Elsevier

Biological Psychiatry

Volume 51, Issue 4, 15 February 2002, Pages 273-279
Biological Psychiatry

Original article
Reduced volume of orbitofrontal cortex in major depression

https://doi.org/10.1016/S0006-3223(01)01336-1Get rights and content

Abstract

Background: Functional neuroimaging studies have implicated dysfunction of orbitofrontal cortex in the symptoms of depression, and a recent postmortem study of depressed patients found reduced density of neurons and glia in this area. The purpose of this study was to measure volume of orbitofrontal cortex and other frontal cortical subregions in patients with major depression.

Methods: Magnetic resonance imaging was used to measure volume of the orbitofrontal cortex and other frontal cortical regions in patients with major depression in remission (n = 15) and comparison subjects (n = 20).

Results: Patients with depression had a statistically significant 32% smaller medial orbitofrontal (gyrus rectus) cortical volume, without smaller volumes of other frontal regions including anterior cingulate Brodmann’s area 24 (subgenual gyrus), anterior cingulate Brodmann’s area 32, subcallosal gyrus (Brodmann’s area 25), or whole brain volume. The findings were significant after statistically controlling for brain size.

Conclusions: These findings are consistent with smaller orbitofrontal cortical volume in depression.

Introduction

Major depression affects 15% of the population at some time in their lives and is associated with considerable morbidity and loss of economic productivity. Understanding the neural correlates of depression may be helpful in the development of treatments for this disorder. Neuroimaging of brain structure and function in patients with depression has developed as a promising tool for the assessment of neural correlates of depression. Studies have used assessment of both brain structure (in earlier studies measured with computed tomography and more recently with magnetic resonance imaging [MRI]) and function (measured with positron emission tomography [PET] or single photon emission tomography [SPECT] measurement of blood flow or metabolism) in the study of patients with depression.

These studies have been most consistent in demonstrating dysfunction of the prefrontal cortex in depression (George et al 1994). Decreased blood flow and metabolism was shown in several areas of prefrontal cortex in patients with depression, including dorsolateral prefrontal cortex Buchsbaum et al 1984, Baxter et al 1989, Hurwitz et al 1990, Martinot et al 1990, Ebert et al 1991, Austin et al 1992, Bench et al 1992, Mayberg et al 1994, Biver et al 1994, Mann et al 1996, medial prefrontal cortex/anterior cingulate (Brodmann’s areas [BA] 24, 32 and 25) Bench et al 1992, Drevets et al 1997, George et al 1997, Mayberg et al 1997, and orbitofrontal cortex Mayberg et al 1990, Mayberg et al 1992, Ring et al 1994. We found that experimentally induced depressive relapse provoked by a tryptophan depleting drink, which lowers brain serotonin levels, was associated with decreased function in dorsolateral prefrontal and orbitofrontal cortex (Bremner et al 1997). Treatment of depression resulted in a reversal of these deficits and/or was related to baseline function in these regions Baxter et al 1989, Martinot et al 1990, Ebert et al 1991, Wu et al 1992, Goodwin et al 1993, Ebert et al 1994, Rubin et al 1994, Scott et al 1994, Nobler et al 1994. These findings implicated dysfunction of prefrontal cortex in depression, including dorsolateral prefrontal, anterior cingulate, and orbitofrontal cortex.

Studies using structural imaging in depression have not consistently looked at frontal cortex. Early studies using computed tomography in patients with bipolar disorder found ventricular enlargement and widening of the cortical sulci Pearlson and Veroff 1981, Kellner et al 1986, Andreasen et al 1990. Magnetic resonance imaging studies in patients with unipolar depression showed abnormalities in subcortical white matter Krishnan et al 1992, Aylward et al 1994, and some studies Husain et al 1991, Krishnan et al 1992, but not others Aylward et al 1994, Bremner et al 2000, showed smaller volume of caudate. Magnetic resonance (MR) imaging studies showed smaller right hippocampal volume (Swayze et al 1992) and temporal lobe volume (Altschuler et al 1991) in bipolar patients, and alterations in hippocampal T1 relaxation time (reflective of changes in water content) (Krishnan et al 1991) with reductions in gray matter in the left temporal lobe (Sha et al 1998) in unipolar depression. Some studies Sheline et al 1996, Bremner et al 2000 found reduction in hippocampal volume in unipolar depression, while studies in various affective disorders found larger volume of the amygdala Bremner et al 2000, Altschuler et al 1998, Stratowski 1999, Tebartz van Elst 1999 (although, see Sheline et al 1998), which may explain the finding of no change in combined amygdala/hippocampal volume in unipolar depression (Axelson et al 1993). Studies in elderly patients with depression found an increase in subcortical white matter lesions on T2-weighted MR Pantel et al 1997, Krishnan et al 1988. Most studies of prefrontal cortical structure have examined whole prefrontal cortical volume (Narayan et al 1999). Kumar et al 1997, Kumar et al 1998 demonstrated a reduction in whole prefrontal cortical volume in late onset depression, although other studies in late onset (Pantel et al 1997) and midlife (Bremner et al 2000) depression did not find a significant difference in whole frontal cortical volumes. One study of subregions of frontal cortex published to date found a reduction in volume of an area of the anterior cingulate (BA 24) (subgenual gyrus) (Drevets et al 1997). A review of this research suggests that additional studies are needed to look at structural changes in subregions of prefrontal cortex identified in functional imaging studies of depression.

Recent postmortem studies have been consistent with morphologic changes in the prefrontal cortex in depression. One study looked at the same frontal cortical regions (dorsolateral prefrontal cortex and medial orbitofrontal cortex [gyrus rectus]) identified in our study using functional brain imaging in depression, and found a decrease in density of neurons and glia in these areas (Rajkowska et al 1999). Other studies have found reduced density of glia (but not neurons) in anterior cingulate (BA 24) (subgenual area) (Ongur et al 1998). Until recently, there have been no neuroimaging studies to examine volume of the orbitofrontal cortex in patients with depression. Lai et al (2000) recently reported a reduction in orbitofrontal cortical volume in patients with geriatric depression. The purpose of this study was to measure volume of the orbitofrontal cortex and other prefrontal subregions in middle-aged patients with major depression and controls. We hypothesized smaller volume of the orbitofrontal cortex in midlife patients with unipolar depression.

Section snippets

Methods and materials

The study sample consisted of 15 patients with a history of depression based on the Structured Interview for DSMIV (SCID) (Spitzer et al 1987) currently treated on an outpatient basis with antidepressant medication (paroxetine, fluoxetine, or desipramine). All subjects provided written informed consent for participation as approved by a local IRB. Patients were excluded if they had a history of meningitis, traumatic brain injury, neurologic disorder, loss of consciousness of greater than 10

Results

Patients with major depression had 32% smaller volume of the medial orbitofrontal cortex (gyrus rectus) compared with controls which was statistically significant based on analysis of variance (ANOVA) (Table 1; Figure 1; Figure 2). This difference was also seen after controlling for differences in whole brain size using ANOVA with whole brain volume added as a factor in the analysis (F = 6.77; df = 2,32; p < .05). There were no differences in size of other prefrontal cortical regions measured

Discussion

Patients with remitted major depression in this study showed a 32% smaller volume of the orbitofrontal cortex (gyrus rectus) in comparison with control subjects. There were no differences in volumes of other subregions of prefrontal cortex, including subcallosal gyrus (BA 25), anterior cingulate-BA 24 (subgenual gyrus) or BA 32, or in whole brain volume. We have previously reported no difference in volume of the entire prefrontal cortex in patients with major depression relative to controls

Acknowledgements

The authors thank Kathy Colonese, Jacque Piscitelli, and Lisa Roach for assistance in patient assessments and data management; Hedy Sarofin for expert assistance in MRI acquisition; and Helen Sayward for image processing and data analysis. This study was supported by the National Center for PTSD Grant and a Veterans Administration Career Development Award Grant to Dr. Bremner.

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