The absence of biologically relevant diagnostic markers of bipolar disorder (BD) results in misdiagnosis of the illness as recurrent unipolar disorder (UD) depression in 60% of BD individuals seeking treatment for depression, leading to poor clinical outcomes (Hirschfeld et al. 2003
; Langenecker et al. 2010
). It is therefore crucial that objective markers of BD are identified to help distinguish BD from UD as early as possible in depressed individuals. A first stage toward this ultimate goal is the identification of biological markers reflecting pathophysiologic processes that may differ between BD and UD depression (Strakowski et al. 2002
; Drevets, 2003
; Almeida et al. 2010
Emotional over-reactivity and emotion dysregulation characterize BD. A better understanding of functional abnormalities in neural circuitry supporting emotion regulation may help to provide biological measures reflecting pathophysiologic processes distinguishing BD from recurrent UD depression. To date, the majority of neuroimaging studies in BD depressed (BDd) and recurrent UD depressed (UDd) individuals have focused on examination of neural circuitry supporting emotion processing. These studies reported abnormally elevated amygdala and striatal activity to negative and positive emotional stimuli in BDd (and subsyndromally depressed) adults (Lawrence et al. 2004
; Malhi et al. 2004
; Chen et al. 2006
). In UDd adults, studies reported abnormally elevated amygdala and striatal activity to negative emotional stimuli, but less consistently to positive emotional stimuli (Fu et al. 2004
; Surguladze et al. 2005
; Anand et al. 2007
; Dannlowski et al. 2007
; Fales et al. 2008
), and abnormally reduced activity in the striatum to positive emotional and rewarding stimuli (Surguladze et al. 2005
; Epstein et al. 2006
; McRae et al. 2008
Emotion regulation neural circuitry comprises regions implicated in early appraisal of emotional information during ‘automatic’ or implicit subprocesses of emotion regulation. These areas include rostral and subgenual regions of the anterior cingulate cortex (ACC; Brodmann areas BA 24/25 respectively), orbitofrontal cortex (OFC: BA 11), mediodorsal prefrontal cortex (mdPFC: medial BA 9/10), and medial components of the ventrolateral prefrontal cortex (VLPFC: medial BA 47). Regions implicated in more demanding executive and attentional control processes, which support more effortful, emotion regulation processes, include the dorsal ACC (dorsal BA 24/32) and, in particular, the dorsal anterior midcingulate cortex (dAMCC: the most dorsal parts of BA 24/32), lateral VLPFC (BA 47) and dorsolateral prefrontal cortex (DLPFC: BA 44/46 and lateral BA 9) (Ochsner & Gross, 2005
; Langenecker et al. 2007
; Phillips et al. 2008
To date, only one study has examined emotion regulation neural circuitry in BDd adults (Deckersbach et al. 2008
). A combination n
-back working memory (WM) task and sad or neutral mood induction was used. Participants either maintained or suppressed a sad or neutral mood induced during the first 30 s of the WM task. This study reported greater left rostral/dorsal ACC (BA 32) activity during the sad condition and greater right rostral/dorsal ACC (BA 32) during the neutral mood induction condition for BDd relative to healthy females. In addition, BDd females had more activity than healthy females in DLPFC (BA 9/46) to the sad condition. Greater activity in these regions suggested greater demand for recruitment of neural regions supporting more effortful regulation of emotion in BDd than in healthy females.
In UDd adults, numerous studies have examined activity in emotion regulation neural circuitry during paradigms involving either effortful direction of attention away from emotionally distracting information or more automatic emotion regulation subprocesses. Reduced DLPFC activity in UDd versus
healthy adults was shown during a WM task following negative emotional word stimuli (Siegle et al. 2007
). Other studies reported reduced DLPFC activity in UDd adults attempting to ignore negative stimuli (Fales et al. 2008
), and during both unattended and attended emotional judgment (Grimm et al. 2008
). Studies examining effortful emotion regulation showed greater left dorsal ACC (BA 32) activity during an emotional Stroop task in UDd versus
healthy adults (Mitterschiffthaler et al. 2008
), and greater activity in rostral/dorsal ACC during an affective go/no-go task in UDd versus
healthy adults to sad targets and in healthy versus
UDd adults to happy targets (Elliott et al. 2002
). The latter study also showed greater DLPFC activity in healthy versus
UDd adults to neutral targets and in UDd versus
healthy adults to sad targets. Additionally, one study reported abnormal recruitment of bilateral DLPFC, together with abnormal positive subgenual ACC–amygdala functional connectivity, in UDd versus
healthy adults during cognitive appraisal of emotion, an effortful emotion regulation subprocess (Johnstone et al. 2007
The above studies suggest overlapping, but distinct, functional abnormalities in neural circuitry supporting emotion regulation subprocesses in UDd and BDd adults. No neuroimaging studies, however, have compared neural circuitry directly during emotion regulation paradigms in BDd and UDd adults. Furthermore, no neuroimaging studies have evaluated the extent to which neutral stimuli (neutral faces) may serve as distracters during the performance of executive and attentional control tasks.
This is the first study to our knowledge to compare neural activity during effortful emotion regulation in BDd, UDd and healthy females. The overall aim of this study was to examine activity in neural circuitry supporting emotion regulation in BDd and UDd adults, using an emotional WM paradigm, as a first stage toward identification of biomarkers reflecting pathophysiological processes that differentiate BDd from UDd. We focused on females, given the higher prevalence of depression in females (Weissman et al. 1996
), and gender differences in neural activity during emotion processing and regulation (Schienle et al. 2005
; Koch et al. 2007
; McRae et al. 2008
). We also focused on BD type I depression (BDId) rather than BD type II (BDII) depression, given the few studies and limited understanding of the pathophysiology of BDII. We chose to examine neural circuitry supporting effortful emotion regulation specifically, maintaining executive control throughout emotional and emotionally ambiguous distraction using an emotional n
-back paradigm. Similar paradigms have been used to separately examine emotion regulation neural circuitry in BDd or UDd. The task requires direction of attention away from negative (fear), positive (happy) or neutral face distracters in order to perform a 2-back WM task. The task has the advantage of being able to be used to examine neural activity during WM task performance in the presence of emotional and neutral face distracters. The latter is important because findings suggest that neutral faces may be perceived as ambiguous and potentially more salient or threatening in mood-disordered relative to healthy individuals (Langenecker et al. 2005
; Rich et al. 2006
In our primary hypotheses, we focused on an examination of activity within key a priori neural regions implicated in executive and attentional control (DLPFC, rostral/dorsal ACC, dAMCC). In our secondary hypotheses, we focused on key regions implicated in emotion processing (amygdala, striatum).
Our two primary hypotheses were guided by findings in UDd adults of abnormally reduced DLPFC activity during a WM task in the context of negative emotional distraction (Siegle et al. 2002
) and also abnormal recruitment of dorsal ACC during an affective go/no-go task (Elliott et al. 2002
). We hypothesized that, relative to healthy females:
(1) UDd females would show significantly reduced DLPFC activity but abnormally elevated rostral/dorsal ACC and dAMCC activity during the 2-back memory load condition with negative emotional (fearful face-versus-no face) distracters.
Findings from the one existing study in BDd adults examining neural circuitry during a WM task in the context of negative mood induction (Deckersbach et al. 2008
) allowed us to hypothesize that, relative to healthy females:
(2) BDId females would show significantly elevated DLPFC rostral/dorsal ACC, and dAMCC activity during the 2-back memory load condition with both negative and positive emotional (fearful face-versus-no face and happy face-versus-no face) distracters.
With no extant studies directly comparing neural activity in BDId and UDd adults during emotion regulation tasks, we were unable to make specific hypotheses regarding the comparison of BDId and UDd females.
(3) UDd females would show significantly greater activity in amygdala and striatum during the 2-back memory load condition with negative emotional (fearful) distracters, but significantly reduced activity in striatum during the 2-back memory load condition with positive emotional (happy) distracters.
(4) BDId females would show elevated activity in amygdala and striatum during the 2-back memory load condition with negative emotional (fearful) or positive emotional (happy) distracters.