Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression

Abstract

The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger "default system" of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies.

Fig. 1

Regions and anatomical projections that form the extended visceromotor network. The cytoarchitectonic subdivisions of the human orbital (upper left) and medial prefrontal cortical surfaces (lower left) are distinguished here as being predominantly in the visceromotor (pink) or sensory (green) networks described in (Ongür and Price 2000). These portions of the figure are modified from Ongür et al. (2003), with the lighter shade of pink reflecting more recent work regarding the portions of the medial wall that share the connectional features of the visceromotor network. The area shown in blue, the sulcal portion of BA 47 [47 s; which corresponds to orbital portion of Walker area 12 (i.e., 12o) of the monkey; see Fig. 2], shares features of both the visceromotor and sensory networks. This region and the anterior (agranular) insula (Ia) continue into the lateral cortical wall, so are better viewed in the coronal sections shown in Ongür et al. 2003). The major structures that receive efferent projections from the visceromotor component of the OMPFC are indicated on the right panel over the brain diagram. These include the posterior cingulate cortex, the anterior temporal cortex, and the entorhinal and parahippocampal cortex, all of which are implicated in the “default system” (Hsu and Price ; Kondo et al. , ; Price ; Saleem et al. 2007, 2008). C cortex, MD mediodorsal nucleus of the thalamus, PAG periaqueductal gray; PV periventricular nucleus of the thalamus

Fig. 2

Architectonic maps of the orbital (upper and right-center panels) and medial prefrontal cortical surfaces (left-center panel) of the macaque brain, modified from Carmichael and Price (1994). The upper panel shows the areas hypothesized to form the “sensory” network of the orbital cortex based upon their afferent connections with various sensory domains, which are indicated next to each set of regions. This sensory network projects into the “visceromotor” network (middle panel). This latter network shares extensive, reciprocal connections with the amygdala, periaqueductal gray and hypothalamus (shown in coronal sections at the lower right, center and left, respectively), areas which play major roles in organizing or mediating the endocrine, autonomic, and behavioral aspects of emotional behavior. The specific cytoarchitectonic areas of the visceromotor component of the orbitomedial PFC are color coded according to the specific nuclei of the amygdala and hypothalamus or the column of the PAG to which they predominantly project (Carmichael and Price ; Ongür and Price ; Floyd et al. 2000, 2001). Bvl ventrolateral part of the basal nucleus of the amygdala, Ce central nucleus of the amygdala, DH dorsal hypothalamic area, LH lateral hypothalamic area, MH medial hypothalamic area; dlPAG, lPAG, vlPAG dorsolateral, lateral, and ventrolateral columns of the PAG, respectively

Fig. 3

Areas of abnormally increased physiological activity in familial MDD shown in images of unpaired t values, which were computed using a statistical parametric mapping approach to compare activity between depressives and controls (Drevets et al. 1992, 1997). Upper left the positive t values in this sagittal section located 17 mm left of midline (X = −17) show areas were CBF is increased in depressives versus controls in the amygdala and medial (MED) orbital cortex (reproduced from Price et al. 1996). Upper right positive t values in a sagittal section 41 mm left of midline (X = −41) show areas where CBF is increased in the depressives in the left ventrolateral PFC (VLPFC), lateral orbitofrontal C, and anterior insula (reproduced from Drevets et al. 2004). Lower right positive t values in a coronal section located 19 mm posterior to the anterior commissure (Y = −19) shows an area where CBF is increased in the depressives in the left medial thalamus (reproduced from Drevets and Todd 2005). Lower left coronal (31 mm anterior to the anterior commissure; Y = 31) and sagittal (3 mm left of midline; X = −3) sections showing negative voxel t values where glucose metabolism is decreased in depressives relative to controls. The reduction in activity in this prefrontal cortex (PFC) region located in the anterior cingulate gyrus ventral to the genu of the corpus callosum (i.e., subgenual) appeared to be accounted for by a corresponding reduction in cortex volume (Table 1; reproduced from Drevets et al. 1997). Anterior or left is to left

Fig. 4

Reduced muscarinic type 2 (M2) receptor binding in the cingulate cortex in depressed subjects with bipolar disorder relative to healthy controls. The statistical parametric map shows voxel t values corresponding to areas where the uptake of [¹⁸F]FP-TZTP, a PET radioligand which selectively binds M2 receptors, was significantly reduced (at P < 0.005) in bipolar depressives relative to healthy controls. The areas of maximal difference between groups were located in the anterior cingulate cortex. Reproduced from Cannon et al. (2006a)

Fig. 5

Anatomical circuits involving the medial PFC (MPFC) and amygdala reviewed within the context of a model in which MPFC dysfunction results in disinhibition of limbic transmission through the amygdala, yielding the emotional, cognitive, endocrine, autonomic and neurochemical manifestations of depression. The basolateral amygdala sends efferent projections to the central nucleus of the amygdala (ACe) and the bed nucleus of the stria terminalis (BNST). The efferent projections from these structures to the hypothalamus, periaqueductal gray (PAG), nucleus basalis, locus ceruleus, raphe and other diencencephalic and brainstem nuclei then organize the neuroendocrine, neurotransmitter, autonomic, and behavioral responses to stressors and emotional stimuli (Davis and Shi ; LeDoux 2003). The MPFC shares reciprocal projections with all of these structures (although only the connections with the amygdala are illustrated) which function to modulate each component of emotional expression (Ongür et al. 2003). Impaired MPFC function thus may disinhibit or dysregulate limbic outflow through the ACe and BNST. Solid white lines indicate some of the major anatomical connections between structures, with closed arrowheads indicating the direction of projecting axons. Solid yellow lines show efferent pathways of the ACe and BNST, which generally are monosynaptic, but in some cases are bisynaptic connections (e.g., Herman and Cullinan 1997). Other abbreviations: 5-HT serotonin, ACh acetylcholine, DA dopamine, DL dorsolateral column of PAG; N nucleus, NE norepinephrine, NTS nucleus tractus solitarius, PVN paraventricular N of the hypothalamus, VL ventrolateral column of PAG, VTA ventral tegmental area. Reproduced from Drevets (2007)