Biomedical subjects

Alan P Koretsky

Publications and source records attributed to Alan P Koretsky.

At least 19 recordsLinked to original sources

PubMed2006

Cocaine increases the intracellular calcium concentration in brain independently of its cerebrovascular effects.

Cocaine abuse increases the risk of life-threatening neurological complications such as strokes and seizures. Although the vasoconstricting properties of cocaine underlie its cerebrovascular effects, the mechanisms underlying its neurotoxicity remain incompletely understood. Here, we use optical techniques to measure cerebral blood volume, hemoglobin oxygenation (S(t)O(2)), and intracellular calcium ([Ca(2+)](i)) to test the hypothesis that cocaine increases [Ca(2+)](i) in the brain. The effects of cocaine were compared with those of methylphenidate, which has similar catecholaminergic effects as cocaine (except for serotonin increases) but no local anesthetic properties, and of lidocaine, which has similar local anesthetic effects as cocaine but is devoid of catecholaminergic actions. To control for the hemodynamic effects of cocaine, we assessed the effects of cocaine in animals in which normal blood pressure was maintained by infusion of phenylephrine, and we also measured the effects of transient hypotension (mimicking that induced by cocaine). We show that cocaine induced significant increases ( approximately 10-15%) in [Ca(2+)](i) that were independent of its hemodynamic effects and of the anesthetic used (isofluorance or alpha-chloralose). Lidocaine but not methylphenidate also induced significant [Ca(2+)](i) increases ( approximately 10-13%). This indicates that cocaine at a dose within the range used by drug users significantly increases the [Ca(2+)](i) in the brain and its local anesthetic, but neither its catecholaminergic nor its hemodynamic actions, underlies this effect. Cocaine-induced [Ca(2+)](i) increases are likely to accentuate the neurotoxic effects from cocaine-induced vasoconstriction and to facilitate the occurrence of seizures from the catecholaminergic effects of cocaine. These findings support the use of calcium channel blockers as a strategy to minimize the neurotoxic effects of cocaine.

Anesthetics, Local↗

PubMed2006

Extensive heterogeneity in white matter intensity in high-resolution T2*-weighted MRI of the human brain at 7.0 T.

MRI at high magnetic field strength potentially allows for an increase in resolution and image contrast. The gains are particularly dramatic for T(2)(*)-weighted imaging, which is sensitive to susceptibility effects caused by a variety of sources, including deoxyhemoglobin, iron concentration, and tissue microstructure. On the other hand, the acquisition of high quality whole brain MRI at high field is hampered by the increased inhomogeneity in B(o) and B(1) fields. In this report, high-resolution gradient echo MRI was performed using an 8-channel detector to obtain T(2)(*)-weighted images over large brain areas. The high SNR achieved with the multi-channel array enabled T(2)(*)-weighted images of the brain with an unprecedented spatial resolution of up to 0.2 x 0.2 x 0.5 mm(3). This high resolution greatly facilitated the detection of microscopic susceptibility effects. In addition to the expected contrast between gray, white matter, cerebral spinal fluid, and veins, a large degree of heterogeneity in contrast was observed throughout the white matter of normal brain. The measured T(2)(*) values in white matter varied as much as 30% with some of the variation apparently correlating with the presence of large fiber bundles.

Adult↗

PubMed2006

Magnetic resonance imaging of the migration of neuronal precursors generated in the adult rodent brain.

Neural progenitor cells (NPCs) reside within the subventricular zone (SVZ) in rodents. These NPCs give rise to neural precursors in adults that migrate to the olfactory bulb (OB) along a well-defined pathway, the rostral migratory stream (RMS). Here we demonstrate that these NPCs can be labeled, in vivo, in adult rats with fluorescent, micron-sized iron oxide particles (MPIOs), and that magnetic resonance imaging (MRI) can detect migrating neural precursors carrying MPIOs along the RMS to the OB. Immunohistochemistry and electron microscopy indicated that particles were inside GFAP(+) neural progenitor cells in the SVZ, migrating PSA-NCAM(+) and Doublecortin(+) neural precursors within the RMS and OB, and Neu-N(+) mature neurons in the OB. This work demonstrates that in vivo cell labeling of progenitor cells for MRI is possible and enables the serial, non-invasive visualization of endogenous progenitor/precursor cell migration.

Animals↗

PubMed2006

Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia.

The spatial and temporal response of the cerebral microcirculation to mild hypercapnia was investigated via two-photon laser-scanning microscopy. Cortical vessels, traversing the top 200 microm of somatosensory cortex, were visualized in alpha-chloralose-anesthetized Sprague-Dawley rats equipped with a cranial window. Intraluminal vessel diameters, transit times of fluorescent dextrans and red blood cells (RBC) velocities in individual capillaries were measured under normocapnic (PaCO2= 32.6 +/- 2.6 mm Hg) and slightly hypercapnic (PaCO2= 45 +/- 7 mm Hg) conditions. This gentle increase in PaCO2 was sufficient to produce robust and significant increases in both arterial and venous vessel diameters, concomitant to decreases in transit times of a bolus of dye from artery to venule (14%, P < 0.05) and from artery to vein (27%, P < 0.05). On the whole, capillaries exhibited a significant increase in diameter (16 +/- 33%, P < 0.001, n = 393) and a substantial increase in RBC velocities (75 +/- 114%, P < 0.001, n = 46) with hypercapnia. However, the response of the cerebral microvasculature to modest increases in PaCO2 was spatially heterogeneous. The maximal relative dilatation (range: 5-77%; mean +/- SD: 25 +/- 34%, P < 0.001, n = 271) occurred in the smallest capillaries (1.6 microm-4.0 microm resting diameter), while medium and larger capillaries (4.4 microm-6.8 microm resting diameter) showed no significant changes in diameter (P > 0.08, n = 122). In contrast, on average, RBC velocities increased less in the smaller capillaries (39 +/- 5%, P < 0.002, n = 22) than in the medium and larger capillaries (107 +/- 142%, P < 0.003, n = 24). Thus, the changes in capillary RBC velocities were spatially distinct from the observed volumetric changes and occurred to homogenize cerebral blood flow along capillaries of all diameters.

Animals↗

PubMed2006

High-resolution mapping of tumor redox status by magnetic resonance imaging using nitroxides as redox-sensitive contrast agents.

PURPOSE: There is considerable research directed toward the identification and development of functional contrast agents for medical imaging that superimpose tissue biochemical/molecular information with anatomical structures. Nitroxide radicals were identified as in vivo radioprotectors. Being paramagnetic, they can provide image contrast in magnetic resonance imaging (MRI) and electron paramagnetic resonance imaging (EPRI). The present study sought to determine the efficacy of nitroxide radioprotectors as functional image contrast agents. EXPERIMENTAL DESIGN: Nitroxide radioprotectors, which act as contrast agents, were tested by EPRI and MRI to provide tissue redox status information noninvasively. RESULTS: Phantom studies showed that the nitroxide, 3-carbamoyl-PROXYL (3CP), undergoes time-dependent reduction to the corresponding diamagnetic hydroxylamine only in the presence of reducing agents. The reduction rates of 3CP obtained by EPRI and MRI were in agreement suggesting the feasibility of using MRI to monitor nitroxide levels in tissues. The levels of 3CP were examined by EPRI and MRI for differences in reduction between muscle and tumor (squamous cell carcinoma) implanted in the hind leg of C3H mice simultaneously. In vivo experiments showed a T1-dependent image intensity enhancement afforded by 3CP which decreased in a time-dependent manner. Reduction of 3CP was found to be the dominant mechanism of contrast loss. The tumor regions exhibited a faster decay rate of the nitroxide compared to muscle (0.097 min(-1) versus 0.067 min(-1), respectively). CONCLUSIONS: This study shows that MRI can be successfully used to co-register tissue redox status along with anatomic images, thus providing potentially valuable biochemical information from the region of interest.

Animals↗

PubMed2006

In vivo detection of single cells by MRI.

The use of high-relaxivity, intracellular contrast agents has enabled MRI monitoring of cell migration through and homing to various tissues, such as brain, spinal cord, heart, and muscle. Here it is shown that MRI can detect single cells in vivo, homing to tissue, following cell labeling and transplantation. Primary mouse hepatocytes were double-labeled with green fluorescent 1.63-microm iron oxide particles and red fluorescent endosomal labeling dye, and injected into the spleens of recipient mice. This is a common hepatocyte transplantation paradigm in rodents whereby hepatocytes migrate from the spleen to the liver as single cells. One month later the animals underwent in vivo MRI and punctuated, dark contrast regions were detected scattered through the livers. MRI of perfused, fixed samples and labeled hepatocyte phantoms in combination with histological evaluation confirmed the presence of dispersed single hepatocytes grafted into the livers. Appropriate controls were used to determine whether the observed contrast could have been due to dead cells or free particles, and the results confirmed that the contrast was due to disperse, single cells. Detecting single cells in vivo opens the door to a number of experiments, such as monitoring rare cellular events, assessing the kinetics of stem cell homing, and achieving early detection of metastases.

Animals↗

PubMed2006

BOLD and CBV-weighted functional magnetic resonance imaging of the rat somatosensory system.

A multislice spin echo EPI sequence was used to obtain functional MR images of the entire rat brain with blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) contrast at 11.7 T. Maps of activation incidence were created by warping each image to the Paxinos rat brain atlas and marking the extent of the activated area. Incidence maps for BOLD and CBV were similar, but activation in draining veins was more prominent in the BOLD images than in the CBV images. Cerebellar activation was observed along the surface in BOLD images, but in deeper regions in the CBV images. Both effects may be explained by increased signal dropout and distortion in the EPI images after administration of the ferumoxtran-10 contrast agent for CBV fMRI. CBV-weighted incidence maps were also created for 10, 20, and 30 mg Fe/kg doses of ferumoxtran-10. The magnitude of the average percentage change during stimulation increased from 4.9% with the 10 mg Fe/kg dose to 8.7% with the 30-mg Fe/kg dose. Incidence of activation followed a similar trend.

Animals↗

PubMed2006

Cell labeling for magnetic resonance imaging with the T1 agent manganese chloride.

There is growing interest in using MRI to track cellular migration. To date, most work in this area has been performed using ultra-small particles of iron oxide. Immune cells are difficult to label with iron oxide particles. The ability of adoptively infused tumor specific T cells and N cells to traffic to the tumor microenvironment may be a critical determinant of their therapeutic efficacy. We tested the hypothesis that lymphocytes and B cells would label with MnCl2 to a level that would allow their detection by T1-weighted MRI. Significant signal enhancement was observed in human lymphocytes after a 1 h incubation with 0.05-1.0 mM MnCl2. A flow cytometry-based evaluation using propidium iodide and Annexin V staining showed that lymphocytes did not undergo apoptosis or necrosis immediately after and 24 h following a 1 h incubation with up to 1.0 mM MnCl2. Importantly, NK cells and cytotoxic T cells maintained their in vitro killing capacity after being incubated with up to 0.5 mM MnCl2. This is the first report to describe the use of MnCl2 to label lymphocytes. Our data suggests MnCl2 might be an alternative to iron oxide cell labeling for MRI-based cell migration studies.

Cell Movement↗

PubMed2005

Catheter confocal fluorescence imaging and functional magnetic resonance imaging of local and systems level recovery in the regenerating rodent sciatic nerve.

The goal of the present work was to develop minimally invasive imaging techniques to monitor local regeneration of peripheral nerves and to determine the extent of return to function of brain cortical regions associated with that nerve. The sciatic nerve crush model was applied to Sprague-Dawley rats and conventional histological staining for myelin, axons and cell architecture was carried out, as well as traditional behavioral testing, to verify that nerve regeneration was occurring. The rate of sciatic nerve regeneration was measured by determining the distance a lipophilic, fluorescence probe (DiO) would move along the nerve's membrane following a direct injection into the sciatic nerve. This movement was monitored using a catheter based, confocal fluorescence microscope. Two to five days after the crush, the dye moved 1.4 + 0.6 mm/day, as compared to a distance of 5.3 + 0.5 mm/day in the normal nerve. Between 9 and 13 days following the crush, the distance the dye moved increases to 5.5 + 0.5 mm/day, similar to the control, and by 15 days following the crush, the distance increased to 6.5 + 0.9 mm/day. Functional Magnetic Resonance Imaging (fMRI) measurements were performed on alpha-chloralose anesthetized rats to monitor the return of somatosensory cortical functions, which were activated by the stimulation of the lesioned peripheral nerve. fMRI results showed the return of cortical activation around 15 days following the crush procedure. However, the somatosensory cortical region activated by stimulating the crushed hindpaw was significantly smaller in extent than the intact hindpaw stimulation. These findings demonstrate that fluorescence imaging and fMRI can integrate local and system level correlates of nerve regeneration in a non-destructive manner, thus enabling serial imaging of individual animals.

Animals↗

PubMed2005

Sizing it up: cellular MRI using micron-sized iron oxide particles.

There is rapidly increasing interest in the use of MRI to track cell migration in intact animals. Currently, cell labeling is usually accomplished by endocytosis of nanometer-sized, dextran-coated iron oxide particles. The limitations of using nanometer-sized particles, however, are that millions of particles are required to achieve sufficient contrast, the label can be diluted beyond observability by cell division, and the label is biodegradable. These problems make it difficult to label cells other than macrophages in vivo, and to conduct long-term engraftment studies. It was recently demonstrated that micron-sized iron oxide particles (MPIOs) can be taken up by a number of cell types. In this study we examined the MRI properties of single MPIOs with sizes of 0.96, 1.63, 2.79, 4.50, and 5.80 microm. Furthermore, the capacity of cells to endocytose these MPIOs was investigated, and the MRI properties of the labeled cells at 7.0 and 11.7 Tesla were measured as a function of image resolution and echo time (TE). Cells labeled with MPIOs generally contained iron levels of approximately 100 pg, which is approximately threefold higher than those obtained with the best strategies to label cells using nanometer-sized particles. On occasion, some cells had levels as high as approximately 400 pg. We demonstrate that these large particles and the cells labeled with them can be detected by spin echo (SE)-based imaging methods. These measurements indicate that MPIOs should be useful for improving cell tracking by MRI.

Animals↗

PubMed2005

Manganese-enhanced magnetic resonance imaging of mouse brain after systemic administration of MnCl2: dose-dependent and temporal evolution of T1 contrast.

Manganese is a useful contrast agent for MRI of animals. Previously, it has been shown that systemic doses of MnCl(2) provide unique contrast in the rodent brain, enabling visualization of neuroarchitecture. The present work investigates the dose and temporal dependence of brain enhancement after i.v. administration of MnCl(2). Varying doses of MnCl(2) (9-175 mg/kg) were administered to mice from 0 to 24 h prior to T(1)-weighted manganese-enhanced MRI (MEMRI) at 11.7 T. Pre-MnCl(2) T(1) values measured in different brain regions ranged from 1.17 +/- 0.03 to 1.76 +/- 0.01 s. Post-MnCl(2) T(1) measured 24 hr after administration of MnCl(2) were significantly decreased, even after the lowest dose of MnCl(2). The largest decreases occurred in the pituitary gland, where post-MnCl(2) T(1) ranged from 231 +/- 23 ms following the lowest dose to 143 +/- 43 ms after the highest dose, while the smallest decreases were observed in cortex (post-MnCl(2) T(1) = 1060 +/- 5 ms for low dose and 637 +/- 5 ms for high dose). The contrast resulting after 14 hr did not change up to 24 hr. Enhancement first occurred in subarachnoid spaces, followed by ventricles and periventricular tissues, and finally reached the remainder of the brain. Cortical layers were detected at higher doses (>88 mg/kg) and olfactory bulb layers were detected with the lowest dose (9 mg/kg). Temporal evolution of the enhancement of the olfactory bulb layers was observed. In some regions of the brain, such as hippocampus and thalamus, the changes in contrast detected between 2 and 14 hr used very specific pathways. These results demonstrate that both the dose and the time after MnCl(2) can be manipulated to optimize brain contrast in a region-specific manner.

Animals↗

PubMed2005

Manganese enhanced magnetic resonance imaging of normal and ischemic canine heart.

The ability of MnCl2 to enhance canine myocardium and to delineate ischemic areas is demonstrated. A dose-response curve was measured using T1 weighted images in 11 dogs. MnCl2 (36, 113, 360, and 3600 micromol) was infused over a period of 3 min. Signal intensity increased linearly with MnCl2 dose. At 113 micromol ( approximately 10 micromol/kg) the steady-state increase in intensity averaged 212 +/- 34%. No significant physiologic effects due to the infused MnCl2 were detected except at the highest dose where there was a cardiac depressive effect. Ischemia was induced by occluding the left anterior descending coronary artery in 5 dogs. At an infused dose of 113 micromol, MnCl2 clearly demarcated the ischemic zone during coronary occlusion. Contrast enhancement in the ischemic zone was less than 30% compared with normal tissue (P < 0.03). In conclusion, the intracellular contrast agent MnCl2 enhances the canine heart and shows promise in detecting ischemia at doses that do not cause adverse cardiac effects.

Animals↗

PubMed2005

Simultaneous detection of blood volume, oxygenation, and intracellular calcium changes during cerebral ischemia and reperfusion in vivo using diffuse reflectance and fluorescence.

We describe an approach to measure changes in intracellular calcium along with changes in blood volume and oxygenation directly from the exposed rat cortex in vivo during cerebral ischemia and reperfusion. Measurements were made using a catheter-based optical system. The endface of a Y-shaped bifurcated fiber optic bundle was mounted on the cortical surface. It delivered the light at three wavelengths of 548, 555, and 572 nm to the brain through a fast monochromator coupled to a xenon lamp, and collected the calcium-dependent fluorescence emission from Rhod2 at 589 nm (excited at 548 nm) along with the diffuse reflections at the wavelengths of 555 and 572 nm to determine the changes in blood volume and hemoglobin oxygenation. The feasibility of this approach was experimentally examined by inducing transient cerebral ischemia and reperfusion in the rat. The ischemia induced an 8.5%+/-1.7% fluorescence increase compared with the preischemic control values. Blood volume and tissue hemoglobin oxygenation decreased by 57.4%+/-12.6% and 47.3%+/-12.5%, respectively. All signals normalized on reperfusion. The ischemia-induced change in Rhod2-Ca2+ fluorescence was blocked using a calcium channel blocker, nimodipine, confirming that intracellular changes in calcium were responsible for the fluorescence changes. Thus, changes in cerebral hemodynamics and intracellular calcium concentration changes were measured simultaneously, facilitating future studies of the interrelationship between neuronal activation and metabolic and vascular processes in normal and diseased brain.

Animals↗

PubMed2004

Temporal dynamics of the BOLD fMRI impulse response.

Using computer simulations and high-resolution fMRI experiments in humans (n=6) and rats (n=8), we investigated to what extent BOLD fMRI temporal resolution is limited by dispersion in the venous vasculature. For this purpose, time-to-peak (TTP) and full-width at half-maximum (FWHM) of the BOLD impulse response (IR) function were determined. In fMRI experiments, a binary m-sequence probe method was used to obtain high-sensitivity model-free single-pixel estimates of IR. Simulations of postcapillary flow suggested that flow-related dispersion leads to a TTP and FWHM increase, which can amount to several seconds in larger pial veins. fMRI experiments showed substantial spatial variation in IR timing within human visual cortex, together with a correlation between TTP and FWHM. Averaged across the activated regions and across subjects, TTP and FWHM were 4.51+/-0.52 and 4.04+/-0.42 s, respectively. In regions of interest (ROI) weighted toward the larger venous structures, TTP and FWHM increased to 5.07+/-0.64 and 4.32+/-0.48 s, respectively. In rat somatosensory cortex, TTP and FWHM were substantially shorter than in humans (2.73+/-0.60 and 2.28+/-0.63 s, respectively). These results are consistent with a substantial macrovascular dispersive contribution to BOLD IR in humans, and furthermore suggest that neurovascular coupling is a relatively rapid process, with a resolution below 2.3 s FWHM.

Adult↗

PubMed2004

Troponin I protein kinase C phosphorylation sites and ventricular function.

OBJECTIVE: Cardiac Troponin I (cTnI) phosphorylation by protein kinase C (PKC) results in a reduction of maximal actomyosin ATPase activity, an effect that is more marked at higher levels of calcium (Ca2+) and is likely to reduce active force development. We postulated that there would be greater Ca2+-dependent changes in ventricular function in hearts of cTnI transgenic (TG) mice expressing mutant troponin I lacking PKC sites compared to wild-type (WT). METHODS: We studied left ventricular function in isolated perfused hearts over a wide range of left ventricular volumes (Frank-Starling relationships) and mechanical restitution at three levels of perfusate Ca2+ (1.5, 2.5, and 3.5 mM). Manganese-enhanced magnetic resonance imaging (MRI) was used to study in-vivo sarcolemmal Ca2+ influx. The phosphorylation status of cTnI was examined by western blot analysis. RESULTS: Systolic contractile function in TG mice was altered in a calcium-dependent manner such that ventricular contractility was significantly greater in TG mice only at 3.5 mM perfusate Ca2+. The relaxation process and passive mechanical properties were unaltered in TG mice. Mechanical restitution parameters were abnormal in TG mice only at 1.5 mM perfusate Ca2+. In-vivo MRI data demonstrated up to 48% reduction in Mn2+-induced contrast enhancement, indicating reduced sarcolemmal Ca2+ influx. Western blot analysis indicated increased cTnI phosphorylation in TG mice. CONCLUSIONS: (1) TG mice exhibit calcium-dependent positive inotropy without slowed relaxation and this phenotype is mitigated by concomitant (compensatory) changes of reduced intracellular Ca2+ and increased phosphorylation of remaining cTnI sites. (2) The contractile phenotype in TG mice can be interpreted as an amplification of the normal response to changes in cellular Ca2+ observed in WT mice. Thus, PKC phosphorylation sites on cTnI play a role in attenuating contractile responses to changes in intracellular Ca2+.

Animals↗

PubMed2004

MRI detection of single particles for cellular imaging.

There is rapid growth in the use of MRI for molecular and cellular imaging. Much of this work relies on the high relaxivity of nanometer-sized, ultrasmall dextran-coated iron oxide particles. Typically, millions of dextran-coated ultrasmall iron oxide particles must be loaded into cells for efficient detection. Here we show that single, micrometer-sized iron oxide particles (MPIOs) can be detected by MRI in vitro in agarose samples, in cultured cells, and in mouse embryos. Experiments studying effects of MRI resolution and particle size from 0.76 to 1.63 microm indicated that T(2)* effects can be readily detected from single MPIOs at 50-microm resolution and significant signal effects could be detected at resolutions as low as 200 microm. Cultured cells were labeled with fluorescent MPIOs such that single particles were present in individual cells. These single particles in single cells could be detected both by MRI and fluorescence microscopy. Finally, single particles injected into single-cell-stage mouse embryos could be detected at embryonic day 11.5, demonstrating that even after many cell divisions, daughter cells still carry individual particles. These results demonstrate that MRI can detect single particles and indicate that single-particle detection will be useful for cellular imaging.

Animals↗

PubMed2004

Functional MRI of the rodent somatosensory pathway using multislice echo planar imaging.

A multislice EPI sequence was used to obtain functional MR images of the entire rat brain with BOLD contrast at 11.7 T. Ten to 11 slices covering the rat brain, with an in-plane resolution of 300 microm, provided enough sensitivity to detect activation in brain regions known to be involved in the somatosensory pathway during stimulation of the forelimbs. These regions were identified by warping a digitized rat brain atlas to each set of images. Data analysis was constrained to four major areas of the somatosensory pathway: primary and secondary somatosensory cortices, thalamus, and cerebellum. Incidence maps were generated. Electrical stimulation at 3 Hz led to significant activation in the primary sensory cortex in all rats. Activation in the secondary sensory cortex and cerebellum was observed in 70% of the studies, while thalamic activation was observed in 40%. The amplitude of activation was measured for each area, and average response time courses were calculated. Finally, the frequency dependence of the response to forepaw stimulation was measured in each of the activated areas. Optimal activation occurred in all areas at 3 Hz. These results demonstrate that whole-brain fMRI can be performed on rodents at 11.7 T to probe a well-defined neural network.

Animals↗

PubMed2004

Manganese-enhanced magnetic resonance imaging (MEMRI).

Manganese ion (Mn2+) is an essential metal that participates as a cofactor in a number of critical biological functions, such as electron transport, detoxification of free radicals and synthesis of neurotransmitters. Mn2+ can enter excitable cells using some of the same transport systems as Ca2+ and it can bind to a number of intracellular sites because it has high affinity for Ca2+ and Mg2+ binding sites on proteins and nucleic acids. Paramagnetic forms of manganese ions are potent MRI relaxation agents. Indeed, Mn2+ was the first contrast agent proposed for use in MRI. Recently, there has been renewed interest in combining the strong MRI relaxation effects of Mn2+ with its unique biology, in order to further expand the already broad assortment of useful information that can be measured by MRI. Such an approach has been continuously developed in the past several years to provide unique tissue contrast, to assess tissue viability, to act as a surrogate marker of calcium influx into cells and to trace neuronal connections. This special issue of NMR in Biomedicine on manganese-enhanced MRI (MEMRI) is aimed at providing the readers of this journal with an extensive review of some of the most prominent applications of MEMRI in biological systems. Written by several of the leaders in the field, the reviews and original research articles featured in this special issue are likely to offer an exciting and inspiring view of the broad range of applications of MEMRI.

Animals↗