Abstract
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.
Introduction
Magnetic resonance imaging (MRI) is an excellent non-invasive tool for providing anatomical information of biological systems (1–6) due to its unique soft tissue contrast and relatively high-spatial resolution.
With a large variety of MRI applications being proposed, great effort has been made to develop contrast agents that may add physiological and/or molecular information to anatomical images (7). Along this line, the potential use of the paramagnetic manganese ion (Mn2+), which induces a strong reduction in both longitudinal (T1) and transversal (T2) relaxation times, has been investigated (8). As Mn2+ has a high-chemical similarity with calcium (Ca2+), it may enter neurons and other excitable cells through voltage-gated calcium channels and the Na+/Ca2+ exchanger (9).
Over the last decade, Mn2+ has been used as a contrast agent in various manganese-enhanced MRI (MEMRI) applications. These may be grouped in three major classes: neuronal tract tracing (10–14), morphological (15–18), and functional imaging (19–23). Typically, during neuronal tract-tracing studies manganese is directly injected into a specific brain region (24–29). In other classes of applications, this ion is administered either systemically into the bloodstream (30–39) or directly into the cerebrospinal fluid (CSF) (40, 41).
Neuronal tract-tracing explores the transport of Mn2+ across synapses. In contrast, morphological and functional studies using MEMRI are dependent on local neuronal cell density, the permeability of the blood–brain barrier, and neuronal activation (42). In Mn2+-based functional MRI (fMRI), tissue contrast may be correlated with activity-dependent ion accumulation in excitable cells (43). As such, the contrast in MEMRI is more directly related to neural activity then fMRI blood oxygenation level dependent (BOLD) (44, 45). Another advantage is that Mn2+ uptake after systemic injections takes place over an extended period of time in awake and freely moving animals (46). As a result, only the MRI acquisition needs to be performed under anesthesia. This is another advantage of MEMRI over BOLD fMRI, which requires both stimuli and acquisition to be performed under sedation.
A major drawback of the use of Mn2+ is the toxic side effects observed at high concentrations (47–51). This is of concern as high-Mn2+ tissue levels are often required to enhance the contrast between structures (52–54). In fact, toxicity is one of the main limitations for the full development of Mn2+ as an MRI contrast agent for humans. Even in animal studies, there needs to be a compromise between avoiding toxicity and delivering adequate doses of manganese. The ultimate goal is to reduce systemic side effects while guaranteeing animal well-being and maximizing contrast and imaging quality (8, 17, 55).
Several methodological developments have been recently proposed to improve MEMRI as a technique to study functional neural circuits and in vivo brain anatomy. In the present work, we provide a brief overview of MEMRI and illustrate the potential applications of this method in small animal models.
Manganese-Enhanced MRI
Historical perspective
The first use of Mn2+ in nuclear magnetic resonance (NMR) coincides with the early days of this technique (56). Together with other ions, Mn2+ was employed in tests to measure the exchange rate of bulk water molecules with those in the first coordination sphere of paramagnetic ions (56). These findings played an important role in our understanding and optimization of water-exchange effects, a crucial step in the development of efficient T1-shortening MRI contrast agents (57–59). Later, Mn2+ was also used in experiments that enabled quantitative structural information to be obtained from biological molecules, which led to the development of techniques to determine protein structure using NMR (60).
Mn2+ has also been present since the earliest stages of MRI. Lauterbur (61) has used MnSO4 to change the longitudinal relaxation time of water and prove that relaxation times could affect signal intensity. This was an important step to demonstrate the feasibility of MRI, since, at that time, the technique was believed to be limited due to the small variations of water density in biological tissues (62). Mn2+ can then be considered as the first reported MRI contrast agent. Since then, it has contributed to our understanding of relaxation effects in biological systems (63). These are still considered to be helpful in establishing strategies to alter MRI contrast with exogenous agents and are extremely useful, not only in clinical practice but also in preclinical models (64, 65).
Dosage and toxicity
The ion Mn2+ is essential for a normal development and cellular function. Disruptions in manganese homeostasis in humans are associated with neurological disorders, skin lesions, bone diseases, and among others (66–68). Chronic exposure to this heavy metal leads to manganism, a progressive neurodegenerative condition that resembles Parkinson’s disease (47, 50, 69, 70). An acute overexposure to Mn2+, which happens when a high-systemic dose of contrast agents is administered to patients, may result in cardiac toxicity, hepatic failure, and even death (48, 49, 71).
As the MEMRI contrast is proportional to the accumulation of tissue Mn2+ (52–54), the successful application of this technique depends on the delivery of appropriate ionic doses to the regions of interest. The most common way for delivering Mn2+ is through the injection of MnCl2 solutions (8). Depending on the application, MnCl2 can be delivered directly into the brain. This minimizes toxicity, since the exposure to lower doses of Mn2+ is restricted to the injection site and adjacent regions. Though focal toxicity may still occur (72), this approach has been successfully used in several studies of neuronal tract tracing (24–29).
For systemic injections targeting the brain, MnCl2 can be injected intravenously, intraperitoneally, or subcutaneously. So far, all have been widely used, as there is no strong evidence suggesting that one route is better or causes more toxicity than the others (30, 31, 33–39). One of the major drawbacks of using systemic injections is that, prior to reaching the brain manganese reaches the liver, heart, and kidneys. This increases the risk of acute toxic effects, including cardiac, renal, and liver failure.
In the intact brain [i.e., without blood–brain barrier (BBB) breakdown], the time-course and distribution of MnCl2 varies across brain regions (34, 73). Under these circumstances, contrast enhancement seems to reach its equilibrium 24 h following administration. As this is particularly slow for brain activation studies, one strategy is to disrupt the BBB to accelerate uptake (19, 43, 46). An alternative to avoid BBB disruption (40, 41) is to administer MnCl2 directly into the CSF. In this case, Mn2+ is uniformly supplied to the whole brain in a reasonable timescale for a variety of chronic functional activation studies.
The use of systemic fractionated injections (limited to small daily doses) was proposed as an alternative for delivering high doses of Mn2+ with fewer side effects in preclinical models (52, 53). A similar increase in contrast delivery with low toxicity has been observed with the use of subcutaneous mini-osmotic pumps (74). It is important to mention, however, that studies using these techniques were designed to demonstrate alternative ways of improving MRI contrast enhancement. Every attempt to use similar protocols should take into account reported changes in behavioral, neurochemical, electrophysiological, and histological signs of toxicity, especially when considering long-term effects (75–78).
Routes of administration
In general, the route of delivery (i.e., systemic or intracerebral) is chosen based on the application. After the systemic administration, most Mn2+ likely reaches the brain through the blood–CSF barrier (79), enhancing the visualization of the cerebral cytoarchitecture and demarcating active brain regions. The focal cerebral administration enables mapping of neuronal tracts in the living brain, where Mn2+ is stored and transported along axonal tracts (75). As already mentioned, MEMRI applications can be grouped into three major classes: morphological (15–18), neuronal tract tracing (6, 10–14), and functional imaging (19–23).
In contrast to gadolinium-based agents that are typically intravascular and remain in the cerebral vasculature, MEMRI contrast achieved after the systemic administration of Mn2+ comes from the brain parenchyma itself. Mn2+ may enter the brain basically through three different routes are as follows: (i) from the bloodstream via a fast transport system in the choroid plexus. Through this route, Mn2+ gets very rapidly into the CSF and brain (80, 81); (ii) from the nasal space through the olfactory nerve via olfactory epithelium (25, 82, 83); (iii) from the bloodstream across the BBB at cerebral capillaries (84–87). In the intact brain, MEMRI signal enhancement following Mn2+ administration begins in the ventricles and periventricular regions prior to reaching more distant areas of brain parenchyma (34, 80, 88).
Once in the brain, manganese may be transported along axons (89) or across synapses (26). The time-course and distribution of MnCl2 varies across brain regions (34, 73). Those with an initial poor access to manganese may be supplied over time by axonal transport from areas with a strong initial uptake (88). Contrast enhancement seems to reach its equilibrium 24 h following administration. Thereafter, manganese has an extremely slow clearance rate that can take up to 300 days, with a half-life of 51–74 days in different brain regions, as shown by autoradiography (90). MRI-based studies showed a reduced Mn2+ half-life of 5–12 days, but not of the same magnitude (54, 91, 92). Since the regional signal enhancement following manganese administration is proportional to the propensity of each brain region to uptake this metal, MEMRI is a powerful tool for visualizing brain architecture.
Manganese entrance into excitable cells
Overall, Mn2+ presents a high-chemical similarity with calcium (Ca2+), being handled in an analogous manner by many biological systems (93). This means that the Mn2+ can enter neurons and other excitable cells through calcium pathways, such as voltage-gated calcium channels and the Na+/Ca2+ exchanger (9, 86). In addition, Mn2+ can bind to intracellular proteins and nucleic acids. Once in the cell, Mn2+ accumulates in the endoplasmic reticulum (25, 26), being subsequently packaged into vesicles and transported anterogradely in axonal tracts. Upon reaching the presynaptic membrane (27, 89), it is finally released and taken up by the next neuron (25, 27). This property, along with the fact that Mn2+ is MRI-detectable, has contributed to its labeling as an in vivo trans-synaptic tracer.
Prior to MEMRI, tract-tracing studies employed invasive techniques (94, 95), requiring tracers to be injected and animals sacrificed in order for these agents to be visualized. A major limitation of this methodology is that longitudinal studies cannot be carried out in the same animals. As MEMRI can be conducted multiple times, it has contributed to the in vivo temporal assessment of connectivity and integrity of neuronal tracts in several animal models (i.e., from small rodents to non-human primates) (13, 26, 28, 96).
The ability of manganese to be taken up via voltage-gated Ca2+ channels has not only been explored for non-invasive tract tracing but also to functionally assess the rate of neuronal transport. This latter plays a crucial role in the normal functioning of neurons. In fact, perturbations in axonal transport and its machinery have been associated with disease states, such as Alzheimer’s disease, diabetes, as well as with normal aging (97–99). In contrast to Mn2+, large tracer molecules may not accurately represent the axonal transport in in vivo systems.
Activity-induced manganese MRI
The main concept underlying the use of MEMRI for the assessment of neuronal activity is the fact that activated brain regions have elevated Ca2+ influx through Ca2+ channels. As mentioned before, in the presence of extracellular Mn2+ active regions will have greater Mn2+ influx, since manganese competes with Ca2+ to enter the cells. Thus, the accumulation of Mn2+ is directly related to brain activation and may provide information about brain function. This approach, which has been named activity-induced manganese MRI (46), led to the development of a Mn2+-based fMRI technique. It differs from traditional methods, because it does not take into account information on hemodynamic fluctuations and deoxy-hemoglobin concentration. Hence, the activity-induced manganese-dependent contrast (AIM) MRI produces maps with better spatial localization than those produced by conventional fMRI (19).
A particular concern related to AIM MRI experiments is that the Mn2+ cannot efficiently penetrate the BBB. The CSF route is particularly slow for this purpose (87, 100) and the amount of Mn2+ entering the brain is minimal compared to cases where the BBB is disrupted. As a result, several AIM MRI studies have been performed in conjunction with BBB disruption. On the other hand, some studies showing activation of the auditory (22, 23) and visual pathways (30, 101) following auditory and visual stimulation, respectively, were performed in mice without BBB disruption.
An interesting aspect of AIM MRI is that, after BBB disruption and upon brain stimulation, Mn2+ accumulates in active regions at a short time scale. Once accumulated, Mn2+ does not leave these regions for several hours. This allows Mn2+ to be delivered outside the scanner, while the animal is being freely moving or carrying out behavioral tasks. When compared with conventional fMRI protocols, this represents a new horizon in terms of functional evaluation. One of its disadvantages, however, is the intrinsic temporal resolution of the technique, which prevents the assessment of rapid changes in activity, particularly tissue deactivation (102). Besides providing valuable information to answer physiological questions, AIM MRI was proven to be an important tool for the study of spatial BOLD signal changes in the cortex (19, 45, 103, 104). This is particularly important because BOLD is the MRI-based “gold standard” method for measuring brain activity in humans and several methodological questions still remain to be addressed.
MEMRI: Recent Applications in Experimental Animal Models
Over the last years, MEMRI has been extensively used in neurosciences. Studies using this technique have addressed neurophysiological and neuroanatomical problems in animal models of nociception (105, 106), neurodegeneration (35, 36, 99, 107–111), and psychiatric disorders (112).
Activity-dependent signaling
In animals, MEMRI has been used to determine high versus low activation of brain areas after specific stimuli or in models of brain disease. One example is the sequence of activation of the hypothalamic paraventricular nucleus, supraoptic nucleus, and preoptic area, which are thought to be involved in central osmotic regulation after intracarotid injection of hypertonic NaCl (113). In another study, mice exposed to an odorant showed localized T1 MRI signal enhancements in the olfactory epithelium and bulb (25). MEMRI has also been shown to be effective for mapping the mouse auditory brainstem (22). Chronic tinnitus (the perception of sounds in the absence of acoustic stimulation) in rats was associated with elevated focal activity in the auditory brainstem (114). On the other hand, a reduction in Mn2+ uptake was demonstrated in the rodent visual cortex in depression-like states (sickness behavior) induced by interferon-α (IFN-α), which was related to altered local functionality (112).
Epilepsy
At first sight, these results may suggest a positive correlation between MEMRI enhancement and cell activation. However, other factors, such as tissue edema, neurodegeneration, and cell density (8), may also determine signal changes, as shown in animal models of epilepsy. Several rodents and non-human primate models have been used to study cellular mechanisms that underlie temporal lobe epilepsy (TLE), including those following pilocarpine, kainic acid (115–121), and pentylenetetrazol injections (122). In these models, status epilepticus (SE) represents an acute phase, after which the animals enter the silent period that ends with the occurrence of spontaneous recurrent seizures (chronic phase). The temporal sequence and the neuropathological alterations that characterize these chronic models resemble those observed in human TLE. In rodents, the acute phase of the kainic acid model is characterized by a poorly defined MEMRI signal in areas with high-cellular activity (i.e., hippocampus) (107, 108). A possible explanation for this finding is that the MEMRI signal may have been obscured by cell damage that occurs at this early phase, especially when SE lasts more than 30 min. Similar results have been shown during the acute phase of the pilocarpine model (35, 109), even when SE lasted only from 5 to 30 min (Figure 1). A proposed mechanism to explain this finding is that reductions in MEMRI signal could be related to hippocampal cell edema rather than apoptotic cell death (35). Both edema and cell death have to be taken into account when one is planning to map active or inactive brain areas with MEMRI.
Figure 1
As mentioned above, both the kainic acid and pilocarpine models exhibit spontaneous recurrent seizures in the chronic phase, which, as described in humans, are accompanied by hippocampal sclerosis and mossy fiber sprouting (MFS) (115, 116, 123, 124). MRI has been largely used to study the chronic phase of TLE, since it allows a non-invasive longitudinal follow up using different approaches. These include anatomical imaging for evaluating hippocampal and amygdala volumetric changes (110, 125–128) and relaxometry for estimating relaxation times changes in different brain areas (i.e., hippocampus, amygdala, piriform cortex, and/or thalamus) (127, 129–131). Longitudinal studies may also be used to evaluate changes in spectroscopy so that biochemical changes may be characterized. As an example, the hippocampi of lithium–pilocarpine-treated rats have reduced N-acetylaspartate (NAA) and choline (Cho) peaks, as well as an increase in lactate compared to non-epileptic controls (131). Besides these MRI approaches, MEMRI is used as a molecular imaging technique (35, 36, 107–110). The focal and systemic administration of MnCl2 results in an increased hippocampal dentate gyrus MEMRI signal in kainic acid (108, 110) and pilocarpine-chronic epileptic rats (36). In these animals, signal changes correlates with aberrant MFS.
The relationship between MFS and MEMRI hyperintensity in pilocapine animals can be observed in Figure 2. Chronic pilocarpine rats that show aberrant MFS also show MEMRI hyperintensity. These signal changes have not been observed in pilocarpine animals in which MFS was suppressed by cycloheximide, suggesting that (1) MEMRI is able to detect hippocampal changes during the course of epileptogenesis and (2) a relationship exist between manganese enhancement and spontaneous seizure outcome (132). From the above-mentioned results, we conclude that MEMRI is a useful tool to follow important aspects related to neuronal plasticity, including those related to aberrant MFS and spontaneous recurrent seizures. Unfortunately, however, MEMRI may not be useful to study-activated areas during the acute phase of these models, as injury-related edema interferes in the signal.
Figure 2
Pain
In pain-related studies, MEMRI has been used to delineate functional connections between cortical and non-cortical areas; electrical stimulation of the left forepaw increased MEMRI signal in the contralateral anterior cingulate cortex, midcingulate cortex, retrosplenial cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala. Of those, signal changes in the retrosplenial cortex were attenuated by morphine injections (106). The efficacy of MEMRI to trace anatomical connections was indeed confirmed by Mn2+ transportation from the medial thalamus to the cingulate cortex and medial striatum, but not the motor cortex (106).
A recent study has shown reduced reactivity to thermal pain in the dorsal spinal cord following repeated amphetamine injections (133). The authors showed a temporal correlation between reduced pain sensitivity and increased MEMRI signals in the dorsal horn following repeated amphetamine administration. MEMRI has also been valuable in demonstrating the involvement of the hippocampus in the processing of pain during early development (105). As shown by different studies, noxious stimulation of newborn rats not only causes sex-specific long-term effects on the natural behavioral repertoire during adulthood (35, 134–136) but also dentate hippocampal cell activation.
In a rat model of pruritus, MEMRI has been used to investigate brain regions activated during itching. These were the parafascicular thalamic nucleus, superior/inferior colliculus, periaqueductal gray, cingulate cortex, amygdala, midbrain regions, lateral habenula, and hypothalamic areas (137). Gabapentin-treated itching rats decreased scratching behavior and had an attenuation of functional activity in the brain regions described above. Together, these results suggest that MEMRI hyperintensity is related to stimulus-induced activation of specific brain regions and that this techniques may be used as a strategy for understanding mechanisms of pain-related diseases.
Axonal transport
Axonal transport is an essential physiological function. Its disruption severely interfere with neuronal viability and leads to distinct neurological disorders. As an example, axonal transport impairment occurs at the onset of optic neuritis in an experimental murine model of autoimmune encephalomyelitis (EAE). Using the MEMRI technique, it was demonstrated that Mn2+ accumulation and axonal transport were significantly decreased not only in these animals (138) but also in rTg4510 mice, which comprise a model of fronto-temporal dementia and parkinsonism (139). In a mouse model of Alzheimer’s, axonal transport rates were shown to be reduced as soon as amyloid-beta (Aβ) deposition begins. This reduction becomes even more pronounced after plaque formation (99). In this particular case, MEMRI showed that in vivo reduction in axonal transport can be detected prior to plaque formation.
Mechanisms of pathological Mn2+ enhancement
Bearing in mind that Mn2+ enters neurons through Ca2+ channels and is transported along axonal transport systems, MEMRI has been used to trace the recovery of neuronal connectivity in experimental models of stroke (111). According to the authors, loss or dysfunction of neuronal connections, even outside the ischemic lesion, may explain the lasting impairment of function. Systemic Mn2+ injections in the acute phase of neonatal mild hypoxic–ischemia provide an enhanced MEMRI signal indicative of cortical gray matter lesion. This would be otherwise undetectable with conventional MRI techniques (140–142). In the late phase of the hypoxic–ischemia model, MEMRI signal was intense in the dorsolateral thalamus, hippocampus, and the remaining cortex of the injured hemisphere. This was co-localized with reactive astrocytes, dying neurons, and activated microglia on histological analysis. MEMRI enhancement in this study had higher correlation with activated microglia (suggesting inflammatory process) than with dying cells (143).
Conclusions
Based on the above-mentioned studies, MEMRI may be considered as a powerful approach for in vivo studies to determine stimulus-dependent brain areas of activation, axonal transport, neuronal connectivity, and brain lesion in several experimental animal models. However, few challenges still have to be overcome so that researchers may take full advantage of all the benefits that this technique has to offer. Since dose-related toxicity is a major concern, there is a need to develop and further refine MRI pulse sequences in order to make them more sensitive to small changes in relaxation times. Also, it is important to develop better strategies to deliver the Mn2+ to the region of interest, reducing the risk of side effects after systemic MnCl2 injections. The combination of all of these aspects will likely allow MEMRI to be an even more powerful, versatile, and useful tool for modern neurosciences studies.
Statements
Acknowledgments
Financial Support: FAPESP 2009/53646-0; FAPESP CInAPCe Program 2005/56663-1; JM was supported by a FAPESP fellowship 07/52911-6.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
BernasconiABernasconiNCaramanosZReutensDCAndermannFDubeauFet alT2 relaxometry can lateralize mesial temporal lobe epilepsy in patients with normal MRI. Neuroimage (2000) 12:739–46.10.1006/nimg.2000.0724
2
BernasconiNBernasconiAAndermannEDubeauFFeindelWReutensD. Entorhinal cortex in temporal lobe epilepsy. A quantitative MRI study. Neurology (1999) 52:1870–6.10.1212/WNL.52.9.1870
3
CendesFAndermannFGloorPEvansAJones-GotmanMWatsonCet alMRI volumetric measurement of amygdala and hippocampus in temporal lobe epilepsy. Neurology (1993) 43:719–25.10.1212/WNL.43.4.719
4
MamaniJBMalheirosJMCardosoEFTannusASilveiraPHGamarraLF. In vivo magnetic resonance imaging tracking of C6 glioma cells labeled with superparamagnetic iron oxide nanoparticles. Einstein (Sao Paulo) (2012) 10(2):164–70.10.1590/S1679-45082012000200009
5
MartinsPCAyub-GuerrieriDMartins-BachABOnofre-OliveiraPMalheirosJMTannusAet alDmdmdx/Largemyd: a new mouse model of neuromuscular diseases useful for studying physiopathological mechanisms and testing therapies. Dis Model Mech (2013) 6(5):1167–74.10.1242/dmm.011700
6
PelledGBergmanHBen-HurTGoelmanG. Manganese-enhanced MRI in a rat model of Parkinson’s disease. J Magn Reson Imaging (2007) 26(4):863–70.10.1002/jmri.21051
7
JasanoffA. MRI contrast agents for functional molecular imaging of brain activity. Curr Opin Neurobiol (2007) 17(5):593–600.10.1016/j.conb.2007.11.002
8
SilvaACLeeJHAokiIKorestkyAP. Manganese-enhanced magnetic resonance imaging (MEMRI): methodological and pratical considerations. NMR Biomed (2004) 17:532–43.10.1002/nbm.945
9
TakedaA. Manganese action in brain function. Brain Res Brain Res Rev (2003) 41:79–87.10.1016/S0165-0173(02)00234-5
10
ChuangKHKoretskyA. Improved neuronal tract tracing using manganese enhanced magnetic resonance imaging with fast T(1) mapping. Magn Reson Med (2006) 55:604–11.10.1002/mrm.20797
11
ChuangKHKoretskyAP. Accounting for nonspecific enhancement in neuronal tract tracing using manganese enhanced magnetic resonance imaging. Magn Reson Imaging (2009) 27:594–600.10.1016/j.mri.2008.10.006
12
Van der LindenAVan MeirVTindemansIVerhoyeMBalthazartJ. Applications of manganese-enhanced magnetic resonance imaging (MEMRI) to image brain plasticity in song birds. NMR Biomed (2004) 17(8):602–12.10.1002/nbm.936
13
Van der LindenAVerhoyeMVan MeirVTindemansIEensMAbsilPet alIn vivo manganese-enhanced magnetic resonance imaging reveals connections and functional properties of the songbird vocal control system. Neuroscience (2002) 112(2):467–74.10.1016/S0306-4522(02)00070-2
14
Van MeirVVerhoyeMAbsilPEensMBalthazartJVan der LindenA. 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(3):914–23.10.1016/j.neuroimage.2003.10.007
15
AokiINaruseSTanakaC. Manganese-enhanced magnetic resonance imaging (MEMRI) of brain activity and applications to early detection of brain ischemia. NMR Biomed (2004) 17(8):569–80.10.1002/nbm.941
16
NattOWatanabeTBoretiusSRadulovicJFrahmJMichaelisT. High-resolution 3D MRI of mouse brain reveals small cerebral structures in vivo. J Neurosci Methods (2002) 120(2):203–9.10.1016/S0165-0270(02)00211-X
17
SilvaACBockNA. Manganese-enhanced MRI: an exceptional tool in translational neuroimaging. Schizophr Bull (2008) 34(4):595–604.10.1093/schbul/sbn056
18
WatanabeTFrahmJMichaelisT. Functional mapping of neural pathways in rodent brain in vivo using manganese-enhanced three-dimensional magnetic resonance imaging. NMR Biomed (2004) 17:554–68.10.1002/nbm.937
19
DuongTQSilvaACLeeSPKimSG. Functional MRI of calcium-dependent synaptic activity: cross correlation with CBF and BOLD measurements. Magn Reson Med (2000) 43:383–92.10.1002/(SICI)1522-2594(200003)43:3<383::AID-MRM10>3.0.CO;2-Q
20
LuHXiZXGitajnLReaWYangYSteinEA. Cocaine-induced brain activation detected by dynamic manganese-enhanced magnetic resonance imaging (MEMRI). Proc Natl Acad Sci U S A (2007) 104:2489–94.10.1073/pnas.0606983104
21
ParkinsonJRChaudhriOBBellJD. Imaging appetite-regulating pathways in the central nervous system using manganese-enhanced magnetic resonance imaging. Neuroendocrinology (2009) 89(2):121–30.10.1159/000163751
22
YuXWadghiriYZSanesDHTurnbullDH. In vivo auditory brain mapping in mice with Mn-enhanced MRI. Nat Neurosci (2005) 8:961–8.10.1038/nn1477
23
YuXZouJBabbJSJohnsonGSanesDHTurnbullDH. Statistical mapping of sound-evoked activity in the mouse auditory midbrain using Mn-enhanced MRI. Neuroimage (2008) 39(1):223–30.10.1016/j.neuroimage.2007.08.029
24
MurayamaYWeberBSaleemKSAugathMLogothetisNK. Tracing neural circuits in vivo with Mn-enhanced MRI. Magn Reson Imaging (2006) 24(4):349–58.10.1016/j.mri.2005.12.031
25
PautlerRGKoretskyAP. Tracing odor-induced activation in the olfactory bulbs of mice using manganese-enhanced magnetic resonance imaging. Neuroimage (2002) 16:441–8.10.1006/nimg.2002.1075
26
PautlerRGMongeauRJacobsRE. In vivo trans-synaptic tract tracing from the murine striatum and amygdala utilizing manganese enhanced MRI (MEMRI). Magn Reson Med (2003) 50(1):33–9.10.1002/mrm.10498
27
PautlerRGSilvaACKoretskyAP. In vivo neuronal tract tracing using manganese-enhanced magnetic resonance imaging. Magn Reson Med (1998) 40(5):740–8.10.1002/mrm.1910400515
28
SaleemKSPaulsJMAugathMTrinathTPrauseBAHashikawaTet alMagnetic resonance imaging of neuronal connections in the macaque monkey. Neuron (2002) 34(5):685–700.10.1016/S0896-6273(02)00718-3
29
WatanabeTMichaelisTFrahmJ. 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):424–9.10.1002/mrm.1209
30
BissigDBerkowitzBA. Manganese-enhanced MRI of layer-specific activity in the visual cortex from awake and free-moving rats. Neuroimage (2009) 44(3):627–35.10.1016/j.neuroimage.2008.10.013
31
de SousaPLde SouzaSLSilvaACde SouzaREde CastroRM. Manganese-enhanced magnetic resonance imaging (MEMRI) of rat brain after systemic administration of MnCl2: changes in T1 relaxation times during postnatal development. J Magn Reson Imaging (2007) 25(1):32–8.10.1002/jmri.20792
32
JacksonSJHusseyRJansenMAMerrifieldGDMarshallIMacLullichAet alManganese-enhanced magnetic resonance imaging (MEMRI) of rat brain after systemic administration of MnCl(2): hippocampal signal enhancement without disruption of hippocampus-dependent behavior. Behav Brain Res (2011) 216(1):293–300.10.1016/j.bbr.2010.08.007
33
KuoYTHerlihyAHSoPWBhakooKKBellJD. In vivo measurements of T1 relaxation times in mouse brain associated with different modes of systemic administration of manganese chloride. J Magn Reson Imaging (2005) 21(4):334–9.10.1002/jmri.20285
34
LeeJHSilvaACMerkleHKorestkyAP. 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) 53:640–8.10.1002/mrm.20368
35
MalheirosJMPersikeDSCastroLUSanchesTRAndrade LdaCTannusAet alReduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: edema or apoptosis?Epilepsy Res (2014) 108(4):644–52.10.1016/j.eplepsyres.2014.02.007
36
MalheirosJMPolliRSPaivaFFLongoBMMelloLESilvaACet alManganese-enhanced magnetic resonance imaging detects mossy fiber sprouting in the pilocarpine model of epilepsy. Epilepsia (2012) 53(7):1225–32.10.1111/j.1528-1167.2012.03521.x
37
WadghiriYZBlindJADuanXMorenoCYuXJoynerALet alManganese-enhanced magnetic resonance imaging (MEMRI) of mouse brain development. NMR Biomed (2004) 17(8):613–9.10.1002/nbm.932
38
WatanabeTNattOBoretiusSFrahmJMichaelisT. In vivo 3D MRI staining of mouse brain after subcutaneous application of MnCl2. Magn Reson Med (2002) 48:852–9.10.1002/mrm.10276
39
WatanabeTRadulovicJBoretiusSFrahmJMichaelisT. Mapping of the habenulo-interpeduncular pathway in living mice using manganese-enhanced 3D MRI. Magn Reson Imaging (2006) 24(3):209–15.10.1016/j.mri.2005.10.034
40
GallezBDemeureRBaudeletCAbdelouahabNBegheinNJordanBet alNon invasive quantification of manganese deposits in the rat brain by local measurement of NMR proton T1 relaxation times. Neurotoxicology (2001) 22(3):387–92.10.1016/S0161-813X(01)00020-1
41
LiuCHD’ArceuilHEde CrespignyAJ. Direct CSF injection of MnCl(2) for dynamic manganese-enhanced MRI. Magn Reson Med (2004) 51(5):978–87.10.1002/mrm.20047
42
PautlerRG. In vivo, trans-synaptic tract-tracing utilizing manganese-enhanced magnetic resonance imaging (MEMRI). NMR Biomed (2004) 17:595–601.10.1002/nbm.942
43
AokiITanakaCTakegamiTEbisuTUmedaMFukunagaMet alDynamic activity-induced manganese-dependent contrast magnetic resonance imaging (DAIM MRI). Magn Reson Med (2002) 48:927–33.10.1002/mrm.10320
44
KoretskyAP. Is there a path beyond BOLD? Molecular imaging of brain function. Neuroimage (2012) 62(2):1208–15.10.1016/j.neuroimage.2012.02.076
45
SilvaAC. Using manganese-enhanced MRI to understand BOLD. Neuroimage (2012) 62(2):1009–13.10.1016/j.neuroimage.2012.01.008
46
LinYJKoretskyAP. Manganese ions enhances T1-weighted MRI during brain activation: an approach to direct imaging of brain function. Magn Reson Med (1997) 38:378–88.10.1002/mrm.1910380305
47
BarbeauA. Manganese and extrapyramidal disorders (a critical review and tribute to Dr. George C. Cotzias). Neurotoxicology (1984) 5(1):13–35.
48
ChandraSVShuklaGS. Role of iron deficiency in inducing susceptibility to manganese toxicity. Arch Toxicol (1976) 35(4):319–23.10.1007/BF00570272
49
CrossgroveJZhengW. Manganese toxicity upon overexposure. NMR Biomed (2004) 17:544–53.10.1002/nbm.931
50
DobsonAWEriksonKMAschnerM. Manganese neurotoxicity. Ann N Y Acad Sci (2004) 1012:115–28.10.1196/annals.1306.009
51
GorellJMJohnsonCCRybickiBAPetersonELKortshaGXBrownGGet alOccupational exposure to manganese, cooper, lead, iron, mercury and zinc and the risk of Parkinson’s disease. Neurotoxicology (1999) 20:239–47.
52
BockNAPaivaFFSilvaAC. Fractionated manganese-enhanced MRI. NMR Biomed (2008) 21(5):473–8.10.1002/nbm.1211
53
GruneckerBKaltwasserSFPeterseYSamannPGSchmidtMVWotjakCTet alFractionated manganese injections: effects on MRI contrast enhancement and physiological measures in C57BL/6 mice. NMR Biomed (2010) 23(8):913–21.10.1002/nbm.1508
54
GruneckerBKaltwasserSFZappeACBedenkBTBickerYSpoormakerVIet alRegional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese-enhanced MRI. NMR Biomed (2013) 26(5):542–56.10.1002/nbm.2891
55
InoueTMajidTPautlerRG. Manganese enhanced MRI (MEMRI): neurophysiological applications. Rev Neurosci (2011) 22(6):675–94.10.1515/RNS.2011.048
56
ConnickREPoulsonRE. Effect of paramagnetic ions on the nuclear magnetic resonance of O-17 in water and the rate of elimination of water molecules from the 1st coordination sphere of cations. J Chem Phys (1959) 30:759–61.10.1063/1.1730039
57
LaufferRB. Magnetic resonance contrast media: principles and progress. Magn Reson Q (1990) 6(2):65–84.
58
SherryADWuY. The importance of water exchange rates in the design of responsive agents for MRI. Curr Opin Chem Biol (2013) 17(2):167–74.10.1016/j.cbpa.2012.12.012
59
Siriwardena-MahanamaBNAllenMJ. Strategies for optimizing water-exchange rates of lanthanide-based contrast agents for magnetic resonance imaging. Molecules (2013) 18(8):9352–81.10.3390/molecules18089352
60
WuthrichK. NMR studies of structure and function of biological macromolecules (Nobel Lecture). J Biomol NMR (2003) 27(1):13–39.10.1023/A:1024756526171
61
LauterburPC. Image formation by induced local interactions: examples employing nuclear magnetic resonance. Nature (1973) 242:190–1.10.1038/242190a0
62
ToftsP. Quantitative MRI of the Brain: Measuring Changes Caused by Disease. Chichester: Wiley (2003). xvi p.
63
KangYSGoreJC. Studies of tissue NMR relaxation enhancement by manganese. Dose and time dependences. Invest Radiol (1984) 19(5):399–407.10.1097/00004424-198409000-00012
64
CaravanPEllisonJJMcMurryTJLaufferRB. Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev (1999) 99(9):2293–352.10.1021/cr980440x
65
ShokrollahiH. Contrast agents for MRI. Mater Sci Eng C Mater Biol Appl (2013) 33(8):4485–97.10.1016/j.msec.2013.07.012
66
FriedmanBJFreeland-GravesJHBalesCWBehmardiFShorey-KutschkeRLWillisRAet alManganese balance and clinical observations in young men fed a manganese-deficient diet. J Nutr (1987) 117(1):133–43.
67
Gonzalez-ReyesREGutierrez-AlvarezAMMorenoCB. Manganese and epilepsy: a systematic review of the literature. Brain Res Rev (2007) 53(2):332–6.10.1016/j.brainresrev.2006.10.002
68
WedlerFCDenmanRB. Glutamine synthetase: the major Mn(II) enzyme in mammalian brain. Curr Top Cell Regul (1984) 24:153–69.10.1016/B978-0-12-152824-9.50021-6
69
MenaIMarinOFuenzalidaSCotziasGC. Chronic manganese poisoning: clinical picture and managanese turnover. Neurology (1967) 17(2):128–36.10.1212/WNL.17.2.128
70
RacetteBAAntenorJAMcGee-MinnichLMoerleinSMVideenTOKotagalVet al[18F]FDOPA PET and clinical features in parkinsonism due to manganism. Mov Disord (2005) 20(4):492–6.10.1002/mds.20381
71
WolfGLBaumL. Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dog and rabbit. AJR Am J Roentgenol (1983) 141(1):193–7.10.2214/ajr.141.1.193
72
CanalsSBeyerleinMKellerALMurayamaYLogothetisNK. Magnetic resonance imaging of cortical connectivity in vivo. Neuroimage (2008) 40(2):458–72.10.1016/j.neuroimage.2007.12.007
73
ShazeebMSSotakCH. Dose dependence and temporal evolution of the T1 relaxation time and MRI contrast in the rat brain after subcutaneous injection of manganese chloride. Magn Reson Med (2012) 68(6):1955–62.10.1002/mrm.24184
74
SepulvedaMRDresselaersTVangheluwePEveraertsWHimmelreichUMataAMet alEvaluation of manganese uptake and toxicity in mouse brain during continuous MnCl2 administration using osmotic pumps. Contrast Media Mol Imaging (2012) 7(4):426–34.10.1002/cmmi.1469
75
BouilleretVCardamoneLLiuCKoeASFangKWilliamsJPet alConfounding neurodegenerative effects of manganese for in vivo MR imaging in rat models of brain insults. J Magn Reson Imaging (2011) 34(4):774–84.10.1002/jmri.22669
76
DaoustASaoudiYBrocardJCollombNBatandierCBisbalMet alImpact of manganese on primary hippocampal neurons from rodents. Hippocampus (2014) 24(5):598–610.10.1002/hipo.22252
77
EschenkoOCanalsSSimanovaIBeyerleinMMurayamaYLogothetisNK. Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: implication for longitudinal studies. Neuroimage (2010) 49(3):2544–55.10.1016/j.neuroimage.2009.10.079
78
EschenkoOCanalsSSimanovaILogothetisNK. Behavioral, electrophysiological and histopathological consequences of systemic manganese administration in MEMRI. Magn Reson Imaging (2010) 28(8):1165–74.10.1016/j.mri.2009.12.022
79
BornhorstJWeheCAHuwelSKarstUGallaHJSchwerdtleT. Impact of manganese on and transfer across blood-brain and blood-cerebrospinal fluid barrier in vitro. J Biol Chem (2012) 287(21):17140–51.10.1074/jbc.M112.344093
80
AokiIWuYLSilvaACLynchRMKorestkyAP. In vivo detection of neuroarchiteture in the rodent brain using manganese-enhanced MRI. Neuroimage (2004) 22:1046–59.10.1016/j.neuroimage.2004.03.031
81
MurphyVAWadhwaniKCSmithQRRapoportSI. Saturable transport of manganese(II) across the rat blood-brain barrier. J Neurochem (1991) 57(3):948–54.10.1111/j.1471-4159.1991.tb08242.x
82
TjalveHHenrikssonJTallkvistJLarssonBSLindquistNG. Uptake of manganese and cadmium from the nasal mucosa into the central nervous system via olfactory pathways in rats. Pharmacol Toxicol (1996) 79(6):347–56.10.1111/j.1600-0773.1996.tb00021.x
83
TjalveHMejareCBorg-NeczakK. Uptake and transport of manganese in primary and secondary olfactory neurones in pike. Pharmacol Toxicol (1995) 77(1):23–31.10.1111/j.1600-0773.1995.tb01909.x
84
CrossgroveJSAllenDDBukaveckasBLRhineheimerSSYokelRA. Manganese distribution across the blood-brain barrier. I. Evidence for carrier-mediated influx of managanese citrate as well as manganese and manganese transferrin. Neurotoxicology (2003) 24(1):3–13.10.1016/S0161-813X(02)00089-X
85
CrossgroveJSYokelRA. Manganese distribution across the blood-brain barrier III. The divalent metal transporter-1 is not the major mechanism mediating brain manganese uptake. Neurotoxicology (2004) 25(3):451–60.10.1016/j.neuro.2003.10.005
86
CrossgroveJSYokelRA. Manganese distribution across the blood-brain barrier. IV. Evidence for brain influx through store-operated calcium channels. Neurotoxicology (2005) 26(3):297–307.10.1016/j.neuro.2004.09.004
87
RabinOHegedusLBourreJMSmithQR. Rapid brain uptake of manganese(II) across the blood-brain barrier. J Neurochem (1993) 61(2):509–17.10.1111/j.1471-4159.1993.tb02153.x
88
BockNAPaivaFFNascimentoGCNewmanJDSilvaAC. Cerebrospinal fluid to brain transport of manganese in a non-human primate revealed by MRI. Brain Res (2008) 1198:160–70.10.1016/j.brainres.2007.12.065
89
SlootWNGramsbergenJB. Axonal transport of manganese and its relevance to selective neurotoxicity in the rat basal ganglia. Brain Res (1994) 657(1–2):124–32.10.1016/0006-8993(94)90959-8
90
TakedaASawashitaJOkadaS. Biological half-lives of zinc and manganese in rat brain. Brain Res (1995) 695(1):53–8.10.1016/0006-8993(95)00916-E
91
ChuangKHKoretskyAPSotakCH. Temporal changes in the T1 and T2 relaxation rates (DeltaR1 and DeltaR2) in the rat brain are consistent with the tissue-clearance rates of elemental manganese. Magn Reson Med (2009) 61:1528–32.10.1002/mrm.21962
92
HanJHChungYHParkJDKimCYYangSOKhangHSet alRecovery from welding-fume-exposure-induced MRI T1 signal intensities after cessation of welding-fume exposure in brains of cynomolgus monkeys. Inhal Toxicol (2008) 20(12):1075–83.10.1080/08958370802116634
93
HunterDRKomaiHHaworthRAJacksonMDBerkoffHA. Comparison of Ca2+, Sr2+, and Mn2+ fluxes in mitochondria of the perfused rat heart. Circ Res (1980) 47(5):721–7.10.1161/01.RES.47.5.721
94
LanciegoJLWouterloodFG. A half century of experimental neuroanatomical tracing. J Chem Neuroanat (2011) 42(3):157–83.10.1016/j.jchemneu.2011.07.001
95
NaumannTHartigWFrotscherM. 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. J Neurosci Methods (2000) 103(1):11–21.10.1016/S0165-0270(00)00292-2
96
WatanabeTRadulovicJSpiessJNattOBoretiusSFrahmJet alIn vivo 3D MRI staining of the mouse hippocampal system using intracerebral injection of MnCl2. Neuroimage (2004) 22(2):860–7.10.1016/j.neuroimage.2004.01.028
97
CrossDJFlexmanJAAnzaiYMaravillaKRMinoshimaS. Age-related decrease in axonal transport measured by MR imaging in vivo. Neuroimage (2008) 39:915–26.10.1016/j.neuroimage.2007.08.036
98
SharmaRBurasETerashimaTSerranoFMassaadCAHuLet alHyperglycemia induces oxidative stress and impairs axonal transport rates in mice. PLoS One (2010) 5(10):e13463.10.1371/journal.pone.0013463
99
SmithKDKallhoffVZhengHPautlerRG. In vivo axonal transport rates decrease in a mouse model of Alzheimer’s disease. Neuroimage (2007) 35(4):1401–8.10.1016/j.neuroimage.2007.01.046
100
LondonREToneyGGabelSAFunkA. Magnetic resonance imaging studies of the brains of anesthetized rats treated with manganese chloride. Brain Res Bull (1989) 23(3):229–35.10.1016/0361-9230(89)90152-4
101
BerkowitzBAGradianuMBissigDKernTSRobertsR. 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(5):2351–8.10.1167/iovs.08-2918
102
LeeJHKoretskyAP. Manganese enhanced magnetic resonance imaging. Curr Pharm Biotechnol (2004) 5:529–37.10.2174/1389201043376607
103
FaZZhangPHuangFLiPZhangRXuRet alActivity-induced manganese-dependent functional MRI of the rat visual cortex following intranasal manganese chloride administration. Neurosci Lett (2010) 481(2):110–4.10.1016/j.neulet.2010.06.063
104
FaZZhangPWuWWangZHuangFYangLet alFunctional mapping of rat brain activation following rTMS using activity-induced manganese-dependent contrast. Neurol Res (2011) 33(6):563–71.10.1179/1743132810Y.0000000009
105
LimaMMalheirosJNegrigoATescarolloFMedeirosMSucheckiDet alSex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats. Neuropharmacology (2014) 77:268–76.10.1016/j.neuropharm.2013.10.007
106
YangPFChenDYHuJWChenJHYenCT. Functional tracing of medial nociceptive pathways using activity-dependent manganese-enhanced MRI. Pain (2011) 152(1):194–203.10.1016/j.pain.2010.10.027
107
AlvestadSGoaPEQuHRisaOBrekkenCSonnewaldUet alIn vivo mapping of temporospatial changes in manganese enhancement in rat brain during epileptogenesis. Neuroimage (2007) 38(1):57–66.10.1016/j.neuroimage.2007.07.027
108
ImmonenRJKharatishviliISierraAEinulaCPitkanenAGrohnOH. Manganese enhanced MRI detects mossy fiber sprouting rather than neurodegeneration, gliosis or seizure-activity in the epileptic rat hippocampus. Neuroimage (2008) 40(4):1718–30.10.1016/j.neuroimage.2008.01.042
109
MalheirosJMLongoBMTannusACovolanL. Manganese-enhanced magnetic resonance imaging in the acute phase of the pilocarpine-induced model of epilepsy. Einstein (Sao Paulo) (2012) 10(2):247–52.10.1590/S1679-45082012000200023
110
NairismägiJPitkänenAKettunenMIKauppinenRAKubovaH. Status epilepticus in 12-day-old rats leads to temporal lobe neurodegeneration and volume reduction: a histologic and MRI study. Epilepsia (2006) 47(3):479–88.10.1111/j.1528-1167.2006.00455.x
111
van der ZijdenJPWuOvan der ToornARoelingTPBleysRLDijkhuizenRM. Changes in neuronal connectivity after stroke in rats as studied by serial manganese-enhanced MRI. Neuroimage (2007) 34(4):1650–7.10.1016/j.neuroimage.2006.11.001
112
DaducciATambaloSFioriniSOsculatiFTetiMFabenePFet alManganese-enhanced magnetic resonance imaging investigation of the interferon-α model of depression in rats. Magn Reson Imaging (2014) 32(5):529–34.10.1016/j.mri.2014.02.006
113
MoritaHOginoTSeoYFujikiNTanakaKTakamataAet alDetection of hypothalamic activation by manganese ion contrasted T(1)-weighted magnetic resonance imaging in rats. Neurosci Lett (2002) 326(2):101–4.10.1016/S0304-3940(02)00330-0
114
BrozoskiTJCiobanuLBauerCA. Central neural activity in rats with tinnitus evaluated with manganese-enhanced magnetic resonance imaging (MEMRI). Hear Res (2007) 228(1–2):168–79.10.1016/j.heares.2007.02.003
115
Ben-AriY. Limbic seizure and brain damage prouced by kainic acid: mechanisms and relevance to human temporal lobe epilepsy. Neuroscience (1985) 14(2):375–403.10.1016/0306-4522(85)90299-4
116
CavalheiroEARicheDALe gal La SalleG. Long-term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol (1982) 53:581–9.10.1016/0013-4694(82)90134-1
117
LeiteJPBortolottoZACavalheiroEA. Spontaneous recurrent seizures in rats: an experimental model of partial epilepsy. Neurosci Biobehav Rev (1990) 14:511–7.10.1016/S0149-7634(05)80076-4
118
MelloLECavalheiroEATanAMKupferWRPretoriusJKBabbTLet alCircuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting. Epilepsia (1993) 34:985–95.10.1111/j.1528-1157.1993.tb02123.x
119
Perez-MendesPBlancoMMCalcagnottoMECininiSMBachiegaJPapotiDet alModeling epileptogenesis and temporal lobe epilepsy in a non-human primate. Epilepsy Res (2011) 96(1–2):45–57.10.1016/j.eplepsyres.2011.04.015
120
TurskiLIkonomidouCTurskiWABortolottoZACavalheiroEA. Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse (1989) 3:154–71.10.1002/syn.890030207
121
TurskiWACavalheiroEABortolottoZAMelloLMSchwarzMTurskiL. Seizures produced by pilocarpine in mice: a behavioral, electroencephalographic and morphological analysis. Brain Res (1984) 321:237–53.10.1016/0006-8993(84)90177-X
122
BachiegaJCBlancoMMPerez-MendesPCininiSMCovolanLMelloLE. Behavioral characterization of pentylenetetrazol-induced seizures in the marmoset. Epilepsy Behav (2008) 13(1):70–6.10.1016/j.yebeh.2008.02.010
123
CovolanLMelloLE. Assessment of the progressive nature of cell damage in the pilocarpine model of epilepsy. Braz J Med Biol Res (2006) 39(7):915–24.10.1590/S0100-879X2006000700010
124
MelloLECovolanL. Spontaneous seizures preferentially injure interneurons in the pilocarpine model of chronic spontaneous seizures. Epilepsy Res (1996) 26(1):123–9.10.1016/S0920-1211(96)00048-4
125
BouilleretVNehligAMarescauxCNamerIJ. Magnetic resonance imaging follow-up of progressive hippocampal changes in a mouse model of mesial temporal lobe epilepsy. Epilepsia (2000) 41:642–50.10.1111/j.1528-1157.2000.tb00223.x
126
NairismägiJGröhnOHJKettunenMINissinenJKauppinenRAPitkänenA. Progression of brain damage after status epilepticus and its association with epileptogenesis: a quantitative MRI study in a rat model of temporal lobe epilepsy. Epilepsia (2004) 45(9):1024–34.10.1111/j.0013-9580.2004.08904.x
127
PolliRSMalheirosJMDos SantosRHamaniCLongoBMTannusAet alChanges in hippocampal volume are correlated with cell loss but not with seizure frequency in two chronic models of temporal lobe epilepsy. Front Neurol (2014) 5:111.10.3389/fneur.2014.00111
128
WolfOTDyakinVPatelAVadaszCde LeonMJMcEwenBSet alVolumetric structural magnetic resonance imaging (MRI) of the rat hippocampus following kainic acid (KA) treatment. Brain Res (2002) 934:87–96.10.1016/S0006-8993(02)02363-6
129
DubeCYuHNalciogluOBaramTZ. Serial MRI after experimental febrile seizures: altered T2 signal without neuronal death. Ann Neurol (2004) 56(5):709–14.10.1002/ana.20266
130
JuppBWilliamsJPTesiramYAVosmanskyMO’BrienTJ. Hippocampal T2 signal change during amygdala kindling epileptogenesis. Epilepsia (2006) 47(1):41–6.10.1111/j.1528-1167.2006.00368.x
131
Van EijsdenPNotenboomRGEWuOde GraanPNEVan NieuwenhuizenONicolayKet alIn vivo 1H magnetic resonance spectroscopy, T2-weighted and diffusion-weighted MRI during lithium-pilocarpine induced status epilepticus in the rat. Brain Res (2004) 1030:11–8.10.1016/j.brainres.2004.09.025
132
DedeurwaerdereSFangKChowMShenYTNoordmanIvan RaayLet alManganese-enhanced MRI reflects seizure outcome in a model for mesial temporal lobe epilepsy. Neuroimage (2013) 68:30–8.10.1016/j.neuroimage.2012.11.054
133
LeiBHChenJHYinHS. Repeated amphetamine treatment alters spinal magnetic resonance signals and pain sensitivity in mice. Neurosci Lett (2014) 583:70–5.10.1016/j.neulet.2014.09.031
134
LeslieATGuinsburgRMelloLECovolanL. Repetitive nociceptive stimuli in newborn rats do not alter the hippocampal neurogenesis. Pediatr Res (2008) 63(2):154–7.10.1203/PDR.0b013e31815ef75d
135
LeslieATFSAkersKMartinez-CanabalAMelloLCovolanLGuinsburgR. Neonatal inflammatory pain increases hippocampal neurogenesis in rat pups. Neurosci Lett (2011) 501:78–82.10.1016/j.neulet.2011.06.047
136
NegrigoAMedeirosMGuinsburgRCovolanL. Long-term gender behavioral vulnerability after nociceptive neonatal formalin stimulation in rats. Neurosci Lett (2011) 490:196–9.10.1016/j.neulet.2010.12.050
137
JeongK-YKangJ-H. Investigation of the pruritus-induced functional activity in the rat brain using manganese-enhanced MRI. J Magn Reson Imaging (2014).10.1002/jmri.24832
138
LinTHKimJHPerez-TorresCChiangCWTrinkausKCrossAHet alAxonal transport rate decreased at the onset of optic neuritis in EAE mice. Neuroimage (2014) 14:244–53.10.1016/j.neuroimage.2014.06.009
139
MajidTAliYOVenkitaramaniDVJangMKLuHCPautlerRG. In vivo axonal transport deficits in a mouse model of fronto-temporal dementia. Neuroimage Clin (2014) 31(4):711–7.10.1016/j.nicl.2014.02.005
140
YangJKhongPLWangYChuACHoSLCheungPTet alManganese-enhanced MRI detection of neurodegeneration in neonatal hypoxic-ischemic cerebral injury. Magn Reson Med (2008) 59(6):1329–39.10.1002/mrm.21484
141
YangJWuEX. Manganese-enhanced MRI detected the gray matter lesions in the late phase of mild hypoxic-ischemic injury in neonatal rat. Conf Proc IEEE Eng Med Biol Soc (2007) 2007:51–4.10.1109/IEMBS.2007.4352220
142
YangJWuEX. Detection of cortical gray matter lesion in the late phase of mild hypoxic-ischemic injury by manganese-enhanced MRI. Neuroimage (2008) 39(2):669–79.10.1016/j.neuroimage.2007.09.009
143
WideroeMOlsenOPedersenTBGoaPEKavelaarsAHeijnenCet alManganese-enhanced magnetic resonance imaging of hypoxic-ischemic brain injury in the neonatal rat. Neuroimage (2009) 45(3):880–90.10.1016/j.neuroimage.2008.12.007
Summary
Keywords
manganese, tracing method, epilepsy, nociception, anatomy, MRI
Citation
Malheiros JM, Paiva FF, Longo BM, Hamani C and Covolan L (2015) Manganese-Enhanced MRI: Biological Applications in Neuroscience. Front. Neurol. 6:161. doi: 10.3389/fneur.2015.00161
Received
29 December 2014
Accepted
29 June 2015
Published
10 July 2015
Volume
6 - 2015
Edited by
Amir Shmuel, McGill University, Canada
Reviewed by
Galit Pelled, Johns Hopkins School of Medicine, USA; Kai-Hsiang Chuang, Singapore Bioimaging Consortium, Singapore
Copyright
© 2015 Malheiros, Paiva, Longo, Hamani and Covolan.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Luciene Covolan, Rua Botucatu, 862 5° andar, São Paulo, SP 04023-062, Brazil, lcovolan@unifesp.br
†Both are first authors.
Specialty section: This article was submitted to Brain Imaging Methods, a section of the journal Frontiers in Neurology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.