Jiun-Jie Wang

Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain

The superparamagnetic properties of magnetic nanoparticles (MNPs) allow them to be guided by an externally positioned magnet and also provide contrast for MRI. However, their therapeutic use in treating CNS pathologies in vivo is limited by insufficient local accumulation and retention resulting from their inability to traverse biological barriers. The combined use of focused ultrasound and magnetic targeting synergistically delivers therapeutic MNPs across the blood–brain barrier to enter the brain both passively and actively. Therapeutic MNPs were characterized and evaluated both in vitro and in vivo, and MRI was used to monitor and quantify their distribution in vivo. The technique could be used in normal brains or in those with tumors, and significantly increased the deposition of therapeutic MNPs in brains with intact or compromised blood–brain barriers. Synergistic targeting and image monitoring are powerful techniques for the delivery of macromolecular chemotherapeutic agents into the CNS under the guidance of MRI.

Accelerating SENSE using compressed sensing

Both parallel MRI and compressed sensing (CS) are emerging techniques to accelerate conventional MRI by reducing the number of acquired data. The combination of parallel MRI and CS for further acceleration is of great interest. In this paper, we propose a novel method to combine sensitivity encoding (SENSE), one of the standard methods for parallel MRI, and compressed sensing for rapid MR imaging (SparseMRI), a recently proposed method for applying CS in MR imaging with Cartesian trajectories. The proposed method, named CS‐SENSE, sequentially reconstructs a set of aliased reduced‐field‐of‐view images in each channel using SparseMRI and then reconstructs the final image from the aliased images using Cartesian SENSE. The results from simulations and phantom and in vivo experiments demonstrate that CS‐SENSE can achieve a reduction factor higher than those achieved by SparseMRI and SENSE individually and outperform the existing method that combines parallel MRI and CS. Magn Reson Med, 2009.

Blood-Brain Barrier Disruption with Focused Ultrasound Enhances Delivery of Chemotherapeutic Drugs for Glioblastoma Treatment

PURPOSE To demonstrate the feasibility of using focused ultrasound to enhance delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to glioblastomas in rats with induced tumors and determine if such an approach increases treatment efficacy. MATERIALS AND METHODS All animal experiments were approved by the animal committee and adhered to the experimental animal care guidelines. A 400-kHz focused ultrasound generator was used to transcranially disrupt the blood-brain barrier (BBB) in rat brains by delivering burst-tone ultrasound energy in the presence of microbubbles. The process was monitored in vivo by using magnetic resonance (MR) imaging. Cultured C6 glioma cells implanted in Sprague-Dawley rats were used as the tumor model. BCNU (13.5 mg/kg) was administered intravenously and its concentration in brains was quantified by using high-performance liquid chromatography. MR imaging was used to evaluate the effect of treatments longitudinally, including analysis of tumor progression and animal survival, and brain tissues were histologically examined. Methods including the two-tailed unpaired t test and the Mantel-Cox test were used for statistical analyses, with a significance level of .05. RESULTS Focused ultrasound significantly enhanced the penetration of BCNU through the BBB in normal (by 340%) and tumor-implanted (by 202%) brains without causing hemorrhaging. Treatment of tumor-implanted rats with focused ultrasound alone had no beneficial effect on tumor progression or on animal survival up to 60 days. Administration of BCNU only transiently controlled tumor progression; nevertheless, relative to untreated controls, animal survival was improved by treatment with BCNU alone (increase in median survival time [IST(median)], 15.7%, P = .023). Treatment with focused ultrasound before BCNU administration controlled tumor progression (day 31: 0.05 cm(3) + or - 0.1 [standard deviation] vs 0.28 cm(3) + or - 0.1) and improved animal survival relative to untreated controls (IST(median), 85.9%, P = .0015). CONCLUSION This study demonstrates a means of increasing localized chemotherapeutic drug delivery for brain tumor treatment and strongly supports the feasibility of this treatment in a clinical setting.

Detection of lymph node metastasis in cervical and uterine cancers by diffusion‐weighted magnetic resonance imaging at 3T

To evaluate diffusion‐weighted imaging (DWI) for detection of pelvic lymph node metastasis in patients with cervical and uterine cancers.

Myometrial Invasion in Endometrial Cancer: Diagnostic Accuracy of Diffusion-weighted 3.0-T MR Imaging—Initial Experience

PURPOSE To assess the diagnostic accuracy of fused T2-weighted and high-b-value diffusion-weighted (DW) magnetic resonance (MR) images at 3 T for evaluation of myometrial invasion in patients with endometrial cancer. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. From May 2006 to October 2007, 48 consecutive patients aged 25-80 years (mean age, 57 years) who had endometrial cancer were prospectively enrolled for preoperative evaluation by using a 3-T MR unit. Two radiologists interpreted the depth of myometrial invasion on T2-weighted images, dynamic contrast material-enhanced MR images, and fused T2-weighted and DW MR images (b = 1000 sec/mm(2)). Statistical methods included kappa statistics for reader agreement, Pearson analysis for pathologic correlation, accuracy assessment, and receiver operating characteristic analysis for diagnostic performance comparison. Surgical pathologic findings were the reference standard. RESULTS Reader agreement was excellent for fused T2-weighted and DW images (weighted kappa, 0.79), with a significant pathologic correlation regarding the depth of myometrial invasion (r = 0.94, P < .0001). For assessing any myometrial involvement, addition of fused T2-weighted and DW imaging to dynamic contrast-enhanced or dynamic contrast-enhanced and T2-weighted imaging was significantly better compared with dynamic contrast-enhanced imaging alone (P < .001) or dynamic contrast-enhanced and T2-weighted (P = .001) imaging; T2-weighted imaging combined with fused T2-weighted and DW imaging also was better than dynamic contrast-enhanced and T2-weighted imaging (P = .001). Tumor apparent diffusion coefficients were 0.60-1.32 x 10(-3) mm(2)/sec (median, 0.75 x 10(-3) mm(2)/sec), with no significant correlation with the depth of myometrial invasion (P = .31, r = -0.15). CONCLUSION Fused T2-weighted and high-b-value DW images at 3 T can provide accurate information for preoperative evaluation of myometrial invasion.

Parkinson Disease: Diagnostic Utility of Diffusion Kurtosis Imaging

PURPOSE To examine the usefulness of diffusion kurtosis imaging for the diagnosis of Parkinson disease (PD). MATERIALS AND METHODS Examinations were performed with the understanding and written consent of each subject, with local ethics committee approval, and in compliance with national legislation and Declaration of Helsinki guidelines. Diffusion-weighted magnetic resonance imaging was performed in 30 patients with idiopathic PD (mean age, 64.5 years ± 3.4 [standard deviation]) and 30 healthy subjects (mean age, 65.0 years ± 5.1). Mean kurtosis, fractional anisotropy, and mean, axial, and radial diffusivity of the basal ganglia were compared between the groups. Disease severity was assessed by using Hoehn and Yahr staging and the motor section of the Unified Parkinsons Disease Rating Scale (mean scores, 2.0 and 33.6, respectively). Receiver operating characteristic (ROC) analysis was used to compare the diagnostic accuracies of the indexes of interest. Pearson correlation coefficient analysis was used to correlate imaging findings with disease severity. RESULTS Mean kurtosis in the putamen was higher in the PD group (0.93 ± 0.15) than in the control group (0.71 ± 0.09) (P < .000416). The area under the ROC curve (AUC) was 0.95 for both the ipsilateral putamen and the ipsilateral substantia nigra. The mean kurtosis for the ipsilateral substantia nigra had the best diagnostic performance (mean cutoff, 1.10; sensitivity, 0.92; specificity, 0.87). In contrast, AUCs for the tensor-derived indexes ranged between 0.43 (axial and radial diffusivity in substantia nigra) and 0.65 (fractional anisotropy in substantia nigra). CONCLUSION Diffusion kurtosis imaging in the basal ganglia, as compared with conventional diffusion-tensor imaging, can improve the diagnosis of PD.

Hemorrhage detection during focused-ultrasound induced blood-brain-barrier opening by using susceptibility-weighted magnetic resonance imaging.

High-intensity focused ultrasound has been discovered to be able to locally and reversibly increase the permeability of the blood-brain barrier (BBB), which can be detected using magnetic resonance imaging (MRI). However, side effects such as microhemorrhage, erythrocyte extravasations or even extensive hemorrhage may also occur. Although current contrast-enhanced T1-weighted MRI can be used to detect the changes in BBB permeability, its efficacy in detecting tissue hemorrhage after focused-ultrasound sonication remains limited. The purpose of this study is to investigate the feasibility of magnetic resonance susceptibility-weighted imaging (MR-SWI) for identifying possible tissue hemorrhage associated with disruption of the BBB induced by focused ultrasound in a rat model. The brains of 42 Sprague-Dawley rats were subjected to 107 sonications, either unilaterally or bilaterally. Localized BBB opening was achieved by delivering burst-mode focused ultrasound energy into brain tissue in the presence of microbubbles. Rats were studied by T2-weighted and contrast-enhanced T1-weighted MRI techniques, as well as by SWI. Tissue changes were analyzed histologically and the extent of apoptosis was investigated with the terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling method. The results demonstrated that SWI is more sensitive than standard T2-weighted and contrast-enhanced T1-weighted MRI techniques in detecting hemorrhages after brain sonication. Longitudinal study showed that SWI is sensitive to the recovery process of the damage and, therefore, could provide important and complementary information to the conventional MR images. Potential applications such as drug delivery in the brain might be benefited.

Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma treatment

Malignant glioma is a common and severe primary brain tumor with a high recurrence rate and an extremely high mortality rate within 2 years of diagnosis, even when surgical, radiological, and chemotherapeutic interventions are applied. Intravenously administered drugs have limited use because of their adverse systemic effects and poor blood-brain barrier penetration. Here, we combine 2 methods to increase drug delivery to brain tumors. Focused ultrasound transiently permeabilizes the blood-brain barrier, increasing passive diffusion. Subsequent application of an external magnetic field then actively enhances localization of a chemotherapeutic agent immobilized on a novel magnetic nanoparticle. Combining these techniques significantly improved the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea to rodent gliomas. Furthermore, the physicochemical properties of the nanoparticles allowed their delivery to be monitored by magnetic resonance imaging (MRI). The resulting suppression of tumor progression without damaging the normal regions of the brain was verified by MRI and histological examination. This noninvasive, reversible technique promises to provide a more effective and tolerable means of tumor treatment, with lower therapeutic doses and concurrent clinical monitoring.

The characteristics, biodistribution, magnetic resonance imaging and biodegradability of superparamagnetic core-shell nanoparticles.

An efficient contrast agent for magnetic resonance imaging (MRI) is essential to enhance the detection and characterization of lesions within the body. In this study, we described the development of biodegradable nanoparticles with a core-shell structure to formulate superparamagnetic iron oxide (CSNP-SPIO) for MRI. The developed nanoparticles were composed of a hydrophobic PLGA core and a positively-charged glycol chitosan shell. The results obtained by transmission electron microscopy, energy dispersive X-ray analysis, electron energy loss spectroscopy, and X-ray diffraction measurement confirmed that the prepared nanoparticles had a core-shell structure with SPIO in their core area. No aggregation of nanoparticles was observed during storage in water, as a result of the electrostatic repulsion between the positively-charged nanoparticles. The magnetic properties of nanoparticles were examined by a vibrating sample magnetometer and a superconducting quantum interference device; the results showed that the superparamagnetism of SPIO was preserved after the CSNP-SPIO formulation. In tracking their cellular internalization pathway, we found that CSNP-SPIO accumulated in lysosomes. In the biodistribution study, a high level of radioactivity was observed in the liver shortly after administration of the (99m)Tc-labeled CSNP-SPIO intravenously. Once taken up by the liver cells, the liver turned dark on T(2)* images. Following cellular internalization, CSNP-SPIO were broken down gradually; therefore, with time increasing, a significant decrease in the darkness of the liver on T(2)* images was found. The aforementioned results indicate that the developed CSNP-SPIO can serve as an efficient MRI contrast agent and could be degraded after serving their imaging function.

The effect of continuous theta burst stimulation over premotor cortex on circuits in primary motor cortex and spinal cord

OBJECTIVE To understand the effect of continuous theta burst stimulation (cTBS) given to the premotor area, we studied the circuits within the primary motor cortex and spinal cord after cTBS over the dorsal premotor area (PMd). METHODS Three sets of parameters, including corticospinal excitability, short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) and forearm reciprocal inhibition (RI) were tested. RESULTS Paralleling the effects of cTBS applied directly to the primary motor cortex, cTBS over the left PMd suppressed corticospinal excitability as measured by the change in the size of MEPs evoked by single pulse TMS over primary motor cortex. Premotor cTBS appeared to have a longer lasting, but no more powerful effect on corticospinal excitability than motor cTBS, however, unlike motor cTBS it had no effect on SICI or ICF. Finally, although premotor cTBS had no effect on spinal H-reflexes, it did reduce the third phase of RI between forearm extensor and flexor muscles. CONCLUSIONS Premotor cTBS is a quick and useful way of modulating excitability in cortical and possibly subcortical motor circuits. SIGNIFICANCE Premotor cTBS can be used as an alternative to regular rTMS to evaluate cortical function, motor behaviours and the response to disease therapy.