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      Noninvasive MR Imaging–guided Focal Opening of the Blood-Brain Barrier in Rabbits

      , , ,
      Radiology
      Radiological Society of North America (RSNA)

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          Abstract

          To determine if focused ultrasound beams can be used to locally open the blood-brain barrier without damage to surrounding brain tissue and if magnetic resonance (MR) imaging can be used to monitor this procedure. The brains of 18 rabbits were sonicated (pulsed sonication) in four to six locations, with temporal peak acoustic power ranging from 0.2 to 11.5 W. Prior to each sonication, a bolus of ultrasonographic (US) contrast agent was injected into the ear vein of the rabbit. A series of fast or spoiled gradient-echo MR images were obtained during the sonications to monitor the temperature elevation and potential tissue changes. Contrast material-enhanced MR images obtained minutes after sonications and repeated 1-48 hours later were used to depict blood-brain barrier opening. Whole brain histologic evaluation was performed. Opening of the blood-brain barrier was confirmed with detection of MR imaging contrast agent at the targeted locations. The lowest power levels used produced blood-brain barrier opening without damage to the surrounding neurons. Contrast enhancement correlated with the focal signal intensity changes in the magnitude fast spoiled gradient-echo MR images. The blood-brain barrier can be consistently opened with focused ultrasound exposures in the presence of a US contrast agent. MR imaging signal intensity changes may be useful in the detection of blood-brain barrier opening during sonication.

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          Most cited references22

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          Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means.

          This article reviews historical aspects of the blood-brain barrier (BBB) and recent advances in mechanisms to deliver therapeutic agents across the BBB for the treatment of intracerebral tumors and other neurological diseases. The development of the osmotic BBB disruption procedure as a clinically useful technique is described. Osmotic BBB disruption is contrasted with alternative methods for opening or bypassing the BBB, including pharmacological modification of the BBB with bradykinin and direct intracerebral infusion. Laboratory studies have played a fundamental role in advancing our understanding of the BBB and delivery of agents to brain. Preclinical animal studies will continue to serve an integral function in our efforts to improve the diagnosis and treatment of a number of neurological disorders. Techniques involving the modification of the BBB and/or blood-tumor barrier to increase delivery of therapeutic agents have been advanced to clinical trials in patients with brain tumors with very favorable results. Improving delivery of agents to the brain will play a major role in the therapeutic outcome of brain neoplasms. As techniques for gene therapy are advanced, manipulation of the BBB also may be important in the treatment of central nervous system genetic disorders.
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            Demonstration of potential noninvasive ultrasound brain therapy through an intact skull.

            Utilization of therapeutic ultrasound in the brain has been seriously limited by the commonly accepted view that these exposures would require that a piece of the skull bone be removed to allow the ultrasound beam to propagate into the brain. In this paper, the feasibility of delivering ultrasound therapy through the intact skull was studied. Sonications were performed through a piece of human skull with focused transducers at 0.248, 0.559, 1.0 and 1.68 MHz. The skull attenuated and distorted the field; however, a sharp focal spot was created at frequencies of 1 MHz or lower. At the higher frequency, the focus was destroyed. To investigate the feasibility of compensating for the ultrasound field distortion caused by the bone, phased array experiments were performed. Two arrays with 64 elements, operating at 0.6 MHz and 1.58 MHz, were used in these experiments. The phase shifts caused by the skull were measured for each element of the arrays and then compensated for by phase-control circuitry. These phase corrections allowed a sharp focus to be generated at both frequencies. Finally, tissue destruction was induced by using pulsed sonication through a piece of human skull in a rabbit brain in vivo at the frequency of 0.559 MHz. In summary, the results showed that transcranial delivery of therapeutic ultrasound into the brain may be feasible.
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              Transporting therapeutics across the blood-brain barrier.

              In 1996, we are half-way through the Decade of the Brain, yet we still have few effective treatments for major disorders of the central nervous system. These include affective disorders, epilepsy, neurodegenerative disorders, brain tumours, infections and HIV encephalopathy; sufferers far outnumber the morbidity of cancer or heart disease. Increased understanding of the pharmacology of the brain and its blood supply, and methods for rational drug design, are leading to potential new drug therapies based on highly specific actions on particular target sites, such as neurotransmitter receptors and uptake systems. These methods are capable of reducing the side effects that are common with more general treatments. However, all these treatments and potential treatments meet a formidable obstacle--the blood-brain barrier. In this article, we review the properties of this barrier that complicate drug delivery to the brain, and some of the most hopeful strategies for overcoming or bypassing the barrier in humans.
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                Author and article information

                Journal
                Radiology
                Radiology
                Radiological Society of North America (RSNA)
                0033-8419
                1527-1315
                September 2001
                September 2001
                : 220
                : 3
                : 640-646
                Article
                10.1148/radiol.2202001804
                11526261
                c8302bc8-a3ef-473e-9d64-6a5da2cdefbf
                © 2001
                History

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