Neurocircuitry of mood disorders

Abstract

This review begins with a brief historical overview of attempts in the first half of the 20th century to discern brain systems that underlie emotion and emotional behavior. These early studies identified the amygdala, hippocampus, and other parts of what was termed the 'limbic' system as central parts of the emotional brain. Detailed connectional data on this system began to be obtained in the 1970s and 1980s, as more effective neuroanatomical techniques based on axonal transport became available. In the last 15 years these methods have been applied extensively to the limbic system and prefrontal cortex of monkeys, and much more specific circuits have been defined. In particular, a system has been described that links the medial prefrontal cortex and a few related cortical areas to the amygdala, the ventral striatum and pallidum, the medial thalamus, the hypothalamus, and the periaqueductal gray and other parts of the brainstem. A large body of human data from functional and structural imaging, as well as analysis of lesions and histological material indicates that this system is centrally involved in mood disorders.

Figure 1

Drawing of the limbic system centered around the hippocampus (shown as a sea-horse) from the review by MacLean (1949). (HYP=hypothalamus; the circles dorsal to the hypothalamus represent the anterior thalamic nuclei.).

Figure 2

Summary of amygdaloid outputs. Left: diagram of amygdaloid circuits involving the striatum pallidum medial thalamus and prefrontal cortex and output to the hypothalamus and brainstem. Right: diagram of areas of the cerebral cortex that receive axonal projections from the amygdala. The dark, medium, and lightly shaded areas represent high, medium, and low density of amygdaloid fibers. Modified from Amaral et al, 1992.

Figure 3

The architectonic areas of the OMPFC (above) and LPFC (below) grouped into networks or systems. Areas within each system are preferentially connected with other areas in the same system and have similar connections to other cortical areas. There are also three areas (blue) that are connected to more than one system.

Figure 4

A comparison of the cortico-cortical connections of the ‘orbital' and ‘medial' prefrontal networks labeled by injections of different retrograde axonal tracers in the same animal. Panels a, b, and c illustrate patterns of retrograde neuronal labeling (red and blue dots) on the lateral, ventral, and medial surfaces of the cerebral cortex, related to injections in area 13m of the orbital network (in red, panel d) and in areas 32, 10m, and 14r of the medial network (in blue, panel e). From Saleem et al, 2008.

Figure 5

Summary of the major cortico-cortical connections of the systems in the prefrontal cortex that are described in the text.

Figure 6

Illustration of the Cortico-Stiato-Pallido-Thalamic loops related to the medial prefrontal network (on left) and the orbital prefrontal network (on right). Note that the two networks are related to parallel but distinct loops that involve adjacent parts of the cortex MD thalamus striatum and pallidum. Limbic structures such as the amygdala and hippocampus are primarily related to the medial network.

Figure 7

Diagram of connections between the dorsal midline paraventricular nucleus of the thalamus (PVT) with areas of the frontal cortex striatum hypothalamus amygdala and dorsal midbrain.

Figure 8

Areas of abnormally increased physiological activity in familial MDD shown in images of unpaired t-values, computed to compare activity between depressives and controls (Drevets et al, 1992, 1997a). Upper left: positive t-values in a sagittal section located 17 mm left of midline (X=−17) show areas where CBF is increased in depressives vs 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 depressives in the left ventrolateral PFC (VLPFC) areas corresponding approximately to the intrasulcal portion of BA 47 (area 47/12s) and to BA 45a (reproduced from Drevets et al, 2004a). 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 depressives in the left medial thalamus (from Drevets and Todd, 2005b). 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 in which metabolism is decreased in depressives vs controls. The reduction in prefrontal cortex (PFC) activity localized to in the anterior cingulate gyrus ventral to the genu of the corpus callosum (ie, subgenual) (Table 1; reproduced from Drevets et al, 1997a). Anterior or left is to left.

Figure 9

The cytoarchitectonic subdivisions of the human medial prefrontal (right) and orbital (left) cortex surfaces are distinguished here as being predominantly in the medial (red) and orbital (yellow) prefrontal networks. The orange areas are part of the dorsal prefrontal system. Modified from Öngür et al, 2003.

Figure 10

Anatomical circuits involving the medial prefrontal network (medial prefrontal network) and amygdala. Glutamatergic, presumed excitatory projections are shown in green, GABAergic projections are shown in orange, and modulatory projections in blue. In the model proposed here, dysfunction in the amygdala and/or the medial prefrontal network results in dysregulation of transmission throughout an extended brain circuit that stretches from the cortex to the brainstem, yielding the emotional, cognitive, endocrine, autonomic, and neurochemical manifestations of depression. Intra-amygdaloid connections link the basal and lateral amygdaloid nuclei to the central and medial nuclei of the amygdala and the bed nucleus of the stria terminalis (BNST). Parallel and convergent efferent projections from the amygdala and the medial prefrontal network to the hypothalamus, periaqueductal gray (PAG), nucleus basalis, locus ceruleus, dorsal raphe, and medullary vagal nuclei organize neuroendocrine, autonomic, neurotransmitter and behavioral responses to stressors and emotional stimuli (Davis and Shi, 1999, LeDoux, 2003). In addition, the amygdala and medial prefrontal network interact with the same cortico-striatal-pallidal-thalamic loop, through prominent connections both with the accumbens nucleus and medial caudate, and with the mediodorsal and paraventricular thalamic nuclei, which may function to control and limit responses to stress. Finally, the medial prefrontal network is a central node in the cortical ‘default system' that appears to support self-referential functions such as mood. Other abbreviations: 5-HT—serotonin; ACh—acetylcholine; Cort.—corticosteroid; CRH—corticotrophin releasing hormone; Ctx—cortex; NorAdr—norepinephrine; PVN—paraventricular nucleus of the hypothalamus; PVZ—periventricular zone of hypothalamus; STGr—rostral superior temporal gyrus—VTA—ventral tegmental area.