Metabolic imaging of rat brain during pharmacologically-induced tinnitus.

Although much is known about the perceptual characteristics of tinnitus, its neural origins remain poorly understood. We investigated the pattern of neural activation in central auditory structures using positron emission tomography (PET) imaging in a rat model of salicylate-induced tinnitus. Awake rats were injected with the metabolic tracer, fluorine-18 fluorodeoxyglucose (FDG), once in a quiet state (baseline) and once during salicylate-induced tinnitus. Tinnitus was verified using a behavioral technique. Brain imaging was performed using a high-resolution microPET scanner. Rats underwent magnetic resonance imaging (MRI) and reconstructed MRI and microPET images were fused to identify brain structures. FDG activity in brain regions of interest were quantified and compared. MicroPET imaging showed that FDG activity in the frontal pole was stable between baseline and tinnitus conditions, suggesting it was metabolically inert during tinnitus. Inferior colliculi (p=0.03) and temporal cortices (p=0.003) showed significantly increased FDG activity during tinnitus relative to baseline; activity in the colliculi and temporal cortices increased by 17%+/-21% and 29%+/-20%, respectively. FDG activity in the thalami also increased during tinnitus, but the increase did not reach statistical significance (p=0.07). Our results show increased metabolic activity consistent with neuronal activation in inferior colliculi and auditory cortices of rats during salicylate-induced tinnitus. These results are the first to show that microPET imaging can be used to identify central auditory structures involved in tinnitus and suggest that microPET imaging might be used to evaluate the therapeutic potential of drugs to treat tinnitus.

Functional magnetic resonance (fMR) imaging of a rat brain tumor model: implications for evaluation of tumor microvasculature and therapeutic response.

Functional MR (fMR) imaging techniques based on blood oxygenation level dependent (BOLD) effects were developed and applied to a rat brain tumor model to evaluate the potential utility of the method for characterizing tumor growth and regression following treatment. Rats bearing 9L brain tumors in situ were imaged during inhalation of room air and after administration of 100% oxygen + acetazolamide (ACZ) injected 15 mg/kg intravenously. Pixel-to-pixel fMR maps of normalized signal intensity change from baseline values were calculated from T2 weighted spin echo (SE) images acquired pre- and post- oxygen + ACZ administration. Resultant fMR maps were then compared to gross histological sections obtained from corresponding anatomical regions. Regions containing viable tumor with increased cellular density and localized foci of necrotic tumor cells consistent with hypoxia were visualized in the fMR images as regions with decreased signal intensities, indicating diminished oxyhemoglobin concentration and blood flow as compared to normal brain. Histological regions having peritumor edema, caused by increased permeability of tumor vasculature, were visualized in the fMR images as areas with markedly increased signal intensities. These results suggest that fMR imaging techniques could be further developed for use as a non-invasive tool to assess changes in tumor oxygenation/hemodynamics, and to evaluate the pharmacologic effect of anti-neoplastic drugs.

Magnetic resonance imaging of response to chemotherapy in orthotopic xenografts of human bladder cancer.

Although orthotopic xenografts offer the potential for improved modeling of tumor development and response to therapy, noninvasive methods are not readily available to serially monitor tumors growing at internal sites in small rodents. In this study, magnetic resonance (MR) imaging techniques were developed using a clinical 1. 5 T whole body scanner to routinely monitor tumor growth kinetics of orthotopic UCRU-BL13 human bladder cancer xenografts after systemic chemotherapy. As a vehicle to test the system, comparisons were made between a standard agent, doxorubicin (DOX), and a novel formulation of liposome-encapsulated doxorubicin (DOXIL) to determine whether liposome encapsulation would alter chemosensitivity of BL13 in an orthotopic model. High resolution MR images acquired using direct three-dimensional data acquisitions yielded accurate volumetric measurements and detected tumors calculated to be

Suspect breast lesions: findings at dynamic gadolinium-enhanced MR imaging correlated with mammographic and pathologic features.

PURPOSE: To prospectively correlate dynamic contrast enhancement at magnetic resonance (MR) imaging with mammographic and pathologic features of suspect breast lesions. MATERIALS AND METHODS: Forty-nine patients with 51 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging at 1.5 T, as well as excisional biopsy or cyst aspiration. RESULTS: Twenty-two of 22 (100%) invasive carcinomas 8 mm or more in diameter, including three (12%) not evident on dense mammograms, enhanced 2.0 or more times the unenhanced intensity. One of three predominantly ductal carcinomas in situ and 10 of 26 (38%) benign lesions enhanced 2.0 or more times. Time-intensity curves were not statistically significantly different among enhancing carcinomas, fibroadenomas, or other benign lesions and showed no statistically significant correlations with pathologic size, nodal status, or hormone receptor status of invasive carcinomas. CONCLUSION: MR imaging enhancement of 2.0 or more times had high sensitivity (100%) for invasive carcinomas 8 mm or more in diameter, with moderate specificity (65%). Time-intensity curves showed no significant difference between enhancement of benign and malignant lesions.

Breast MRI as an adjunct in the diagnosis of a carcinoma partially obscured on mammography.

The role of unenhanced breast MRI as an adjunct to mammography in the diagnosis of a breast carcinoma presenting as architectural distortion partially obscured by dense tissue on film-screen mammography is illustrated.

Boronated metalloporphyrins: a novel approach to the diagnosis and treatment of cancer using contrast-enhanced MR imaging and neutron capture therapy.

Porphyrins are a unique class of metal chelating agents that have shown specific affinity for neoplasms. The water-soluble free-base derivative, tetrakiscarborane carboxylate ester of 2,4-(alpha,beta-dihydroxyethyl) deuteroporphyrin IX (BOPP), an agent designed for neutron capture therapy, has previously demonstrated selective localization and retention in a C6 murine glioma. In the present work, the authors demonstrate that the manganese chelate of BOPP also selectively localizes in a rat 9L gliosarcoma and preferentially enhances the tumor-normal brain contrast of T1-weighted images for at least 92 hours. The data indicate a maximal enhancement of contrast between tumor and normal brain at 24 hours after injection, compared with 5 minutes for manganese (III) tetraphenylporphine sulfonate (TPPS4). The results also indicate that Mn-BOPP may have a slower uptake in the 9L glioma than Mn-TPPS4 but a longer retention in the tumor. Mn-BOPP is unique in that it represents, to the authors' knowledge, the first example of a single agent that can enhance contrast between tumor and normal tissue and be potentially effective as an agent for boron neutron capture therapy.

On the origin of paramagnetic inhomogeneity effects in whole blood.

Asymmetric 7 T proton NMR signals of water in RBC suspensions containing intracellular deoxyhemoglobin are composites of chemically shifted extracellular and intracellular resonances broadened by gradient diffusion and modulated by transmembrane water exchange. This allows assessment of field dependences of acute hematoma intensities in proton MRIs at lower field strengths (less than or equal to 1.5 T).

Magnetic resonance imaging and histopathology of hydronephrosis in the rat.

Magnetic resonance imaging revealed conspicuously hyperintense regions in the papillary area of kidneys of three untreated rats. When the kidneys were examined histologically, a hydronephrosis associated with the presence of bacteria was found. This study relates magnetic resonance images of an early stage of hydronephrosis to its histological picture.

Magnetic resonance imaging (MRI) and pathophysiology of the rat kidney in streptozotocin-induced diabetes.

Proton magnetic resonance imaging was performed on rats before induction of diabetes with streptozotocin (STZ) and at 2 and 12 days postinduction. Images revealed an increase in maximal longitudinal and axial dimensions of the kidneys at 2 days and a further increase at 12 days. Similarly, an increase in the size of the remaining kidney was seen in a rat which underwent uninephrectomy as a positive control. Two major differences were observed between the kidney undergoing compensatory hypertrophy and those developing diabetic nephropathy: (i) Expansion of the renal vasculature was seen only in images of the diabetic rat; (ii) A loss in conspicuity of the normal corticomedullary junction was seen in the T2-weighted images of the diabetic rat but not in the uninephrectomized rat. Histologic examination revealed that the medulla increased to a size greater than the cortex during diabetic nephropathy whereas the medullary volume was less than that of the cortex during compensatory hypertrophy. In vitro T1 relaxation times in cortex, outer medulla and inner medulla of kidneys from control rats were measured and compared with the same respective regions in diabetic rats. When these values were correlated with tissue water content, a linear increase in relaxation rate versus percent water content from cortex to inner medulla was found in the control kidneys, but this correlation was absent in diabetic nephropathy. These studies demonstrate that MRI is an effective noninvasive tool for studying the course of renal hypertrophy and hydration changes in the development of renal disease in STZ-induced diabetes in the rat.

A comparative study of manganese meso-sulfonatophenyl porphyrins: contrast-enhancing agents for tumors.

Four manganese meso-sulfonatophenyl porphyrins were prepared, characterized and investigated for their potential as tumor-specific MRI contrast-enhancing agents in mice bearing subcutaneous implants of a mammary carcinoma (SMT-F). The trisulfonated tetraphenyl porphyrin, MnTPPS3 presented the most favorable profile: bio-distribution, tumor concentration and tumor relaxivity, when compared at 24 hr postinjection. Imaging experiments revealed that a time-dependent delineation of tumor morphology occurs in response to MnTPPS3 that appears to correlate with necrotic regions of the tumor.

The line shapes of the water proton resonances of red blood cells containing carbonyl hemoglobin, deoxyhemoglobin, and methemoglobin: implications for the interpretation of proton MRI at fields of 1.5 T and below.

The 300 MHz (7 T) water proton resonances of suspensions of red blood cells containing paramagnetic deoxyhemoglobin or methemoglobin can be resolved into two broad lines assignable to intra- and extracellular water which undergoes rapid T2 relaxation by diffusion in magnetic field gradients induced by the intracellular paramagnets. The width of the resolved lines allowed an estimate of the maximum contribution that diffusion makes to T2 relaxation at 7 T. The dependence of the diffusion contribution on the square of the strength of the static magnetic field suggest that diffusion makes a small contribution to water proton T2 relaxation at 1.5 T compared to 7 T, and a negligible one at 0.5 T in early and intermediate hematomas containing deoxyhemoglobin or methemoglobin in intact red blood cells. At the lower field strengths, water proton T2 relaxation is apparently dominated by the rapid chemical exchange (mean lifetime tau = 10 msec) between the intra- and extracellular environments.