Microscopic Magnetic Stimulation of Neural Tissue

Electrical stimulation is currently used to treat a wide range of cardiovascular, sensory and neurological diseases. Despite its success, there are significant limitations to its application, including incompatibility with magnetic resonance imaging, limited control of electric fields and decreased performance associated with tissue inflammation. Magnetic stimulation overcomes these limitations but existing devices (that is, transcranial magnetic stimulation) are large, reducing their translation to chronic applications. In addition, existing devices are not effective for deeper, sub-cortical targets. Here we demonstrate that sub-millimeter coils can activate neuronal tissue. Interestingly, the results of both modelling and physiological experiments suggest that different spatial orientations of the coils relative to the neuronal tissue can be used to generate specific neural responses. These results raise the possibility that micro-magnetic stimulation coils, small enough to be implanted within the brain parenchyma, may prove to be an effective alternative to existing stimulation devices

Molecular MR Imaging of Liver Fibrosis: A Feasibility Study Using Rat and Mouse Models

Background & Aims: Liver biopsy, the current clinical gold standard for fibrosis assessment, is invasive and has sampling errors, and is not optimal for screening, monitoring, or clinical decision-making. Fibrosis is characterized by excessive accumulation of extracellular matrix proteins including type I collagen. We hypothesize that molecular magnetic resonance imaging (MRI) with a probe targeted to type I collagen could provide a direct and non-invasive method of fibrosis assessment. Methods: Liver fibrosis was induced in rats with diethylnitrosamine and in mice with carbon tetrachloride. Animals were imaged prior to and immediately following i.v. administration of either collagen-targeted probe EP-3533 or non-targeted control Gd-DTPA. Magnetic resonance (MR) signal washout characteristics were evaluated from T1 maps and T1-weighted images. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for gadolinium and hydroxyproline. Results: EP-3533-enhanced MR showed greater signal intensity on delayed imaging (normalized signal enhancement mice: control = 0.39 ± 0.04, fibrotic = 0.55 ± 0.03, p <0.01) and slower signal washout in the fibrotic liver compared to controls (liver t1/2 = 51.3 ± 3.6 vs. 42.0 ± 2.5 min, p <0.05 and 54.5 ± 1.9 vs. 44.1 ± 2.9 min, p <0.01 for fibrotic vs. controls in rat and mouse models, respectively). Gd-DTPA-enhanced MR could not distinguish fibrotic from control animals. EP-3533 gadolinium concentration in the liver showed strong positive correlations with hydroxyproline levels (r = 0.74 (rats), r = 0.77 (mice)) and with Ishak scoring (r = 0.84 (rats), r = 0.79 (mice)). Conclusions: Molecular MRI of liver fibrosis with a collagen-specific probe identifies fibrotic tissue in two rodent models of disease

Molecular MRI of Collagen to Diagnose and Stage Liver Fibrosis

Background & Aims The gold standard in assessing liver fibrosis is biopsy despite limitations like invasiveness and sampling error and complications including morbidity and mortality. Therefore, there is a major unmet medical need to quantify fibrosis non-invasively to facilitate early diagnosis of chronic liver disease and provide a means to monitor disease progression. The goal of this study was to evaluate the ability of several magnetic resonance imaging (MRI) techniques to stage liver fibrosis. Methods A gadolinium (Gd)-based MRI probe targeted to type I collagen (termed EP-3533) was utilized to non-invasively stage liver fibrosis in a carbon tetrachloride (CCl4) mouse model and the results were compared to other MRI techniques including relaxation times, diffusion, and magnetization transfer measurements. Results The most sensitive MR biomarker was the change in liver:muscle contrast to noise ratio (ΔCNR) after EP-3533 injection. We observed a strong positive linear correlation between ΔCNR and liver hydroxyproline (i.e. collagen) levels (r = 0.89) as well as ΔCNR and conventional Ishak fibrosis scoring. In addition, the area under the receiver operating curve (AUR0C) for distinguishing early (Ishak ⩽3) from late (Ishak ⩾4) fibrosis was 0.942 ± 0.052 (p <0.001). By comparison, other MRI techniques were not as sensitive to changes in fibrosis in this model. Conclusions We have developed an MRI technique using a collagen-specific probe for diagnosing and staging liver fibrosis, and validated it in the CCl4 mouse model. This approach should provide a better means to monitor disease progression in patients

Is Macrocycle a Synonym for Kinetic Inertness in Gd(III) Complexes? Effect of Coordinating and Noncoordinating Substituents on Inertness and Relaxivity of Gd(III) Chelates with DO3A-like Ligands

Gadolinium chelates with octadentate ligands are widely used as contrast agents for magnetic resonance imaging (MRI), with macrocyclic ligands based on DO3A being preferred for the high kinetic inertness of their Gd chelates. A major challenge in the design of new bifunctional MRI probes is the need to control the rotational motion of the chelate, which greatly affects its relaxivity. In this work we explored facile alkylation of a secondary amine in macrocyclic DO3A-like ligands to create a short, achiral linkage to limit the undesired internal motion of chelates within larger molecular constructs. The acetate moiety on the <i>trans</i> nitrogen was also replaced with either a bidentate (ethoxyacetate, <b>L1</b> or methyl picolinate, <b>L2</b>) or bulky monodentate (methyl phosphonate, <b>L3</b>) donor arm to give octa- or heptadentate ligands, respectively. The resultant Gd­(III) complexes were all monohydrated (<i>q</i> = 1) and exhibited water residency times that spanned 2 orders of magnitude (τ_M = 2190 ± 170, 3500 ± 90, and 12.7 ± 3.8 ns at 37 °C for Gd<b>L1</b>, Gd<b>L2</b>, and Gd<b>L3</b>, respectively). Alkylation of the secondary amine with a noncoordinating biphenyl moiety resulted in coordinatively saturated <i>q</i> = 0 complexes of octadentate ligands <b>L1</b> and <b>L2</b>. Relaxivities were limited by slow water exchange and/or lack of water coligand. All complexes showed decreased inertness compared to [Gd­(DO3A)] despite higher ligand denticity, and inertness was further decreased upon N-alkylation. These results demonstrate that high kinetic inertness and in vivo safety of Gd chelates with macrocyclic ligands should not be generalized

Molecular MR imaging of fibrosis in a mouse model of pancreatic cancer

Fibrosis with excessive amounts of type I collagen is a hallmark of many solid tumours, and fibrosis is a promising target in cancer therapy, but tools for its non-invasive quantification are missing. Here we used magnetic resonance imaging with a gadolinium-based probe targeted to type I collagen (EP-3533) to image and quantify fibrosis in pancreatic ductal adenocarcinoma. An orthotopic syngeneic mouse model resulted in tumours with 2.3-fold higher collagen level compared to healthy pancreas. Animals were scanned at 4.7 T before, during and up to 60 min after i.v. injection of EP-3533, or of its non-binding isomer EP-3612. Ex-vivo quantification of gadolinium showed significantly higher uptake of EP-3533 compared to EP-3612 in tumours, but not in surrounding tissue (blood, muscle). Uptake of EP-3533 visualized in T1-weighted MRI correlated well with spatial distribution of collagen determined by second harmonic generation imaging. Differences in the tumour pharmacokinetic profiles of EP-3533 and EP-3612 were utilized to distinguish specific binding to tumour collagen from non-specific uptake. A model-free pharmacokinetic measurement based on area under the curve was identified as a robust imaging biomarker of fibrosis. Collagen-targeted molecular MRI with EP-3533 represents a new tool for non-invasive visualization and quantification of fibrosis in tumour tissue

Molecular MRI of collagen to diagnose and stage liver fibrosis

Available in PMC 2014 November 01.Background & Aims: The gold standard in assessing liver fibrosis is biopsy despite limitations like invasiveness and sampling error and complications including morbidity and mortality. Therefore, there is a major unmet medical need to quantify fibrosis non-invasively to facilitate early diagnosis of chronic liver disease and provide a means to monitor disease progression. The goal of this study was to evaluate the ability of several magnetic resonance imaging (MRI) techniques to stage liver fibrosis. Methods: A gadolinium (Gd)-based MRI probe targeted to type I collagen (termed EP-3533) was utilized to non-invasively stage liver fibrosis in a carbon tetrachloride (CCl[subscript 4]) mouse model and the results were compared to other MRI techniques including relaxation times, diffusion, and magnetization transfer measurements. Results: The most sensitive MR biomarker was the change in liver:muscle contrast to noise ratio (ΔCNR) after EP-3533 injection. We observed a strong positive linear correlation between ΔCNR and liver hydroxyproline (i.e. collagen) levels (r = 0.89) as well as ΔCNR and conventional Ishak fibrosis scoring. In addition, the area under the receiver operating curve (AUR0C) for distinguishing early (Ishak ⩽3) from late (Ishak ⩾4) fibrosis was 0.942 ± 0.052 (p <0.001). By comparison, other MRI techniques were not as sensitive to changes in fibrosis in this model. Conclusions: We have developed an MRI technique using a collagen-specific probe for diagnosing and staging liver fibrosis, and validated it in the CCl4 mouse model. This approach should provide a better means to monitor disease progression in patients.National Cancer Institute (U.S.) (CA140861)Whitehead Institute for Biomedical Research (Grant EB009062)Sanofi Aventis (Firm) (Innovation Award