Frontal and limbic activation during inhibitory control predicts treatment response in major depressive disorder

Abstract

Background: Inhibitory control or regulatory difficulties have been explored in major depressive disorder (MDD) but typically in the context of affectively salient information. Inhibitory control is addressed specifically by using a task devoid of affectively-laden stimuli, to disentangle the effects of altered affect and altered inhibitory processes in MDD.

Methods: Twenty MDD and 22 control volunteer participants matched by age and gender completed a contextual inhibitory control task, the Parametric Go/No-go (PGNG) task during functional magnetic resonance imaging. The PGNG includes three levels of difficulty, a typical continuous performance task and two progressively more difficult versions including Go/No-go hit and rejection trials. After this test, 15 of 20 MDD patients completed a full 10-week treatment with s-citalopram.

Results: There was a significant interaction among response time (control subjects better), hits (control subjects better), and rejections (patients better). The MDD participants had greater activation compared with the control group in frontal and anterior temporal areas during correct rejections (inhibition). Activation during successful inhibitory events in bilateral inferior frontal and left amygdala, insula, and nucleus accumbens and during unsuccessful inhibition (commission errors) in rostral anterior cingulate predicted post-treatment improvement in depression symptoms.

Conclusions: The imaging findings suggest that in MDD subjects, greater neural activation in frontal, limbic, and temporal regions during correct rejection of lures is necessary to achieve behavioral performance equivalent to control subjects. Greater activation in similar regions was further predictive of better treatment response in MDD.

Figure 1

Parametric Go/No-go task. The task includes three levels of difficulty, the latter two of which include set shifting and inhibitory control.

Figure 2

Behavioral performance interaction between major depressive disorder (MDD) and control groups. The MDD group was significantly slower and marginally less likely to respond to target stimuli. The MDD group was also less likely to respond to lure trials (e.g., commissions) if not significantly so.

Figure 3

Panels A–D illustrate statistically significant activation for control (red) and depressed (blue) groups in the random effects analysis for correct target trials, at +50, +4, −4, and −50 mm right to left, respectively. Panels E–H depict activation for control (red) and depressed (blue) groups in the random effects analysis for correct inhibitory trials (rejections) at +54, +4, −13, and −54 mm right to left, respectively. Panels I–L illustrate activation for control (red) and depressed (blue) groups in the random effects analysis for incorrect inhibitory trials (commissions) at +50, +4, −4, and −50 mm right to left, respectively. Images are displayed on an anatomically standardized magnetic resonance image. Threshold is T > 3.4, p < .0001, cluster > 160 mm³ for all images.

Figure 4

Figure demonstrating statistically greater activation in the major depressive disorder (MDD) group compared with the control group for correct (rejections, panel A, blue, Left 10 mm) and incorrect (commissions, panel B, blue, Left 17 mm) inhibitory trials. The figure also illustrates statistically greater activation in the control group compared with the MDD group for incorrect (commissions, panel C, red, right 2 mm) inhibitory trials. The viewing threshold on these images was relaxed to T > 2.8, p < .003, cluster > 10 mm³ for ease in viewing.

Figure 5

Activation during successful inhibition (rejections, blue) and failed inhibitory trials (commissions, red) significantly correlated with degree of post-treatment change in the Hamilton Depression Rating Scale (HDRS). Activation foci indicate significantly increased activation during rejections (panels A and B, blue) and commission events (panel C, red). Images are right to left +50, −19,and +4mm; respectively. Correlations of percent depression change in HDRS after treatment are plotted against mean signal change from the Statistical Parametric Mapping (SPM) analyses for each region of interest (black lines indicate the region of interest[ROI]). The percent change in HDRS is computed with the following formula (HDRS1 – HDRS2)/HDRS1 and thus represents the percentage of symptoms that have dissipated with treatment.