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Original Investigation
January 2017

Altered Brain Activity in Unipolar Depression RevisitedMeta-analyses of Neuroimaging Studies

Author Affiliations
  • 1Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
  • 2Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany
  • 3Department of Physics, Florida International University, Miami
  • 4Research Imaging Institute, University of Texas Health Science Center, San Antonio
  • 5Research Service, South Texas Veterans Administration Medical Center, San Antonio
  • 6State Key Laboratory for Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, China
JAMA Psychiatry. 2017;74(1):47-55. doi:10.1001/jamapsychiatry.2016.2783
Key Points

Question  How consistent are results of experiments investigating aberrant brain activity in unipolar depression and previous meta-analyses testing this topic?

Findings  This conceptual replication of meta-analyses of 99 neuroimaging experiments in unipolar depression did not reveal any convergence, which is at odds with the findings of previous meta-analyses.

Meaning  This result highlights the importance of reproducing previous results to be able to discover real effects for individual neuroimaging studies and for meta-analyses.


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.