MASSACHUSETTS GENERAL HOSPITAL • DEPARTMENT OF RADIOLOGY • HARVARD MEDICAL SCHOOL • *THOMAS JEFFERSON UNIVERSITY, PA Arash Anvari, MD; Flemming Forsbeg, PhD*; Anthony E. Samir, MD, MPH A Primer on the Physical Principles and Clinical Applications of Tissues Harmonic Imaging on the Liver and Kidney Concepts & Terminology Nonlinear and Linear Ultrasound Propagation US is mechanical energy that propagates through the tissue as longitudinal (compressional) waves with alternating zones of compression and rarefaction. Linear and nonlinear systems are physical terms that describe the response of a system to the US waves (Fig 1). Linear Propagation When the applied pressure of the ultrasound pulse is very small (<0.5 MPa), tissue will behave like a linear system, which means that it becomes completely elastic and tissue compression and rarefaction occur at the same rate. Non-Linear Propagation Nonlinear propagation occurs when higher-pressure ultrasound pulses (>0.5 MPa) propagate through a soft tissue medium and the compressional nature of the transmitted ultrasound pulse induces less contraction in the medium than rarefaction. This is termed non-linear elastic behavior and it results in the formation of harmonic waves within the tissue (Fig 2). These waves are progressively asymmetrical and contain higher frequencies (harmonic waves) and lower frequencies (subharmonic waves) than the transmitted ultrasound pulse. Fundamental Frequency The fundamental frequency is deined for a continuously emitted sine wave as the single frequency f in the pulse spectrum. In reality, an ultrasound system transducer emits short pulses in a frequency spectrum with center frequency fc. These pulses and their resultant echoes form the ultrasound image in conventional B-mode sonography. The frequency of the transmitted pulses and their echoes are the same (Fig 3). Harmonic Frequencies Energy from the fundamental frequency is partly absorbed, partly scattered, and partly converted into harmonic and subharmonic waves during nonlinear propagation of the fundamental wave through the tissue. Harmonic wave frequencies are integer multiples of the fundamental frequency (so, if the fundamental frequency is f, the harmonics have frequencies 2f, 3f, and so on). The amplitudes of the harmonic waves are typically lower than that of the fundamental frequency component (Fig 4). Subharmonic frequencies are less than fundamental frequency (1/2 f, 1/3 f, and so on). There are also higher harmonics of the subharmonic frequency component i.e., 3/2, 5/2, 7/2 … x f/2, which are called ultraharmonic frequencies. Over time, tissue nonlinearity distorts the fundamental sine wave pattern during propagation through the tissue; the peaks within the pulse waves propagate with a higher speed than the troughs of the wave. This is because the speed of propagation is slightly greater in the compressed regions of the tissue than in the expanded regions. The resulting waveform distortion depends on the emitted pulse amplitude and distance travelled. The distortion is negligible for low amplitude pulses, but it is signiicant for large amplitude pulses. At the skin level, tissue harmonics are virtually zero; however, their intensity increases with depth up to the point where tissue attenuation overcomes this build-up and causes them to decrease (Fig 5). The production of harmonic waves is proportional to the square of the fundamental intensity. So, the center of fundamental beam generates harmonic beams predominantly. The region of maximal production of harmonics is at the focal zone, because beam intensity is highest at central location. Little or no harmonics are produced by weak waves, such as those from the edges of ultrasound beam, side lobes, grating lobes and scattered echoes (Fig 6). Tissue Harmonic Imaging The majority of clinical US systems use second harmonic (2f) echoes for THI image formation, with limited utilization of higher frequency harmonics. The reasons for this include: 1. The limitation of bandwidth of current transducers for higher frequencies. 2. Higher frequency harmonic waves (3f, 4f and so on) are attenuated more rapidly during passage through tissue. The quality of THI depends primarily on achieving complete elimination of echoes from the transmitted pulse. Fundamental Wave Elimination Techniques Various techniques are used to remove transmitted pulse echoes: 1. Receive Filtering: Filtration is a signal processing technique to ilter out the spectrum of frequencies that are likely to arise from the fundamental beam and provide better information from narrower bandwidth higher frequency harmonic echoes. In this technique, noise diminishes and contrast is improved. However, narrowing the received transmitted bandwidth will reduce axial resolution (Fig 7). 2. Pulse Inversion: Pulse inversion is another technique in which two pulses with a 180° phase diference (opposite phase) are created sequentially along the same line. This results in cancelation of the fundamental echoes and odd harmonics and a doubling of the amplitude of the even harmonic waves (Fig 8). This technique has been termed a temporal cancellation technique. The principal advantage of this technique is that axial resolution is not degraded. However, pulse inversion imaging inherently depends on a ixed tissue frame. Tissue motion may markedly degrade the US image. 3. Side-by-Side Phase Cancellation: This method is similar to pulse inversion, but instead it transmits two pulses with opposite phase along adjacent lines of sight. These adjacent lines are then added to cancel fundamental echoes and odd harmonics. This technique is also termed a spatial cancellation technique. Like pulse inversion, it preserves harmonic frequency bandwidth. 4. Pulse Encoding/Coded Harmonics: Pulse encoding technique transmits relatively complex pulse sequences into the body with a unique, recognizable code imprinted on each pulse. The unique code is then recognized in the echoes by a special decoder that is part of the equipment/matched ilter. Because the linear, fundamental echoes have a speciic code, they can be identiied and canceled (Fig 9). The remaining harmonic echo is then processed to form the image. This technique is especially useful in the near ield. References: 1. Chiou, S., Forsberg, F., Fox, T. & Needleman, L. 2007, “Comparing diferential tissue harmonic imaging with tissue harmonic and fundamental gray scale imaging of the liver”, vol. 26, no. 11, pp. 1557. 2. Choudhry, S., Gorman, B., Charboneau, J., Tradup, D., Beck, R., Koler, J. & Groth, D. 2000, “Comparison of tissue harmonic imaging with conventional US in abdominal disease”, vol. 20, no. 4, pp. 1127. 3. Desser, T. & Jefrey, R. 2001, “Tissue harmonic imaging techniques: physical principles and clinical applications”, vol. 22, no. 1, pp. 1. 4. Hoskins, P. et al. 2010, “Diagnostic Ultrasound Physics and Equipment”. 5. Kollmann, C. 2007, “New sonographic techniques for harmonic imaging--underlying physical principles”, vol. 64, no. 2, pp. 164. 6. Kotani, A., Hirano, Y., Yasuda, C. & Ishikawa, K. 2007, “A new ultrasonographic technique for diagnosing deep venous insuiciency--imaging and functional evaluation of venous valves by ultrasonography with improved resolution”, vol. 23, no. 4, pp. 493. 7. Lencioni, R., Cioni, D. & Bartolozzi, C. 2002, “Tissue harmonic and contrast-speciic imaging: back to gray scale in ultrasound”, vol. 12, no. 1, pp. 151. 8. Nowicki, A., Wojcik, J. & Secomski, W. 2007, “Harmonic imaging using multitone nonlinear coding”, vol. 33, no. 7, pp. 1112. 9. Ralls, PW. 2001, “Tissue harmonic imaging update” http://www.sonocredits.com/ sonocredits/article.asp?TestID=41. 10. Tranquart, F., Grenier, N., Eder, V. & Pourcelot, L. 1999, “Clinical use of ultrasound tissue harmonic imaging”, vol. 25, no. 6, pp. 889. 11. Uppal, T. 2010, “Tissue harmonic imaging”, AJUM; 13 (2):29-31. www.minnisjournals.com.au/ajum/ article/Tissue-harmonic-imaging-63#. 12. Yucel, C., Ozdemir, H., Asik, E., Oner, Y. & Isik, S. 2003, “Beneits of tissue harmonic imaging in the evaluation of abdominal and pelvic lesions”, vol. 28, no. 1, pp. 103. Objective Tissue Harmonic Imaging (THI) and Diferential Tissue Harmonic Imaging (DTHI) are nonlinear sonographic image processing technologies designed to improve the quality of conventional grayscale imaging. This exhibit will explain the physical principles of THI and DTHI and their impact on ultrasound (US) of liver and kidney disorders. Background of Tissue Harmonic Imaging (THI) First introduced by Averkiou et al. (1997), THI is a signal processing technique for improved grayscale resolution and reduced speckle. Researchers studying the contrast efect of microbubbles and the harmonic frequencies arising from insonating such microbubbles unexpectedly realized the potential of non-contrast based THI. Harmonic frequencies originate from tissues during US imaging, even without injection of contrast agents (i.e., microbubbles). Exploiting this fact for THI improves some features of the US image. Thus, this technique is also called native harmonic imaging. Diferential Tissue Harmonic Imaging (DTHI) is a more recent technology development introduced in 2005 that combines the advantages of conventional fundamental sonography (increased penetration) and THI (superior border and tissue deinition with reduced speckle). Advantages of Tissue Harmonic Imaging over Conventional Grayscale Sonography Images produced with THI are often superior to conventional grayscale images for cystic lesions and lesions containing fat, calcium or air because THI has some technical advantages: A. Improved Contrast Resolution: Increased signal-to-noise ratio results in better tissue contrast, which improves the conspicuity of subtle parenchymal lesions. B. Improved Lateral Resolution, Reduced Slice Thickness: The nonlinear dependency of harmonic wave generation described above results in generation of harmonic waves predominantly at the center of the ultrasound beam. This narrows the imaging plane and improves lateral resolution. C. THI Impacts on Artifacts: THI reduces some artifacts and enhances others: 1. THI reduces reverberation artifact, side lobe artifact, and grating lobe artifact, which have their origin in weaker beams, produced on either side of the main lobe of the transmitted beam. 2. Increases acoustic enhancement in luid, which is useful for depicting cystic lesions, enhanced acoustic shadowing, and enhanced comet tail artifacts. D. Reduced Noise (Clutter) in the Near Field: Harmonics are not produced in the supericial part of tissue, which reduces noise (clutter) in the near ield. It can also provide better image quality in some patients with unfavorable body habitus like obese patients (BMI ≥ 30). Disadvantages of Tissue Harmonic Imaging over Conventional Grayscale Ultrasonography As iltering decreases bandwidth, the resolution in harmonic images may be worse in some situations such as difuse fatty liver (Fig 10) or not add information additional to fundamental imaging (Fig 11). 1. Compromise of Axial Resolution: THI can reduce axial resolution slightly due to the reduction of bandwidth in iltration technique. 2. Higher Attenuation and Less Penetration: Attenuation of the harmonic component is greater due to its higher frequency. This results in poor visualization of deeper structures. Clinical Applications of Tissue Harmonic Imaging THI provides more imaging information for radiologists to diagnose certain pathologies or normal structures more conidently than fundamental imaging. A. Hepatobiliary: THI has been shown to improve image quality in hepatobiliary system sonography such as gallstones or some focal lesions (Figs 12, 13) through a variety of mechanisms: 1. Reduced reverberation and side lobe artifacts from the body wall (especially in obese patients and in narrow intercostal acoustic windows). This can improve visualization of small anatomic structures such as peripheral portal veins and smaller biliary radicles. 2. Improved visualization of focal lesions, due to reduced artifacts and improved lesion- tissue contrast. 3. Improve characterization of lesions that contain luid such as cystic lesions and luid collections owing to a reduction in reverberation artifact. This is particularly useful for distinguishing hypoechoic solid lesions such as lymphomatous lymph nodes from cystic lesions. 4. THI increases the conspicuity of posterior acoustic shadowing from gallstones especially in obese patients. 5. THI improves conspicuity of the comet tail artifact that is diagnostic of adenomyomatosis of the gallbladder. B. Kidney: THI is also useful in renal imaging. Clinically signiicant improvements include: 1. Improved capability to distinguish between cysts and solid renal lesions. Conident characterization of a lesion as a simple cyst depends on establishing the complete absence of internal echoes, nodules, or septa. Image artifacts or noise may make it diicult to determine whether a cystic renal lesion is simple or complex. Simple renal cysts can often be deinitively diagnosed on harmonic images when fundamental images are equivocal, reducing the need for follow-up CT exams (Figs 14,15). 2. Improved detection of the shadowing from urinary stones. 3. Improved renal cell carcinoma/renal parenchymal tissue contrast. Diferential Tissue Harmonic Imaging (DTHI) THI is not optimal for sonography, because it uses the only half of the available transducer bandwidth for image formation, the lower half for transmission and the upper half during reception. However, an alternative technique - DTHI - uses the entire transducer bandwidth, combining the advantages of conventional gray scale sonography with that of THI, especially at greater depths (>8 cm). Diferential Frequencies and Image Processing: In DTHI, two pulses are transmitted at diferent frequencies simultaneously, f 1 and f 2 . In addition to their harmonic frequencies (2f 1 and 2f 2 ), the sum and diference of the transmitted frequencies (f 2 + f 1 and f 2 – f 1 , respectively) are generated within the tissue. The second harmonic signal of the lower frequency (f 1 ) and the diference frequency (f 2 – f 1 ) are detected by the transducer, but other generated frequency components do not fall within the transducer’s bandwidth, and both fundamental frequencies are cancelled by the subtraction technique (a technique similar to pulse inversion) and are thus not present in the detected signal. By receiving both the second harmonic 2f 1 and the diferential frequencies (f 2 – f 1 ), the efective bandwidth of the tissue harmonic signals are signiicantly expanded. In fact, the total bandwidth of the transducer can be covered. Using DTHI, higher resolution, better penetration and fewer artifacts can be achieved (Fig 16). Comparison of Diferential Tissue Harmonic Imaging with Tissue Harmonic Imaging DTHI and THI are signiicantly better than fundamental sonography with respect to noise reduction, detail resolution, image quality, lesion margin sharpness and penetration for hepatic imaging. DTHI also performed better than THI with respect to detail resolution, image quality and contrast to noise ratio in focal hepatic lesions (Fig 17). All illustrations: Sahar Anvari Fig1. Linear and nonlinear interaction of ultrasound waves with the medium (tissues). Transmitted pulse is of high energy and consists of range of frequencies centering on f 0 . In linear medium the echo pulse similar frequency but lower energy (left), but in nonlinear medium it also has harmonic waves with higher frequency and lower energy (Courtesy of James DT et al). Fig 2. As fundamental frequency propagates through nonlinear medium, harmonic waves are generated. The shape of waves becomes distorted and the sharp crests travel faster than rounded troughs (Courtesy of James DT et al). Fig 3. Fundamental frequency imaging process, in this method bandwidth of received is the same of transmitted frequency and it is used for image processing (Courtesy of Kotani, A et al). Fig 4. THI imaging process, in this method only 2f harmonic frequency is used for image processing (red) (Courtesy of Kotani, A. et al). Fig 5. The relationship between fundamentals and harmonics strength with imaging depth (Courtesy of Thomas JD, et al). Fig 6. Production of harmonic waves in THI, transmitted echoes blue are blue and harmonic waves are created in the focal zone which avoid scattering of received echoes some artifacts like side lobes and grating lobes (shown in red) (Courtesy of Uppal T). Fig 7. Filtration technique for fundamental frequency removal (Courtesy of Hoskin P). Fig 8: Pulse inversion (PI) technique for fundamental frequency removal. On Line 1, a pulse (f0) is transmitted and the line of echoes stored. A second pulse with inverted phase is transmitted along the same beam. The resulting line of echoes (Line 2) is added to Line 1. Low- amplitude echo signals (f0) cancel out while distorted, high-amplitude signals (2 f0) do not (Courtesy of Hoskin P). Fig 9: Pulse encoding for fundamental frequency removal (Courtesy of Hoskin P). Fig 10: Difuse fatty liver, conventional ultrasound (A) has better penetration ultrasound beam than THI (B) (Courtesy of Choudhry et al). Fig 11: Liver abscess. No additional information between fundamental image (A) and THI (B). (Courtesy of Choudhry et al). Fig 12: Gallbladder stones. Conventional imaging (A) and THI (B). By elimination of side lobes and improved resolution multiple stones become visible on THI scan. (Courtesy of C. Yu¨ cel et al). Fig 13. Liver metastasis with Fundamental (A) and THI (B). THI has higher contrast and gives more precise information on the posterior images ascites. (Courtesy of Tranquart et al.) Fig14: Renal cyst. THI demonstrate septations and a mural nodule within the cyst better (B). Fig15. A 2.5 cm renal angiomyolipoma. Sonograms were obtained with (A) conventional imaging and (B) THI. The increased echogeneity of the lesion and better delineation of its boundaries on THI. (Courtesy of C. Yu¨ cel et al). Fig 16. Diferential tissue harmonic imaging (DTHI). (Courtesy of Kotani, A et al). Fig17: Diferences of two small hepatic focal lesions in fundamental imaging (A), THI (B), DTHI (C), Note the superior deinition of the liver parenchyma and focal liver lesions. A A A A A A A B C B B B B B B