Transcranial Magnetic Brain Stimulation & Genetic Epilepsies - Simona Balestrini, University Hospital Meyer (Italy) & UCL Queen Square Institute of Neurology (UK)
Asst. Prof. Simona Balestrini, an adult and paediatric neurologist, shares her epilepsy research into the use of transcranial magnetic stimulation (TMS) as a tool for understanding genetic forms of epilepsy! She explains the methodology of TMS, its applications in clinical and research settings, and the importance of safety in its use for people with an epilepsy. The chat also explores future directions for TMS, including its potential as a treatment option! Transcription and links are below! 👇🏻
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Simona Balestrini
“When we do the TMS-EMG with the electromyography, you don't even need the cap with the electrodes. You only basically have a coil that is put on top of the scalp. It's non-invasive, so nothing like… it's just external here. And then you may hear the click from the simulation. That's it.”
00:22 Torie Robinson
Who knows about TMS or Transcranial Magnetic Stimulation)? Well, it’s a form of neuromodulation (it’s not painful!) that’s been used rather well in helping some people with depression. But now, research is being performed to see how how it could be used to help people with a refractory epilepsy! It could potentially be used as a biomarker to treat epilepsies more effectively but it could also even end up being a treatment in itself! Today we hear from the fabulous adult and child (!) neurologist, Simona Balestrini.
If you haven’t done so already, please press the thumbs-up in this episode, comment below, and subscribe to our channel, so that we can get way more people around the world - clinicians, patients, and the general public - learning facts about the epilepsies!
01:02 Simona Balestrini
I am an adult neurologist by training. I did train in Italy and then I moved to the UK to do a fellowship, to do my PhD, and I worked there as an adult neurologist and I'm still working there at UCL Department of Epilepsy. And then five years ago (almost) I also took on a position as a paediatric neurologist in Italy. So now I'm working between both sides. And so I work as both paediatric neurologist and adult neurologist with special interest in epilepsy and even more in genetic forms of epilepsy.
01:36 Torie Robinson
Goodness. And so how much of your time is spent (like, say, percentage-wise) on clinical work versus research?
01:42 Simona Balestrini
On average, let's say I do 60% clinical work both in Italy and the UK and then 40% research work.
01:50 Torie Robinson
And actually, you know what, I was just thinking… we say that, but it probably amounts to more like 150% in total, doesn't it?
1:58 Simona Balestrini
Exactly, absolutely, absolutely. And you know, in the end, it's also all mixed up because, you know, sometimes, of course, you try to put your research in clinic to try to give additional information and the other way around as well.
02:09 Torie Robinson
I really am not very familiar with - and I know heaps of our listeners are not familiar with -TMS. What is that? What does it stand for? And what is this thing, this service?
02:20 Simona Balestrini
TMS stands for “transcranial magnetic stimulation” and is a methodology which is actually not so new because it's been used now for decades, and the way works is that it gives a magnetic stimulation, a very small magnetic field; similar to the one that is used in a brain MRI scan but the magnetic field is much smaller. And this small magnetic field is able to activate some neurons in the brain, so to stimulate the brain so there is some electrical activity. And what it is very useful for is to record how the brain responds to the stimulation. So, it gives us an -additional layer of information compared, for example, to MRI scans (where you get structural information from the brain) or spontaneous EEG when we have EEG during resting we have information on brain activity, but in addition with TMS, we try to understand how the brain responds to a perturbation. So, it's a sort of active probe for the brain.
03:34 Torie Robinson
So, it's like you can zap a little bit, a targeted part of the brain, to see how it will behave upon that zap?
03:40 Simona Balestrini
Correct. That's very good, yes.
03:42 Torie Robinson
How are you researching the epilepsies or a particular type of epilepsy using this method?
03:47 Simona Balestrini
So, we've started applying TMS in people with epilepsy by using TMS coupled with EMG because the TMS, it just gives a stimulation. But then we need a way to record the output from the stimulation. And the most widely used way is to combine TMS with EMG (electromyography). So, basically, we put an electrode on the hand muscle and so we stimulate on the motor cortex and then we'll basically obtain some twitches from the hand, and of course we measure, then they sort of respond, because then the stimulus goes from the brain to the spinal cord to the muscle, and that's the output. But that's a bit limited because you only probe the motor cortex. When we combine TMS with EEG, then we can get information from the whole cortex. So that's the added value.
04:42 Torie Robinson
Can you describe what it looks like?
04:44 Simona Balestrini
When we do the TMS-EMG (with the electromyography), you don't even need the cap with the electrodes. You only, basically, have a coil that is put on top of the scalp. It's non-invasive, so nothing like… it's just external here. And then you may hear the click from…
05:04 Torie Robinson
Oh!
05:04 Simona Balestrini
…the simulation.
05:05 Torie Robinson
What, like “Click, click” - like that?
05:07 Simona Balestrini
It's like a... “click, click”
05:09 Torie Robinson
Ahh!
05:09 Simona Balestrini
I’m sorry, I may not be able to reproduce it well, but that's the sort. It's a click. Sometimes you can have a little feeling like a prickle, something like... It depends also on the intensity of the simulation. And then if it's with EMG, you will have a twitches from the hand, like this.
05:27 Torie Robinson
Ahh.
05:28 Simona Balestrini
Okay, so that's the EMG. With EEG, you have no twitches. It depends on where you simulate. But then, of course, you have at the same time the classic EEG recording with the EEG cap
05:40 Torie Robinson
And so, it doesn't hurt or anything and there's no scraping of the scalp.
05:44 Simona Balestrini
It’s the same procedure required to put an EEG cap on. You do some scratching just to put the gel to do the sort of…, but that's it. There is no other sort of invasive procedure required.
05:56 Torie Robinson
And so, I'm going to refer to one of your very interesting papers about this now: “TMS: transcranial magnetic stimulation as a tool to understand genetic conditions associated with epilepsy”. How on earth does it help you understand the genetic ones more?
06:11 Simona Balestrini
That’s a very important question. Well, one of the first questions we had was, okay, how do we go from a person who has a genetic mutation to understand how that mutation leads to an epilepsy with additional issues like sometimes learning difficulties, you know very well, psychiatric problems, and so on. So, of course, we always do our sort of more routine procedures such as MRI to see if there are structural abnormalities, a normal EEG to see how active/how severe is the epilepsy, we do psychological tests. But then we also wanted to add an additional layer of information through TMS because we know that when there is epilepsy, there is an imbalance between activation, excitability process (so when the neurons are more active), and on the other hand; inhibition. This is a normal process that happens all the time in the brain, but sometimes this excitation and inhibition processes get some imbalance and that in many also model seems to lead to epilepsy. So, we know that, especially with the TMS-EMG that is much more used, some specific protocol we do correlates with some level of excitation and inhibition. And so we applied, for example, TMS in Dravet syndrome, where we know that one of the problems is that the sodium channel doesn't work properly, and this mainly affected the inhibitory neurons (so some neurons that are mostly involved in inhibition). And in fact, we saw a nice correlation between people with the syndrome and their output in the TMS-EMG.
08:03 Torie Robinson
Huh.
08:03 Simona Balestrini
And the same has been done for other single gene epilepsies, so where there were mutations in other specific genes where we know what gets wrong. But, of course, now, our question is to extend this to other genetic causes because genetic causes can be many, many different ones. And also, so far, this evidence is mainly from EMG (so just from the motor cortex). But we think it makes more sense, also to extend the study to the whole brain through the EEG. So that's why we are now trying to explore also what TMS-EEG can add to this understanding.
08:41 Torie Robinson
I'm just imagining that you're getting these readings and the professions required to actually analyse this data together from different sources. It must be a pretty big deal, right? Collating all of this and then looking at it as one.
08:55 Simona Balestrini
It's not easy, even just acquiring the data is not easy because, you know, it's a long process, it's not immediate, it's not like we do a scan. It's a complex procedure, it's time-consuming, sometimes people get tired, so yeah, it's not straightforward, at the moment it's still on a research basis to try to answer this question, but we believe it's potentially interesting.
09:18 Torie Robinson
How long does each reading usually take? I mean, I'm sure it's different for each case, but, like, is there an average amount of time you spend with each patient having this?
09:26 Simona Balestrini
For the actual procedure, so when we give the stimulation, I think an average session lasts probably 2-3 hours per patient.
09:35 Torie Robinson
Oh, so it's good while.
09:36 Simona Balestrini
So it's long, yeah. And then, of course, we then do the reading separately. And we may not also immediately feedback information on the patient because we then analyse the data all together. It's not like an immediate feedback that we can give to the patient.
09:50 Torie Robinson
No, of course. So, we could be looking at weeks, and that's just having access to the right people who know how to analyse this. You think about zapping one's brain, and that idea scares quite a lot of people who have an epilepsy because they're like “Mate, I already feel zapped enough with my seizures (if they have them still)”. So, I know that you've done a paper just to prove that it is safe for people with an epilepsy. Can you tell us about that, please?
10:16 Simona Balestrini
Well we also wanted to establish safety first because of course we give a stimulation to the brain so we could not exclude 100% that we are not eliciting some additional activity. But then what we did, because there are different ways to deliver the stimulation, so what we use for research purposes is single pulse or pair pulse. So, it means we just give one of stimulus and of course we still repeat them (but with a large interval in between) or too close stimuli, that's it. There is another way which is repetitive which I may mention if we have time which is more useful treatment (although not in epilepsy - yet). We are also looking into that and hopefully we will have some more answers. But this is just to say that when we checked whether the single pulse or pair pulse protocols were safe, we of course apply this different type of stimuli in people with epilepsy and we compared first of all the EEG (pre and post) but also their seizure frequency the three months before and the three months after and we confirmed that there was no significant change in their EEG activity burden of abnormalities and also on their actual seizure frequency. We are now actually extending this study. We have many more people than how we have tested with TMS and we can confirm that this technique with this sort of different type of stimuli is safe and does not worsen seizure control, which of course is the main concern.
11:56 Torie Robinson
And also, from what I read, you even include people with sort of the rarer epilepsies who often have more frequent seizures anyway, and their seizures were not worsened or made more frequent. So that's really quite reassuring, I think.
12:09 Simona Balestrini
Indeed.
What we are exploring is, of course, what additional information TMS can give us in terms of underlying mechanisms (so genetic basis or sometimes there are other causes), so we want to see whether it can give us additional understanding of the processes.
12:26 Torie Robinson
Mm-hmm.
12:27 Simona Balestrini
But also, we would like to see whether it can also help us to have a sort of measurement of treatment response. So, for example, if I do TMS in a person with a specific type of epilepsy, let's say Dravet syndrome, and I see an abnormal response. Then I start them on a treatment, they improve, and perhaps also their TMS response improves.
12:49 Torie Robinson
Mmm.
12:50 Simona Balestrini
So, then I would like to go back and see how their initial response looks like and see whether somehow, I see in that response a marker of… that can predict treatment response, and so, then I will go back to other people and I will [say] you know, look “It's quite likely that you respond to it. Because, as you know, at the moment, we don't have predictors of response.”. Say ‘OK, we start this medication, we hope it works. But we don't know 100%.” And maybe we can add some biomarker from the TMS perspective. This is another direction we are taking. But also, what we are interested in is to see whether TMS can also be a treatment. You know, neuromodulation as a non-pharmacological treatment has been more and more explored, at least in epilepsy, with some positive results and some validated ones like vagus nerve stimulation, which is also considered neuromodulation. Also in rare cases: deep brain stimulation. But these are all invasive in a way. TMS, in epilepsy there have been very few studies, very, very few, with contrasting evidence. Some showed benefit, some didn't show benefit. While in other fields such as psychiatric conditions, for example in depression, actually it is considered an effective treatment…
14:13 Torie Robinson
Mmm.
14:13 Simona Balestrini
…and it is used on a routine basis to treat depression, to treat obsessive-compulsive disorder. So, on this basis, we are now designing a clinical trial to see whether perhaps we can use it also as a treatment, but at the moment, there is no evidence, so we don't really know.
14:31 Torie Robinson
So, studies are required first, and that's what you're in the middle of, right.
14:34 Simona Balestrini
We are, yes, we are hoping to be able to do that.
14:37 Torie Robinson
This is exciting stuff, and as you know, you're mentioning - the psychiatric side of what affects a person's quality of life, as well as the seizure frequency or severity. So, bringing those two together and helping improve the person's life for both those things would just be brill, I think.
14:54 Simona Balestrini
Yes, exactly. It will be a nice complementary effect.
14:57 Torie Robinson
Thank you to Simona for telling us all about TMS and getting us excited about the potential it may bring to improving the lives of people with an epilepsy in the future!
Check out more about Simona at the website torierobinson.com where you can access this podcast, the video, and the transcription of the entire episode all in one place. And if you haven’t done so already, please press the thumbs-up for this episode, comment below, and subscribe to our channel, so that we can get way more people around the world - clinicians, patients, and the general public - learning facts about the epilepsies! See you next week!
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Dr Simona Balestrini qualified in medicine and completed her specialist training in neurology at the Polytechnic University of Marche, Ancona, Italy. She was awarded her PhD in human health at the same University in 2017. During her training, Simona spent some time at UCL as a research fellow in the field of epilepsy genetics, and also visited the “C. Munari” Epilepsy Surgery Unit at Niguarda Hospital, Milan, Italy where she focused on neurophysiology and surgical treatment of epilepsy. Dr Simona is an Associate Professor of Child Neurology and Psychiatry at the Department of Neuroscience and Medical Genetics, Meyer Children's Hospital IRCSS, and the University of Florence, Italy. She is also a Consultant Neurologist at the Chalfont Centre for Epilepsy and the National Hospital for Neurology and Neurosurgery, UCLH, as well as a Senior Clinical Research Fellow at the UCL Queen Square Institute of Neurology.
Simona specialises in epilepsy genetics, rare and complex neurodevelopmental disorders, and neurophysiology. Her research focuses on genomic and neurophysiological tools to understand the causes, course, and treatment response of epilepsy, with the aim of translating findings into personalised treatments. She has made significant contributions to rare and complex neurological conditions, including studies on genotype-phenotype correlations, neuroimaging, and biomarkers for neurological disorders.
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University Hospital Meyer meyer.it
UCLH dr-simona-balestrini
Neurology Academy dr. simona-balestrini
Epilepsy Society simona-balestrini
VJ Neurology simona-balestrini
ORCiD 0000-0001-5639-1969