Manganese-Enhanced MRI: Biological Applications in Neuroscience

Magnetic resonance imaging (MRI) is an excellent non-invasive tool to investigate biological systems. The administration of the paramagnetic divalent ion manganese (Mn2+) enhances MRI contrast in vivo. Due to similarities between Mn2+ and calcium (Ca2+), the premise of manganese-enhanced MRI (MEMRI) is that the former may enter neurons and other excitable cells through voltage-gated Ca2+ channels. As such, MEMRI has been used to trace neuronal pathways, define morphological boundaries, and study connectivity in morphological and functional imaging studies. In this article, we provide a brief overview of MEMRI and discuss recently published data to illustrate the usefulness of this method, particularly in animal models.

[1]  Ruxiang Xu,et al.  Activity-induced manganese-dependent functional MRI of the rat visual cortex following intranasal manganese chloride administration , 2010, Neuroscience Letters.

[2]  L. Gamarra,et al.  In vivo magnetic resonance imaging tracking of C6 glioma cells labeled with superparamagnetic iron oxide nanoparticles. , 2012, Einstein.

[3]  James R C Parkinson,et al.  Imaging Appetite-Regulating Pathways in the Central Nervous System Using Manganese-Enhanced Magnetic Resonance Imaging , 2008, Neuroendocrinology.

[4]  Mathias V. Schmidt,et al.  Fractionated manganese injections: effects on MRI contrast enhancement and physiological measures in C57BL/6 mice , 2010, NMR in biomedicine.

[5]  C. Sotak,et al.  Dose dependence and temporal evolution of the T1 relaxation time and MRI contrast in the rat brain after subcutaneous injection of manganese chloride , 2012, Magnetic resonance in medicine.

[6]  L. Covolan,et al.  Manganese-enhanced magnetic resonance imaging in the acute phase of the pilocarpine-induced model of epilepsy. , 2012, Einstein.

[7]  Terence J O'Brien,et al.  Confounding neurodegenerative effects of manganese for in vivo MR imaging in rat models of brain insults , 2011, Journal of magnetic resonance imaging : JMRI.

[8]  R. Pautler,et al.  In vivo axonal transport deficits in a mouse model of fronto-temporal dementia , 2014, NeuroImage: Clinical.

[9]  L. Covolan,et al.  Assessment of the progressive nature of cell damage in the pilocarpine model of epilepsy. , 2006, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[10]  A. Barbeau,et al.  Manganese and extrapyramidal disorders (a critical review and tribute to Dr. George C. Cotzias). , 1984, Neurotoxicology.

[11]  J. Frahm,et al.  High-resolution 3D MRI of mouse brain reveals small cerebral structures in vivo , 2002, Journal of Neuroscience Methods.

[12]  Shoji Naruse,et al.  Manganese‐enhanced magnetic resonance imaging (MEMRI) of brain activity and applications to early detection of brain ischemia , 2004, NMR in biomedicine.

[13]  M. Calcagnotto,et al.  Modeling epileptogenesis and temporal lobe epilepsy in a non-human primate , 2011, Epilepsy Research.

[14]  W. Feindel,et al.  Entorhinal cortex in temporal lobe epilepsy , 1999, Neurology.

[15]  Robert E. London,et al.  Magnetic resonance imaging studies of the brains of anesthetized rats treated with manganese chloride , 1989, Brain Research Bulletin.

[16]  Neda Bernasconi,et al.  T2 Relaxometry Can Lateralize Mesial Temporal Lobe Epilepsy in Patients with Normal MRI , 2000, NeuroImage.

[17]  Jens Frahm,et al.  Manganese-enhanced magnetic resonance imaging. , 2011, Methods in molecular biology.

[18]  Shu-Leong Ho,et al.  Manganese‐enhanced MRI detection of neurodegeneration in neonatal hypoxic‐ischemic cerebral injury , 2008, Magnetic resonance in medicine.

[19]  Kurt Wüthrich,et al.  NMR studies of structure and function of biological macromolecules (Nobel Lecture)* , 2003, Journal of biomolecular NMR.

[20]  Magnetic resonance contrast media: principles and progress. , 1990, Magnetic resonance quarterly.

[21]  Y. Ben-Ari,et al.  Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy , 1985, Neuroscience.

[22]  Jyh-Horng Chen,et al.  Repeated amphetamine treatment alters spinal magnetic resonance signals and pain sensitivity in mice , 2014, Neuroscience Letters.

[23]  P. Carlier,et al.  Dmdmdx/Largemyd: a new mouse model of neuromuscular diseases useful for studying physiopathological mechanisms and testing therapies , 2013, Disease Models & Mechanisms.

[24]  T. Videen,et al.  [18F]FDOPA PET and clinical features in parkinsonism due to manganism , 2005, Movement disorders : official journal of the Movement Disorder Society.

[25]  Jyh-Horng Chen,et al.  Functional tracing of medial nociceptive pathways using activity-dependent manganese-enhanced MRI , 2011, PAIN®.

[26]  L. Covolan,et al.  Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: Edema or apoptosis? , 2014, Epilepsy Research.

[27]  R. Connick,et al.  Effect of Paramagnetic Ions on the Nuclear Magnetic Resonance of O17 in Water and the Rate of Elimination of Water Molecules from the First Coordination Sphere of Cations , 1959 .

[28]  Xin Yu,et al.  Statistical mapping of sound-evoked activity in the mouse auditory midbrain using Mn-enhanced MRI , 2008, NeuroImage.

[29]  E. Wu,et al.  Manganese-enhanced MRI detected the gray matter lesions in the late phase of mild hypoxic-ischemic injury in neonatal rat , 2007, 2007 29th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[30]  E. A. Waters,et al.  Contrast agents for MRI , 2008, Basic Research in Cardiology.

[31]  Alejandra Sierra,et al.  Manganese enhanced MRI detects mossy fiber sprouting rather than neurodegeneration, gliosis or seizure-activity in the epileptic rat hippocampus , 2008, NeuroImage.

[32]  C. Hamani,et al.  Changes in Hippocampal Volume are Correlated with Cell Loss but Not with Seizure Frequency in Two Chronic Models of Temporal Lobe Epilepsy , 2014, Front. Neurol..

[33]  Ichio Aoki,et al.  Manganese‐enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations , 2004, NMR in biomedicine.

[34]  Luiz E. A. M. Mello,et al.  Spontaneous seizures preferentially injure interneurons in the pilocarpine model of chronic spontaneous seizures , 1996, Epilepsy Research.

[35]  L. Covolan,et al.  Long-term gender behavioral vulnerability after nociceptive neonatal formalin stimulation in rats , 2011, Neuroscience Letters.

[36]  Alan Jasanoff,et al.  MRI contrast agents for functional molecular imaging of brain activity , 2007, Current Opinion in Neurobiology.

[37]  M. Verhoye,et al.  Applications of manganese‐enhanced magnetic resonance imaging (MEMRI) to image brain plasticity in song birds , 2004, NMR in biomedicine.

[38]  R. Demeure,et al.  Non invasive quantification of manganese deposits in the rat brain by local measurement of NMR proton T1 relaxation times. , 2001, Neurotoxicology.

[39]  Yanjun Zeng,et al.  Functional mapping of rat brain activation following rTMS using activity-induced manganese-dependent contrast , 2011, Neurological research.

[40]  L. Covolan,et al.  Neonatal inflammatory pain increases hippocampal neurogenesis in rat pups , 2011, Neuroscience Letters.

[41]  O. Wu,et al.  In vivo 1H magnetic resonance spectroscopy, T2-weighted and diffusion-weighted MRI during lithium–pilocarpine-induced status epilepticus in the rat , 2004, Brain Research.

[42]  John D. Newman,et al.  Cerebrospinal fluid to brain transport of manganese in a non-human primate revealed by MRI , 2008, Brain Research.

[43]  B S Larsson,et al.  Uptake of manganese and cadmium from the nasal mucosa into the central nervous system via olfactory pathways in rats. , 1996, Pharmacology & toxicology.

[44]  Takashi Ogino,et al.  Detection of hypothalamic activation by manganese ion contrasted T1-weighted magnetic resonance imaging in rats , 2002, Neuroscience Letters.

[45]  Yihong Yang,et al.  Cocaine-induced brain activation detected by dynamic manganese-enhanced magnetic resonance imaging (MEMRI) , 2007, Proceedings of the National Academy of Sciences.

[46]  J. Freeland-Graves,et al.  Manganese balance and clinical observations in young men fed a manganese-deficient diet. , 1987, The Journal of nutrition.

[47]  Kai-Hsiang Chuang,et al.  Temporal changes in the T1 and T2 relaxation rates (ΔR1 and ΔR2) in the rat brain are consistent with the tissue‐clearance rates of elemental manganese , 2009, Magnetic resonance in medicine.

[48]  David Bissig,et al.  Manganese-enhanced MRI of layer-specific activity in the visual cortex from awake and free-moving rats , 2009, NeuroImage.

[49]  Yusuke Murayama,et al.  Tracing neural circuits in vivo with Mn-enhanced MRI. , 2006, Magnetic resonance imaging.

[50]  T. Dresselaers,et al.  Evaluation of manganese uptake and toxicity in mouse brain during continuous MnCl2 administration using osmotic pumps. , 2012, Contrast media & molecular imaging.

[51]  David Bissig,et al.  Retinal ion regulation in a mouse model of diabetic retinopathy: natural history and the effect of Cu/Zn superoxide dismutase overexpression. , 2009, Investigative ophthalmology & visual science.

[52]  H. Tjälve,et al.  Uptake and transport of manganese in primary and secondary olfactory neurones in pike. , 1995, Pharmacology & toxicology.

[53]  C. C. Johnson,et al.  Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease. , 1999, Neurotoxicology.

[54]  M. Fukunaga,et al.  Dynamic activity‐induced manganese‐dependent contrast magnetic resonance imaging (DAIM MRI) , 2002, Magnetic resonance in medicine.

[55]  P. Lauterbur,et al.  Image Formation by Induced Local Interactions: Examples Employing Nuclear Magnetic Resonance , 1973, Nature.

[56]  Robert A Yokel,et al.  Manganese distribution across the blood-brain barrier III. The divalent metal transporter-1 is not the major mechanism mediating brain manganese uptake. , 2004, Neurotoxicology.

[57]  Robia G. Pautler,et al.  Manganese enhanced MRI (MEMRI): neurophysiological applications , 2011, Reviews in the neurosciences.

[58]  Oliver Natt,et al.  In vivo 3D MRI staining of the mouse hippocampal system using intracerebral injection of MnCl2 , 2004, NeuroImage.

[59]  R. Pautler.  In vivo, trans‐synaptic tract‐tracing utilizing manganese‐enhanced magnetic resonance imaging (MEMRI) , 2004, NMR in biomedicine.

[60]  Kai-Hsiang Chuang,et al.  Improved neuronal tract tracing using manganese enhanced magnetic resonance imaging with fast T1 mapping , 2006, Magnetic resonance in medicine.

[61]  Q R Smith,et al.  Rapid Brain Uptake of Manganese(II) Across the Blood‐Brain Barrier , 1993, Journal of neurochemistry.

[62]  Yusuke Murayama,et al.  Magnetic resonance imaging of cortical connectivity in vivo , 2008, NeuroImage.

[63]  Luisa Ciobanu,et al.  Central neural activity in rats with tinnitus evaluated with manganese-enhanced magnetic resonance imaging (MEMRI) , 2007, Hearing Research.

[64]  Kai-Hsiang Chuang,et al.  Accounting for nonspecific enhancement in neuronal tract tracing using manganese enhanced magnetic resonance imaging. , 2009, Magnetic resonance imaging.

[65]  D. Turnbull,et al.  In vivo auditory brain mapping in mice with Mn-enhanced MRI , 2005, Nature Neuroscience.

[66]  Afonso C. Silva,et al.  Fractionated manganese‐enhanced MRI , 2008, NMR in biomedicine.

[67]  Z. Bortolotto,et al.  Seizures produced by pilocarpine in mice: A behavioral, electroencephalographic and morphological analysis , 1984, Brain Research.

[68]  H. D'Arceuil,et al.  Direct CSF injection of MnCl2 for dynamic manganese‐enhanced MRI , 2004, Magnetic resonance in medicine.

[69]  J. Frahm,et al.  Mapping of the habenulo-interpeduncular pathway in living mice using manganese-enhanced 3D MRI. , 2006, Magnetic Resonance Imaging.

[70]  Jens Frahm,et al.  Functional mapping of neural pathways in rodent brain in vivo using manganese‐enhanced three‐dimensional magnetic resonance imaging , 2004, NMR in biomedicine.

[71]  Floris G. Wouterlood,et al.  A half century of experimental neuroanatomical tracing , 2011, Journal of Chemical Neuroanatomy.

[72]  D. Riche,et al.  Long-term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures. , 1982, Electroencephalography and clinical neurophysiology.

[73]  W. Sloot,et al.  Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia , 1994, Brain Research.

[74]  Irina Simanova,et al.  Behavioral, electrophysiological and histopathological consequences of systemic manganese administration in MEMRI. , 2010, Magnetic resonance imaging.

[75]  L. Covolan,et al.  Repetitive Nociceptive Stimuli in Newborn Rats Do Not Alter the Hippocampal Neurogenesis , 2008, Pediatric Research.

[76]  Alan P. Koretsky,et al.  Tracing Odor-Induced Activation in the Olfactory Bulbs of Mice Using Manganese-Enhanced Magnetic Resonance Imaging , 2002, NeuroImage.

[77]  Ian Marshall,et al.  Manganese-enhanced magnetic resonance imaging (MEMRI) of rat brain after systemic administration of MnCl2: Hippocampal signal enhancement without disruption of hippocampus-dependent behavior , 2011, Behavioural Brain Research.

[78]  Jens Frahm,et al.  In vivo 3D MRI staining of mouse brain after subcutaneous application of MnCl2 , 2002, Magnetic resonance in medicine.

[79]  T. Babb,et al.  Circuit Mechanisms of Seizures in the Pilocarpine Model of Chronic Epilepsy: Cell Loss and Mossy Fiber Sprouting , 1993, Epilepsia.

[80]  Hellmut Merkle,et al.  Manganese‐enhanced magnetic resonance imaging of mouse brain after systemic administration of MnCl2: Dose‐dependent and temporal evolution of T1 contrast , 2005, Magnetic resonance in medicine.

[81]  Yusuke Murayama,et al.  Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies , 2010, NeuroImage.

[82]  R. Lauffer,et al.  Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications. , 1999, Chemical reviews.

[83]  R. Jacobs,et al.  In vivo trans‐synaptic tract tracing from the murine striatum and amygdala utilizing manganese enhanced MRI (MEMRI) , 2003, Magnetic resonance in medicine.

[84]  Hui Zheng,et al.  In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease , 2007, NeuroImage.

[85]  Asla Pitkänen,et al.  Progression of Brain Damage after Status Epilepticus and Its Association with Epileptogenesis: A Quantitative MRI Study in a Rat Model of Temporal Lobe Epilepsy , 2004, Epilepsia.

[86]  Jon Skranes,et al.  Manganese-enhanced magnetic resonance imaging of hypoxic–ischemic brain injury in the neonatal rat , 2009, NeuroImage.

[87]  L. Covolan,et al.  Behavioral characterization of pentylenetetrazol-induced seizures in the marmoset , 2008, Epilepsy & Behavior.

[88]  Gary F. Egan,et al.  Manganese-enhanced MRI reflects seizure outcome in a model for mesial temporal lobe epilepsy , 2013, NeuroImage.

[89]  J. Frahm,et al.  Mapping of retinal projections in the living rat using high‐resolution 3D gradient‐echo MRI with Mn2+‐induced contrast , 2001, Magnetic resonance in medicine.

[90]  A. Koretsky,et al.  Manganese ion enhances T1‐weighted MRI during brain activation: An approach to direct imaging of brain function , 1997, Magnetic resonance in medicine.

[91]  Bianca Jupp,et al.  Hippocampal T2 Signal Change during Amygdala Kindling Epileptogenesis , 2006, Epilepsia.

[92]  Asla Pitkänen,et al.  Status Epilepticus in 12‐day‐old Rats Leads to Temporal Lobe Neurodegeneration and Volume Reduction: A Histologic and MRI Study , 2006, Epilepsia.

[93]  Rick M. Dijkhuizen,et al.  Changes in neuronal connectivity after stroke in rats as studied by serial manganese-enhanced MRI , 2007, NeuroImage.

[94]  M. Czisch,et al.  Regional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese‐enhanced MRI , 2013, NMR in biomedicine.

[95]  M. Verhoye,et al.  In vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system , 2002, Neuroscience.

[96]  Alan P. Koretsky,et al.  Is there a path beyond BOLD? Molecular imaging of brain function , 2012, NeuroImage.

[97]  Afonso C. Silva,et al.  In vivo neuronal tract tracing using manganese‐enhanced magnetic resonance imaging , 1998, Magnetic resonance in medicine.

[98]  G L Wolf,et al.  Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dog and rabbit. , 1983, AJR. American journal of roentgenology.

[99]  P. Gloor,et al.  MRI volumetric measurement of amygdala and hippocampus in temporal lobe epilepsy , 1993, Neurology.

[100]  Jimmy D Bell,et al.  In vivo measurements of T1 relaxation times in mouse brain associated with different modes of systemic administration of manganese chloride , 2005, Journal of magnetic resonance imaging : JMRI.

[101]  Z. Bortolotto,et al.  Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: A novel experimental model of intractable epilepsy , 1989, Synapse.

[102]  Hagai Bergman,et al.  Manganese‐enhanced MRI in a rat model of Parkinson's disease , 2007, Journal of magnetic resonance imaging : JMRI.

[103]  Uwe Karst,et al.  Impact of Manganese on and Transfer across Blood-Brain and Blood-Cerebrospinal Fluid Barrier in Vitro* , 2012, The Journal of Biological Chemistry.

[104]  Z. Bortolotto,et al.  Spontaneous recurrent seizures in rats: An experimental model of partial epilepsy , 1990, Neuroscience & Biobehavioral Reviews.

[105]  M. Maier.  Quantitative MRI of the brain—measuring changes caused by disease , 2004 .

[106]  Atsushi Takeda,et al.  Manganese action in brain function , 2003, Brain Research Reviews.

[107]  Shoji Okada,et al.  Biological half-lives of zinc and manganese in rat brain , 1995, Brain Research.

[108]  Annemarie van der Linden,et al.  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 , 2004, NeuroImage.

[109]  S. Gabriel,et al.  Systematic Review of the Literature , 2021, Adherence to Antiretroviral Therapy among Perinatal Women in Guyana.

[110]  Afonso C. Silva,et al.  Using manganese-enhanced MRI to understand BOLD , 2012, NeuroImage.

[111]  Wei Zheng,et al.  Manganese toxicity upon overexposure , 2004, NMR in biomedicine.

[112]  J C Gore,et al.  Studies of tissue NMR relaxation enhancement by manganese. Dose and time dependences. , 1984, Investigative radiology.

[113]  Orhan Nalcioglu,et al.  Serial MRI after experimental febrile seizures: Altered T2 signal without neuronal death , 2004, Annals of neurology.

[114]  S. Rapoport,et al.  Saturable Transport of Manganese(II) Across the Rat Blood‐Brain Barrier , 1991, Journal of neurochemistry.

[115]  Seong-Gi Kim,et al.  Functional MRI of calcium‐dependent synaptic activity: Cross correlation with CBF and BOLD measurements , 2000, Magnetic resonance in medicine.

[116]  Satya V. Chandra,et al.  Role of iron deficiency in inducing susceptibility to manganese toxicity , 1976, Archives of Toxicology.

[117]  Hong Qu,et al.  In vivo mapping of temporospatial changes in manganese enhancement in rat brain during epileptogenesis , 2007, NeuroImage.

[118]  Yoshimi Anzai,et al.  Age-related decrease in axonal transport measured by MR imaging in vivo , 2008, NeuroImage.

[119]  Nicholas A Bock,et al.  Manganese-enhanced MRI: an exceptional tool in translational neuroimaging. , 2007, Schizophrenia bulletin.

[120]  R. Pautler,et al.  Hyperglycemia Induces Oxidative Stress and Impairs Axonal Transport Rates in Mice , 2010, PloS one.

[121]  Ichio Aoki,et al.  In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI , 2004, NeuroImage.

[122]  L. Covolan,et al.  Sex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats , 2014, Neuropharmacology.

[123]  F C Wedler,et al.  Glutamine synthetase: the major Mn(II) enzyme in mammalian brain. , 1984, Current topics in cellular regulation.

[124]  B. Mcewen,et al.  Volumetric structural magnetic resonance imaging (MRI) of the rat hippocampus following kainic acid (KA) treatment , 2002, Brain Research.

[125]  Anne H. Cross,et al.  Axonal transport rate decreased at the onset of optic neuritis in EAE mice , 2014, NeuroImage.

[126]  M. Frotscher,et al.  Retrograde tracing with Fluoro-Gold: different methods of tracer detection at the ultrastructural level and neurodegenerative changes of back-filled neurons in long-term studies , 2000, Journal of Neuroscience Methods.

[127]  Janelle S. Crossgrove,et al.  Manganese distribution across the blood-brain barrier. IV. Evidence for brain influx through store-operated calcium channels. , 2005, Neurotoxicology.

[128]  Jian Yang,et al.  Detection of cortical gray matter lesion in the late phase of mild hypoxic–ischemic injury by manganese-enhanced MRI , 2008, NeuroImage.

[129]  Robert A Yokel,et al.  Manganese distribution across the blood-brain barrier. I. Evidence for carrier-mediated influx of managanese citrate as well as manganese and manganese transferrin. , 2003, Neurotoxicology.

[130]  A. Sherry,et al.  The importance of water exchange rates in the design of responsive agents for MRI. , 2013, Current opinion in chemical biology.

[131]  Angelo Bifone,et al.  Manganese-enhanced magnetic resonance imaging investigation of the interferon-α model of depression in rats. , 2014, Magnetic resonance imaging.

[132]  M. Aschner,et al.  Manganese Neurotoxicity , 2004, Annals of the New York Academy of Sciences.

[133]  C. Marescaux,et al.  Magnetic Resonance Imaging Follow‐up of Progressive Hippocampal Changes in a Mouse Model of Mesial Temporal Lobe Epilepsy , 2000, Epilepsia.

[134]  Keun-Yeong Jeong,et al.  Investigation of the pruritus‐induced functional activity in the rat brain using manganese‐enhanced MRI , 2015, Journal of magnetic resonance imaging : JMRI.

[135]  R. González-Reyes,et al.  Manganese and epilepsy: A systematic review of the literature , 2007, Brain Research Reviews.

[136]  E. Barbier,et al.  Impact of manganese on primary hippocampal neurons from rodents , 2014, Hippocampus.

[137]  R. Haworth,et al.  Comparison of Ca2+, Sr2+, and Mn2+ fluxes in mitochondria of the perfused rat heart. , 1980, Circulation research.