Review
Emotional valence modulates brain functional abnormalities in depression: Evidence from a meta-analysis of fMRI studies

https://doi.org/10.1016/j.neubiorev.2012.11.015Get rights and content

Abstract

Models describing the neural correlates of biased emotion processing in depression have focused on increased activation of anterior cingulate and amygdala and decreased activation of striatum and dorsolateral prefrontal cortex. However, neuroimaging studies investigating emotion processing in depression have reported inconsistent results. This meta-analysis integrates these findings and examines whether emotional valence modulates such abnormalities. A systematic literature search identified 26 whole-brain and 18 region-of-interest studies. Peak coordinates and effect sizes were combined in an innovative parametric meta-analysis. Opposing effects were observed in the amygdala, striatum, parahippocampal, cerebellar, fusiform and anterior cingulate cortex, with depressed subjects displaying hyperactivation for negative stimuli and hypoactivation for positive stimuli. Anterior cingulate activity was also modulated by facial versus non-facial stimuli, in addition to emotional valence. Depressed subjects also showed reduced activity in left dorsolateral prefrontal cortex for negative stimuli and increased activity in orbitofrontal cortex for positive stimuli. Emotional valence is a moderator of neural abnormalities in depression, and therefore a critical feature to consider in models of emotional dysfunction in depression.

Highlights

► Activation of emotion identification and regulation areas is altered in depression. ► Limbic areas show mirroring effects for negative and positive emotion. ► Prefrontal areas show valence-specific activation abnormalities. ► Emotional valence modulates neural abnormalities in depression.

Introduction

Major depressive disorder is characterized by maladaptive and persistent emotional responses to stressors (Hammen, 2005). Such an emotional response has the potential to interfere with functioning in all aspects of daily life. Therefore, depression is likely to be associated with fundamental abnormalities in emotional processing, which continuously influence the processing of incoming sensory information (Harmer et al., 2009). Research has indeed demonstrated preferential processing of negative compared to positive information in depressed patients for multiple cognitive domains, such as perception, attention and memory (Disner et al., 2011, Roiser et al., 2012). Neuroimaging research provides a tool to visualize the core of the emotional dysfunction that occurs in the brain of depressed patients.

Several models of emotion processing in the depressed brain have been proposed, in which several brain regions are hypothesized to play a key role, with models differing in their emphases regarding the functions involved (for instance compare (Drevets et al., 2008, Krishnan and Nestler, 2008, Leppanen, 2006, Mayberg, 1997, Phillips et al., 2003). Emotion identification is generally attributed to subcortical structures such as the ventral striatum and amygdala, integration of somatic responses is subserved by the insula and anterior cingulate cortex (ACC) and affective state monitoring is related to medial and dorsolateral prefrontal cortex (DLPFC) function. However, the predictions arising from these models have not been systematically evaluated in the light of recent literature. Moreover, the models do not make clear predictions regarding interactions between activation abnormalities and emotional valence.

Emotional processing could be abnormal in depressed patients at different levels of processing. The initial appraisal of incoming information may be biased, leading to preferential processing of negative information and an amplified emotional response. In particular, it has been suggested that the amygdala may be highly sensitive to negative information (Murray et al., 2011), whereas the ventral striatum, an area predominantly involved in processing positive information, has been hypothesized to be less sensitive in depressed patients (Diekhof et al., 2008). Monitoring of the affective state may also be compromised by reduced cognitive control from the DLPFC and ACC, leading to insufficient capacity to downregulate the response of the amygdala (Beck, 2008, Pizzagalli, 2011). Although these general models of emotional dysfunction in depression lead to specific predictions, empirical studies investigating the neural correlates of emotional dysfunction in depressed patients have produced inconsistent results. It is still insufficiently known which levels are affected during the basic processing of emotional stimuli in emotion perception tasks and whether activation abnormalities are modulated by emotional valence at different levels of processing.

Meta-analysis of functional magnetic resonance imaging (fMRI) studies in depressed patients is critical to validate and advance models of emotional dysfunction in depression. To date, two such meta-analyses have been performed (Diekhof et al., 2008, Fitzgerald et al., 2008). Their findings however were not fully consistent. In particular, while Fitzgerald and colleagues found that processing negative stimuli resulted in hypoactivation in depressed patients in pregenual anterior cingulate, Diekhoff and colleagues found that negative stimuli resulted in hyperactivation of the same area. Similarly, the amygdala is identified as hyperactive during negative emotional processing in one of the meta-analyses (Fitzgerald et al., 2008), but not the other one. This variation in results is probably due to methodological limitations, as these previous meta-analyses included a limited sample of studies (6 in Fitzgerald et al., 2008; 10 in Diekhof et al., 2008), and employed a potentially biased fixed-effects meta-analytical approach that does not adequately incorporate between-study variance, and as a consequence has since been superseded (Eickhoff et al., 2009). Furthermore, these studies did not take into account negative findings or region-of-interest studies, and thereby introduced bias in their selection of study samples.

In the present work, the brain activation patterns of depressed patients were compared to healthy subjects in a meta-analysis on the processing of negative and positive emotion. An up-to-date systematic literature search was conducted to identify a larger number of studies relative to previous meta-analyses. In addition, an innovative analytical procedure for the pooling of results was employed. This approach employs not only the locations of significant effects, but also their effect size. Because statistical thresholds are taken into account during this analysis, this method allows for the combination of results from studies investigating the whole brain and specific regions of interest. It was hypothesized that depressed patients would show greater activation in amygdala and anterior cingulate cortex and less activation in ventral striatum and prefrontal areas. Furthermore, the consistency of results across emotional valence and stimulus type was explored.

Section snippets

Literature search

A literature search was performed to identify relevant fMRI studies investigating processing of emotional information in depressed patients. The search was conducted using standardized search strings capturing the key elements “(f)MRI AND depression OR MDD AND emotion(*) OR affect(*) OR reward”. Articles were retrieved from the electronic databases PubMed, EMBASE and Web of Science until September 1, 2011. The search string was constructed to comprise the following Medical Subject Headings

Study selection

The initial database search elicited 2896 results (search strategy depicted in Fig. 1). In the title-abstract review 197 articles were selected that fulfilled the inclusion criteria. The inter-rater reliability of the two independent observers was good (Cohens κ = 0.90). In total, 44 studies met our inclusion criteria (described in Table 1), including data from a total of 795 depressed patients and 792 healthy controls (HC). A variety of emotional tasks were represented in every contrast. The

Discussion

A meta-analysis of neuroimaging studies on emotion processing in major depression was conducted to test predictions from models about the brain areas involved in dysfunctional emotion processing and to examine whether emotional valence modulates activation abnormalities. We were able to include 44 studies that contrasted MDD patients to healthy controls performing tasks with emotional stimuli during fMRI measurements. For the processing of negative emotion, depressed patients showed more

Acknowledgement

Dr. Costafreda is supported by a Academic Clinical Lectureship from the National Institute for Health Research (UK).

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