The Subcortical Default Mode Network and Alzheimer’s Disease: A systematic review and Activation Likelihood Estimation Meta-Analysis

The default mode network is a central cortical brain network suggested to play a major role in several disorders, and to be particularly vulnerable to the neuropathological hallmarks of Alzheimer’s disease. Subcortical involvement in the default mode network and its alteration in Alzhimer’s disease remains largely unknown. We performed a systematic review, meta-analysis, and empirical validation of the subcortical default mode network in healthy adults, combined with a systematic review, meta-analysis, and network analysis of the involvement of subcortical default mode areas in Alzheimer’s disease. Our results show that, besides the well-known cortical default mode network brain regions, the default mode network consistently includes subcortical regions, namely the thalamus, lobule and vermis IX and right Crus I/II of the cerebellum, and the amygdala. Network analysis also suggests the involvement of the caudate nucleus. In Alzheimer’s disease, we observed a left-lateralized cluster of decrease in functional connectivity which covered the medial temporal lobe and amygdala and showed overlap with the default mode network in a portion covering parts of the left anterior hippocampus and left amygdala. An increase in functional connectivity was also found in the right anterior insula. These results confirm the consistency of subcortical contributions to the default mode network in healthy adults and highlight the relevance of the subcortical default mode network alteration in Alzheimer’s disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by grants TESIS2019010146 and EST2022010045 from the Board of Economy, Industry, Trade and Knowledge of the Canarian Government with a European Social Fund co-financing rate to SLS, and PSI2017-84933-P and PSI2017-91955-EXP to NJ. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is a systematic review, meta-analysis and empirical validation. We used data published in research articles for the meta-analysis, and the Human Connectome Project neuroimaging data available at I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All brain maps derived from this study will be made available on NeuroVault upon peer-review publication.