Neuroplasticity in mood disorders

Abstract

Neuroimaging and neuropathological studies of major depressive disorder (MDD) and bipolar disorder (BD) have identified abnormalities of brain structure in areas of the prefrontal cortex, amygdala, striatum, hippocampus, parahippocampal gyrus, and raphe nucleus. These structural imaging abnormalities persist across illness episodes, and preliminary evidence suggests they may in some cases arise prior to the onset of depressive episodes in subjects at high familial risk for MDD. In other cases, the magnitude of abnormality is reportedly correlated with time spent depressed. Postmortem histopathological studies of these regions have shown abnormal reductions of synaptic markers and glial cells, and, in rare cases, reductions in neurons in MDD and BD. Many of the regions affected by these structural abnormalities show increased glucose metabolism during depressive episodes. Because the glucose metabolic signal is dominated by glutamatergic transmission, these data support other evidence that excitatory amino acid transmission is elevated in limbic-cortical-striatal-pallidal-thalamic circuits during depression. Some of the subject samples in which these metabolic abnormalities have been demonstrated were also shown to manifest abnormally elevated stressed plasma cortisol levels. The co-occurrence of increased glutamatergic transmission and Cortisol hypersecretion raises the possibility that the gray matter volumetric reductions in these depressed subjects are partly accounted for by processes homologous to the dendritic atrophy induced by chronic stress in adult rodents, which depends upon interactions between elevated glucocorticoid secretion and N-meihyl-D-aspartate (NMDA)-glutamate receptor stimulation. Some mood-stabilizing and antidepressant drugs that exert neurotrophic effects in rodents appear to reverse or attenuate the gray matter volume abnormalities in humans with mood disorders. These neurotrophic effects may be integrally related to the therapeutic effects of such agents, because the regions affected by structural abnormalities in mood disorders are known to play major roles in modulating the endocrine, autonomic, behavioral, and emotional experiential responses to stressors.

Keywords: bipolar disorder; major depressive disorder; neuro-imaging abnormalities; neuroplasticity; postmortem studies.

Figure 1. Summary of neuroimaging abnormalities in early-onset, primary, major depressive disorder (MDD). The regions where neurophysiological imaging abnormalities have been consistently reported in unmedicated MDD samples are listed and approximately shown on this midsagittal brain diagram in which subcortical structures are highlighted onto the medial surface. Because only the medial wall of the cortex is shown, the location of the lateral orbital/ventrolateral prefrontal cortex (PFC)/anterior insular region is better illustrated in Figure 2B. The “ventral anterior cingulate” region refers to both pregenual and subgenual portions (see text and Figure 2). The arrows in front of each region name indicate the direction of resting state abnormalities in glucose metabolism in unmedicated, depressed MDD samples relative to healthy control samples. In some cases, abnormalities in both directions have been reported which may depend either on the specific region involved or on the clinical state (eg, treatment responsive vs nonresponsive; see text). The red arrows have indicate histopathological and/or gray matter volumetric abnormalities in postmortem studies of primary mood disorders.

Figure 2. Altered metabolism in the prefrontal cortex (PFC) ventral to the genu of the corpus callosum (c.c.) (ie, subgenual PFC) in mood disorders. A. Negative voxel t values where glucose metabolism is decreased in dépressives relative to controls in coronal (31 mm anterior to the anterior commissure, or y=31)and sagittal (3 mm left of midline, or x=-3) planes of a statistical parametric image comparing depressives relative to controls. This image localized an abnormality in the subgenual portion of the anterior cingulate cortex (subgenual ACC), which was subsequently shown to be accounted for by a corresponding reduction in cortex volume on the left side (see text). Anterior (or left) is to the left of the image. B. Mean, normalized, glucose metabolic values for the left subgenual ACC measured using magnetic resonance imaging (MRI)-based region-of-interest analysis. Metabolism is decreased in depressed subjects with either bipolar disorder (BD) or major depressive disorder (MDD) relative to healthy controls. In contrast, subjects scanned in the manic phase of BD (“bipolar manic”) have higher metabolism than either depressed or control subjects in this region. *P<0.025 controls versus depressed; tP<0.01 depressed versus manic; P<0.05 controls versus manic. Although none of these subjects were involved in the study that generated the images shown in Figure 3, the mean glucose metabolism in this independent sample of depressives and controls also confirmed the areas of abnormally increased activity in the depressives in the amygdala, lateral orbital cortex, ventrolateral PFC, and medial thalamus (not shown in A, which only illustrates negative f values corresponding to hypometabolic areas in the depressives). Figure 2A reproduced with permission from reference 6: Drevets WC, Price JL, Simpson JR, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386:824-827. Copyright © 1997, Nature Publishing Group. Figure 2B reproduced with permission from reference 94: Drevets WC. Neuroimaging and neuropathological studies of depression: Implications for the cognitive emotional manifestations of mood disorders. Curr Opin Neurobiol. 2001;11:240-249. Copyright © 2001 , Elsevier.

Figure 3. Areas of abnormally increased blood flow in subjects with major depressive disorder (MDD). The image sections shown are from an image of t values, produced by a voxel-by-voxel computation of the unpaired t statistic to compare regional CBF between a depressed sample selected according to criteria for familial pure depressive disease (FPDD) (n=13) and a healthy control sample (n=33). The positive t values shown correspond to areas where flow is increased in the depressives relative to the controls. The abnormal activity in these regions was replicated using glucose metabolism imaging in independent subject samples.^,, A. Sagittal section at 17 mm left of midline illustrating areas of increased CBF in depression in the amygdala and orbital cortex. B. Area of increased flow extended through the lateral orbital cortex to the ventrolateral prefrontal cortex (VLPFC) and anterior insula.^, The x coordinate locates sagittal sections in millimeters to the left of midline. The PET images in A and B from which the t image was generated have been stereotaxically transformed to the coordinate system of Talairach and Tournoux, from which the corresponding atlas outline is shown. Anterior is left. Figure 3A reproduced with permission from reference 126: Price JL, Carmichael ST, Drevets WC. Networks related to the orbital and medial prefrontal cortex: a substrate for emotional behavior? Prog Brain Res. 1996;107:523-536. Copyright © 1996, Elsevier. Figure 3B reproduced with permission from reference 138: Drevets WC, Videen TO, Snyder AZ, MacLeod AK, Raichle ME. Regional cerebral blood flow changes during anticipatory anxiety. Soc Neurosci Abstr. 1994;20:368. Copyright © 1994, Society for Neuroscience.