Treatment Envelope Adjacent to Calvarium
There are different considerations for the cranial vault, as opposed to the skull base. Significant thermal energy is deposited on first penetrating the calvarium. Cavitation may need to occur closer to the skull. Acoustic reflections off of the skull base are observed. There is less energy per square cm just under the cranial vault, away from the deep focus. If the US focus is near the skull base, there is more concentrated thermal energy adjacent to that focus than one encounters widely over the calvarium, which can yield up to 10X as much thermal energy deposition.
It has been proposed that treatment of lesions adjacent to the calvarium will require the low-frequency unit (230 kHz), though that may not be necessary for lesions at the skull base. However, without cavitation, working at low frequency will require more power at focus as the absorption coefficient is lower. Although absorption in the skull is higher at higher frequency, the focal spot is smaller (so antenna gain is better). Moreover, the question of absorption coefficient value in the skull bone does not reach a consensus. Finally, control of cavitation near the skull was not addressed properly today. So, the question is much more complex.
Microbubbles (either natural or injected) can be utilized, with shorter pulses (by two orders of magnitude), to decrease skull base heating and could be tailored to create apoptosis. Depending on the gain, one can encounter gas bubbles in animal brains with 1-3 cycles in short bursts, which can be visualized with ultrasound.
With homogeneous amplitude, one can generate a bubble cloud using low frequency pressure waves at a 4 mm focus. Ultrasound energy is absorbed, creating a reflecting wall, which absorbs energy and is associated with further energy reflection. The specific interaction of the beam with the bubble cloud is related to the vector of flow propagation. One should be able to prevent expansion by controlling the amount of bubbles in the cloud. Bubble behavior may be easier to control adjacent to the skull base than near the cranial vault, because of the smaller focal zone. The phenomenon has not been well studied. Animal studies are ongoing at the University of Toronto, with advances in treatment planning accomplished at the Brigham & Women's Hospital in Boston.
Thermal lesions may be too difficult to attain close to the calvarium and skull base. Cavitation may offer a better option to ablate in these regions. Further 3D and skull phantom simulations (best performed with supercomputers, given their complexity), and confirmatory animal experiments are required. Simulations would compare various frequencies, focal shapes, reflections, etc.
There was consensus among the technical teams to collaborate on ing the simulations. Thilo Hoelscher at UCSD mentioned his proposal to FUSF for funding of a study to generate a database of human skulls analyzed with high resolution CT scanning. The group goal is to enable practical clinical treatment of these tumors within five years (by 2014), with FUSF providing the appropriate start-up funding.
Through a separate breakout session, the FUSF organized collaboration between four centers to assess remote effects within the skull, especially in response to a case of hemorrhage in a brain tumor case. These investigators include Shuki Vitek and Eyal Zadicario of Insightec in Israel, Mickael Tanter in Paris, France, Greg Clement at the Brigham & Women's Hospital in Boston, all led by Kullervo Hynynen at the University of Toronto.
Sensitivity of Cranial Nerves
The thermal history over time, length-heating histogram, and specific microvascular relationships are all-important parameters. Assessing temperature alone is not very revealing. Even in the case of defined target temperature, the actual temperature of the nerve is difficult to determine exactly. Cranial nerve thermal sensitivity is dependent on the proportion of myelinated fibers, and to nerve size, although heat over 60 deg C even for seconds can permanently destroy nerves. The acoustic nerve has different thermal sensitivity in the internal auditory canal, versus outside the canal, due to changes in myelination. A stretched or compressed nerve will have less thermal tolerance, related in part to lower fiber number and demyelination.
The optic and olfactory nerves represent two extremes. The optic nerve is relatively easy to monitor using stimulation and recording (Visual Evoked Responses). Sagi Harnof ed optic nerve sensitivity to thermal effects of FUS and found the exposure to 45 deg C and less was tolerated, and that temperatures of 45-55 deg C were safe based on histology (functional studies were not performed). Temperatures above 55 deg C caused histologic changes, and above 65 deg C a clear lesion in the nerve was seen (reported at the FUSF Symposium, Oct 2008, Tyson's Corner, VA).
Experience from surgery and radiosurgery suggests that the optic nerve is extraordinarily sensitive to damage. Empirical observations in clinical cases may provide the best data, as they did in assessing cranial nerve tolerance to stereotactic radiosurgery in the early 1990's.
Between 45 and 60 deg C, non-myelinated fibers are rendered nonfunctional. Most nerves will at least suffer temporary dysfunction in that range. This principle is utilized by anesthesiologists for temporary anesthesia. Short exposures under 45 deg C should be well-tolerated. Animal models of non-cranial nerves are not relevant to cranial nerve conclusions.
Microbubbles might allow enhanced safety of treatment adjacent to cranial nerves, by avoidance of the thermal threshold limit. However, destructive tissue effects are far less controllable with microbubbles, compared to purely thermal effects.
Remote Effects of Intracranial FUS
Cytotoxic, blood brain barrier, and vasodilatory effects in the near and far fields
Vasodilatation can occur without invoking thermal effects. Thermal effects are related to vascular changes through BBB opening, but these are limited to a few mm from the focus using the high and mid-frequency Insightec system. Spreading depolarization occurs at lower energy threshold than BBB disruption. Vasodilation occurs in the myocardial vasculature with low-pressure ultrasound. Edema is transient and limited to the immediate boundary around the target. Within the thermal target zone one finds mainly necrosis, with a thin rim of apoptotic cells.
Nature of the transient penumbra around thermal ablation
The transient penumbra around a region of thermal ablation is likely vasogenic edema extending out for 2 mm or so, although it is not well visualized on diffusion-weighted imaging. Vasogenic edema extends beyond the region of BBB opening. Animal studies do not appear to reveal gliosis later in the edematous zone.
Standing waves and Ringing
In cadaveric studies and by computer simulations, intracranial acoustic reflections cause an increased pressure, which can be as high as 5% of the pressure in the focus, which is less than 1% of the energy (thermally insignificant, from an energy standpoint). The pressure change can result in cavitation, although one should be well below the cavitation threshold established by Kullervo Hynynen.
In 2007, based on the Umemura publication, Jean-Francois Aubry hypothesized that, as the cavitation threshold in standing waves was less than that seen in propagating waves, it could explain the dramatic effects that occurred in the TRUMBI study at low frequency (300 kHz). He proposed that the cavitation threshold in standing waves is lower by a factor of 10x. This is a key question that requires further analysis and confirmation in experimental work.
In standing waves, the pressure can be doubled, in theory. Larry Crum showed that cavitation is increased with long bursts. Iron deposition in vessel walls can alter the cavitation threshold. Knowing the cavitation threshold elucidates the safety margin.
If identified as a potential risk, standing waves can be minimized by adjusting the frequency. This leaves the question of whether there are areas in the brain where ~5% of the pressure change encountered in the focus leads to significant risk, such as tissue interfaces or regions of calcification. This still needs evaluation and further research.
The most important point is to know the cavitation threshold for monochromatic sonifications in the case of waves traveling in one direction, waves traveling in counter directions and finally standing waves. The case of waves traveling in opposite and parallel directions is as important as the case of standing waves.
Dealing with phenomena involving less than 1% of the energy is insignificant from a thermal standpoint, but not in terms of potential bioeffects of the ultrasound energy (such as cortical spreading depression). Animal models are still important, although skull shape and thickness differences limit applicability of the results to humans. The overall safety margin is still poorly defined.
The in vivo model is far from perfect, and interpretation of results in cadavers is hampered by the lack of blood flow and post mortem bubble formation. Study in the closed skull phantom will likely yield useful results. This should then be followed by appropriate in vivo animal studies for verification of the cavitation phenomenon, then raise the power by a factor of 3 to perform the requisite safety studies. Even then, one might expect additional empirical data from experience in diseased patients.
A collaborative work group was assembled to further investigate standing waves and hot spots using 3-D whole brain acoustic simulation via a common database. This work will be supported financially by the Foundation and is expected to take 6 months to complete. The work will be led by Kullervo Hynynen of the University of Toronto, and will involve Greg Clement in Boston, Mickael Tanter in Paris and Shuki Vitek in Israel.
MRI volume rendering for treatment monitoring
Work is proceeding on 3-D volumetric thermal mapping, which generates a slab of adjacent MR slices around a region of interest. Current models enable construction of 20 slices each 10 mm thick. One needs to select the sensitive regions for analysis. The technique requires imaging as quickly as possible, which is limited by STN. One generally requires a single shot image, and EPI bandwidth is critical. This might necessitate thinner slice thickness. Planar thermometry is inferior, often resulting in disorientation.
The potential of volumetric imaging is a key safety element in this technology, and efforts should be invested in developing imaging tools.
Microcalcifications not appreciated on CT
Microcalcifications may cause local heating, but the overall effect depends on size and location. The physics is similar to that in bone, but the density is much less. Calcium close to the thermal focus can undergo significant heating. Blocking phased array transducers that aim through regions of calcium can reduce the heating. Within a tumor, this excessive heating might even enhance therapy. However, it can cause complications near critical structures. Excessive calcification near sensitive neural structures might be an absolute contraindication to treatment. Ultrashort TE imaging (UTE) with MR (~ 200 usec) can visualize calcium, and might replace CT for detecting calcifications. Besides, it might also replace CT for skull modeling.
Further work and analysis needs to compare, in human brain imaging, that MR techniques can be just as good (or better) than CT in identifying local calcifications.
MRI Determination of Bone Density - Potential Obviation of CT Scan
Ultrashort TE Sequences
Bone contains much less free water than soft tissue, and the resultant T2 in bone ranges from 10s to 100s of usecs. Ultrashort TE imaging (UTE) may be useful for defining bone and calcium, and detecting bound water (protons). GE scanners can measure 8 usec T2 yielding high resolution bone images. It requires the readout sequence in addition to the short echo time, which will add to overall scanning time.
This issue is of practical importance in the management of stroke, where time to treatment is of the essence. If one is able to save time by bypassing the CT scan (used for detecting hemorrhage and performing skull modeling for phased array corrections), then clinical results might be improved.
Acoustic force radiation imaging
Acoustic force radiation imaging is another technique offering significant benefit. It may be used to change the phasing of the transducer elements to optimize the sharpness of the acoustic focus. The principle is similar to auto-focusing in a camera. Displacement varies with beam intensity. The algorithm is based on the energy at the focus to recover the phases for the array. At low frequency the skull base can be transparent, and radiation force imaging may be useful. Acoustic radiation force imaging works even better at high frequency as the force is proportional to the brain absorption coefficient. The system ed in Paris uses 1000 shots over a few minutes to correct the beam focusing. It has been patented and ed in vitro within a 1.5T MRI system and will be incorporated in the Brain System being developed there by the end of the year.