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TAP: Transcutaneous Acoustic Palpation

            My name is Rowen Tych, and I’m a junior working under Dr. Pierre Mourad in the Neurosurgery Department of the UWMC. Our lab specializes in utilizing an experimental type of ultrasound, called HIFU (High Intensity Focused Ultrasound). This type of ultrasound can be used to create a thermal and mechanical force some distance from the surface of a transducer (usually 1-2 cm away with our cones). In the past, this technology has been used to cauterize blood vessels, create lesions in tissues and in low enough doses can temporarily open the blood brain barrier. One side of our lab is currently looking into its effectiveness as a non-invasive ICP device, while the other half, which I work in, is examining HIFU to see if it may be a better diagnostic tool for lower back pain.

Our lab hopes to eventually create a device that can push on potential pain generating structures in a human, more specifically, in the spine. While pain is usually the first indication that something is not right in the body, it is notoriously non-specific in some locations, and diagnostic tests may have only limited value. For example, for up to 85% of patients with lower back pain, neither imaging, physical examination nor provocative diagnostic tests can pinpoint the anatomical structures causing the pain (Jarvik and Deyo 2002). Most of the time, an invasive procedure is required in order to diagnose the disorder. However, these procedures, such as discography, are uncomfortable for the patient, have uncertain sensitivities and specificity, can only test a few potential sources and as with any invasive procedure, carry some amount of risk to the patient (Caragee et al. 2000). We propose that with our device, a physician will instead be able to simply target a few potential structures that could be causing the pain and push on them with ultrasound, with no risks associated with surgery and better accuracy than MRI’s and X-rays alone. Pain generating sources around the spine would be painful when palpated with our device. Our non-invasive method of diagnosis would be extremely helpful in diagnosing a patient with lower back pain.

The goal of our studies so far on TAP has been to show proof of concept on animal models. In our CFA study, we took rats and made their right paws inflamed and tender via a injection of an adjuvant (Nagakura et al. 2003). After the swelling had manifested, we gave their inflamed and normal paws increasing levels of our HIFU until we observed the animal withdraw a paw from the stimulus. After two positive responses at a given level of ultrasound, we did another six tests at that threshold to test for sensitivity and specificity. If we did not observe two positive responses at that level, we continued ramping the ultrasound up in small steps until a double yes was achieved. We recorded which paw withdrew and how many responses out of six were positive or negative. To test the both for relative sensitivity and specificity of our animals, and also to check for any sensory changes our HIFU might have produced, we accompanied each TAP session with a Hargreaves heat and light stimulus test, adapted from Hargreaves et al. (1988).

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Figure 1 – At a given threshold of ultrasound, most rats withdrew their inflamed foot 6 out of 6 times, while most normal paws did not withdraw from the same stimulus.

Our results from this study showed that our HIFU does not affect the responses of our Hargreaves tests, or vice versa. We also showed that our HIFU can be used to distinguish between inflamed and normal tissue, as inflamed tissue will be painful when beamed with HIFU that would otherwise elicit no response from normal tissue. These results have been submitted to the journal Pain, and is awaiting publishing. Having showed our device was good for nonspecific inflammatory pain, we decided to try a purely neuropathic model to show that our device can work on this model as well. To do this, we decided to use a partial sciatic nerve ligation model, where the sciatic nerve in rats is irritated and the footpad becomes sensitive and painful (Shir et al 2000). My work on this is near its conclusion, and from the preliminary data we have analyzed so far, it seems that our device can successfully distinguish between neuropathic sensitive tissue and normal control tissue. However, there is more work to be done on this model before it can be published.

Our proposed research for the next year is to continue to push our TAP towards the clinic. We recently received approval for some preliminary human studies using our device. Our first study, set to take place at the end of summer and into the fall, will be to find the thresholds for sensation of HIFU in human volunteers. I will be working with our subjects in a clinic near the patient areas of the medical center, and be responsible for managing both the subjects, our test procedures and interpreting the data we will collect. I am really excited to get into this side of the project, as I eventually want to pursue a career somehow related to healthcare. Doing tests on human models will be very exciting, as the idea all of my research over the years is slowly getting closer to its intended location; the clinic. Our primary goal with our human studies is just to find the level of perception for our ultrasound, as previously mentioned, but depending on the results of our current sciatic nerve work, we may skip collecting animal tissue for safety analysis and actually begin trying our device on patients with various injuries to see its effectiveness as a diagnostic tool.

            I was introduced to my lab the summer before I started attending classes at the University of Washington. Over the first summer, I learned the basics of our lab, such as how to operate our wide array of HIFU devices, how to properly use our animal facilities and how to handle and perform surgery on our animals we use in our preliminary studies. After I was sufficiently trained, Dr Mourad decided to put me in charge of his latest idea, TAP, which would from then on occupy most of my time in the lab. I believe Dr Mourad gave me an amazing opportunity in this research. While most undergraduates only work on projects for a year or two at most, I have been with this lab for nearly three years. In doing so, I’ve seen the entire process of research and development, from initial idea to published paper, which few students get to see. Furthermore, it has been an amazing and educational experience to lead the research and move the project forward, doing everything from collecting our data, interpreting our results, writing up our findings and getting them published. Research was always an area of fascination for me, and Dr Mourad has given me an incredible view of how the process works. I have no doubt that the skills and knowledge I’ve learned from being integrated into every part of research will benefit me when I graduate.

            Biology was always an area of interest for me. I grew up in a small house surrounded by five acres of dense Northwest forest, and spent endless hours scouring the woods for anything new and interesting. I remained mesmerized by animals into high school, and when I took AP Biology in my senior year, I knew what I was going to major in the next year when I attended college. Working in the Mourad lab helped me immensely during my classes at the University of Washington, especially during my freshman year. Freshman year, and much of sophomore year, was spent doing chemistry and math prerequisites, and at times, I sometimes felt I wasn’t working towards my goals. My lab during that time kept me looking ahead and reminded me of what the amazing things I would soon be doing once I had completed my prerequisites. Over the years the research been a wonderful way to focus and re-center on what I find my true interests. Not only has the lab helped me to keep working towards my goals, but it’s also helped me in many of my major’s courses. I’m already ahead of many of my peers when it comes to anatomy and physiology, especially in mammals, and doing assignments in a laboratory setting is so second nature that I’ve never had to learn or adjust to the new environment. Even in my human anatomy class that I am enrolled in now, having worked with doctors and with such in depth animal models has given me a tremendous advantage, just for sheer familiarity with the body and how it works, especially neurologically.

            I think my interest in anatomy and human physiology emerged right about when I began my work at the Mourad lab, and since then, my research has only deepened the passion I have for the body and how it works. Dr Michel Kliot, one of the collaborators on our research, allowed me to shadow him for a week during the summer, and seeing everything from brachial plexus surgery to brain surgery was nothing short of astounding. At the end of that summer, I knew I wanted a future in healthcare. Over the years I’ve found the research I’ve done to be a perfect match for my interests. Learning and understanding animal physiology is an essential part of my work, and it ties directly in with my passion for human medicine. Seeing and operating on actual nerve fibers and learning stitching techniques from Neurosurgery interns may seem mundane and even gross to some people, but for me, there is no other place I would want to work. I hope to continue my research project over the summer and publish a second paper on the sciatic model, but what is most appealing is starting up the clinic and human studies with our device. It will be amazing to see the full process of how just a simple idea can be transformed into a useful tool that will help real people, and it’s truly remarkable to think that the work and research I’ve done over the years will soon be put into a tangible and vital new tool for doctors and their patients.

References

            Carragee EJ, Tanner CM, Kurana S, Hayward C, Walsh J, Date E, Truong T, Rossi M, Hagle C, The rates of false-positive lumbar discography in select patients without low back pain symptoms. Spine 2000;25:1375-1381.

            Hargreaves K, Dubner R, Brown F, Flores C, Jorris J. A new and sensitive method for measuring the thermal nociception in cutaneous hyperalgesia. Pain 1988;32:77-88.

            Jarvik JG, Deyo RA. Diagnostic evaluation of low back pain with emphasis on imaging. Ann Intern Med 2002;137:586-597.

Nagakura Y, Okada M, Khoara A, Kiso T, Toya T, Iwai A, Wanibuchi F, Yamaguchi T. Allodynia and Hyperalgesia in adjuvant-induced arthritic rats: time course of progression and efficiency of analgesics. J Pharmacol Exp Ther 2003;306:490-497.