Background and Purpose Gas bubbles of ultrasound contrast agents resonate at frequencies used for diagnostic ultrasound and produce harmonics or multiples of the transmitted frequency. Processing of the second harmonic frequency results in a reduction of the signal-to-noise ratio and the signal-to-tissue artifacts. This study is the first to evaluate second harmonic imaging in the cerebral circulation.
Methods We used a duplex system (HP SONOS 2500) in connection with a 1.8/3.6-MHz (second harmonic) and a 2.5-MHz (conventional) sector transducer. Levovist (6.5 mL; 400 mg/mL) was injected intravenously for second harmonic and conventional color duplex imaging in 13 healthy volunteers (age range, 23 to 34 [median, 29] years).
Results When second harmonic imaging was compared with conventional color duplex imaging, more cerebellar arteries were detected (35 versus 31), the duration of blooming artifact was significantly reduced (7.9 versus 29.9 seconds; P=.03), and the duration of diagnostically useful signal enhancement was increased (248.5 versus 117.4 seconds; P=.0003), but the maximal investigation depth was reduced (8.4 versus 9.3 cm; P=.001). When conventional and second harmonic duplex were compared, there was a significant (P<.04) difference in the systolic blood flow velocity in the vertebral and basilar arteries.
Conclusions Second harmonic color duplex imaging in the vertebrobasilar system increases the time of diagnostic useful signal enhancement and produces a better spatial resolution compared with conventional color duplex imaging.
Transcranial color-coded sonography allows simultaneous imaging of brain parenchyma and the two-dimensional display of intracranial blood flow velocity in the major branches of the basal cerebral arteries and the vertebrobasilar system.1 2 3 4 The visualization of vertebrobasilar arteries is limited because of the low spatial resolution and the low signal-to-noise ratio of conventional color duplex used for transcranial and transnuchal insonation.
UCAs that pass through the pulmonary capillaries were originally designed to enhance the backscatter of the blood in echocardiology.5 6 Through the use of UCAs in the vertebrobasilar system, the number of displayed cerebellar arteries was able to be increased.3
Harmonic imaging (2nd TCCS) utilizes the phenomenon that gas bubbles of UCAs that pass the capillary bed of the lungs are highly resonant at the frequency used for diagnostic ultrasound. When a gas bubble vibrates at near resonance it produces harmonics, or multiples of the transmitted frequency. Second harmonic Doppler systems work to transmit at one frequency (fundamental) and receive at twice that frequency (second harmonic). The advantage of this procedure is that the tissues respond primarily at the fundamental frequency, and the bubbles of the UCA respond at the fundamental and the second harmonic frequencies. The ultrasound system removes the unwanted fundamental frequency (noise), leaving only the second harmonic frequency from the UCA. Therefore, signal-to-noise and signal-to-tissue artifacts are reduced by second harmonic Doppler and parenchymal imaging.7 The use of this method enabled imaging of UCAs in color-coded or B-mode ultrasound with a high spatial resolution.
Subjects and Methods
Transcranial sonography was carried out in 13 healthy volunteers (5 women and 8 men; age range, 23 to 34 [median, 29] years). Exclusion criteria were pregnancy or lactation, or a history of galactosemia. Informed consent was obtained from each volunteer before entry into the study.
Ultrasound Contrast Agent
We used Levovist (Schering), a galactose-based ultrasound contrast agent (99% of the microbubbles have a diameter of less than 4 μm) intravenously (right antecubital vein) in a dose of 6.5 mL (400 mg/mL) per injection, with a continuous injection speed of 1 mL/s.8 Immediately after the UCA injection, a 10-mL bolus of 0.9% NaCl solution was injected to clean the venous injection route.
Intracranial sections of the vertebrobasilar system were investigated with a standard 64-channel, 2.5-MHz 90° sector probe for the conventional TCCS investigation (native and contrast enhanced) and with a 94-channel, 1.8/3.6-MHz 90° sector probe for the 2nd TCCS. These two probes were used in connection with a Hewlett-Packard Ultrasound system (HP SONOS 2500). Using the 2nd TCCS probe, the B-mode gain was increased compared with conventional TCCS because of the lower backscatter of the parenchymal structures in the harmonic imaging mode.
Before administration of the UCA in the conventional investigation mode (2.5 MHz), the color amplification was reduced so that parenchymatous structures but not the color coding of the intracranial arteries were still visible.
The maximal systolic and end-diastolic BFVs in both VAs and the BA after angle correction were measured for the three investigational modes (native and Levovist 227 -enhanced TCCS [2.5 MHz] as well as 2nd TCCS [1.8/3.6 MHz]). We evaluated the number of visible VA segments (V3 and V4 segments), cerebellar arteries (PICA and AICA), and the BA. The maximal depth of BA color Doppler signals were measured for the three investigational modes.
Four phases of signal enhancement were evaluated for conventional and second harmonic color Doppler as defined in the literature9 10 : first, the time to UCA arrival in the vertebrobasilar arteries (latency phase); second, the duration of excessive enhancement of the color signal, the “blooming” artifact phase; third, the diagnostically useful enhancement time, with optimum imaging quality of the vertebrobasilar arteries; and last, a phase of color signal fragmentation, the “bubble noise” phase. The end of the “blooming” artifact was defined if the diameter of the color signal of the VA decreased to a stable level. The end of the diagnostically useful contrast enhancement was reached if the color signal of the VA was fragmented.
The entire investigation was recorded on videotape.
2nd TCCS and TCCS were compared during the statistical treatment of the data using a nonparametric test for related samples (Friedman two-way ANOVA).
The number of visible arterial segments of the vertebrobasilar system was increased using Levovist (Fig 1⇓) in the TCCS and 2nd TCCS modes. Comparing conventional UCA-enhanced TCCS with 2nd TCCS, there was no difference in the imaging of the major branches (V4 segment and the BA) and only a minor increase in the number of detected cerebellar arteries (PICA and AICA).
A striking difference between UCA-enhanced TCCS and 2nd TCCS was the increased spatial resolution of the latter; ie, branches of the cerebellar arteries could be displayed more often. Branches of the cerebellar arteries could be identified in 10 of 23 and 5 of 20 PICAs as well as 3 of 12 and 1 of 11 AICAs using 2nd TCCS and UCA-enhanced TCCS, respectively. Moreover, the venous plexus of the spinal cord could only be displayed using 2nd TCCS (in 9 of 13 volunteers) (Fig 2⇓).
There was a statistically significant (P=.03) increase in the detection of arterial (n=7) and venous (n=1) structures through the transnuchal approach.
Time of Signal Enhancement
Comparing Levovist-enhanced 2nd TCCS and conventional TCCS, there was a significant reduction in the duration of the blooming phase (7.9 versus 29.9 seconds, respectively; P=.03) and an increase in the phase of the diagnostically useful ultrasound enhancement (248.5 versus 117.4 seconds, respectively; P=.0003). The latency phase (16.0 versus 15.7 seconds; P=.6) and the duration of bubble noise (116.5 versus 95.3 seconds; P=.4) were not statistically different (Fig 3⇓).
Blood Flow Velocity and Investigation Depth
We evaluated the maximal investigation depth and the BFV of the VAs and the BA in the native TCCS investigation and after Levovist enhancement using the conventional and second harmonic modes (Table⇓). There was a significant difference in the maximal systolic BFV in all investigated artery segments but not when comparing end-diastolic BFV. The BFV measured with conventional enhanced color duplex imaging was higher in all segments compared with native and 2nd TCCS, which showed only minor differences (Table⇓).
The maximal investigation depth was significantly different using the three methods, with the same values for native and second harmonic imaging and an increase of investigation depth of 0.9 cm using conventional enhanced TCCS (Table⇑).
This clinical study in normal subjects evaluating three different methods for imaging the vertebrobasilar arteries has disclosed preliminary but nevertheless exciting findings for Levovist-based harmonic imaging. More cerebellar arteries were displayed than with conventional UCA enhancement, the spatial resolution of color Doppler imaging was increased, and the duration of diagnostically useful ultrasound enhancement was prolonged. In the literature, UCA-enhanced conventional color-coded duplex investigation of the vertebrobasilar system is described in only a small number of patients using SHU 508 A (Levovist).3 In this study the number of detected cerebellar arteries was increased compared with that in the native scan.
As shown in our study, the velocity measurements were increased using Levovist in the conventional TCCS mode compared with the native and second harmonic modes. This is a well known artifact after UCA injection when comparing native and conventional UCA-enhanced BFV measurements.9
To date, no study is available for 2nd TCCS in the cerebral circulation. In vitro videodensitometry studies showed the higher sensitivity of second harmonic imaging compared with the nonharmonic mode in detecting the ultrasound contrast agent Aerosomes.11 In cardi-ology, second harmonic imaging enables the visualization of coronary arteries and the measurement of coronary blood flow in an animal model using UCA Imagent US,12 which again confirms a higher sensitivity for 2nd TCCS. This is in accordance with our findings of increased spatial resolution using 2nd TCCS in the vertebrobasilar system.
The decrease of maximal investigation depth and increase in spatial resolution comparing the conventional and second harmonic modes could be explained by the higher receiving frequency in the second harmonic mode (2.5 MHz versus 3.6 MHz). With harmonic imaging less blooming artifact occurred, diminishing the need for manipulation during UCA studies.
In conclusion, 2nd TCCS improves the signal-to-noise and signal-to-tissue ratios, leading to a better visualization of UCA in the vessels. The limitation of this promising new method is the correct match of the UCA and the transducer frequency. In the vertebrobasilar system, conventional frequencies between 1 and 2 MHz have to be used because the resulting second harmonic frequency is between 2 and 4 MHz, which is a compromise between a low spatial resolution (2 MHz) and the decreasing maximal investigation depth (4 MHz).
Our study indicates that the combination of Levovist and 2nd TCCS using the fundamental frequency of 1.8 MHz is useful and increases the diagnostic information in the vertebrobasilar system.
Selected Abbreviations and Acronyms
|AICA||=||anterior inferior cerebellar artery|
|BFV||=||blood flow velocity|
|PICA||=||posterior inferior cerebellar artery|
|TCCS||=||transcranial color-coded sonography|
|2nd TCCS||=||second harmonic transcranial color-coded sonography|
|UCA||=||ultrasound contrast agent|
|V3 segment||=||tortuous segment of the vertebral artery within the transverse process of the atlas|
|V4 segment||=||intracranial segment between the V3 segment and origin of the basilar artery|
We are indebted to Mrs A. Jahn and Mrs M. Vidal-Langwasser, MD, for their technical help.
- Received February 19, 1997.
- Revision received May 14, 1997.
- Accepted May 14, 1997.
- Copyright © 1997 by American Heart Association
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