E152 | How Brain Stimulation Cured Lifelong Depression (w/ Prof. Ziad Nahas)

Prof. Ziad Nahas is a psychiatrist  and researcher who treats adult patients with mood disorders and treatment resistant depression and specializes in performing deep brain stimulation and electro-convulsive therapy. Dr. Nahas is Professor and Vice-Chair for Clinical Affairs in the Department of Psychiatry at the University of Minnesota Medical School.

Today we discuss a case study of a 44 year old man with treatment resistant depression treated with PACE (Personalized Adaptive Cortical Electro-stimulation) a novel, personalised form of brain stimulation. 

The Case Study and video of the study patient (alias Mike) can be found here:

https://www.linkedin.com/posts/ziad-nahas-67526015a_neuroscience-mentalhealthinnovation-functionalmri-activity-7360347911529910272-C08F?utm_source=share&utm_medium=member_desktop&rcm=ACoAAFjWpikBGe7Oel-gcC_2ZupvuXI-t9RkwCM

Interviewed by Dr. Alex Curmi. Dr. Alex is a consultant psychiatrist and a UKCP registered psychotherapist in-training.

Check out Alex on the Examined Life Podcast here:

https://podcasts.apple.com/gb/podcast/dr-alex-curmi-how-should-we-prepare-for-a/id1680728280?i=1000738070553

If you would like to invite Alex to speak at your organisation please email alexcurmitherapy@gmail.com with "Speaking Enquiry" in the subject line.

Alex is not currently taking on new psychotherapy clients, if you are interested in working with Alex for focused behaviour change coaching , you can email - alexcurmitherapy@gmail.com with "Coaching" in the subject line.

Check out The Thinking Mind Blog on Substack: https://substack.com/home/post/p-174371597

Episode produced by Ellis Ballard and Alex Curmi. 

Give feedback here - thinkingmindpodcast@gmail.com Follow us here: Twitter @thinkingmindpod Instagram @thinkingmindpodcast

Transcript

Speaker: [00:00:00] Welcome back. One of my hopes for the future of psychiatry is that we're gonna be able to come up with treatments which are more specific, more individualized, more precise in helping people with their mental health. And this can of course include biological treatments as well. This is exactly what we're gonna be talking about on the podcast today.

We're gonna be looking at a case study that looks at a 44-year-old man with the alias mic. Who has suffered lifelong with treatment resistant depression and was enrolled in the study to try and treat this depression with a new form of brain stimulation called pace. PACE stands for personalized adaptive cortico electrostimulation.

That doesn't quite roll of the tongue so easily, but we're gonna explain all of that today and we're gonna explain why this new form of brain stimulation is so exciting. With me to have this conversation is the lead author of this [00:01:00] case study, professor Zha. Professor Nahas is the Executive Vice Chair at the Department of Psychiatry and Behavioral Sciences at the University of Minnesota.

He's a psychiatrist and researcher who specializes in the treatment of mood disorders like depression and bipolar, and specifically in the use of deep brain stimulation techniques to treat these conditions. He's been running studies using brain stimulation techniques for a long time. This is his latest case study, which has just come out and it looks at how this personalized adaptive form of brain stimulation can look into treating something like treatment resistant depression, which is depression, which has not really responded to a number of different treatments.

Before we go into depth into Mike's case, the specific kinds of difficulties he was experiencing. How this form of brain stimulation works and the procedure that he underwent, how they recorded his brain activity, how they adapted [00:02:00] the stimulation specifically to his brain, and what parts of his brain they stimulated.

How he progressed with this treatment, how well he did, whether or not he actually recovered from his depression, what this treatment may reveal about the biology of depression, which is fascinating and much more. We've had a number of conversations about brain stimulation on the podcast, and I'd like to take this moment to make a distinction between the different kinds of brain stimulation.

So if you like, you can go from superficial to deep. We talked to the guys at Flow Neuroscience a couple of months ago, so they produce brain stimulation headsets that are more superficial. They're headsets you can use at home. They apply what's called direct current stimulation, so it's a little bit safer.

Generally used for something like mild to moderate depression. Then there's something kind of in the middle, like transcranial magnetic stimulation, so that uses a machine that you need to access in a clinic on the [00:03:00] supervision. So it's a little bit more intense and can be used perhaps for somewhat more severe depression.

And then we have the kinds of stimulation techniques that we're gonna be talking about today where you actually do an operation, open up the skull and implant electrodes onto the brain, and these are electrodes which remain active and remain usable for long periods of time. With that in mind, I hope you get a lot out of today's conversation.

I learned a lot, I had to learn a lot to prepare for this conversation, and I definitely learned a lot having it and listening back. One more brief announcement. I was recently on the Examined Live podcast, which I really enjoyed. That's hosted by Kenneth Primrose, and I really like this podcast. It has a nice format where every conversation is centered around the question for this conversation, the question was, how should we prepare for an increasingly technological future?

A question I am perplexed and fascinated by, and I enjoyed talking to Kenneth about this. I'll put a [00:04:00] link. To this podcast in the show notes of this conversation, I have a couple of exciting announcements for the new year, which I'm not at liberty to share yet, but I will be soon. So stay tuned for that.

Otherwise, enjoy today's conversation. If you like the podcast, if you want to support it, do like follow or subscribe on whatever platform you're listening on. Share it with a friend who you think will like it. Give us a rating or a review if we end up on your Spotify app. Don't hesitate to post that on your story and you can tag us at Thinking Mind Podcast on Instagram or Thinking Mind Pod on Twitter.

Thanks for listening to today's episode, and here's our conversation with Professor Ziad nha. Professor Nahas, thank you so much for joining us. 

Speaker 2: Thank you, Alex, for inviting me. 

Speaker: I am so keen to discuss this case study with you and it is a study looking at a very specific treatment. Looks of it a very new treatment and that's called [00:05:00] pace, which stands for personalized Adaptive Cortico electrostimulation.

Having read about it in the research for this podcast, it does seem like something out of science fiction and wonderful to get the opportunity to learn more about it today. Could you, you did this case study looking at a 44-year-old man, his alias was Mike. Could you tell us a bit about. What were Mike's problems?

What, what were his difficulties going into the study? 

Speaker 2: So Mike is someone that currently meets the criteria for recurrent treatment, resistant depression and post-traumatic stress disorders. Mike is in his late forties. He. Experienced depression as a teenager had had multiple hospitalization between the age of 20 and 30, including suicide attempt and self harm.

Underwent a [00:06:00] series. Pharmacological treatment with partial responses. Found himself in need to apply for disability and got off the workforce. Initially received electroconvulsive therapy for his severe depression. Had a partial response. Felt encouraged somehow. So. With his sense of duty and ethics, he dropped his disability, attempted to go back to the workforce, realized that he couldn't do it, went back on disability for the second time.

In the meantime, he tried ECT twice since that first. Attempt. And whereas in the first round he received some partial response. He didn't really respond at all to the two other courses of ECT, and it's culminated to a level of depression and. Hopelessness that he had a very serious [00:07:00] suicide attempt. He was discovered accidentally by a sheriff, him and his car unconscious, trying to asphyxiate himself with a carbon monoxide, but also having ingested hypnotics.

And so it was a fortuitous discovery that got him into the hospital and eventually he left. He approached us about this study almost a year before we actually enrolled him. At the time, we were still trying to figure out the logistics and resources to pull it up, and he showed. Honestly, a great intentionality.

He was, he knew his options. They were limited, but nevertheless, he still had options and he wanted to pursue and wait until we got our act together ready to, to, to actually implant them. And, and we managed to obtain almost a year long baseline assessment. 

Speaker: He had a year of his baseline [00:08:00] mood, baseline mental state.

Exactly, 

Speaker 2: and so, and ultimately he took a leap of faith. When we had asked him what are the. Scales we actually have in the study is expectations of response and his were a 30%, meaning that at best I'm gonna get a little bit better. And so that give you a sense of some hope. Obviously, it's hard to imagine that somebody is getting ready to have brain surgery for their depression.

Wouldn't have some hope. To, to, to, to take such a leap of faith, but it's also minimal compared to ultimately. What he ended up experiencing as a life changing treatment. 

Speaker: And I, I think I read that he had tried some 19 different antidepressants. Is that right? Correct. 

Speaker 2: I mean, he, he really part of, part of [00:09:00] those particular type of research is.

And severe treatment resistant depression, is it become really very important to do the proper homework in assessing the level of severity, but also of severity of the symptom at the presentation, but also the number of treatment that have not worked for you. And there's a big distinction that I think is very important for patient in general.

Oftentimes I see patient not to the severity of mics and certainly not necessarily candidate for brain surgery because a lot of stuff haven't been tried out to treat their depressive symptoms. Patient need to distinguish between taking a medication, experiencing some side effect. I'm getting nauseous.

I couldn't handle it. I stopped it after two weeks versus really taking the dose at the high enough [00:10:00] milligram. Equivalent and then long enough, at least four to six weeks before you say, this medication didn't work for me. 

Speaker: So you're making the distinction between ineffectiveness of the medication versus too many side effects.

Speaker 2: Too many. So if they having side effect and cannot. Take it anymore. It's true. It's no longer an option for them. And so in that respect, that's the medication that is likely not to be tried again. However, it doesn't predetermine the likelihood of responding to the next treatment because historically in treatment depression, the more you truly fail treatment coming into.

This current treatment, the less likely you're gonna respond to it. Right? And so doing that exact homework becomes really important. 

Speaker: Yes. And I, I would like to point out for the listeners that, um, even though this does [00:11:00] sound like a quite a severe case of treatment resistant depression, it's more common than you might think, and it's something I've encountered a lot.

Um, there is a national service set up in the UK specifically aimed at treating people with. Treatment resistant depression. But even in a local community mental health team in London, you would expect to see patients pretty similar to Mike reasonably often. So treatment resistant depression really is quite, quite a big deal and and it affects a lot of people.

It is a big deal, Alex, and 

Speaker 2: as a clinician as well. Over the last 20 years, I've also witnessed a worsening of the TRD. Presentation. I am involved in other brain stimulation research, for instance, vagus nerve stimulation. When we first tested it out, the first case to be ever implanted for depression was in 1998.

It was in a lab where I was in Charleston, South Carolina. [00:12:00] The average number of failed treatment in a current depressive episode was about four. Fast forward 25 years to now with the recovered trial that is sponsored by Levan Nova, where they studied 500 unipolar patient. The average number of failed treatment lifetime is 13.

So it give you a sense that over. Decades, two decades, we have substantially, we are witnessing a substantial worsening of the TRD presentation and it begs the answer as to what is it that we as clinician might be doing wrong to contribute iatrogenically to this. It's not an antip psychiatry statement.

I'm clearly a psychiatrist and I'm from within. But I think we need to be mindful that sometimes our medication may [00:13:00] modulate plasticity. And plasticity is the idea that the more you, you, you push synopsis to communicate to each other, the stronger that relationship is people. Seem to associate plasticity to something positive, but in fact, it's just a fact, right?

It's more connection and it could be positive or negative. And so if you are. Not specifically addressing underlying reason behind a depression, not teaching someone new coping skills, and yet giving them a suboptimal antidepressant drug that could be modulating plasticity. You would worry that it's not only, not an effect not effective to treating the symptoms, but you have to wonder to what extent it's actually perpetuating.

Poor coping skills because [00:14:00] now those connections are becoming stronger. By virtue of taking that drug. And so it's a very hard scientific question to truly investigate if, if I wanted to write one paper, that really would be the focus. Is, is, is how could we go about understanding that? Because the other fundamental thing that has happened primarily since the.

Mid eighties, early nineties when we started having very. Safe and often tolerable antidepressant drugs is that we have lowered the threshold quite a bit in administering those drugs. And as you probably know, there's a number of studies that shows that if you have mild to moderate depressive symptom, the antidepressant drug is really not better than placebo and it's only start working when it.

Was [00:15:00] in the, in the moderate to severe, severe symptoms, and so. A, a, a careful prescribing habit to these patient. An increased utilization of evidence-based psychotherapy are, are, are not, you know, are needed. And, and we need it. It, as much as we're talking sci-fi today, there are certain basic principle, I think for the general community to, to hear and to rethink if, if one of your listeners.

Is depress taking antidepressant to be able to, to understand fundamentally what that is and what else should they be doing to optimize that treatment as opposed to passively just taking the drug itself? 

Speaker: Right. You know, certainly the idea that there's a large population of people with mild to moderate depression.

We seem to [00:16:00] be leaning too hard on drugs. Not that drugs can't be useful, but we may be leaning too hard on drugs and not leaning hard enough on psychological approaches, teaching better coping strategies, helping people deal with stress. Even making, we've made the argument for making certain societal change on this podcast help actually make people's lives a little bit easier and hopefully a bit less stressful.

These are all topics very dear to our heart on the podcast, so I'm glad you brought them up. Getting back to, to this case study and pace. So, so we've heard about Mike and, and he's a 44 4-year-old man who's had, sounds like pretty severe treatment resistant depression for a long time. What is the treatment that he underwent with yourselves?

Speaker 2: To transition a little bit from medication to brain stimulation. I think the way people might be able to better conceptualize the fundamental differences is that with drugs, [00:17:00] you are introducing an exogenous compound to the system to modulate it with brain stimulation. You're banking. On the endogenous property of the system to respond because at the end of the day, with brain stimulation, you're either gonna depolarize a neuron or you're not.

And whatever you're mustering as a neuronal response or an orchestrated network response is really from within that system as opposed to an exogenous compound coming into it. So that's, I think is, is, is a crucial. Important fact. So when, when, when we were conceptually thinking about this study, and mind you, my preliminary work leading to what I call now pace or prefrontal cortical stimulation 2.0 was the 1.0 version of it, which I had done in in [00:18:00] Charleston couple of decades earlier.

Whereas now I'm at the University of Minnesota. The, the idea being is that depression. A heterogeneous presentation, right? If you look at the DSM criteria, you have eight listed. You need to choose a combination of five out of eight in order to make a diagnosis and make sure they've been lasting for two weeks.

I don't know how good you are in math, but a combination of five to eight is certainly a lot, and so you can imagine that there can be multiple subtypes. Of depression that we are lumping under one particular umbrella, calling it unipolar depression. And back. Early in, in 2000, we had begun making really sensible gains and understanding the functional neuroanatomy mood [00:19:00] dysregulation.

And whereas there were key target areas, people were targeting the dorsal later prefrontal cortex, which is that front part of the brain on the left side to treat it with transcranial magnetic simulation, or people are targeting deep into the brain structure, the subgenual singlet to treat it with deep brain termination.

I argued that given how little we know about the pathophysiology of depression, truly know and the heterogeneity of the symptom, why don't we. Approach treatment with multi target treat stimulation, so that roughly speaking, the lateral networks, the networks that are typically are on the lateral side of the brain are the one that most likely you and I are currently [00:20:00] utilizing the most by engaging, being attentive.

I'm paying attention to your question. You're listening to my responses and formulating. Comeback. So that is very much engaging the lateral network. Whereas if you were to introspect, think about yourself, think about yourself in relationship to others, that is the medial networks. And so for a depressed patient who may be getting overwhelmed, if you tells them plan.

Two days in advance for a task you're about to engage in. That's really a failing of the lateral networks. Whereas their emotional pain, their social isolation, their inability to feel. Emotions even to their closest relatives, their kids, their spouse. That's, that is a failing of the medial [00:21:00] network. And so why don't we modulate both complementary network at the same time?

And that's what we originally did 20 years ago. So we implanted four paddles long, kind of a rectangular shape with contact electrodes on them. And whereas they're typically placed on the surface of the spinal cord to treat pain or other condition, we've appropriated them to place them intracranial. So inside the skull, never through the brain tissue, but laying them on the surface of the cortex.

And we placed those paddles onto these regions and. Reported that three out of five patient achieved remission within seven months, and that was sustained till five years. So that was the original. Whereas with Mike, we wanted to catch on to 21st [00:22:00] century kind of advances and really take it to the next level, which is the sci-fi part you are talking about.

Can we truly individualize our approach so that we can get better outcomes? If we don't have the full understanding of how depression come about and how depression is biologically sustained, let's utilize the patient's own responses as a guide. In addition to obviously the theoretical knowledge we're coming in, in terms of this area, does this and this area does that.

And so with personalized and adaptive cortical electrostimulation pace, there's two key component here, and I'm gonna try to break them down. The personalized part, the personalized part is really coming in in [00:23:00] terms of where are we gonna stimulate. We already agreed we're gonna go with multiple target.

Because depression is heterogeneous and there may be psychomotor slowing, but also emotional pain, but anxiety, et cetera. So we know there are a plethora of symptoms and we wanna multi targett, and so we are taking advantage of. Great advancement in functional neuroimaging whereby you could take a resting state, functional MRI.

So this is not just looking at the structure of the brain. This is trying to give you a sense how the 

Speaker: brain is working in real time, 

Speaker 2: how the brain is working in real time. And whereas a lot of people have utilized this technique, but acquired data for, I don't know. 6, 8, 10 minutes long. It turned out that when you're [00:24:00] acquiring.

This length of data, you have a huge variability within the data, right? Data in general inherently is noisy, and so all you could do with this type of scan is do a group statement in general. On average, this is the brain activity when engaging in doing X or is this, if you scan up to. An hour long. All of a sudden, because you're acquiring more data, your variance, that variability, the noise in your data is gonna become less.

It'll never go away, but it'll becomes really much less than than it would be if you were acquiring 10 minutes of data and that. Turned out a really important element to be able to make individual statement on the topography of these different [00:25:00] functional network in the brain and to be rather millimeter precise in the borders, let's say, between a network that is really important and.

Executive control versus a network that may be really scanning the environment and your internal state to look for. Flag red flags where you need to pay extra attention and consequently act on it or divert emotional energy towards solving a problem. And so that allowing us now to take Mike. Put him in a scanner and when we're looking at his brain, be able to identify these different functional network.

And I, we mentioned, I'm gonna repeat the word complimentary network because each one of them is doing somewhat different and [00:26:00] yet they're all in, in, in cohesion, so to speak, to present you as a full. Functioning person and, and so we were able to identify that. And I'm gonna, I want to come back to how unusually abnormal his brain functional anatomy was, but I'll come back to that in a second.

So that's the personalized part. But we know in brain stimulation. The parameters to use to engage those neurons is wide open. You can stimulate one pulse per second, like a one hertz, or you can stimulate 120 hertz. Anything in between. You can give a train, a stimulation, a few seconds and pause, or you can give it continuously.

You can change how fat each electrical pulse is. That's the pulse width. You can [00:27:00] change the. Amplitude of the stimulus itself. That's the intensity of the stimulation. We can see the, the choices can really be overwhelming. In, in, in drug therapy. We have milligram to worry about, and if we're lucky, we have.

Medication like nortriptyline where we can take a blood level and get the minimum blood level you need to be effective, but also the maximum by which you're not gaining anymore and you're only getting side effects. In brain stimulation, the choices are substantially more. And so the adaptive part of the study is essentially taking the feedback from the patient.

Their preference of the settings they've just been exposed to and pairing it against another four or five choices, and let the patient [00:28:00] experience those at home. They toggle through those settings. They don't know exactly what they're getting. We are assigning those by setting 1, 2, 3, 4, 5. So they're masked to the parameters they likely are getting, and yet they're giving us daily report on their mood, on their quality of sleep, the number of hours of sleep, and critically their rank ordering.

I like this one substantially more than I like the other one. They come in the following month. We carry over the best setting, but we're now exploring yet four or five other new settings, and we do that iteratively six times. In the first six months of the study until we have identified what seemingly is the preferred setting for this one particular patient, out of those million of parameters [00:29:00] option that otherwise we would be just picking out of a hat.

We keep those settings fixed and we say, okay, now we're no longer changing those settings and we're gonna hold them on. The same from month seven to 12 from the time you got implanted, and we gonna call our primary outcome measure. Did this work? Are your clinical symptoms substantially improved at a one year mark?

So the first six mo uh, six months are optimal targeting, but also optimal search for the right parameters to use for this one particular individual. And the next six months is really testing it out a little bit longer 'cause there's something about chronic. Stimulation, especially in, in my book, where we're giving intermittent stimulation [00:30:00] as opposed to continuous like is done with Parkinson's disease and deep brain stimulation, for instance, where, where the effect can have acute modulation and that what we described in our paper.

Immediate change in attention, immediate clarity in the visual that I'm seeing, and the colors and how vivid and, and crisp things are as opposed to having a foggy brain. Right. But those don't necessarily translate to an immediate antidepressant effect. The patient is still depressed when you're considering the totality of their presentation.

They are, however, experiencing these kind of unique, immediate responses to us switching stimulation parameter over time. However, Mike began also to improve clinically and manage. [00:31:00] To almost get remission by six months. Not quite. And remission is. By definition, absence of depressive symptoms, really as opposed to somewhat improved where or greatly improved, and yet reach ultimately that threshold at nine months.

Lost it at 12 just because the few days before he contracted COVID and lost on his rating scales. Couple of points on sleep and energy as understandable, but that's how research work goes. And then since then, he has been in full remission. Now, I just saw him two weeks ago, actually last week, and I believe we were at months 39 from his first enrollment.

So he's been two and a half years, [00:32:00] essentially in a full remission, something that he had not experienced the prior 30 years. 

Speaker: Wow. How long did it take for him to begin to feel his mood lift for him to begin to feel a bit less depressed? After the, after the devices were implanted, 

Speaker 2: we tested him first in the ICU to be able to just test out our own hypothesis.

If we are stimulating executive control, are we really seeing more attention and focus or we're stimulating? And this is where we were able to elicit that. Positive emotional response by stimulating his default network, that that surprised us, but clearly surprised him. But as I mentioned, he was obviously clearly still depressed, but that kind of got it in his brain that, oh.

It is biologically active. I am experiencing something. 

Speaker: It is possible to feel better, 

Speaker 2: and I'm sure that it, that [00:33:00] contributed to, to a sense of hope. Hopefulness his, his first two, three months, and remember we were asking him to change the settings every so often, every three days. We gave him the option. If you change the setting and really don't like it, just don't force yourself to stay at the three setting at the three days.

Just let us know and move on to the next setting. He found those actually quite stressful. Because if he liked a setting or he felt somewhat relieved, his anxiety may be reduced. He would be apprehensive, okay, I'm switching to a different setting. What if I'm gonna lose that little bit of positivity that I gained?

And so that actually was quite, I shouldn't say unexpected, but for us. But nevertheless, we didn't anticipate it to be. This burdensome [00:34:00] psychologically, but you can see how the patient's contribution to the data is really critical in this process and that the personalized aspect of it. Eventually, I would say that if you follow the.

Curb of of his serial ratings. We were really studying to feel encouraged probably by month three where he was studying to. Report an overall decrease of the intensity of his symptom. He was symptomatic. That was the last, but not at the severity that he was before. So probably around three, four months, as I mentioned, six months, he was already close to being symptom free, so it happened somewhere in between, but it certainly wasn't immediate.

Going back to a comparison with other brain stimulation that aim to be faster [00:35:00] or pharmacological intervention or psychedelic for that matter that you brought up earlier in our conversation. 

Speaker: How many different parts of Mike's brain are being stimulated? We have 

Speaker 2: four paddles that are targeting three to four, and I, I'll, I'll, I'll clarify that in a minute.

Unique. Large scale networks, so we have left and right, and you can imagine that the data control network exists both on the left and the right in the same way that the salient network and the default network exists both on the left and the right. Generally speaking, and so we we're using four paddles, but we are placing them and activating pa the electrode on each paddle to only specifically modulate one of the network.

And so the three that we are after are. [00:36:00] Frontal polar or executive controls, that's the lateral network that I referred to earlier, and we are accessing also the salient network that is the network that keep track of your environment and internal homeostasis and alert you to shift attention. It's also most likely quite relevant in modulating anxiety and.

The default mode network, which is that unique network of me versus you, the emotional experience of things, the internal representation of things, which is also a. Critical network to modulate in the context of depression. So, so we have this choice of network. Keep in mind that anatomy often will make it difficult for you.

[00:37:00] So it could be that the bulk of the area you wanna stimulate is buried deep in the SOAs and your electrode can only be. At the bridging between the two gyri, right? And, and, and therefore you may end up bleeding over and stimulating beyond that network. But we're, we're trying very hard to be very select because.

In addition to us wanting to treat the totality of the symptoms, what we are hoping from our research is that we will gain basic neuroscience knowledge about the contribution of each of those networks separately, right? And so we wanna treat complementary network because that's a clinical goal. The neuroscience.

Goal is to understand the contribution of each of those networks [00:38:00] separately and how pushing and pulling each one of those lead to a different expression of symptoms and possibly a different result. 

Speaker: That, that's was gonna be my next question because do you think that from this case study and studies like it, we are meaningfully closer to getting, uh, reliable biomarkers for depression?

Speaker 2: Alex, there's a big difference between writing a grant and getting people excited about your idea and the clarity of where you wanna go, and the reality of where we are in the field right now. Certainly, yes, different brain will have different signatures and that can be informative about. What makes them unique and possibly how to best modulate it.

Right. But if I wanna step back a little bit [00:39:00] with TMS, which is a non-invasive way to use magnetic pulses to depolarize. It's the first brush of cortex, so just surface of the brain in order to lead to an antidepressant effect, I was one of the first to begin publishing about the importance of where you're stimulating in the prefrontal cortex in order to get an antidepressant effect.

But the reality is most of our effort. To individually target based on functional neuro imaging has been a wash, right? I mean there's, there's been early enthusiasm about individualized targeting for TMS and then come. Studies that look at it head to head and still cannot, cannot distinguish a dramatic advantage to using individualized targeting.

And this is why in my [00:40:00] clinic, for instance, I have not instituted, we will obtain an FMRI on every single patient coming to our clinic in order to optimize their treatment. Right? And so. I wanna be a little bit cautious about this issue of biomarker because that's, that's a, that's a goal we have. We have some way to go before we can fine tune it in the same way that we are.

Recording from these electrode in the, at least in the first four days after surgery, when they are still in the ICU, we're able to hook up these leads to a machine so we can record the brain activity and to be able to stimulate. From that machine, the brain, after the four days, they're back to the or they get implanted with their RPGs, their battery, and they [00:41:00] go home and we are no longer getting that sensing opportunity.

But in those four days, we also have an opportunity to start looking at the electrical signatures of either. The state of depression in these different networks, or more importantly, the state of the network once you've stimulated it and another topic of mind and one of the colleagues that is now part of our lab with a heavy.

Mathematics and chaos theory, non linear, dynamic understanding of data or complex data. We've been kind of conceptually thinking about how can we take those type of conversations, electrophysiological conversation, I mean, and understand them at the complex, non-linear dynamic level, [00:42:00] because one of. The difficulty that our field has had to deal with is the delicate song and dance between us fully appreciating that the brain is a self-organizing system, that there are.

Non-linear dynamics happening all the time, and us, even when we're doing EEG, we're really stretching the limit to trying to interpret something within the linear system as opposed to the chaos theory system. And so there may be complexity there. In addition, one would argue our approach is complex, right?

Four paddles. Imaging personal optimizations is certainly not a, you know, one hat fits all, but there may be even more room for. Introducing yet an extra layer of [00:43:00] complexity to understand ultimately how these neuronal ensembles manage to keep a coherent conversation. I sometime equate the brain to this beautiful symphony and multiple instrument being played when you're introducing a drug.

And we were talking about it earlier, this idea of an exogenous compound that you're introducing into the system. In my mind, you're forcing many different instrument to play The same 

Speaker: note. Feels like a blunt instrument, 

Speaker 2: right? And so it, it, it end up reducing the complexity of. That melody that you're hearing with brain stimulation, the promise by again, being banking on the endogenous property of the system, that you could revive that complexity in a different [00:44:00] way than what pharmacology could do.

Yet I have patient that have come to me and says, I don't know what it is, but somewhere, somehow my brain always wants to come back to the spot of feeling miserable despite anything we do. And I'm sure you heard it from your patient as well. What does that mean in terms of this, this attractor that is pushing this neuronal ensemble to be stuck in a very limited.

Range of, of musical notes as opposed to really expanding. It is a, is is I think for me the next. Challenge to understand and to overcome. 

Speaker: And what's next for the future of research specifically for PACE for this treatment? 

Speaker 2: So pace, we have a proof of concept. We are far from saying this is a [00:45:00] viable, available antidepressant treatment for severe treatment resistant depression.

We have to do the work and the work is essentially building up. To having a randomized control trial, which we're still prepping to get there. In the meantime, I'm not sure when this gonna air, but we are expecting that in the next couple of days. There will be an announcement for a recent grant we have received, focusing specifically on using pace in bipolar depression, and even more sci-fi, if you want to go back to that word is trying to use our combined.

Individualized targeting, intracranial brain activity, recording, and the testing we're doing in the ICU. To see if we could really understand what's [00:46:00] behind mood. Switching from a depression to arm mania, that is one of the very, very unique phenomena in the brain that we are completely in the dark about really.

We know certain things. It can switch you into a hypomanic manic phase, sleep deprivation maybe, or an antidepressant if you have a predisposition to bipolarity. But we don't fully understand what that constitutes really at the electrophysiological level. And so our task is gonna be to do more of the brain imaging and bipolar patient to understand that.

Biomarker profile and take a handful of those patient and get them implanted with pace. And now look about, look at what happened when you modulate each one of those key large scale [00:47:00] network. Can you get to replicate that immediate switch? Could that help us truly understand the top pathophysiology and the mechanism behind bipolar disorder to then develop treatment that are.

Better informed with, with a true pathophysiology of the illness. So, and, and we're gonna obviously continue to, to enroll a participant in our unipolar study like Mike did. We've had two enrolled participants so far. One has been implanted, the second one, surgery's coming up in a few weeks and hopefully.

Will keep adding to this bank of knowledge so that it can be useful to us, but also to other treatment modalities. Have no illusions that this complicated [00:48:00] functional brain surgery is gonna have massive widespread application because it's too sophisticated, it's too expensive and and is only available.

And, and, and, and. Complex academic centers, but the knowledge about modulating these network could translate to non-invasive brain stimulation. 

Speaker: Right. So that, I was gonna ask about that because when I spoke to the co-founder of Flow Neuroscience, so they work very much at the other end of brain stimulation.

They have headsets which use, um, direct current stimulation, low, low amplitude, superficial. But you know, having has good evidence that it works. And their main question was, we need to understand who it works for and why. And so I'm imagining there can be some portability, if you like your research, understanding what's happening at the brain level could help [00:49:00] inform these more, uh, superficial, non-invasive, if you like.

Uh, brain stimulation treatments, perhaps. 

Speaker 2: Absolutely. At the end of the day, we're also gonna start learning more what happened to these networks when you're approaching them through vagus nerve stimulation versus transcranial magnetic stimulation versus pace versus deep brain stimulation, and there's a common pathway, or they really completely.

Independent in terms of how they get around doing what they do and ultimately treating depressive symptoms. So yeah, I mean there's, there's, I don't think there's a better time to be doing neuroscience and, and, and specifically advancing the, the field when it comes down to, to psychiatry and, and some of our key psychiatric disorders.

But we certainly have. How's the work [00:50:00] cut out for us? The brain turned out to be a little bit more complicated than what we anticipated it to be when we declared the decade of the brain whenever that was in the nineties. I think 

Speaker: just, just before we finish, has, it sounds like this treatment has been of tremendous benefit to Mike.

I'm wondering, has Mike experienced any side effects besides, you know, some stress when switching between different settings, any side effects? How has Mike coped with this psychologically? 'cause I would imagine even though his depression has gotten better, my intuition would be any big change. Must be a little bit weird and needs some adjusting.

So firstly, side effects, and secondly, how has Mike coped with this big change in his life? 

Speaker 2: Sure. In the paper. We have described specificity of which electrode we're activating to tap into one particular network or the other, and that's really a match [00:51:00] of the size of the paddle and let's say the, the geography of what you wanna stimulate.

And so if your, if your paddle is substantially bigger, then you may wanna just activate. Four of the eight electrode on that pedal to only be limited to that area. And so we activated in the D-L-P-F-C, so on the dos lateral prefrontal cortex below what would be the window to modulating the executive control network.

And we had Mike having difficulty. Expressing his words, so almost like a, a facial. We've also had in different locations, we pushed Mike into experiencing a level of internal restlessness and anxiety that made him quite uncomfortable and we had to [00:52:00] quiet it down. So, which, which speaks. To the specificity of what we're doing, right?

Because if everywhere we're stimulated, we got a positive response. You would wanna, you wouldn't wanna be skeptic about it. So we've had those kind of side effect, but we clearly don't, we stop stimulating there, and so those haven't surface. Mike is honestly, and I've had a. Many, many research participant.

He's one of those people that is remarkably eloquent and observant, and so his description of. His psychological journey has been a delight to read, but even more importantly, very informative at the neuroscience level. I'll give you an example. I had mentioned earlier, I had mentioned that Mike had a very, very unusual looking [00:53:00] functional neuroanatomy.

His salient network seemed to have. Expanded so large that it migrate, it, it it expanded and occupied what should have been a node part of the executive control. 

Speaker: Is that what is termed in the paper called expansion? Exactly, because I didn't know what that meant. Okay, so, so expansion of a particular network beyond the norm.

Speaker 2: Beyond an exactly, and so then the other network is being encroached upon and therefore smaller, and also the functional connectivity of that network was scarce compared to what you would see in the healthy control in the lab. When I test. Mike, I'm constantly, okay, how do you feel now? So how do you feel now?

And he had to pause me at one point and he said, doc, you need to [00:54:00] understand something about me. It takes me at least a day or two for me to pick up on what's going on in my own body. Now, you and I were just talking about the Salient network. You and I know that the Salient network is monitoring internal homeostasis, but.

Imagine yourself in my shoes. I'm looking at a very abnormal MRI, highlighting the salient network and how dysfunctional it really looks. And I'm having the patient himself telling me I have a hard time reading my own internal signals of my own homeostasis and they match, right? And so that what I mean by.

Eloquent and, and descriptive to the level that is really informative. To his credit, Mike never stopped going to psychotherapy or group therapy, [00:55:00] even in his, even in, in the years prior to coming into our study. So he kept with that and he came back to us and he said, I now have. What it take to implement what I've learned in psychotherapy before, I couldn't get around actually doing it, and a couple of months ago.

He who has stayed away from, from social gathering and isolated himself from his family. Went on a road trip with a couple of his relative and his significant other from Alaska down to Las Vegas or somewhere, and he was sending us, it wasn't a vlog actually, but he sent a couple of email along the way, marveling at.

Marveling at the beauty of the world that he was traveling through, and every so often pinching himself along the way saying, [00:56:00] is that real? It is because it has lasted close to three years now, or two and a half. 

Speaker: And there's the striking video which you posted online where you see Mike, I looks like he's still in the ICU and it, it looks as though he's describing, experiencing positive emotions, really.

For the first time in a long time, and I think that's what you described earlier in the conversation where you said, you know, we could stimulate certain areas and we could start to feel good, maybe not representing a, an immediate remission of his depression, but oh, we're starting to realize, okay, we can meaningfully change his psychological experience with this tool.

Speaker 2: Yeah, and, and, and, and that's something for us to also understand better. And I know it has been reported with deep brain stimulation as well, where you could stimulate someone in the OR have that experience. To what extent this immediate [00:57:00] acute response to a stimulation translate to long-term antidepressant effect.

That we don't know. It's, the story is, is probably way more complicated at, at a minimum. For me, the way I interpret it is that I'm in a right place. I can, I can say that much to what extent it predicts the antidepressant response we see at one year that that remains to be seen. 

Speaker: We'll have to find out. I will, I will put a link to the video.

In the description because it's quite striking. Thank you so much for coming on and sharing this. It's been an education for me. I've had to learn a lot in a very short space of time, but I've appreciated hearing your insights. We look forward to seeing more about what PACE can bring us in terms of scientific data and meaningful improvements to people's lives.

In the meantime, thank you so much for spending some time with me today. 

Speaker 2: [00:58:00] Oh, my pleasure. And, and Alex also don't underestimate the work you're doing in this particular podcast because we often get caught in our own language. And to have someone who can translate that and make it tangible and real is part of the, part of the narrative.

And, and so thank you for doing that as well, and thank you for inviting me. 

Speaker: Thank you. I appreciate that. 

Speaker 2: Bye-Bye.