Frontocingulate dysfunction in depression: toward biomarkers of treatment response

Abstract

Increased rostral anterior cingulate cortex (rACC) activity has emerged as a promising predictor of treatment response in depression, but neither the reliability of this relationship nor the mechanisms supporting it have been thoroughly investigated. This review takes a three-pronged approach to these issues. First, I present a meta-analysis demonstrating that the relationship between resting rACC activity and treatment response is robust. Second, I propose that the rACC plays a key role in treatment outcome because of its 'hub' position in the default network. Specifically, I hypothesize that elevated resting rACC activity confers better treatment outcomes by fostering adaptive self-referential processing and by helping to recalibrate relationships between the default network and a 'task-positive network' that comprises dorsolateral prefrontal and dorsal cingulate regions implicated in cognitive control. Third, I support this hypothesis by reviewing neuropsychological, electrophysiological, and neuroimaging data on frontocingulate dysfunction in depression. The review ends with a discussion of the limitations of current work and future directions.

Figure 1

Selected findings implicating the rACC in treatment response in MDD. (a) Mayberg et al (1997): Increased pre-treatment rACC metabolism in responders relative to nonresponders (yellow). This finding was replicated in a larger sample of 25 responders vs 20 nonresponders (Brannan et al, 2000) (see right panel). (b) Pizzagalli et al (2001): Increased pre-treatment resting rACC theta activity in responders relative to nonresponders (red). (c) Holthoff et al (2004): Decreased rACC rCBF with symptom remission (yellow). (d) Davidson et al (2003): Increased BOLD signal in the rACC in response to emotional pictures correlated with lower post-treatment depressive symptoms (yellow). (Modified with permission from Mayberg, 2003 (with permission by Oxford University Press), Pizzagalli et al, 2001 (with permission by American Psychiatric Associations), Holthoff et al, 2004 (with permission by John Wiley and Sons), and Davidson et al, 2003 (with permission by American Psychiatric Associations)).

Figure 2

The default network (orange colors) includes regions that deactivate during processing of external stimuli, including the vmPFC/rACC, posterior cingulate (PCC), retrosplenial cortex (Rsp), lateral parietal cortex (LPC), lateral temporal cortex (LTC), dorsal medial PFC (dmPFC), and hippocampal formation (HF+), which includes the entorhinal cortex and surrounding cortex (eg, parahippocampal cortex). The task-positive network (blue color) includes, among others, the DLPFC, dACC, intraparietal sulcus (IPS), and middle temporal (MT) area and becomes activated during tasks requiring cognitive and attentional control. Blue colors: regions that negatively correlate with the default network; red: regions that positively correlate with the default network. (Modified with permission from Buckner et al, 2008; with permission by John Wiley and Sons).

Figure 3

(a) Schematic representation of frontocingulate and frontolimbic interactions associated with adaptive forms of reflective, self-focused processing, as well as adaptive regulation of cognition and emotions. In controls, increased resting rACC activity as well as functional coupling (positive correlations) between the rACC and amygdala (see arrow 1) are observed during resting states (Margulies et al, 2007) and self-referential processing (Schmitz and Johnson, 2006). When confronted with cognitive or affective challenges, healthy controls show increased coupling (positive correlations) between the (1) rACC and DLPFC (arrow 2; Holmes and Pizzagalli, 2008b; Etkin et al, 2006) and (2) DLPFC and dACC (arrow 3; Aizenstein et al, 2009; Fox et al, 2005; Margulies et al, 2007; Schmitz and Johnson, 2006). The interplay among these regions is hypothesized to reduce task-induced rACC activation (arrow 4; Drevets and Raichle, 1998; Fox et al, 2005; Margulies et al, 2007) and downregulate amygdala activation, fostering adaptive regulation of cognition and emotions. (b) Relative to controls, MDD subjects show stronger functional coupling (positive correlations) between the rACC and the amygdala during negative self-referential processing (arrow 1; Yoshimura et al, 2010) as well as reduced structural connectivity between these two regions (arrow 5; Cullen et al, 2010). In addition, relative to controls, MDD subjects show reduced functional connectivity between the (1) rACC and DLPFC (arrow 2; Holmes and Pizzagalli, 2008b; Siegle et al, 2007) and (2) DLPFC and dACC (arrow 3; Aizenstein et al, 2009; Schlösser et al, 2008), but abnormally elevated functional connectivity between the dACC and rACC (arrow 4; Schlösser et al, 2008) during cognitive and/or affective challenges. The dysregulated interplay among these regions is hypothesized to lead to failures to deactivate the rACC and amygdala during affective and cognitive challenges, fostering the emergence of maladaptive forms of rumination, and ultimately treatment nonresponse. Numbers do not reflect chronological unfolding of interactions among brain regions.

Figure 4

Relative to healthy controls, unmedicated individuals with MDD showed (a) potentiated rACC responses 80 ms after committing an error in a Stroop task, and (b) decreased functional connectivity between rACC activation 80 ms post-error and left DLPFC 472 ms post-error. Among the depressed sample, individuals with the highest left DLPFC activation 472 ms post-error showed more adaptive post-error behavioral adjustments (higher accuracy after errors) relative to MDD participants with the lowest DLPFC recruitment. (Modified with permission from Holmes and Pizzagalli, 2008b. Copyright © 2008 American Medical Association. All rights reserved).