Original articleReduced volume of orbitofrontal cortex in major 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.
References (63)
- et al.
Single photon emission tomography with 99 mTc-exametazime in major depression and the pattern of brain activity underlying the psychotic/neurotic continuum
J Affect Disord
(1992) - et al.
Hypercortisolemia and hippocampal changes in depression
Psychiatry Res
(1993) - et al.
Frontal and parietal metabolic disturbances in unipolar depression
Biol Psychiatry
(1994) Does stress damage the brain?
Biol Psychiatry
(1999)- et al.
Development and reliability of a method for using magnetic resonance imaging for the definition of regions of interest for positron emission tomography
Clin Positron Imaging
(1998) - et al.
Effects of sleep deprivation on the limbic system and the frontal lobes in affective disordersA study with Tc-99 m-HMPAO SPECT
Psych ResNeuroimaging
(1991) - et al.
Increased limbic flow and total sleep deprivation in major depression with melancholia
Psychol Res
(1994) - et al.
A magnetic resonance imaging study of putamen nuclei in major depression
Psych Res Neuroimaging
(1991) - et al.
Cerebral ventricular size and cognitive impairment in depression
J Affect Disord
(1986) - et al.
Leukoencephalopathy in patients diagnosed as major depressives
Biol Psychiatry
(1988)
Reduction of orbital frontal cortex volume in geriatric depression
Biol Psychiatry
Paradoxical effects of adrenal steroids on the brainProtection versus degeneration
Biol Psychiatry
Extinction of emotional learningContribution of medial prefrontal cortex
Neurosci Lett
Quantitative magnetic resonance imaging in geriatric depression and primary degenerative dementia
J Affect Disord
Computerized tomographic changes in manic depression
Lancet
Short-term effects of electroconvulsive treatment on the uptake of 99 mTc-exametazime into brain in major depression shown with single photon emission tomography
J Affect Disord
Subcortical and temporal structures in affective disorder and schizophreniaA magnetic resonance imaging study
Biol Psychiatry
Amygdala enlargement in dysthymia-A volumetric study of patients with temporal lobe epilepsy
Biol Psychiatry
Amygdala enlargement in bipolar disorder and hippocampal reduction in schizophreniaAn MRI study demonstrating neuroanatomic specificity
Arch Gen Psychiatry
Reduction of temporal lobe volume in bipolar disorderA preliminary report of magnetic resonance imaging (letter)
Arch Gen Psychiatry
Ventricular abnormalities in affective disorderClinical and demographic correlates
Arch Gen Psychiatry
Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder
Am J Psychiatry
Reduction of prefrontal cortex glucose metabolism common to three types of depression
Arch Gen Psychiatry
The anatomy of melancholiaFocal abnormalities of cerebral blood flow in major depression
Psychol Med
PET measurement of cerebral metabolic correlates of depressive relapse
Arch Gen Psychiatry
Hippocampal volume reduction in major depression
Am J Psychiatry
MRI-based measurement of hippocampal volume in posttraumatic stress disorder
Am J Psychiatry
Anteroposterior gradients in cerebral glucose use in schizophrenia and affective disorders
Arch Gen Psychiatry
The return of Phineas GageClues about the brain from the skull of a famous patient
Science
Subgenual prefrontal cortex abnormalities in mood disorders
Nature
The Human BrainSurface Three-Dimensional Anatomy and MRI
Cited by (467)
Transdiagnostic symptom of depression and anxiety associated with reduced gray matter volume in prefrontal cortex
2024, Psychiatry Research - NeuroimagingGray and white matter abnormalities in major depressive disorder patients and its associations with childhood adversity
2023, Journal of Affective DisordersAnterior cingulate cortex in individuals with depressive symptoms: A structural MRI study
2022, Psychiatry Research - Neuroimaging