Decreased hypothalamic functional connectivity with subgenual cortex in psychotic major depression

Abstract

Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the hypothalamic pituitary adrenal (HPA) axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting-state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized that this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation. Resting-state functional magnetic resonance imaging (fMRI) scans were collected to observe low-frequency resting-state functional connectivity patterns of the hypothalamus in 39 healthy participants, 39 patients with major depression, and 22 patients with major depression with psychotic symptoms. Hourly overnight measures of cortisol secretion and multiple measures of psychiatric symptom severity were also collected on all. Strong hypothalamic functional connectivity with the subgenual cortex was observed in healthy participants. This connectivity was significantly reduced in patients with psychotic major depression. Increased cortisol secretion during the circadian nadir and reduced connectivity were both associated with symptom severity. Reduced connectivity and high cortisol secretion during the circadian nadir are both useful for explaining a significant amount of variance in symptom severity that occurs between healthy participants and depressed patients. However, only cortisol secretion was useful for explaining the severity of symptoms within the depressed groups. This study suggests that the communication between the hypothalamus and the subgenual cortex is disrupted in patients with major depression with psychotic features. It also suggests that these disruptions are associated with increased symptom severity and may be a cause or a consequence of cortisol dysregulation.

Figure 1

Anatomically defined regions of interest (ROI) were used for Broadmann areas (BA) 24, BA25, and BA32. The ROIs were smoothed to match to spatial resolution of the functional connectivity data and then converted to binary mask images. The spatial extent was also limited to reflect the typical boundaries of subgenual cortex (ie, limited to cortex inferior to the genu of the corpus callosum).

Figure 2

Healthy group, red; the non-psychotic major depression group (NPMD; green); psychotic major depression group, blue; healthy and NPMD overlap, yellow; healthy and psychotic major depression overlap, violet; NPMD and psychotic major depression overlap, cyan; and all three groups overlap, white. Conjunction maps demonstrate shared and differential spatial patterns of hypothalamic connectivity. The healthy group demonstrated significant hypothalamic connectivity to the subgenual cortex, insula, middle, and superior temporal gyri. The healthy group and the NPMD group showed some common connectivity patterns but a reduced spatial extent of hypothalamic connectivity with the subgenual cortex. The spatial extent of this connectivity is further reduced in the psychotic major depression group. All functional maps are subject to a p<0.001 (unc.) voxel threshold and a cluster threshold of k=10 for display purposes (see Table 2 for SVC, FWE-corrected statistics).

Figure 3

Whole-brain group comparison maps indicate that hypothalamic functional connectivity to the subgenual cortex is decreased in both the psychotic major depression and non-psychotic major depressiongroups (3rd row, 4th column in both maps). Functional maps are subject to a p<0.001 (unc.) voxel threshold and a cluster threshold of k=10 for display purposes (see Table 2 for SVC, FWE-corrected statistics, and comparisons between psychotic and non-psychotic depression groups).

Figure 4

Age/gender corrected region of interest extractions represent connectivity between the hypothalamus seed and each of the subgenual regions averaged across all voxels. Hypothalamus connectivity is decreased in both subgenual regions BA24 and BA32, but not BA25.

Figure 5

Cortisol secretion is elevated in the psychotic major depression group during the 1800–0100-hour window, which typically represents the circadian nadir.