressive disorder Separation anxiety disorder Panic disorder Bulimia nervosa Oppositional deﬁant disorder Enuresis
1.9 1.9 3.1 3.2 5.5
Signiﬁcance X2 /t P 0.316 −.512 −1.173 6.494 6.152 7.060
0.574 .610 .244 .000 .000 .000
ADHD, attention-deﬁcit/hyperactivity disorder. a Current or lifetime.
determine relevant WM abnormalities by comparing a large sample of child and adolescent OCD subjects with a control group matched for age, gender, and estimated intelligence quotient (IQ). We hypothesized, based on previous studies, that pediatric OCD patients would show altered WM microstructure mainly in the CC, cingulum, and parietal and occipital regions. A complementary aim was to investigate whether these WM abnormalities differ between patients according to symptoms dimensions.
MATERIAL AND METHODS PATIENTS AND CONTROLS The sample comprised 63 children and adolescents and 37 healthy controls of both genders and ranging in age from 11 to 18 years. All patients had a current diagnosis of OCD according to DSM-IV criteria. The Schedule for Affective Disorders and Schizophrenia for School-age Children—present and lifetime version (K-SADS-PL) interview —was administered with both parents and the child as informants. Exclusion criteria were psychiatric comorbidity with psychotic disorder, autism spectrum disorder, somatic or neurological illness, and IQ