Major depressive disorder is associated with abnormal interoceptive activity and functional connectivity in the insula

Abstract

Background: Somatic complaints and altered interoceptive awareness are common features in the clinical presentation of major depressive disorder (MDD). Recently, neurobiological evidence has accumulated demonstrating that the insula is one of the primary cortical structures underlying interoceptive awareness. Abnormal interoceptive representation within the insula may thus contribute to the pathophysiology and symptomatology of MDD.

Methods: We compared functional magnetic resonance imaging blood oxygenation level-dependent responses between 20 unmedicated adults with MDD and 20 healthy control participants during a task requiring attention to visceral interoceptive sensations and also assessed the relationship of this blood oxygenation level-dependent response to depression severity, as rated using the Hamilton Depression Rating Scale. Additionally, we examined between-group differences in insula resting-state functional connectivity and its relationship to Hamilton Depression Rating Scale ratings of depression severity.

Results: Relative to the healthy control subjects, unmedicated MDD subjects exhibited decreased activity bilaterally in the dorsal mid-insula cortex (dmIC) during interoception. Activity within the insula during the interoceptive attention task was negatively correlated with both depression severity and somatic symptom severity in depressed subjects. Major depressive disorder also was associated with greater resting-state functional connectivity between the dmIC and limbic brain regions implicated previously in MDD, including the amygdala, subgenual prefrontal cortex, and orbitofrontal cortex. Moreover, functional connectivity between these regions and the dmIC was positively correlated with depression severity.

Conclusions: Major depressive disorder and the somatic symptoms of depression are associated with abnormal interoceptive representation within the insula.

Keywords: Depression severity; fMRI; functional connectivity; insula; interoception; major depressive disorder.

Figure 1. Group differences in heartbeat interoception

Depressed subjects (MDD) exhibited decreased hemodynamic activity compared to healthy subjects (HC) within multiple brain regions during attention to heartbeat sensations. Group differences in heartbeat interoception were observed in bilateral dmIC, bilateral OFC, as well as right amygdala. Importantly, the group differences in heartbeat interoception within the insula were confined to regions of the dmIC that have been implicated in primary viscerosensory representation within the insula (15). All results shown were corrected for multiple comparisons at p_corrected < .05. dmIC – Dorsal Mid-Insula, Amyg. - Amygdala; OFC - Orbitofrontal Cortex, sgPFC - Subgenual Prefrontal Cortex

Figure 2. Dorsal mid-insula activation during heartbeat interoception is correlated with depression severity and the severity of somatic symptoms

Within the left dmIC – which was identified in Figure 1– a significant negative correlation was observed between depressed subjects’ hemodynamic response during heartbeat interoceptive attention and scores on the Hamilton Depression Rating Scale (HDRS). A significant negative correlation was also observed between hemodynamic response and the HDRS somatization sub-scale (48) (See Supplemental Methods). Values on the X-axis indicate scores on the HDRS, which was administered prior to the fMRI scan. Values on the Y-axis are beta coefficients representing percent signal change during heartbeat interoception within the left dmIC cluster from Figure 1. Circular ROIs in Left dmIC are for illustrative purposes only.

Figure 3. Group Differences in BOLD resting-state functional connectivity to the dorsal mid insular cortex

The left and right dmIC regions – identified in Figure 1 – were used as seeds for a comparison of resting state functional connectivity between healthy and depressed subjects. Many of the circled regions, including the amygdala and orbitofrontal cortex, have previously been implicated in the pathophysiology of MDD. In the present study, depressed participants exhibited significantly stronger resting state functional connectivity between these regions and the dmIC. All results corrected for multiple comparisons at p_corrected < .05. dmIC – Dorsal Mid-Insula, Amyg. - Amygdala; OFC - Orbitofrontal Cortex