Brainwide functional networks associated with anatomically- and functionally-defined hippocampal subfields using ultrahigh-resolution fMRI

The hippocampus is critical for learning and memory and may be separated into anatomically-defined hippocampal subfields (aHPSFs). Many studies have shown that aHPSFs, and their respective functional networks, are differentially vulnerable to a variety of disorders. Hippocampal functional networks, particularly during resting state, are generally analyzed using aHPSFs as seed regions, with the underlying assumption that the function within a subfield is homogeneous, yet heterogeneous between subfields. However, several prior studies that have utilized aHPSFs and assessed brain-wide cortical connectivity have observed similar resting-state functional connectivity profiles between aHPSFs. Alternatively, data-driven approaches offer a means to investigate hippocampal functional organization without a priori assumptions. However, insufficient spatial resolution may lead to partial volume effects at the boundaries of hippocampal subfields, resulting in a number of caveats concerning the reliability of the results. Hence, we developed a functional Magnetic Resonance Imaging (fMRI) sequence on a 7T MR scanner achieving 0.94 mm isotropic resolution with a TR of 2s and brain-wide coverage to 1) investigate whether hippocampal functional segmentation with ultrahigh-resolution data demonstrate similar anatomical, lamellar structures in the hippocampus, and 2) define and compare the brain-wide FC associated with fine-grained aHPSFs and functionally-defined hippocampal subfields (fHPSFs). Using a spatially restricted hippocampal Independent Component Analysis (ICA) approach, this study showed that fHPSFs were arranged along the longitudinal axis of the hippocampus that were not comparable to the lamellar structures of aHPSFs. Contrary to the anatomically defined hippocampal subfields which are bilaterally symmetrical, 13 out of 20 fHPSFs were unilateral. For brain-wide FC, the fHPSFs rather than aHPSFs revealed that a number of fHPSFs connected specifically with some of the functional networks. The visual and sensorimotor networks preferentially connected with different portions of CA1, CA3 and CA4/DG. The DMN was also found to connect more extensively with posterior subfields rather than anterior subfields. Finally, the frontoparietal network (FPN) was anticorrelated with the head portion of CA1. The investigation of functional networks associated with the fHPSFs may enhance the sensitivity of biomarkers for a range of neurological disorders, as network-based approaches take into account disease-related alterations in brain-wide interconnections rather than measuring the regional changes of hippocampus.