Automated measurement of hippocampal subfields in PTSD: Evidence for smaller dentate gyrus volume

Abstract

Smaller hippocampal volume has been consistently observed as a biomarker of posttraumatic stress disorder (PTSD). However, less is known about individual volumes of the subfields composing the hippocampus such as the dentate gyrus and cornu ammonis (CA) fields 1–4 in PTSD. The aim of the present study was to examine the hypothesis that volume of the dentate gyrus, a region putatively involved in distinctive encoding of similar events, is smaller in individuals with PTSD versus trauma-exposed controls. Ninety-seven recent war veterans underwent structural imaging on a 3T scanner and were assessed for PTSD using the Clinician-Administered PTSD Scale. The hippocampal subfield automated segmentation program available through FreeSurfer was used to segment the CA4/dentate gyrus, CA1, CA2/3, presubiculum, and subiculum of the hippocampus. Results showed that CA4/dentate gyrus subfield volume was significantly smaller in veterans with PTSD and scaled inversely with PTSD symptom severity. These results support the view that dentate gyrus abnormalities are associated with symptoms of PTSD, although additional evidence is necessary to determine whether these abnormalities underlie fear generalization and other memory alterations in PTSD.

Introduction

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric condition that develops following exposure to highly distressing life events. One of the most consistently observed biological markers of PTSD is smaller hippocampal volume, with several meta-analyses now supporting a small but significant association (Kitayama et al., 2005, Smith, 2005, Karl et al., 2006, O'Doherty et al., 2015). The hippocampal formation is composed of several subfields that are thought to mediate different memory functions including the dentate gyrus (DG), cornu ammonis (CA) 1–4, presubiculum, and subiculum. The DG subfield is putatively involved in “pattern separation,” which is the process by which incoming neural signals are made more distinct from each other at the time of encoding (O'Reilly and McClelland, 1994). Recently, it has been proposed that pattern separation deficits may underlie fear generalization (Kheirbek et al., 2012), a process that occurs in anxiety and stress based disorders including PTSD (Morey et al., 2015).

Consistent with the notion that the DG may be impaired in PTSD, Wang et al. (2010) observed smaller DG/CA3 volume in 17 subjects with PTSD relative to 17 trauma-exposed control subjects. Further, lower CA1 volume was found as a function of age but not PTSD. This study used manual tracing of hippocampal subfield regions, the gold standard in the field. However, manual tracing is an extremely time-consuming and labor intensive process. As trends in science have moved toward large datasets to study subtle relationships between brain anatomy, psychiatric symptoms and other behavioral outcome measures, hand-tracing of hippocampal subfields has become prohibitive in terms of cost and time. Further, the wide range in manual tracing methods with lack of consistent protocols (Geuze et al., 2005) is a key limitation of manual volumetric assessment. By contrast, automated segmentation can foster standardization of methods across different laboratories and represents a time-efficient strategy to segment the hippocampus without sacrificing inter-rater reliability.

Recent developments in automated measures put forth by the creators of FreeSurfer provide a method to delineate hippocampal subfield volume on standard T1 high resolution images (Van Leemput et al., 2009). This method is based on a Bayesian modeling approach that predicts the location of neuroanatomical labels based on probabilistic atlases and learned locations of manual hippocampal segmentations from training subjects. The automated segmentations have been validated against manual morphometric measurements of ultra-high resolution scans. The automated hippocampal subfield extraction tool outputs left and right volumes of the following structures: CA4/DG, CA1, CA2/3, presubiculum, subiculum, fimbria, hippocampal fissure, and the tail of the hippocampus. Several studies have now used these methods to examine differences among psychiatric groups including schizophrenia and bipolar disorder (Mathew et al., 2014, Haukvik et al., 2015). In the current study, we examined hippocampal subfield volumes in a large group of trauma-exposed individuals. We hypothesized that we would observe lower DG volume in the PTSD group, similar to the findings reported by Wang et al. (2010). As age was shown to influence certain volumes in that study, we also examined the effects of age and the PTSD by age interaction on subfield volumes.