Dr. David Blake - #25 - June 14, 2025

Mike: 00:00:15

Welcome to the Neurostimulation Podcast.

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I'm Michael Passmore, clinical

associate professor in the Department

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of Psychiatry at the University of

British Columbia in Vancouver, Canada.

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The Neurostimulation Podcast is all

about exploring the world of neuroscience

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and clinical neurostimulation.

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We talk about the brain, how it works,

the latest research breakthroughs

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in neurostimulation, and how that

research is being translated into

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real world treatments that can

improve health and wellbeing.

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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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Accordingly, I would like to emphasize

that the information shared in

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this podcast is for educational

purposes only and is not intended

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as medical advice or a substitute

for professional medical guidance.

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Today's episode is presented

by ZipStim Neurostimulation.

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ZipStim is the neurostimulation

clinic that I operate.

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You can find out more about our

clinical programs at zipstimcom.

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That's Z-I-P-S-T-I-M.com.

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Today I'm really looking

forward to a discussion with Dr.

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David Blake, professor of neuroscience

and regenerative medicine at

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Augusta University in Georgia.

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Dr.

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Blake's lab is pioneering work in deep

brain stimulation and its effects on

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aging and cognitive function, particularly

through the use of cerebrospinal fluid

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markers in non-human primate models.

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In this episode, we're gonna dig into Dr.

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Blake's lab's recent findings as

they presented at the: 2025

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Stimulation Conference in Kobe, Japan,

and we're going to explore what those

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findings could mean for the future

of neurotherapeutics, particularly

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in age-related cognitive decline.

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The title of their poster is a bit of a

mouthful, but I'm gonna give it a shot.

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Exploration of Deep Brain Stimulation

Effects on Neurotrophic Markers in

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Cerebrospinal Fluid in Aged Rhesus

Macaqueque Monkeys using an Ommaya.

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Dr.

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Blake's lab in this poster offered

the following background as a way of

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setting the stage for this project.

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They noted that the losses in cognitive

function with aging occur in parallel

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with decreases in function in the

forebrain's cholinergic systems.

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Now, this is the primary target

for the medications that are

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approved for stabilization of mild

to moderate Alzheimer's disease

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due to the targeting of that exact

forebrain cholinergic system.

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The cognitive impairment is concentrated

in executive function and memory loss, and

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the team noted that prior work

applying electrical stimulation to

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the nucleus basalis of Meynert has

documented that intermittent but

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not continuous stimulation for one

hour per day improved working memory

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task performance in adult monkeys.

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So this team's study tested the

impact of intermittent stimulation

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on behavior in Macaqueque monkeys

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and control animals either delivered a

donepezil intervention or unstimulated.

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So we're gonna have a discussion

about this particular study

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and other relevant work in Dr.

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Blake's lab.

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Welcome back to the

Neurostimulation Podcast.

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I'm here today with Dr.

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David Blake, professor of neuroscience

at Augusta University in Georgia.

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Dr.

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Blake, thanks so much

for joining us today.

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David: Oh, I'm happy to be here.

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Mike: Maybe, if you don't mind, could

you introduce yourself and talk a

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little bit about your position there,

your team's work, and then I'd love to

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get into some more detailed discussion

about the research in particular, your

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lab's work that was presented at the

recent conference in Japan in February.

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David: Yeah, so my work, my, my lab's work

for most of the last decade is focused

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on stimulation of the basal forebrain.

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In, in monkeys or in humans.

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That would be the nucleus

basalis of Meynert.

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That area has neurons that project

to the cerebral cortical mantle.

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And those, most of those neurons

are at least acetylcholine, so

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we think that we're controlling

or have some control over the

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acetylcholine tone in the cerebral

cortex by virtue of our stimulation.

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And the observations that we made

suggest that we can use it to improve

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executive function in a wide variety of

mammals, mice, rats, monkeys, and humans.

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And so we're both studying the

process and also pushing into

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getting it into the clinical realm.

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My background is in

biomedical engineering.

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I trained in neurophysiology.

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My graduate work was at Johns Hopkins

studying sensory processes, and I studied

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sensory cortex plasticity at UCSF for a

decade, and then serendipitously backed

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into a corner of neurostimulation, and

then it's all been taking off from there.

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Mike: Fantastic.

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Yeah it's interesting how things go

in terms of when one gets through

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the, the training and then you

get interested in one direction or

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another, and then these, the, these

interests and opportunities coalesce.

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So that's, it's been it's, yeah.

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Great to hear about how

that all evolved for you.

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I, in fact,

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David: for a little segue, I tell all

of our trainees that if you observe

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something that just seems too fantastic

and is not really related to your

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primary scientific question, it's often

worth investigating a little bit more

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because it can really become a launching

pad for a new scientific question.

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You shouldn't just ignore it if it's

not suiting your immediate goal.

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Mike: Yeah.

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Yeah, for sure.

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No, I think that would be an interesting

part of the discussion too, is

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talking a bit about t hings like

mentorship and encouraging trainees.

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So this study in particular, I was looking

back through and reviewing the poster.

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Exploration of deep brain stimulation

effect on neurotrophic markers in

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cerebrospinal fluid in aged Rhesus

Macaqueque monkeys using an Ommaya.

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So maybe, do you mind helping

us to understand a bit about

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that study in particular?

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David: Yeah, so this was the

newest thing that was added to the

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paper that was published in brain

stimulation this past January.

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So people can go look up that paper

and see the fine details and study

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them at as much detail as they like.

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We got interested in deep brain

stimulation because it caused plasticity

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and sensory cortex, and then started

studying what happens if we stimulate

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while the animal's doing a behavior.

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Then we switched to studying executive

function behaviors and found that

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we could cause enduring improvements

in executive function behaviors.

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Now we are really interested

in how this all worked and

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being an electrophysiologist.

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We did some recordings.

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I worked on this, I worked on

this, a lot of this jointly with

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Christos at Vanderbilt and the

electrophysiological correlates

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that related to the magnitude of the

cognitive effects just weren't there.

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We would apply the deep brain stimulation.

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We'd see very subtle effects

happening in neural responses.

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It just something else had to be

happening that we couldn't really see and.

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We did a mouse study that we

published in Cerebral Cortex a few

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years ago where we could do protein

expression and look and see what's

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really changing in the neural tissue.

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And the big hits that came outta that

were the receptors for nerve growth factor

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and brain derived neurotrophic factor.

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Now those are neurotrophic receptors,

so if they're activated, they

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cause the part of the cell on

which they're expressed to grow.

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And these cells are growing

well what activates them?

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Nerve growth factor is part of the

cholinergic signaling pathway in, in the

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forebrain and in the cerebral cortex.

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So tissue that produces nerve growth

factor draws cholinergic axons in and

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causes them to release more acetylcholine.

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So we were excited to see

that we were a little.

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Wondering why we saw the BDNF

at the same time, brain derived

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neurotrophic factor, which doesn't

relate so directly to the cholinergic

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pathways that we're stimulating.

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But both of those neurotrophic factors are

activated in six hour long processes where

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the nerve growth factor peptide binds

to the receptor, it gets internalized.

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It gets phosphorylated, transported

back to the nucleus, changes gene and

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protein expression in the cell, which

causes that part of the cell to grow.

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So it's not something you could

see electrophysiologically.

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So we were wondering, how can we see

the immediate result of this process?

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And we started sampling

cerebrospinal fluid.

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And of course the way you typically do

that is through a spinal tap, and that's

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what we did to get our initial data.

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But I worked on this collaboratively

with the neurosurgical team.

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The chair of neurosurgery

is very interested.

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He's a functional neurosurgeon, which

means he does deep brain stimulation

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clinically, and so he is interested in new

applications of deep brain stimulation.

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So he came in and started doing our

monkey surgeries with us which by

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the way is fantastic if you have a

neurosurgeon helping you with your

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monkey surgeries 'cause you they

get done better and you learn a lot

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more about your surgical skills.

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He said, we can try using this Ommaya.

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Now for those who are not neurologists

or neurosurgeons, an Ommaya is an extra

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ventricular drain and reservoir, so it's a

little tube that goes into the ventricular

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system of the brain that's about two or

three millimeters wide, and the tube goes

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through a small hole in the cranium to a

reservoir that's under the skin, and the

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whole system doesn't hold very much fluid.

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It holds about 50 microliters, but, you

can stick a needle into it and allow

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the positive pressure of the CSF to

allow cerebrospinal fluid to flow out

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so you can sample cerebrospinal fluid.

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Now this is really interesting and

there's been, tons of studies on

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the neurotrophic receptors and the

neurotrophins in rodents and in culture.

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You can't do the cerebrospinal

fluid studies in small mammal models

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because you can't sample large enough

volumes of cerebrospinal fluid to be

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able to measure protein expression.

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Now, the Macaqueque

doesn't have that problem.

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We could easily sample and we actually

went through studies and how much

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can we sample over what length of

time, and it seemed like a quarter

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CC could be sampled every 30 minutes.

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Which is about one fourth of

the production of CSF from the

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Macaque ongoing production.

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We could sample that every 30 minutes,

and so that's more than enough to do

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really nice protein expression, which

is the next phase of the project.

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So with all those things in place,

we took the monkeys, we were

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studying cognitive changes in.

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We would stimulate them and then draw

cerebrospinal fluid after a half hour.

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After an hour.

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And we did, the first things we looked

at were the pathways we thought should

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be involved in the cerebrospinal

fluid for the neurotrophic receptors.

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So that's, again, that's the nerve

growth factor receptor and the brain

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derived neurotropic factor receptor.

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We should see their peptides and we

should see tissue plasminogen activator.

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Tissue plasminogen activator is well

known for people that study stroke

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because it's given to, ischemic

stroke patients, if they're caught

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in the first six or seven hours and

they meet other certain criteria,

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'cause it, it breaks the clots up.

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It does other things to activate

biochemical pathways in the

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cerebrospinal fluid, it activates

nerve growth factor and it activates

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brain derived neurotrophic factor.

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So these were just the first

things we wanted to look for.

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And we found them in spades.

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And so we're actually really excited

about the next phase of study where

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we'll go in and use a more comprehensive

proteomic approach to look at,

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'cause we're interested in these two

neurotrophins and this activator.

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There's gonna be hundreds of

proteins that change in their

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expression levels when we stimulate.

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And we need to get a more holistic picture

of what's going on, which we just can't

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do looking at one protein at a time.

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Mike: Yeah.

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Wow.

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That's fantastic.

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It's such an interesting evolution

in terms of the inception the theory

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behind it, and then these practical

matters that you're describing.

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It's really interesting.

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It's fascinating how you have

these intersections between,

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and the access to experts, like

with the neurosurgeon as well.

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David: We started to look

at the cerebrospinal fluid.

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We're like, why?

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Why hasn't anyone else done this?

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And you can't draw serial samples

in rodents and humans that, you

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know, especially like a subarachnoid

hemorrhage patient would have an

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extra ventricular drain placed anyway.

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People haven't done systematic

manipulations and drawn

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fluid in those cases.

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'cause probably they're not working

in the neuro ICU and thinking about

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these questions, but it's, once

you're set up, there's a whole set

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of really interesting questions about

what's happening in cerebrospinal

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fluid and we just don't know.

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For example, if you do an executive

function behavior for an hour, you're

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thinking really hard for an hour.

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What changes in the cerebrospinal fluid?

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You don't really know, or aerobic

exercise improves executive function in

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virtually every mammal that we know of.

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There's gotta be markers that are

changing in the cerebrospinal fluid

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when aerobic exercise happens.

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We don't really have a good clue

as to what those are, either.

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We have some hypotheses, but the direct

assessment hasn't really been done,

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and this preparation will allow those

questions to be addressed directly.

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Mike: Yeah, for sure.

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It's really interesting because I

think that hopefully that is gonna

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be something, there's real, there's

obvious real value in getting in,

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getting this kind of detailed data.

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From these tissue sources and

the CSF sources, because then

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that can allow for that analysis.

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And then the, as you say the sampling of

the proteins and the analysis of how the

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genomics perhaps are changing in real time

depending on what the functional correlate

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is that's being studied at the same time.

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And I imagine that in a

broader sense, that can.

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Integrated into other types of approaches

like neuro imaging approaches that

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perhaps provide a more of a broad picture?

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No, actually, I guess pun intended, a

broad, broader picture of the whole system

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as opposed to these more detailed and

in vivo sampling kind kinds of ideas.

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David: You can certainly customize

ligands based on what you find.

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But the other thing that I think is really

timely is that the proteomic approaches

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and I'm particular to one vendor, but

I'm not gonna mention the vendor's

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name, but using very small volumes

of fluid, like cerebrospinal fluid.

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You can measure the levels of

thousands of proteins now and, it's

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expensive to do but it's scientifically

worthwhile if you have the.

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The wherewithal to do it.

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So one of, one of the experiments we're

proposing in our next round of studies

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is to sample the cerebrospinal fluid and

sample the blood at the same time points.

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And then you can measure thousands

of proteins in both spots, and you'll

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see which proteins that show up in the

cerebrospinal fluid show up in the blood.

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And thus give you a better biomarker.

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You can imagine doing this with

Alzheimer's patients and people have

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you take cerebrospinal fluid from a

few hundred Alzheimer's patients and

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you take blood from them and you do

proteomics in both of the samples.

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What are the real markers that relate

to cognitive status that are in the

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cerebrospinal fluid and which of

those show up in the bloodstream?

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And you could use such a powerful

approach to look at biomarkers, accelerate

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the development of new biomarkers.

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Mike: Yeah.

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Yeah.

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That's fantastic.

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I think it would, I've heard recently

that there's a, hopefully there's

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gonna be a blood test that's gonna

be available fairly soon in terms of

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early stage Alzheimer's diagnostics.

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But it would be interesting

then to continue on in that.

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In that vein, as you're describing,

and perhaps get even more specific

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tests around perhaps looking at being

able to predict whether or not someone

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is likely to improve on a colonist or

his inhibitor, because right now they

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have this, as I'm sure you're aware,

this typically this rule of thirds

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that they talk about clinically that

maybe a third of people will do well.

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A cholinesterase inhibitor, a third of

people, it's equivocal and a third of

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people probably don't gain much benefit.

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So being able to anticipate that ahead

of time with these kinds of more targeted

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biomarker tests would be really helpful.

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David: Yeah.

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And then, they don't know if it's the

metabolism rate of the cholinesterase

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inhibitor for its ability to elicit

action v aries by person, either Obviously

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since we're studying acetylcholine

we've actually used those in our lab

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animals and gotten some more cognitive

effects in the short term anyway.

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Mike: Yeah, I was interested because

I can recall when I was at that

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poster session and talking to your

colleague there, Kendyl Pennington

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that this particular study did involve

some comparison with donepezil.

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Do you mind maybe helping us

understand how that worked?

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So the

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David: particular study our, and

again, it's published in brain

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simulation this past January with

Kendyl Pennington as first author.

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We provided deep brain stimulation to

Macaque monkeys for about an hour a day,

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and we measured their working memory

duration using a two alternative force

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choice delayed match to sample and we

set up the behavioral tasks so that it

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would automatically get harder if the

animal got a few trials in a row correct,

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and easier if the animal got some wrong

So it would automatically adjust to

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the animal, the animal would choose

its own task difficulty, and by simply

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recording the task difficulty the animal

worked through, we could see what the

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animal's working memory duration was.

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And so over a 12 week period, they

got stimulated for an hour a day.

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The animals got on average, 50% increased

duration of their working memory.

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And that was then sustained

for a period of time after that

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without further stimulation.

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The donepezil comparison, we took

separate groups of animals and

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simply gave them donepezil each

day and have them do the same task.

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But because donepezil causes an acute

effect in the task, we gave them

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the donepezil right after the task.

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So, t he donepezil would be loaded

into a date, which monkeys like to eat

306

: 00:18:16

dates, and so the monkey would do his

behavior for the day and then he'd get

307

: 00:18:19

a date as his reward, which had the

cholinesterase inhibitor donepezil in it.

308

: 00:18:24

And we used as high a dose of

donepezil as we could get, 'cause

309

: 00:18:27

the animals were doing appetite of

treat training, so they'd work for a

310

: 00:18:31

little food pellets that they liked.

311

: 00:18:33

But if you give them too much

donepezil, they don't really

312

: 00:18:35

like food as much anymore.

313

: 00:18:36

So we had to back off on some of the

monkeys, but we gave all of them the most

314

: 00:18:41

that we could thought they could tolerate.

315

: 00:18:43

And one of those five animals had

a pretty pronounced improvement.

316

: 00:18:47

But the other four, we didn't see

anything which matches the rule of

317

: 00:18:50

thirds with donepezil and the clinical

data too, that, a small fraction of

318

: 00:18:54

patients seem to do quite well with

donepezil and that most of them, it,

319

: 00:18:58

it seems like it's not doing anything.

320

: 00:19:01

Mike: Yeah, that's interesting.

321

: 00:19:02

For sure.

322

: 00:19:03

And so those four, so the, what I was

recalling from reading the poster was

323

: 00:19:08

that, oh, and then the other thing I was

gonna mention for viewers and listeners

324

: 00:19:11

is I'm gonna put links to, in the show

notes, to the relevant papers and to Dr.

325

: 00:19:15

Blake's lab, so that I would encourage

people to, to check that information out.

326

: 00:19:19

But then, so yeah, so then

just going back to the results.

327

: 00:19:23

So the four that were, help me understand

that the four that were stimulated showed

328

: 00:19:28

the improved working memory duration.

329

: 00:19:30

David: Yeah we measured their

working memory in terms of duration.

330

: 00:19:32

Because the task automatically

adjust per 5% correct.

331

: 00:19:35

So they all got the same percent correct.

332

: 00:19:37

But they worked up to harder levels after

they started to receive stimulation.

333

: 00:19:41

We measured that by the time between

the sample and the potential matching s

334

: 00:19:47

timulus in the delayed match to sample.

335

: 00:19:49

If they're working at they're

matching a covered square.

336

: 00:19:52

The covered square might

be yellow is the sample.

337

: 00:19:55

The screen goes blank for five

seconds and they have to choose

338

: 00:19:57

between yellow and blue and choose

the yellow to get a food reward.

339

: 00:20:01

After we started stimulating, they would

do what they used to do at five seconds.

340

: 00:20:05

They could do after nine seconds

or nine and a half seconds.

341

: 00:20:09

It's about the size of the effect.

342

: 00:20:11

Mike: I see.

343

: 00:20:11

And so the stimulation was in that,

as you said, the nucleus basalis

344

: 00:20:15

of Meynert, is that correct?

345

: 00:20:16

Yes.

346

: 00:20:18

Okay.

347

: 00:20:19

Huh.

348

: 00:20:19

David: And so I guess we targeted

it and for those who aren't and most

349

: 00:20:22

people don't know where the nucleus

basalis of Meynert is off the top of

350

: 00:20:25

their heads, even, I gave neurology

grand rounds most of them don't even

351

: 00:20:28

know off the top of their heads.

352

: 00:20:29

But I think the easy way to explain it

to people is that it's a sheet of neurons

353

: 00:20:33

and you could argue whether it's distinct

from the globus pallidus or not, but

354

: 00:20:37

it's at the floor of the globus pallidus

are slightly below, and it's contiguous

355

: 00:20:41

with the globus pallidus structure.

356

: 00:20:43

So if you're, if you can find the

globus pals right underneath it, you'll

357

: 00:20:46

find the nucleus basalis of Meynert.

358

: 00:20:50

Mike: Yeah.

359

: 00:20:50

And then I guess again, for folks maybe

who don't have the necessary sort of

360

: 00:20:54

background, then my understanding is

that's basically the the nucleus of

361

: 00:20:59

neuronal cell bodies then that project

forward with those cholinergic pathways,

362

: 00:21:03

that seems to be really important in terms

of not only pathology of neurocognitive

363

: 00:21:08

disorders like Alzheimer's in particular,

but important as far as therapeutic

364

: 00:21:12

targets with the cholinesterase

inhibitor class of medications.

365

: 00:21:17

David: I usually explain to people

that there are projection neurons there

366

: 00:21:21

in the nucleus basalis of Meynert.

367

: 00:21:22

90, over 90% of those projection

neurons release acetylcholine and

368

: 00:21:27

that they're most active during

periods of high alertness and arousal.

369

: 00:21:32

And so you can think of it as

almost circadian rhythm driven.

370

: 00:21:36

You're gonna have higher rates occurring

in the middle of the day than you

371

: 00:21:39

will close to the ends of the day.

372

: 00:21:40

Very little during slow wave sleep.

373

: 00:21:42

They're paradoxically quite

active during REM sleep also.

374

: 00:21:46

But that's, so we go into that

structure and in these animals

375

: 00:21:49

we max it out for about an hour.

376

: 00:21:52

We just take it to the highest level

of acetylcholine release that we can.

377

: 00:21:55

And we, it took us quite a while

to figure out how to do that.

378

: 00:22:00

But that's the basic gist of the idea,

is we give their brain a a big alertness

379

: 00:22:04

and arousal workout for about an hour

each day via the electrical stimulation.

380

: 00:22:10

Mike: Yeah, and I guess that's interesting

too because I think conceivably these

381

: 00:22:13

kinds of results could have broader

implications outside of neurodegenerative

382

: 00:22:19

disorders and into things like

potentially, shorter term neurocognitive

383

: 00:22:23

disorders like delirium or even

earlier life neurocognitive disorders,

384

: 00:22:27

like Attention deficit disorder.

385

: 00:22:30

David: Yeah, I think that the,

there's actually a large number

386

: 00:22:32

of applications we, we think

about and talk about in the lab.

387

: 00:22:35

I'm pushing into Alzheimer's first

because I think it's the greatest

388

: 00:22:39

need is there, and I think it's got

the greatest chance of working there.

389

: 00:22:43

But yeah, if it has positive effects

in some application, then all the other

390

: 00:22:48

applications become much more explorable.

391

: 00:22:52

Mike: And then, yeah, I guess also in

terms of that existing patient population

392

: 00:22:57

where deep brain stimulation already

has a presence, say for Parkinson's.

393

: 00:23:01

'cause obviously with Parkinson's

there's a cognitive component

394

: 00:23:04

later on in the illness generally.

395

: 00:23:05

So you could imagine that there may

be, again, neurosurgical colleagues

396

: 00:23:10

that might be interested in exploring,

additional targets for deep brain

397

: 00:23:14

stimulation in that kind of patient

population also, not only to improve

398

: 00:23:18

the movement disorder, but potentially

also to improve the cognitive component.

399

: 00:23:23

David: So that's been done

actually 5, 4, 5 times already.

400

: 00:23:27

Joaquin Freun in Cologne, Germany led

the studies of this, 15, 16 years ago and

401

: 00:23:34

with Volcker Stern as the neurosurgeon

and they applied stimulation nucleus

402

: 00:23:38

basalis of Meynert in Parkinson's

patients, as you note, 'cause they're

403

: 00:23:42

already getting deep brain stimulation,

so they put in an extra lead and stimulate

404

: 00:23:46

the nucleus based sali of Maynard.

405

: 00:23:47

But they used a different

stimulation pattern.

406

: 00:23:50

And the same thing happened in several

other trials in Parkinson's patients

407

: 00:23:55

and Lewy body dementia patients.

408

: 00:23:57

And in fact they ran it in

Alzheimer's patients always using

409

: 00:24:00

the same pattern of stimulation

that Joaquin Frey had developed.

410

: 00:24:04

We use a different pattern of stimulation.

411

: 00:24:06

We get different results.

412

: 00:24:06

So I noticed that.

413

: 00:24:10

A new group from the University of Toronto

led by Alfonso Fasano is the PI, the

414

: 00:24:15

neurologist, and his fellow Sanskriti

was the the point person for the study.

415

: 00:24:20

They took six patients with Parkinson's

that were getting GPI stimulation,

416

: 00:24:24

globus pallidus stimulation, and they

inserted the lead in a way that allowed

417

: 00:24:28

the lowest contact on the lead to be

in the nucleus basalis of Meynert.

418

: 00:24:32

They applied the same stimulation that had

been developed by Joaquin Freun this 20

419

: 00:24:36

pulses per second stimulation, continuous

pulse strains, and they didn't see a

420

: 00:24:41

long-term positive cognitive benefit.

421

: 00:24:43

And so as it turns out, this is

one of those strange terms, right?

422

: 00:24:47

One of my friends emailed me their

paper and said, how are this what you're

423

: 00:24:50

doing different from what they're doing?

424

: 00:24:52

So I read their paper and I said, wow,

I might be able to help these people.

425

: 00:24:56

So I sent them an email and I said,

Hey, we study the same things.

426

: 00:24:59

I'd love to talk to you guys

and show you what we're doing.

427

: 00:25:01

We always see positive cognitive benefits.

428

: 00:25:04

So we had a Zoom session, and by

the end of the zoom session, Fasano

429

: 00:25:08

was instructing Sanskriti to go

reconsent to all their subjects that

430

: 00:25:11

already had the electrodes in place.

431

: 00:25:13

And so they did that and they got a

very nice cognitive effect, which was

432

: 00:25:16

published in about a year and a half ago

in also in brain stimulation in a letter

433

: 00:25:20

of update to their prior manuscript that

did not show positive cognitive change.

434

: 00:25:25

So the pattern of stimulation does

matter and you've gotta get it right.

435

: 00:25:29

And it did help cognition in

those Parkinson's patients, but.

436

: 00:25:33

I think that the quality of life

for a Parkinson's patient at the

437

: 00:25:36

point where they're getting the DBS

leads, if you improve their executive

438

: 00:25:39

function a little it's positive.

439

: 00:25:41

It's something I wanna

say, it's not worth doing.

440

: 00:25:43

It's definitely worth doing.

441

: 00:25:44

But if you could prevent an Alzheimer's

patients from losing their activities

442

: 00:25:48

of daily living, I think that would

be a far larger impact than the

443

: 00:25:52

altering the executive function.

444

: 00:25:54

And the Parkinson's patient was

already at the stage where they're

445

: 00:25:56

getting deep brain stimulation.

446

: 00:25:58

In any case, I'm collaborating

with a group at Stanford and

447

: 00:26:02

Helen Bronte-Stewart's Group.

448

: 00:26:04

She is taking patients who are

getting STN stimulation for movement

449

: 00:26:08

disorders, Parkinson's patients,

and they're also getting a second

450

: 00:26:12

lead in each hemisphere to stimulate

the nucleus basalis of Meynert.

451

: 00:26:15

They think that they can improve

on the stimulation we developed

452

: 00:26:19

using tractography to find the

right white matter tracks and

453

: 00:26:22

put the stimulating lead there.

454

: 00:26:24

I told them, you should just copy

what we're doing to get started

455

: 00:26:27

with and then do whatever you want.

456

: 00:26:28

Just see if what we do translates.

457

: 00:26:30

I.

458

: 00:26:30

First, and so they're actually doing both.

459

: 00:26:33

And they're starting to implant

subjects right around now.

460

: 00:26:36

I was told it was gonna be last

month, may, I haven't heard from them.

461

: 00:26:39

We have an update in a few weeks.

462

: 00:26:41

I'll know more then.

463

: 00:26:41

But there should be stuff coming out of

Stanford and it's an open label trial.

464

: 00:26:45

So there, that'll be reported in neurology

conferences in the next year or so.

465

: 00:26:51

Mike: Wow.

466

: 00:26:51

That's fantastic.

467

: 00:26:52

Yeah, we were talking a little bit about,

just before the recording started, about

468

: 00:26:56

how there's just been such a dramatic

acceleration in terms of all of this

469

: 00:27:01

research and the associated clinical

implications over the past five, 10 years.

470

: 00:27:05

It's really fascinating.

471

: 00:27:08

David: Yeah, I think I, two things

really strike my mind right now

472

: 00:27:12

is just absolutely exploding.

473

: 00:27:14

One of them is vagal nerve stimulation

and the other is the SAINT protocol

474

: 00:27:18

from Stanford the trans transcranial

magnetic stimulation for for depression.

475

: 00:27:23

Such pronounced positive effects

and just growing like crazy.

476

: 00:27:29

Mike: Yeah.

477

: 00:27:29

No, it's fantastic.

478

: 00:27:30

The other thing is that with the more

of the invasive stuff, it's, obviously

479

: 00:27:34

there's there's a lot of the hype

and the hyperbole maybe, or maybe not

480

: 00:27:38

with, these companies like Neuralink

talking about implantation and all

481

: 00:27:43

the things that they're working on.

482

: 00:27:44

I think it's, obviously, it's great that

there are folks who are benefiting in

483

: 00:27:47

terms of the motor function recovery

that they have been showcasing, but think

484

: 00:27:54

yeah doing all of this, careful and very

diligent sort of groundwork including

485

: 00:27:59

the basic science and just making sure

that, obviously there's, when it comes to

486

: 00:28:03

invasive kinds of interventions, there's

a huge safety aspect to it that has to

487

: 00:28:07

be very carefully researched in terms

of making sure that, you know, when it

488

: 00:28:12

gets to the point of being clinically

available that it's going to be safe for

489

: 00:28:17

people to have this kind of thing done.

490

: 00:28:19

David: Yeah, no, I think it,

there, there is a huge burden,

491

: 00:28:22

threshold burden to cross to be

able to do what we're trying to do.

492

: 00:28:26

And there should be, we're talking

about doing, inserting a device

493

: 00:28:29

inside somebody's cranium, and

there's a neurocritical care

494

: 00:28:33

recovery associated with that.

495

: 00:28:35

And that's not something anyone should

take lightly, but at the same time,

496

: 00:28:39

I think there's a really good chance

that we can back up the cognitive aging

497

: 00:28:43

clock in somebody with Alzheimer's

more than two years and give them a

498

: 00:28:47

few more years in which they have their

activities of daily living intact.

499

: 00:28:50

And I think that would what

be well worth the investment.

500

: 00:28:53

But we've gotta get there first.

501

: 00:28:54

One step at a time.

502

: 00:28:56

Mike: Yeah, for sure.

503

: 00:28:56

And I think there's a huge clinical need.

504

: 00:28:58

I know from my own practice and we

were saying, there's, the majority

505

: 00:29:01

of folks really don't improve much

with cholinesterase inhibitors.

506

: 00:29:05

And I think from a pharmaceutical

perspective, there doesn't really

507

: 00:29:08

seem to be anything on the horizon

that's promising around, c ertainly

508

: 00:29:13

disease modifying, but even

symptomatic treatments for Alzheimer's.

509

: 00:29:16

So I think that's fantastic

what your vision is.

510

: 00:29:18

I think there's a huge

clinical need for that.

511

: 00:29:21

David: Yeah, no, I've talked to several

people who have been really active in

512

: 00:29:24

developing therapeutics for Alzheimer's,

and they both said the same thing, that

513

: 00:29:30

there's no sign of anything that has a

positive effect on executive function.

514

: 00:29:36

Everything is designed to,

to slow the degradation.

515

: 00:29:40

And we'll see.

516

: 00:29:41

We've gotta do clinical trial.

517

: 00:29:42

There's, it's a long road from here to

there, and even if it works, there's.

518

: 00:29:47

6 million, 7 million Alzheimer's

patients in the US right now.

519

: 00:29:50

About a million new patients each

year, and there's about 150 functional

520

: 00:29:54

neurosurgeons, and it doesn't take

very much math to see that getting

521

: 00:29:58

150 neurosurgeons don't plan a million

people a year is a daunting task.

522

: 00:30:02

Mike: Yeah.

523

: 00:30:04

I'm just curious going back before we

lead the nitty gritty of the study, one

524

: 00:30:08

of the things I was curious about that

you mentioned that you assessed measured

525

: 00:30:12

the changes in things like BDNF and NGF.

526

: 00:30:18

So I'm just curious, can you talk a little

bit more about that, then what would be

527

: 00:30:22

the implications around the changes that

you found and how those the implications

528

: 00:30:28

around the impact that the brain

stimulation had on that, as you say the

529

: 00:30:33

proteomics and the genomic implications

of changes in the levels of those factors.

530

: 00:30:38

David: So nerve growth factor

is part of the axon pathfinding

531

: 00:30:43

process for cholinergic axons.

532

: 00:30:45

And cholinergic axons in the cerebral

cortex are responsible for things like

533

: 00:30:50

angiogenesis, and so the thickness

of the cortex, the blood supply

534

: 00:30:54

to the cortex, all those things

are being boosted when you have.

535

: 00:30:58

Larger amounts of nerve growth factor

activating its receptor, and so we

536

: 00:31:03

would expect to see the cholinergic axon

should be branching more and releasing

537

: 00:31:08

more acetylcholine, and the cortex

should get thicker and there should

538

: 00:31:11

be more blood vessels in the cortex.

539

: 00:31:13

Those should all happen as

a result of the stimulation.

540

: 00:31:16

BDNF is a little more promiscuous.

541

: 00:31:19

It has less selectivity for the specific

cell types of which it's activating,

542

: 00:31:23

but the most prominent are the par

albumin sensitive or parmal albumin

543

: 00:31:28

expressing inhibitory inter neurons

that synapse on the parameter neurons.

544

: 00:31:33

And so that's a large part

of the cortical circuit.

545

: 00:31:36

Primary inhibitory neurons, synapsing

on the excitatory neurons, so you have

546

: 00:31:40

a stronger, more numerous connectivity.

547

: 00:31:44

Between those types of neurons

in the cerebral cortex as well

548

: 00:31:47

as a result of our stimulation.

549

: 00:31:49

What we observe practically is that the

animal's working memory gets better,

550

: 00:31:53

the monkey's working memory gets better,

and the mouse, we saw better spatial

551

: 00:31:57

learning and the mors water maze.

552

: 00:31:58

But the magnitude of the effect, I think

is something that I don't speak about

553

: 00:32:03

enough and I need to speak about more.

554

: 00:32:05

We fine tuned the stimulation in

that paper, published in brain

555

: 00:32:08

stimulation earlier this year,

and we found that we could get.

556

: 00:32:12

Reasonably expect to increase

working memory duration by about 90%.

557

: 00:32:18

In these monkeys that are 25

to 30 years old, the equivalent

558

: 00:32:21

of 75 to 90-year-old humans.

559

: 00:32:24

So a 90% increase in working memory in

a monkey is equal to about one third of

560

: 00:32:30

the lifespan of age-related cognitive

decline in working memory duration.

561

: 00:32:35

So we're taking 30 years off

of their cognitive brain age.

562

: 00:32:40

By applying our stimulation for

a few weeks and that magnitude of

563

: 00:32:44

effect is why I'm really positive

about taking, why I would even think

564

: 00:32:47

about going into human studies and

suggesting somebody get an elective

565

: 00:32:51

neurosurgery, which sounds like you

gotta have a pretty high bar to pass it.

566

: 00:32:55

Be willing to do that.

567

: 00:32:56

But I think I'm confident

that we can pass that bar.

568

: 00:33:01

Mike: That's fantastic.

569

: 00:33:02

I think it, it really helps to put it

in those terms for people to understand.

570

: 00:33:05

That's really interesting.

571

: 00:33:07

Yeah, its really exciting.

572

: 00:33:10

David: We'll see.

573

: 00:33:10

One step at a time

574

: 00:33:12

Mike: for sure.

575

: 00:33:13

To the fda.

576

: 00:33:13

David: A

577

: 00:33:15

Mike: Yeah.

578

: 00:33:15

Yeah.

579

: 00:33:15

That's the thing.

580

: 00:33:16

Yeah.

581

: 00:33:16

So maybe that could lead into some

discussion about how, I guess in a broader

582

: 00:33:20

context, how do you see that kind of work?

583

: 00:33:23

Potentially fitting in, in terms

of the broader landscape of that

584

: 00:33:27

interface between neuromodulation

and aging, particularly cognitive

585

: 00:33:32

function, but aging research in general.

586

: 00:33:36

David: So right now there's not much

of a footprint of neuromodulation in

587

: 00:33:41

aging research outside of, obviously

for movement disorders but not for

588

: 00:33:45

executive function treatment and.

589

: 00:33:48

It, there's a huge need and so if we're

successful, obviously it would take

590

: 00:33:52

off, but it, as I said, it's gonna be

limited by the number of functional

591

: 00:33:55

neurosurgeons that are out there.

592

: 00:33:57

But it can also recenter research if more

people were really focused on how we can

593

: 00:34:02

boost the function of the basal forebrain.

594

: 00:34:04

I.

595

: 00:34:05

Because it has positive effects on

executive function in aged individuals,

596

: 00:34:10

then there can be other treatments

that develop, that have less burden

597

: 00:34:14

on the patient and are more scalable.

598

: 00:34:16

I think that's the worst case scenario

for if we go in, in humans and it

599

: 00:34:19

works, and then we have this problem.

600

: 00:34:22

We can only do it for so many

people each year, but I think other

601

: 00:34:25

people will notice and they'll

start to study the same processes.

602

: 00:34:30

Mike: Yeah.

603

: 00:34:30

That's interesting.

604

: 00:34:31

So what kinds of projects is your

lab focusing on now in terms of

605

: 00:34:36

continuing on in, in this path

or sort of future considerations?

606

: 00:34:40

David: Yeah, so we, we have

a mouse lab where we use the.

607

: 00:34:45

Neuromodulator sensors GA 3.0

608

: 00:34:49

or grab NA 2.0.

609

: 00:34:52

These are molecules that insert

into cell membranes and they

610

: 00:34:55

change their fluorescence when

they bind a neuromodulator in the

611

: 00:34:59

case of the acetylcholine one.

612

: 00:35:01

So we, we inject a viral vector into

the cerebral cortex, and then we can

613

: 00:35:05

image changes in acetylcholine in the

cerebral cortex of the awake mouse.

614

: 00:35:09

We do this in combination with the

deep brain stimulation electrode.

615

: 00:35:12

Then we have a direct readout

of the neuromodulatory release

616

: 00:35:16

caused by our stimulation.

617

: 00:35:18

One of the interesting things about

our stimulation is that it has to be

618

: 00:35:20

applied in an intermittent pattern.

619

: 00:35:23

You need to apply a large number of

stimulation pulses in about 10 seconds,

620

: 00:35:28

and then you need to wait for recovery,

and then you need to apply a ten second

621

: 00:35:32

period with a large number of pulses.

622

: 00:35:34

Again, we can watch this happen

in the mouse preparation using the

623

: 00:35:38

fluorescent sensor, and we can see

the fluorescence go up and down and.

624

: 00:35:42

Timing with the stimulation

pulses that we're delivering.

625

: 00:35:44

And we can use that to fine tune

the stimulation in ways that we

626

: 00:35:47

don't, we can't really do when

we're only assessing cognition in

627

: 00:35:50

monkeys or just guessing otherwise.

628

: 00:35:53

'cause in, in movement disorders,

when they start stimulating a

629

: 00:35:56

patient, they have them hold their

hand up and they hand shaking.

630

: 00:35:58

And then the hands stop shaking

when they start stimulating

631

: 00:36:01

and they're in the right spot.

632

: 00:36:02

We don't have that kind of instant

feedback for executive function, and

633

: 00:36:06

so we're seeking to get something

that's more directly measurable.

634

: 00:36:08

So we have stuff going on in,

in the mouse lab to do that.

635

: 00:36:13

The monkey project, we're looking

at more proteomic approach of

636

: 00:36:17

measuring CE of spinal fluid centered

around deep brain stimulation Also.

637

: 00:36:21

Centered around doing

executive function behaviors.

638

: 00:36:24

We, the same approach can be used.

639

: 00:36:26

We can draw a cerebrospinal

fluid before, during, and after.

640

: 00:36:29

The monkey does an hour of working

memory behavior and see what changes the

641

: 00:36:32

brain normally encounters when you just.

642

: 00:36:34

Really hard for about an hour.

643

: 00:36:36

And we may add exercise to that as well.

644

: 00:36:39

And on the human side, I'm

pushing through to get the first

645

: 00:36:42

human trial paperwork in order.

646

: 00:36:45

So I'm talking to the FDA this

week and I'll be talking to

647

: 00:36:47

the IRB probably next week.

648

: 00:36:49

And then there's a process and hopefully

by the end of the year we'll have

649

: 00:36:52

our first subject implanted and we'll

be stimulating and trying to see to

650

: 00:36:56

what extent these effects translate.

651

: 00:37:00

Mike: Yeah.

652

: 00:37:00

Wow that's so exciting and I think it's

really important to emphasize that.

653

: 00:37:05

It so interesting how you're

describing, in studies these real time.

654

: 00:37:10

The investigation of the real time

changes, as you say in the fluorescence

655

: 00:37:15

kinds of studies in the mice.

656

: 00:37:17

And then in the, it's also really

interesting to think about how

657

: 00:37:21

you're actually measuring the

real time changes in things like

658

: 00:37:25

cognitive performance in the monkey

studies, during the stimulation.

659

: 00:37:29

And particular is

interesting in terms how.

660

: 00:37:33

Measurement of those realtime changes in

executive function, for example, might

661

: 00:37:37

reflect some sort of like an additive

effect that is partially dependent

662

: 00:37:41

on the nature of the cognitive task

that the animals actually undertaking.

663

: 00:37:46

While the stimulation is so that

there maybe, there's almost like a

664

: 00:37:49

synergistic effect that wouldn't.

665

: 00:37:54

Is creating a, I don't know, it's

more of a boosting or perhaps like

666

: 00:37:58

a potentiation kind of effect.

667

: 00:38:00

Is that what your team is finding?

668

: 00:38:03

David: We, I really wanna apply

stimulation in a human and ask them

669

: 00:38:06

because you can't ask the monkeys.

670

: 00:38:08

Mike: No.

671

: 00:38:10

David: It's all reasonably consistent

with them having a he heightened

672

: 00:38:13

level of alertness and arousal.

673

: 00:38:15

We all.

674

: 00:38:16

Go through daily lives and some hours

were sharper and more productive.

675

: 00:38:19

And sometimes you get to the late,

especially me at my age, get to

676

: 00:38:22

the late afternoon and it's wow, I

can't do that stuff I need to do.

677

: 00:38:26

I'll do some stuff that has less cognitive

demand for the next couple hours.

678

: 00:38:29

And so maybe we're just elevating all

of that and that ability to be alert

679

: 00:38:35

and aroused for longer periods of time.

680

: 00:38:37

I'll love to find out and

hopefully I will get to do

681

: 00:38:39

Mike: yeah, it makes me think it would

be interesting to, to potentially look

682

: 00:38:44

at an additional factor as far as, a

medication like Modafinil or something

683

: 00:38:49

that, you know, could potentially even in

enhance that even more, or even looking at

684

: 00:38:54

the implications of medications that are

known to block that kind of thing, like

685

: 00:38:58

an anticholinergic type agent and see how

the deep brain stimulation may or may not.

686

: 00:39:02

Counteract that.

687

: 00:39:04

And so the interface, again between

the pharma, the pharmacologic

688

: 00:39:08

factors could be an interesting

approach as well to look at.

689

: 00:39:11

David: Yeah.

690

: 00:39:12

And we've done some of those studies in

the monkey with the short term effects.

691

: 00:39:15

It's much easier to do that sort of

study where you're looking at effects

692

: 00:39:18

that happen within two minutes or so.

693

: 00:39:20

Because you can go through different

conditions faster when you're looking

694

: 00:39:22

at something that takes weeks to accrue.

695

: 00:39:24

Which is what the cognitive effects of

the deep brain stimulation are right now.

696

: 00:39:28

It becomes a lot more, you have to

choose your studies more carefully.

697

: 00:39:31

Create a priority list and you

don't get to do very many of them.

698

: 00:39:34

'cause once the monkeys get smarter,

it's not so sile to make them

699

: 00:39:39

go back to where they started.

700

: 00:39:42

Mike: Yeah.

701

: 00:39:42

I'm curious, I think that there's, like I

was saying just now there's been a lot of.

702

: 00:39:47

These brain computer interface

initiatives and that, and on the

703

: 00:39:51

one hand I can, just from, I'm,

obviously, I'm a clinician primarily.

704

: 00:39:56

And from that perspective, from the

perspective of an interested member of

705

: 00:39:59

the general public, it sounds interesting,

but I could also imagine that, from

706

: 00:40:03

the perspective of a researcher who's.

707

: 00:40:08

Perhaps there's a little bit of skepticism

with these high tech kinds of approaches.

708

: 00:40:14

So I'm just curious, what are

some of your thoughts around that

709

: 00:40:17

whole landscape in terms of this

BCI, the tech world descending and

710

: 00:40:22

innovating around this kind of thing?

711

: 00:40:25

David: So my previous career I designed

and built cortical implants and we

712

: 00:40:29

used them to study sensory cortex, but

other were doing the same work at the

713

: 00:40:33

same time looking at motor systems.

714

: 00:40:35

And those became the early

brain computer interfaces.

715

: 00:40:38

So I've been following the field.

716

: 00:40:40

I know a lot of the primary

investigators in that field.

717

: 00:40:44

I think that there will be brain computer

interfaces that really help people.

718

: 00:40:49

I think the first one and now

I am gonna mention a company

719

: 00:40:51

name is gonna be Synchron.

720

: 00:40:54

And what Synchron does is they have a

stent that has contacts on it and it gets

721

: 00:41:00

inserted in the sagittal sinus, which

for those who aren't familiar is a blood

722

: 00:41:03

vessel, goes right on top of the brain

and they can insert it endovascularly.

723

: 00:41:09

So it's an outpatient procedure and.

724

: 00:41:12

The wiring for it then runs down through

the jugular and crosses the wall of

725

: 00:41:17

the jugular, right, right around here.

726

: 00:41:18

And they have a device that

they can communicate with.

727

: 00:41:22

So they place it in an

outpatient procedure.

728

: 00:41:25

The next day, the subject can control

a cursor on a computer and can click.

729

: 00:41:32

In so doing, they can type

words in 10 or 12 seconds.

730

: 00:41:36

And they couldn't do that today.

731

: 00:41:37

This is, we're talking about somebody

like an a ALS-trapped patient.

732

: 00:41:40

And all of a sudden they can

tell their wife, I love you

733

: 00:41:44

for the first time in months.

734

: 00:41:46

And it's just brilliant and

inspiring to see the function of it.

735

: 00:41:50

It's not very high.

736

: 00:41:51

It doesn't convey as much information

as those Neuralink probes do, but

737

: 00:41:55

it does convey enough information

to allow the patient to type slowly.

738

: 00:41:59

And it's very safe and it's

gonna be very inexpensive at

739

: 00:42:02

least in the relative sense.

740

: 00:42:05

There are others that I'm really

positive about are the ones that

741

: 00:42:08

are gonna use the ECOG grids to

generate a brain computer interface.

742

: 00:42:13

Now, an ECOG grid is a plastic

flexible plastic sheet that gets

743

: 00:42:18

inserted on the surface of the brain.

744

: 00:42:20

And the benefit of using the ECOG grid

is that you get stable signals from

745

: 00:42:24

most of your contacts for long periods

of time, and you get a reasonable

746

: 00:42:28

reflection since it's grossly averaged.

747

: 00:42:31

You're not recording from single neurons,

but you're getting a average over

748

: 00:42:35

millimeters of cortical tissue each.

749

: 00:42:38

Of what the cortical activity is,

and people have shown that you can

750

: 00:42:41

actually get a pretty good brain

machine interface if you have an ECOG

751

: 00:42:44

grid that has enough contacts on it.

752

: 00:42:46

But even if you only have a few contacts

on it, you can probably get a highly

753

: 00:42:49

functional brain computer interface.

754

: 00:42:51

And again, it's gonna be low cost

and low burden on the patient, the

755

: 00:42:56

neural link approach, which because

of who's behind it and the budget and

756

: 00:43:00

so forth, has gotten a lot more press.

757

: 00:43:02

But I'm not convinced that the penetrating

electrode approach is going to be.

758

: 00:43:06

That useful and my, and I remain to

be convinced, I'm skeptical because

759

: 00:43:13

those were the probes that we developed

three decades ago and we could do

760

: 00:43:18

the same things Ling could do then.

761

: 00:43:21

The problem is consistency from subject

to subject and also consistency over time.

762

: 00:43:27

And the ECOG grids and syn

Ron don't have those problems.

763

: 00:43:29

They're consistent over time and

they're the same in every person.

764

: 00:43:33

And that those are beautiful things when

you're trying to make a commercial device.

765

: 00:43:35

I.

766

: 00:43:36

If you're losing most of your contacts

or most of your recording sites in the

767

: 00:43:40

first month, but you still have some,

but the yield from subject to subject

768

: 00:43:45

can vary by a factor by an order of

magnitude, which is what we always

769

: 00:43:48

found with the penetrating electrodes.

770

: 00:43:50

It becomes much harder to turn

that into a commercial reality.

771

: 00:43:54

I think that, just at the planning

stages, the ECOG grids and the Synchron

772

: 00:43:58

approach, the stint and the sagittal

sinus, those are really gonna help

773

: 00:44:01

people and I think they'll both be

FDA approved in just a few years.

774

: 00:44:05

Mike: Yeah.

775

: 00:44:05

No, that's very interesting.

776

: 00:44:06

I had definitely heard of Synchron, and

I think what you're saying makes total

777

: 00:44:09

sense, partly because, as you alluded

to a couple times earlier, is that I

778

: 00:44:14

think a rate limiting step is probably

gonna be access to the neurosurgeons

779

: 00:44:18

or the interventional neurologist.

780

: 00:44:21

I guess maybe that's gonna become

an increasing clinical area is the

781

: 00:44:24

limiting factor for accessibility

and commercial sort of scaling.

782

: 00:44:29

David: I don't I don't know if you've

been in the neurosurgical and neurological

783

: 00:44:32

training units much lately, but we are

sure training an awful lot, large number

784

: 00:44:37

of interventional neurologists these days.

785

: 00:44:39

It seems like a lot of the, our

neurosurgical residents want to

786

: 00:44:42

do that, but also a lot of our

neurology residents want to do it.

787

: 00:44:45

They say, unequivocally you can

help a stroke patient, for example,

788

: 00:44:49

in, in ways that are really

almost impossible to do otherwise.

789

: 00:44:52

It's really the biggest advance

in stroke treatment in decades.

790

: 00:44:55

And on top of that, there's new things

coming along, like the cron stent that

791

: 00:44:59

would be put in endovascularly as well.

792

: 00:45:02

And so I think there's every reason

to think there's a big future

793

: 00:45:04

for those folks in that practice.

794

: 00:45:06

I.

795

: 00:45:07

Mike: Yeah that's super, that's

really exciting for sure.

796

: 00:45:10

I guess maybe wrapping up, I'm curious

to know in, in terms of your career in

797

: 00:45:14

providing mentorship and training grad

students and postdoc fellows in your lab.

798

: 00:45:18

For any of those, such folks that are

watching, listening trainees, early career

799

: 00:45:23

neuroscientists, interested in this kind

of translational neuromodulation research,

800

: 00:45:28

is there any thoughts or advice you.

801

: 00:45:31

Terms, choosing terms like we talked

about at the very beginning, choosing

802

: 00:45:35

impactful research questions or

pursuing specific research ideas.

803

: 00:45:40

David: Yeah.

804

: 00:45:40

I always advise trainees to work

in areas that are growing and

805

: 00:45:45

not in areas that are shrinking.

806

: 00:45:46

That's just seems you could make that

same advice if somebody was working in

807

: 00:45:49

business or sales or just about anything.

808

: 00:45:52

You wanna work in something

that's gonna be more desirable

809

: 00:45:55

10 years from now than it is now.

810

: 00:45:57

And so most of neuromodulation

fit that fits that I would think

811

: 00:46:00

deep brain stimulation does, and

also vagal nerve stimulation and

812

: 00:46:03

also non-invasive stimulation.

813

: 00:46:06

They're all growing fast.

814

: 00:46:08

And so those are all good things.

815

: 00:46:10

There's really a critical shortage.

816

: 00:46:15

Of people with biomedical

engineering training that look at

817

: 00:46:19

the biological interface and the

effects on the biological interface.

818

: 00:46:23

And I say there's a critical shortage

'cause all five of us know each other.

819

: 00:46:27

There's more than five of us but

there's far fewer than you might think.

820

: 00:46:30

And we all know each other and.

821

: 00:46:32

That excludes most of the clinicians

who don't really have such a grasp

822

: 00:46:36

of what the stimulation pulses are

doing with respect to the biophysics.

823

: 00:46:40

How do you make a contact

on that will work?

824

: 00:46:44

What metals do you use?

825

: 00:46:45

How much current can you push?

826

: 00:46:47

What is the effect of the pulse?

827

: 00:46:48

How do, what happens when

you change the pulse width?

828

: 00:46:51

What is the volume of

tissue activated and.

829

: 00:46:53

And how do the fields that are caused by

transcranial magnetic stimulation, how

830

: 00:46:57

are they the same or different from those

you would do with deep brain stimulation?

831

: 00:47:01

And so I think, that those are areas

really to go into if you're go into

832

: 00:47:06

biomedical engineering and Duke has

good people, Case Western has good

833

: 00:47:10

people that, that train in those areas.

834

: 00:47:13

And I, if you went to one of those

two and you've worked on those

835

: 00:47:15

you would have a firm job and

neuromodulation to ad infinitum.

836

: 00:47:20

The, the more neurosciencey

oriented people.

837

: 00:47:23

I think you, I really like working at

least part in humans because that's

838

: 00:47:29

where the rubber hits the road, and

that's where you feel like you can

839

: 00:47:31

really make the world a better place.

840

: 00:47:33

And if you can do that and do some animal

work, which is what I've been trying

841

: 00:47:36

to do for the last decade, I, that's

where I wanna be because I can both be

842

: 00:47:41

aware the rubber hits the road and also

see what's going on under the hood.

843

: 00:47:46

Mike: Yeah, no, I think that's,

thanks for that offering, that wisdom.

844

: 00:47:49

I think that's really inspiring.

845

: 00:47:51

And in general, thanks again for a really

interesting conversation and I think just

846

: 00:47:54

with the sentiment that you just offered,

I think that's really it's fantastic

847

: 00:47:59

and just wanna congratulate you and

your team on your research to date and

848

: 00:48:03

your, I wish you all the best with your

future endeavors and Yeah, I think it's.

849

: 00:48:08

The more that we can all collaborate

in the interest of helping people and

850

: 00:48:13

reducing the burden of disease that

people are facing so much the better.

851

: 00:48:16

So thank you again and yeah,

just really appreciate your time

852

: 00:48:20

and your and your expertise.

853

: 00:48:22

And I think it's just gonna be really

valuable for folks to watch and listen to.

854

: 00:48:27

David: Thank you and thanks

for having this podcast.

855

: 00:48:28

This, these sorts of things are

part of the new media and getting

856

: 00:48:32

the word out there is something

we all wish we could do more of.

857

: 00:48:35

Thank you.

858

: 00:48:36

Mike: Fantastic.

859

: 00:48:37

Yeah, you're, yeah.

860

: 00:48:37

No, that's great.

861

: 00:48:38

I'm glad to be a part of it.

862

: 00:48:39

I, it is just growing, but hopefully

the more conversations like this

863

: 00:48:42

that I can have and put out there,

then the more interest it'll

864

: 00:48:45

generate and then we can Yeah.

865

: 00:48:46

As you say, start to spread the word.

866

: 00:48:48

Yeah, appreciate your time and yeah.

867

: 00:48:50

All the best.

868

: 00:48:51

Thanks again.

869

: 00:48:52

Okay.

870

: 00:48:52

David: Thank you.

871

: 00:48:54

Mike: Thanks for joining us today

on the Neurostimulation Podcast.

872

: 00:48:57

A huge thank you to Dr.

873

: 00:48:59

David Blake for sharing his

team's groundbreaking work at the

874

: 00:49:04

intersection of deep brain stimulation,

neuroplasticity, and cognitive function.

875

: 00:49:10

If you would like to

find out more about Dr.

876

: 00:49:12

Blake's work, please visit his

lab's website at Augusta University

877

: 00:49:17

using the links in the show notes.

878

: 00:49:19

You'll find everything that you

need to dive deeper into this topic.

879

: 00:49:23

And please join the conversation,

I would love to hear your thoughts.

880

: 00:49:27

Please leave questions or comments

in the comment section below.

881

: 00:49:31

Your questions, ideas and

feedback make this podcast better.

882

: 00:49:36

And as always, I would encourage

you to like and subscribe to this

883

: 00:49:40

podcast, share it with someone

that you think might be interested.

884

: 00:49:44

I really appreciate your attention,

your time, and your interest.

885

: 00:49:48

Until next time, be well.

886

: 00:49:51

Stay curious and I'll see you again

on the Neurostimulation podcast.