Multifrequency excitation and safety for transcranial sonothrombolysis

Author(s)

Hermes Arytto Salles Kamimura

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
• Defense date: 2016-01-29

Examining board members

Antonio Adilton Oliveira Carneiro; Eduardo Tavares Costa; Sergio Shiguemi Furuie; Taiza Elaine Grespan dos Santos Pontelli; Octávio Marques Pontes Neto

• Advisor: Antonio Adilton Oliveira Carneiro; Octávio Marques Pontes Neto

Abstract

Sonothrombolysis by combining ultrasound (US) and microbubbles with thrombolytic drugs has been demonstrated capable of breaking blood clots in in vitro studies, due to cavitation effects. However, in vivo drug delivery studies have demonstrated that cavitation of microbubbles is also capable of opening locally and transiently the blood-brain barrier (BBB) - structure with selective permeability that protects the Central Nervous System. A sonothrombolysis clinical study was interrupted prematurely because of the occurrence of intracerebral hemorrhages after treatment associated with damages in the BBB and standing waves formation. In this dissertation, in vitro and in vivo studies evaluated techniques of multifrequency US for thrombolysis. Furthermore, the ultrasound pressure threshold to obtain the BBB opening and neuromodulation effects were explored during transcranial insonation. It has been demonstrated that the double US beam and the time variation of frequencies (coded excitation) are capable of reducing standing wave formation and generating more confined focus zones than monofrequency focused beams. The double US beam was not capable of generating low frequency waves for thrombolysis (less than or equal to 1 Pa obtained from primary beams with 1.58 MPa). Histological exams and magnetic resonance images demonstrated that microbubbles cavitation can damage the brain tissue with acoustic pressures of the same level necessary to observe thrombolytic effects. Furthermore, it was observed motor responses and other responses associated with cognitive activity triggered by US. The capability of multifrequency excitation in focusing US beams is an important advance for sonothrombolysis. However, the enhancement of fibrinolytic effect of US by microbubbles cavitation and with thrombolytic drugs is limited by associated damages to the BBB and by exclusion criteria for the use of the thrombolytic drugs. (AU)

• FAPESP's process: 11/10809-6 - Sonothrombolysis by focused and modulated acoustic radiation force using double beam
• Grantee: Hermes Arytto Salles Kamimura
• Support Opportunities: Scholarships in Brazil - Doctorate