Mechanism and Safety at the Threshold of the Blood-Brain Barrier Opening In Vivo

Konofagou, Elisa E.; Choi, James J.; Baseri, Babak; Selert, Kirsten; Tung, Yu-Chi; Hynynen, Kullervo; Souquet, Jacques

doi:10.1063/1.3367134

Cited by 5 publications

(5 citation statements)

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“…Apart from size dependence, greater fluorescence in the thalamus compared with the hippocampus was observed, thus indicating regional variations. Preliminary histological evaluation indicated that our in-house manufactured, size-isolated bubbles do not induce histological damage at pressures near the threshold for BBB opening [48]. …”

Section: Discussionmentioning

confidence: 99%

Microbubble-Size Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening in MiceIn Vivo

Choi

Feshitan

Baseri

et al. 2010

IEEE Trans. Biomed. Eng.

234

188

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The therapeutic efficacy of neurological agents is severely limited, because large compounds do not cross the blood–brain barrier (BBB). Focused ultrasound (FUS) sonication in the presence of microbubbles has been shown to temporarily open the BBB, allowing systemically administered agents into the brain. Until now, polydispersed microbubbles (1–10 μm in diameter) were used, and, therefore, the bubble sizes better suited for inducing the opening remain unknown. Here, the FUS-induced BBB opening dependence on microbubble size is investigated. Bubbles at 1–2 and 4–5 μm in diameter were separately size-isolated using differential centrifugation before being systemically administered in mice (n = 28). The BBB opening pressure threshold was identified by varying the peak-rarefactional pressure amplitude. BBB opening was determined by fluorescence enhancement due to systemically administered, fluorescent-tagged, 3-kDa dextran. The identified threshold fell between 0.30 and 0.46 MPa in the case of 1–2 μm bubbles and between 0.15 and 0.30 MPa in the 4–5 μm case. At every pressure studied, the fluorescence was greater with the 4–5 μm than with the 1–2 μm bubbles. At 0.61 MPa, in the 1–2 μm bubble case, the fluorescence amount and area were greater in the thalamus than in the hippocampus. In conclusion, it was determined that the FUS-induced BBB opening was dependent on both the size distribution in the injected microbubble volume and the brain region targeted.

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Section: Discussionmentioning

confidence: 99%

Microbubble-Size Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening in MiceIn Vivo

Choi

Feshitan

Baseri

et al. 2010

IEEE Trans. Biomed. Eng.

234

188

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“…Zhou et al, 2016). Furthermore, combination of pHIFU with microbubbles produces consistent, reproducible and transient blood-brain barrier (BBB) opening (Burgess & Hynynen, 2014;Konofagou et al, 2012). 20 ms pHIFU pulse in mice brain; by triggering signaling pathways in neurons and localization of brain-derived neurotrophic factor (BDNF) into its nucleus thought to be helpful in generating downstream effects at cellular and molecular level and reversing the disease (Konofagou et al, 2012).…”

Section: Biological Effects Of Phifumentioning

confidence: 99%

“…Moreover pulsed high intensity focused ultrasound (pHIFU) is capable of inducing structural and functional changes to cells in vivo (Feng-Yi Yang et al, 2009;Hancock et al, 2009;Konofagou et al, 2012;Liu, 2019)(add references for this claim). In this study, it is hypothesized that acoustic pressure pulses generated by pHIFU can induce biomechanical forces on an in-vitro sample of brain endothelial cells (bEND.3) that could alter cells' morphology.…”

Section: Hypothesis and Specific Aimsmentioning

confidence: 99%

Use of pulsed high intensity focused ultrasound to study the response of brain endothelial cells to mechanical injury

Kaur

2023

Preprint

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<p>This work investigated the significance of a sublethal primary mechanical injury induced by pulsed high intensity focused ultrasound (pHIFU) and mechanical stretching techniques to mouse brain endothelial cell (bEND.3) nuclei in vitro followed by secondary hypoxia. The lateral size of the pHIFU beam’s focal spot (~ 1.7 mm) was obtained by characterizing the pHIFU system, and the transparency of the membrane on which the cells were to be cultured was determined theoretically and experimentally. Preliminary assessment of injury using a MTT assay (3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) at high acoustic pressures (3.15 MPa and 1.04 MPa for 50 ms) demonstrated cell damage. In the subsequent experiments, the cells were sublethally exposed to either pHIFU (0.57 MPa for 50ms) or stretch injuries (0.012 – 0.014 MPa for 50 ms). After each primary injury, the cells were either fully normoxic for 24 h or were subjected to a 6 h hypoxic environment followed by an 18 h recovery under normoxic conditions. The morphological parameters (area and circularity) of bEND.3 nuclei post-treatment were measured using an image analysis tool (ImageJ) for three primary treatments (control, pHIFU and stretch) and evaluated by plotting the scatterplots. Compared to the control group, a statistically significant decrease in circularity of bEND.3 nuclei was observed when the cells were subjected to 6 h hypoxia following a primary injury whereas nuclear area remained unchanged. The percentage of deformed nuclei also increased to ~ 19 % for pHIFU and stretch injury groups after 18 h normoxia following primary and secondary insult (6 h hypoxia), demonstrating cells’ inability to recover due to injury. However, when this hypoxic-normoxic regimen was not preceded by a pHIFU (or mechanical stretch) primary injury, nuclei recovered their original shape successfully. In conclusion, as shown in this study, cells became more susceptible to secondary hypoxic injury after being exposed to an initial mechanical insult. </p>

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“…Transcranial focused ultrasound (tFUS) is a non-invasive neuromodulation tool that focuses and delivers ultrasound energy to localized areas of the brain to modulate neuronal activity (Min et al, 2011;Lescrauwaet et al, 2022;Armstrong et al, 2023). The subsequent biological models (Konofagou et al, 2012;Zou, 2020;Yan et al, 2021;Cain et al, 2022) have found a significant reduction in the number and duration of seizures after low-intensity tFUS stimulation, providing important experimental evidence for clinical translation. Preliminary evidence that tFUS has a role in modulating the therapeutic and tumor suppressor activity of abnormal neural networks.…”

Section: Introductionmentioning

confidence: 99%

A transducer positioning method for transcranial focused ultrasound treatment of brain tumors

Gao,

Sun,

Zhang

et al. 2023

Front. Neurosci.

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PurposeAs a non-invasive method for brain diseases, transcranial focused ultrasound (tFUS) offers higher spatial precision and regulation depth. Due to the altered path and intensity of sonication penetrating the skull, the focus and intensity in the skull are difficult to determine, making the use of ultrasound therapy for cancer treatment experimental and not widely available. The deficiency can be effectively addressed by numerical simulation methods, which enable the optimization of sonication modulation parameters and the determination of precise transducer positioning.MethodsA 3D skull model was established using binarized brain CT images. The selection of the transducer matrix was performed using the radius positioning (RP) method after identifying the intracranial target region. Simulations were performed, encompassing acoustic pressure (AP), acoustic field, and temperature field, in order to provide compelling evidence of the safety of tFUS in sonication-induced thermal effects.ResultsIt was found that the angle of sonication path to the coronal plane obtained at all precision and frequency models did not exceed 10° and 15° to the transverse plane. The results of thermal effects illustrated that the peak temperatures of tFUS were 43.73°C, which did not reach the point of tissue degeneration. Once positioned, tFUS effectively delivers a Full Width at Half Maximum (FWHM) stimulation that targets tumors with diameters of up to 3.72 mm in a one-off. The original precision model showed an attenuation of 24.47 ± 6.13 mm in length and 2.40 ± 1.42 mm in width for the FWHM of sonication after penetrating the skull.ConclusionThe vector angles of the sonication path in each direction were determined based on the transducer positioning results. It has been suggested that when time is limited for precise transducer positioning, fixing the transducer on the horizontal surface of the target region can also yield positive results for stimulation. This framework used a new transducer localization method to offer a reliable basis for further research and offered new methods for the use of tFUS in brain tumor-related research.

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Mechanism and Safety at the Threshold of the Blood-Brain Barrier Opening In Vivo

Cited by 5 publications

References 0 publications

Microbubble-Size Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening in MiceIn Vivo

Microbubble-Size Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening in MiceIn Vivo

Use of pulsed high intensity focused ultrasound to study the response of brain endothelial cells to mechanical injury

A transducer positioning method for transcranial focused ultrasound treatment of brain tumors

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