title: Detection of aberrant hippocampal mossy fiber connections: Ex vivo mesoscale diffusion MRI and microtractography with histological validation in a patient with uncontrolled temporal lobe epilepsy.
abstract: Understanding the neurobiology and functional connectivity of hippocampal structures is essential for improving the treatment of mesial temporal lobe epilepsy. At the macroscale, in vivo MRI often reveals hippocampal atrophy and decreased fractional anisotropy, whereas at the microscopic scale, there frequently is evidence of neuronal loss and gliosis. Mossy fiber sprouting in the dentate gyrus (DG), with evidence of glutamatergic synapses in the stratum moleculare (SM) putatively originating from granule cell neurons, may also be observed. This aberrant connection between the DG and SM could produce a reverberant excitatory circuit. However, this hypothesis cannot easily be evaluated using macroscopic or microscopic techniques. We here demonstrate that the ex vivo mesoscopic MRI of surgically excised hippocampi can bridge the explanatory and analytical gap between the macro- and microscopic scale. Specifically, diffusion- and T2 -weighted MRI can be integrated to visualize a cytoarchitecture that is akin to immunohistochemistry. An appropriate spatial resolution to discern individual cell layers can then be established. Processing of diffusion tensor images using tractography detects extra- and intrahippocampal connections, hence providing a unique systems view of the hippocampus and its connected regions. Here, this approach suggests that there is indeed an aberrant connection between the DG and SM, supporting the sprouting hypothesis of a reverberant excitatory network. Mesoscopic ex vivo MR imaging hence provides an exciting new avenue to study hippocampi from treatment-resistant patients and allows exploration of existing hypotheses, as well as the development of new treatment strategies based on these novel insights. Hum Brain Mapp 37:780-795, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.|Centre for the Neural Basis of Behavior, Pittsburgh, Pennsylvania.
authors.forename: Michel
authors.initials: M
authors.lastname: Modo
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: T Kevin
authors.initials: TK
authors.lastname: Hitchens
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Liu
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.|Centre for the Neural Basis of Behavior, Pittsburgh, Pennsylvania.|Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Richardson
mesh_terms: D038481:Anterior Temporal Lobectomy; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D000069279:Drug Resistant Epilepsy / Q000473:pathology* / Q000601:surgery; D004833:Epilepsy, Temporal Lobe / Q000473:pathology* / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000473:pathology* / Q000601:surgery; D009434:Neural Pathways / Q000473:pathology / Q000601:surgery; D055815:Young Adult
keywords: MR histology; cytoarchitecture; diffusion tensor imaging; ex vivo MRI; intractable epilepsy; mossy fibers; sprouting hypothesis; surgical resection; tractography; ultra high field MRI