Longitudinal manganese‐enhanced magnetic resonance imaging of neural projections and activity

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 voltagegated 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

Advances in the application of manganese dioxide and its composites for theranostics

“…T 1 -Based MRI contrast agents could reduce the T 1 relaxation time, resulting in higher signal intensities in T 1 -weighted MR images and thus T 1 contrast agents are called “positive contrast agents”. 69 Mn( ii ) 70 and Gd( iii ) 71 are the most common MR contrast agents, thus improving proton relaxation and leading to high signals in T 1 -weighted imaging. 70 The T 1 relaxation rate depends on the spin quantum number ( S ) and is inversely proportional to the distance between the metal ion and the water proton.…”

“…Two properties of Mn( ii ) determine its ability to act as a MRI contrast agent: (1) with five unpaired electrons in the ground state, it has a considerable degree of paramagnetism (Fig. 3a); 70 (2) the inner layer and the outer layer of water molecules undergo rapid dissociative exchange (Fig. 3b and c).…”

“…Different disease states produce significantly different intra-cellular environments, including oxidative mediators with high concentrations of H 2 O 2 in mitochondria and reducing mediators with increased glutathione or cysteine concentrations in the endosomes and cytoplasm. 70 This results in differences in various cytoplasmic metabolites and biomolecules. Based on these differences in disease states, manganese dioxide nanoparticles which are highly sensitive to weakly acidic and reducing mediators, can decompose and release Mn( ii ).…”

“…However, the concentrations of most enzymes are too low to be directly detected by MR probes. 70 Nevertheless, Mn-based MR probes have been designed to detect pathogens by producing detectable changes in signal. 100 These probes can chemically react with enzymes and be retained at active enzyme sites in the tissue, allowing for high-precision imaging of inflammatory sites.…”

“…In contrast to Gd( iii ) contrast agents, Mn( ii ) can enter active neurons through voltage-gated Ca( ii ) channels, enabling the mapping of neuronal activity and projection tracing. 70 Despite Mn( ii ) entry via the decisive metal transporter (DMT), it does not affect the generation of Mn( ii )-based signals in the brain. Mn( ii ) enhances MR contrasts at low doses, permitting longitudinal imaging of the same individual over short or long scan intervals.…”