Longitudinal manganese‐enhanced magnetic resonance imaging of neural projections and activity. (6th March 2022) - Uselman, Taylor W.
Abstract : Manganese‐enhanced magnetic resonance imaging (MEMRI) holds exceptional promise for preclinical studies of brain‐wide physiology in awake‐behaving animals. The objectives of this review are to update the current information regarding MEMRI and to inform new investigators as to its potential. Mn(II) is a powerful contrast agent for two main reasons: (1) high signal intensity at low doses; and (2) biological interactions, such as projection tracing and neural activity mapping via entry into electrically active neurons in the living brain. High‐spin Mn(II) reduces the relaxation time of water protons: at Mn(II) concentrations typically encountered in MEMRI, robust hyperintensity is obtained without adverse effects. By selectively entering neurons through voltage‐gated calcium channels, Mn(II) highlights active neurons. Safe doses may be repeated over weeks to allow for longitudinal imaging of brain‐wide dynamics in the same individual across time. When delivered by stereotactic intracerebral injection, Mn(II) enters active neurons at the injection site and then travels inside axons for long distances, tracing neuronal projection anatomy. Rates of axonal transport within the brain were measured for the first time in "time‐lapse" MEMRI. When delivered systemically, Mn(II) enters active neurons throughout the brain via voltage‐sensitive calcium channels and clears slowly. Thus behavior can be monitored during Mn(II) uptake and hyperintense signals due to Mn(II) uptake captured retrospectively, allowing pairing of behavior with neural activity maps for the first time. Here we review critical information gained from MEMRI projection mapping about human neuropsychological disorders. We then discuss results from neural activity mapping from systemic Mn(II) imaged longitudinally that have illuminated development of the tonotopic map in the inferior colliculus as well as brain‐wide responses to acute threat and how it evolves over time. MEMRI posed specific challenges for image data analysis that have recently been transcended. We predict a bright future for longitudinal MEMRI in pursuit of solutions to the brain‐behavior mystery. Abstract : This comprehensive review of MEMRI details: the chemical and physical properties of Mn(II); considerations for safe dosing; perspectives on scanning parameters; discussions of biological mechanisms of projection and neural activity mapping; contributions yielded by MEMRI; procedures for image processing; strategies for computational analysis; and concludes with remarks for future directions. This paper will provide a resource to guide investigators when applying MEMRI to critical neurobiological problems.