Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗

Abstract

Background: This report provides histopathological evidence to support prior neuroimaging findings of decreased volume and altered metabolism in the frontal cortex in major depressive disorder.

Methods: Computer-assisted three-dimensional cell counting was used to reveal abnormal cytoarchitecture in left rostral and caudal orbitofrontal and dorsolateral prefrontal cortical regions in subjects with major depression as compared to psychiatrically normal controls.

Results: Depressed subjects had decreases in cortical thickness, neuronal sizes, and neuronal and glial densities in the upper (II–IV) cortical layers of the rostral orbitofrontal region. In the caudal orbitofrontal cortex in depressed subjects, there were prominent reductions in glial densities in the lower (V–VI) cortical layers that were accompanied by small but significant decreases in neuronal sizes. In the dorsolateral prefrontal cortex of depressed subjects marked reductions in the density and size of neurons and glial cells were found in both supra- and infragranular layers.

Conclusions: These results reveal that major depression can be distinguished by specific histopathology of both neurons and glial cells in the prefrontal cortex. Our data will contribute to the interpretation of neuroimaging findings and identification of dysfunctional neuronal circuits in major depression.

Introduction

Although depressive illnesses can be serious, and even lead to suicide, nearly 80 percent of people suffering from depression can be treated successfully with medication, psychotherapy, or a combination of both. Pharmacologic, biochemical and neuroanatomical studies are beginning to establish that depressive disorders are brain diseases with unique histopathological features. Profuse neurochemical research suggests that the disruption of monoaminergic neurotransmitter pathways may be critical in the pathophysiology of major depressive disorder (MDD). In particular, the serotonin and norepinephrine systems have been implicated, because nearly all clinically effective antidepressant medications affect these neurotransmitters Heninger and Charney 1987, Hollister and Claghorn 1993.

In contrast to the neurochemical literature, there are no systematic histopathological studies of neurons and glia on major depression or other mood disorders. Such studies may be highly relevant because reports in depressed patients and suicide victims reveal changes in monoamine receptors and transporters and related second messenger systems Arango et al 1995, Biver et al 1997, Klimek et al 1997, Ordway et al 1994, Pacheco et al 1996, Stockmeier et al 1998 suggesting parallel cellular changes in the cortical projection areas of monoaminergic neurons. The prefrontal cortex is a particularly good candidate for a site of cellular pathology, because this region is an important target of extensive monoamine projections originating in the brainstem nuclei including the dorsal raphe, locus coeruleus and ventral tegmental area. Evidence for histopathology of glia in the subgenual region of the prefrontal cortex in major depression was recently reported by Öngür et al. (1998).

Interest in the long overlooked morphopathology of mood disorders has recently been kindled with the emergence of in vivo brain-imaging techniques. Although the results of neuroimaging studies are sometimes conflicting, the majority of such reports have implicated the prefrontal cortex as a site of functional and structural abnormalities in mood disorders (for review see Rajkowska 1997). Inmajor depression at least two different regions, the dorsolateral prefrontal cortex (dlPFC) and the orbitofrontal-ventral region have been implicated. For example, patients with MDD consistently have reduced glucose metabolism in the left dlPFC Baxter et al 1989, Bench et al 1993, Biver et al 1994. Decreased brain metabolism was found recently in dlPFC as well as in orbitofrontal cortex (ORB) in patients with a relapse in depression induced by depletion of tryptophan (Bremner et al 1997). Abnormally decreased metabolic activity was also localized in the ventromedial subgenual region of the frontal lobe in MDD and bipolar disorder (Drevets et al 1997). In contrast, earlier studies report increased metabolism or blood flow in orbitofrontal and ventrolateral prefrontal regions in MDD patients Biver et al 1994, Buchsbaum et al 1986, Drevets and Raichle 1992, although blood flow tended to be lower in subjects with the greatest severity of depression (Drevets et al 1992). These apparent inconsistencies found in the orbitofrontal/ventral region indicate either the existence of different metabolic patterns in specific subareas of this region or imprecise anatomical localization of the observed changes.

Pathology of cortical cells may be related to the recent neuroimaging findings in patients with mood disorders. A 7% reduction of the total volume of the frontal lobe was reported in MDD (Coffey et al 1993) and substantial 39–48% decreases in the subgenual prefrontal gray matter volume were found in patients with MDD and bipolar depression (Drevets et al 1997). The specific neuronal and glial pathology underlying these gross morphological changes has not been determined to date. The present study is the first attempt to use state-of-the art morphometric methods to test whether neuronal or glial cell pathology can be identified in ORB or dlPFC regions. We also tested whether the pattern of specific cortical pathology is similar or different between prefrontal regions as suggested by the neuroimaging studies.