Right anterior insula hypoactivity during anticipation of homeostatic shifts in major depressive disorder

Abstract

Objective: To use functional magnetic resonance imaging (fMRI) to examine how shifts in homeostatic state affect anticipatory insular activity in major depressive disorder (MDD). An intact ability to mount preparatory emotional, cognitive, and bodily responses to anticipated environmental change is necessary for adaptive responding. Although abnormal insula activity during aversive anticipation has been observed in individuals with MDD, the extent to which shifts in homeostatic state during anticipation affect insular activity in MDD subjects has not been reported.

Methods: Cued hot and warm stimuli were delivered as subjects either passively viewed a fixation cross or performed an attentional task during fMRI. The task was designed so that anticipatory brain activation related to the following three types of shifts could be measured: 1) anticipatory shifts in stimulus intensity; 2) anticipatory shifts in cognitive demand; and 3) dual anticipatory shifts (i.e., shifts in both stimulus intensity and cognitive demand). Brain activation related to each of these three contrasts was compared between 15 (12 females) unmedicated subjects with current MDD and 17 (10 females) age- and education-comparable healthy control (HC) subjects.

Results: MDD vs. HC subjects showed lower right anterior insula activity related to anticipatory shifts in stimulus intensity, and altered brain activation during anticipatory shifts in cognitive demand and dual anticipatory shifts.

Conclusions: These results indicate that MDD individuals show altered brain responses to shifts in homeostatic state during anticipation, and may suggest that MDD is associated with an impaired ability to effectively prepare for changes in the environment.

Figure 1. Experimental Paradigm

(A) All subjects completed the anticipation paradigm in the scanner. In order to manipulate cognitive demand, subjects were asked to engage in the continuous performance task (“Task”) [circle – LEFT, square – RIGHT button, 1 trial/2 secs]. The stimuli change color (red – anticipate pain, green –anticipate warmth, 4–8 seconds) for the anticipation condition. Stimulus consisted of a hot-painful or warm-non-painful stimulus for 5 seconds and followed anticipation. Four different anticipatory trial types for a total of 40 anticipatory periods (10 times/trial type) were delivered: A1: painful heat + task, A2: non-painful warmth + task, A3: painful heat + fixation, A4: non-painful warmth + fixation. (B) In order to construct anticipatory shift regressors all 40 original anticipation periods were divided into three different types of anticipatory shifts relative to the preceding anticipatory period: 1) Intensity Shift Anticipation shift in intensity of the stimulus only (from painful heat to non-painful warmth and vice versa) and no shift in cognitive demand (task condition stays the same), 2) Cognitive Shift Anticipation – shift in cognitive demand only (from “fixation” to “task” condition and vice versa) and no shift in stimulus intensity (temperature stays the same), and 3) Dual Shift Anticipation – shift in stimulus intensity and cognitive demand (temperature stimulus and task demand both change). Insert indicates the distribution of shifting trials relative to the original anticipatory trials (see text for details)

Figure 2

Significant Group Differences in BOLD activation during A) Intensity Shift Anticipation; B) Cognitive Shift Anticipation and C) Dual Shift Anticipation. Bar graphs show % BOLD changes for the Intensity and Cognitive Shifts for MDD and CON groups. C.f. Table 1, 2, and 3 for details. Images are shown in neurological orientation.

Figure 3. Right AI activation during Stimulus Intensity Shift Anticipation

A) Significant group differences in RAI activation. Bar graphs show % BOLD changes for the Intensity, Cognitive and Dual Shifts for MDD and CON groups. Exploratory examination of RAI activation during positive (i.e., shift from painful heat to non-painfully warm temperature stimulus) and negative (i.e., shift from non-painful warmth to painfully hot temperature stimulus) separately showed no valence-specific activation within this region.