The subgenual anterior cingulate cortex in mood disorders

Abstract

The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this "subgenual" ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended "visceromotor network" of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.

FIGURE 1. The area of reduced glucose metabolism in the subgenual PFC is illustrated in images composed of voxel t-values that compare depressives and controls, shown in sagittal (left) and coronal (right) sections,

This image was produced by a voxel-by-voxel computation of the unpaired t-statistic to identify inherent differences in metabolism between samples of familial bipolar and unipolar depressives relative to healthy controls. The t-images shown were generated to provide optimal localization of a regional metabolic abnormality identified using other techniques, which included comparisons involving independent subject samples, The negative t-values, shown in a coronal section at 31 mm anterior to the anterior commissure (y=31 mm) and a sagittal section at 3 mm left of the midline (x=−3 mm), correspond to areas where metabolism is decreased in the depressives relative to the controls. Both the stereotaxic center-of-mass of the peak metabolic difference shown here (x=−2, y=32, z=−2; interpreted as in Table 1) and that of the peak blood flow difference computed in an independent subject set(x=1, y=25, z=−6) localized to the agranular region of the anterior cingulate gyrus ventral to the corpus callosum. The mean normalized metabolism for each group is shown from Drevets and colleagues. However, the area of reduced metabolism in the sgACC was at least partly accounted for by a corresponding reduction in cortex in both the bipolar disordered and the unipolar depressed groups relative to the control group (Figure 3). While the spatial resolution of PET precludes clear laterality distinctions in midline structures, the MRI-based neuromorphometric measures showed the grey matter volume reduction to be left-lateralized. Anterior is to the left and dorsal toward the top. * P<.025, control versus depressed. † P<.05, control versus manic. ‡ P<.01, depressed versus manic. PFC=prefrontal cortex; CC=corpus callosum; SgACC=subgenual anterior cingulate cortex; PET=positron emission tomography; MRI=magnetic resonance imaging Drevets WC, Price JL, Simpson JR Jr, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386:824–827. Mazziotta JC, Phelps ME, Plummer D, Kuhl DE. Quantitation in positron emission computed tomography, 5. Physical—anatomical effects. J Comput Assist Tomogr. 1981;5:734–743.

FIGURE 2. Sagittal section through the midline of a human brain photographed postmortem and marked to show the cytoarchitectonic areas established by dissection and histological characterization of other human brain specimens^*

^*The human subgenual (or “subcallosal”) anterior cingulate gyrus consists of agranular cortex characterized as BA 24 anteriorly and BA 25 posteriorly. C=cotex; BA=Brodmann area. Ongür D, Ferry AT, Price JL. Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol. 2003;460:425–449.

FIGURE 3. Mean (±SEM) MRI-based volumes of the left sgACC gray matter differed between the bipolar disordered, unipolar depressed, and control groups

The left subgenual PFC/whole brain volume ratio also was reduced in the bipolar and unipolar groups relative to the control group. Although the bipolar subjects who underwent PET imaging had been unmedicated prior to scanning, additional bipolar subjects were included in the MRI portion of the study who had been chronically medicated with lithium (n=4) or divalproex (n=2). The mean volume for this medicated subsample is shown separately, and differed significantly (P<.05) from both the unmedicated bipolar disorder and MDD groups, but did not differ significantly from the healthy control group. SEM=standard error of the mean; MRI=magnetic resonance imaging; sgACC=subgenual anterior cingulate cortex; PFC=prefrental cortex, Li/VPA=lithium/divalproex; MDD=major depressive disorder; PET=positron emission tomography. Drevets WC, Price JL, Simpson JR Jr. et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386:824–827.