Non-invasive ultrasonic modulation of visual evoked response by GABA delivery through the blood brain barrier

AbstractWe demonstrate the feasibility of non-invasively modulating the visual cortex activity of non-human primates by local ultrasound-induced delivery of an inhibitory neurotransmitter (GABA). GABA was injected intravenously after the blood brain barrier (BBB) was transiently disrupted with focused ultrasound (FUS) coupled with ultrasound contrast agents (UCA). Visual evoked potentials exhibited a significant and progressive decrease of the activity. Combined effects of neuromodulation and BBB opening were shown to be 8.7 times less important than GABA-induced inhibition. During the sonication, the UCA harmonic response was monitored to estimate the level of stable cavitation (signature of BBB opening efficiency) and to avoid damages due to inertial cavitation (automatic shutdown of the sonication when detected). As recent developments in beam forming have shown that ultrasound beams can be focused non-invasively in deep-seated human brain locations, our results hold promise to explore and treat the brain with a non-invasive, controllable, repeatable and reversible method.

Download Full-text

Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates

Scientific Reports ◽

10.1038/s41598-021-94188-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Antonios N. Pouliopoulos ◽

Nancy Kwon ◽

Greg Jensen ◽

Anna Meaney ◽

Yusuke Niimi ◽

...

Keyword(s):

Blood Brain Barrier ◽

Safety Profile ◽

Focused Ultrasound ◽

Multiple Case Study ◽

Brain Barrier ◽

Non Invasive ◽

Blood Brain ◽

Multiple Case ◽

Bbb Opening

AbstractAn emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.

Download Full-text

BOT-01 BLOOD-BRAIN BARRIER OPENING USING 220-KHZ TRANSCRANIAL MRI-GUIDED FOCUSED ULTRASOUND AND MICROBUBBLES IN MOUSE AND RAT

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.053 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii12-ii12

Author(s):

Michiharu Yoshida ◽

Kazuo Maruyama ◽

Yasutaka Kato ◽

Rachmilevitch Itay ◽

Syuji Suzuki ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Focused Ultrasound ◽

Brain Barrier ◽

Maximum Temperature ◽

Non Invasive ◽

Therapeutic Drugs ◽

Blood Brain ◽

Mri Guided ◽

Bbb Opening

Abstract OBJECTIVE In neuro-oncology, it is believed that one major obstacle to effective chemotherapy is the high vascularity and heterogenous permeability of brain tumors. Focused ultrasound (FUS) exposure with the microbubbles has been shown to transiently open the blood-brain barrier (BBB) without depositing thermal energy, and thus may enhance the delivery of various therapeutic drugs into brain tumors. The aim of this study was to evaluate the BBB opening using 220-kHz transcranial MRI-guided FUS (TcMRgFUS) device and microbubbles in mouse and rat. METHODS The experiments were performed with the 220-kHz ExAblate Neuro TcMRgFUS system (InSightec) and novel lipid bubbles (LB, Teikyo Univ.). Normal mouse and rat brains were irradiated with TcMRgFUS (output power, 5W; duration of irradiation, 30 s; duty cycle 100%) following intravenous injection of 6x107 LB per mouse and rat, respectively. On irradiation, target temperature rise & cavitation signal were monitored by MR thermometry and cavitation receiver, respectively. Immediately after irradiation, BBB opening and complications were detected based on T1, T2, T2*, and Gadolinium (Gd) enhanced T1-weighted images. RESULTS The maximum temperature of brain tissue was under 42 C. There were no risky-cavitation signals causing hemorrhage. The FUS-LB exposure induced successful BBB opening effect in both mouse and rat, confirmed by Gd enhancement in the target region, lateral ventricles, and sulcus. In addition, there were no complications such as edema, coagulation, and hemorrhage. CONCLUSIONS Although there remain many conditions to be optimized, BBB opening using a 220-kHz TcMRgFUS device and LB can offer a non-invasive and feasible drug delivery for brain malignancies.

Download Full-text

Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood − brain barrier using MRI-guided focused ultrasound

Journal of Controlled Release ◽

10.1016/j.jconrel.2014.06.031 ◽

2014 ◽

Vol 189 ◽

pp. 123-132 ◽

Cited By ~ 132

Author(s):

Elizabeth Nance ◽

Kelsie Timbie ◽

G. Wilson Miller ◽

Ji Song ◽

Cameron Louttit ◽

...

Keyword(s):

Blood Brain Barrier ◽

Focused Ultrasound ◽

Brain Barrier ◽

Non Invasive ◽

Blood Brain ◽

Mri Guided

Download Full-text

A non-viral suicide gene delivery system traversing the blood brain barrier for non-invasive glioma targeting treatment

Journal of Controlled Release ◽

10.1016/j.jconrel.2016.10.027 ◽

2016 ◽

Vol 243 ◽

pp. 357-369 ◽

Cited By ~ 38

Author(s):

Shiqian Gao ◽

Huayu Tian ◽

Zhenkai Xing ◽

Dawei Zhang ◽

Ye Guo ◽

...

Keyword(s):

Gene Delivery ◽

Blood Brain Barrier ◽

Delivery System ◽

Suicide Gene ◽

Brain Barrier ◽

Gene Delivery System ◽

Non Invasive ◽

Blood Brain

Download Full-text

A Noninvasive Approach to Optogenetics Using Focused Ultrasound Blood Brain Barrier Disruption for the Delivery of Radioluminescent Particles

10.1101/2020.08.20.248302 ◽

2020 ◽

Author(s):

Megan Rich ◽

Eric Zhang ◽

Ashley Dickey ◽

Haley Jones ◽

Kelli Cannon ◽

...

Keyword(s):

Blood Brain Barrier ◽

Focused Ultrasound ◽

Brain Regions ◽

Brain Barrier ◽

Receptor Subtype ◽

Spatiotemporal Resolution ◽

Light Emitting ◽

Non Invasive ◽

Blood Brain ◽

Essential Components

AbstractOptogenetics, the genetic incorporation of light-sensitive proteins such as Channelrhodopsin-2 (ChR2) into target mammalian neurons, has enabled activation, silencing, and receptor subtype specific neuromodulation with high spatiotemporal resolution. However, the essential components of the ontogenetic system require invasive procedures with very few non-invasive alternatives preventing its use as a translational tool. The implantation of light emitting fibers deep within brain structures is both technically demanding and causes tissue scarring in target brain regions. To overcome these limitations, while maintaining the highly-tuned components of optogenetics we have developed a novel noninvasive alternative. Our approach replaces fibers with light-emitting radioluminescent particles (RLPs) that can be activated non-invasively with X-ray exposure. Here, we report successful noninvasive delivery of RLPs to target brain regions using MRI-guided focused ultrasound (FUS) blood brain barrier opening. In addition, FUS BBBO can be used to deliver viral vectors for light sensitive channel expression. Combined, these components can provide a completely non-invasive optogenetic system.

Download Full-text

Non-invasive delivery of small interfering rubonucleic acid for reduction of Huntingtin expression in the brain is achieved using focused ultrasound to disrupt the blood-brain barrier

10.1121/1.4800368 ◽

2013 ◽

Author(s):

Alison Burgess ◽

Yuexi Huang ◽

William Querbes ◽

Dinah W. Sah ◽

Kullervo Hynynen

Keyword(s):

Blood Brain Barrier ◽

Focused Ultrasound ◽

Brain Barrier ◽

Non Invasive ◽

Blood Brain ◽

The Brain

Download Full-text

Non-invasive transferrin targeted nanovesicles sensitize resistant glioblastoma multiforme tumors and improve survival in orthotopic mouse models

Nanoscale ◽

10.1039/d1nr05460k ◽

2021 ◽

Author(s):

Puja Sandbhor ◽

Jayant Goda ◽

Bhabani Mohanty ◽

Pradip Chaudhari ◽

Shilpee Dutt ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Clinical Outcomes ◽

Blood Brain Barrier ◽

Mouse Models ◽

Tumor Heterogeneity ◽

Brain Barrier ◽

Therapeutic Regimen ◽

Non Invasive ◽

Blood Brain

The blood–brain barrier (BBB) and tumor heterogeneity have resulted in abysmally poor clinical outcomes in glioblastoma (GBM) with the standard therapeutic regimen.

Download Full-text