Characterizing BOLD activation patterns in the human hippocampus with laminar fMRI

The human hippocampus has been extensively studied at the macroscale using functional magnetic resonance imaging (fMRI) but the underlying microcircuits at the mesoscale (i.e., at the level of layers) are largely uninvestigated in humans. We target two questions fundamental to hippocampal laminar fMRI: How does the venous bias affect the interpretation of hippocampal laminar responses, and is it possible to establish a benchmark laminar fMRI experiment which robustly elicits single-subject hippocampal activation utilizing the most widely applied GRE-BOLD contrast. We comprehensively characterized GRE-BOLD responses as well as T₂*, tSNR, and physiological noise as a function of cortical depth in individual subfields of the human hippocampus. Our results show that the vascular architecture differs between subfields leading to subfield-specific laminar biases of GRE-BOLD responses. Using an autobiographical memory paradigm, we robustly acquired depth-specific BOLD responses in hippocampal subfields. In the CA1 and subiculum subregions, our results indicate a more pronounced trisynaptic path input rather than dominant direct inputs from the entorhinal cortex during autobiographical memory retrieval. Our study provides unique insights into the hippocampus at the mesoscale level, will help interpreting hippocampal laminar fMRI responses and allow researchers to test mechanistic hypotheses of hippocampal function.