Brain and behavioral correlates of insulin resistance in youth with depression and obesity

Abstract

Depression, together with insulin resistance, is increasingly prevalent among youth. These conditions have traditionally been compartmentalized, but recent evidence suggests that a shared brain motivational network underlies their co-occurrence. We posit that, in the context of depressive symptoms, insulin resistance is associated with aberrant structure and functional connectivity in the Anterior Cingulate Cortex (ACC) and hippocampus. This motivational neural circuit underlies dysfunctional behavioral responses and increased sensitivity to rewarding aspects of ingesting high calorie food that lead to disinhibition of eating even when satiated. To investigate this shared mechanism, we evaluated a sample of forty-two depressed and overweight (BMI > 85th%) youth aged 9 to 17. Using ACC and hippocampus structural and seed-based regions of interest, we investigated associations between insulin resistance, depression, structure (ACC thickness, and ACC and hippocampal area), and resting-state functional connectivity (RSFC). We predicted that aberrant associations among these neural and behavioral characteristics would be stronger in insulin resistant compared to insulin sensitive youth. We found that youth with greater insulin resistance had higher levels of anhedonia and more food seeking behaviors, reduced hippocampal and ACC volumes, and greater levels of ACC and hippocampal dysconnectivity to fronto-limbic reward networks at rest. For youth with high levels of insulin resistance, thinner ACC and smaller hippocampal volumes were associated with more severe depressive symptoms, whereas the opposite was true for youth with low levels of insulin resistance. The ACC-hippocampal motivational network that subserves depression and insulin resistance separately, may represent a critical neural interaction that link these syndromes together.

Keywords: Insulin resistance; Neural structure; Obesity; Pediatric depression; Resting state functional connectivity.

Figure 1

Average blood insulin level across time after glucose challenge

Figure 2

Relation between Fasting Insulin and Matsuda Index (after glucose challenge)

Figure 3

Age, sex, and Matsuda Index adjusted Anterior Cingulate Cortex Area correlated with depression severity (CDRS-R score).

Figure 4

Significant insulin and depression related resting state functional connectivity A. Orange clustered regions of significant insulin-correlated connectivity with the Anterior Cingulate Cortex (ACC) seed. B. ACC-Subcallosal connectivity estimates correlated with fasting insulin and with depression severity (CDRS-R scores). C. Blue clustered regions of significant Matsuda Index-correlated connectivity with the Hippocampus seed. D. Hippocampus-Middle Frontal Gyrus connectivity estimates correlated with Matsuda Index and with depression severity. Hippocampus-Lingual Gyrus connectivity estimates correlated with Matsuda Index and with depression severity.