Ultrasound and the Blood-Brain Barrier

Patrick, James T.; Nolting, Mark N.; Goss, S. A.; Dines, K.A.; Clendenon, Jeffrey L.; Rea, Michael A.; Heimburger, Robert F.

doi:10.1007/978-1-4684-5766-7_36

Cited by 63 publications

(32 citation statements)

References 7 publications

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“…Other biological effects that may play a role are vasodilatation from ultrasound 22,23 and opening of the blood-brain barrier. 17,24 There are a few clinical observations that show effectiveness 12,19,20 with higher numbers of patients showing fast remission of symptoms. Our study did not show a positive effect on recanalization or clinical/functional outcome.…”

Section: Discussionmentioning

confidence: 99%

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia

Daffertshofer

Gass

Ringleb

et al. 2005

Stroke

383

204

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Background— Clinical studies using ultrasound at diagnostic frequencies in transcranial Doppler devices provided encouraging results in enhancing thrombolysis with tissue plasminogen activator (tPA) in acute stroke. Low-frequency ultrasound does not require complex positioning procedures, penetrates through the skull better, and has been demonstrated to accelerate thrombolysis with tPA in animal experiments in wide cerebrovascular territories without hemorrhagic side effects. We therefore conducted the first multicenter clinical trial to investigate safety of tPA plus low-frequency ultrasound (300 kHz). Methods— Acute stroke patients within a 6-hour time window were included (National Institutes of Health Stroke Scale scores >4). Magnetic resonance imaging (MRI) was used to document vascular occlusion and to rule out cerebral hemorrhage. Patients were allocated to combination therapy alternately; the first patient received tPA only, the second patient received tPA plus ultrasound, etc. Follow-up included serial MRI directly thereafter and 24 hours later to confirm recanalization and tissue imaging. Clinical recovery was measured after treatment and 3 months later. Results— 26 patients (70.4±9.7 years) entered the trial (12 tPA, 14 tPA plus ultrasound). The study was prematurely stopped because 5 of 12 patients from the tPA only group but 13 of 14 patients treated with the tPA plus ultrasound showed signs of bleeding in MRI ( P <0.01). Within 3 days of treatment, 5 symptomatic hemorrhages occurred within the tPA plus ultrasound group. At 3 months, neither morbidity nor treatment-related mortality or recanalization rates differed between both groups. Conclusions— This study demonstrated bioeffects from low-frequency ultrasound that caused an increased rate of cerebral hemorrhages in patients concomitantly treated with intravenous tPA.

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Section: Discussionmentioning

confidence: 99%

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia

Daffertshofer

Gass

Ringleb

et al. 2005

Stroke

383

204

View full text Add to dashboard Cite

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“…Neuronal damage with BBB opening induced by ultrasound at or near ablation intensities was initially reported in some studies (Bakay et al 1956 ;Ballantine et al 1960 ;Patrick et al 1990 ) but not in others (Vykhodtseva et al 1995 ). After reducing the acoustic intensity and duty cycle, BBB opening was still observed, but macroscopic damage was avoided (Mesiwala et al 2002 ).…”

Section: Bbb Opening Using Fus and Microbubblesmentioning

confidence: 93%

Emerging Engineering Technologies for Opening the BBB

Konofagou

2013

Drug Delivery to the Brain

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Current treatments of neurological and neurodegenerative diseases are limited due to the lack of a truly noninvasive, transient, and regionally selective brain drug delivery method. The brain is particularly diffi cult to deliver drugs to because of the blood-brain barrier (BBB). The impermeability of the BBB is due to the tight junctions between adjacent endothelial cells and highly regulatory transport systems of the endothelial cell membranes. The main function of the BBB is ion and volume regulation to ensure the conditions necessary for proper synaptic and axonal signaling. However, the same permeability properties that keep the brain healthy also present tremendous obstacles to its pharmacological treatment. Until a solution to the trans-BBB delivery problem is found, treatments of neurological diseases will remain impeded. Over the past decade, methods that combine focused ultrasound (FUS) and microbubbles have been shown to offer the unique capability to noninvasively, locally, and transiently open the BBB. Four of the main challenges to the application of FUS are (1) to assess its safety profi le, (2) to unveil the mechanism by which the BBB opens and closes, (3) to control and predict the opened BBB properties and duration of the opening, and (4) to assess its promise for brain drug delivery. In this chapter, we discuss all of these challenges, along with fi ndings in both small (mice) and large (nonhuman primates) animals, and emphasize the clinical potential for this technique.

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“…32 By focusing the ultrasound energy using a focused ultrasound technique, the acoustic energy can be concentrated in a millimeter-order size target, thus restricting the bioeffects caused by ultrasound only within or around the aimed target. Although the possibility of using ultrasound for BBB disruption has been previously documented, 32 reproducible and reliable opening of the BBB was difficult. Creating BBB opening without or only an acceptable magnitude of tissue damage is one of the most challenging issues.…”

Section: Development Of Focused Ultrasound-induced Bbb Disruption Methodsmentioning

confidence: 99%

Targeted Drug Delivery to the Brain Using Focused Ultrasound

Kinoshita¹

2006

Topics in Magnetic Resonance Imaging

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Drug delivery to the brain remains a challenging field. The presence of a physiological barrier, the blood-brain barrier (BBB), complicates the delivery of drugs to the brain. Although several methods have been developed for drug delivery to the brain, they have problems such as being invasive or lacking in target specificity. On the other hand, ultrasound has emerged as a treatment method and a diagnostic technology. Several studies have shown the feasibility of using ultrasound for the localized and reversible disruption of the BBB. In this review, I would like to review the recent advancement of ultrasound-induced MRI-guided BBB disruption technique and other methods for delivering drugs to the brain.

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Ultrasound and the Blood-Brain Barrier

Cited by 63 publications

References 7 publications

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia

Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia

Emerging Engineering Technologies for Opening the BBB

Targeted Drug Delivery to the Brain Using Focused Ultrasound

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