Voxel-based analyses of gray/white matter volume and diffusion tensor data in major depression
Introduction
There is converging evidence from both post mortem and in vivo studies that frontolimbic dysfunction may play an important role in the pathophysiology of major depressive disorder (Drevets, 2000, Tekin and Cummings, 2002, Sheline, 2003). Previous neuroimaging studies have revealed reduced gray matter volumes in the prefrontal cortex (Coffey et al., 1993, Drevets et al., 1997, Kumar et al., 1998), hippocampus (Steffens et al., 2000, Bell-McGinty et al., 2002), anterior cingulate cortex, gyrus rectus, and orbitofrontal cortex in the depressive state (Ballmaier et al., 2004). Hypoperfusion and hypometabolism in the anterior brain structures, especially in the prefrontal cortex and paralimbic regions, have been the most consistently replicated findings in functional neuroimaging studies on late-life depression (Lesser et al., 1994, Oda et al., 2003). In addition, neuroimaging and neuropathological studies have suggested deep white matter hyperintensities, especially those located at the level of the dorsolateral prefrontal cortex, as one of the primary neurobiological substrates of elderly depression (Coffey et al., 1993, Thomas et al., 2002, Oda et al., 2003). Although most of these neuroimaging results have been from geriatric samples, some recent reports have found that first-episode, untreated young adults with major depressive disorder exhibited significantly lower fractional anisotropy (FA) than healthy subjects in frontal lobes (Li et al., 2007, Ma et al., 2007). These findings may indicate that white matter lesions are present early in the course of major depressive disorder, and may disrupt the neural circuits involved in mood regulation, resulting in impaired cortical and subcortical function, which in turn contributes to the pathogenesis of depression.
In biological systems, the diffusion of water is impeded by tissue structures such as cell membranes, myelin sheaths, intracellular microtubules, and associated proteins. An important consequence of the interaction between water molecules and sub-cellular structures is “diffusion anisotropy”; this term describes the fact that diffusion occurs most freely in a direction parallel, rather than perpendicular, to an axon or myelin sheath (Moseley et al., 1990). Diffusion tensor imaging (DTI) measures include mean diffusivity (MD), a general measure of diffusion which may serve as a surrogate marker for fiber density, and FA, which measures the direction of water diffusion and has been proposed to be a surrogate marker for white matter orientation and organization. The measurement of anisotropy using diffusion tensor analysis is a promising method for non-invasively detecting the degree of fiber damage in depressive disorders (Alexopoulos et al., 2002, Nobuhara et al., 2004, Nobuhara et al., 2006, Taylor et al., 2004, Ma et al., 2007). Most previous studies have utilized manual or semi-automated region-of-interest (ROI) guided measurements. The parameters of ROI measurements can be defined such that they are highly reliable; however, the validity of investigator-determined ROI analyses is questionable, given the high degree of inter- and intra-individual variability. Bias can also be introduced as a result of the small number of regions and metrics used in classical morphometrics that are insensitive to differences elsewhere in the brain.
A number of unbiased whole-brain techniques are currently emerging as a result of the improved resolution of structural magnetic resonance imaging (MRI) scans and the development of sophisticated image-processing tools. For example, the voxel-based approach has advantages over manual ROI analysis when searching for abnormalities throughout the entire brain. Voxel-based morphometry (VBM) has provided objective and reliable results in several studies, eliminating the effects of operator bias (Richardson et al., 1997, Wright et al., 1999, Kubicki et al., 2002), although some authors have suggested that voxel-based and ROI-based methods provide different types of information and voxel-based analysis can be used as an exploratory whole-brain approach to identify abnormal brain regions, which should then be validated by using ROI-based analyses (Giuliani et al., 2005, Honea et al., 2005).
In the current study, we used voxel-based analyses to characterize and quantify group differences between unipolar major depressive patients with a wide range of age and normal volunteers in terms of gray and white matter volume and diffusion properties such as MD and FA. Previous studies have addressed either diffusion characteristics (Alexopoulos et al., 2002, Nobuhara et al., 2004, Nobuhara et al., 2006, Taylor et al., 2004, Ma et al., 2007) or morphometry (Coffey et al., 1993, Kumar et al., 1998, Bell-McGinty et al., 2002, Ballmaier et al., 2004) alone; consequently, these structural and diffusional neuroimaging findings of depression have been poorly integrated in the past.
Structural changes in the depressive brain, especially in gray matter volume, are intimately related to abnormal neural pathways, which can be estimated using DTI data. The goals of the current research were therefore to document the group differences in brain volume and diffusion properties in order to determine their relevance, and to assess their underlying mechanisms. Although it was hypothesized that depressive patients would show abnormal volume and diffusional changes in the frontolimbic system, and adjacent cortex or subcortical white matter compared with normal subjects on the basis of the findings of previous studies investigating morphology and functional alteration (Kumar et al., 1998, Alexopoulos et al., 2002, Bell-McGinty et al., 2002, Ballmaier et al., 2004, Nobuhara et al., 2004, Nobuhara et al., 2006, Taylor et al., 2004, Li et al., 2007, Ma et al., 2007), voxel-based analysis, unlike ROI-based analysis, would allow us to explore the entire brain and to find the unpredicted location of abnormality in subjects with depression.
Section snippets
Subjects
The subjects consisted of 21 patients with unipolar major depressive disorder (10 females and 11 males; 48.1 ± 13.5 years old) and age- and gender-matched normal subjects (20 females and 22 males; 48.0 ± 13.2 years old). Clinical assessment was conducted by two psychiatrists (H. Yamasue, M.S.) experienced in the use of the Diagnostic Interview for Genetic Studies (DIGS) on the same day as the MR scanning. The DIGS is a structured interview with high reliability (Nurnberger et al., 1994) that was used
Group differences in gray and white matter volumes
There were no significant differences in total gray and white matter volumes or TIV between depressive patients and normal controls (Table 1). Local areas showing significant gray matter volume reduction in depressive patients compared with normal controls were observed in the right parahippocampal gyrus, hippocampus, bilateral middle frontal gyri, bilateral anterior cingulate, left parietal and occipital lobes, and right superior temporal gyrus (Table 2; Fig. 1). There were no local areas
Discussion
To our knowledge, this is the first report to simultaneously study cerebral volumetric and diffusion differences between unipolar major depressive patients and normal controls in a voxel-wise manner. The principal findings of this study are that the depressed subjects had significantly smaller volumes in the right parahippocampal gyrus, hippocampus, and prefrontal cortex (e.g., bilateral middle frontal gyri and anterior cingulate), and higher MD values in the bilateral parahippocampal gyri,
Acknowledgment
This study was supported by grants-in-aid for scientific research (C) (No. 18591330) from Japan Society for the Promotion of Science.
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