Elsevier

NeuroImage

Volume 49, Issue 1, 1 January 2010, Pages 121-126
NeuroImage

Reduced serotonin transporter binding in the insular cortex in patients with obsessive–compulsive disorder: A [11C]DASB PET study

https://doi.org/10.1016/j.neuroimage.2009.07.069Get rights and content

Abstract

The serotonin transporter (5-HTT) and other markers of the serotonergic system have been of interest in the pathophysiology of obsessive-compulsive disorder (OCD). Previous studies using single photon emission computed tomography (SPECT) with [123I]β-CIT or positron emission tomography (PET) with [11C]McN5652 have not shown consistent findings about 5-HTT in OCD patients. The aim of the present study was to investigate 5-HTT binding using [11C]DASB, which has higher selectivity or specific binding-to-nonspecific binding ratios for 5-HTT compared to the aforementioned radioligands. Four drug-naive and 6 drug-free patients with OCD who were free of comorbid depression and 18 gender and age-matched healthy subjects underwent PET scans with [11C]DASB. The severity of OCD was assessed by Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) (mean ± SD: 22 ± 7.6, range: 7–32). The binding potential (BPND) of [11C]DASB was calculated using a two-parameter multilinear reference tissue model (MRTM2). The parametric images of BPND were analyzed using a statistical parametric mapping system. Significant reductions of BPND were observed in the right posterior and left anterior insular cortices in patients with OCD compared to controls. Region-of-interest analysis has also confirmed significant reduction of BPND in the insular cortex. Although significantly reduced BPND in the orbitofrontal cortex was also observed in patients with OCD compared to controls, this finding should be considered with caution because of the very low 5-HTT binding in the region. On the other hand, no significant correlation was observed between the Y-BOCS score and BPND. The change in [11C]DASB binding in the insular cortex suggests that dysfunction of the serotonergic system in the limbic area might be involved in the pathophysiology of OCD.

Introduction

Obsessive–compulsive disorder (OCD) is a common chronic psychiatric disorder characterized by recurrent obsessions and compulsions. OCD has a high lifetime prevalence rate of 2–3% in the general population and is considered to be among the twenty leading causes of disability in the United States and other countries (Michaud et al., 2006). Based on a number of pertinent findings, such as the effect of serotonin reuptake inhibitors (SSRIs), high comorbidity of depression, reduced densities of platelet serotonin transporter (5-HTT), and the association of 5-HTT gene polymorphism in OCD (Greist and Jefferson, 1998, Greist et al., 1995, Lin, 2007, March et al., 1997), the serotonergic system including 5-HTT has attracted considerable attention in relation to the pathophysiology of OCD.

5-HTT in living human brain can be measured by positron emission tomography (PET) and single photon emission computed tomography (SPECT) with several radioligands. Inconsistent findings in [123I]β-CIT binding in the thalamus and midbrain of patients with OCD were reported by SPECT studies (Hesse et al., 2005, Pogarell et al., 2003, Simpson et al., 2003, Stengler-Wenzke et al., 2004, Zitterl et al., 2007). Since [123I]β-CIT also has affinity to dopamine transporter, it is not an ideal radioligand for quantifying 5-HTT. In a prior PET study using [11C]McN5652, a selective radioligand for 5-HTT, no significant differences were observed in patients with OCD compared to normal subjects (Simpson et al., 2003). However, [11C]McN5652 shows relatively higher nonspecific binding and lower specific binding-to-nonspecific binding ratios compared to [11C]DASB (Huang et al., 2002), a radioligand with higher specific binding to 5-HTT (Wilson et al., 2002) that allows the quantification of binding of not only 5-HTT-rich regions but also relatively low density regions such as cerebral cortices (Ichise et al., 2003, Kim et al., 2006). The aim of the present study was to investigate 5-HTT in the brain of patients with OCD using [11C]DASB.

Section snippets

Subjects

Ten patients with OCD and 18 healthy control subjects participated in this study. All patients met DSM-IV criteria for OCD. Clinical diagnosis was completed by three trained psychiatrists. Based on conventional unstructured interviews and medical histories, we excluded patients with psychiatric disorders other than OCD, such as current major depressive disorder, schizophrenia, bipolar disorders, other anxiety disorders, and substance abuse. To rule out somatic disorders, all patients underwent

Results

SPM analysis of BPND parametric images revealed significant reductions in the right posterior and left anterior insular cortex in the patients with OCD compared to healthy controls (Fig. 1).

ROI analysis revealed that the BPND values of the OCD patients had a tendency to be lower compared to control subjects in all regions (Table 2). Among them, the BPND values showed significant reductions compared to healthy controls in the insular cortex (p = 0.0008 < 0.001) and orbitofrontal cortex (p = 0.0005 < 

Discussion

In the present study, significantly lower BPND values in the insular cortex were observed by [11C]DASB PET study in OCD patients free of comorbid depression, compared to healthy controls. Especially, voxel-based analysis of parametric images over the whole brain contributed to the above new finding. Intriguingly, the [11C]DASB BPND values in the orbitofrontal cortex also showed a significant reduction in OCD patients compared to healthy controls. The orbitofrontal cortex is one of the regions

Acknowledgments

This study was supported by a Grant-in-Aid for the Molecular Imaging Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government. We are grateful to all members of the cyclotron team at the National Institute of Radiological Sciences for their technical support in radioisotope production and all the radiological technicians for their help with the PET experiment. We also thank Ms. Yoshiko Fukushima for her help as clinical research coordinator.

References (46)

  • ShapiraN.A. et al.

    Brain activation by disgust-inducing pictures in obsessive–compulsive disorder

    Biol. Psychiatry

    (2003)
  • SimpsonH.B. et al.

    Serotonin transporters in obsessive–compulsive disorder: a positron emission tomography study with [11C]McN 5652

    Biol. Psychiatry

    (2003)
  • StarkR. et al.

    Hemodynamic responses to fear and disgust-inducing pictures: an fMRI study

    Int. J. Psychophysiol.

    (2003)
  • WilsonA.A. et al.

    Radiotracer synthesis from [11C]-iodomethane: a remarkably simple captive solvent method

    Nucl. Med. Biol.

    (2000)
  • WilsonA.A. et al.

    In vitro and in vivo characterisation of [11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography

    Nucl. Med. Biol.

    (2002)
  • AdamsK.H. et al.

    Patients with obsessive–compulsive disorder have increased 5-HT2A receptor binding in the caudate nuclei

    Int. J. Neuropsychopharmacol.

    (2005)
  • AndersonI.M. et al.

    Citalopram modulation of neuronal responses to aversive face emotions: a functional MRI study

    Neuroreport

    (2007)
  • ArceE. et al.

    Escitalopram effects on insula and amygdala BOLD activation during emotional processing

    Psychopharmacology (Berl)

    (2008)
  • BenmansourS. et al.

    Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level

    J. Neurosci.

    (1999)
  • El MansariM. et al.

    Responsiveness of 5-HT(1A) and 5-HT2 receptors in the rat orbitofrontal cortex after long-term serotonin reuptake inhibition

    J. Psychiatry. Neurosci.

    (2005)
  • FristonK.J. et al.

    Statistical parametric maps in functional imaging; a general linear approach

    Human Brain Mapping

    (1995)
  • GoodmanW.K. et al.

    The Yale–Brown Obsessive–Compulsive Scale. II. Validity

    Arch. Gen. Psychiatry

    (1989)
  • GoodmanW.K. et al.

    The Yale–Brown Obsessive–Compulsive Scale. I. Development, use, and reliability

    Arch. Gen. Psychiatry

    (1989)
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