How Ultrasound Can Deactivate Parts of the Brain

[Derek] How do you fix a brain that's not working properly? Well, until now the only real option has been to open up the skull, implant electrical or optical fibers, or even remove parts of the brain. If you do something like surgery or ablation, even with ultrasound, that's an irreversible one-time procedure. But this scientist has a different idea.

Do you wanna introduce yourself?

[Mikhail] Yeah, sure. Yeah, I'm Mikhail Shapiro.

[Derek] Where should I look?

[Mikhail] You can look at me, yeah!

[Mikhail] Yeah, I'm Mikhail Shapiro. I'm a professor of chemical engineering at Caltech. Everything that we try to do is to make it non-invasive, meaning that we don't want to have any kind of surgery to open up the skull and implant an electrode, or we don't want to have to open up the skull to shine light onto the neurons.

We want to do it using sound waves, which is one of the few forms of energy that can be focused deep inside of the tissue and can actually permeate through things like the skull, even the human skull. This is a curved transducer, so you can see there is a slight curvature in it that will cause the sound waves to get concentrated a few centimeters in front of the face of this transducer.

[Derek] For now, the research is being conducted on mice, and the idea is to be able to turn on and off specific brain regions at will, without invasive surgery.

[Mikhail] So the trick that we employ here is that we take something that's traditionally been a really big problem in neuroscience—drugs—and we turn it into an advantage.

So the problem is that the brain has what's called the blood-brain barrier which lines the blood vessels of the brain and prevents molecules moving from the bloodstream into the brain.

[Derek] But in their procedure, they open the blood-brain barrier in carefully targeted regions of the brain.

[Mikhail] So to do this, we introduce little bubbles into the bloodstream.

[Derek] Air bubbles.

[Mikhail] Bubbles of air, but they are safe bubbles. So this is an FDA-approved clinically used—

[Derek] Like tiny bubbles?

[Mikhail] They're microns in scale.

[Derek] Okay. Tiny air bubbles.

[Mikhail] So tiny little air bubbles that we introduce into the bloodstream, and so they're circulating everywhere. And then wherever we apply the ultrasound, the sound waves cause the bubbles to expand and contract in size, and as they're doing that they push against the blood vessel walls, and kind of massage them open.

So they get that blood-brain barrier that's normally caused by really tight junctions between cells to open just a crack, so that now molecules can get out, into the brain.

[Derek] And by using the ultrasound you can target just specific areas of the brain where you want to open the blood-brain barrier and leave the rest of the brain alone.

[Mikhail] Exactly.

[Derek] Once the blood-brain barrier is open, the scientists inject a specially made virus that would normally not be able to pass into the brain.

[Mikhail] These viral vectors, which are viruses that we have hijacked, so that instead of them introducing their DNA to the cells, they're going to introduce the DNA that we want, and what this gene produces are these receptors that will go on to the neuron.

These receptors have been modified so they no longer respond to neurotransmitters that are natively present inside the brain and will instead respond to a drug that we can inject that will activate just those receptors and not act on anything else.

I'll tell you when we get to a part where your camera's going to get sucked into the magnet before it happens.

[Derek] Thank you. I appreciate that.

[Mikhail] So this big machine here is what generates the sound waves that we use. This little device will get installed on here, and then we're gonna have a mouse underneath, and then this entire thing is going to go into the MRI scanner.

[Derek] Is this a special ultrasound for... mice?

[Mikhail] Both the MRI is special for mice, because as you can see from the bore that's in the middle of it.

[Derek] Yeah. A human's not gonna fit in there!

[Mikhail] Yeah, well it'd have to be a really small human. And then our ultrasound system also is designed for these kind of small animals.

[Derek] And that squeaking sound that I'm hearing. That's not actually mice in there—That's the MRI?

[Mikhail] Yeah.

[Derek] How strong is the magnetic field in there?

[Mikhail] Inside the scanner it's 7 Tesla.

[Derek] Whoa!

[Mikhail] Yeah. So it's going to give us an image of the anatomy of the brain and allow us to target the focus of this ultrasound transducer to precisely the part of the brain where we want to open the blood-brain barrier.

[Jerzy] There will be four bright spots that will appear on the brain just about here. So this is the opening of the barrier between the blood and the brain. That allows a diffusion of what is essentially a magnetic resonance imaging dye that shows up during the MRI imaging.

This is the hippocampus. The hippocampus is a fairly large structure that's important in the formation of memory, and this is the one that we targeted in our recent study to modulate the memory of mice.

[Mikhail] We targeted the hippocampus, which is this part of the brain that's necessary for the formation of certain kinds of memories, and using our technique, we can address just the neurons within the hippocampus.

And when we give a drug, those neurons get shut down. And then we can do behavioral experiments where we did a memory task, where we put the mice into a particular environment and checked the next day by bringing the mice back into that same environment whether or not they could remember it.

And for the mice that were treated with the ultrasound, with the receptors through the viral vectors, and given the drug that activates these receptors, that shut down the hippocampus. Those mice were not able to remember, so we could tell that we were successfully able to inhibit or prevent memory formation.

Because the effect depends on when you give this drug and how much of the drug you give, you can have reversible turning on or off of the effect that you're trying to produce.

So for example, shutting down the part of the brain that's causing a seizure. So another part of the brain that we're pretty interested in is called the ventral tegmental area, which is a part of the brain that uses the neurotransmitter dopamine and is involved in things like motivation, and addiction, and initiation and control of movement.

And if we can gain control over the neurons in that area, it might someday be useful treatments for some of these motivational or affective disorders like addiction and our depression.

[Derek] Could you use this to control people's brains? Like by playing ultrasound into some area?

[Mikhail] No, there is not a chance, at least using our technology, that you could be walking around and we could be controlling your brain remotely... if that's what you're worried about.

[Derek] Not yet, anyway.

[Mikhail] That is not our goal!

[Derek] Right.

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