Manganese-enhanced magnetic resonance imaging (MEMRI)

Abstract

The use of manganese ions (Mn(2+)) as an MRI contrast agent was introduced over 20 years ago in studies of Mn(2+) toxicity in anesthetized rats (1). Manganese-enhanced MRI (MEMRI) evolved in the late nineties when Koretsky and associates pioneered the use of MEMRI for brain activity measurements (2) as well as neuronal tract tracing (3). Currently, MEMRI has three primary applications in biological systems: (1) contrast enhancement for anatomical detail, (2) activity-dependent assessment and (3) tracing of neuronal connections or tract tracing. MEMRI relies upon the following three main properties of Mn(2+): (1) it is a paramagnetic ion that shortens the spin lattice relaxation time constant (T(1)) of tissues, where it accumulates and hence functions as an excellent T(1) contrast agent; (2) it is a calcium (Ca(2+)) analog that can enter excitable cells, such as neurons and cardiac cells via voltage-gated Ca(2+) channels; and (3) once in the cells Mn(2+) can be transported along axons by microtubule-dependent axonal transport and can also cross synapses trans-synaptically to neighboring neurons. This chapter will emphasize the methodological approaches towards the use of MEMRI in biological systems.

Fig. 7.1

T₁-weighted MRI after systemic MnCl₂ administration in the rat. T₁-weighted MRI of a control rat (column A) and a rat 1 day after IV infusion of MnCl₂ solution (column B). Top row shows transverse slices at the level of the olfactory bulb (OB, Bregma: +7 mm). The middle row shows horizontal slices including the hippocampal formation (Bregma: −6 mm). The bottom row shows sagittal slices. The signal intensity of the T₁-weighted MRI was enhanced prominently 1 day after systemic administration of MnCl₂ in the rat. There were characteristic signal enhancements that were large in the olfactory bulb (OB), hippocampus, cerebellum, and pituitary. Reprinted from Aoki et al. (44), copyright 2004, with permission from Elsevier.

Fig. 7.2

Three consecutive slices of the averaged Mn²⁺-enhanced T₁WIs under urethane anesthesia a. Mn²⁺ enhancement was observed in right cortical barrels. The color maps of the averaged Mn²⁺-enhanced T₁WIs b. Reprinted from Weng et al. (50), copyright 2007, with permission from Elsevier.

Fig. 7.3

MEMRI enhancement in brainstem auditory nuclei was altered in mice with conductive hearing loss (CHL). Comparisons of individual mice with bilateral CHL (bi-CHL) (a), mice with unilateral CHL (uni-CHL) (b), and normal mice (c) demonstrated marked differences in MEMRI signals in the cochlear nucleus (CN) (arrow heads) and inferior colliculus (IC) (arrows), but not in non-auditory caudate putamen (CPu). Adapted by permission from (48), copyright 2005.

Fig. 7.4

Detecting odor-dependent Mn²⁺ enhancement in mouse olfactory bulb by MRI. MEMRI maps after stimulation by acetophenone, carvone, octanal, and control in four mice, respectively, show distributed enhancement in the glomerular layer with each odorant having its own distinct spatial pattern. High signal change at the interface between the olfactory nerve layer and olfactory turbinates (arrow) indicates where Mn²⁺ flowed in. Scale bars represent 1 mm. Reprinted from Chuang et al. (52), copyright 2009, with permission from Elsevier.

Fig. 7.5

Signal enhancement of the rat visual pathway (24 h after Mn²⁺-injection into the left eye) in oblique sections 235° (top left), 210° (top right), 15° (bottom left), and 137.5° (bottom right) relative to a transverse reference plane. Enhanced structures are (1) left retina, (2) left optic nerve, (3) optic chiasm, (4) right optic tract, (5) right lateral geniculate nucleus, (6) right brachium of the superior colliculus, (7) right pretectal region, and (8) right superior colliculus. Reprinted from (62), copyright 2001, with permission from John Wiley & Sons, Inc.

Fig. 7.6

a Three sagittal slices of a mouse treated with Mn²⁺ in the naris from a representative 3D T₁-weighted MRI sequence. Note the highlighting of the olfactory bulb as well as the primary olfactory cortex leading from the bulbs. b Four axial slices from the same mouse treated with Mn²⁺ in the naris from a 3D T₁-weighted MRI sequence. Note the highlighting of the outer layers of the olfactory bulbs where the olfactory glomeruli are located. In addition, the enhanced contrast continues caudally into the primary olfactory cortex. Due to the length of the scan, mice were sacrificed before 3D imaging. Reprinted from (3), copyright 1998, with permission from John Wiley & Sons, Inc.

Fig. 7.7

T₁-weighted, 2D spin-echo MR image (A) before MnCl₂ administration and T₁-weighted, 3D gradient-echo image (B) after 12 h of MnCl₂ administration at the left cochlea in the guinea pig. The images’ orientation was obtained at the coronal section, and the voxel resolution was 195×195×200 μm (3). The post-injection image shows signal enhancement of the auditory pathway. Enhanced structures are as follows: (a) cochlear nucleus (CN), (b) lateral lemniscus (LL), (c) inferior colliculus (IC), (d) medial geniculate nucleus (MGN), and (e) trigeminal tract (TT). Reprinted from Lee et al. (63), copyright 2007, with permission from Elsevier.