Your Complex Brain

The Future of DBS

April 18, 2023 Krembil Brain Institute Season 2 Episode 3
The Future of DBS
Your Complex Brain
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Your Complex Brain
The Future of DBS
Apr 18, 2023 Season 2 Episode 3
Krembil Brain Institute

Deep brain stimulation (DBS) is complex brain surgery in which electrodes are placed at strategic, predetermined targets within a patient's brain. The electrodes are then connected to a battery pack which is surgically inserted under the skin of the chest, like a pacemaker.

When DBS was first introduced as a treatment option for people living with Parkinson’s disease more than 20 years ago, it was a game changer.

In this episode of Your Complex Brain, we’ll speak with Krembil Brain Institute neurosurgeon, Dr. Suneil Kalia, and neurologist, Dr. Alfonso Fasano, about the future of DBS – and how it could be used to help many more patients improve their quality of life, including those living with other neurological diseases.

We’ll also hear from CBC journalist Harry Forestell about his DBS journey.

Featuring:
Dr. Suneil Kalia – Neurosurgeon & Senior Scientist at the Krembil Brain Institute & Associate Professor in the Division of Neurosurgery, Department of Surgery, University of Toronto. As a stereotactic and functional neurosurgeon, Dr. Kalia focuses on the surgical management of movement disorders, epilepsy and pain. He holds the R.R. Tasker Chair in Stereotactic and Functional Neurosurgery.

Dr. Alfonso Fasano – Neurologist & Clinician Investigator with the Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, at the Krembil Brain Institute (Toronto Western Hospital). Dr. Fasano is a Professor of Medicine, Department of Neurology, at the University of Toronto. He holds the Chair in Neuromodulation at UHN.

Harry Forestell – Long-time CBC journalist who has reported on some of the biggest stories of our time, and is the current host of CBC News New Brunswick at 6. At the age of 53, Harry was diagnosed with Parkinson’s disease and subsequently had DBS surgery. Harry is first and foremost a family man; he is married to Jennifer and they have two beautiful daughters.

Additional resources:
Krembil Brain Institute’s Movement Disorders Clinic (Toronto Western Hospital)
Krembil Brain Institute’s DBS Surgery Information Page
CBC story about Harry Forestell’s DBS experience & surgery
VIDEO – Harry Forestell story ‘See the instantaneous effects o

The Your Complex Brain production team is Heather Sherman, Jessica Schmidt, Dr. Amy Ma, Kim Perry, Sara Yuan, Meagan Anderi, Liz Chapman, and Lorna Gilfedder.

The Krembil Brain Institute, part of University Health Network, in Toronto, is home to one of the world's largest and most comprehensive teams of physicians and scientists uniquely working hand-in-hand to prevent and confront problems of the brain and spine, such as Parkinson's, Alzheimer's, epilepsy, stroke, spinal cord injury, chronic pain, brain cancer or concussion, in their lifetime. Through state-of-the-art patient care and advanced research, we are working relentlessly toward finding new treatments and cures.

Do you want to know more about the Krembil Brain Institute at UHN? Visit us at: uhn.ca/krembil

To get in touch, email us at krembil@uhn.ca or message us on social media:
Instagram - @krembilresearch
Twitter - @KBI_UHN
Facebook - https://www.facebook.com/KrembilBrainInstitute

Thanks for listening!

Show Notes Transcript

Deep brain stimulation (DBS) is complex brain surgery in which electrodes are placed at strategic, predetermined targets within a patient's brain. The electrodes are then connected to a battery pack which is surgically inserted under the skin of the chest, like a pacemaker.

When DBS was first introduced as a treatment option for people living with Parkinson’s disease more than 20 years ago, it was a game changer.

In this episode of Your Complex Brain, we’ll speak with Krembil Brain Institute neurosurgeon, Dr. Suneil Kalia, and neurologist, Dr. Alfonso Fasano, about the future of DBS – and how it could be used to help many more patients improve their quality of life, including those living with other neurological diseases.

We’ll also hear from CBC journalist Harry Forestell about his DBS journey.

Featuring:
Dr. Suneil Kalia – Neurosurgeon & Senior Scientist at the Krembil Brain Institute & Associate Professor in the Division of Neurosurgery, Department of Surgery, University of Toronto. As a stereotactic and functional neurosurgeon, Dr. Kalia focuses on the surgical management of movement disorders, epilepsy and pain. He holds the R.R. Tasker Chair in Stereotactic and Functional Neurosurgery.

Dr. Alfonso Fasano – Neurologist & Clinician Investigator with the Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, at the Krembil Brain Institute (Toronto Western Hospital). Dr. Fasano is a Professor of Medicine, Department of Neurology, at the University of Toronto. He holds the Chair in Neuromodulation at UHN.

Harry Forestell – Long-time CBC journalist who has reported on some of the biggest stories of our time, and is the current host of CBC News New Brunswick at 6. At the age of 53, Harry was diagnosed with Parkinson’s disease and subsequently had DBS surgery. Harry is first and foremost a family man; he is married to Jennifer and they have two beautiful daughters.

Additional resources:
Krembil Brain Institute’s Movement Disorders Clinic (Toronto Western Hospital)
Krembil Brain Institute’s DBS Surgery Information Page
CBC story about Harry Forestell’s DBS experience & surgery
VIDEO – Harry Forestell story ‘See the instantaneous effects o

The Your Complex Brain production team is Heather Sherman, Jessica Schmidt, Dr. Amy Ma, Kim Perry, Sara Yuan, Meagan Anderi, Liz Chapman, and Lorna Gilfedder.

The Krembil Brain Institute, part of University Health Network, in Toronto, is home to one of the world's largest and most comprehensive teams of physicians and scientists uniquely working hand-in-hand to prevent and confront problems of the brain and spine, such as Parkinson's, Alzheimer's, epilepsy, stroke, spinal cord injury, chronic pain, brain cancer or concussion, in their lifetime. Through state-of-the-art patient care and advanced research, we are working relentlessly toward finding new treatments and cures.

Do you want to know more about the Krembil Brain Institute at UHN? Visit us at: uhn.ca/krembil

To get in touch, email us at krembil@uhn.ca or message us on social media:
Instagram - @krembilresearch
Twitter - @KBI_UHN
Facebook - https://www.facebook.com/KrembilBrainInstitute

Thanks for listening!

00:00:01 Dr Kalia 

After having done this operation, hundreds and hundreds of times, that moment that you turn on the simulator and you see a tremor disappear or Parkinson's symptoms improve to five or ten years ago in an instant, never grows tiring for me. 

00:00:21 Heather 

This is your complex brain, a podcast all about the brain, the diseases that impact it, and the path to finding cures. 

00:00:31 Heather 

I'm your host, Heather Sherman, and I have the great pleasure of working alongside the team at the Crimble Brain Institute in Toronto, Canada. A leader in brain research. 

00:00:40 Heather 

And patient care. 

00:00:42 Heather 

In each episode, we'll take you behind the scenes into our clinics and research labs to meet the game changers of the future. 

00:00:51 Heather 

We'll also empower you with the latest research to help you take charge of your own health. You'll hear directly from people who are living with brain disease as well as. 

00:01:00 Heather 

Their loved ones. 

00:01:01 Heather 

And the care teams who support them. 

00:01:04 Heather 

Join us on a journey to unravel the mystery of your complex brain. 

00:01:11 Heather 

Today we're talking about deep brain stimulation, a complex brain surgery in which electrodes are placed at strategic, predetermined targets within a patient's brain. 

00:01:21 Heather 

The electrodes are then connected to a battery pack which is surgically inserted under the skin of the chest, kind of like a pacemaker for many patients. 

00:01:31 Heather 

Living with Parkinson's disease and other neurological disorders, deep brain stimulation, also known as DBS, can be a game changer. 

00:01:41 Heather 

But DBS is not always the answer, and doctors and researchers at the crumble Brain Institute are working hard to improve and personalize the technology to be able to help as many patients as possible. More on that later in today's episode. First, we'd like you to meet Harry. 

00:02:00 Heather 

Forestell, a familiar face in Canadian media. 

00:02:04 Heather 

Harry is a respected, longtime journalist and currently the host of CBC's Supper Time newscast in New Brunswick. Harry was 53 years old when he was diagnosed with Parkinson's and referred to the Movement Disorders Clinic at the Crumble Brain Institute, a world leading team that performs more DBS surgeries than anywhere else in Canada. 

00:02:26 Heather 

After meeting with Harry, the team determined that he was a candidate for the DBS surgery, which he had in September of 2022. Here's Harry's story in his own words. 

00:02:48 Harry 

My name is Harry Forestell. I'm a journalist with CBC Television. I've been a reporter and producer and host for about 35 years. 

00:02:58 Harry 

It was voted in 2013, the year my mother passed away, that I began to notice the tremor in my right hand. 

00:03:07 Harry 

I'm left-handed, so it didn't bother me that much, but it was noticeable and it was something that I thought, hmm, I've had that checked out. So the next time I was at the doctor, I did. 

00:03:18 Harry 

My doctor at the time was uncertain what it was, whether it was something called essential tremor, which I never heard of, but it sounded pretty benign, or whether it was something more serious, like Ms. ALS or Parkinson's. 

00:03:32 Harry 

So that was a bit of a worry. It took over the next two years to confirm the diagnosis of. 

00:03:38 Harry 

Sorry, continue. 

00:03:39 Harry 

And in that time, my neurologist in New Brunswick had referred me to doctor Tony Lang and the team at Toronto Western Hospital, moving to Serta Clinic and. 

00:03:49 Harry 

That was where. 

00:03:50 Harry 

In 2015, I really had my diagnosis confirmed as Parkinson. 

00:03:58 Harry 

My sentence at the time were mostly the tremor and I was shaking my left leg a lot at work. 

00:04:04 Harry 

Now I was always a leg shaker. Doesn't mean to extending excess energy. I guess when I was young, so that didn't really worry me, but it was noticeable that it was doing it when I wasn't really. 

00:04:16 Harry 

Intending for it to happen, and then the thing that really sort of blew my mind and frustrated me was that I was finding it was taking more and. 

00:04:25 Harry 

For focus and attention just to walk normally. Now I live on a hill quite a grade and walking up that hill after dropping my daughter at school became a real task because I was so focused on swinging my arms in time to the movement of my legs and I thought this can't be right. 

00:04:46 Harry 

It shouldn't take this much time and attention. I'm just walking. It's very simple. Why? 

00:04:51 Harry 

Is it so hard? 

00:04:53 Harry 

And that was what really was beginning to annoy and disconcert me. 

00:04:59 Harry 

The team that traveled to Western was very, very supportive and they were very thoughtful and concerned about not just me as a patient, but about my career. 

00:05:07 Harry 

What I did for a living, and knowing that I had to appear on television on a regular basis and knowing that I still had some career ahead of him and I was only 53. 

00:05:17 Harry 

54 years old and I still had career ahead of me to go and Doctor Lang said. Don't worry, we'll get you back on there. It'll be OK. So he was very reassuring nonetheless. The symptoms continued to go. 

00:05:35 Harry 

And that was dispiriting. However, I did notice that the use of drugs like levodopa especially was huge in terms of helping me deal with the symptoms and control them. But overtime, as my volume of the levodopa increased. 

00:05:50 Harry 

The side effects of that especially dyskinesia begin to be more and more of a factor in my mental health and my physical health. 

00:05:59 Harry 

Dyskinesia is the side effect that comes from levodopa. Levodopa is a precursor drug. When it gets into the body, the brain transforms it into dopamine, which is a critical neurotransmitter that helps smoothly relay messages from the brain to muscle groups and parts of the body like the legs and arms. 

00:06:19 Harry 

Dyskinesia is the side effect of levodopa that causes your body to twist and torque in a very fluid fashion, so it isn't like the tremors of Parkinson's. 

00:06:31 Harry 

But you will notice people who are being treated for Parkinson's very often their head will move their shoulders, will glide around, and it's very difficult to stay still. 

00:06:43 Harry 

I had heard sometime earlier that there was a thing called deep brain stimulation and I understood the broad principles of it. 

00:06:52 Harry 

But I thought brain surgery sounds pretty serious and it's nothing that I want to get into right now. 

00:06:57 Harry 

As we discussed it, doctor and said, you know, we've got to see whether you would qualify. 

00:07:02 Harry 

For it or not? 

00:07:03 Harry 

And as my sentence grew more serious. 

00:07:06 Harry 

It became more apparent to me that. 

00:07:07 Harry 

Maybe DBS would? 

00:07:08 Harry 

Be, you know a more appropriate solution. The longer term solution and a more satisfactory solution. 

00:07:17 Harry 

I spent a weekend in November, 32 years ago, going through to see if I would be a satisfactory candidate and much to my pleasure and surprised I pass. 

00:07:28 Harry 

I guess for want of a. 

00:07:29 Harry 

Better phrase. I was delighted with that. 

00:07:31 Harry 

To have that prospect of another option rather than just. 

00:07:35 Harry 

Continuing with the growing volume of oral drugs. 

00:07:39 Harry 

But a year? 

00:07:40 Harry 

Later, then came the opportunity to actually have seizure done. I went up to Toronto. I was there for about a month. 

00:07:47 Harry 

I was impressed and surprised by how. 

00:07:50 Harry 

Quickly and how? 

00:07:52 Harry 

Little fuss was involved in what had always seemed to me to be as complicated as brain surgery. I was quite chatty, apparently. 

00:08:00 Harry 

Marcus has entered Dr. Cali have both remarked on how my line of questioning through the operation surprising a little bit when they're doing brain surgery. 

00:08:08 Harry 

They're more used to speaking to one another than they are, I think answering questions and being interrogated by the patient. But I was curious about what was going on. 

00:08:18 Harry 

The recovery was very quick. I was at a hospital within 36 hours with my implant and the neurotransmitter in my chest and all the wires connected and everything ready to go. 

00:08:30 Harry 

But they wanted me to heal up. Of course I spent. I think 3 weeks in recovery in Toronto on my own. 

00:08:37 Harry 

That all happened from the end of September to the end of October. On December the 6th, I returned to Toronto and spent a week there. 

00:08:47 Harry 

I had the device. 

00:08:48 Harry 

Turned on. I was not alone. I was in front of a bevy of clinicians. 

00:08:53 Harry 

When it was turned on and the effect was immediate and very, very pleasing, my tremors, my shakes, abated completely with the bonus that I didn't have to experience. 

00:09:04 Harry 

The dyskinesia that goes along with the increasing doses of levodopa and that was a real life changer. So since then. 

00:09:13 Harry 

I came home to New Brunswick. I've had, I think 3 sessions with the DBS clinical team to set the device because it very much involved a fair amount of tweaking here and there to ensure that it delivers the best result that is possible. 

00:09:29 Harry 

The use of DVS has allowed me to return to work not only to work in the office but in front of the camera, which is a huge bonus for me and I can't say enough about how it has returned my life to me. 

00:09:48 Harry 

I subsequently did a story on my treatment. 

00:09:51 Harry 

And included in it an illustration of me turning off my DBS and turning it back on. 

00:10:00 Harry 

And I recorded that with a colleague of mine at work. And then I sat down and watched the edited video that he put together. 

00:10:07 Harry 

And even though it was me even. 

00:10:09 Harry 

Though I recorded it, knew what I. 

00:10:11 Harry 

Was doing and. 

00:10:12 Harry 

Even though I knew it was coming, it was very emotional moment for me to see how vulnerable I am. 

00:10:18 Harry 

With our DBS. 

00:10:22 Harry 

The fact of the matter is that video has probably gone around the world and has just led to an avalanche of inquiries. That encouragement and good wishes from friends and family and people I've never met before. 

00:10:38 Harry 

I would like people with bargains to know first and foremost that there is hope. It may not come in the form of deep brain stimulation. For them, it may come in through other treatments, but there is hope. This is not. 

00:10:50 Harry 

Not by any stretch, necessarily. A death sentence or even a life sentence. There is work being done every day to encourage people to live full and wholesome lives with movement disorders. 

00:11:08 Harry 

The team at the Crumble Brain Institute are doing a remarkable job and you know, if I am an example of the work that they're doing, so be it. 

00:11:18 Harry 

I'm impressed by my treatment and where I am right now. I know this may only give me another 10 to 15 years, but Holy smokes 10 to 15 years. 

00:11:28 Harry 

It can be a lifetime. 

00:11:30 Harry 

And to improve my quality of life as much as this has is truly a remarkable circumstance, and for that I have to thank them. 

00:11:38 Harry 

I can't say enough about the care and the quality of the treatment I received, and I just hope so many other people have the opportunities that I've had with the results that I've had. 

00:11:59 Heather 

Joining us now to talk about the future of DBS and some of the more recent advances in research with this technology is Doctor Sunil Kalia, a neurosurgeon and senior scientist with the Crimble Brain Institute. 

00:12:12 Heather 

And the Tasker chair in stereotactic and functional Neurosurgery and Dr. Alfonso Pisano, a neurologist and clinician investigator with the Kremple Brain Institute who holds the chair in neuromodulation at Uhn. 

00:12:40 Heather 

OK, so you two are probably the busiest people I know. I think it's a bit of a miracle that we were even able to coordinate your schedules to have you on the podcast today. So thank you so much for. 

00:12:49 Heather 

Being here. 

00:12:50 Dr Fasano 

Thank you, Heather. Our pleasure. Thank you. 

00:12:53 Heather 

Doctor Kalia, I know you've performed hundreds of these DBS surgeries, if not more, including hairy forestalls. Can you tell us a little bit more about the procedure itself and what's involved in a surgery as complex as this one? 

00:13:07 Dr Kalia 

So this is an operation. 

00:13:08 Dr Kalia 

Where we have to balance a lot of technical goals and to keep as safe as possible. There are many steps to the surgery. Basically the ultimate goal of the surgery is to. 

00:13:19 Dr Kalia 

To implant electrodes that are just over a millimeter in diameter to targets in the brain that are selected by the team that will give the best possible results for a patient and these targets are quite small in the range of five to seven millimeters deep in the brain. In terms of the operation. 

00:13:39 Dr Kalia 

Itself, we do the surgery with a lot of advanced technology, and that technology includes imaging, such as specialized MRI's, that allow us to have a map, a GPS map, if you will, of a patient. 

00:13:52 Dr Kalia 

This brain and using that map we define a safe entry point for our electrode and we define a safe target and path down to that target. 

00:14:04 Dr Kalia 

We tailor the surgery to the needs of the patient so we could do this operation with the patient relatively awake and this allows for. 

00:14:13 Dr Kalia 

Detailed testing and fine tuning of the position of the electrodes or for certain patients. We can do this mostly. 

00:14:20 Dr Kalia 

Be asleep. It's a matter of balancing patient preference against the goals of the surgery. Throughout the surgery, we use other types of technology that allow us to further fine tune the position of the electrodes, and this includes, but isn't limited to recording individual brain cells to identify the regions of the brain. 

00:14:41 Dr Kalia 

And further refine our target and using 3 dimensional imaging to see the position of the elect. 

00:14:48 Dr Kalia 

Throats. That's part one of the surgery, and once that's complete, Part 2 of the surgery involves connecting those two small electrodes that are deep in the brain. 

00:14:58 Dr Kalia 

Two extension wires that run under the skin behind the ear down to a computer that's implanted in the chest area, and the total amount of. 

00:15:08 Dr Kalia 

Surgical time varies, but part one takes about 3 to 4 hours to do, and Part 2 is about one to two hours to come. 

00:15:16 Dr Kalia 

Right. 

00:15:17 Heather 

It's amazing. I mean, just that you're able to determine exactly where to place the electrodes and which areas of the brain to target. 

00:15:25 Heather 

Doctor Fasano. Harry obviously had a very positive outcome from the surgery, but how often is that the case? I mean, what is the success rate for DBS overall? 

00:15:33 Dr Fasano 

This is a question that we get all the time and it's not an easy question to answer because this is not cancer surgery where you have a success rate in terms of, you know, being alive at a certain time after few years or or not. So it's difficult really to define success. 

00:15:49 Dr Fasano 

And usually my answer is that success rate is close to 100% if the right patient is identified and the electrode is placed in the right target and the patient undergoes the right programming and the right medication adjustments. 

00:16:04 Dr Fasano 

So as you can tell, it's a very complex process and success rate is also difficult to define because every person. 

00:16:10 Dr Fasano 

Comes with different goals. For example, in the case of airy, we've been talking a lot about the effect of DBS on speech given his job, so he could have been much, much better looking at the overall picture. But if DBS per se was to cause speech problem, then it would be. 

00:16:27 Dr Fasano 

Big problem for him and so he would probably not hold that successful. So that's why it's so difficult to identify success. 

00:16:34 Dr Fasano 

It's so dependent on the patient functions needs. Overall, our goal is to improve the quality of life and This is why we we spend a lot of time discussing with them and their family what their expectations are. 

00:16:47 Dr Fasano 

A well known problem of this procedure is disappointment after surgery because unfortunately, even though this is quite remarkable, it helps a lot of people. This is just a treatment, it's not a cure. 

00:17:00 Dr Fasano 

And unfortunately, a lot of people go to surgery even when they say that they know that the disease won't go away. 

00:17:08 Dr Fasano 

But in the back of their mind, they think that this will be it. It will be the the resolution of their problem. 

00:17:13 Dr Fasano 

And unfortunately, we don't have anything like that. So that's why the search is still very important to improve these conditions from really the bottom of the problem. 

00:17:20 Dr Fasano 

But the the real issue, that is the degeneration going on in the brain. 

00:17:24 Dr Fasano 

That's the short answer to your question head. 

00:17:27 Heather 

Well, I guess the other part too is that once somebody arrives at DBS surgery, they've already seen you and your team first as a neurologist. 

00:17:34 Heather 

They've often tried different options and medications long before you know they're considered for surgery. How do you even determine if someone is a good candidate for DBS? 

00:17:43 Dr Fasano 

Yeah, this is an excellent question. Often we rely on the referring neurologist assessment. There are not many movement disorder specialists in the country. So I would say I know very well them all. 

00:17:53 Dr Fasano 

And I don't have any reason to question if the right medications were used in the best interest of the patient. 

00:17:58 Dr Fasano 

We work as a network. We try to get as much information as possible in a short time, which is what we call the two day assessment. 

00:18:06 Dr Fasano 

We put a battery of test that is meant to really give us an. 

00:18:10 Dr Fasano 

Understanding of what's going. 

00:18:11 Dr Fasano 

On and this includes neuropsychological testing. 

00:18:14 Dr Fasano 

To assess memory, attention all the brain function. An important evaluation by the psychiatrist also to assess. 

00:18:20 Dr Fasano 

Patients, depression, psychiatric problems, Parkinson's. Not just a motor disorder. We need to clarify that. And we also do a liver DOPA challenge and developer challenge means that we see how levodopa helps patients because that helps us understand what type of target to choose, what type of prediction of improvement we can tell the patient. We also look at the brain anatomy with an MRI. 

00:18:42 Dr Fasano 

Importantly, we spend, I would say at least an hour discussing what they. 

00:18:45 Dr Fasano 

From it, what's their goal? Is they truly believe that patients and their family are part of the team and therefore they have to share some responsibilities in deciding what's best for them. 

00:18:56 Dr Fasano 

And eventually it's a team decision. We have an additional meeting with Sunil, other colleagues of ours, all the people involved in this complex, multidisciplinary process to finally say, OK, this is a go. 

00:19:07 Dr Fasano 

It's a DBS yes, because we also consider alternative treatments. It is for one side of the brain for two sides of the brain in this target. In this other target with this type of battery with this type of. 

00:19:18 Dr Fasano 

Electrode and then the timing. 

00:19:20 Heather 

Yeah, it's no easy decision any which way. You mentioned levadopa. We haven't actually talked about that yet. So just wanted to ask if you can just explain to the audience, you know, what is levadopa? 

00:19:30 Dr Fasano 

Dopa is the main drug used for Parkinson's disease in a very simplistic way. In Parkinson's, there's lack of dopamine in the brain and liver. 

00:19:39 Dr Fasano 

Dopa gets converted into dopamine in the brain, so it's like giving insulin to someone with diabetes. So you give them what they miss. 

00:19:47 Dr Fasano 

There are, however, a few problems. Not all the signs of Parkinson's improve with levodopa. A classic example is tremor. 

00:19:54 Dr Fasano 

And also over the years, Libra still remains effective, but the duration of effect can shorten or levodopa can be causing involuntary movements that we call dyskinesias. 

00:20:06 Dr Fasano 

So in other words, the brain wants something constant, not something it goes up and down in the bloodstream like levodopa does. And this is actually when deep brain stimulation. 

00:20:14 Dr Fasano 

Has a role. 

00:20:15 Heather 

So I've been really fortunate to actually be in the room with you, with a patient in the past, that first moment that you've actually turned on the device, it was pretty spectacular to see the patients reaction and some of the changes in some of the symptoms that they had been experiencing before. 

00:20:31 Heather 

Tell me what it's like for you as a physician, that first moment that you turn on the device. 

00:20:36 Dr Fasano 

Oh well, this question brings me a lot of memories because it's the reason why I decided to become a neurologist. 

00:20:42 Dr Fasano 

I saw my first DBS patient when I was 20 years old. I was in an anatomy class in Rome and Italy where I was trained and someone came because he had at this point we know everything in theory, but we don't really understand why we need to know. 

00:20:56 Dr Fasano 

For example, that we have a target in the brain called subthalamic. So our professor brought to the class patient who had just undergone this procedure. The patient was off and the simulation was turned on, simulating the supplements in this case. 

00:21:09 Dr Fasano 

And the patient went from being Parkinsonian to being normal, and that was mind blowing. And 25 years later, I'm doing what I saw in that room on a regular basis. 

00:21:19 Dr Fasano 

The field has changed profoundly, and there's actually nice. I think I've been a privileged position because I have seen the evolution of the field and I can tell you that the more I do this, the more I realize that the real revolution here is the human relationship between the patient and the doctor. You know, you can talk about technology for hours and hours. All these fancy pictures that we see. 

00:21:40 Dr Fasano 

In Internet or publications, but what really makes a difference is that connection that you establish with the person that you turned on on that particular. 

00:21:50 Heather 

Doctor Cayley, I wanted to ask you as well, I mean, your role is really focused on the OR and the surgery itself. 

00:21:55 Heather 

But what is it like for you to see a positive result in a? 

00:21:58 Heather 

Patient that you've operated on? 

00:22:00 Dr Kalia 

For me, after having done this operation hundreds and hundreds of times with many patients that are awake, that moment that you turn on the stimulator and you see a tremor disappear or someone's Parkinson's symptoms improved to a point that it was like. 

00:22:20 Dr Kalia 

5 or 10 years ago, in an instant never grows tiring for me, and similar to Alfonso. 

00:22:27 Dr Kalia 

Seeing those operations was the inspiration to enter in this area of neurosurgery and help advance the field. The seeds were planted early when you could see the immediate difference that you can make in patients quality of life. 

00:22:43 Dr Fasano 

Sunil is a special individual and I would say I'm lucky enough that I work with a lot of your surgeons and and in particular the team at the Western Sunil being one of them. 

00:22:54 Dr Fasano 

There is an ongoing discussion not just about what to do next, but also how things are going in general and this is really the key of being really part. 

00:23:02 Dr Fasano 

Of a team. 

00:23:02 Dr Fasano 

That puts the patient and the family at the centre that we work together. 

00:23:06 Dr Fasano 

And this is one of the things that make Toronto Western, but in general Canadian centres the best because they're really an interest. 

00:23:14 Dr Fasano 

In helping and understanding at the same time, while in other countries it's really a separate process, the neurologist sees the patients before and after, and the neurosurgeon sees the patients only during the operation and that's it. 

00:23:28 Dr Kalia 

I echo that because part of this is working as a team and combining the expertise of many team members to deliver the best care possible. 

00:23:39 Dr Kalia 

I'm sure for a given patient going through a DBS journey, the amount of combined training that all the team members have that are looking after the. 

00:23:49 Dr Kalia 

Patient, I'm sure would be, you know, 75 to 100 years worth of training. 

00:23:54 Dr Kalia 

I think it's amazing to take all these very high level experts and speak a common language and work to improve someone's quality of life. And I drive a lot of satisfaction from that approach. 

00:24:11 Heather 

Can you speak a little bit more about the unique approach at Crumble Brain Institute in terms of some of the other team members who were involved? 

00:24:18 Dr Kalia 

Sure. So for deep brain stimulation, the journey for the patient starts with a neurologist and then the patient will be referred on if that neurologist feels that they may be a candidate for deep brain stimulation. And I know we're speaking on Parkinson's disease, but I just want to also highlight. 

00:24:37 Dr Kalia 

That the surgery is done for other types of movement disorders, including essential tremor dystonia as well as epilepsy and very select cases of patients with severe types of pain. 

00:24:51 Dr Kalia 

So the journey starts with a neurologist and then is referred to the DBS team, which here we have two. 

00:24:59 Dr Kalia 

Neurologist Dr. Fasano is one of them. Doctor Munoz is the. 

00:25:02 Dr Kalia 

Mother and a quarterback, a much larger team that includes neuropsychiatrists neuropsychologists, nurse practitioners. And then there's the neurosurgeons. And then we have additional team members during the surgery, including neurophysiologists that help us record and interpret recordings from the human brain. 

00:25:22 Dr Kalia 

There's the anesthesia team, the nursing teams, and then the journey continues back to the neurology teams with Doctor Fasano, Dr. Munoz and as different issues creep up in the patients journey, it may be that someone's mood is affected by the surgery or their reaction to the surgery. 

00:25:42 Dr Kalia 

Then then that hub can then go along the spokes of the wheel back to the experts on the matter and try and help the patient either related to any issues that arise with the surgery, or optimize the setting so they can drive the best result that we have to keep the expectations. 

00:26:03 Dr Kalia 

Realistic and so part of our job is to also temper expectations that might be beyond what the therapy can deliver in the 1st place and temper expectations as. 

00:26:15 Dr Kalia 

To what may be coming down the road in the next 5 or 10 years, so that's also part of our job and sometimes that means delivering difficult news or difficult decisions with the patient and the patients family. 

00:26:28 Dr Fasano 

If I may say, there is another important part of the team that doesn't receive enough credit and these are well, there are two parts, the assistant, the staff that is in charge of booking, speaking to patients and their families, and it requires a lot of efforts also. 

00:26:43 Dr Fasano 

Condition. As you can imagine, when you deal with so many team members and and also learners, we can probably do 1/4 of what we do without international and national postdoc fellows who come from really everywhere to learn what we do. They are highly motivated neurologists in my case, but also in your surgeons in case of. 

00:27:03 Dr Fasano 

To your team and they come from everywhere to stay a year to year, some of them with young kid. 

00:27:08 Dr Fasano 

They move here with their own family and they do it with us. The strong motivation of learning this technology and this treatment so that they can take the whole package with them when they. 

00:27:18 Dr Fasano 

Go back home. 

00:27:19 Dr Fasano 

And in a way, this helps us tremendously. 

00:27:21 Dr Fasano 

But also we give back to them and to the people and patients that this fellow will eventually meet in their career. 

00:27:29 Dr Fasano 

So our reach really goes beyond Canada. And the beauty of an international program like the one we are working in at each given time, we have between 4:00 and 6:00 fellows only in the DBS neurology part, just to give you an idea of the. 

00:27:42 Dr Fasano 

Volume of these motivated neurologists, but so far in the 10 years I've been in Toronto, I trained close to 40 neurologists on this technology. 

00:27:52 Dr Kalia 

For our program training the next generation, the people that are going to look after me and Alfonso in the future, it's is absolutely critical and it's very rewarding. 

00:28:01 Dr Kalia 

It's like we're planting seeds globally of the leaders of tomorrow and it's rewarding now watching those people that were our fellows now. 

00:28:13 Dr Kalia 

And leaders at meetings and starting to develop programs of their own in many parts of the world. So it's actually quite exciting to see. 

00:28:20 Dr Kalia 

OK. 

00:28:21 Heather 

Well, as long as you're not planning your retirement. 

00:28:26 Heather 

Doctor Kalia, you know, oftentimes when we we speak about DBS, the term neuromodulation comes up quite a lot. 

00:28:32 Heather 

And I think that term might be confusing to people who, you know, don't live in this world. So can you explain? Are the electrodes that you're implanting actually changing the circuitry of the? 

00:28:43 Dr Kalia 

To mean neuromodulation is anything that can change or. 

00:28:49 Dr Kalia 

Adjust circuits within the brain with the goal of improving their function or restoring their function back towards normal. So shifting away from a disease state and resulting in improved quality of life. 

00:29:02 Dr Kalia 

So in terms of DBS, it's been around for a long time now and the field is evolving, but it's one of these home runs that. 

00:29:10 Dr Kalia 

To feel this. 

00:29:11 Dr Kalia 

Had for which the benefit was realized much before how it works was understood, substantial progress has been made as to how DBS might work, but there are still remain significant mysteries. In a nutshell, depending on the disease that you're treating and the target. 

00:29:32 Dr Kalia 

The mechanism of action of DBS may be quite different. What you're doing is you're applying electrical energy in a location in the brain, and you can look at it as the flow of information like traffic lights, and you may be turning some traffic lights that are now red because of the disease. 

00:29:52 Dr Kalia 

Act agreed and the flow of information with these circuits then is reset or restored back towards a more normal state. 

00:30:02 Dr Kalia 

And that manifests as symptoms that are improved and this can occur immediately. So for example, in the case of essential tremor, as you turn the device on and off, you can see the tremor disappear and reemerge, or it can occur over time. So there may be some type of plasticity. 

00:30:22 Dr Kalia 

That occurs in these dysfunctional circuits, so that would be for example. 

00:30:26 Dr Kalia 

Epilepsy or dystonia, where the benefits of stimulation can take weeks to months to manifest, and if you turn the stimulation off, it may actually take weeks for the benefits of the stimulation to disappear. So it's quite remarkable that even with the same technology, the same electrodes. 

00:30:46 Dr Kalia 

That you can have very different effects on brain circuits depending on where the device is positioned and how it's programmed by the neurologists and the neurology team. 

00:30:56 Dr Kalia 

The number of settings and parameters that they can utilize for this purpose is infinite. Part of this and the evolution of the field is to understand how to find the best target, but then once you're there. 

00:31:10 Dr Kalia 

How do you? 

00:31:11 Dr Kalia 

Narrow down the infinite parameters that may help this patient. 

00:31:16 Dr Kalia 

To drive the most benefit in a practical manner. 

00:31:19 Heather 

Well, Doctor Kaylia, I know you work as you mentioned, with a lot of patients who are living with epilepsy and the goal of DBS there would be, I'm assuming to help reduce their seizures. 

00:31:28 Heather 

So this is the part that really fascinates me. Is this whole idea of how do you identify where in the brain seizures are coming from? 

00:31:36 Dr Kalia 

That's actually a very complicated question and there is an entire team and expertise in place for that at crimble. 

00:31:43 Dr Kalia 

So a patient with seizures that are not well controlled on medications should be evaluated by an epilepsy team as we have at the crimble and that team will then do a series of. 

00:31:57 Dr Kalia 

Tests, including admitting a patient with epilepsy on the ward and studying their brain over a period of a few. 

00:32:05 Dr Kalia 

Can be indexed and if the seizure location cannot be identified, then the patient may be recommended for surgery in which we and by we I mean myself and my colleague Dr. Tofiq Valiente. We together implant many electrodes. It can be in the range of 8 to 15. 

00:32:25 Dr Kalia 

Electrodes deep in the brain, and in this case, unlike deep brain stimulation, these electrodes are listening to circuits in the brain, and we can use that information to identify where the seizures are coming from. So it's a diagnostic surgical procedure. 

00:32:42 Dr Kalia 

From that, then, the team convenes and then decides what's the best next operation, and those can fall into two categories, and so that can be resection or ablation. 

00:32:54 Dr Kalia 

So meaning you remove with open surgery or with a laser, the area of the brain that is causing seizures. 

00:33:02 Dr Kalia 

Or neuromodulation, which would involve implanting a vagal nerve stimulator or a deep brain stimulator. And so that's the part that Alfonso and I work on together as well with the other epilepsy team members. Again, this very collaborative approach to working. 

00:33:18 Dr Kalia 

Defining the right settings that may help a patient's seizures. So that's another example of neuromodulation, a group of patients with epilepsy and how that team works together as well. 

00:33:30 Dr Fasano 

If I may add, we are really interested in the deep brain stimulation for epilepsy. She Canada was one of the first countries in the world to approve this therapy for epilepsy 5-6 years before the states, for example. 

00:33:42 Dr Fasano 

And so there's a lot more of opportunities for patients. Again, this requires a multidisciplinary team and sometimes we will even work with teams from the sick. 

00:33:50 Dr Fasano 

Children's Hospital because this is another procedure that sometimes we do in kids, so many more things for. 

00:33:58 Heather 

Well, Speaking of that and sort of the advances in the technology related to epilepsy, I know that there's one technology that you're using that actually helps patients who receive this procedure monitor their seizures remotely. So can you? 

00:34:10 Heather 

Tell me a little bit about that. 

00:34:11 Dr Fasano 

Yeah, technology is in constant evolution. There are certain devices able to record the brain activity more reliably than just a brain diary, see what happens over the years in the brain of the. 

00:34:24 Dr Fasano 

Patient yesterday with Sunil. Actually we saw the patient and we could tell from the recording in the brain when this person was having seizure and he matched entirely what the mother had taken note of on her phone. 

00:34:37 Dr Fasano 

That was actually quite nice to see that there was a complete. 

00:34:40 Dr Fasano 

Match and this. 

00:34:41 Dr Fasano 

Helps because not always, there is a caregiver or parent or spouse able to. 

00:34:45 Dr Fasano 

Keep track of what's happening, but also sometimes seizures are not necessarily being identified by the person, or they're happening in the middle of the night, so there are advantage to better monitoring of what happens, and we are not able to do remote monitoring in order to access the brain activity that is recorded while the patient is at home. We need to. 

00:35:04 Dr Fasano 

Anyways, the patient with us, the remote care portion comes with another type of device where we are able to program remotely using the Internet and this is important also to increase the opportunity to people who live far from our centre. 

00:35:18 Dr Fasano 

Sometimes we say no, even in people coming from Ontario itself, Ontario is a big province as we know, and some people are too far. 

00:35:24 Dr Fasano 

Simply too far for them to be receiving the treatment in a safe manner, but because of remote programming you can turn it off. 

00:35:31 Dr Fasano 

We can adjust settings very easily. It's like FaceTime call basically because of this. Now a lot of people are more interested than they can have access to this treatment while in the past it was simply too danger. 

00:35:43 Heather 

Doctor Kelly I. 

00:35:44 Heather 

Just wanted to follow up on epilepsy for a moment. If you can monitor seizures remotely, is it possible that the technology could one day stop seizures as they're happening, or even detect them before they start? 

00:35:55 Dr Kalia 

Yes, so versions of that technology are already available on label in the US so this type of technology is called closing the loop or closed loop stimulation. 

00:36:07 Dr Kalia 

In general terms, what that is is you sense some signal, possibly from a wearable device, and then you adjust the stimulation accordingly. 

00:36:18 Dr Kalia 

And so your example with monitoring a patient's brain and and changing stimulation at the time of detection of seizures. 

00:36:26 Dr Kalia 

Is actually available on a device that's been available for some years in the US, not available in Canada, but some of the current devices that we use will have that capability in the future. That capability is available for research, so part of our job at the Centre. 

00:36:45 Dr Kalia 

Cars is test these technologies. Do they have value for our patients, a newer and more complex doesn't automatically mean better or better results for the patient. 

00:36:57 Dr Kalia 

And so these are things that we would like to study in the future, not just for epilepsy, but for Parkinson's tremor, other types of disorders of the. 

00:37:06 Dr Kalia 

Brain is can we define signals that we can detect and respond to and what that will do for our patients is the disease and the symptoms from the disease are not the same throughout the day. So to have responsive type of stimulation. 

00:37:23 Dr Kalia 

That closes the loop will then give the patients the best symptom control throughout the day, even if the disease is fluctuating. 

00:37:33 Dr Kalia 

So that's the concept of closing the loop, and that's something that we will see very soon in the clinic. 

00:37:41 Heather 

It's amazing, doctor Kelly, you're also working on imaging work, looking at individual brain cells all the way up to imaging a whole brain. So what is the goal of that research? What can? 

00:37:51 Heather 

Tell you. 

00:37:52 Dr Kalia 

So that's not my research, specifically of where a collaborative team and that's one of the beauties of working at crimble, we have imaging experts. 

00:38:01 Dr Kalia 

And so we're looking at a few different things. And so one is even though MRI images look beautiful, when you see them, they're spatial resolution. 

00:38:12 Dr Kalia 

They call it may not be accurate, so if you see your brain target and it looks as it would in an anatomy textbook, but it doesn't appear geometrically in the right location. 

00:38:24 Dr Kalia 

That could be a limitation for using that beautiful image or surgical planning. So that's a scenario where what you see isn't what you get. 

00:38:33 Dr Kalia 

And so working out paradigms to improve that type of imaging to make it accurate spatially. And we may end up doing that. 

00:38:44 Dr Kalia 

With using MRI's that are actually less powerful magnets that allow for higher spatial accuracy and equally good images. 

00:38:54 Dr Kalia 

So that's one example improving the images so they're useful for surgery. And the more you can see accurately will allow for safer. 

00:39:02 Dr Kalia 

Planning another example is can you use types of imaging with stimulation on and off to understand how the brain circuit is changing. 

00:39:13 Dr Kalia 

And that may have implications in reducing programming time in the future. A third example is once the electrodes are in place, can we use the imaging to show exactly where they are. And then when Alfonso and his team have a patient after surgery. 

00:39:34 Dr Kalia 

And they can potentially substantially reduce their programming time because they'll know exactly in that given. 

00:39:41 Dr Kalia 

Patient with that patient's own anatomy, know exactly the configuration of where the electrode is relative to the target, and possibly give them a starting point that's closer to what the patient needs and reduce the significant amount of labour that they have to put in at the beginning. 

00:40:02 Dr Kalia 

To test that infinite parameter space that I was referring to earlier. So those are three examples of various teams that are looking at improving the surgery itself or improving the programming that comes after the surgery. 

00:40:18 Heather 

It's really incredible. 

00:40:20 Heather 

For all this time in Parkinson's and many of these other brain diseases, there really haven't been any disease modifying therapies. 

00:40:27 Heather 

And so the focus has always been on treating the symptoms and improving the quality of life for these patients. 

00:40:32 Heather 

Are you optimistic that some of the advances, exciting advances that we've talked about today will actually lead to better therapies for patients? 

00:40:40 Dr Fasano 

First, obviously, research requires a lot of funding. 

00:40:43 Dr Fasano 

For a long time, there's been too much interest in finding a cure and not much in funding new treatment, and this is something that everybody wants initially. 

00:40:53 Dr Fasano 

But then when they start having their problems and talking about patients and their families, they start saying ohh, why do we still have levadopa? That it's been around for 40 years or more and DBS is the same thing. 

00:41:05 Dr Fasano 

Over and over some. 

00:41:05 Dr Fasano 

Other 50 years has been around for three decades now. One, we have new symptomatic treatment. So this. 

00:41:11 Dr Fasano 

Search for the. 

00:41:12 Dr Fasano 

Sure can backfire, because we can forget for a second that we also need research to find symptomatic solution. Think about balance disorder, memory problems, speech disorders. 

00:41:23 Dr Fasano 

So there are many things, let alone all the research that is missing in rehabilitation sciences. Rehab is fundamental for these problems, and yet there's very few. 

00:41:33 Dr Fasano 

Search the turning point is being recognizing that Parkinson's disease doesn't exist. We should call it Parkinson's syndrome, or we should use the plural of disease because every person with Parkinson's has Parkinson's for a variety of different reasons. 

00:41:47 Dr Fasano 

And sometimes more than one reason at the same time, there are some subsets of Parkinson's where we know what's happening at the molecular level, and this is precision medicine. 

00:41:57 Dr Fasano 

So identifying the reason patient by patient and intervening on that particular reason for that particular patient. So the consequence of this approach is that. 

00:42:07 Dr Fasano 

We will have therapies and I'm sure we will have very soon actually that are tailored to a specific group of people. 

00:42:14 Dr Fasano 

So it won't be a one. 

00:42:15 Dr Fasano 

Size fits all for. 

00:42:16 Dr Fasano 

Sure, some people even argue what's the difference between a symptomatic treatment? 

00:42:20 Dr Fasano 

It's so effective that removes all the problems and a cure at the end of the day, we're. 

00:42:24 Dr Fasano 

Actually dealing with the same thing. 

00:42:25 Heather 

Doctor Ken. 

00:42:26 Dr Kalia 

Yeah. Yeah. So I think Alfonso highlights exactly the challenge we have and the advocacy that's required in the field that if we're in a scenario where with limited funds, care versus cure is being pitted against each other, we need heavy investments in both for the reasons that Alfonso outlined on the care side, neuromodulation. 

00:42:47 Dr Kalia 

Can only do so much, and for each patient we need to figure out ways to personalize the therapy and that can be at the molecular level. This is exactly been the challenge in the field for generations. Now is, how do you? 

00:43:03 Dr Kalia 

Cure, a neurodegenerative disease or a condition in which brain cells are being lost, and this is an extremely challenging problem requiring a lot of expertise. 

00:43:13 Dr Kalia 

And what I think will happen is that for a cure, the field will have what's called the disease modifying therapy. So to slow the progression. 

00:43:24 Dr Kalia 

Of a disease like Parkinson's would be a major milestone. So turning something from having a progression over a certain amount of time to having a progression over many decades that the worst of Parkinson's may never come for a patient with a disease. 

00:43:41 Dr Kalia 

And I have to say, our patients have been very generous. Many of them want to work with us on the studies, understanding that it's not necessarily going to benefit them. 

00:43:50 Dr Kalia 

It will benefit the future patients with the disease, but we also want to see if there's ways to do this and strategies that are being employed by. 

00:44:01 Dr Kalia 

Scientists at Crimble, including our lab, include repurposing drugs, for example, so using ways to identify drugs that are known to be safe and seeing if they may have a benefit in something like Parkinson's. 

00:44:16 Dr Kalia 

Disease repurposing technology. So as Alfonso mentioned, we've had DBS now for the better part of three decades. A lot of people may not be aware, but for patients with Parkinson's over the last two decades, gene therapy has been tried injecting growth factors in the brain stem cells have been tried. 

00:44:37 Dr Kalia 

So these therapies to date have. 

00:44:40 Dr Kalia 

Not resulted in a home run or a disease modifying therapy, but they've established safety. They've been very important studies. 

00:44:47 Dr Kalia 

So in the future, are there ways that we can take and repurpose DBS to control gene therapy or regulate the biology of disease or deliver new growth? 

00:45:00 Dr Kalia 

Vectors and control them in the brain. So that's the concept called molecular neuromodulation. These are all things that I think. 

00:45:08 Dr Kalia 

Are within our grasp. 

00:45:10 Dr Kalia 

Over the next decade but require substantial amounts of research. 

00:45:15 Dr Kalia 

So there are a lot of exciting things happening in the field, including new ways of delivering things into the brain safely without incisions. 

00:45:24 Dr Kalia 

For example, using focus ultrasound, all of us wish we had more time and funding to investigate. We have all the expertise here to embark on these, and so it's clearly something that requires. 

00:45:36 Dr Kalia 

Advocacy because we need excellent care for patients today and continue to develop and study the new technologies and treatments as they come out. But we also should, as teams still work on that very difficult problem of disease. 

00:45:54 Heather 

All right. It's all about the patience and patient outcomes. I really enjoyed our conversation today and I'm sure our listeners did too. So I just want to thank you so much for taking the time to be here. 

00:46:03 Dr Kalia 

Thank you. Thank you. 

00:46:19 Harry 

The reality of my life is that I have lived about 35 years telling stories of 1 sort and another. 

00:46:27 Harry 

The fact that I'm at the centre of this story really is neither here nor there. It isn't about me. 

00:46:32 Harry 

It's about the treatment and it's about the remarkable results that can come from it and does that gives? 

00:46:38 Harry 

Comfort and direction and hope to. 

00:46:40 Harry 

Other than my job is done, I mean the benefit of me being at the centre of the story that I didn't have to chase around and find someone who is in this situation because I'm right here so. 

00:46:53 Harry 

You know I. 

00:46:53 Harry 

Know the story is about me, but I tried to find a way of telling that story from a more scientific and clinical point of view. 

00:47:01 Harry 

As well as from a personal point of view. 

00:47:30 Heather 

Thank you to Doctor Sunil Kalia, Dr. Alfonso Pisano and to Harry Forestell for joining me on the podcast. 

00:47:37 Heather 

Today, if you'd like to hear more about Harry's Parkinson's diagnosis and his DBS journey, head to our website at uhn.ca/cramble and make sure to click on the show notes for today's episode. 

00:47:52 Heather 

Episode of your complex Brain was produced by Jessica Schmidt. Our executive producer is Carly. 

00:47:58 Heather 

McPherson, thanks also to doctor Amy Ma, Twayne Pereira, Suzanne Weiss and Megan and Dairy for their production assistants. 

00:48:13 Heather 

I hope you enjoyed today's episode, and if you did, I would love for you to tell your family and friends about your complex brain. And don't forget to leave a review on your favorite podcast app. Thanks for listening. 

00:48:29 Heather 

We'll be back in two weeks with another exciting episode. 

00:48:33 Heather 

Have a great day.