Altered Brain Activity in Unipolar Depression Revisited: Meta-analyses of Neuroimaging Studies

Abstract

Importance: During the past 20 years, numerous neuroimaging experiments have investigated aberrant brain activation during cognitive and emotional processing in patients with unipolar depression (UD). The results of those investigations, however, vary considerably; moreover, previous meta-analyses also yielded inconsistent findings.

Objective: To readdress aberrant brain activation in UD as evidenced by neuroimaging experiments on cognitive and/or emotional processing.

Data sources: Neuroimaging experiments published from January 1, 1997, to October 1, 2015, were identified by a literature search of PubMed, Web of Science, and Google Scholar using different combinations of the terms fMRI (functional magnetic resonance imaging), PET (positron emission tomography), neural, major depression, depression, major depressive disorder, unipolar depression, dysthymia, emotion, emotional, affective, cognitive, task, memory, working memory, inhibition, control, n-back, and Stroop.

Study selection: Neuroimaging experiments (using fMRI or PET) reporting whole-brain results of group comparisons between adults with UD and healthy control individuals as coordinates in a standard anatomic reference space and using an emotional or/and cognitive challenging task were selected.

Data extraction and synthesis: Coordinates reported to show significant activation differences between UD and healthy controls during emotional or cognitive processing were extracted. By using the revised activation likelihood estimation algorithm, different meta-analyses were calculated.

Main outcomes and measures: Meta-analyses tested for brain regions consistently found to show aberrant brain activation in UD compared with controls. Analyses were calculated across all emotional processing experiments, all cognitive processing experiments, positive emotion processing, negative emotion processing, experiments using emotional face stimuli, experiments with a sex discrimination task, and memory processing. All meta-analyses were calculated across experiments independent of reporting an increase or decrease of activity in major depressive disorder. For meta-analyses with a minimum of 17 experiments available, separate analyses were performed for increases and decreases.

Results: In total, 57 studies with 99 individual neuroimaging experiments comprising in total 1058 patients were included; 34 of them tested cognitive and 65 emotional processing. Overall analyses across cognitive processing experiments (P > .29) and across emotional processing experiments (P > .47) revealed no significant results. Similarly, no convergence was found in analyses investigating positive (all P > .15), negative (all P > .76), or memory (all P > .48) processes. Analyses that restricted inclusion of confounds (eg, medication, comorbidity, age) did not change the results.

Conclusions and relevance: Inconsistencies exist across individual experiments investigating aberrant brain activity in UD and replication problems across previous neuroimaging meta-analyses. For individual experiments, these inconsistencies may relate to use of uncorrected inference procedures, differences in experimental design and contrasts, or heterogeneous clinical populations; meta-analytically, differences may be attributable to varying inclusion and exclusion criteria or rather liberal statistical inference approaches.

Figure 1. Schematic Illustration of the Steps of a Meta-analysis

In step 1, coordinates reported in the experiments included in the analysis are extracted by creating a table with all x, y, and z coordinates in either Montreal Neurological Institute (MNI) or Talairach space. In this example, the coordinates of more than 3 experiments were included indicated by the ellipses at the end of the example table. In step 2, these coordinates are transformed into the same coordinate space and projected on a brain template for display. For example, the first coordinate reported in experiment 1 is projected on a brain template based on its x, y, and z coordinates (marked in blue). In step 3, the spatial uncertainty associated with each coordinate is accounted for by modeling gaussian probability distributions around each coordinate. In step 4, the resulting activation likelihood estimation scores are compared with a null distribution reflecting a random spatial association between experiments, and results are thresholded and corrected for multiple comparisons.

Figure 2. Illustration of Reported Peak Coordinates of Convergence Found in Previous Meta-analyses Investigating Aberrant Brain Activation in Unipolar Depression

Mixed processing indicates analyses across cognitive and emotional experiments. Each color represents a separate meta-analysis. Hardly any overlap is seen between colors, showing that results of previous meta-analyses investigating a similar topic are inconsistent. A, Previous meta-analyses of emotional processing experiments only include Fitzgerald et al, Hamilton et al, Lai et al, and Palmer et al. B, Previous meta-analyses of cognitive processing experiments includes Palmer et al; of mixed processing, Diener et al and Graham et al.

Figure 3. Flowchart of the Different Steps Conducted

In total 16 different meta-analyses including 57 studies and 99 experiments were calculated. ALE indicates activation likelihood estimation; ROI, region of interest; and UD, unipolar depression.

Figure 4. Render of the Distribution of Coordinates Included in the Present Meta-analysis

Red indicates increased activation in unipolar depression (UD), whereas blue shows all foci reported as decreased activity in UD. Color transparency indicates the depth of the coordinate related to the cortical surface.