A Sound future for Noninvasive Therapies

The black and white image of a developing fetus, also known as Sonogram, is a familiar sight for most of us and the imagery already has an iconic status in the story of humanity. From prenatal sonograms and real-time images of various other parts of human anatomy to advanced applications in monitoring blood flow and elastography, ultrasound (US) imaging or sonography is central to our medical diagnostic capabilities. But can the same technology be used for therapeutic purposes as well?

Ultrasound image sequence from a study of valves in a patient’s heart. Generated by Kieran Maher using OsiriX and ImageJ (https://commons.wikimedia.org/wiki/File:Valves_Of_Heart_Ultrasound.gif)

The diagnostic US has been around for clinical use since the 1950s. It uses high-frequency sound waves, inaudible to human ears, which are emitted and received by a transducer device placed topically on the skin near the region of interest. Sound waves are focused deep into the human body and the reflected sound carries information about the physical properties of the focal region. The information is then analyzed either to form a real-time image or provide advanced properties of the probed anatomic structure, such as its elasticity, which for example, can indicate the presence of fibrosis or a tumor. The technology has been shown to be completely safe and without any significant side effects. However, this depends upon very particular US settings that are used for diagnostic purposes. For example, higher intensities can ablate tissue or even brake kidney stones, which were indeed among the first therapeutic applications of ultrasound.

The technology is now at an advanced stage that allows focusing US precisely on various internal organs with different intensities and frequencies. This despite the complexity of human anatomy and its very heterogeneous nature as an acoustic medium. High intensity focused ultrasound (HIFU), for example, has recently become available in clinics as an alternative to removing tumors via surgery(1). In HIFU, no harm is done to the skin or the intermediate tissue as only the focal region of a couple of millimeters has enough energy (10000 times the diagnostic US energy) to ablate the tissue reaching temperatures of up to 80 deg C. Similar procedures are also under trial for creating lesions in particular regions of the brain for dyskinesia(2) and essential tremor(3) that accompany Parkinson’s disease. Conventionally, the lesions are created via surgery or inserting electrodes and heating electrically.

The state of the art is thus capable of providing noninvasive alternatives to sensitive surgeries by precisely controlling the destructive capabilities of HIFU. However, with advances in our fundamental understanding of the mechanism underlying human physiology, we are beginning to tap into subtle bio-effects of US on innate physiological processes(4). But how can sound waves alter biochemical processes? Sound waves are vibrations or density variations resulting from microscopic displacements that propagate through a media. However, in complex materials and biological materials in particular, a sound wave is not a simple density perturbation anymore, but it can also reversibly alter pH, electrical potential or protein confirmations(5, 6). Regarded as biophysical action of soundwaves, it is currently a hot topic for fundamental research in life sciences.

For example, the US has been shown to reversibly alter the mobility of drugs across cell membranes as well as cell-cell junctions, which has many applications in delivering various drugs to diseased organs. For example, the first successful human trials in the US induced opening of the blood-brain barrier (BBB) were conducted recently(7). Made of endothelial cells connected via tight junctions, BBB allows selective transport between the blood and extracellular brain fluid blocking most drugs designed for brain diseases. It will be several years before it becomes clinically viable, but transient and reversible US induced opening of the BBB will eventually allow pharmaceuticals and chemotherapeutics access to brain diseases, including tumors, Alzheimer’s and Parkinson’s disease.

Finally, direct acoustic stimulation or blockage of neuronal activity holds immense potential for noninvasive, drug-free treatment of diseases like depression and epilepsy(8). Tapping into the autonomous control of our immune system by modulating the central nervous system, can potentially provide noninvasive and drug-free alternatives for managing, for example, rheumatoid arthritis(9), type II diabetes and asthma(10). Acoustic neuromodulation is still in very early stages of research, and as before, will require concerted efforts in fundamental and applied research to reach the level of selectivity required for such advanced therapeutic applications. Can acoustics affect signaling pathways and on what time scales? How these effects manifest at biomolecular, cellular and organ level? What US characteristics, frequency, amplitude, duty cycle, duration are needed to see an effect? Are there thresholds for different bioeffects and can they be resolved for selectivity? These are some of the questions that we need to answer before the true potential of US as a therapeutic technology can be realized, potentially making it an end to end solution for our medical needs, from diagnostics to therapeutics.

References

1. Cranston D (2015) A review of high intensity focused ultrasound in relation to the treatment of renal tumours and other malignancies. Ultrason Sonochem 27:654–658.

2. Na YC, Chang WS, Jung HH, Kweon EJ, Chang JW (2015) Unilateral magnetic resonance-guided focused ultrasound pallidotomy for Parkinson disease. Neurology 85(6):549–51.

3. Elias WJ, et al. (2013) A Pilot Study of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med 369(7):640–648.

4. Mueller JK, Tyler WJ (2014) A quantitative overview of biophysical forces impinging on neural function. Phys Biol 11(5):51001.

5. Fichtl B, Shrivastava S, Schneider MF (2016) Protons at the speed of sound: Predicting specific biological signaling from physics. Sci Rep 6. doi:10.1038/srep22874.

6. Shrivastava S, Schneider MF, Cleveland RO (2016) Acoustic response of phospholipid membranes: Estimating thermodynamic susceptibilities from fluorescence spectrum. ArXiv e-prints:1612.06709.

7. Carpentier A, et al. (2016) Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med 8(343). Available at: http://stm.sciencemag.org/content/8/343/343re2 [Accessed March 31, 2017].

8. Legon W, et al. (2014) Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci 17(2):322–9.

9. Koopman FA, et al. (2016) Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A 113(29):8284–9.

10. Weintraub A (2016) How GSK And Google’s Verily Will Tackle Diseases With Nerve-Altering Chips. Forbes. Available at: https://www.forbes.com/sites/arleneweintraub/2016/08/02/how-gsk-and-googles-verily-will-tackle-diseases-with-nerve-altering-chips.