Heritability and reliability of automatically segmented human hippocampal formation subregions

Christopher D Whelan,Derrek P Hibar,Laura S Van Velzen,Anthony S Zannas,Tania Carrillo-Roa,Katie Mcmahon,Gautam Prasad,Sinéad Kelly,Joshua Faskowitz,Greig Dezubiracay,Juan E Iglesias,Theo G.M Van Erp,Thomas Frodl,Nicholas G Martin,Margaret J Wright,Neda Jahanshad,Lianne Schmaal,Philipp G Sämann,Paul M Thompson

doi:10.1016/j.neuroimage.2015.12.039

Abstract

The human hippocampal formation can be divided into a set of cytoarchitecturally and functionally distinct subregions, involved in different aspects of memory formation. Neuroanatomical disruptions within these subregions are associated with several debilitating brain disorders including Alzheimer's disease, major depression, schizophrenia, and bipolar disorder. Multi-center brain imaging consortia, such as the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) consortium, are interested in studying disease effects on these subregions, and in the genetic factors that affect them. For large-scale studies, automated extraction and subsequent genomic association studies of these hippocampal subregion measures may provide additional insight. Here, we evaluated the test–retest reliability and transplatform reliability (1.5T versus 3T) of the subregion segmentation module in the FreeSurfer software package using three independent cohorts of healthy adults, one young (Queensland Twins Imaging Study, N=39), another elderly (Alzheimer's Disease Neuroimaging Initiative, ADNI-2, N=163) and another mixed cohort of healthy and depressed participants (Max Planck Institute, MPIP, N=598). We also investigated agreement between the most recent version of this algorithm (v6.0) and an older version (v5.3), again using the ADNI-2 and MPIP cohorts in addition to a sample from the Netherlands Study for Depression and Anxiety (NESDA) (N=221). Finally, we estimated the heritability (h2) of the segmented subregion volumes using the full sample of young, healthy QTIM twins (N=728). Test–retest reliability was high for all twelve subregions in the 3T ADNI-2 sample (intraclass correlation coefficient (ICC)=0.70–0.97) and moderate-to-high in the 4T QTIM sample (ICC=0.5–0.89). Transplatform reliability was strong for eleven of the twelve subregions (ICC=0.66–0.96); however, the hippocampal fissure was not consistently reconstructed across 1.5T and 3T field strengths (ICC=0.47–0.57). Between-version agreement was moderate for the hippocampal tail, subiculum and presubiculum (ICC=0.78–0.84; Dice Similarity Coefficient (DSC)=0.55–0.70), and poor for all other subregions (ICC=0.34–0.81; DSC=0.28–0.51). All hippocampal subregion volumes were highly heritable (h2=0.67–0.91). Our findings indicate that eleven of the twelve human hippocampal subregions segmented using FreeSurfer version 6.0 may serve as reliable and informative quantitative phenotypes for future multi-site imaging genetics initiatives such as those of the ENIGMA consortium.

Highlights

The mammalian hippocampal formation is one of the most important brain regions for spatial navigation (O'Keefe, 1990), episodic memory retrieval (Burgess et al, 2002), and associative learning processes (Morris, 2006)
Neuroanatomical abnormalities within these hippocampal subregions are associated with a broad range of neurological and psychiatric disorders, from ischaemic stroke, encephalitis, temporal lobe epilepsy, transient global amnesia and multiple sclerosis (Bartsch, 2012; Das et al, 2011) to bipolar disorder (BPD), major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) (Sala, 2008)
Recent advances in genome-wide association (GWA) meta-analysis and large-scale collaborative brain imaging (e.g. Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA), the Early Growth Genetics (EGG) consortium, and the Cohorts of Heart and Aging Research in Genomic Epidemiology (CHARGE)) have helped identify several common genetic variants associated with structural variation in the hippocampus (Bis et al, 2012; Hibar et al, 2015; Stein et al, 2012) as well as other brain regions including the putamen, caudate nucleus (Hibar et al, 2015), intracranial volume (Ikram et al, 2012; Stein et al, 2012) and head circumference (Taal et al, 2012)

Summary

Introduction

The mammalian hippocampal formation is one of the most important brain regions for spatial navigation (O'Keefe, 1990), episodic memory retrieval (Burgess et al, 2002), and associative learning processes (Morris, 2006). The subiculum, a subregion that exerts control over the hippocampal output, has been associated with spatial memory functions, but its ventral part may play an additional regulatory role in inhibition of the HPA axis (O'Mara, 2006) Neuroanatomical abnormalities within these hippocampal subregions are associated with a broad range of neurological and psychiatric disorders, from ischaemic stroke, encephalitis, temporal lobe epilepsy, transient global amnesia and multiple sclerosis (Bartsch, 2012; Das et al, 2011) to bipolar disorder (BPD), major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) (Sala, 2008). Recent advances in genome-wide association (GWA) meta-analysis and large-scale collaborative brain imaging (e.g. Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA), the Early Growth Genetics (EGG) consortium, and the Cohorts of Heart and Aging Research in Genomic Epidemiology (CHARGE)) have helped identify several common genetic variants associated with structural variation in the hippocampus (Bis et al, 2012; Hibar et al, 2015; Stein et al, 2012) as well as other brain regions including the putamen, caudate nucleus (Hibar et al, 2015), intracranial volume (Ikram et al, 2012; Stein et al, 2012) and head circumference (Taal et al, 2012)

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