Regulatory difficulties were explored in MDD with a PGNG, which comprises stimuli without obvious emotional characteristics, characteristics that might complicate cognitive data interpretation in patients diagnosed with MDD. The control and MDD groups seemed to have a different approach to the task, with a significant interaction between percent correct rejections, percent correct hits, and response time for hits. The control group was faster and made fewer errors of omission, or had more correct hits “Go.” They also had nominally more incorrect “No-go” responses compared with the MDD group but not significantly so. The MDD group seemed more willing to accept errors of omission, or missed “Go” responses, putatively in the context of greater behavioral inhibition, or reduced errors of commission for “No-go” events. The present results provide greater contextual differences to demonstrate executive functioning performance decrements in MDD (Alexopoulos et al. 2005
; Channon and Green 1999
; Degl'Innocenti et al. 1998
; Jones et al. 1988
; Watkins and Brown 2002
). The MDD patients do show greater behavioral inhibition or decreased responding, whereas behavioral activation or approach behaviors are decreased (Campbell-Sills et al. 2004
; Kasch et al. 2002
The MDD patients had greater functional activation compared with the control group during successful rejections in areas known to be important for successful inhibitory control (Rubia et al. 2001
). The increased activation in the MDD patients in AC, inferior frontal/superior temporal gyri, insula, and inferior parietal lobe are consistent with recruitment to aid in successful task completion, similar to work with healthy aging and other clinical groups (Fitzgerald et al. 2005
; Langenecker et al. 2004
; Robinson and Starkstein 1989
). It is also possible that behavioral inhibition control systems involving regulation of behavior and emotions are overactive in MDD to counteract the intense emotional experiences of this group or as an intrinsic part of their symptom constellation. It is also possible that, because of recent negative life events, depressed patients are less likely to engage in any behaviors, which is why psychotherapies aimed at increasing proactive behaviors are as effective as pharmacotherapies in treating MDD and seem to be less prone to relapse.
The increased activation for MDD patients in primarily frontal areas during inhibitory control is consistent with a recent study of the cognitive Stroop test by Wagner et al. (2006)
as well as with two other studies of MDD using a working memory (Harvey et al. 2005
) and a continuous performance (Holmes et al. 2005
) task. It should be noted that increased activation during rejection in the present study was during correct trials only, or better performance, which suggests that this activation is compensatory in nature, opposite to the pattern observed by Wagner et al. (2006)
, where increased left DLPFC and AC activation was associated with greater interference, or worse performance. These studies underline the importance of obtaining behavioral performance markers during functional imaging tasks and in using this information to understand the nature of group activation differences.
In contrast to the activation for the rejection trials, commission trials led to increased activation for the control group in the supplementary motor area (SMA) and for the MDD group in the anterior superior frontal gyrus. The SMA activation in the control group, which was significantly greater than the MDD group, is in a prominent area in the inhibitory control literature, thought to reflect the stopping or withholding component of the motoric response (Humberstone et al. 1997
). The activation for the MDD adults in the anterior portion of the rostral anterior cingulate gyrus extending into the medial frontal gyrus, is a known site related to error processing and error correction (Botvinick et al. 1999
; Carter et al. 2000
). The activation differences herein suggest that the MDD patients might be processing the errors more intensely toward engaging in better strategies to avoid future errors, whereas for the control subjects the increased activation might represent attempts at stopping the current response. Noting that increased activation for commission errors was related to greater treatment responsivity, as noted in the preceding text, this activation might be related to the preserved ability of some MDD subjects to observe and learn from their own errors.
Perhaps most noteworthy was the increased activation in right dorsolateral prefrontal and left ventral cingulate, amygdala, nucleus accumbens, and insula areas during successful inhibitory trials and rostral cingulate during failed inhibitory trials that were associated with the extent of treatment response. This is the first fMRI study to show that pretreatment activation patterns during a cognitive challenge were related to therapeutic response after a standard antidepressant trial. Increased AC resting metabolic function and activity has been associated with greater response to treatment with another SSRI (fluoxetine) in two studies, a prior positron emission tomography and an electroencephalogram study (Mayberg et al. 1997
; Pizzigalli et al. 2001
). Activation in this area has also been shown to more closely approximate activation patterns in healthy control subjects after successful treatment with venlafaxine (Davidson et al. 2003
). In the present study, the greater rostral AC activation associated with treatment response was observed during incorrect inhibitory trials (commissions). The increased rostral AC activation during errors associated with greater treatment response suggests that there might be fundamental changes in the ability to detect errors in those who respond less well to treatment, whereas this activation pattern remains intact in those who will respond to treatment with SSRIs (Botvinick et al. 1999
). It further implicates the function of the rostral, pregenual AC in treatment response (Mayberg et al. 1997
) and pathophysiology (Drevets 1998
) of MDD.
Limitations in the present study are typical for functional neuroimaging studies of depression. The sample sized was relatively small if larger than most imaging studies of MDD. Regardless, the significant differences between groups were robust and meaningful. Furthermore, our ability to show treatment related effects in activation that were not present in behavioral performance or clinical data is compelling. The present study avoided risks of including patients with high severity or duration of symptoms as well as showing medication and partial treatment activation effects. While avoiding these confound, we were still able to recruit a moderately to severely depressed group of patients who had an average of 13 years of illness, which is likely representative of the larger sample of patients with MDD. The inclusion of one left-handed subject in each of the groups might have weakened any laterality affects that could be related to motoric responses in inhibitory control, or set-shifting. Analyses without these two subjects were nearly identical to those presented herein. Finally, because we used an uncorrected threshold, there is a greater possibility of type I error. To guard against this possibility, we also used a combined cluster × volume threshold, which generally protects against excessive type I error (Ward et al. 1998
). A final potential limitation of the present study was that all subjects completed an emotion processing task within the scanner 5–10 min before beginning the PGNG. It was possible that this might have changed the subjects approach to the task but was unlikely to affect an event-related fMRI analysis as conducted herein. The different approaches to the PGNG evident in the MDD and control groups could have been caused by emotional “priming” effects.
In summary, the present study supports an excessive or hyperactive inhibitory control system in MDD, both in behavioral data and in functional activation, in a sample of patients who were moderately to severely depressed and who were unmedicated at the time of the assessment. Notably, the increased behavioral performance in inhibition was related to worse performance in obtaining correct hits and, subsequently, nonsignificantly related to treatment response. In contrast, for correct rejections, greater activation in the inhibitory and emotion-processing systems was related to a better treatment response. The present study does support the contention that regulatory ability is potentially disrupted in MDD, even for stimuli and tasks that do not have overt emotional stimuli or processing requirements.