Signal Over Noise: How Transcutaneous VNS Optimizes Cognition with Dr. Ronan Denyer

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Welcome back to the Neurostimulation Podcast.

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I'm Dr.

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Michael Passmore, clinical associate

professor in the Department of Psychiatry

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at the University of British Columbia.

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Today's episode is going to be a

fascinating deep dive into one of the

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most exciting and rapidly evolving

areas in neuromodulation, transcutaneous

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vagus nerve stimulation, or tvNS.

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My guest today is Dr.

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Ronan Denyer, who recently completed

his PhD in neuroscience at the

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University of British Columbia

under the supervision of Dr.

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Lara Boyd.

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His work integrates brain stimulation,

neuroimaging, and behavioral neuroscience

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to understand how the brain prepares

and executes movement, particularly

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through the dorsal premotor cortex.

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He's now a postdoctoral fellow in

the Coactions Lab working with Dr.

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Julie Duque, where his research is

expanding into the intersection of

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TMS, vagus nerve stimulation, and

the locus coeruleus noradrenaline

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system, a key neuromodulatory system

involved in things like attention,

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arousal, and decision-making.

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And so one of the papers that we're

gonna be discussing today explores how

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non-invasive vagus nerve stimulation

can actually improve perceptual

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decision-making accuracy, shedding light

on a long-standing debate about how the

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locus coeruleus shapes human cognition.

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Ronan, welcome to the podcast.

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Speaker: Yeah.

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Thanks so much for having me.

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Looking forward to the conversation.

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Speaker 2: So maybe if you can just,

provide a bit of an explanation about

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your academic background and some of the

things that your lab is currently working

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on, just so that we can get to know you.

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Speaker: Yeah, sure.

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so I'm from Ireland.

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and so I grew up in the northwest of

Ireland, and I actually, pursued my

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undergrad in Trinity College, Dublin.

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and so during my time there,

I, in my final year, I did--

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had to do a final year project.

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and so I ended up working with a

professor there, Richard Carson,

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and he works, with, a lot with

transcranial magnetic stimulation,

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and within the motor control space.

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and so that's where I started my

journey with brain stimulation.

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and I enjoyed the process.

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and then through Richard, I ended up,

being introduced to Lara in, UBC, and, I

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decided I wanted to pursue a PhD and, it

just ended up working out that I ended

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up in Vancouver, so a nice coincidence.

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and so yeah, when I...

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In Vancouver, I worked a lot with TMS.

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my thesis work was m-more focused on

kind of young, healthy populations,

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on more basic neuroscience questions,

motor control questions, bimanual

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coordination and stuff like that.

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and then I also working in Lara's

lab, worked quite a bit with clinical

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populations, particularly people

who've had a stroke, so trying to apply

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the methods in that population too.

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And then, yeah, after I finished

my PhD, I decided I wanted to move

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a bit back a bit closer to home.

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so I I was looking through

potential locations and ended up

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in Brussels with, Julie Duque.

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and yeah, just when I arrived, a former

post-doc who has just moved on to

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another position, Sue Xiang, she had

just finished a project looking at, using

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TVNS, within a decision-making paradigm.

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And I wasn't exactly sure what I was gonna

do when I joined the lab because I had

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just finished and, hadn't fully figured

out what experiments I wanted to do.

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but I was yeah, very intrigued by

her results using TVNS and, then

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I thought about pursuing that.

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so yeah, that's h- how I

ended up working in TVNS.

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It wasn't like this sort of grand plan.

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It was oh, they're doing it here, and

it seems like an interesting area.

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So yeah, that's how I ended

up working with the method.

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Speaker 2: Yeah, cool.

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Thanks for explaining that.

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It's, it is really interesting how an

academic journey can go in that way.

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You, you make connections, you

network, and then you f- you

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get drawn in certain directions.

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And so I'm excited to discuss,

your current projects.

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But one of the papers in particular,

just for viewers and listeners as a

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kind of a preview, is that I think

I'd like to explore today is this

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idea about how non-invasive vagus

nerve stimulation can actually

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improve perceptual decision-making

accuracy, which is so interesting.

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And I think it helps to shed light on

what I understand is a long-standing

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debate about how specific areas of

the brain, like the locus coeruleus,

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can shape human cognition in general.

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Yeah.

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So maybe, wh- why don't we

just follow up with that?

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So for viewers and listeners who are

not as familiar, and I don't admit

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to being particularly familiar with

these specifics either, so why is the

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locus coeruleus specifically such a

big deal for that, what we're talking

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about in neuroscience in general?

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Speaker: Yeah.

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So it's a really interesting part

of the brain, I think the reason why

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people are interested in is because

it has this reputation as, very

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small nucleus but very big influence.

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so it's really, just in the brainstem,

posterior part of the brainstem.

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And it's very small, and it

has this blue color, which is

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actually what it means in Latin.

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Locus coeruleus means blue place.

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and so if you were to do dissection,

it's blue because- actually there's a

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lot of neuromelan- melanin in that area.

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and the reason there's neuromelanin

is because the cells there are

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noradrenergic, so it's a byproduct of

the process of creating, noradrenaline,

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just to have this blue color.

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and so that's really what

the, those neurons do.

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They, reach far and wide into the

central nervous system, from the

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spine into subcortical regions

and then also to the cortex.

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and so they have the capacity

to modulate activity in the,

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almost every part of the brain.

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and so that's how it has this

potential for a big influence.

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And then on the other side, it

receives, so many inputs, from

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lots of different regions too.

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So it's just like this

very dynamic region.

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and so yeah, it's interesting

because it's, I would say the,

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has this big influence, but the

function isn't really s- the specific

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function isn't that well understood.

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and so that's opened up a

lot of different questions.

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And then I think there's also this,

other kind of clinical angle that

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people are interested in it because,

when we're thinking about brain

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stimulation in, in clinical populations,

often, researchers are looking for

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regions that we can stimulate to

maybe induce some sort of increase

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in activity or to induce plasticity.

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So I think that's, another reason why

people are interested in the region.

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Yeah.

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Speaker 2: Yeah.

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Yeah, for sure.

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Thanks for explaining that.

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and yeah, it does remind me a little

bit of some forces in that the locus

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really is, as you say, primary source of

noradrenaline or norepi- norepinephrine.

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I can never remember.

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Is noradrenaline the European

phrase and norepinephrine-

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Yeah ... the North American phrase?

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Speaker: Yeah, I think

that's the way it is.

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Yeah.

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it's the same thing, but yeah.

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Speaker 2: Great.

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So it's interesting because yeah, as

you say, it's such a kind of a way

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station in that sense, an important

way station and a, in terms of the

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global modulation of brain function,

but particularly for aspects, of, I

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suppose mind and consciousness that

relate specifically to the noradrenergic

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system, attention, motivation, mood,

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Speaker: Yeah.

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Speaker 2: yeah.

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So walk us through a

little bit about tvNS then.

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So transcranial vagus nerve stimulation.

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Yeah.

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Yeah.

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What exactly is it and how

does stimulating the ear

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actually influence the brain?

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'Cause it, in- intuitively

may not exactly make sense.

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So how, yeah, help us to

understand how that works.

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Speaker: Yeah.

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So I think, I'm not sure what the

order was, but there's also an invasive

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version of vagus nerve stimulation

where, you actually do a surgery and

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implant a simulator onto the vagus nerve.

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similar to a, I'm trying to

remember what you call the

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thing you implant for a heart.

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pacemaker.

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Yeah, similar kind of surgery.

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and so the idea is that you

stimulate the vagus nerve.

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the vagus nerve actually, has connections

into an area called the nucleus tractus

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solitarius in the brainstem, and that

itself connects to the locus coeruleus.

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it's a way to increase activity

in the locus coeruleus.

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But of course, it's a

very invasive procedure.

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It's more so like a kind of

experimental clinical procedure for now.

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we can't just have people come into

the lab and do that type of experiment.

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So there's been this, idea of

is there other ways that we

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could stimulate the vagus nerve?

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and so the vagus nerve actually has,

connections with the ear, so afferents

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from the ear into the vagus nerve.

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and so in particular, the kind of central

part of your ear here, called the scala

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tympani, and around the tragus part

of your ear, has these nerve endings

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which connect with the, with the vagus

nerve or a branch of the vagus nerve.

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And so the idea is that if we stimulate

those, can we stimulate up into the

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nucleus tractus solitarius and then also

the lo- locus coeruleus and provide a

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way to modulate activity and increase

release of noradrenaline, in the brain?

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and so that's that's where it all started.

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and yeah.

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I could keep going, but that's where

we started with tvNS and why they're--

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why we were looking at the ear.

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Speaker 2: Yeah.

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Thanks so much for explaining that.

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I think that's extremely helpful to

differentiate from implanted VNS as well.

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It makes me wonder, there's this newly

approved device, called the ProLiv RX.

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I'll have to just refresh my

memory about that, but it strikes

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me that perhaps that's a s-

similar-- This is for depression.

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and I'm just-... think that there's

probably a similar kind of approach

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as far as, the non-invasive, cranial

nerve stimulation,... to improve mood.

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But, yeah, maybe I'll clarify

that, and maybe we can-- I

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can try and link to that, Yeah

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if there's relevance at some point.

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But then just getting back

to your lab's research.

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maybe, yeah, what would be a way...

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I guess obviously there's a

difference between the specifics

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that your lab's been looking at and

more broader clinical applications.

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Although obviously, as you're

describing, that's part of what the

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research is geared towards, furthering,

is the knowledge translation there.

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But what- how would you say that

the transcutaneous VNS, Could be

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considered in comparison to other

technologies like transcranial magnetic

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stimulation or transcranial direct

current stimulation, those kinds of

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techniques that are being more routinely

applied in the clinical setting.

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Speaker: Yeah.

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So on the face of it, it's, the kind of

physics of it are quite similar to tDCS,

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I would say, where you have, an electrode

on the skin and another one near to it

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on another part of the ear, and you're

just passing current through, which is

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increasing activity in the vagus nerve and

then, then up into the locus coeruleus.

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I suppose with, with tDCS, it's more like

you're just directly hitting the cortex.

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You're not doing this kind of, other

pathway into a subcortical region.

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and then TMS or repetitive TMS protocols,

yeah, are more similar, but it's

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a magnetic pulse and it's pulsing.

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It's not like a continuous--

you're creating an electrical

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field using a magnetic field.

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but, yeah, I think it's probably more

similar to tDCS but it's its own thing

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too, I think one thing I really l- that

is appealing to me about the method is,

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is just being able to measure response,

because the locus coeruleus has this very,

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clear, actual connection with our pupils.

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and so if you change activity in

the locus coeruleus, there's these

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kind of like maybe three or four

synapses away, connectivity with

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the muscles which, increase and

decrease the size of our pupils.

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so I think one real benefit for tvNS is

that if you turn it on, you can really

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track, the effect it's having in a

specific subject because you can just use

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a pupil, pupillometry setup to measure

changes in the eye or in the pupil rather.

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so that's something that really appealed

to me having used repetitive TMS in

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my PhD, in a more, trying to do like a

virtual lesion and see how it affected

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behavior on this particular task.

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It's often difficult or expensive

to really understand what the

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stimulation is doing to the brain.

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and so you sometimes have to take a

bit of a leap of faith, whereas I like

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the tvNS because you have this clear,

you know-- You're measuring once every

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millisecond, getting this kind of

clear picture of what's happening, at

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least just from looking at the pupils.

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so I think, yeah, that's maybe a

sort of an edge that tvNS has maybe-

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Speaker 2: yeah, that's super interesting.

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Those little details, it's fascinating to

understand the specifics of that, and I

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can completely understand your perspective

on, yeah, the advantages there, for sure.

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So the paper, one of the papers that I

was interested in, talking about with

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you is the publication in the journal

Brain Stimulation- called Transcutaneous

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Vagus Nerve Stimulation Boosts Accuracy

During Perceptual Decision Making.

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and yeah, maybe if you're able to

help us to understand, the idea behind

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the particular study and the results

and why that's an important paper.

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Speaker: Yeah.

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So I'll do my best.

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I- it was, just after I got here, but

I'm fairly familiar with the work.

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and so basically the idea is, to look

at the effect, the effects of TVNS on

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what we call perceptual decision-making.

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And so what we mean by perceptual

decision-making is, really what

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we call a random dot motion task.

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And so just for the listeners, the

viewers, basically the participant's

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sitting down and they see, this kind

of cloud of dots basically i- in the

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center of the screen, and they're,

able to respond left or right.

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and so they just see the dots moving in

these random directions at first, and then

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at some point they, get a cue to-- and are

told that, the dots are gonna start moving

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in one way or the other, and they have

to do their best to estimate if they're

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moving left or they're moving right.

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and it's basically calibrated for

it to be quite difficult, where a

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certain proportion are moving right,

certain are moving left, and you have

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to do your best to assess basically,

which direction they're moving in.

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and it's a very, a nice task because

it's been used a lot in neuroscience.

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so there's all these kind of, ways in

which people model the data, establish

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methods for modeling the data.

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but I would say basically what Sue

found in her study is that, when-- So

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what she did is basically did the task

like that, but she had two conditions.

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So in one condition, just before they had

to start deciding or make a decision, the

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TVNS was turned on for four seconds, so

a burst of four seconds on each trial.

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and then there's a kind of

control condition, so just a

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sham stimulation condition.

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And We need to have a sham control

because just having this sensation

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on your ear, can maybe in of itself

change your behavior without maybe

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having these direct effects on locus

coeruleus that we think it might have.

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So we compare the results

against a condition where we

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stimulate just on the earlobe.

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And so that part of your ear is

not innervated by the vagus nerve.

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So it's a nice control because it's

similar sensation, but it doesn't

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have this vagal aspect to it.

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And so when she looked at the

data, what she found was people

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were significantly more accurate.

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Now, not by a huge amount, but were more

accurate with the TVNS versus the sham.

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And sometimes when you see a change

in accuracy in a task like this, it

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can be strategic where instead of,

they're more accurate, but they're

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also slowing down their responses.

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So they're allowing more time

for the evidence to accumulate.

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But she didn't find any

difference in the reaction time.

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So it's like they just got this free boost

in accuracy of their perceptual decision.

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And yeah, I guess there's evidence

that the TVNS is boosting the

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decision process in some way.

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And then she went a bit more deep in

into the data and found that it was,

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yeah, the effect was even stronger

when considering basically how

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people reacted after an error.

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So you have some people who after they

make an error, they become, they're

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negatively affected by it and it decreases

their performance on the next trial.

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Then you also have some people who

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if they get something correct,

then they relax and then that

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actually they see a decrease in

their performance on the next trial.

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And so what she found is like by grouping

people into those groups, the TVNS

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particularly had a strong effect when in

these challenge modes where you typically

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see a drop off in sham, it had this

kind of rescue effect, you could say.

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And yeah, I think you have this

kind of global effect on accuracy,

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but it might be driven more by

these specific circumstances where

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there needs to be this input or

there can be this boosting effect.

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So that's, yeah, very interesting.

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It speaks to the more global view on what

this neuroadrenaline is actually doing.

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There's this idea that it the function

is really to, it boosts ongoing activity.

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And so reduces the signal to

noise ratio or increases rather.

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And so that's how you get

this free accuracy, so yeah,

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that was the crux of it.

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and yeah, so from there we've gone

a few different directions, but

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: 00:17:42

that was the foundational work,

when we're really getting into tvNS.

303

: 00:17:47

Speaker 2: Yeah.

304

: 00:17:47

That's fantastic.

305

: 00:17:48

Yeah.

306

: 00:17:48

Thanks for explaining that,

and it'll be great to talk more

307

: 00:17:51

about the other directions that

your lab has gone in since then.

308

: 00:17:54

Yeah.

309

: 00:17:55

But it's so interesting because I think,

yeah, it was a great explanation of

310

: 00:17:58

this historical controversy to a certain

degree between the gain hypothesis or

311

: 00:18:05

the improvement in the signal-to-noise,

which is leading to better accuracy.

312

: 00:18:09

That the-... the locus coeruleus

in the noradrenergic system is, is

313

: 00:18:13

implicated in, versus this kind of more

of an urgency hypothesis where- Yeah

314

: 00:18:17

decision-making is accelerated,

but potentially less accurate.

315

: 00:18:21

And yeah, as I was understanding,

so the, this finding about...

316

: 00:18:25

the findings highlighted that there

was, as you say, that improved

317

: 00:18:29

accuracy but not really a change

in reaction time- Yeah ... which I

318

: 00:18:32

suppose supports the gain hypothesis.

319

: 00:18:35

Speaker: Yeah.

320

: 00:18:36

Yeah, I think so.

321

: 00:18:37

yeah, you're not seeing a slowing or

a quickening, it's just, in fact that

322

: 00:18:41

there's use this model called the

drift-diffusion model to model this

323

: 00:18:44

data and yeah, it assumes that there's

some sort of decision process going on.

324

: 00:18:50

and so there's, the evidence is

accumulating at a certain rate,

325

: 00:18:55

and then eventually you hit

these bounds, in the, which are

326

: 00:18:58

represented in the brain somewhere,

and that's what drives the decision.

327

: 00:19:01

And so Sue did some modeling

using that me- method and found

328

: 00:19:05

that the drift rate increased.

329

: 00:19:06

So the speed at which evidence

is accumulating is increasing

330

: 00:19:09

and, Yeah ... and so that leads

to more accurate decisions.

331

: 00:19:13

Yeah.

332

: 00:19:14

Speaker 2: Yeah.

333

: 00:19:14

And it was really interesting the finding

that the effect was strongest after

334

: 00:19:18

errors, and it makes me wonder if maybe

the tvNS is helping people to recover

335

: 00:19:23

from attentional lapses or that kind

of thing, some subtle things- Yeah.

336

: 00:19:28

Yeah ... that could be speculated.

337

: 00:19:30

Speaker: Yeah, I think so.

338

: 00:19:30

I think, the way I...

339

: 00:19:32

I'm constantly rethinking, how I think

about the region, but I think certainly

340

: 00:19:36

it seemed like there's this kind of

resetting process or something, where,

341

: 00:19:41

yeah, you maybe get lost in thinking

about the error that you just created, in

342

: 00:19:47

under sham, and then a sham doesn't help

that, whereas the tvNS maybe locks you

343

: 00:19:50

back in to the task, and to the relevant

aspects of the task instead of this kind

344

: 00:19:55

of, process of thinking about the error.

345

: 00:19:57

Yeah.

346

: 00:19:58

Speaker 2: Yeah.

347

: 00:19:59

Maybe a metaphor, I don't know

if this is- Obviously it's too

348

: 00:20:02

simplistic, but maybe something

that can help viewers and listeners

349

: 00:20:06

and me wrap my head around this is-

350

: 00:20:08

Speaker: Yeah

351

: 00:20:08

... Speaker 2: maybe the locus coeruleus

is, can be conceived of in the sense

352

: 00:20:12

that we're investigating or talking

about that you investigated, that the

353

: 00:20:16

locus coeruleus is less like a gas

pedal and more like a signal optimizer.

354

: 00:20:21

Speaker: Yeah.

355

: 00:20:22

Yeah, I think so.

356

: 00:20:23

Yeah.

357

: 00:20:23

Like it's really boosting what's

already going on in the brain.

358

: 00:20:27

it's not really changing the dynamics.

359

: 00:20:29

It's more just, coming in.

360

: 00:20:31

If there's activity going on,

that's gonna be increased.

361

: 00:20:33

If there's activity-- if there's,

less activity between these

362

: 00:20:36

synapses, that's decreased.

363

: 00:20:38

And so you just kinda get

this sharper, more HD signal.

364

: 00:20:42

and so that has benefits.

365

: 00:20:44

and then I think that there's also this

energy management aspect to it 'cause

366

: 00:20:49

I think the, a natural reply is, why

aren't we just like that all the time?

367

: 00:20:52

Wouldn't it be better to

just be HD all the time?"

368

: 00:20:55

But, we don't actually need to be,

so that's why we have this pulsing.

369

: 00:21:00

It's more so in circumstances

that we might need this input

370

: 00:21:03

to to push our speed-accuracy

trade-off, not to navigate it.

371

: 00:21:06

and so yeah, that sort of makes sense

in an energy optimization viewpoint,

372

: 00:21:12

which, the brain is very much energi-

is optimized to not use too much energy

373

: 00:21:16

when it doesn't need to and all that.

374

: 00:21:18

yeah.

375

: 00:21:19

Yeah, interesting-... kind of question.

376

: 00:21:21

Speaker 2: Yeah, definitely.

377

: 00:21:22

yeah, so you alluded to just now

some other branches, some other

378

: 00:21:26

pathways that your lab has chosen to

follow based on the findings there.

379

: 00:21:29

So yeah, maybe talk a bit about some

of the projects that you have going

380

: 00:21:33

on now that you're excited about.

381

: 00:21:35

Speaker: Yeah.

382

: 00:21:35

I just finished and published,

a project, using tVNS.

383

: 00:21:40

actually it was when I just first got

here, and I wanted to get going on

384

: 00:21:43

something that like quickly that I could

have going while I, while I also started

385

: 00:21:47

to develop something else, And yeah,

because I had this experience using TMS, I

386

: 00:21:52

decided to combine the two and, it's very

basic question, but actually there, just

387

: 00:21:58

wasn't a lot of information out there.

388

: 00:22:00

so what I was interested in is

what the, what's the effect of

389

: 00:22:03

these four second bursts of tVNS

on our corticospinal excitability?

390

: 00:22:09

So I guess for some background, like the,

as I said earlier, locus coeruleus has

391

: 00:22:14

all these kind of vast broad connections.

392

: 00:22:17

and so through kind of these anatomical

tracer studies, it's known that

393

: 00:22:21

there is this, these c- connections

with the motor cortex or direct

394

: 00:22:25

connections in the motor cortex.

395

: 00:22:27

so I was interested in if we

stimulate TVNS, is there this, a

396

: 00:22:31

change in the balance of excito-

excitability in the motor cortex?

397

: 00:22:35

and so when we use single pulse

TMS, we can just do pulses over

398

: 00:22:40

the motor cortex and it creates

like a twitch in the muscle, which

399

: 00:22:43

we call a motor evoked potential.

400

: 00:22:45

And so that is just a measure of what's

the state of the corticospinal tract

401

: 00:22:49

or the excitability within the tract.

402

: 00:22:52

so basically what I did was, sat people

down, just did trains on the ear, sham

403

: 00:22:58

and TVNS, and at these kind of set time

points within the train, I just did a

404

: 00:23:03

ME- or elicited MEPs using T- using TMS.

405

: 00:23:07

and then, measured the size of the

tw- twitch and averaged all the data.

406

: 00:23:12

and so what we found was...

407

: 00:23:14

So we measured just before as a

baseline, and then very shortly

408

: 00:23:18

after the train on the stimulation

onset, and then at one second, two

409

: 00:23:22

second, three second and four seconds.

410

: 00:23:25

And then also, at five seconds, so one

second after the TV- the stimulation

411

: 00:23:29

had finished, and at six seconds.

412

: 00:23:32

this was all like across different trials.

413

: 00:23:35

And so what we found was

there was an increase.

414

: 00:23:38

the TVNS did create an increase in the

corticospinal excitability, but it was

415

: 00:23:43

really specific to the, the time points

at which the TVNS was actually turned on.

416

: 00:23:48

So not so much after it turned, was turned

off at those five and six time points,

417

: 00:23:53

but more so in the train, particularly

in the kind of last section of the train.

418

: 00:23:58

so if we turn on TVNS and then we measure

at three, we make MEPs at three and

419

: 00:24:03

four, those are typically bigger than

the ones at the start of the train.

420

: 00:24:07

and so yeah, it's just showing that

there does seem to be, when we, elicit

421

: 00:24:12

a change in activity in locus coeruleus,

there does seem to be this, increase in

422

: 00:24:17

excitability in the motor cortex as well.

423

: 00:24:20

so yeah, that was we wanted to

really do that as maybe a foundation

424

: 00:24:23

into seeing how this changes in

behavior and stuff like that.

425

: 00:24:26

But, the TV- TMS experiments are quite

time costly,... because you have to

426

: 00:24:31

do a lot of different trials, because

it, the MEPs can be quite noisy.

427

: 00:24:36

And then with TVNS itself,

we also measured pupil size.

428

: 00:24:40

And between each of the stimulations,

we wanted to allow enough time for the

429

: 00:24:45

pupil size to come back to baseline.

430

: 00:24:48

yeah, it ended up being

quite a long experiment.

431

: 00:24:50

but I think, yeah, it's an Interesting

outcome and opens new avenues,

432

: 00:24:54

I think, and is also, I think,

interesting from a cl- clinical

433

: 00:24:57

perspective as well, particularly

for, stroke and stuff like that,

434

: 00:25:00

Speaker 2: Mm-hmm.

435

: 00:25:01

Yeah.

436

: 00:25:01

I was gonna ask a bit about

possible clinical translation.

437

: 00:25:03

One thing I'm just curious about is the

relevance of the pupil size, 'cause i-

438

: 00:25:07

it's come up a couple of times here, and

I just was thinking for my own curiosity-

439

: 00:25:12

... but also for viewers and listeners

who might be curious about what's the

440

: 00:25:16

relevance of measuring the pupil size.

441

: 00:25:18

Speaker: Yeah.

442

: 00:25:20

Yeah.

443

: 00:25:20

So I suppose, given that it's known that

locus coeruleus, has this, relationship

444

: 00:25:26

with pupil size, where pupil size is

really driven by changes in activity

445

: 00:25:30

in the region, and this is known,

quite well-established from animal

446

: 00:25:33

studies but also in human studies,

like in fMRI studies, for example.

447

: 00:25:38

If you do TVNS, you see an increase in

pupil, you typically also see an increase

448

: 00:25:43

in the brain region, through fMRI.

449

: 00:25:47

and so it's an established way of tracking

the effect or tracking if there's a

450

: 00:25:51

change in the state of locus coeruleus.

451

: 00:25:54

And so the reason we ha- we included

it in the study is because it

452

: 00:26:00

gives us a more of a gold standard

of whether there is an effect.

453

: 00:26:04

and so we did also see this clear

effect in the pupil size too.

454

: 00:26:07

so that gives us a, a good feeling that

we're not just seeing things, that there

455

: 00:26:11

is this clear effect on s- something

that we would expect there to be an

456

: 00:26:14

effect, and then we also have this effect

on the motor evoked potentials too.

457

: 00:26:19

so that's, yeah.

458

: 00:26:20

The, and the thing is it's, experimentally

it's very easy to implement.

459

: 00:26:24

You just have to quickly calibrate it,

and it's, then it's just continuously

460

: 00:26:29

recording, and you just get the data.

461

: 00:26:30

It's quite easy to work

with, that's why we like

462

: 00:26:33

Speaker 2: it.

463

: 00:26:33

Yeah, that's interesting.

464

: 00:26:34

It's like a real time live biomarker just

as a confirmation of a proxy in a sense

465

: 00:26:39

of just all the changes lining up and

coming together, and it, yeah, that's-

466

: 00:26:44

Yeah ... that's really interesting.

467

: 00:26:45

Speaker: Yeah.

468

: 00:26:46

Yeah.

469

: 00:26:46

It was interesting.

470

: 00:26:47

I think that there, there's actually

some interesting stuff that came from it.

471

: 00:26:50

it's good to see the effect, the

clear effect, and it was actually

472

: 00:26:53

very similar, shape to what we'd seen

in a n- in our previous experiment.

473

: 00:26:58

one thing that was interesting is, even

though at the group level there is these,

474

: 00:27:02

both these changes in the MEPs and in the

pupils, they weren't actually correlated.

475

: 00:27:07

and the timing was quite different too.

476

: 00:27:09

So with the pupil, you see a

peak after about one and a half

477

: 00:27:13

seconds, and then it dela- decays.

478

: 00:27:15

Whereas, as I said, with the MEPs,

it's more like a ramp, a slower ramp

479

: 00:27:19

through the, the onset of the TVNS.

480

: 00:27:22

so- Yeah, that's interesting as to

why, both t- as I said, MFPs are quite

481

: 00:27:28

noisy so that could be contributing.

482

: 00:27:30

but there's also this idea that

the locus coeruleus might have

483

: 00:27:34

these different sort of, nodes.

484

: 00:27:36

So it's not like this, it's

not like one area that, that

485

: 00:27:41

kind of reacts to everything.

486

: 00:27:43

There might be little nodes and

maybe one node is more affected,

487

: 00:27:46

is having a bigger effect on the

pupil and another node is having a

488

: 00:27:49

bigger effect on the motor cortex.

489

: 00:27:51

So that might be why we

see a lack of correlation.

490

: 00:27:54

But, yeah, there's a lot more questions,

but, yeah, we'll need to do more

491

: 00:27:57

studies to, to fully figure it out.

492

: 00:28:00

Speaker 2: Yeah.

493

: 00:28:00

Maybe how, like how the thalamus as a sort

of like an, uh, way station is all divided

494

: 00:28:06

into various different components- itself.

495

: 00:28:08

Yeah.

496

: 00:28:08

Speaker: Yeah, exactly.

497

: 00:28:09

Yeah.

498

: 00:28:10

Speaker 2: in terms of that potential for

clinical translation, I was interested

499

: 00:28:14

in your team's paper suggesting how,

not suggesting, but just explicating

500

: 00:28:19

how locus coeruleus dysfunction is

implicated in disorders like ADHD,

501

: 00:28:24

depression, neurodegenerative disorders.

502

: 00:28:27

So I'm curious, particularly in

your work pairing tvNS with TMS,

503

: 00:28:33

what would be some of your thoughts

about where you might foresee that

504

: 00:28:36

tvNS could be applied clinically?

505

: 00:28:40

Speaker: Yeah.

506

: 00:28:40

I think there's a lot of

different, possibilities.

507

: 00:28:44

I guess I'm coming more from a

motor neuroscience perspective.

508

: 00:28:47

I think, and then having worked a bit

in stroke, I think a lot of the time in

509

: 00:28:52

neurorehabilitation and stroke, people

are looking for ways to potentially

510

: 00:28:58

change the excitation balance in the

brain, through brain stimulation,

511

: 00:29:02

as a means to promote, plasticity.

512

: 00:29:05

'cause obviously after you, you

have a stroke, usually affects

513

: 00:29:07

motor cortex, to some degree.

514

: 00:29:10

and so I think there's this kind of idea

if we can find ways to target changes

515

: 00:29:15

in excitation in that region through

simulation, then maybe we could pair

516

: 00:29:20

that with a, therapy like bimanual,

unimanual therapy or something like that.

517

: 00:29:26

And then that would promote these

kind of plastic effects that

518

: 00:29:28

would help the brain to recover.

519

: 00:29:31

so yeah, I think having seen, this

effect that we saw, that there does

520

: 00:29:34

seem to be this effect on motor

cortex, I think it's, yeah, it's grand

521

: 00:29:39

to maybe continue to pursue that.

522

: 00:29:42

And I think, as well, the kind

of fact that we saw the effects,

523

: 00:29:44

what we call online, so when we're

actually applying the stimulation,

524

: 00:29:48

not after is important too.

525

: 00:29:50

Because it suggests that it should be,

these bursts that you pair with some

526

: 00:29:54

sort of behavior, rather than sometimes

what you can see happen in, in rehab

527

: 00:29:59

is like, "Oh, we'll sit the person down

and we'll do a priming brain stem for

528

: 00:30:04

20 minutes, and then we'll do therapy."

529

: 00:30:07

but I guess this speaks to more maybe

doing the two together, while- whilst

530

: 00:30:12

you're, stimulating on the ear to

also be doing some sort of motor task.

531

: 00:30:16

And, like that's maybe a strength

of the method is that it's actually

532

: 00:30:20

amenable to that because it's quite...

533

: 00:30:23

You can be mobile.

534

: 00:30:24

you don't have to be...

535

: 00:30:25

with TMS, you're stuck

under the coil a bit.

536

: 00:30:28

and so yeah, I'm at-- I think

it's a, an interesting area.

537

: 00:30:32

there's also the invasive vagus nerve

that we talked about, and that's a focus

538

: 00:30:35

as well in that region or in that zone.

539

: 00:30:39

and I think there starts, start-- there's

starting to be a consensus that the

540

: 00:30:42

two should be paired together, within

that literature as well, I think so.

541

: 00:30:47

so yeah.

542

: 00:30:47

And then, that's just stroke.

543

: 00:30:49

I think there, there's

also Parkinson's disease.

544

: 00:30:52

so we know that Parkinson's

disease is really, driven by, the

545

: 00:30:56

motor-- at least the motor symptoms

are driven by the, death or the

546

: 00:31:00

degradation of the dopaminergic

neurons, in the basal ganglia.

547

: 00:31:04

But, a- actually before that happens,

there's also a degradation in the

548

: 00:31:09

noradrenergic, in the locus coeruleus.

549

: 00:31:12

And so there's maybe possibility

for exploring the use of

550

: 00:31:15

tVNS in that disease as well.

551

: 00:31:19

Speaker 2: Yeah.

552

: 00:31:19

it's really interesting.

553

: 00:31:20

I think obviously the advantages in

terms of the possible, applications with

554

: 00:31:27

something that's non-invasive that perhaps

the device would be portable, something

555

: 00:31:31

that people could use, as you say,

while they're engaged in other kinds of

556

: 00:31:35

rehabilitative activities or even outside

of a, enclosed clinical setting, something

557

: 00:31:41

that might be possibly home-based with

remote supervision like tDCS has become.

558

: 00:31:46

So- Yeah ... that by itself, the

technology lends itself to exploration

559

: 00:31:51

or along those lines, I can imagine.

560

: 00:31:53

Speaker: Yeah.

561

: 00:31:54

Yeah.

562

: 00:31:54

And it's-- I've-- we have, a custom

setup, but I think that there's

563

: 00:31:58

ways to make it cheaper and, yeah.

564

: 00:32:01

So I'm interested to see what

happens in, in that area.

565

: 00:32:03

maybe I'd li- I'd like to work with

it in s- in the stroke populations

566

: 00:32:07

as well, maybe someday, 'cause yeah,

I think it does have some potential.

567

: 00:32:12

Speaker 2: I can remember, an episode

from a few months ago with Dr.

568

: 00:32:17

Bernard Hommel, and Dr.

569

: 00:32:19

Col Sado, they were talking a bit about,

in China where they're researching

570

: 00:32:24

now currently, that they have these

sort of, uh, helmets, for lack of a

571

: 00:32:29

better term, that s- sometimes some

young kids are wearing and they're

572

: 00:32:33

having them, you know- Really?

573

: 00:32:34

you see them around in the schoolyard

and it's, intended to help with

574

: 00:32:38

ADHD or something along those lines.

575

: 00:32:40

So this is the kind of thing,

that I wonder, 'cause with, yeah.

576

: 00:32:43

Do you think there may be some future

applications, for example, like in

577

: 00:32:47

attention deficit disorders or other kinds

of, maybe neurodegenerative disorders?

578

: 00:32:53

Speaker: Yeah.

579

: 00:32:53

I think, I think there is

a hypothesis about ADHD.

580

: 00:32:56

for me, I think it's interesting, but

it's ... I would say there needs to

581

: 00:33:01

be quite a bit more, basic work to

really be sure if it's worth pursuing,

582

: 00:33:06

at, on a wide scale clinically.

583

: 00:33:08

But I think there is a clear

potential for, for ADHD partly, at

584

: 00:33:13

least partly being, driven by s-

deficits in the locus coeruleus.

585

: 00:33:19

So I think the idea with ADHD is,

yeah, with the locus coeruleus

586

: 00:33:23

I've-- there's a interesting kind

of a- aspect about the region.

587

: 00:33:28

It has these kind of

different firing modes.

588

: 00:33:30

so just at rest or in daily life

it has this kind of this, what

589

: 00:33:34

we call the tonic firing rate.

590

: 00:33:36

and so, this is just when you're in

daily life, whatever the baseline firing

591

: 00:33:42

rate is, it's called the tonic firing.

592

: 00:33:44

And then, when you're engaged in a

task, there's this phasic effect where

593

: 00:33:49

there's this kind of sudden increase.

594

: 00:33:51

and so I think the idea

with ADHD is that...

595

: 00:33:54

And so to go back, sorry.

596

: 00:33:55

So the t- the tonic firing is thought

to relate to, your arousal level.

597

: 00:34:00

and it's said to follow this inverted

U-shape in the typical way we would think.

598

: 00:34:03

So when your tonic firing is low,

you're this, in a sleepy state.

599

: 00:34:07

it's, after you just woke up or it's, or

as you're supposed to go to bed, it might

600

: 00:34:11

be promoting you trying to go to be- bed.

601

: 00:34:13

and then in the middle when it's

at a moderate level, that's called,

602

: 00:34:17

the optimal, task engaged zone,

where you have that feeling of

603

: 00:34:21

being really locked in to a task.

604

: 00:34:24

and then when it gets high, it's in

this, yeah, a- Where you can't really

605

: 00:34:30

focus or having difficulty focus.

606

: 00:34:33

and there's this hypothesis about

the tonic that it has this kind

607

: 00:34:37

of metacognitive, role, mediating

between explore and exploit modes.

608

: 00:34:43

So when we're in an environment

where we need to engage in a task

609

: 00:34:47

to maximize rewards from a task,

we're put into that moderate zone.

610

: 00:34:51

because it's moderate, it

maximizes the effect of the phasic

611

: 00:34:55

inputs, when we're doing a task.

612

: 00:34:57

and then as it starts to drift

forward, maybe as the rewards are

613

: 00:35:01

becoming h- more hard to come by,

it's a signal to explore or to move

614

: 00:35:05

somewhere else in our environment.

615

: 00:35:07

I think the idea with ADHD is that, and

I think the evidence-- there is evidence

616

: 00:35:11

that, that the tonic, firing is higher

than a typically developing population.

617

: 00:35:17

And so the idea is that because

the tonic firing is higher,

618

: 00:35:21

they're stuck in this explore mode.

619

: 00:35:23

And so that's partly why they f- they

find it difficult to engage in tasks

620

: 00:35:28

because this phasic input that kind of

contrasts against the tonic isn't really

621

: 00:35:33

having an effect because there's just

this too high a level of tonic firing.

622

: 00:35:38

and so then, yeah, I think, some of

the literature in terms of different

623

: 00:35:42

drugs that are used with ADHD, and I'm

struggling to remember the precise names,

624

: 00:35:46

but some of them have shown to improve

symptoms and also reduce, tonic firing in

625

: 00:35:51

the locus coeruleus, which is why there

is this, maybe this idea has emerged.

626

: 00:35:57

but yeah, I me- I've looked

into it a bit recently.

627

: 00:35:59

I'd say like the literature base isn't

that strong, but it's hopefully gonna

628

: 00:36:04

start to improve, 'cause yeah, it's, it

definitely makes sense when you think

629

: 00:36:07

about this explore versus exploit.

630

: 00:36:10

but yeah, I sometimes wonder,

yeah, is that the driver?

631

: 00:36:15

Is it the cause?

632

: 00:36:15

You know what I mean?

633

: 00:36:16

Like-

634

: 00:36:17

... it could be the case that the tonic

is firing because of something

635

: 00:36:20

else, and then that's what's

putting them in this explore mode.

636

: 00:36:22

it might not be just because

of the locus coeruleus.

637

: 00:36:25

So that's the thing that's

difficult to parse out,

638

: 00:36:29

Speaker 2: Yeah.

639

: 00:36:29

Yeah.

640

: 00:36:29

So it's, it is interesting though,

just even this idea about the subtle

641

: 00:36:33

differences in neurocognitive systems,

between arousal and attention.

642

: 00:36:39

'Cause you could see how those could

get conflated quite easily, but they're,

643

: 00:36:43

they are understandably different, right?

644

: 00:36:45

That whole wa- the idea about the

arousal being on that spectrum

645

: 00:36:48

of hypervigilant, to comatose.

646

: 00:36:51

And then the attention- Yeah ... being

perhaps more, as you say, s-

647

: 00:36:56

somewhat related, but in some

ways not so related, right?

648

: 00:37:00

Or as a subset.

649

: 00:37:01

Yeah.

650

: 00:37:02

and yeah, so figuring that out and then

mapping that onto different circuits

651

: 00:37:06

and then understanding the relevance, as

you say, in what in real time in these

652

: 00:37:10

kinds of studies with those types of-

tonic versus phasic, changes in, in how

653

: 00:37:15

activity is being measured, over time.

654

: 00:37:17

Speaker: Yeah.

655

: 00:37:18

Yeah.

656

: 00:37:18

It's just, yeah, it's an interesting

area and, it's-- we haven't really--

657

: 00:37:23

we've tried to, in our experiments, try

to keep the tonic sort of, consistent

658

: 00:37:28

between the sham and the tVNS, so that's

why we typically have more time after

659

: 00:37:32

our trials to let everything settle down.

660

: 00:37:34

... but maybe-- and so when we do the trains,

we're kind of-- our thought is more that

661

: 00:37:38

we're more affecting the phasic part.

662

: 00:37:41

I see ... but yeah.

663

: 00:37:43

It's something maybe we'll try to

manipulate the tonic in future.

664

: 00:37:46

I'm not sure.

665

: 00:37:46

yeah, I think that there's maybe a couple

people in the lab who are interested

666

: 00:37:51

in looking at these types of tasks in,

in people with ADHD or with anxiety.

667

: 00:37:57

The kind of-- there's a similar

hypothesis about anxiety as well.

668

: 00:38:01

and also with, PTSD as well, as

that's emerged as maybe having some

669

: 00:38:06

sort of loc- locus coeruleus base,

or deficits or kind of unusual

670

: 00:38:11

activity in the locus coeruleus,

671

: 00:38:13

Speaker 2: Definitely.

672

: 00:38:13

Yeah.

673

: 00:38:14

You mentioned Parkinson's disease,

which is interesting because

674

: 00:38:16

typically, the focus with Parkinson's

is on the dopaminergic system, not

675

: 00:38:20

so much the noradrenergic system.

676

: 00:38:23

But it's understandably involved

because of all the various different

677

: 00:38:26

neuropsychiatric symptoms that,

that usually arise with Parkinson's.

678

: 00:38:31

Yeah.

679

: 00:38:31

But what in-- what would be the sense

that, tVNS might be applicable to

680

: 00:38:36

help with symptoms of Parkinson's?

681

: 00:38:39

Speaker: Yeah.

682

: 00:38:39

I think it's, I think

there's a few things.

683

: 00:38:42

I think one thing more, maybe not as a

treatment, but as a way to identify, a

684

: 00:38:47

deficit, because what typically happens in

Parkinson's disease is that you have these

685

: 00:38:53

kind of, precursor non-motor symptoms.

686

: 00:38:56

and then what's happening in the

background is the degradation

687

: 00:39:01

then of the dopaminergic

neurons is, has already started.

688

: 00:39:04

And then by the time that you typically

get a di- like, you start to see

689

: 00:39:07

an onset of motor symptoms, that's

typically the point where you get a

690

: 00:39:11

diagnosis and then you get treatment.

691

: 00:39:14

And yeah, there's treatments for the,

reasonably effective treatments for the,

692

: 00:39:17

the death of dopaminergic neurons, which

can kind of- stave off the worst of the

693

: 00:39:23

motor symptoms and eventually let them

plateau, whereas if there's no treatment,

694

: 00:39:26

they just go very bad very fast.

695

: 00:39:29

But I think, the kind of more what we--

the locus really starts to degrade earlier

696

: 00:39:34

and actually a lot of the non-motor

symptoms match up with what we would think

697

: 00:39:38

of as, changes in noradrenergic activity.

698

: 00:39:41

So we have often difficulty sleeping,

which is if we think of this, curve

699

: 00:39:45

where the tonic is setting moving

us into more like a sleep state.

700

: 00:39:49

you have, yeah, sometimes difficult

cognitive, cognitive deficits, cognitive,

701

: 00:39:54

difficulty with different kind of

cognitive tasks, which is also in

702

: 00:39:59

some way related or could be related.

703

: 00:40:00

And then, so yeah, you have these

kind of symptoms and maybe there

704

: 00:40:04

could be some sort of system where...

705

: 00:40:08

And then as I said, we have this

way of measuring the effects

706

: 00:40:11

or measuring activity in the

locus areas through the pupils.

707

: 00:40:13

So maybe, you could have kind of checkups

earlier ahead of time where you have a

708

: 00:40:17

TVNS set up, and then you look at how

the TVNS is affecting the pupil size.

709

: 00:40:22

And then maybe you might have someone who

comes in to some sort of, routine checkup

710

: 00:40:27

and oh, they're not actually showing a

response in their pupils to the TVNS.

711

: 00:40:30

That could be maybe a way to assess

if they have-- they're starting to see

712

: 00:40:34

degradation in the locus coeruleus.

713

: 00:40:37

versus there's not really a

way to do that with imaging.

714

: 00:40:40

and then you can imagine like

the time point at which you start

715

: 00:40:43

getting treatment really, affects

how the disease progresses.

716

: 00:40:47

So if you come in and, then maybe

you can go to another sort of

717

: 00:40:51

more, dopaminergic-based test.

718

: 00:40:53

You're like, "Okay, they show deficits

in the pupil size test, and now we're

719

: 00:40:56

gonna t-see if they actually have

the loss of dopaminergic neurons."

720

: 00:41:00

And then that would allow you

to more quickly diagnose maybe

721

: 00:41:04

Parkinson's before you start to see

the onset of the motor symptoms.

722

: 00:41:08

and so yeah, obviously that would improve

the outcome because people are getting

723

: 00:41:14

treatment earlier and that the time

at which you start getting treatment

724

: 00:41:16

really affects how you progress.

725

: 00:41:18

I see that's not really a treatment,

but more like a way to yeah,

726

: 00:41:20

assess a biomarker, of whether

there should be a diagnosis.

727

: 00:41:24

And then the other kind of aspect is

the treatment for Parkinson's disease is

728

: 00:41:29

very much, centered on the motor symptoms

or addressing the dopaminergic deficit.

729

: 00:41:36

whereas the non-motor symptoms can often

just continue to progress and they don't

730

: 00:41:39

really, They're not really targeted.

731

: 00:41:41

so maybe you could also have TVNS

later on as a, as a way to treat

732

: 00:41:46

the non-motor symptoms as well.

733

: 00:41:47

that's a bit more, uncertain

I'd say, but, I think, yeah,

734

: 00:41:51

it's worth maybe looking into.

735

: 00:41:53

Speaker 2: Yeah, absolutely.

736

: 00:41:54

Thanks for explaining that.

737

: 00:41:55

That's exciting both in terms

of, a functional biomarker for

738

: 00:42:01

preclinical diagnostic purposes, but

also targeting, as you say, these

739

: 00:42:05

under-recognized non-motor symptoms.

740

: 00:42:07

so for clarity, it would be things

like, disorders of arousal, like as

741

: 00:42:11

you say, like the sleep problems that

are o- often arise, attentional- Yeah

742

: 00:42:16

more subtle kind of cog-

neurocognitive deficits.

743

: 00:42:19

Speaker: Yeah.

744

: 00:42:19

Yeah, exactly.

745

: 00:42:20

So maybe you'd have someone come into

their family doctor and, they report

746

: 00:42:25

these symptoms, and as I suppose right

now, probably not much is done or

747

: 00:42:30

there's, there's certain things that

can be done, but there maybe is not

748

: 00:42:33

a focus on whether, oh, this might be

the start of Parkinson's, And in an

749

: 00:42:36

alternate reality then even the doctor

in their office could have some kind of

750

: 00:42:41

setup with a pupil, camera that measures

pupil size and like a small stimulator

751

: 00:42:47

just to get a sense of whether there

is maybe, oh, this person doesn't show

752

: 00:42:51

any change in their pupil size in r- in

response to the TVNS compared with sham.

753

: 00:42:56

actually I'm gonna refer them to,

to go and see if they have, the

754

: 00:42:59

start of the degradation of...

755

: 00:43:01

Because the degradation is occurring

in the dopaminergic neurons,

756

: 00:43:04

it's just not really noticeable,

So you can catch it earlier.

757

: 00:43:08

so yeah, it could be like more

of a change in the procedure.

758

: 00:43:11

I think that's an idea that there

is out there, but not yet met.

759

: 00:43:16

Speaker 2: Yeah.

760

: 00:43:16

yeah.

761

: 00:43:16

No, it's very interesting.

762

: 00:43:18

It's, it strikes me that the more we

understand about this and the more

763

: 00:43:21

that there are these interesting

technologies that, perhaps we're moving

764

: 00:43:25

towards more precise, both in terms of

the diagnostic side, early diagnosis,

765

: 00:43:31

allowing for earlier intervention,

but also precision neuromodulation

766

: 00:43:35

of specific cognitive functions like

attention, arousal, these kinds of things.

767

: 00:43:40

So it's really interesting.

768

: 00:43:42

Speaker: Yeah.

769

: 00:43:43

Yeah.

770

: 00:43:43

I think there's a lot of potential ways

to go, like on, yeah, certainly on the,

771

: 00:43:48

we do more basic neuroscience trying to

figure out how the brain works, but also

772

: 00:43:52

applying that in the clinical space.

773

: 00:43:53

I think there's, yeah, a lot of questions

emerging that are very interesting.

774

: 00:43:58

Speaker 2: Yeah, for sure.

775

: 00:43:59

thanks so much, Dr.

776

: 00:44:00

Denyer.

777

: 00:44:01

Ronan, thanks again for, joining us

today here, and it's just been super

778

: 00:44:05

interesting to hear about your work and

your lab's work and, future directions.

779

: 00:44:10

What kinds of projects are you focusing

on these days that, you're embarking on?

780

: 00:44:13

Is there anything in particular, any

one study in particular that you're

781

: 00:44:17

particularly looking forward to starting-

Yeah ... or getting further into?

782

: 00:44:22

Speaker: Yeah.

783

: 00:44:22

So I'm just in the middle of

collecting data for a new project.

784

: 00:44:26

and it's, it's a behavioral

project with TVNS.

785

: 00:44:29

so yeah, we're using this paradigm

called a forced response task.

786

: 00:44:33

and actually it's a reaching variant.

787

: 00:44:35

So we have this device called the

KinArm, where you can have people

788

: 00:44:38

reach into this space and measure

their, the kinematics of their reach.

789

: 00:44:42

and so they basically hear these

four tones and they're instructed

790

: 00:44:47

you always need to move in some

direction on the fourth tone.

791

: 00:44:51

and then shortly before that fourth

tone, we show the target that

792

: 00:44:54

they should go to if they can.

793

: 00:44:57

And so, we vary the time

that we show the target.

794

: 00:45:01

And so you can imagine if you have half a

second, then you're gonna hit the target.

795

: 00:45:05

whereas if you have maybe only

100 milliseconds, it's gonna

796

: 00:45:07

be hard, to hit the target.

797

: 00:45:10

And so by basically analyzing, their

success rate at these different times, we

798

: 00:45:14

can create like a speed accuracy curve.

799

: 00:45:17

and so one thing we're looking

at is whether TVNS, shifts that

800

: 00:45:22

s- that, speed accuracy curve.

801

: 00:45:23

So if you give a person, 100

milliseconds with TVNS versus sham,

802

: 00:45:28

does that increase their success rate?

803

: 00:45:30

and then, a related thing, within

the task, we're also looking at the

804

: 00:45:34

effect on the vigor of the reach,

so how fast the person reaches or

805

: 00:45:39

how ... the peak velocity of the reach.

806

: 00:45:41

and so yeah, there's this kind of

idea that when we increase the speed

807

: 00:45:46

at which we, decide, we also increase

the speed at which we move, and

808

: 00:45:50

this we call like a co-regulation

of, decision and movement vigor.

809

: 00:45:55

And so yeah, I'll be looking

into the reach too and, whether

810

: 00:45:58

that is increased, with the TVNS.

811

: 00:46:00

So a, yeah, more basic

motor neuroscience study.

812

: 00:46:04

But, it's a really cool task and

I think having the reach, it gives

813

: 00:46:09

like a real kind of richness to

the data, which is new for me.

814

: 00:46:11

yeah, I'm looking forward

to exploring the data more.

815

: 00:46:15

Speaker 2: Yeah.

816

: 00:46:15

Yeah, that's super interesting.

817

: 00:46:16

and you can see how, learning more about

the basic neuroscience in that regard

818

: 00:46:21

could have potential clinical applications

for things like stroke rehabilitation

819

: 00:46:25

that you were discussing beforehand.

820

: 00:46:27

Speaker: Yeah.

821

: 00:46:27

Yeah.

822

: 00:46:28

Yeah.

823

: 00:46:28

So in, in Dr.

824

: 00:46:30

Voigtlab in UBC, she has a Ken

arm, and we use it all the time

825

: 00:46:33

for different studies in stroke.

826

: 00:46:36

and so it can be used as a device to

diagnose but also to administer rehab on.

827

: 00:46:41

so yeah, certainly relevant to that.

828

: 00:46:45

Speaker 2: Yeah.

829

: 00:46:45

That's great.

830

: 00:46:46

thanks again, Dr.

831

: 00:46:47

Denyer Ronan.

832

: 00:46:48

It's been really interesting.

833

: 00:46:50

today's conversation really

highlighted something profound.

834

: 00:46:53

I think that it, relatively simple,

non-invasive interventions-- Not simple,

835

: 00:46:58

but I guess seemingly simple Yeah

836

: 00:47:00

non-invasive interventions like

TDNS really can give us causal

837

: 00:47:05

access to understanding deep brain

systems like the locus coeruleus.

838

: 00:47:09

and I think for me, what's particularly

compelling is really the shift in

839

: 00:47:14

understanding that it's not just

speeding up cognition but more, like

840

: 00:47:18

optimizing it, improving the signal

to noise, stabilizing the attention,

841

: 00:47:23

helping us understand the subtle

differences between systems like arousal

842

: 00:47:26

and attention, and maybe even helping

the brain recover from errors in real

843

: 00:47:31

time, which I think has really enormous

implications, not just for neuroscience,

844

: 00:47:37

but for how we think about treating

conditions like ADHD, depression, stroke,

845

: 00:47:42

neurocognitive disorders that we've been

discussing, and maybe even enhancing

846

: 00:47:47

performance in healthy individuals.

847

: 00:47:48

That's a whole other discussion

as well around ethics and such.

848

: 00:47:51

But anyway, maybe we'll have to have

a follow-up discussion about those

849

: 00:47:55

other interesting things, Ronan.

850

: 00:47:56

And, yeah.

851

: 00:47:57

But in the meantime, just wanna

wish you all the best, and thank

852

: 00:48:00

you so much for joining me today.

853

: 00:48:01

It's been such an

interesting conversation.

854

: 00:48:03

Speaker: Yeah.

855

: 00:48:04

Thanks so much for having me.

856

: 00:48:05

It was, great chatting today.

857

: 00:48:07

Speaker 2: Okay.

858

: 00:48:07

Take care.

859

: 00:48:08

All the best, and good luck

with all the projects that you

860

: 00:48:10

and your lab are involved with.

861

: 00:48:12

And, yeah, we're just looking

forward to seeing the papers

862

: 00:48:14

that come out of your research.

863

: 00:48:16

Speaker: Yeah.

864

: 00:48:16

Thanks so much.

865

: 00:48:17

Yeah, look forward to it.

866

: 00:48:18

Speaker 2: Okay.

867

: 00:48:19

Take care.

868

: 00:48:19

All the best.

869

: 00:48:19

Bye bye now.

870

: 00:48:20

Speaker: Bye.

871

: 00:48:20

Bye.

872

: 00:48:21

Speaker 2: Happy St.

873

: 00:48:21

Patrick's Day, by the

874

: 00:48:23

Speaker: way.

875

: 00:48:23

Oh, yeah.

876

: 00:48:24

Technically, the perfect day.

877

: 00:48:25

Yeah.

878

: 00:48:26

Speaker 2: Yeah.

879

: 00:48:26

Yeah.

880

: 00:48:26

Perfect.

881

: 00:48:26

Awesome.

882

: 00:48:27

Okay.

883

: 00:48:27

Cheers.

884

: 00:48:27

All right.

885

: 00:48:28

Speaker: All right.

886

: 00:48:29

See you later.

887

: 00:48:29

Speaker 2: Take care.

888

: 00:48:29

All right.

889

: 00:48:30

Bye bye.

890

: 00:48:30

Thanks.