FreeSurfer-based segmentation of hippocampal subfields: A review of methods and applications, with a novel quality control procedure for ENIGMA studies and other collaborative efforts

Philipp G. Sämann*, Juan Eugenio Iglesias, Boris Gutman, Dominik Grotegerd, Ramona Leenings, Claas Flint, Udo Dannlowski, Emily K. Clarke-Rubright, Rajendra A. Morey, Theo G.M. van Erp, Christopher D. Whelan, Laura K.M. Han, Laura S. van Velzen, Bo Cao, Jean C. Augustinack, Paul M. Thompson, Neda Jahanshad, Lianne Schmaal

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review


Structural hippocampal abnormalities are common in many neurological and psychiatric disorders, and variation in hippocampal measures is related to cognitive performance and other complex phenotypes such as stress sensitivity. Hippocampal subregions are increasingly studied, as automated algorithms have become available for mapping and volume quantification. In the context of the Enhancing Neuro Imaging Genetics through Meta Analysis Consortium, several Disease Working Groups are using the FreeSurfer software to analyze hippocampal subregion (subfield) volumes in patients with neurological and psychiatric conditions along with data from matched controls. In this overview, we explain the algorithm's principles, summarize measurement reliability studies, and demonstrate two additional aspects (subfield autocorrelation and volume/reliability correlation) with illustrative data. We then explain the rationale for a standardized hippocampal subfield segmentation quality control (QC) procedure for improved pipeline harmonization. To guide researchers to make optimal use of the algorithm, we discuss how global size and age effects can be modeled, how QC steps can be incorporated and how subfields may be aggregated into composite volumes. This discussion is based on a synopsis of 162 published neuroimaging studies (01/2013–12/2019) that applied the FreeSurfer hippocampal subfield segmentation in a broad range of domains including cognition and healthy aging, brain development and neurodegeneration, affective disorders, psychosis, stress regulation, neurotoxicity, epilepsy, inflammatory disease, childhood adversity and posttraumatic stress disorder, and candidate and whole genome (epi-)genetics. Finally, we highlight points where FreeSurfer-based hippocampal subfield studies may be optimized.

Original languageEnglish
Pages (from-to)207-233
Number of pages27
JournalHuman Brain Mapping
Issue number1
Publication statusPublished - Jan 2022

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