Interview
MRI-Guided Focused Ultrasound: Neurosurgery Without
Scalpels – An Interview with Dr. Todd Mainprize
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thalamus in patients with tremor. Using lower energy,
we can transiently disrupt the blood-brain barrier,
which is a significant impediment to different types
of therapeutics for nervous disorders. My interest in
neuro-oncology means that there are a lot of drugs
that we’d like to deliver to patients with brain tumours
that simply don’t get to the tumour because of the
blood-brain barrier. By injecting micro-bubbles into
the circulation – usually 3-5 µm in diameter – they
circulate through the brain vasculature, and we hit a
focused area of the brain with an ultrasound pulsation
that causes the micro-bubbles to expand and contract.
They don’t have to expand much to break through
the tight junctions in the endothelium of the brain
-- that opens the blood-brain barrier. The barrier repairs itself in around 6-8 hours, so it’s the perfect way
to do blood-brain barrier disruption – it’s not permanent, it doesn’t seem to cause any haemorrhages or
focal damage and it’s reversible. It’s also highly regionalized; we can essentially open up any area from
as small as 1x1 mm to the whole brain.
Introduction
D
r. Todd Mainprize is a neurosurgeon at Sunnybrook
Hospital, Toronto and is a Surgeon Scientist affiliated with The Arthur and Sonia Labatt Brain Tumour
Research Centre. Dr. Mainprize’s research involves the use of
MRI-guided, focused ultrasound in the destruction and treatment of brain tumors. This interview examines the exciting
new frontier of MRI-guided focused ultrasound, which allows
neurosurgeons like Dr. Mainprize to perform brain surgery
without cutting through the skull.
UTMJ: I’m here with Dr. Todd Mainprize, and we’re going
to be discussing his research into MRI-focused ultrasound.
Can you describe for our readers, what exactly is
MRI-focused ultrasound?
TM:
Focused ultrasound of the brain is a technique that
was pioneered by Dr. Hynynen here at Sunnybrook.
We use over a thousand different transducers to focus
waves in the skull. The main problem with focused ultrasound in the brain is that the skull stops them from
going through. But Dr. Hynynen had the brilliant idea
of using the curvature of the skull as a lens itself to
help focus it - and through a massive amount of very
difficult calculation he is able to do that. So, using the
skulls, these transducers and the MRI to guide it, we
can put focused ultrasound essentially anywhere in
the brain. Depending on how much energy we want
to use, the skull can be a detriment because it heats
up. To make a thermal lesion, we heat up a part of the
brain to 55°C and cause the proteins in that area to
coagulate. In a human that area has to be 2.5 cm away
from the skull otherwise the skull heats up too much
and causes third degree burns of the scalp. There’s a
special helmet the patient has to go into, putting the
brain and the skull into essentially a water bath to cool
the skull as we do the ultrasound.
We do two types of ultrasound with these machines
- one is the thermal ablation. We give a high dose
of ultrasound energy and heat up the brain to 55°C
and thermal ablate it. This can target things like tumours, or we can target parts of the brain that aren’t
functioning normally. For example, we can ablate the
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UTMJ: Fascinating. You mentioned how it is capable of coagulating any part of the brain. In your opinion is this
technology a magic bullet? Is it essentially making the
term ‘inoperable tumour’ a relic of the past?
TM:
That depends. We still are at the phase 1 trial. We have
a trial that has been open for a year and are trying to
recruit patients who have no more options, such as
those who cannot have any more radiation. We would
like to get somebody with a small tumour that is growing, and we would ablate that tumour thermally. Currently, the problem with thermal ablation is that we
are restricted to a small area of the brain -- it has to
be 2.5 cm from any part of the skull in all directions,
which essentially gives you only the central core of
the brain. We’re limited in the treatment envelope
we can present to patients. That has been the biggest
limitation. Will it be a magic bullet? I don’t think so,
but it will give us another tool. The way I look at the
thermal ablation aspect in treating tumours is that it’s
like surgery. What do we do in surgery? We cut out
a lesion. What can we do with [MRI-guided focused
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Interview
MRI-Guided Focused Ultrasound: Neurosurgery Without Scalpels – An Interview with Dr. Todd Mainprize
This will open up a huge opportunity to treat diseases
you can’t normally treat. Alzheimer’s drugs will become more effective as you can open the blood-brain
barrier and have it delivered to the neuron. Parkinson’s disease -- the same kind of thing. There’s a whole
therapeutic spectrum that we couldn’t look at before.
Many of the novel treatments being discovered due to
advances in molecular biology do not cross the bloodbrain barrier. All the drugs being made to combat
Parkinson’s, Alzheimer’s currently are not useful in a
clinical setting and this will help that.
ultrasound]? We can burn the lesion. Same way we kill
those cells immediately -- we either cut them out or
burn them. Theoretically it will give the same benefit
as an operation, but in areas where you cannot do an
operation, such as the central core of the brain.
UTMJ: Could it make traditional surgery obsolete, such as
with scalpels and saws?
TM:
It currently cannot. We can only use it on those
deep lesions that we wouldn’t operate on anyways.
So, they’re complementary at the moment if we can
prove [MRI-guided focused ultrasound] useful. It’s
still experimental at this stage. But with all the work
Dr. Hynynen has done, it looks like a very exciting
field.
UTMJ: Is MRI focused ultrasound actually used in clinic today or is it still very much experimental?
TM:
UTMJ: In your opinion, do you think by the time my colleagues and I are practicing - say five or ten years from
now - will this be common place?
TM:
Already it’s becoming commonplace, and not just in
the brain, but focused ultrasound ablation of liver
tumours. It’s already used for the treatment of uterine fibroids and had very good results, reduced pain
scores and the fibroids will shrink. It is being used
now in a phase two trial to look at bone metastases.
One of the problems with focused ultrasound is that it
heats up bone. However, in patients with a metastasis
to a boney rib cage or to the arm, we exploit the fact
that bone heats up. Heating of the bone itself actually aids in the coagulation of the tumour and kills it.
Patients have had significant reductions in the pain
of their boney metastasis. Many of these will become
commonplace practices very soon. The brain is still
difficult and thermal ablation is a little bit trickier
than the other ones because it’s encased in the skull.
UTMJ: How did you become involved in this research?
TM:
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I’m a neurosurgeon who is very interested in neurooncology. When I started working in Sunnybrook, I
was approached by Dr. Hynynen, who has done a phenomenal amount of work and is essentially the grandfather of MRI focused ultrasound of the brain. He was
telling me all the different things they could do, and
I thought this was an excellent opportunity to bring
it to clinical research trials. We have one trial going
right now with the thermal ablation, and we’re going
to open up another trial in the near future to open up
the blood-brain barrier and see if we can increase delivery of a different type of chemotherapy that would
not normally cross the blood-brain barrier very well.
Worldwide, there are only a few centers that have the
technology to deliver focused ultrasound to the brain.
We have two trials at Sunnybrook - one regarding
thermal ablation of brain tumours and one looking at
patients with a central tremor and causing a thermal
ablation lesion in the thalamus trying to control tremor. There is another place in Virginia that has done 13
patients to date with focused ultrasound with central
tremor and with good result. Switzerland has done
thermal ablation of the thalamus in trying to control
neuropathic pain with good results, and they’re up to
18 or so patients. That’s what’s being done inside the
skull. In terms of focused ultrasound outside of the
brain, removal of uterine fibroids is becoming very
commonplace and in other places in the world, liver
ablations are becoming more and more commonplace.
UTMJ: I was investigating a company known as InsightTec, an
Israeli company, and GE recently invested 14 million
dollars into the company. There is talk that they’re
stagnant and their stock price has levelled. My concern is that this focused ultrasound technology isn’t
economical. Can it be expanded to the point that everyone who needs it can get it?
TM:
The machine itself is still a prototype. Where do I
think the best bang for the buck would be? In opening the blood-brain barrier for chemotherapies that
have shown to be very effective against various types
of tumours have shown to be ineffective in clinical
trial essentially because it doesn’t get to the tumour.
Opening that up will likely affect the longevity of the
patient. If that’s true, every center that treats brain tumours will get one of these machines. This will drive
the price down. InsightTech is actually the company
that made the two machines in this hospital.
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Interview
MRI-Guided Focused Ultrasound: Neurosurgery Without Scalpels – An Interview with Dr. Todd Mainprize
UTMJ: In terms of regulation, do you think this will be a discipline that is widely spread? Or rather, do you think
this will be the domain of strictly neurosurgeons or
will it be expandable to other fields? Does it require
extensive training and expertise - or is it more of an
automated process?
UTMJ: That’s very exciting!
TM:
UTMJ: You mentioned it was pioneered at Sunnybrook?
TM:
TM:
I look at it akin to the way certain types of radiation
are delivered. You’ve all heard of gamma knife. Generally there are four people involved in gamma knife:
a neurosurgeon, a radiation therapist, a radiation oncologist, and a radiation physicist. I think for focused
ultrasound it will be the same - you will need a treating
neurosurgeon, and you will need somebody who understands the physics of it better than the neurosurgeon. It will be a team approach.
It’s very good.
Dr Kullervo Hynynen, the physicist who pioneered
high frequency ultrasound into the brain is now
at Sunnybrook. He did much of his work in Boston
and came to Sunnybrook a number of years ago. Dr.
Hynynen has done phenomenal work.
UTMJ: Would you say that Canada has taken the lead in the
research?
TM:
UTMJ: Do you feel confident that it will go forward and complete the trials along the way? Or, do you have reservations?
There are four centers world-wide that are leading:
Sunnybrook, Boston, University of Virginia, and Switzerland. They are leaders in focused ultrasound, especially when it comes to patient translation.
UTMJ: What are the main limitations of this technology?
TM:
I think its well on its way along the trials and hopefully we’ll see it help. Right now, the two main fields I
see this being significant in advancing is what we call
‘functional neurosurgery’ where we currently make
lesions in peoples’ thalamus, globus pallidus, and
other areas like that to treat Parkinson’s, tremors,
pain, dystonia and others where we commonly make
lesions. Currently what we do is we drill a hole in the
skull and pass an electrode down under guidance to
the area of the brain and coagulate it from the tip of
the wire. We can do the same thing with the focused
ultrasound without making the hole and have real
time MRI visualization. One of the great things about
the MRI guided focused ultrasound is that we have
live pictures that is real-time data. The MRI scan can
detect changes in temperature: we can use the MRI
as a thermometer so we can see the part of the brain
we’re aiming at and watch it heat up and know we’re
making the lesion in the correct place. The way we do
it currently, surgically, is we cut that hole in the skull
and look at a CT scan and plan it. But, do we know
for sure that the tip of the needle is in the correct
place? No - we assume it is based on the pre-operative
measurements we make, but it’s not guaranteed. Using the MRI scan, we can see it in real time affecting
the parts of the brain.
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TM:
The main limitations are we do not know how well
it works in humans. The human trials have not been
done yet, and so that’s what we’re doing. We’re starting off with the phase 1 trials - is it safe? Then we’re
moving on to phase 2 trials - does it help? And then
on to phase 3 trials - is it better than what we currently
use? We don’t know yet. The other limitation with the
thermal ablations is that we are stuck with the current
limitation 2.5 cm from the skull. With different changes in the physics of the ultrasound waves, we may be
able to shrink that and get closer and closer to the
skull. Those are the things that we are currently looking at.
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