targeted-neuronal-injury-for-non-invasive-disconnection-brain

Targeted Neuronal Injury for the Non-Invasive Disconnection of Brain Circuitry

Surgical intervention can be quite effective for treating certain types of medically intractable neurological diseases. This approach is particularly ...

Stanford University

Disturbances in the function of neuronal circuitry contribute to most neurologic disorders. As knowledge of the brain's connectome continues to improve, a more refined understanding of the role of specific circuits in pathologic states will also evolve. Tools capable of manipulating identified circuits in a targeted and restricted manner will be essential not only to expand our understanding of the functional roles of such circuits, but also to therapeutically disconnect critical pathways contributing to neurologic disease. This study took advantage of the ability of low-intensity focused ultrasound (FUS) to transiently disrupt the blood-brain barrier (BBB) to deliver a neurotoxin with poor BBB permeability (quinolinic acid [QA]) in a guided manner to a target region in the brain parenchyma. Ten male Sprague-Dawley rats were divided into two groups receiving the following treatments: (i) magnetic resonance-guided FUS + microbubbles + saline (n = 5), or (ii) magnetic resonance-guided FUS + microbubbles + QA (n = 5). Systemic administration of QA was well tolerated. However, when QA and microbubbles were systemically administered in conjunction with magnetic resonance-guided FUS, the BBB was disrupted and primary neurons were destroyed in the targeted subregion of the hippocampus in all QA-treated animals. Administration of vehicle (saline) together with microbubbles and FUS also disrupted the BBB but did not produce neuronal injury. These findings indicate the feasibility of non-invasively destroying a targeted region of the brain parenchyma using low-intensity FUS together with systemic administration of microbubbles and a neurotoxin. This approach could be of therapeutic value in various disorders in which disturbances of neural circuitry contribute to neurologic disease.

Non-Invasive, Focal Disconnection of Brain Circuitry Using Magnetic Resonance-Guided Low-Intensity Focused Ultrasound to Deliver a Neurotoxin.

This study aimed at evaluating the diagnostic performance of quantitative shear wave elastography (SWE) in differentiating metastatic cervical lymph nodes from benign nodes in patients with thyroid nodules.

The value of quantitative shear wave elastography in differentiating the cervical lymph nodes in patients with thyroid nodules.

Iron oxides nanoparticles tailored for magnetic particle imaging (MPI) have been synthesized, and their MPI signal intensity is three-times that of commercial MPI contrast (Ferucarbotran, also called Vivotrax) and seven-times that of MRI contrast (Feraheme) at the same Fe concentration. MPI tailored iron oxide nanoparticles were encapsulated with semiconducting polymers to produce Janus nanoparticles that possessed optical and magnetic properties for MPI and fluorescence imaging. Janus particles were applied to cancer cell labeling and in vivo tracking, and as few as 250 cells were imaged by MPI after implantation, corresponding to an amount of 7.8 ng of Fe. Comparison with MRI and fluorescence imaging further demonstrated the advantages of our Janus particles for MPI-super sensitivity, unlimited tissue penetration, and linear quantitativity.

Janus Iron Oxides @ Semiconducting Polymer Nanoparticle Tracer for Cell Tracking by Magnetic Particle Imaging.

The goal of this study was to test different combinations of acoustic pressure and doses of quinolinic acid (QA) for producing a focal neuronal lesion in the murine hippocampus without causing unwanted damage to adjacent brain structures. Sixty male CD-1 mice were divided into 12 groups that underwent magnetic resonance-guided focused ultrasound at high (0.67 MPa), medium (0.5 MPa) and low (0.33 MPa) acoustic peak negative pressures and received QA at high (0.012 mmol), medium (0.006 mmol) and low (0.003 mmol) dosages. Neuronal loss occurred only when magnetic resonance-guided focused ultrasound with adequate acoustic power (0.67 or 0.5 MPa) was combined with QA. The animals subjected to the highest acoustic power had larger lesions than those treated with medium acoustic power, but two mice had evidence of bleeding. When the intermediate acoustic power was used, medium and high dosages of QA produced lesions larger than those produced by the low dosage.

Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound.

Respiratory motion correction is necessary for the quantitative analysis of liver contrast-enhanced ultrasound (CEUS) image sequences. Most respiratory motion correction methods are based on the dual mode of CEUS image sequences, including contrast and grayscale image sequences. Due to free-breathing motion, the acquired two-dimensional (2D) ultrasound cine might show the in-plane and out-of-plane motion of tumors. The registration of an entire 2D ultrasound contrast image sequence based on out-of-plane images is ineffective. For the respiratory motion correction of CEUS sequences, the reference image is usually considered the standard for the deletion of any out-of-plane images. Most methods used for the selection of the reference image are subjective in nature. Here, a quantitative selection method for an optimal reference image from CEUS image sequences in the B mode and contrast mode was explored.

Respiratory motion correction for liver contrast-enhanced ultrasound by automatic selection of a reference image.

Surgery to treat drug-resistant epilepsy can be quite effective but remains substantially underutilized. A pilot study was undertaken to test the feasibility of using a non-invasive, non-ablative, approach to produce focal neuronal loss to treat seizures in a rodent model of temporal lobe epilepsy. In this study, spontaneous, recurrent seizures were established in a mouse model of pilocarpine-induced status epilepticus. After post-status epilepticus stabilization, baseline behavioral seizures were monitored for 30 d. Non-invasive opening of the blood-brain barrier targeting the hippocampus was then produced by using magnetic resonance-guided, low-intensity focused ultrasound, through which a neurotoxin (quinolinic acid) administered intraperitoneally gained access to the brain parenchyma to produce focal neuronal loss. Behavioral seizures were then monitored for 30 d after this procedure, and brains were subsequently prepared for histologic analysis of the sites of neuronal loss. The average frequency of behavioral seizures in all animals (n = 11) was reduced by 21.2%. Histologic analyses along the longitudinal axis of the hippocampus revealed that most of the animals (n = 8) exhibited neuronal loss located primarily in the intermediate aspect of the hippocampus, while sparing the septal aspect. Two other animals with damage to the intermediate hippocampus also exhibited prominent bilateral damage to the septal aspect of the hippocampus. A final animal had negligible neuronal loss overall. Notably, the site of neuronal loss along the longitudinal axis of the hippocampus influenced seizure outcomes. Animals that did not have bilateral damage to the septal hippocampus displayed a mean decrease in seizure frequency of 27.7%, while those with bilateral damage to the septal hippocampus actually increased seizure frequency by 18.7%. The animal without neuronal loss exhibited an increase in seizure frequency of 19.6%. The findings indicate an overall decrease in seizure frequency in treated animals. And, the site of neuronal loss along the longitudinal axis of the hippocampus appears to play a key role in reducing seizure activity. These pilot data are promising, and they encourage additional and more comprehensive studies examining the effects of targeted, non-invasive, neuronal lesions for the treatment of epilepsy.

Effects of Non-invasive, Targeted, Neuronal Lesions on Seizures in a Mouse Model of Temporal Lobe Epilepsy.

Carotid artery plaque is a measure of atherosclerosis and is associated with future risk of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary, cerebrovascular, and peripheral arterial diseases. With advanced imaging techniques, computerized tomography (CT) and magnetic resonance imaging (MRI) have shown their potential superiority to routine ultrasound to detect features of carotid plaque vulnerability, such as intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), fibrous cap (FC), and calcification. The correlation between imaging features and histological changes of carotid plaques has been investigated. Imaging of carotid features has been used to predict the risk of cardiovascular events. Other techniques such as nuclear imaging and intra-vascular ultrasound (IVUS) have also been proposed to better understand the vulnerable carotid plaque features. In this article, we review the studies of imaging specific carotid plaque components and their correlation with risk scores.

Article	Year
Non-Invasive, Focal Disconnection of Brain Circuitry Using Magnetic Resonance-Guided Low-Intensity Focused Ultrasound to Deliver a Neurotoxin. Ultrasound in medicine & biology\| PubMed ID: 27260243	2016
The value of quantitative shear wave elastography in differentiating the cervical lymph nodes in patients with thyroid nodules. Journal of medical ultrasonics (2001)\| PubMed ID: 28905143	2018
Janus Iron Oxides @ Semiconducting Polymer Nanoparticle Tracer for Cell Tracking by Magnetic Particle Imaging. Nano letters\| PubMed ID: 29232142	2018
Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound. Ultrasound in medicine & biology\| PubMed ID: 30309748	2019
Respiratory motion correction for liver contrast-enhanced ultrasound by automatic selection of a reference image. Medical physics\| PubMed ID: 31444798	2019
Effects of Non-invasive, Targeted, Neuronal Lesions on Seizures in a Mouse Model of Temporal Lobe Epilepsy. Ultrasound in medicine & biology\| PubMed ID: 32081583	2020
Carotid plaque imaging and the risk of atherosclerotic cardiovascular disease. Cardiovascular diagnosis and therapy\| PubMed ID: 32968660	2020

Yanrong Zhang

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