Technical NoteAdvances in high-resolution imaging and computational unfolding of the human hippocampus
Introduction
The hippocampal area, including subregions of the hippocampus such as the dentate gyrus, the cornus amonis fields (CA1–3), and the subiculum, together with surrounding cortices (i.e., entorhinal, perirhinal, and parahippocampal cortices), plays critical and selective roles in learning and memory. Studies employing electrophysiological recordings in the rodent have elucidated separate roles in memory encoding and retrieval for the dentate gyrus (Leutgeb et al., 2007), CA3 (Lee et al., 2004), CA1 (Lee et al., 2004, Wilson and McNaughton, 1993), and subiculum (Sharp, 2006, Sharp and Green, 1994). Primate and rodent electrophysiological studies have also revealed distinct roles for the surrounding entorhinal, perirhinal, and parahippocampal in memory (Aggleton and Brown, 2006, Brown and Aggleton, 2001, Ekstrom et al., 2003, Fyhn et al., 2004). Despite this extensive body of knowledge from single cell recordings, little progress has been made in gaining similar knowledge about the roles of hippocampal subregions in human memory. This is largely because current non-invasive imaging methods (i.e., fMRI) typically lack the spatial resolution to image subregions of the human hippocampal area.
Recent advances in imaging of the hippocampus, though, have made some progress in visualizing subregions of the hippocampus such as CA1, subiculum, CA23/dentate gyrus, and surrounding cortex. These methods have approached the challenge of imaging the hippocampus using two distinct techniques. The first involves using high-resolution anatomical T1-weighted MP-RAGE sequences (Bakker et al., 2008, Kirwan et al., 2007, Miller et al., 2005) to produce isotropic voxels of 0.75 mm. A second line of investigation employs anatomical T2-weighted images with high in-plane resolution (0.4 mm in the oblique coronal plane) and 3 mm in the longitudinal plane (Burggren et al., 2008, Ekstrom et al., 2008, Eldridge et al., 2005, Zeineh et al., 2000, Zeineh et al., 2001, Zeineh et al., 2003). The hippocampus is then manually segmented, interpolated, and computationally unfolded to a final voxel size of 0.4 mm. In both methods, group maps are produced based on “warping” individual hippocampi into a common plane, thus basing group maps on individual hippocampi rather than fitting to a template (Miller et al., 2005, Stark and Okado, 2003, Thompson et al., 2000). Both methods then rely on high-resolution blood oxygen level-dependent (BOLD) sequences (1.5 mm isotropic for the first vs. 1.6 mm × 1.6 × 3 mm for the second) to image and localize functional activity. Other methods using high-field structural imaging offer promise for significantly greater resolution but are currently limited to post-mortem brains (Augustinack et al., 2005).
One limitation of current high-resolution anatomical imaging methods is that they have not been able to discriminate anterior CA fields from dentate gyrus or dentate gyrus from CA23 in the posterior plane due to insufficient MR resolution. The methods that we present here expand on our previous methods (e.g., Zeineh et al., 2000, Zeineh et al., 2001, Zeineh et al., 2003) using high-resolution T2 weighted anatomical images prescribed to the hippocampal area coupled with high-resolution echo-planar imaging (EPI). We present several new imaging sequences that simultaneously improve our resolution in the longitudinal plane from 3 mm to 1 mm and furthermore enhance our ability to visualize subregions of the hippocampus. We also present a novel application of a computational interpolation method that improves our ability to detect changes along the longitudinal axis of the hippocampus. The software we present is now compatible with other functional imaging software packages such as SPM (Friston et al., 1995), FSL (Woolrich et al., 2001), and AFNI (Cox, 1996) and are available for download from our website. Together, the methods we present here improve over earlier techniques in allowing visualization of changes in hippocampal activity.
Section snippets
Data acquisition
A series of nine scan sets were collected with the purpose of decreasing slice thickness and increasing the number of oblique slices through the hippocampus. These sequences were run with a total of 6 different subjects each (3 male, 3 female) with a mean age of 30 (range: 22–52), each of whom provided informed consent. Structural MRI scans were collected on a Siemens Allegra 3 T scanner (Siemens AG) with an eight-channel head coil at the Ahmanson-Lovelace Brain Mapping Center (Los Angeles,
Discussion
A critical challenge in neuroimaging is improving our detection of task-related, neural activity changes in subcortical structures and sub-structures in human brain. The hippocampus, a structure central to learning and memory, has proven difficult to image. Our prior work improved the resolution of functional and structural images of the hippocampus and surrounding cortex (Zeineh et al., 2001, 2003) and enhanced our ability to visualize activations in the hippocampus in groups of subjects. We
Acknowledgments
We thank Paul Thompson and Mark Cohen for contributing the computer code and technical guidance on the results in this manuscript. We thank John Melanokas for generous sharing of computer code central to the interpolation software. We thank Saba Movishari for technical assistance. We also thank NINDS F32 NS50067 for financial support to AE. For generous support the authors thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The
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