Abstract
The use of manganese ions (Mn2+) as an MRI contrast agent was introduced over 20 years ago in studies of Mn2+ 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 Mn2+: (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 (Ca2+) analog that can enter excitable cells, such as neurons and cardiac cells via voltage-gated Ca2+ channels; and (3) once in the cells Mn2+ 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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
London, R. E., Toney, G., Gabel, S. A., Funk, A. Magnetic resonance imaging studies of the brains of anesthetized rats treated with manganese chloride. Brain Res Bull 1989;23:229–235.
Lin, Y. J., Koretsky, A. P. Manganese ion enhances T1-weighted MRI during brain activation: An approach to direct imaging of brain function. Magn Reson Med 1997;38:378–388.
Pautler, R. G., Silva, A. C., Koretsky, A. P. In vivo neuronal tract tracing using manganese-enhanced magnetic resonance imaging. Magn Reson Med 1998;40(5):740–748.
Santamaria, A. B. Manganese exposure, essentiality & toxicity. Indian J Med Res 2008;128:484–500.
Hurley, L. S., Keen, C. L. Manganese. In: Trace Elements in Human Health and Animal Nutrition, Underwood, E., Mertz, W. (eds.) New York, NY: Academic Press; 1987, pp 185–225.
Zwingmann, C., Leibfritz, D., Hazell, A. S. Brain energy metabolism in a sub-acute rat model of manganese neurotoxicity: An ex vivo nuclear magnetic resonance study using [1–13 c]glucose. Neurotoxicology 2004;25:573–587.
Patchett, M. L., Daniel, R. M., Morgan, H. W. Characterisation of arginase from the extreme thermophile ‘Bacillus caldovelox’. Biochim Biophys Acta 1991;1077:291–298.
Wedler, F. C., Denman, R. B. Glutamine synthetase: The major Mn(II) enzyme in mammalian brain. Curr Top Cell Regul 1984;24:153–169.
Keen, C. Nutritional and toxicological aspects of manganese intake: an overview. In: Risk Assessment of Essential Elements, Mertz W., Abernathy C., Olin S. (eds.) Washington, DC: ILSI Press; 1994.
Strause, L. G., Hegenauer, J., Saltman, P., Cone, R., Resnick, D. Effects of long-term dietary manganese and copper deficiency on rat skeleton. J Nutr 1986;116:135–141.
Friedman, B. J., Freeland-Graves, J. H., Bales, C. W., Behmardi, F., Shorey-Kutschke, R. L., Willis, R. A., Crosby, J. B., Trickett, P. C., Houston, S. D. Manganese balance and clinical observations in young men fed a manganese-deficient diet. J Nutr 1987;117:133–143.
Venugopal, B., Luckey, T. Metal Toxicity in Mammals. Chemical Toxicity of Metals and Metalloids. New York, NY: Plenum Press; 1978.
Aschner, M., Guilarte, T. R., Schneider, J. S., Zheng, W. Manganese: Recent advances in understanding its transport and neurotoxicity. Toxicol Appl Pharmacol 2007;221:131–147.
Crossgrove, J., Zheng, W. Manganese toxicity upon overexposure. NMR Biomed 2004;17:544–553.
Sloot, W. N., Gramsbergen, J. B. Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia. Brain Res 1994;657:124–132.
Takeda, A., Kodama, Y., Ishiwatari, S., Okada, S. Manganese transport in the neural circuit of rat CNS. Brain Res Bull 1998;45:149–152.
Tjälve, H., Mejà re, C., Borg-Neczak, K. Uptake and transport of manganese in primary and secondary olfactory neurones in pike. Pharmacol Toxicol 1995;77:23–31.
Takeda, A., Ishiwatari, S., Okada, S. In vivo stimulation-induced release of manganese in rat amygdala. Brain Res 1998;811:147–151.
Barbeau, A. Manganese and extrapyramidal disorders (a critical review and tribute to dr. George C. Cotzias). Neurotoxicology 1984;5:13–35.
Mena, I., Marin, O., Fuenzalida, S., Cotzias, G. C. Chronic manganese poisoning. Clinical picture and manganese turnover. Neurology 1967;17:128–136.
Finley, J. W. Manganese uptake and release by cultured human hepato-carcinoma (hep-G2) cells. Biol Trace Elem Res 1998;64:101–118.
Kerper, L. E., Hinkle, P. M. Cellular uptake of lead is activated by depletion of intracellular calcium stores. J Biol Chem 1997;272:8346–8352.
Mason, M. J., Mayer, B., Hymel, L. J. Inhibition of Ca2+ transport pathways in thymic lymphocytes by econazole, miconazole, and SKF 96365. Am J Physiol 1993;264:C654–C662.
Murphy, V. A., Smith, Q. R., Rapoport, S. I. Saturable transport of ca into CSF in chronic hypo- and hypercalcemia. J Neurosci Res 1991;30:421–426.
Takeda, A. Manganese action in brain function. Brain Res Brain Res Rev 2003;41:79–87.
Chance, B. The energy-linked reaction of calcium with mitochondria. J Biol Chem 1965;240:2729–2748.
Huang, C., Cheng, H., Lin, K., Cheng, J., Tsai, J., Liao, W., Fang, Y., Jan, C. Tamoxifen-induced [Ca2+]i rise and apoptosis in corneal epithelial cells. Toxicology 2009;255:58–64.
Tas, P. W. L., Stössel, C., Roewer, N. Inhibition of the histamine-induced Ca2+ influx in primary human endothelial cells (HUVEC) by volatile anaesthetics. Eur J Anaesthesiol 2008;25:976–985.
Merritt, J. E., Jacob, R., Hallam, T. J. Use of manganese to discriminate between calcium influx and mobilization from internal stores in stimulated human neutrophils. J Biol Chem 1989;264:1522–1527.
Narita, K., Kawasaki, F., Kita, H. Mn and Mg influxes through Ca channels of motor nerve terminals are prevented by verapamil in frogs. Brain Res 1990;510:289–295.
Simpson, P. B., Challiss, R. A., Nahorski, S. R. Divalent cation entry in cultured rat cerebellar granule cells measured using Mn2+ quench of fura 2 fluorescence. Eur J Neurosci 1995;7:831–840.
Cory, D. A., Schwartzentruber, D. J., Mock, B. H. Ingested manganese chloride as a contrast agent for magnetic resonance imaging. Magn Reson Imaging 1987;5:65–70.
Geraldes, C. F., Sherry, A. D., Brown, R. D., Koenig, S. H. Magnetic field dependence of solvent proton relaxation rates induced by Gd3+ and Mn2+ complexes of various polyaza macrocyclic ligands: implications for NMR imaging. Magn Reson Med 1986;3:242–250.
Fornasiero, D., Bellen, J. C., Baker, R. J., Chatterton, B. E. Paramagnetic complexes of manganese(II), iron(III), and gadolinium(III) as contrast agents for magnetic resonance imaging. The influence of stability constants on the biodistribution of radioactive aminopolycarboxylate complexes. Invest Radiol 1987;22:322–327.
Mendonça-Dias, M. H., Gaggelli, E., Lauterbur, P. C. Paramagnetic contrast agents in nuclear magnetic resonance medical imaging. Semin Nucl Med 1983;13:364–376.
Pautler, R. G. Biological applications of manganese-enhanced magnetic resonance imaging. Methods Mol Med 2006;124:365–386.
Silva, A. C., Lee, J. H., Aoki, I., Koretsky, A. P. Manganese-enhanced magnetic resonance imaging (MEMRI): Methodological and practical considerations. NMR Biomed 2004;17:532–543.
Natt, O., Watanabe, T., Boretius, S., Radulovic, J., Frahm, J., Michaelis, T. High-resolution 3D MRI of mouse brain reveals small cerebral structures in vivo. J. Neurosci Methods 2002;120:203–209.
Watanabe, T., Natt, O., Boretius, S., Frahm, J., Michaelis, T. In vivo 3D MRI staining of mouse brain after subcutaneous application of MnCl2. Magn Reson Med 2002;48:852–859.
Watanabe, T., Radulovic, J., Spiess, J., Natt, O., Boretius, S., Frahm, J., Michaelis, T. In vivo 3D MRI staining of the mouse hippocampal system using intracerebral injection of MnCl2. Neuroimage 2004;22:860–867.
Watanabe, T., Radulovic, J., Boretius, S., Frahm, J., Michaelis, T. Mapping of the habenulo-interpeduncular pathway in living mice using manganese-enhanced 3D MRI. Magn Reson Imaging 2006;24:209–215.
Bock, N. A., Paiva, F. F., Nascimento, G. C., Newman, J. D., Silva, A. C. Cerebrospinal fluid to brain transport of manganese in a non-human primate revealed by MRI. Brain Res 2008;1198:160–170.
Silva, A. C., Lee, J. H., Wu, C. W., Tucciarone, J., Pelled, G., Aoki, I., Koretsky, A. P. Detection of cortical laminar architecture using manganese-enhanced MRI. J Neurosci Methods 2008;167:246–257.
Aoki, I., Wu, Y. L., Silva, A. C., Lynch, R. M., Koretsky, A. P. In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI. Neuroimage 2004;22:1046–1059.
Deans, A. E., Wadghiri, Y. Z., Berrios-Otero, C. A., Turnbull, D. H. Mn enhancement and respiratory gating for in utero MRI of the embryonic mouse central nervous system. Magn Reson Med 2008;59:1320–1328.
Duong, T. Q., Silva, A. C., Lee, S. P., Kim, S. G. Functional MRI of calcium-dependent synaptic activity: Cross correlation with CBF and BOLD measurements. Magn Reson Med 2000;43:383–392.
Aoki, I., Tanaka, C., Takegami, T., Ebisu, T., Umeda, M., Fukunaga, M., Fukuda, K., Silva, A. C., Koretsky, A. P., Naruse, S. Dynamic activity-induced manganese-dependent contrast magnetic resonance imaging (DAIM MRI). Magn Reson Med 2002;48:927–933.
Yu, X., Wadghiri, Y. Z., Sanes, D. H., Turnbull, D. H. In vivo auditory brain mapping in mice with Mn-enhanced MRI. Nat Neurosci 2005;8(7):961–968.
Parkinson, J. R. C., Chaudhri, O. B., Bell, J. D. Imaging appetite-regulating pathways in the central nervous system using manganese-enhanced magnetic resonance imaging. Neuroendocrinology 2009;89:121–130.
Weng, J., Chen, J., Yang, P., Tseng, W. I. Functional mapping of rat barrel activation following whisker stimulation using activity-induced manganese-dependent contrast. Neuroimage 2007;36:1179–1188.
Lu, H., Xi, Z., Gitajn, L., Rea, W., Yang, Y., Stein, E. A. Cocaine-induced brain activation detected by dynamic manganese-enhanced magnetic resonance imaging (MEMRI). Proc Natl Acad Sci USA 2007;104:2489–2494.
Chuang, K., Lee, J. H., Silva, A. C., Belluscio, L., Koretsky, A. P. Manganese enhanced MRI reveals functional circuitry in response to odorant stimuli. Neuroimage 2009;44:363–372.
Wendland, M. F. Applications of manganese-enhanced magnetic resonance imaging (MEMRI) to imaging of the heart. NMR Biomed 2004;17:581–594.
Murayama, Y., Weber, B., Saleem, K. S., Augath, M., Logothetis, N. K. Tracing neural circuits in vivo with Mn-enhanced MRI. Magn Reson Imaging 2006;24:349–358.
Saleem, K. S., Pauls, J. M., Augath, M., Trinath, T., Prause, B. A., Hashikawa, T., Logothetis, N. K. Magnetic resonance imaging of neuronal connections in the macaque monkey. Neuron 2002;34:685–700.
Tindemans, I., Verhoye, M., Balthazart, J., Van Der Linden, A. In vivo dynamic ME-MRI reveals differential functional responses of RA- and area X-projecting neurons in the HVC of canaries exposed to conspecific song. Eur J Neurosci 2003;18:3352–3360.
Van der Linden, A., Verhoye, M., Van Meir, V., Tindemans, I., Eens, M., Absil, P., Balthazart, J. In vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system. Neuroscience 2002;112:467–474.
Van der Linden, A., Van Meir, V., Tindemans, I., Verhoye, M., Balthazart, J. Applications of manganese-enhanced magnetic resonance imaging (MEMRI) to image brain plasticity in song birds. NMR Biomed 2004;17:602–612.
Van Meir, V., Verhoye, M., Absil, P., Eens, M., Balthazart, J., Van der Linden, A. Differential effects of testosterone on neuronal populations and their connections in a sensorimotor brain nucleus controlling song production in songbirds: A manganese enhanced-magnetic resonance imaging study. Neuroimage 2004;21:914–923.
Pautler, R. G. In vivo, trans-synaptic tract-tracing utilizing manganese-enhanced magnetic resonance imaging (MEMRI). NMR Biomed 2004;17:595–601.
Pautler, R. G., Koretsky, A. P. Tracing odor-induced activation in the olfactory bulbs of mice using manganese-enhanced magnetic resonance imaging. Neuroimage 2002;16:441–448.
Watanabe, T., Michaelis, T., Frahm, J. Mapping of retinal projections in the living rat using high-resolution 3D gradient-echo MRI with Mn2+-induced contrast. Magn Reson Med 2001;46(3):424–429.
Lee, J., Park, J., Lee, J., Bae, S., Lee, S., Jung, J., Kim, M., Lee, J., Woo, S., Chang, Y. Manganese-enhanced auditory tract-tracing MRI with cochlear injection. Magn Reson Imaging 2007;25:652–656.
Serrano, F., Deshazer, M., Smith, K. D. B., Ananta, J. S., Wilson, L. J., Pautler, R. G. Assessing transneuronal dysfunction utilizing manganese-enhanced MRI (MEMRI). Magn Reson Med 2008;60:169–175.
Smith, K. D. B., Kallhoff, V., Zheng, H., Pautler, R. G. In vivo axonal transport rates decrease in a mouse model of alzheimer’s disease. Neuroimage 2007;35:1401–1408.
Aoki, I., Naruse, S., Tanaka, C. Manganese-enhanced magnetic resonance imaging (MEMRI) of brain activity and applications to early detection of brain ischemia. NMR Biomed 2004;17:569–580.
Kidoguchi, K., Tamaki, M., Mizobe, T., Koyama, J., Kondoh, T., Kohmura, E., Sakurai, T., Yokono, K., Umetani, K. In vivo X-ray angiography in the mouse brain using synchrotron radiation. Stroke 2006;37:1856–1861.
Zhao, X., Wu, N., Deng, M., Yin, Y., Zhou, J., Fang, Y., Huang, L. An improved method of left ventricular catheterization in rats. Physiol Meas 2006;27:N27–N33.
Brown, R. H., Walters, D. M., Greenberg, R. S., Mitzner, W. A method of endotracheal intubation and pulmonary functional assessment for repeated studies in mice. J Appl Physiol 1999;87:2362–2365.
Bissig, D., Berkowitz, B. A. Manganese-enhanced MRI of layer-specific activity in the visual cortex from awake and free-moving rats. Neuroimage 2009;44:627–635.
Pautler, R. G., Mongeau, R., Jacobs, R. E. In vivo trans-synaptic tract tracing from the murine striatum and amygdala utilizing manganese enhanced MRI (MEMRI). Magn Reson Med 2003;50:33–39.
Watanabe, T., Frahm, J., Michaelis, T. Functional mapping of neural pathways in rodent brain in vivo using manganese-enhanced three-dimensional magnetic resonance imaging. NMR Biomed 2004;17:554–568.
Burnett, K. R., Goldstein, E. J., Wolf, G. L., Sen, S., Mamourian, A. C. The oral administration of MnCl2: A potential alternative to IV injection for tissue contrast enhancement in magnetic resonance imaging. Magn Reson Imaging 1984;2:307–314.
Kita, H., Narita, K., Van der Kloot, W. Tetanic stimulation increases the frequency of miniature end-plate potentials at the frog neuromuscular junction in Mn2+-, CO2+-, and Ni2+-saline solutions. Brain Res 1981;205:111–121.
Drapeau, P., Nachshen, D. A. Manganese fluxes and manganese-dependent neurotransmitter release in presynaptic nerve endings isolated from rat brain. J Physiol (Lond) 1984;348:493–510.
Rabin, O., Hegedus, L., Bourre, J. M., Smith, Q. R. Rapid brain uptake of manganese(II) across the blood-brain barrier. J Neurochem 1993;61:509–517.
Murphy, V. A., Rosenberg, J. M., Smith, Q. R., Rapoport, S. I. Elevation of brain manganese in calcium-deficient rats. Neurotoxicology 1991;12:255–263.
Yu, X., Sanes, D. H., Aristizabal, O., Wadghiri, Y. Z., Turnbull, D. H. Large-scale reorganization of the tonotopic map in mouse auditory midbrain revealed by MRI. Proc Natl Acad Sci USA 2007;104:12193–12198.
Yu, X., Zou, J., Babb, J. S., Johnson, G., Sanes, D. H., Turnbull, D. H. Statistical mapping of sound-evoked activity in the mouse auditory midbrain using Mn-enhanced MRI. Neuroimage 2008;39:223–230.
Berkowitz, B. A., Gradianu, M., Bissig, D., Kern, T. S., Roberts, R. Retinal ion regulation in a mouse model of diabetic retinopathy: Natural history and the effect of Cu/Zn superoxide dismutase overexpression. Invest Ophthalmol Vis Sci 2009;50:2351–2358.
Hu, T. C., Pautler, R. G., MacGowan, G. A., Koretsky, A. P. Manganese-enhanced MRI of mouse heart during changes in inotropy. Magn Reson Med 2001;46:884–890.
Lee, J. H., Silva, A. C., Merkle, H., Koretsky, A. P. Manganese-enhanced magnetic resonance imaging of mouse brain after systemic administration of MnCl2: Dose-dependent and temporal evolution of T1 contrast. Magn Reson Med 2005;53:640–648.
Bock, N. A., Kocharyan, A., Silva, A. C. Manganese-enhanced MRI visualizes V1 in the non-human primate visual cortex. NMR Biomed 2009, Available at: http://www.ncbi.nlm.nih.gov/pubmed/19322808 [Accessed July 21, 2009].
Federle, M. P., Chezmar, J. L., Rubin, D. L., Weinreb, J. C., Freeny, P. C., Semelka, R. C., Brown, J. J., Borello, J. A., Lee, J. K., Mattrey, R., Dachman, A. H., Saini, S., Harmon, B., Fenstermacher, M., Pelsang, R. E., Harms, S. E., Mitchell, D. G., Halford, H. H., Anderson, M. W., Johnson, C. D., Francis, I. R., Bova, J. G., Kenney, P. J., Klippenstein, D. L., Foster, G. S., Turner, D. A. Safety and efficacy of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: Results of the U.S. multicenter phase III clinical trials (safety). J Magn Reson Imaging 2000;12:186–197.
Wolf, G. L., Baum, L. Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dog and rabbit. AJR Am J Roentgenol 1983;141:193–197.
Storey, P., Chen, Q., Li, W., Seoane, P. R., Harnish, P. P., Fogelson, L., Harris, K. R., Prasad, P. V. Magnetic resonance imaging of myocardial infarction using a manganese-based contrast agent (EVP 1001-1): Preliminary results in a dog model. J Magn Reson Imaging 2006;23:228–234.
Storey, P., Danias, P. G., Post, M., Li, W., Seoane, P. R., Harnish, P. P., Edelman, R. R., Prasad, P. V. Preliminary evaluation of EVP 1001-1: A new cardiac-specific magnetic resonance contrast agent with kinetics suitable for steady-state imaging of the ischemic heart. Invest Radiol 2003;38:642–652.
Zuo, C. S., Seoane, P., Lanigan, T., Harnish, P., Prasad, P. V., Storey, P., Li, W., Rofsky, N. M. T1 efficacy of EVP-ABD: A potential manganese-based MR contrast agent for hepatic vascular and tissue phase imaging. J Magn Reson Imaging 2002;16:668–675.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Massaad, C.A., Pautler, R.G. (2011). Manganese-Enhanced Magnetic Resonance Imaging (MEMRI). In: Modo, M., Bulte, J. (eds) Magnetic Resonance Neuroimaging. Methods in Molecular Biology, vol 711. Humana Press. https://doi.org/10.1007/978-1-61737-992-5_7
Download citation
DOI: https://doi.org/10.1007/978-1-61737-992-5_7
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-61737-991-8
Online ISBN: 978-1-61737-992-5
eBook Packages: Springer Protocols