Non-Invasive Deep Brain Stimulation: The Promise of Transcranial Focused Ultrasound with Dr. Samuel Pichardo

In this episode, Dr. Michael Passmore sits down with Dr. Samuel Pichardo, biomedical engineer and researcher at the University of Calgary and the Hotchkiss Brain Institute, to explore one of the most exciting frontiers in neuromodulation: transcranial focused ultrasound stimulation (TUS/tFUS).

Dr. Pichardo's lab is at the cutting edge of ultrasound neuromodulation — investigating how low-intensity pulsed ultrasound can precisely target deep brain structures non-invasively, with lasting effects on neural activity.

What We Cover:

• What is transcranial focused ultrasound (TUS)? How it differs from TMS and tDCS, and why its ability to penetrate to deep brain structures makes it uniquely powerful
• The physics of neuromodulation: How pulsed ultrasound bursts at low frequencies (e.g., ~250 kHz) can produce neuromodulatory effects lasting 30–60 minutes after a single session — and why the underlying mechanism is still an active area of research
• Pulse repetition frequency (PRF): Key findings from Dr. Pichardo's lab comparing 10 Hz, 100 Hz, and 1000 Hz PRF — and why 100 Hz produced the strongest and most sustained inhibitory effect
• The skull barrier: Why lower ultrasound frequencies are used to overcome skull attenuation, and the challenges this creates for precision targeting
• Pilot clinical study — essential tremor and Parkinson's disease: Targeting the ventral intermediate nucleus (VIM) of the thalamus non-invasively, and what the results showed: significant tremor reduction in essential tremor patients, and a promising but less robust trend in Parkinson's patients
• The multi-focus targeting strategy: How Dr. Pichardo's team addressed the precision-vs.-accuracy tradeoff using phased array transducers to enlarge the treatment envelope
• BabelBrain: The open-source, cross-platform (Mac, Windows, Linux) software tool developed by Dr. Pichardo's lab that integrates MRI/CT imaging data to model acoustic intensity, thermal effects, and safety parameters — a turnkey solution for TUS researchers worldwide
• The future of the field: Which neuropsychiatric conditions are most likely to benefit first — including refractory depression, OCD, PTSD, and addiction — and why Dr. Pichardo believes depression may become the "poster child" indication for TUS in the next few years
• Nomenclature: Why the field still hasn't settled on a consistent acronym (TUS, tFUS, LIFU, FUS) — and why that's okay

Key Takeaways:

• Focused ultrasound can reach deep brain targets non-invasively with millimeter precision — something no other non-invasive technology can currently match
• The neuromodulatory effects are real, reproducible, and growing in clinical promise, but replication studies and sham-controlled trials are still essential
• BabelBrain is freely available as an open-source tool for research labs worldwide
• The field is at an inflection point, with rapid growth in FDA applications and commercial investment

Links & Resources:

• Dr. Pichardo's lab at the University of Calgary / Hotchkiss Brain Institute https://www.neurofus.ca/
• BabelBrain (open-source TUS planning software) https://proteusmrighifu.github.io/BabelBrain/
• Pulse repetition frequency study (PRF paper from the Pichardo lab) https://pubmed.ncbi.nlm.nih.gov/38621645/
• VIM thalamic TUS pilot study (essential tremor & Parkinson's) https://pubmed.ncbi.nlm.nih.gov/8109299/
• Focused Ultrasound Neuromodulation Symposium, Paris (July) https://www.itrusst.com/fun26

The Neurostimulation Podcast is hosted by Dr. Michael Passmore, clinical associate professor in the Department of Psychiatry at the University of British Columbia. The content shared is for educational purposes only and is not intended as medical advice. Always consult your healthcare provider regarding your specific health needs.

If you enjoyed this episode, please like, subscribe, and share with anyone who might find it valuable. Drop your questions and comments below — and tune in next time for another journey into the cutting edge of neuroscience and clinical neurostimulation.

Welcome to the Neurostimulation podcast.

2

I'm Dr.

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Michael Passmore, clinical associate

professor in the Department of

4

Psychiatry at the University of British

Columbia in beautiful Vancouver Canada.

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The Neurostimulation Podcast is all

about exploring the fascinating world

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of neuroscience in general and clinical

neurostimulation in particular,

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how it works, the latest research

breakthroughs, and most importantly,

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how that research is being translated

into real world treatments that

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can improve health and wellbeing.

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So whether you're a healthcare

professional, a student, a researcher,

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or someone who's curious about how our

brains work and what we can do to help

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them work better, this podcast is for you.

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My mission is to make the

science accessible, inspiring,

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and relevant to your life.

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This podcast is separate from my clinical

and academic roles and is part of my

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personal effort to bring neuroscience

education to the general public.

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And so I would like to emphasize that

the information shared here is for

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educational purposes only and is not

intended as medical advice or a substitute

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for professional medical guidance.

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I would encourage you to always

consult with your own healthcare

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provider to discuss your specific

health needs and treatment options.

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Today's guest is Dr.

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Samuel Pichardo, a biomedical engineer

and researcher at the University of

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Calgary and the Hotchkiss Brain Institute.

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Dr.

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Pichardo's team is helping to

define the frontier of transcranial

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ultrasound stimulation or TUS.

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His lab focuses on the physics modeling

and clinical translation of a really

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exciting technology: Ultrasound

neuromodulation, which involves

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work on how ultrasound can precisely

target deep brain structures and how

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the stimulation parameters influence

neural inhibition and plasticity.

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And so today we're hoping to

discuss aspects of that particular

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technology and perhaps look at two

particular papers that his lab has

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generated over the past recent while.

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And those papers are really exciting

to me because they're exploring a

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really key question in the field,

which is: Can focused ultrasound

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become a precise, non-invasive way

to modulate deep brain circuits?

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So Sam, thanks so much for joining me.

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Welcome to the podcast.

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Samuel: Michael, it is me who thanks you

for the opportunity to join the podcast.

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I really appreciate

it, so I appreciate it.

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Uh, yeah, so, a little

bit of my background.

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So, I did my undergrad in electrical

engineering back in Mexico and

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with specialization in electronics.

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In '95, I moved to France.

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In '99 I started on my master's and

PhD, and in, in a specialization called

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imaging and systems was pretty much a

lot of physics and image processing.

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And then moved to Sunnybrook in 2006

summer to do a fellowship under the

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supervision of Kullervo Hynynen so people

who are very familiar in the ultrasound

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community in therapy, he's a big name.

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He's the person who invented, among

other things, MRI-focused ultrasound.

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Some approach which now is being used by

example to treat, moving disorders like

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a essential tremor and Parkinson disease.

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Just something, using something

differently than I normally do.

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Something, we can go a

little more detailed later.

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And then I spent a few

years in an institute in

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Northwestern Ontario until 2017,

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and then moved to Calgary.

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Calgary was opening a new program on

focused ultrasound for brain indications.

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And they needed someone with

my background, someone with

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physics and engineering.

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So I joined a very excellent team, imaging

scientists, some functional neurosurgeons

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and movement disorder neurologists.

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And with the mission to

create auto scanner, auto

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stimulation program in Calgary.

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That was my, my mission, which

has been working over the years.

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Different aspects.

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We need to put pieces together

and we need to make it happen.

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Mike: Happy.

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Mm-hmm.

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Yeah.

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Fantastic.

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Well, that's what a, a fascinating

journey and it's, uh mm-hmm.

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It's great to talk to, someone who's

also based in Canada and just highlight

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the Canadian programs that are really

pioneering the investigation of

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this exciting kind of technology.

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Samuel: Actually, Canada is a

strong leader in this field.

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Our close collaborator and friend

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Dr.

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Robert Chen from Toronto West, he has

been one of the leaders in the field

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for several years with many studies

as I also some looking forward to

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applications, some, movement disorder.

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So I think Canada's well represented,

but obviously we can do better.

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Mike: Yeah.

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That's great.

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And it's fascinating because one of the

most interesting things I found about

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ultrasound neuromodulation is that

it's coming from a completely different

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technological lineage than TMS or tDCS.

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So, maybe if you could just kindly

explain for viewers and listeners,

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what is transcranial ultrasound

stimulation and what sort of

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differentiates it from these other

kinds of neurostimulation technologies.

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Samuel: Yeah, of course.

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With pleasure.

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Every single modality is application

of some physical type of energy,

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electrical, magnetic, the way you

apply it will produce certain different

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types of bio-effects in the brain.

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The

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difference in ultrasound is we have the

capability to concentrate mechanical

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energy far away from the source, and

that coming from far away, that's the

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critical aspect of everything here.

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By choosing the right frequencies

in this case, like lower than one

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megahertz, typically 500 kilohertz, we

can use devices that converge in some

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ways, focus, and we can place that

focus either in the cortical regions

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or subcortical regions, which opens

the door to a non-invasive approach.

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And this has been actually explored in

other indications, but in the brain,

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actually, we have a Health Canada and

an FDA approved therapeutic approach.

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They use the high intensity modality,

but the physical principles are the same.

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We send energy and concentrate for

example in the thalamic regions.

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And you can perform non invasive surgery.

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So, by sending high levels of

energy and they can destroy the

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tissue in a very confined way.

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What we do now in the

ultrasound stimulation.

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What the biggest difference

is the level of energy we use.

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We have most tiny little fraction

or energy, much more actually quite

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compatible for the energy levels that

are being used in ultrasound imaging.

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But what the key people we have discovered

in the last 15, maybe 20 years now, is

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by pulsing the ultrasound way in certain

particular things, and then that's the

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key word, the pulse burst, there's a

different bio-effects that are associated

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with the mechanical forces that are being

applied at the focus and which we don't

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have yet a complete definitive answer.

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What is truly the mechanism?

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We have certain hypothesis, but

generally speaking, mechano-receptors,

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the membrane, the membranes modulation,

mechanical modulation that changes the

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functionalities of the brain circuits.

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And you need to think about this

in the context of the circuit.

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It's not even the neurons, it's

astrocytes, neurons that when they get

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under the mechanical forces, the way some

of the the interaction gets modified.

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As mentioned, we don't understand

completely, exactly because still it's

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a very important topic for research.

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But that cascades in a neuromodulatory

effects that our group and many others,

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and we were not the first for the record

start to discover that some of those

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effects can last 30 minutes, or even

60 minutes after one single emission.

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So that has really created a lot of

excitement in the brain stimulation

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community because it opens this

opportunity to go from either

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from cortical to subcortical using

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the same technology in a non-invasive way.

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Mike: Yeah.

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Yeah.

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Thanks so much for explaining that.

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It's fantastic because I think

this is one of the main limitations

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with other types of technology.

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I know you know this, but for viewers and

listeners who may be relatively new to

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the area, it's more like with transcranial

magnetic stimulation, there's certainly

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some limit on how deep, well, except

I suppose, for certain coil structures

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that can reach deeper structures.

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But even then, you're kind of limited

to the essential sort of physics

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of how the magnetic field will

generate the perpendicular electrical

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current in the cortical tissue.

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And then similarly, for technologies

like tDCS, then obviously then

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that's just not going to be

penetrating too much into the cortex.

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But this is fascinating because, as you

say, the ultrasound, focused ultrasound

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is able to penetrate and target these

very deep brain structures, which is

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really interesting and as you say,

what's fascinating as well is what

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you found with the low energy pulsed

ultrasound, which can induce that

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transient neuromodulatory response,

which is lasting 30 to 60 minutes.

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It's so interesting.

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Samuel: Yeah, actually, one of the still,

parts the community we need to continue

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is more replication studies, someone

doing exactly what other people did.

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But, sometimes funding is not,

it's not easy to, to do replication

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studies is not very fundable.

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But we are trying to do our best.

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But we recognize as a

community that will be easier.

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For example, what we doing in

our center, that all the group

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were able to monitor, reproduce.

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Sometimes people use the same parameters

and we observe analogous effects.

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For example and I hate the words

using inhibitory excitatory because

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I know that's a misleading for the

ultrasound community, and I'll have

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probably some of my colleagues get angry

with me, but, certain regions, some

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will applies ultrasound with certain

parameters, it translates to what, uh,

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traditionally people will associate with

an inhibitory response as the paper you

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were highlighting for, for the cortical

regions we did a couple years ago.

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And we take that same hypothesis and

say, well, if this particular parameters,

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this particular setup produces an

inhibitory response, can that for example

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suppress hyperactivity in the beam for

patients that have essential tremor.

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So we follow the hypothesis, and

that was a pilot study we used.

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Probably the one you are referring

to that it seems at least on the

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pilot phase, single arm, and we

need to be very careful, this is

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a single arm motion controlled.

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We start to see some drop on

the tremor arm in patients.

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We measure with accelerometers, and

after one single neurostimulation

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exposures, then at the end, half an hour

later, even by the end of intervention

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with we can see a very, some visible

to the naked eye drops in the tremor.

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Already with the tremor in

Parkinsons, we need to be very,

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very sensitive to sham effects.

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Some of the placebo effects

is well reported, in movement

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disorders is a real thing.

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But despite the potential placebo

effects, that was the first step.

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And now in our centers we're conducting

two separate studies, one for Parkinsons,

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one for essential tremor that were

doing double blind sham controlled.

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And we hope, by the end of this year,

we will have complete data collection

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and we wish that the same effect

we observed in the pilot study are

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going to be produced as observable

in sham-controlled conditions.

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Because that's where you

truly have the real evidence

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is this is real or something.

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When you start to put together

all the different results from so

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many centers, it's very unlikely

that this is purely placebo.

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There has to be a component, but

we still need to do better to

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characterize and to differentiate

from placebo, from placebo effects.

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Mike: Mm-hmm.

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Yeah.

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Yeah.

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So it's so exciting because as you say,

these conditions such as Parkinson's

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disease, essential tremor, so these

are very debilitating neuropsychiatric

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conditions and there's always the

need for new frontier technologies

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to try and help patients who are

struggling with these disorders.

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And yeah, as you're describing, so

the, it's fascinating to me because,

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your lab is really investigating, with

this pulse repetition frequency study.

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And for viewers and listeners, we'll

put links to the papers and to Dr.

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Pichardo's lab, in the show notes, I would

encourage everyone to check that out.

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And, I'll put a visual of the paper up

here for viewers, but listeners, yeah,

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this was a, as you're saying, Sam, a

double blind sham controlled study,

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looking at how differences in the pulse

repetition frequency, as I understand,

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whether these parameters produce the

excitation or the inhibition, which is

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so exciting because depending on how the

parameters can be adjusted, it gives the

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potential for there to be this kind of

fine tuning of that modulation as you say.

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Samuel: Yeah, exactly.

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And, the conundrum, the problem in

the community is we don't have a

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complete parameter space understanding.

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When we start to learn some, especially

from some work in the clinical

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models, we start to get that sense

that actually the response, the same

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parameters might have a different

response in different brain regions.

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Because it is in compositions, the

ratio of astrocytes and neurons.

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We start to have a little bit of

a sense that the composition of

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cell distribution in a particular

region will also play a role.

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We were looking in the case of the

essential tremor study that the

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case move in the right direction.

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So that we wanted to see an

inhibitory response and we

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obtained a inhibitory response.

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But I think we need to be careful

somebody that some people might find the

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pulse if they go, for example,

to, a different target.

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So that's something I would like

to caution listeners, the parameter

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space and the particular effects

may be brain region dependent.

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So that, and that's something we still

little by little have a grasp on that.

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I get it by saying this actually,

while we work mostly in movement

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disorders, psychiatric disorders,

probably one of the most exciting

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areas transcranial ultrasound

stimulation has been exploring right now.

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There are multiple centers, some around

the world trying to explore the different

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targets can be a good candidates to

produce an effect they can translate

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into symptom relief for patients.

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Mike: Hmm.

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Yeah.

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Yeah, it's really interesting.

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I know before we started, we were

chatting a little bit about, how you're

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commenting that there's just an explosion

in interest in recent conferences.

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And just about over a year ago, I was

at the Brain Stimulation conference in

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Japan and there's so many papers and,

presentations on this, and then the Storz

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medical, in Switzerland is looking at

tFUS for treatment of depression, even

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Alzheimer's disease, that kind of thing.

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It's really exciting.

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Samuel: Yeah, exactly.

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And also for the audience,

really the nomenclature is

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still not yet set into stone.

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There's some people you will hear

will call it some low intensity

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focused ultrasound in order to

differentiate with the other one, the

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high intensity focused ultrasound.

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And here will like to use LIFU (Low

Intensity Focused Ultrasound) in order

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to highlight the safety of the aspect.

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In our lab, we have more tendency

to call it transcranial ultrasound

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stimulation to put it on the same

level as the other modalities, like

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rTMS, tDCS which we think now the

evidence is moving in that direction.

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Probably we can start to call, let's call

it less physics based, like maybe it was

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in the early days, but you might find,

yeah, transcranial focused ultrasound

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tFUS or simply focused ultrasound FUS So

for people in the audience, you might,

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you start to look keyword in Google

you might find some other acronyms.

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Right now there is not a

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consistent nomenclature and maybe it

will still take some time probably in

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a few years we hope we start to make

more solid phase two, phase three

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studies, and we start for this to

become potentially, a new tool in the

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arsenal of, for example, psychiatrists.

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And I'm pretty sure that's going to be

the moment we're going to see what's the

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nomenclature people would end up adopting.

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But right now it's still a

little bit diffuse in terms

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how people like to call it.

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And for all the record, all of them

has really some validity why to

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call it one way or the other one.

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Mike: Yeah.

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Yeah.

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So I was just thinking, so just

again, I'm assuming most viewers

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and listeners might not be entirely

familiar with this particular

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study that we were talking about.

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So I thought maybe, if it's okay with

you, if I just kind of summarize my

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understanding and then you can kind of

correct me if I've got anything wrong.

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So it sounds like your lab tested,

the, so this is going back to

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the pulse repetition frequency.

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Mm-hmm.

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So it sounds like there were sort of

three, so the 10 hertz, 100 hertz and

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1000 hertz were compared with sham.

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And that it was interesting as I

understand the findings were that

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the lower frequencies produced

the sustained inhibitory effect.

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So the 10 hertz resulted in inhibition,

lasting about 30 minutes, and then

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the 100 hertz resulted in inhibition

lasting up to, or more than 60 minutes.

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But that a 1000 hertz, there

was no significant effect.

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Samuel: Exactly.

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That's right.

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Yeah.

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So yeah.

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So that was a very first study in Calgary.

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So when we put together the platform

that's describing in that paper, and that

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moment maybe took three, four years ago,

there was even less clarity than today.

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There were very few studies.

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We decided not to try to fully reproduce.

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So let's go more parametric space.

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The pulse repetition frequency

is, for the people in the audience

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is we send ultrasound in little

bursts like we send ultrasound and

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this kind like a narrow frequency.

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What this means they oscillate at

the three fundamental frequencies,

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in this case, 250 kilohertz.

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So this is relatively like a low

ultrasound frequency compared to imaging.

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Imaging between 3, 5, 8, 12 megahertz.

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So this is relatively low frequency.

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One of the reasons we use low frequency

for as a carrier is the skull barrier.

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The skull because it has high attenuation,

high density that can cause the ultrasound

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waves to refract, get attenuated, so makes

ultrasound passage much more difficult.

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So one way to overcome that

is to use lower frequency.

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And that helps to achieve

certain penetration in the brain.

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What

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people have studied over the years

is we send a burst of ultrasound

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waves and then we wait a little and

we turn on the ultrasound again.

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So the rate we turn on that

ultrasound, we have multiple studies

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that we obtain different effects.

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And so that's the reason we want is,

okay, let's see where our equipment,

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what can obtain better engineering

and we discover the 100 Hz seems to

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be to, to show the strongest effect.

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That became the parameters we started

to use in the other new studies.

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Some people might argue how do you know

that this is optimal for essential tremor?

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Yeah, it's a very good question

and definitely we, no, we

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aren't, so we aren't 100% sure.

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They may be, maybe could be 60

Hz, maybe 50 or maybe maybe 120.

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So maybe more optimal to

produce a stronger effect

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in a different brain region.

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But hopefully people in the

audience may be sensitive.

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Sometimes running all parameter space

in the patient population is sometimes

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not technically feasible because

very difficult to do recruitments

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and so sometimes people with doing

this kind of research, we are

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confronted with some decision process.

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Well.

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They stick to this one and we, if

we don't obtain nothing, we maybe

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we decide to change parameters.

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Whereas as people continue to

carry over and see some effects.

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So there is a certain bias unfortunately

in this sense where this, we know this

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is what works and we just keep using it.

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And this is very good conversations, why

certain parameters remain as they are.

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It's just because a couple of stories show

it works and then no one wants to move it.

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So that's something that's not uncommon.

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Mike: Yeah.

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That's really interesting.

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So it sounds to me like some key kind of

takeaway points really on that is that

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with relatively low frequency pulsed

ultrasound waves, right, and that also,

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it seems to be brain regent dependent.

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So where exactly is being targeted

that it sounds like the field is

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looking at investigating specific

parameters for those specific brain

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regions that are being targeted.

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Samuel: Yeah, exactly.

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So I think the field is moving so fast.

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A few years ago people believed, oh, I

can use this parameter for this group

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and it's good to work in my condition.

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Surprised not anything

worse that as expected.

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So then we have forced people to

re-evaluate and go a little more careful

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and avoiding transposing directly by

observing one particular study, it's

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going to have this same analogy in a

different target, a different indication.

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So I think we started to

learn that lesson a little.

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Sure a few years ago, why not?

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So it was probably a good approach

from say some hypothesis, going to

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observe something analogous and that's

how the story then surprised and then

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we, people have to reevaluate a little

again, not as exactly you describe.

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Maybe we need to always look

very brain region specific.

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But

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it is tricky you know because you have to

have a lot of money for agencies to fund

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this so it poses certain challenges in

terms of how you are able to execute this.

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As most people will love to test

which parameters they, sometimes

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even recruitment, you're able

to recruit an, uh, infinite

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number of subjects out the blue.

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So people needs to be sensitive, that

sometimes you have certain barriers from

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funding as to service that sometimes

precludes us from maybe finding the

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ultimate parameters that really work

the best and probably it's going to

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keep us busy for still for many years.

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Mike: Mm-hmm.

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Yeah.

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Yeah.

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I'm sure.

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Yeah.

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And I, we've mentioned this a

couple of times, but I think really

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it's important to focus on focus.

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Yeah.

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No pun intended, but one of the really

exciting aspects of the technology

386

is the ability to reach these deep

brain structures non-invasively,

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because, you know, typically the only

way to kind of modulate very deep

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brain structures has been through

surgical invasive kinds of techniques.

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Right.

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So

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Samuel: That's right.

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Mike: And what I'm also

understanding is that your lab

393

has developed the Babel Brain.

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Maybe you can help us understand more

about that specific program, Babel Brain,

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as I understand, B-A-B-E-L-B-R-A-I-N,

putting together a program that has

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some, ability to simulate how, for

example, ultrasound propagates through

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the skull like you're describing.

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So help us understand more

about what's that, what that's

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Samuel: all about?

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Yeah.

401

As we mentioned a little before,

one barrier for ultrasound

402

in the brain is the skull.

403

Mike: Mm-hmm.

404

Samuel: And the skull composition can

affect, dramatically the passage of

405

ultrasound, especially in attenuation.

406

And then for people who want to do this

type of research there are two aspects

407

they need to be incredibly careful.

408

One is the safety and one is the

efficacy, you need to try to play with

409

those parameters at the same time,

those two aspects at the same time.

410

And the safety is very important because

you don't have the freedom to increase

411

the energy of whatever as you want.

412

No, ultrasound, sent into any tissue

in the body, especially soft tissue

413

and especially the brain and there's

different things that can happen.

414

One is absorption that transforms

the mechanical energy into heat.

415

And, that can increase the temperature.

416

And it can increase so much and so fast,

if the energy is so high, that's what we

417

do in high intensity focused ultrasound,

it can be so high, that it can destroy

418

tissues in the matter of seconds.

419

You really, really just

use too much energy.

420

So, the other effect is the

phenomenon of cavitation.

421

People who are familiar with ultrasound

imaging, they know something we

422

call the "MI" mechanical index that

is a parameter, that recommends

423

the maximum negative peak pressure

that you can see in the ultrasound.

424

Some of that will be some tests,

425

evidence that the chances you can put

something called bubbles also by the

426

negative pressure, will be very low.

427

Because if bubbles manage to form

under the effects of ultrasound,

428

they can be highly destructive.

429

They can really cause a lot of damage.

430

So you have thermal effects and

you have mechanical effects.

431

Then for someone who wants to do this kind

of research, they need to keep in check

432

this thermal risk and this, well, bubble.

433

I have been working on just

kind of ultrasound modeling and

434

characterization for many years from

435

So it has been almost 20

years working on this.

436

And we have developed models that help

to predict what will be the intensities

437

pressures that you obtain by a particular

device with certain parameters.

438

And we put those tools into in a

turnkey solution for experimenters

439

who might not necessarily have

the expertise in acoustics.

440

And we developed these tools

in such a way to be as close as

441

possible to the workflow people do.

442

Very common people during TMS, people

use some kind of neuro-navigation system

443

in order to perform the intervention.

444

Neuro-navigation we do some

co-registration landmarks.

445

We have some trackers on this subject,

and we have some trackers on the device.

446

And we can see how the device

is oriented in the space.

447

And sometimes we have an a screen saying,

well, you know your foci, for example

448

even in TMS is going to be located here.

449

So we use this exactly the

same approach for ultrasound.

450

And then we use that as an

input information in the tool.

451

So this is how you want to introduce

the transducers, here's where it's

452

pointing, this is where you want to go.

453

So we take all the medical imaging

data, MRIs, CTs available, we pass

454

through the complex, but a one push

button solution for experimentors.

455

Behind the scenes is a lot of processing,

but at the end what you obtain is the

456

prediction of the acoustic intensity.

457

So, later, you can run a second simulation

tool we call the thermal simulator.

458

We solve a bio-heat thermal equation

that help us to predict what will be the

459

thermal effects to some usage parameters.

460

And putting all this together.

461

Some experimenters may say,

okay, I want to program my

462

machine with this parameters.

463

What will be some of the potential

safety and the attainable intensity,

464

in intended regions, which ultimately

should have respect to a correlation

465

with the effects we observe.

466

Are we producing an inhibitory

effect when we apply this intensity?

467

So that we have to connect some of those.

468

You have those two things by saying

this Babel Brain is a research

469

tool that we keep improving, and

by saying this, we are discovering

470

limitations almost every month.

471

So we always keep improving.

472

But despite these limitations,

I cannot claim yet

473

oh yeah, it is 100% accurate.

474

No, I will not be that arrogant.

475

My friends will say Sam,

what you talking about?

476

So there's definitely in all these tools,

software will, certain levels inserted

477

into the whole chain, what is the value

of the issue we need to put in scope.

478

So you have certain levels inserted that

accumulates during the process, but at the

479

end of the day, you have something that

can produce, this is the expected thermal

480

effects, this is the expected intensity.

481

And when we connect that with

measurements, where we do for example

482

risk goals and with the hydrophones

and we, what the people are really

483

observing some of them in humans.

484

And since that we are not

completely that far off.

485

Probably not 100%

precise, but not 100% off.

486

For example, I'm glad that the

tool has been used in multiple

487

studies in the group of other ones.

488

At least no one has come to tell me,

Hey, Sam, I used these parameters,

489

and the participant experienced

that he was burning in his skull.

490

It seems to be at least on that

front, I think we have been okay.

491

But this is still, as I mentioned,

I will not fully claim where

492

we have fully narrowed it down.

493

We still have work to do.

494

But what we started for

experimenters, is a turnkey solution.

495

Take the image and input

and do the processing.

496

And they get some assessment,

maintain potential safety, some

497

indications of safety and efficacy.

498

And they use that one to

carry over the experience.

499

Sometimes you do prospectively and

sometimes they do retrospectively,

500

sometimes I apply this, I put my

machine, I put these values, and I

501

want to check retrospectively what

will be the potential, which I, I

502

tend to, people try to think that they

were wrong, but I understand sometimes

503

the way the studies were designed.

504

By saying this, there's

other ways to play safe.

505

Like I use.

506

But it's simple.

507

The rating factors, which

probably plays the safe as well.

508

Assume the, like high transmission.

509

There's other ways you can do this.

510

Other tools that the similar tools.

511

Some people, they in-house their

own tools, their own models,

512

and it's complicated as much

set from their own validation.

513

OK, so those, there's no really the

unique solution, other things can,

514

some people have been implementing.

515

But anyways, hopefully that gives

a high level presentation what the

516

tools system is supposed to do.

517

Hmm.

518

Mike: Yeah, definitely.

519

Yeah.

520

Thanks for explaining that.

521

I think that's, congratulations, to you

and your team for developing that because

522

I think from the perspective of the

knowledge translation, that it's a very

523

valuable resource that other labs can use

and eventually, hopefully even it can be,

524

I mean this is the sort of thing that's

obviously sets the stage for translation

525

into clinical applications, right?

526

And so, yeah, just to have a turnkey

solution like that, a tool for, uh,

527

how to kind of pull together all of

the knowledge that your lab and other

528

similar labs are gaining year by year

and putting it into something that then

529

can help with replication of studies and

eventually with clinical applications.

530

So it makes perfect sense.

531

Samuel: Yeah, exactly.

532

The other aspect that has been very

valuable for us, is that networking

533

has been a very powerful tool for us

to establish new, make new friends,

534

colleagues in the last three for us

535

and, uh, it's almost three years now.

536

Three actually, yeah, three years.

537

We, we are, the brand

has been three years.

538

And the, the amount of the, the,

our network of collaborations

539

exploded after, after that.

540

And now it's very great to learn

what all the groups are doing.

541

And sometimes the tool has, has grown

a lot in terms of new features, thanks

542

to dozens of other studies and people

always, I want to add this new feature.

543

Even before this talk I was

with another group who wanted to

544

add, came with some suggestions.

545

It was actually, that's very cool.

546

Yeah.

547

That's.

548

I figured that's quite smart.

549

So sometimes when we develop at the

beginning, we would kind of shape

550

it where our current needs level

expertise, but then someone comes,

551

Hey, I would like to do maybe this a

different thing because whatever reason.

552

Yeah.

553

Ah, I think that's quite cool.

554

I say, yeah, exactly.

555

Hey, I think we can do it.

556

Let's, let's do it.

557

And that let's do it has become the

mantra over the last couple years.

558

I will say more than 90% of new features

we have added to the tools has been

559

because other groups have requested

to add something into the tool.

560

And for us, we are more than happy to

add it makes the tool more flexible

561

for researchers and the needs of one

researcher is likely is going to become a

562

need for another researcher in the future.

563

So that's probably the power.

564

And because this is open source,

it's full transparency, anyone can

565

take a look at the code, anyone can

criticize, everyone can, can also make

566

some suggestions or submit changes.

567

So that's the power of open source aspects

which has been critical to my people.

568

And the other aspect as on the tools, very

few people, know that the word Babel is

569

for the multi-platform aspect of the tool.

570

Yeah, it is very engineering minded.

571

But actually it also has

some good implications.

572

It runs in Mac and it runs

in Windows and runs in Linux.

573

It supports Apple processors.

574

It supports Invidia processors.

575

It supports AMD processors.

576

So it makes the access to the

tool much easier for people.

577

They don't need to buy a new hardware.

578

They don't need to buy special.

579

Yeah.

580

We use GPU acceleration in all these.

581

So the term Babel is really

like a speak multiple languages.

582

I think that we're confident to report

that was critical to the success

583

of the deployments of the tool.

584

I can check, for example, I check

the stats, how many downloads

585

the tool has been doing.

586

Half of the people are on Windows and the

other one fourth of people are on Mac and

587

the other and other fraction and some are

on Linux, so it's very interesting to see

588

how have you have some snapshot while the

what people, the platforms of people doing

589

anything and giving that level of access

that people can use the coding hardware

590

has facilitated the people start to use

the tool, instead of maybe investing

591

in a much more expensive platform.

592

So that was very critical and we did it

on purpose so much from the very beginning

593

to see how we can be sure people use the

same computer they already have on hand.

594

Because some people get scared.

595

Yeah.

596

Okay.

597

So for people in the audience, ultrasound

modeling, it's a computational heavy task.

598

There's no sugar coating on this.

599

Even when using very traditional methods,

it's still computationally intense.

600

There's no other way around.

601

It takes some computing power to do it.

602

So we wanted to develop something

that people with the current hardware

603

who have some decent acceleration

and be able to get results in a

604

timely way, not to wait for days,

or hours to get one single result.

605

If we say we can manage to get this in

the five minute mark, like somewhere,

606

I think most people will be okay.

607

In practice, it is much faster than that.

608

You do a simulation in a modern Apple

silicon machine, you get your results in

609

one minute and people say, yeah, for most

typical workflows, that's fast enough.

610

Mm-hmm.

611

That's simply, it can do better.

612

We will always trying to do better,

but that's, I think that's kind of what

613

the mindset when we developed this.

614

Mike: Yeah.

615

Yeah.

616

That's fantastic.

617

I'd be really interested to talk a bit

about your clinical pilot study targeting

618

tremor, because I find it really exciting

because it's moving the technology closer

619

to clinical neurology applications.

620

And so I'm understanding we, we mentioned

before these two specific conditions,

621

essential tremor and Parkinson's disease.

622

And so I'm understanding that that

particular study was targeting

623

the, specific area in the thalamus,

the ventral intermediate nucleus.

624

Samuel: Exactly.

625

Mike: Yeah.

626

Can you just walk us through that?

627

Samuel: Yeah, exactly.

628

Yeah.

629

Mike: Yeah.

630

Samuel: So coming back from that

previous study that you highlighted,

631

the one we do in cortical regions, so

we identified parameters, it seems to be

632

working the best and put between quotes.

633

So we pick those, the same parameters

as it can produce change in tremor

634

response hypothesis, what can

be produced, tremor reduction.

635

That was the hypothesis.

636

Why the ventral intermediate nucleus

is because that's a target we use

637

for surgery either for deep brain

stimulation, DBS with electrodes, or

638

also some for people who are doing now

clinically using the high intensity

639

modality, using a machine made by the

vendor Exablate, sorry the vendor is

640

Insightec, the machine is called Exablate.

641

That people have now been doing this

thermal ablation actually using focused

642

ultrasound, using MRI guidance and going

to make a small lesion in the beam.

643

So we know when this is a region

associated with certain brain

644

activity, with the pathologies

associated with tremor.

645

And as for Parkinson's we know

something much more complicated.

646

More complicated, but both

indications has an association

647

with this particular brain region.

648

So the hypothesis was, can we use

these parameters and can we use what

649

some, with what will be the effects

both in essential tremor patients

650

and Parkinson's.

651

And now with people and this is

part the conundrum with ultrasound.

652

Yeah.

653

It can be much more precise compared

for example to TMS, but then we

654

start to discover all the conundrums.

655

Okay.

656

For example, when we are doing

MRI guidance, I have the MRI to

657

tell me where's my focus point?

658

You can clearly see it looks beautiful.

659

100% accuracy.

660

Really like a voxel level accuracy.

661

There's no argument with that.

662

Now people hopefully are sensitive when

we move to a neuro navigated intervention,

663

we don't have a feedback metric that can

tell you are you or are not at the target.

664

And that's a very interesting

situation and people are trying

665

to address in different ways.

666

In this particular study, we have a

big transducer focused spot is supposed

667

to be here, but what about because

the patient optical tracking uh, has

668

some errors and maybe what we have

three, four millimeters off target.

669

Then we're done.

670

We're going to miss the beam.

671

We're going to miss it completely.

672

So what we added in this study is

we call it a multi focused strategy.

673

Our device is a type of transducer,

it is a phase array transducer.

674

That means the device is breaking in

multiple small elements and by breaking

675

multiple elements for people are

familiar with ultrasound, especially

676

ultrasound imaging, that helps we can

move electronically focused spot around.

677

So we put on this device to

enlarge the treatment envelope.

678

Which at some point can seem a

little counterintuitive, you know

679

focused ultrasound can produce a

much smaller focused regions, which

680

is fantastic in order to be sure you

are more precise with your target.

681

But what about, because you're

so precise, other sources for

682

errors might miss your target.

683

And that's a big problem.

684

So we decide to enlarge the treatment

envelope by applying multiple focus,

685

and then going on and on and that

seems to be helping to potentially,

686

we didn't miss the beam, and then

we observed the expected effects.

687

Well at least from, again, this

is one single arm was at least the

688

tremor reduction was so significant,

that hopefully we want to believe

689

that this is not purely placebo.

690

Again, I want to always be very cautious

to people, not get too excited when, you

691

know, when you have stories, single arm,

always be careful somehow to, to take it

692

to very, some with some grain of salt.

693

That's the right mindset.

694

But at the same time, you

can be cautiously optimistic.

695

So by doing this multifocal

strategy, we noticed we saw

696

a significant drop in tremor.

697

And we measured it with accelerometers,

we put multiple accelerometers

698

in the hands of patients.

699

And so we can measure, so it's

a clear quantitative metrics.

700

So we can measure.

701

By saying this in the sub sample of

patients of Parkinson's, which was

702

seven of the 18 patients, we saw a

trend, but it was not significant as it

703

was as was for essential tremor, which

cannot, again, different indications,

704

different brain activity might react

differently to the same parameters.

705

Because even if it was not significant,

we still saw a trend in reduction.

706

We decided now to run a separate

study for Parkinson's on the

707

execution because what it was not

significant but still, we saw a trend.

708

So we are still working to keep working

with these parameters moving forward

709

and see we can, we can learn now, now

we start to run a sham-controlled study.

710

So that's how this study came to be.

711

Hopefully that covers how was

the mindset for that study.

712

Mike: Yeah, yeah.

713

It's, it's fascinating.

714

It makes me think about, you know,

almost 30 years ago I was a wide eyed

715

medical student and helping in, helping,

wasn't really helping, just observing

716

in a neurosurgical procedure, a invasive

ablative, procedure where the target

717

of the invasive ablation was, the, I

think it was the VIM and the ventral

718

intermediate nucleus of the thalamus

for a patient with essential tremor.

719

Samuel: Mm-hmm.

720

Mike: And it was fascinating because

patient was awake, you know, and the

721

tremor was visible and the idea was

hopefully with the procedure that

722

in real time you might be able to

see some reduction in the tremor.

723

And so it was kind of unclear at that

point in time after the actual ablation.

724

But it was just so fascinating to see it

being done, and now, 30 years later, to

725

see that this kind of exciting technology

726

Samuel: Yeah.

727

Mike: Is providing for a

non-invasive option that way.

728

Samuel: And that, for example,

in 30 years, the imaging in many

729

aspects has improved so much.

730

For example, in the MRI-guided high

intensity interventions, we see

731

in real time the tremor reduction.

732

Actually the functional neurosurgeon

is not happy until the tremor pretty

733

much has pretty much disappeared.

734

And we see in real time.

735

So we do, when we do this ablation type

intervention, again, this is the high

736

intensity modality, we are doing neuro

assessment between exposures and we are

737

pretty much making maximum accelerometers.

738

And, but the thing that makes all this

possible was a huge progress in imaging

739

really that, especially on the MR side.

740

So right now, even in the beginning

of these kind of interventions, we

741

used atlas based targeting, which

kind of puts you in the vicinity.

742

But now the majority centers are

using tractography in order to really

743

pinpoint the locations in the VIM.

744

So you refine even and it something as

small as the beam, you can still refine

745

surgical, basically using tractography.

746

And then that intervention takes

less time because you are almost

747

from the very beginning, you are

the start location and so on.

748

So all these things I think need

to happen and we are going to

749

continue to evolve in the next years.

750

Last year and last week I was in a

conference and people, some colleagues

751

were presenting a beautiful results,

um, showing and, uh, for doing

752

now the low intensity modality.

753

They're using MRI, okay?

754

Mike: Mm-hmm.

755

Samuel: But we don't want to use thermal

effects 'cause you do thermal effects.

756

You are not in confirm, in fact, you

start, it's a different conversation.

757

Uh, uh.

758

So this's, another thing we can do in

MRI, like a major tissue displacement.

759

So ultrasound produces

tissue displacement.

760

Can we use that as a marker to

verify if I'm the right target.

761

And two, I can even

use it for calibration.

762

I can maybe calibrate

my energy based on that.

763

It has taken a whole lot of

development because in the early

764

days, so this methods is called

acoustic radiation force imaging.

765

In the early days, you need to

see a lot of ultrasound energy

766

to have something visible.

767

But again, imaging continue to

improve, develop new type of MR

768

sequence and super most sensitive

to smaller tissue displacement.

769

And guess what?

770

Now we're getting now to that point.

771

And maybe a consideration first

imaging down the road for people who

772

wants to experiments in an MRI, might

become, cross fingers, the way people

773

can verify target engagement and

calibration, which will be fantastic.

774

So that also influences people

like us doing in neuro navigated

775

in an office to do experiments.

776

But because I'm pretty sure a lot

we going to learn in MRI-guided

777

interventions is going to help us to

improve that in an office setting.

778

So that's the thing.

779

Still super exciting.

780

So there's still a lot of research

development, some where people are

781

still thinking, um, I'm not gonna be

wrong, this like, I don't know how many

782

companies are there, but there's many

companies who wants to capitalize on this

783

because obviously it's a lot of interest.

784

It's a very.

785

Boiling environment right now.

786

Mm-hmm.

787

Between a lot of research but also

also even also commercial to who

788

wants to really go into, I love it.

789

So all this kind of moving things

in parallel, so it's super exciting.

790

Mike: Yeah, yeah that's great.

791

So just again, for viewers and listeners,

just to kind of quickly summarize

792

the results of the focused, the VIM

Thalamic focused study for tremor,

793

essential tremor and Parkinson's.

794

So, the study found the significant

tremor, reduction in the essential tremor

795

patients, and a signal for improvement

in the Parkinson's patients, but less

796

robust than for the essential tremor.

797

So that's just so fascinating

because obviously it's just

798

really highlighting the promise

for future clinical applications.

799

So I'm just curious now, if you could

put on your predictive kind of hat and

800

think about based on what your lab's

finding and what the field is finding

801

in general, where do you think that

transcranial ultrasound stimulation

802

will have the biggest impact in terms

of specific neuropsychiatric illnesses?

803

Samuel: Wow.

804

Yeah.

805

Some, some definitely.

806

I mean.

807

Depression, OCD, PTSD definitely

addictions, that's another one.

808

So we still have some good, very good

preliminary results from other groups.

809

Um, and it's going to, likely, start

to become, quite, quite some, life

810

changer to them, um, which is good.

811

We have to have this, a lot of companies

will start to bet money on this, for

812

example, very good colleague, friend, lead

on the field, uh, Dr Francois from Bari.

813

He has a company in France and they

have the own intervention, and they

814

are aiming for refratory depression.

815

Again, still unfortunately pilot

study as we know, yeah, patients were

816

experiencing symptom improvement lasting

many days with one single session.

817

So, that aspect of the dosing is going to

continue and important, but if I will pick

818

one indication and may they likely it's

going to make in the next three years that

819

we start to hear more and more, probably

refractory depression will be one.

820

One of the most groups are interesting,

second, many companies right now,

821

they're putting the energy there

and we do have such a big momentum.

822

So we know this is, this is pretty much

just for, for Monte Carlo simulation.

823

You know, one of them is going,

is going to start to nail it and

824

start to show very good results

because you, you are multiplying

825

the different approaches and so on.

826

So, you know, and the French

results are very promising.

827

So now we just continue to push to get

sham controlled dosing studies to see

828

how much effect, how much time, the,

the effort, uh, and the, the, if we

829

took better than TMS that, uh, three,

six months symptoms, improvements,

830

some, uh, um, um, and if we are in

the same ballpark, um, and then we

831

start to feeling combining therapies,

TMS plus ultrasound, I don't think

832

no one in, in the right mindset would

say, oh, this going replace TMS.

833

Not, I don't think so,

especially for depression.

834

It might be like a one, two kind of

maybe intervention and maybe, hopefully

835

more or less, who knows what kind

of combinations might going to do.

836

Pharmacological is going to always

part of the question, some combining.

837

And so, so that's, that's this exciting

aspect, not when you go now to clinical

838

implementation, how things can improve.

839

But even if I.

840

Um, I'm, I'm very movement

disorder oriented,

841

being in Calgary, I'm, I probably can

need to recognize probably the, the

842

depression, especially as refractory

depression might be the, become probably

843

the poster child as a first indication

that is going to be of significance

844

because even for PR perspective

to show, people life some improve.

845

And there from there we know that

for Parkinson's its more tricky.

846

That's a little more, more tricky.

847

What do we do?

848

Multiple locations, what are we

going to do that's more tricky.

849

Essential tremor, we like it because

it's an easy one to demonstrate effect.

850

We need to remember essential

tremor is the number one

851

moment disorder in the world.

852

It doesn't get the same

publicity as Parkinson's,

853

but we need to remember it is the

number one moment disorder in the world.

854

So, coming back to my comment, likely

depression might be maybe become the

855

poster child that's certainly making

a difference and people will get

856

inspired, okay, is this happening here?

857

Then other indications start

to follow and get authority.

858

Mike: Mm-hmm.

859

Samuel: That's my, that's

my, my, my magic ball.

860

Mike: Yeah.

861

Yeah, for sure.

862

That's fantastic.

863

Yeah, the crystal ball.

864

I appreciate that.

865

So, I mean, I think it's great.

866

We talk a lot on the podcast about

how the non-invasive neurostimulation

867

technologies, other kinds of

interventional neuropsychiatric

868

strategies, it's really opening the

door for clients and patients to be

869

able to bring tools, as you say, into

their treatment option toolkit, right?

870

And then allow for personalized

approaches to care.

871

And so,

872

Samuel: mm-hmm.

873

Mike: You know, the

transcranial ultrasound is

874

gonna certainly be part of that.

875

It's really exciting.

876

Sam, this has really been

a fascinating conversation.

877

Yep.

878

And so congratulations to you and

to your team, your lab, all of

879

your work is highlighting how this

fascinating technology of transcranial

880

ultrasound can offer something quite

unique in neuromodulation, which is

881

non-invasive access to deep brain

circuits with this kind of millimeter

882

precision that you're describing.

883

So it's gonna be really

exciting to see how this field

884

evolves in the coming years.

885

Samuel: Now thanks for the invitation.

886

It was a pleasure and definitely some,

hopefully continue to spread the word.

887

I think in the community

and also in general,

888

I think we're going to keep

hearing more and more and more.

889

The FDA was reporting, an amazing

number of applications for approval

890

of studies in the last year.

891

So in the other one column that which

apparently was not seen by the FDA many

892

years for especially physical devices.

893

So, it shows an indication how

active this field is becoming.

894

Now as a community, we need to always be

careful, always need to, or any, group of

895

researchers might be interested in this.

896

So with safety, I would say always

go with that mindset on this.

897

So yeah, definitely we're welcoming more

people and, and joining especially in

898

psychiatry, and then once we start to,

there's not anymore just like a bunch

899

of engineering physicists who start

to get out of the bubble now, actually

900

people, neuroscientists, psychiatry,

movement disorders, neurologists

901

who are really running with this.

902

Anyways, super excited and

thanks again for invitation.

903

Yeah, yeah, thanks.

904

Mike: Yeah, for sure.

905

And so for viewers and listeners

who are interested in exploring, Dr.

906

Pichardo's in his lab's work, I really

would encourage you to check it out.

907

And so I'm gonna include links to their

recent publications in the show notes.

908

Again, Dr.

909

Sam Pichardo, thank you so

much for joining us today.

910

Yes,

911

Samuel: Michael,

912

Mike: thanks so much.

913

And thanks to all of you for watching or

listening to the Neurostimulation podcast.

914

I really appreciate your time,

your interest, and your attention.

915

And until next time, stay curious,

stay well, and we'll see you next

916

time on the Neurostimulation Podcast.

917

Thanks so much.

918

Samuel: Yeah, thank you Michael.

919

Mike: Thanks.

920

Okay.

921

Have a great day.

922

Thanks so much.

923

Thank you so much for joining us

today on the Neurostimulation Podcast.

924

I hope that you enjoyed this exploration

into the fascinating world of noninvasive

925

neurostimulation using transcranial

focused ultrasound to reach these deep

926

brain structures in a noninvasive way

that, up until recently really has only

927

been, possible using invasive strategies.

928

And so this hopefully will open the

door to treatments that can be more

929

accessible to people, with lower risk

and better efficacy in the long run.

930

And so if you found, today's

episode interesting, please do.

931

If you found today's episode

interesting, don't forget to like

932

and subscribe to the podcast.

933

It is the best way to make sure that you

never miss an episode, and it also helps

934

us to reach more curious minds like yours.

935

Also, if you think today's episode might

resonate with a colleague, a friend, or a

936

family member, please share it with them.

937

This kind of knowledge is much

better when it is shared and you

938

never know who might find this

information helpful or inspiring.

939

For more details about this fascinating

research and the technology that we have

940

been discussing today, please do check

out the links in the show notes below.

941

You'll find everything that you need

to dive deeper into the topic, and

942

I would love to hear your thoughts.

943

So I encourage you to join in

the conversation in the comment

944

section with questions, comments,

or suggestions for what you'd like

945

to see covered in future episodes.

946

Finally, don't forget to

tune into the next episode.

947

It's gonna be another exciting

journey into the cutting edge of

948

neuroscience, clinical neurostimulation,

interventional mental health, and

949

general mental health and wellness.

950

So thanks again for listening.

951

Take care.

952

Stay curious, and I'll see you next

time on the Neurostimulation Podcast.