High Incidence of Intracerebral Hemorrhaging Associated with the Application of Low-Intensity Focused Ultrasound Following Acute Cerebrovascular Injury by Intracortical Injection

Abstract

Low-intensity transcranial focused ultrasound (FUS) has gained momentum as a non-/minimally-invasive modality that facilitates the delivery of various pharmaceutical agents to the brain. With the additional ability to modulate regional brain tissue excitability, FUS is anticipated to confer potential neurotherapeutic applications whereby a deeper insight of its safety is warranted. We investigated the effects of FUS applied to the rat brain (Sprague-Dawley) shortly after an intracortical injection of fluorescent interstitial solutes, a widely used convection-enhanced delivery technique that directly (i.e., bypassing the blood–brain-barrier (BBB)) introduces drugs or interstitial tracers to the brain parenchyma. Texas Red ovalbumin (OA) and fluorescein isothiocyanate-dextran (FITC-d) were used as the interstitial tracers. Rats that did not receive sonication showed an expected interstitial distribution of OA and FITC-d around the injection site, with a wider volume distribution of OA (21.8 ± 4.0 µL) compared to that of FITC-d (7.8 ± 2.7 µL). Remarkably, nearly half of the rats exposed to the FUS developed intracerebral hemorrhaging (ICH), with a significantly higher volume of bleeding compared to a minor red blood cell extravasation from the animals that were not exposed to sonication. This finding suggests that the local cerebrovascular injury inflicted by the micro-injection was further exacerbated by the application of sonication, particularly during the acute stage of injury. Smaller tracer volume distributions and weaker fluorescent intensities, compared to the unsonicated animals, were observed for the sonicated rats that did not manifest hemorrhaging, which may indicate an enhanced degree of clearance of the injected tracers. Our results call for careful safety precautions when ultrasound sonication is desired among groups under elevated risks associated with a weakened or damaged vascular integrity.

Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

“…Although FUS is considered a non-/minimally invasive approach, collateral undesired effects, such as cerebral hemorrhage [ 76 , 77 ], have been reported even with low intensity mainly because of the intracerebral thermal rise during the wave traveling and significantly in the focus site [ 78 , 79 ]. Therefore, immunohistochemistry assays have been performed to quantify the FUS impact on nigral dopaminergic neurons and striatal axonal projections more accurately and confirm the immunofluorescence results (Figs.…”

Non-invasive enhancement of intracortical solute clearance using transcranial focused ultrasound

“…Regarding the experimental technique, which involved a post-tracer injection wait time of 30 min prior to the application of FUS, we previously reported that the same intensity of FUS to the rat brain, applied a short time (e.g., 7 min) after intracortical injection of interstitial tracers, caused massive intracranial hemorrhaging in a significant portion of tested animals 61 . We did not, however, observe any hemorrhaging in the present experiment protocol, suggesting that the increased 30 min wait time prior to sonication allowed impaired cerebrovascular structure (caused by the needle injection) to close shut, preventing hemorrhaging.…”

“…FUS, delivered immediately following needle retraction, has previously been found to cause intracranial hemorrhaging 61 . Thus, a 30 min wait period was introduced after the needle retraction.…”

Glioblastoma Therapy: Past, Present and Future

“…All subjects survived over 1 year, while tumor recurrence was noted in two patients at 11 and 16 months [ 1021 ]. These recent results evidence that LIFU-mediated BBB opening increases drug delivery in GB, thus improving tumor control and survival, although larger sample sizes are needed to confirm efficacy and the lack of hemorrhagic complications associated with the procedure [ 1023 ].…”