A primary feature of major depression (MDD) is a preoccupation with negative ideation. Many behavioral studies have documented an enhanced attention to, and memory for, negative emotional stimuli in depression [1
]. However, the source of this bias is unclear. One possibility is that this negativity bias reflects a top-down deficit in the control of attention (for example, a failure to suppress distracting emotional influences), potentially linked to deficits in brain regions supporting cognitive control such as dorsolateral prefrontal cortex (DLPFC) or dorsal anterior cingulate (dorsal ACC) [5
]. Alternatively, this bias may reflect an enhanced bottom-up response to emotional stimuli that dysregulates cognitive control mechanisms, potentially linked to deficits in amygdala and ventromedial prefrontal cortex function.
Recent research [7
] has identified a network of emotion-processing areas that might drive bottom-up influences of emotion on cognitive functioning in depression. These include the amygdala and ventromedial prefrontal cortex (subgenual and pregenual cingulate). It has been proposed that these areas are involved in the perception, evaluation and response to emotion-inducing stimuli and that they mediate the experience of fear, sadness and other negative emotions [8
]. Both ventromedial areas and the amygdala are normally deactivated during cognitive processing, and increase activation during the experience of fear, anxiety or sadness [11
]. Individuals with major depression show hyperactivity of the amygdala when processing emotionally evocative information [12
]. In addition, resting-state overactivity in the subgenual cingulate is consistently found in major depression [9
]. If these emotion regions are hyper-responsive in major depression, they may bias individuals towards the processing of affectively negative stimuli.
A negativity bias might also reflect primary dysfunction in cognitive control areas of the brain. Some studies have shown that the DLPFC plays an important role in the top-down regulation of emotional processing [5
]. In addition, the dorsal ACC is thought to monitor for errors or processing conflicts that could disrupt performance and to recruit the DLPFC to reallocate attentional resources as needed [18
]. Importantly, some research suggests that MDD is characterized by hypoactivity in DLFPC and dorsal ACC [6
] as well as in rostral cingulate [27
As noted above, both excessive activity in the amygdala and reduced activity in DLPFC have been documented in MDD patients [6
]. For example, MDD patients have long been found to show elevated activity in the amygdala during passive resting or during sleep [9
]. They have also shown excessive amygdala activity when exposed to stimuli with negative valence that are presented outside of conscious awareness [12
]. However, less is known about amygdala function in depression when patients are actively engaged in demanding cognitive processing. In such situations, processing in cognitive-control regions of the brain may suppress emotion-processing regions such as the amygdala, since these two circuits are known to work in opposition to each other (Drevets & Raichle, 1998). Recently Siegle and colleagues [29
] tested MDD patients on a demanding executive task and a separate emotion-processing task. They found reduced activation in dorsolateral prefrontal cortex in the executive task, as well as increased amygdala activity in the emotional task. However, these findings do not address the issue of amygdala reactivity in MDD when there could be direct competition between cognitive and emotion circuitry. Such conflict can occur in cognitive tasks that include task-irrelevant emotional information, since these tasks should evoke activity in two networks that would normally suppress each other. Thus the goal of the current study is to investigate the pattern of recruitment seen in these two networks when individuals with MDD were asked to either ignore, or directly attend to, emotionally negative stimuli. In doing so, we hoped to examine top-down and bottom-up influences when cognitive control was needed, and when it was not.
To investigate these questions, we performed an event-related fMRI study in which MDD patients and controls performed a matching task while exposed to emotional interference [30
]. Stimuli were fearful or neutral faces, or houses, and the face stimuli were either targets or distracters. Trials with fearful faces as distracters were considered to generate emotional interference and would therefore require cognitive control. In addition, we considered error trials as possible sources of emotional conflict. As a second test of cognitive control, we examined activation on trials following
emotional conflict trials, since in healthy controls, both errors and conflict trials usually induce increased cognitive control on subsequent trials [32
We made several predictions based on the two hypotheses about the source of negative bias in depression. If this bias reflects deficits in the top down control of attention, then compared to healthy controls, individuals with MDD should show: 1) on correct trials, impaired activity in DLPFC and the dorsal ACC on all trials; (2) on correct trials, enhanced activity in the amygdala and ventromedial PFC when ignoring fearful faces, (and possibly also when attending to them) because of inadequate suppression by cognitive control regions; 3) on error trials, enhanced activity in the amygdala and ventromedial PFC, because negative affect associated with errors could not be appropriately regulated by the DLPFC and the dorsal cingulate; 4) on error trials, reduced dorsal ACC responses and 5) on trials following errors, reduced DLPFC response, reflecting impaired control recruitment.
If the negativity bias in MDD reflects abnormal bottom-up responses to emotional stimuli, we would predict: 1) on correct trials, enhanced activity in the amygdala and subgenual/pregenual ACC when ignoring fearful faces, and possibly also when attending to them (similar to the top down model, but not because of reduced cognitive control); 2) in contrast to the top-down model, for correct trials, impaired DLPFC, but only on trials in which the participant shows enhanced amygdala response to negative stimuli; 3) on error trials, possibly either reduced or enhanced dorsal ACC responses to errors, depending on whether MDD participants experience suppressed cognitive control, or instead more readily detect conflict from emotionally evocative events; and 4) on post-error trials, impaired recruitment of DLPFC if the enhanced bottom-up processing of the negative stimuli impairs DLPFC recruitment.
Amongst all these predictions, we viewed the behavior of DLPFC as key to the distinction between top-down and bottom-up influences, since it might show dysfunction either on all trials (top-down), or only when the amygdala was over-active (bottom-up).