Manganese-enhanced MRI: an exceptional tool in translational neuroimaging

Abstract

The metal manganese is a potent magnetic resonance imaging (MRI) contrast agent that is essential in cell biology. Manganese-enhanced magnetic resonance imaging (MEMRI) is providing unique information in an ever-growing number of applications aimed at understanding the anatomy, the integration, and the function of neural circuits both in normal brain physiology as well as in translational models of brain disease. A major drawback to the use of manganese as a contrast agent, however, is its cellular toxicity. Therefore, paramount to the successful application of MEMRI is the ability to deliver Mn2+ to the site of interest using as low a dose as possible while preserving detectability by MRI. In the present work, the different approaches to MEMRI in translational neuroimaging are reviewed and challenges for future identified from a practical standpoint.

Fig. 1.

Effect of increasing numbers of fractions of MnCl₂ on the signal intensity in MEMRI of the rat brain. The top row shows typical horizontal slices from 3D T₁-weighted images of a rat at increasing cumulative doses of 30 mg/kg MnCl₂ delivered systemically at 48-h intervals between doses. The bottom graph shows the signal magnitude from each brain region normalized to the signal intensity in the temporalis muscle (error bars = ±1 SD, n = 4). Progressive signal enhancement is observed in most regions of the brain, except the cortex, with the number of fractions, up to 6 fractions, after which saturation of the MEMRI signal intensity is reached. Open data points denote significantly higher signal intensity in manganese-injected rats compared with controls (P < .05).

Fig. 2.

Typical horizontal T₁-weighted MEMRI of a rat (A) and a marmoset (B) obtained 48 h after systemic administration of MnCl₂. The rat received a single 180 mg/kg MnCl₂ injection, while the marmoset received 4 fractionated injections of 30 mg/kg MnCl₂ in 48-h intervals. Excellent cytoarchitectonic contrast due to the presence of Mn²⁺ in regions such as the hippocampus (Hip), habenula (Hab), colliculus (Col), cerebellum (CEB), and olfactory bulb (OB). The high dose of administration in the rat allows Mn²⁺ to reveal layers in the OB and in the cortex of the rat (panel A, arrows). In the marmoset (panel B), strong enhancement is observed in the striatum (Str), which is consistent with similar patterns of T₁-weighted MRI enhancement in human patients after chronic overexposure to manganese. Strong enhancement occurs in the primate visual cortex (panel B, V1) that is not observed in the rat.

Fig. 3.

Schematic overview of the adult songbird brain showing the song control nuclei (SCN) and their connections in the telencephalon (top row, left panel). The black arrows represent the anterior forebrain pathway, which originates from the high vocal center (HVC) to area X, while the gray arrows represent the motor pathway, which originates in distinct cell populations within the HVC that project to the nucleus robustus archistriatalis (RA). Sagittal in vivo MEMRI of a male starling brain obtained 6 h after MnCl₂ injection into the HVC (top row, middle panel). The injection area is indicated by the gray arrow in the left panel and by the enhanced superficial area on the MEMRI. The lines indicate the different planes of imaging labeled (1), (2), and (3), which are displayed on the right panel in the top row and on the left and middle panels of the bottom row, respectively. The areas enhanced by Mn²⁺ are indicated in the MEMRI images. Adapted with permission of A. Van der Linden et al. Bottom row, right panel: Changes in the MEMRI relative signal intensity within the 2 song control nuclei (RA and area X) are plotted as a function of time and fitted by nonlinear regression to a sigmoid curve to describe the kinetics of Mn²⁺ accumulation in the RA (top graph) and in area X (bottom graph) and reflects the activity of the respective HVC neuron type. A faster uptake of Mn²⁺ was observed in both areas when the canary was allowed to listen to conspecific canary songs (COS+) while in the magnet relative to the control situation, without song stimulation (COS−). Adapted with permission of Tindemans et al.

Fig. 4.

(A) MEMRI of acute cocaine-induced brain activation. Activation maps are superimposed onto T₂-weighted MRI with corresponding rat brain atlas sections shown on the right. Activated voxels are clustered in the hemisphere with the BBB disrupted by hyperosmolar mannitol. The contralateral hemisphere had an intact BBB and did not show activation. Activated structures include olfactory cortex; medial, ventral, and lateral orbital cortex; pre-limbic cortex; cingulate cortex; nucleus accumbens (NAc), caudate putamen; ventral pallidus; external globus pallidus; agranular insular cortex; thalamus; hypothalamus; retrosplenial dysgranular cortex; hippocampus; and primary and secondary somatosensory and motor cortex. (B) Averaged MEMRI response time course in the NAc from animals receiving saline (n = 6) and 0.5 mg/kg (n = 5) and 2.0 mg/kg (n = 6) cocaine. All time courses were normalized to the baseline signal after bolus injection of mannitol, but before the injection of cocaine or saline. Adapted with permission of Lu et al.