Advances in the MRI study of connectivity structure and functional mechanism of hippocampal subregions in humans

The hippocampus, a structure critical for learning and memory, consists of anatomical heterogenous subfields, including the dentate gyms (DG), cornu ammonis (CA) 1-4, and subiculum (SUB). Evidences from studies on rodents and non-human primates have shown that the hippocampal subfields are richly connected, especially through the canonical trisynaptic pathway to project incoming information from the cortex via the entorhinal cortex (EC) to innervate the DG, and from here, intra-hippocampal connectivity is considered to follow a unidirectional pathway through the CA regions to the SUB, which is the primary region of efferent projection from the hippocampus. However. given their lower spatial resolution. it has been a challenge to map the hippocampal subfields in-vivo in the human brain including their anatomical/functional connectivity and functional specificity. Recent developments in high-resolution structural and functional magnetic resonance imaging (MRI) techniques have allowed for detailed parcellation of the hippocampal subfields in humans and have provided new insights into their structure and function. In this review, we first briefly introduce the anatomical structure of the hippocampal subfields along the tri-synaptic pathway. We then review recent findings regarding the delineated patterns of anatomical and functional connectivity among the hippocampal subfields and neighboring cortical areas using high-resolution structural and functional MRI. In general, patterns of FC between hippocampal subfields and adjoining cortical regions of interest (ROIs) align well with the canonical intra-hippocampal anatomical circuitry (DG -> CA3 -> 4CA1 -> SUB). Next. we discuss functional and computational mechanisms that could be subseived by different hippocampal subfields, with a special focus on two fundamental functional/computational processes: Pattern separation and pattern completion. Here, we start by introducing important findings from rodent studies regarding pattern separation/pattern completion functions in hippocampal subregions and adjacent cortical areas. and then review recent studies using high-resolution functional MRI to explore functional mechanisms of hippocampal subregions in humans, which suggests that hippocampal subfields (specifically the CA3/DG) are biased toward pattern separation while CA1 may be biased toward pattern completion during holistic recollection, representing global contextual regularities across items. Finally, there are amounts of evidence suggests that many neurological and psychiatric diseases disorders (e.g.. Alzheimer's disease and Parkinson's disease) are related to the abnormal changes of subregions and their specific circuits in the hippocampus, which could offer a novel avenue to elucidate pathological mechanisms underlying these neuropsychiatric disorders, and uncover an imaging-based biomarker for early diagnosis and monitoring underlying these neurological diseases. We therefore discuss recent studies on how hippocampal subfields and neighboring cortical areas dysfunction in common neurodegenerative diseases regarding the high-resolution structural and functional MRI. which suggests atrophy of subiculum and presubiculum may be the earliest anatomical marker of Alzheimer's disease and CA1 may be the best predictor of episodic memory impairment in Parkinson's disease patients. Finally, we also raise several challenges and key issues which need to be addressed in the future.