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Tissue Disruption
Thermal Ablation

The same temperature (57-60 deg C over a few seconds) causes tissue ablation in a wide variety of tissues due to the similarities in protein content.  The FUS parameters and energy requirements to achieve that target ablation temperature can vary widely.

The treatment temperature for ablation is 45-60 degrees C for less than 1 minute, and is based on cell biology, not frequency. Temperatures below 45 deg C are probably safe for most tissues. Even brief exposure of 2-4 seconds to temperatures above 56 deg C will guarantee ablation in virtually all mammalian tissues.

The thermal dose, describing the temperature history over time, is an important parameter, more relevant than temperature alone. It should be provided when describing an experiment or treatment. Reaching the same target temperature at different speeds can make significantly different results.  

Gray Matter vs. White Matter Vs Tumor

Even 43 deg C for 5 minutes can affect brain tissue and cause functional changes, such as seizures.  Temperature is an indirect measure of tissue death, given the importance of time of exposure, energy, tissue factors, etc.  The temperature history over time is a better indicator. Even 45 deg C will yield 100% coagulation of tissue over 500 seconds. A more direct indicator of tissue death would be PET imaging.  One must use caution above 45 deg C due to the variability of response in different tissue types in that range. 

It is possible to measure temperature using T1 on MRI, but it is not practical, because the trajectory during cooling may differ from that due to heating because of the possibility of a phase transition.

Can Cavitation be Controlled?

There is always some level of gas in the fluid that potentially, under ultrasound pressure, can create oscillating microbubbles . When the pressure level grows beyond some threshold, sudden collapse of bubbles can release enough energy to damage cells. This is known as inertial cavitation. Bubbles may be also used to enhance the heating effect at the target. When they  oscillate only (without collapsing) they trap much more acoustic energy and cause local heating. This can be beneficial if it occurs within a target tissue, or problematic if it results in excessive heat deposition away from a target tissue. In long bursts ultrasonic excitations, bjerknes forces between bubbles can induce attraction between microbubbles and result in bubble coalescence.

The cavitation threshold is strongly dependant on tissue characteristics and on the acoustic parameters (pressure, frequency etc''). Some people (i.e. Jean-Francois Aubry) claim that the cavitation threshold is reduced by a factor of 10 in the presence of standing waves. Others, (i.e. Shuki Vitek),  claim to have proven that it is absolutely not true.  It is reduced by a non-negligible factor in the presence of standing waves. More experimental work and cross-validation is needed to quantify this factor.

Inertial cavitation cannot be easily controlled, other than to avoid the threshold conditions which lead to its occurrence. The presence of microbubbles in tissues is strongly correlated with the cavitation phenomenon. The threshold varies with the square root of the frequency, and is lower with lower frequencies. Nuclei of small particles enhance the propensity towards cavitation.  Local energy deposition can be quite high due to cavitation, which can alter local membrane permeability.  Several research groups are focusing on controlling cavitation.  Blood brain barrier opening is a good example of the general relationship of microbubbles, wherein increased energy is associated with more negative effects.

Cavitation allows enhancement of ablation, greater effect with less energy delivery. Cavitation can be detected immediately, and has a well-defined acoustic signature. It is more difficult to determine its exact origins, and some techniques need to be developed to confirm its location.    Vascular thrombolysis is based in cavitation.  Lithotripsy and histotripsy are good examples of therapeutic use of cavitation to obliterate kidney stones and atrial cardiac tissue, respectively.

Thermal Ablation vs. Cavitation

Where possible using thermal effects is better controlled and predicted. However cavitation might be essential in some applications in the brain. To provide a solution for these applications the effects need to be predictable and controlled. The technology must be better mastered before it can be widely used.

Cavitation would typically create larger effects in tissue than thermal mechanisms. At 220kHz, the spot dimensions can be as large as ~1cc where as in 650kHz each sonication is ~0.2cc. Each sonication cycle requires cooling of the skull (~2min) so the rate of ablation can be roughly between 0.1-0.5cc per minute.  A 3 cm diameter meningioma (volume 14 cc) would require between 28 (at 220kHz) and 70 (at 650 KHz) sonications.  Treatment time would average approximately 60min @ 220khz and 140min @ 650khz for a 3 cm diameter tumor.  Cavitation could increase the sonication ablative efficiency by a factor of 2-3, or more.   The challenge is to control the cavitation process.

Treatment involving large volumes, such as widespread opening of the blood brain barrier, or delivery of gene fragments or drug to the whole brain, would necessitate cavitation for acceptable treatment times.  Three to four hours is a reasonable upper limit to the amount of time an awake, partially sedated patient can comfortably remain in one position in the MRI for treatment.  The awake patient provides the grea safety factor in terms of avoidance of inadvertent heat injury, given the sensitivity of dura and skin.  Pain would usually be felt prior to the point of irreversible damage. Dural damage might be associated with venous thrombosis if heating occurred near a venous sinus.  For volumes much in excess of 22 cc (3.5 cm diameter), one might consider staged treatment in multiple sessions. 

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