The hippocampus is an archicortical structure, consisting of subfields with unique circuits. Understanding its microstructure, as proxied by these subfields, can improve our mechanistic understanding of learning and memory and has clinical potential for several neurological disorders. One prominent issue is how to parcellate, register, or retrieve homologous points between two hippocampi with grossly different morphologies. Here, we present a surface-based registration method that solves this issue in a contrast-agnostic, topology-preserving manner. Specifically, the entire hippocampus is first analytically unfolded, and then samples are registered in 2D unfolded space based on thickness, curvature, and gyrification. We demonstrate this method in seven 3D histology samples and show superior alignment with respect to subfields using this method over more conventional registration approaches. Hippocampal subfields contain microcircuits that are critical for memory and vulnerable to neurological disease. Hippocampi have variable folding patterns between individuals, making them hard to register or parcellate. We present a surface-based hippocampal registration method that is analogous to neocortical inflation to a sphere and registration. Testing in seven detailed 3D histology samples revealed successful registration with respect to hippocampal subfields, and outperformed more conventional methods. This method provides groundwork for detailed multimodal hippocampal mapping across subjects and datasets in the future. The methodological advancements described here are made easily accessible in the latest version of open source software HippUnfold 1 . Code used in the development and testing of these methods, as well as preprocessed images, manual segmentations, and results, are openly available 2 .

Epilepsy affects about 1% of the world’s population, and up to 30% of all patients will ultimately not achieve freedom from seizures with anticonvulsive medication alone. While surgical resection of a magnetic resonance imaging (MRI) -identifiable lesion remains the first-line treatment option for drug-refractory epilepsy, surgery cannot be offered to all. Neuromodulatory therapy targeting “seizures” instead of “epilepsy” has emerged as a valuable treatment option for these patients, including invasive procedures such as deep brain stimulation (DBS), responsive neurostimulation (RNS) and peripheral approaches such as vagus nerve stimulation (VNS). The purpose of this review is to provide in-depth information on current concepts and evidence on network-level aspects of drug-refractory epilepsy. We reviewed the current evidence gained from studies utilizing advanced imaging methodology, with a specific focus on their contributions to neuromodulatory therapy.