Theoretical evaluation of magnetoreception of power-frequency fields.

Several effects of power-frequency (50/60 Hz) magnetic fields (PF-MF) of weak intensity have been hypothesized in animals and humans. No valid mechanism, however, has been proposed for an interaction between PF-MF and biological tissues and living beings at intensities relevant to animal and human exposure. Here we proposed to consider PF-MF as disrupters of the natural magnetic signal. Under exposure to these fields, an oscillating field exists that results from the vectorial summation of both the PF-MF and the geomagnetic field. At a PF-MF intensity (rms) of 0.5 microT, the peak-to-peak amplitude of the axis and/or intensity variations of this resulting field exceeds the related discrimination threshold of magnetoreception (MR) in migrating animals. From our evaluation of the 50/60 Hz responsiveness of the putative mechanisms of MR, single domain particles (Kirschvink's model) appear unable to transduce that oscillating signal. On the contrary, radical pair reactions are able to, as well as interacting multidomain iron-mineral platelets and clusters of superparamagnetic particles (Fleissner/Solov'yov's model). It is, however, not yet known whether the reception of 50/60 Hz oscillations of the natural magnetic signal might be of consequence or not.

Magnetic resonance relaxation induced by superparamagnetic particles used as contrast agents in magnetic resonance imaging: a theoretical review.

Superparamagnetic nanoparticles are used as contrast agents in magnetic resonance imaging and allow, for example, the detection of tumors or the tracking of stem cells in vivo. By producing magnetic inhomogeneities, they influence the nuclear magnetic relaxation times, which results in a darkening, on the image, of the region containing these particles. A great number of studies have been devoted to their magnetic properties, to their synthesis and to their influence on nuclear magnetic relaxation. The theoretical and fundamental understanding of the behavior of these particles is a necessary step in predicting their efficiency as contrast agents, or to be able to experimentally obtain some of their properties from a nuclear magnetic resonance measurement. Many relaxation models have been published, and choosing one of them is not always easy, many parameters and conditions have to be taken into account. Relaxation induced by superparamagnetic particles is generally attributed to an outersphere relaxation mechanism. Each model can only be used under specific conditions (motional averaging regime, static regime, high magnetic field, etc.) or for a particular sequence (Carr-Purcell-Meiboom-Gill, spin echo, free-induction decay, nuclear magnetic relaxation dispersion profile, etc.). The parameters included in the equations must be carefully interpreted. In some more complex conditions, simulations are necessary to be able to predict the relaxation rates. A good agreement is usually observed between the theoretical predictions and the experimental results, although some data still cannot be fully understood, such as the dependence of the transverse relaxation on the magnetic field. WIREs Nanomed Nanobiotechnol 2017, 9:e1468. doi: 10.1002/wnan.1468 For further resources related to this article, please visit the WIREs website.

Relaxivities of human liver and spleen ferritin.

Ferritin, the iron-storing protein of mammals, is known to darken T2-weighted magnetic resonance images. This darkening can be used to noninvasively measure an organ's iron content. Significant discrepancies exist between T2 data obtained with ferritin-containing tissues and with aqueous solutions of horse spleen ferritin (HSF). The NMR properties of stable human ferritin have never been studied in aqueous solutions. Relaxometry results on human liver and spleen ferritin are reported here, showing that the relaxation induced in aqueous solutions by human ferritins is comparable to that induced by HSF. As a consequence, the differences between ferritin-containing human tissues and ferritin solutions cannot be attributed to different NMR properties of human and horse ferritins, but probably to a clustering of the protein in vivo.

Effect of magnetic field and iron content on NMR proton relaxation of liver, spleen and brain tissues.

Iron accumulation is observed in liver and spleen during hemochromatosis and important neurodegenerative diseases involve iron overload in brain. Storage of iron is ensured by ferritin, which contains a magnetic core. It causes a darkening on T2 -weighted MR images. This work aims at improving the understanding of the NMR relaxation of iron-loaded human tissues, which is necessary to develop protocols of iron content measurements by MRI. Relaxation times measurements on brain, liver and spleen samples were realized at different magnetic fields. Iron content was determined by atomic emission spectroscopy. For all samples, the longitudinal relaxation rate (1/T1 ) of tissue protons decreases with the magnetic field up to 1 T, independently of iron content, while their transverse relaxation rate (1/T2 ) strongly increases with the field, either linearly or quadratically, or a combination thereof. The extent of the inter-echo time dependence of 1/T2 also varies according to the sample. A combination of theoretical models is necessary to describe the relaxation of iron-containing tissues. This can be due to the presence, inside tissues, of ferritin clusters of different sizes and densities. When considering all samples, a correlation (r(2) = 0.6) between 1/T1 and iron concentration is observed at 7.0 T. In contrast the correlation between 1/T2 and iron content is poor, even at high field (r(2) = 0.14 at 7.0 T). Our results show that MRI methods based on T1 or T2 measurements will easily detect an iron overloading at high magnetic field, but will not provide an accurate quantification of tissue iron content at low iron concentrations.

An evaluation of the contributions of diffusion and exchange in relaxation enhancement by MRI contrast agents.

Magnetic compounds are known to enhance water proton relaxation, either by diffusion or by proton exchange. An experimental procedure to distinguish both mechanisms is proposed and validated by relaxation measurements made in water-methanol solutions of Dy(3+), Ni(2+), Gd(3+), Tempo, and AMI-25. The test discriminates according to the character of the transverse relaxation in water-methanol solutions: a mono-exponential decay corresponds to diffusion, while a bi-exponential decay indicates the contribution of a proton exchange. The study of ferritin and akaganeite particle solutions confirms the occurrence of a proton exchange between protons belonging to hydroxyl groups of the particle surface and free water protons.

Cesium adsorption in hydrated iron oxide particles suspensions: an NMR study.

137Cs is an important component of nuclear waste which may pollute water. Its migration in natural environments is slowed down by adsorption on minerals. Cesium adsorption on akaganeite (beta-FeOOH) particles, dextran-coated ferrihydrite (5 Fe(2)O(3)-9H(2)O) particles, and ferritin in aqueous solutions is studied with (133)Cs nuclear magnetic resonance measurements. The longitudinal relaxation time (T(1)) of (133)Cs in the presence of such magnetic particles depends on whether the ions bind to the particle or not. T(1) of (133)Cs ions in aqueous solutions containing the same amount of magnetized particles will not depend on cesium concentration if relaxation is governed by diffusion (when cesium is not able to bind), but it will depend on cesium concentration if exchange governs relaxation (when cesium is able to bind). The method is successfully tested using TEMPO, a nitroxide stable free radical whose relaxation is due to diffusion. (133)Cs relaxation in solutions of ferritin, akaganeite, and dextran-coated ferrihydrite particles is found to result from a cationic exchange of cesium ions between particles surface and bulk ions, owing to adsorption. The effect of pH on (133)Cs relaxation in solutions of the particles is consistent with the adsorption properties of cations on hydrated iron oxides.

Monte Carlo simulation and theory of proton NMR transverse relaxation induced by aggregation of magnetic particles used as MRI contrast agents.

Superparamagnetic particles are widely used in MRI as R2 contrast agents. In this last decade, different studies have focused on aggregation of superparamagnetic particles for important applications such as multimodal agents. A complete study--via simulations--of the influence of aggregation on the MR efficiency of these particles at high magnetic field is presented here. First, an empirical expression is proposed for R2 in the presence of uniformly distributed nanoparticles, taking into account two regimes at once (motional averaging and slow motion regimes). Three cluster shapes are simulated: Sphere, shell and line. An analytical model is proposed to understand water transverse relaxation induced by spherical and shell aggregates. Simulations lead to the conclusion that, in the motional averaging regime, the most efficient aggregate contrast agent is the densest sphere or shell.

NMR relaxation and magnetic properties of superparamagnetic nanoworms.

Maghemite particles are used as T2 contrast agents for magnetic resonance imaging, especially for molecular and cellular imaging. Linear clusters of particles - called nanoworms - were recently developed to enhance the targeting efficiency. In this work, the magnetic and NMR relaxation properties of these nanoworms are studied at multiple magnetic fields. After the usual saturation at 0.5 T, the magnetization of the worms is still increasing, which results in an appreciable increase of the transverse relaxivity at high magnetic fields. The obtained relaxivities are typical of superparamagnetic particles of iron oxide (SPIOs). The transverse relaxation of the worms is clearly more efficient than for the isolated grains, which is confirmed by computer simulations. At high field, the longitudinal relaxation of the worms is less pronounced than for the grains, as expected for SPIOs. The nanoworms thus constitute a promising T2 agent for cellular and molecular imaging.

Magnetic resonance relaxation properties of superparamagnetic particles.

Nanometric crystals of maghemite are known to exhibit superparamagnetism. Because of the significance of their magnetic moment, maghemite nanoparticles are exceptional contrast agents and are used for magnetic resonance imaging (of the liver, spleen, lymph nodes), for magnetic resonance angiography and for molecular and cellular imaging. The relaxivity of these agents depends on their size, saturation magnetization and magnetic field and also on their degree of clustering. There are different types of maghemite particles whose relaxation characteristics are suited to a specific MRI application. The relaxation induced by maghemite particles is caused by the diffusion of water protons in the inhomogeneous field surrounding the particles. This is well described by a theoretical model that takes magnetite crystal anisotropy and Néel relaxation into account. Another type of superparamagnetic compound is ferritin, the iron-storing protein: it contains a superparamagnetic ferrihydrite core. Even if the resulting magnetic moment of ferritin is far smaller than for magnetite nanoparticles, its massive presence in different organs darkens T(2)-weighted MR images, allowing the noninvasive estimation of iron content, thanks to MRI. The relaxation induced by ferritin in aqueous solutions has been demonstrated to be caused by the exchange of protons between bulk water protons and the surface of the ferrihydrite crystal. However, in vivo, the relaxation properties of ferritin are still unexplained, probably because of protein clustering.

Variable-field relaxometry of iron-containing human tissues: a preliminary study.

Excess iron is found in brain nuclei from neurodegenerative patients (with Parkinson's, Alzheimer's and Huntington's diseases) and also in the liver and spleen of cirrhosis, hemochromatosis and thalassaemia patients. Ferritin, the iron-storing protein of mammals, is known to darken T(2)-weighted MR images. Understanding NMR tissue behavior may make it possible to detect those diseases, to follow their evolution and finally to establish a protocol for non-invasive measurement of an organ's iron content using MRI methods. In this preliminary work, the MR relaxation properties of embalmed iron-containing tissues were studied as well as their potential correlation with the iron content of these tissues. Relaxometric measurements (T(1) and T(2)) of embalmed samples of brain nuclei (caudate nucleus, dentate nucleus, globus pallidus, putamen, red nucleus and substantia nigra), liver and spleen from six donors were made at different magnetic fields (0.00023-14 T). The influence of the inter-echo time on transverse relaxation was also studied. Moreover, iron content of tissues was determined by inductively coupled plasma atomic emission spectroscopy. In brain nuclei, 1/T(2) increases quadratically with the field and depends on the inter-echo time in CPMG sequences at high fields, both features compatible with an outer sphere relaxation theory. In liver and spleen, 1/T(2) increases linearly with the field and depends on the inter-echo time at all fields. In our study, a correlation between 1/T(2) and iron concentration is observed. Explaining the relaxation mechanism for these tissues is likely to require a combination of several models. The value of 1/T(2) at high field could be used to evaluate iron accumulation in vivo. In the future, confirmation of those features is expected to be achieved from measurements of fresh (not embalmed) human tissues.

Physico-chemical and NMR relaxometric characterization of gadolinium hydroxide and dysprosium oxide nanoparticles.

Gadolinium hydroxide and dysprosium oxide nanoparticles, which constitute a new interesting class of magnetic nanoparticles, are characterized by different methods, using x-ray diffraction, magnetometry and NMR relaxometry at multiple fields. The rod-like particles are first shown to have a simple paramagnetic behavior, like the bulk compound, without any influence of the nanometric size of the particles. Because of their paramagnetic moment, these particles considerably shorten water relaxation times, especially the transverse relaxation time at high fields. The relaxation induced by gadolinium hydroxide particles is due to a proton exchange between the particle surface and bulk water, while the transverse relaxation caused by dysprosium oxide particles is governed by the diffusion of water protons around the magnetized particles. 1/T(2) increases linearly with the magnetic field for gadolinium hydroxide particles while a quadratic increase is observed for dysprosium oxide nanoparticles. The relaxation results are compared with those from previous studies and interpreted using different theories for the relaxation induced by magnetic particles.

Relaxation by clustered ferritin: a model for ferritin-induced relaxation in vivo.

Ferritin, the iron-storing protein of mammals, is known to darken T(2)-weighted MR images. This darkening could be used for the non-invasive measurement of an organ's iron content. Unexplained discrepancies exist between T(2) data obtained in ferritin-containing tissues and aqueous solutions of ferritin. The clustering of the protein induced by trypsin is used to evaluate the effect of ferritin agglomeration on the relaxation rates. Although the longitudinal relaxation is not significantly influenced by clustering, T(2) depends greatly on the stage of agglomeration: the transverse relaxation rate is higher for a clustered sample than for an unclustered sample. Moreover, the field and inter-echo time dependences of the relaxation rate indicate that the relaxation mechanism may be different between small clusters -- where a linear dependence of 1/T(2) on B(0) is observed -- and large clusters -- where a quadratic dependence is observed. These results help to explain the relaxation induced by ferritin in tissues.

Looking for biogenic magnetite in brain ferritin using NMR relaxometry.

Mammalian cellular iron is stored inside the multisubunit protein ferritin, normally taking the structure of a ferrihydrite-like mineral core. It has been suggested that biogenic magnetite, which has been detected in the brain and may be related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, could initially form in ferritin. Indeed, as ferritin is present in the brain, the ferrihydrite core could be a precursor for biogenic magnetite formation--particularly in cases where the normal functioning of the ferritin protein is disrupted. In this work, NMR relaxometry was used to detect magnetite inside samples of ferritin extracted from normal and Alzheimer-diseased brains. The method was first calibrated with different fractions of horse spleen ferritin and synthetic magnetite particles. The relaxometry results suggest that the proportion of iron contained in brain ferritin in the form of well-crystallized magnetite instead of ferrihydrite must be <1%, which is much less than that reported for 'magnetite-like' phase in recent transmission electron microscopy studies of similar samples. Consequently, the magnetization of this 'magnetite-like' phase must be very low compared with that of magnetite.

Relaxation induced by ferritin: a better understanding for an improved MRI iron quantification.

Ferritin, the iron storing protein, is known to darken T2-weighted MRI. This darkening can be used to non-invasively measure iron content. However, ferritin's behavior is not the same in tissue as in solution, a discrepancy that remains unexplained by the recently developed theory matching the NMR properties of ferritin solutions. A better understanding of the relaxation induced by ferritin in tissue could help for the development of new MRI protocols of iron quantification. In this short review, the main relaxation properties of ferritin in solution and in tissue are presented together with a discussion of the possible reasons for the faster transverse relaxation observed in tissues.

On T(2)-shortening by strongly magnetized spheres: a partial refocusing model.

Computer simulations of water transverse relaxation induced by superparamagnetic particles are shown to disagree with the available theories, covering the slow diffusion domain. Understanding these new simulations, not in the slow diffusion domain, thus requires a new theoretical approach. A "partial refocusing model" is introduced for this purpose; it is based on a spatial division between an inner region where the gradients are too strong for the refocusing pulses to be efficient and an outer region where they are efficient. This model agrees with published simulations of relaxation induced by magnetic dipoles approximated as points. The validity domains of the various models are also compared.

Susceptibility-induced T(2)-shortening and unrestricted diffusion.

In this work, discrepancies between recent theories for susceptibility-induced T(2)-shortening and classical results, namely outer sphere theory and diffusion through local fields with random gradients, are considered. These discrepancies are assigned to the use of unrestricted diffusion in the new theories.

Anomalous nuclear magnetic relaxation of aqueous solutions of ferritin: an unprecedented first-order mechanism.

Ferritin, the iron-storing protein, speeds up proton transverse magnetic relaxation in aqueous solutions. This T(2) shortening is used in MRI to quantify iron in the brain and liver. Current theoretical models underestimate the relaxation enhancement by ferritin at imaging fields, and they do not predict the measured dependence of the rate enhancement on the magnetization of the particles. Here it is shown that a proton exchange dephasing model (PEDM) overcomes these limitations by allowing a first-order relaxation mechanism. The PEDM considers proton exchange between bulk water and exchangeable protons located at the surface of the hydrated iron oxide nanometric core of the protein. Relaxation is shown to depend on the distribution of the frequency shifts of the adsorption sites; the observed properties agree with a Lorentzian distribution. Computer simulations utilizing recent Mössbauer spectroscopy data show that the distribution of these shifts is effectively Lorentzian.

Ferritin-induced relaxation in tissues: an in vitro study.

PURPOSE: To study in vitro the proton relaxation induced in tissues by ferritin, the iron-storing protein of mammals. MATERIALS AND METHODS: Nuclear magnetic relaxation dispersion (NMRD) profiles of liver and spleen from control and iron-overloaded mice are compared with NMRD profiles of ferritin and Fercayl-a ferritin-like akaganeite particle-in aqueous solutions or in 1% agarose gel. RESULTS: The relaxation of water protons induced by ferritin and Fercayl in 1% agarose gel is comparable with the relaxation of aqueous solutions of the same compounds, but slower than the relaxation of liver and spleen. The gel is not a good model of tissues containing ferritin. The longitudinal NMRD profiles of control and iron-overloaded liver and spleen are almost identical: ferritin accumulation has only a slight effect on longitudinal relaxation. The transverse NMRD profiles of liver and spleen tissues are linear, but the slope of the linear regression is larger for iron-loaded organs than for control ones, which is a consequence of a higher ferritin concentration in the former. However, the correlation between the slope of the transverse NMRD profiles and the iron concentration is not very good, probably because transverse relaxation is modified by the clustering of ferritin in cells. CONCLUSION: It could be difficult to develop a general technique for the accurate quantification of ferritin-bound iron by nuclear magnetic resonance or magnetic resonance imaging.

Dy-DTPA derivatives as relaxation agents for very high field MRI: the beneficial effect of slow water exchange on the transverse relaxivities.

Proton longitudinal and transverse relaxivities of Dy(DTPA)(2-) and Dy-DTPA bisamide derivatives (Dy(DTPA-BA): Dy-DTPA bisamide, Dy(DTPA-BEA): Dy-DTPA bisethylamide, Dy(DTPA-BnBA): Dy-DTPA bis-n-butylamide, and Dy(DTPA-BBMA): Dy-DTPA bisbismethylamide) were analyzed between 0.47 T and 18.8 T. Curie longitudinal relaxation was clearly observed at magnetic fields larger than 2.4 T, but the longitudinal relaxivities are limited by the fast rotation of the complexes. Rotational correlation times were separately assessed by deuterium relaxometry of the diamagnetic deuterated lanthanum analogs. Transverse relaxivity, which depends on the square of the magnetic field and on the residence time of the coordinated water molecule (tau(M)), was more than 7.5 times larger at 18.8 T and 310 K for Dy(DTPA-BA) and Dy(DTPA-BEA) as compared to Dy(DTPA)(2-). This difference is mainly related to the slower water exchange of the bisamide complexes, as confirmed by the values of tau(M) measured by oxygen-17 relaxometry. Such Dy-complexes, characterized by relatively long tau(M) values (tauM310 larger than 100 ns but smaller than 1 micros), thus appear to be useful as negative T(2) (or transverse) contrast agents for high-field imaging. This was demonstrated by the spin-echo images of phantoms obtained at 4.7 T on samples containing Dy(DTPA)(2-) and Dy(DTPA-BEA).