Shared Neural Phenotypes for Mood and Anxiety Disorders: A Meta-analysis of 226 Task-Related Functional Imaging Studies

Abstract

Importance: Major depressive disorder, bipolar disorder, posttraumatic stress disorder, and anxiety disorders are highly comorbid and have shared clinical features. It is not yet known whether their clinical overlap is reflected at the neurobiological level.

Objective: To detect transdiagnostic convergence in abnormalities in task-related brain activation.

Data source: Task-related functional magnetic resonance imaging articles published in PubMed, Web of Science, and Google Scholar during the last decade comparing control individuals with patients with mood, posttraumatic stress, and anxiety disorders were examined.

Study selection: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines, articles were selected if they reported stereotactic coordinates of whole-brain-based activation differences between adult patients and control individuals.

Data extraction and synthesis: Coordinates of case-control differences coded by diagnosis and by cognitive domain based on the research domain criteria were analyzed using activation likelihood estimation.

Main outcomes and measures: Identification of transdiagnostic clusters of aberrant activation and quantification of the contribution of diagnosis and cognitive domain to each cluster.

Results: A total of 367 experiments (major depressive disorder, 149; bipolar disorder, 103; posttraumatic stress disorder, 55; and anxiety disorders, 60) were included comprising observations from 4507 patients and 4755 control individuals. Three right-sided clusters of hypoactivation were identified centered in the inferior prefrontal cortex/insula (volume, 2120 mm3), the inferior parietal lobule (volume, 1224 mm3), and the putamen (volume, 888 mm3); diagnostic differences were noted only in the putamen (χ23 = 8.66; P = .03), where hypoactivation was more likely in bipolar disorder (percentage contribution = 72.17%). Tasks associated with cognitive systems made the largest contribution to each cluster (percentage contributions >29%). Clusters of hyperactivation could only be detected using a less stringent threshold. These were centered in the perigenual/dorsal anterior cingulate cortex (volume, 2208 mm3), the left amygdala/parahippocampal gyrus (volume, 2008 mm3), and the left thalamus (volume, 1904 mm3). No diagnostic differences were observed (χ23 < 3.06; P > .38), while tasks associated with negative valence systems made the largest contribution to each cluster (percentage contributions >49%). All findings were robust to the moderator effects of age, sex, and magnetic field strength of the scanner and medication.

Conclusions and relevance: In mood disorders, posttraumatic stress disorder, and anxiety disorders, the most consistent transdiagnostic abnormalities in task-related brain activity converge in regions that are primarily associated with inhibitory control and salience processing. Targeting these shared neural phenotypes could potentially mitigate the risk of affective morbidity in the general population and improve outcomes in clinical populations.

Conflict of interest statement

Conflict of Interest Disclosures: In the past 5 years, Dr Murrough has provided consultation services to Boehreinger Ingelheim, Sage Therapeutics, FSV7, Novartis, Allergan, Fortress Biotech, Janssen Research and Development, Medavante-Prophase, and Global Medical Education and has received research support from Avanir Pharmaceuticals Inc. Dr Murrough is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders. No other disclosures were reported.

Figures

Figure 1.. Transdiagnostic Clusters of Hypoactivation in Patients Relative to Healthy Individuals

A, Activation likelihood estimation identified 3 transdiagnostic clusters of relative hypoactivation in patients centered on right inferior prefrontal cortex/insula (IFG/INS), the right inferior parietal lobule (IPL), and the right putamen. B, Percentage contribution of each research domain criteria (RDoC) to each cluster. Additional details are in eTable 7 in the Supplement.

Figure 2.. Transdiagnostic Clusters of Hyperactivation in Patients Compared With Healthy Individuals

A, Activation likelihood estimation identified 3 transdiagnostic clusters of hyperactivation in the left amygdala/parahippocampal gyrus (PHG), the left thalamus, and the perigenual/dorsal anterior cingulate cortex (dACC). B, Percentage contribution of each research domain criteria (RDoC) to each cluster. Additional details are in eTable 7 in the Supplement.