Coordinate-Based Network Mapping of Brain Structure in Major Depressive Disorder in Younger and Older Adults: A Systematic Review and Meta-Analysis

Abstract

Background: Neuroimaging findings in younger and older adults with major depressive disorder (MDD) are highly heterogeneous. It is unclear whether this heterogeneity is due to methodological limitations, lack of distinction between MDD and late-life depression (LLD), or clinical moderators. Methods: We identified all voxel-based and surface-based morphometry studies comparing younger adults with MDD or older adults with LLD to non-psychiatric control participants (updated search: Oct 27, 2020). We used both an Activation Likelihood Estimation (ALE) analysis and a novel coordinate-based network mapping to identify brain circuits affected in MDD and LLD. We then used meta-regressions to examine the impact of age of onset in older patients with LLD and treatment with antidepressants in younger patients with MDD. Results: We analysed 145 comparisons from 143 articles including 14,318 participants (MDD; 6,362; LDD: 535; controls: 7,421). Our ALE results confirmed previous findings implicating the bilateral parahippocampus (z RIGHT =5.2, z LEFT =4.3, p FWE <0.001) and anterior cingulate (z RIGHT =3.6, z LEFT =4.5 p FWE <0.005) in MDD and anterior cingulate (z RIGHT =3.7, z LEFT =3.6 p FWE <0.005) in LLD. In contrast, coordinate-based network mapping showed differences in the frontoparietal, dorsal attention, and visual networks both in MDD and LLD. Meta-regressions showed that late onset was associated with widespread structural abnormalities in LLD and treatment with antidepressants was associated with abnormalities in the anterior cingulate (BA32, t 1,116 =3.8, p FDR =0.03) and dorsolateral prefrontal cortex (BA9, t 1,116 =3.0, p FDR =0.04) in MDD. Conclusions: While ALE identified specific brain regions affected in MDD, coordinate-based network mapping was more sensitive to disruptions in both MDD and LLD. Meta-regression identified additional differences related to age of onset and treatment with antidepressants. These findings help clarify the shared circuitry of depression across the adult lifespan and highlight some unique circuitry relevant to late-onset depression, which may explain some of the risk for cognitive decline and dementia. Funding Statement: Andrea Cipriani is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP- 2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). Declaration of Interests: PZ was funded by the Labatt Family Postdoctoral Fellowship in Depression Biology. JAEA was funded by Canadian Institute of Health Research CIHR fellowship Grant No. CIHR-IRSC: 0093005620. B.H. Mulsant receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; he currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). He directly owns stocks of General Electric (less than $5,000). Within the past five years, he has also received research support from Eli Lilly (medications and matching placebo pills for a NIH-funded clinical trial) and Pfizer (medications for a NIH-funded clinical trial) and he has been an unpaid consultant to Myriad Neuroscience. Andrea Cipriani has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma. ANV currently receives funding from CIHR, the NIH, the National Sciences and Engineering Research Council (NSERC), the CAMH Foundation, and the University of Toronto.