Decreased regional homogeneity in insula and cerebellum: A resting-state fMRI study in patients with major depression and subjects at high risk for major depression

Abstract

Functional disconnectivity during the resting state has been observed in subjects with major depressive disorder (MDD), and in subjects at high genetic risk for major depression during task performance. It is hypothesized that functional impairments in certain brain areas are present in patients with MDD and in their first-degree relatives. To test this hypothesis, an analysis of regional homogeneity (ReHo) of the whole brain was performed on 45 subjects. Compared with the control group, subjects with MDD and those at high risk for MDD exhibited significantly decreased ReHo in the right insula and in the left cerebellum. These abnormalities may play an important role in the pathophysiology of depression.

Introduction

Major depressive disorder (MDD) is characterized by cognitive impairments, functional disability and mortality, and affects 7%∼11% of the general population. The pathophysiology of depression is unclear. Neurobiological diagnostic markers are not currently established, and the diagnosis of depression is dependent on clinical signs and symptoms.

It is proposed that functional magnetic resonance imaging (fMRI) can provide new insights into the pathophysiology of depression, because of its advantage in not requiring exposure to radioactive tracers. A large number of fMRI studies have focused on cognitive and emotional tasks. Previous fMRI findings have suggested that the brain regions affected in MDD primarily lie in the prefrontal–amygdalar–pallidostriatal–mediothalamic mood regulating circuit (MRC) (Anand et al., 2005b, Anand et al., 2007). This network is involved in the regulation of mood, cognition and behavior, and is considered a contributor in the pathophysiology of MDD. However, the results of these studies are not consistent. For example, some contradictory findings have emerged regarding abnormalities in the prefrontal cortex associated with cognitive and emotion processing. Some studies have reported hypofrontality in MDD subjects compared with controls (Lee et al., 2008, Mitterschiffthaler et al., 2003, Elliott et al., 2002) whereas other research has conversely identified hyperfrontality in MDD (Walter et al., 2007, Fitzgerald et al., 2008, Fu et al., 2004). Several fMRI studies based on tasks using emotional stimuli found that hypoactivation of the cingulate was correlated with depression (Malhi et al., 2004, Anand et al., 2005a). In addition, hypoactivation of the amygdala has been found to play a key role in the neural substrate of negatively biased automatic emotion processing (Dannlowski et al., 2007, Hamilton and Gotlib, 2008). It is certainly difficult for the results obtained from the large variety of task-states to be repeated, because of the complicated designs of these studies.

Recently, resting-state fMRI has attracted more attention as a new branch of this field of study. Low-frequency fluctuations (LFF; < 0.08 Hz) of fMRI signals are considered to be related to spontaneous neuronal activity in resting state and were found to be highly synchronous in healthy subjects (Biswal et al., 1995, Cordes et al., 2000). These resting-state fMRI studies have suggested that patients with many psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), schizophrenia and depression (Zhou et al., 2007, Tian et al., 2006, Greicius et al., 2007) exhibit decreased LFF synchrony in particular brain regions.

More recently, the regional homogeneity (ReHo) method (Zang et al., 2004) was used to analyze the similarities of intra-regional time series across the whole brain. Kendall's coefficient of concordance (KCC) was used to measure the similarity of the time series of one voxel with those of its nearest neighbors in a voxel-wise analysis. ReHo reflects the temporal synchrony of the regional blood oxygen level-dependent (BOLD) signal, which may be potentially helpful to understanding the pathophysiology of psychiatric disorder. This method has been used to explore regional neural activity patterns in healthy volunteers and psychiatric patients in the resting state. Decreased ReHo among remote brain areas has been reported in schizophrenia and ADHD (Liu et al., 2006, Zhu et al., 2005).

Genetic factors play an important role in the pathology of depression. Some fMRI studies have demonstrated that subjects at high genetic risk for depression exhibit impaired modulation of some regions, such as the amygdala and the anterior cingulate cortex during task performance (Wolfensberger et al., 2008, Mannie et al., 2008).

We hypothesize that abnormal ReHo will be discovered in certain regions in patients with MDD, and in their first-degree relatives. These abnormalities may be a stable trait marker for the diagnosis of MDD. To test this hypothesis, the present study compared the ReHo of the whole brain among patients with MDD, their first-degree relatives, and healthy controls.