Abstract
Microbubbles (MB) are widely used as contrast agents to perform contrast-enhanced ultrasound (CEUS) imaging and as acoustic amplifiers of mechanical bioeffects incited by therapeutic-level ultrasound. The distribution of MBs in the brain is not yet fully understood, thereby limiting intra-operative CEUS guidance or MB-based FUS treatments. In this paper we describe a robust platform for quantification of MB distribution in the human brain, allowing to quantitatively discriminate between tumoral and normal brain tissues and we provide new information regarding real-time cerebral MBs distribution. Intraoperative CEUS imaging was performed during surgical tumor resection using an ultrasound machine (MyLab Twice, Esaote, Italy) equipped with a multifrequency (3–11 MHz) linear array probe (LA332) and a specific low mechanical index (MI < 0.4) CEUS algorithm (CnTi, Esaote, Italy; section thickness, 0.245 cm) for non-destructive continuous MBs imaging. CEUS acquisition is started by enabling the CnTI PEN-M algorithm automatically setting the MI at 0.4 with a center frequency of 2.94 MHz–10 Hz frame rate at 80 mm—allowing for continuous non-destructive MBs imaging. 19 ultrasound image sets of adequate length were selected and retrospectively analyzed using a custom image processing software for quantitative analysis of echo power. Regions of interest (ROIs) were drawn on key structures (artery–tumor–white matter) by a blinded neurosurgeon, following which peak enhancement and time intensity curves (TICs) were quantified. CEUS images revealed clear qualitative differences in MB distribution: arteries showed the earliest and highest enhancement among all structures, followed by tumor and white matter regions, respectively. The custom software built for quantitative analysis effectively captured these differences. Quantified peak intensities showed regions containing artery, tumor or white matter structures having an average MB intensity of 0.584, 0.436 and 0.175 units, respectively. Moreover, the normalized area under TICs revealed the time of flight for MB to be significantly lower in brain tissue as compared with tumor tissue. Significant heterogeneities in TICs were also observed within different regions of the same brain lesion. In this study, we provide the most comprehensive strategy for accurate quantitative analysis of MBs distribution in the human brain by means of CEUS intraoperative imaging. Furthermore our results demonstrate that CEUS imaging quantitative analysis enables discernment between different types of brain tumors as well as regions and structures within the brain. Similar considerations will be important for the planning and implementation of MB-based imaging or treatments in the future.
Highlights
Microbubbles (MB) are widely used as contrast agents to perform contrast-enhanced ultrasound (CEUS) imaging and as acoustic amplifiers of mechanical bioeffects incited by therapeutic-level ultrasound
All of the twenty-one acquisitions recorded were successfully analyzed with the in-house designed software, to draw Regions of interest (ROIs) on selected areas (Fig. 1) and to process the data to obtain the corresponding time intensity curves (TICs)
Two data sets were contaminated with motion artifacts that arose during image acquisition and were discarded without further analysis
Summary
Microbubbles (MB) are widely used as contrast agents to perform contrast-enhanced ultrasound (CEUS) imaging and as acoustic amplifiers of mechanical bioeffects incited by therapeutic-level ultrasound. There is a strong nonlinear response that gives rise to a range of sub and super harmonics These harmonic signals allow for high-performance separation of microbubble origin signal from adjacent tissue signal, which only produces a relatively weak harmonic signal. Most of the studies on CEUS in brain lesions have used qualitative (visual assessment) or semi-quantitative analysis only, and only rare attention has been directed towards the distribution and localization of MBs in different areas of the normal human brain[9,10,11]. Quantitative analysis is objectively superior to qualitative a nalysis[14], enhancing the understanding of MB dynamics and distribution in the human brain enabling safer treatments, involving both surgery and FUS, by increasing tissue recognition and, logically, will reduce complications. Gaining insight into brain vascular regulation will be a cornerstone to facilitate further studies on CEUS guided surgery and FUS treatments
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