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[00:00:27] Dr. Anna Sadnicka: Thank you very much, Francesca.
[00:00:28] Dr. Francesca Morgante: With Anna, we will go through the topic of the neural roots of dystonia and in particular, Anna will unravel for us the neural network dysfunction in dystonia. Anna, we know that in dystonia there are at least two major actors that has been associated to degeneration of dystonic symptoms. The first actor are the basal ganglia.
What is the role of the basal ganglia in producing the dystonic symptoms?
[00:00:58] Dr. Anna Sadnicka: Yes, so I think [00:01:00] dystonia has always been quite a difficult disorder to try and encapsulate in terms of finding a causative neuro anatomical node. And so certainly early ideas were very basal ganglia centric.
And so, we knew that lesions of the basal ganglia in particular, the putamen and the caudate could lead to an acquired dystonia and certainly there's then been evidence in both animal and human studies that there is some functional disturbance in the basal ganglia. And obviously with advances in our neurosurgical techniques, we can help a subset of patients with dystonia with their symptoms, with deep brain stimulation to the basal ganglia.
But I think it's always been obvious and even since the early literature that that was not the full story. There's always been evidence that lesions in other parts of the brain, for example, can cause dystonia. Clinical associations with other movement disorders that are more concentrated on the basal ganglia [00:02:00] could also cause dystonia.
And so, I think it's been very interesting how we've been widening our understanding of the disorder to think of a more comprehensive network model for dystonia recently.
[00:02:14] Dr. Francesca Morgante: This is very important to understand, where lies the neural dysfunction, because if we understand the main network that is involved within the generational dystonic symptoms, we might develop neural modulation strategies, but invasive and non-invasive modulation strategies to improve this disorder. And in particular, there is a second actor that may play a major role in the generation of symptoms, and this is the cerebellum. Would you like to explain to us what is the role of the cerebellum in dystonia?
[00:02:51] Dr. Anna Sadnicka: Yes, so again, I think we have very good evidence that the cerebellum is involved. So similar to the basal ganglia, if you have lesions of the [00:03:00] cerebellum, this can cause dystonia.
And there's also early surgical literature and now a more recent surgical literature that neurostimulation to the dentate nucleus and cerebellar outflow tracts can be helpful in the treatment of dystonia. The major missing information for me was certainly, what is the role of the cerebellum?
Okay, it might be involved, but can we get any deeper, can we drill down onto what the actual functional deficit is, and that was the topic of my PhD a number of years ago. Where, I was trying to find a more specific role for the cerebellum and the overall story from many different studies and many different subtypes of dystonia is it's not an easy answer.
So, if you test classic cerebellar paradigms such as adaptation, which is a cerebellar paradigm that you can study in a robotic arm or classical conditioning where you look at eye blinking conditioning in the [00:04:00] cerebellum. If you look overall at these studies, we don't see a clear impairment of these core cerebellar paradigms.
And so I think it's telling us that we need to be a bit more intelligent in the way that we're trying to probe this network. If we go at it with a kind of investigative tool, we may not be capturing how the network dysfunctions. It may not just be a single node.
It may be all of these different nodes acting in orchestrated manner.
[00:04:30] Dr. Francesca Morgante: So I think that you pointed out to one of the major drawbacks, even when interpreting all this research. One of the major problem is that they merge different types of dystonia and maybe the different types of dystonia are under underlying.
By different neural natural dysfunction. For example, recently it came out in movement disorder journal, a very interesting neuroimaging paper by the group of Davide Martino, that pointed out how the [00:05:00] dentatorubrothalamic tract can be relevant into the generation of cervical dystonia. So ultimately, do you think that in designing this neurophysiological or neuroimaging study, should we look more carefully in defining homogeneous group of patient in order to understand which neural networks define a specific dystonic symptom?
[00:05:23] Dr. Anna Sadnicka: Yes, I think that's a major thing that is to decide which dystonia we're talking about. So we can use dystonia in many ways. Are we talking about the phenomenology and its most broad sense and abnormality of posture, a symptom? Or are we talking about a specific syndrome such as a neck dystonia or are we actually drilling down onto a specific disease with a specific genetic mutation, it's likely that each of these has different neural underpinnings, and I think that's certainly one of the factors that could lead to the difficulty we currently have in having a [00:06:00] unifying theory for all of this.
[00:06:02] Dr. Francesca Morgante: One of the most intriguing dystonic condition is a task specific dystonia. Would you like to tell us more about what is task specific dystonia and what do you think is the core abnormality that underline task specific dystonia?
[00:06:19] Dr. Anna Sadnicka: Yeah, I mean this is certainly a subtype of dystonia that's close to my heart because I've done quite a lot of research in this subtype and what really fascinated me with this particular type was that very often there was a clear history for particular risk factors that seem to be predisposing individuals to develop task-specific dystonia.
And this only occurs in a particular task so people can be affected when they're playing the violin, but then if they go to use their hand in another context, they can use their hand normally. And so for me, this speaks of the fact that the pathophysiology is locked into the specific [00:07:00] skill network associated with this disorder.
And if you jump into any skilled literature in neuroscience, then immediately you've got this wealth of information about what all of the different regions of the brain are doing, particularly roles of the sensory motor cortex, association areas of the cortex, which I think probably have a greater role in this subtype of dystonia.
[00:07:23] Dr. Francesca Morgante: So do you think that if the sensory motor cortex has such a pivotal role in task specific dystonia, is there any root for non-invasive treatment of this condition with any type of neuromodulation or this is just a dream that we will never be able to realize?
[00:07:41] Dr. Anna Sadnicka: I think it's just whether that's the right modality. I don't think we have that level of understanding yet.
So that's the dream, isn't it? That we have a model that gives us the information that will inform our treatment strategy. And I don't think we're there yet with many subtypes of dystonia. I certainly find the feature space very interesting. And I think [00:08:00] other methods of retraining movements are also quite interesting.
Cause that's another way to engage the whole network with specific retraining strategies that try and take you into a different motor control space. So I think we have a lot of options. We've got lots of very exciting system level treatments that are really evolving at the moment, and hopefully soon, all of our research is gonna give the information, the understanding, that will allow us to improve those treatments.
[00:08:28] Dr. Francesca Morgante: Where do you think our field should go? How we should design neurophysiological studies to really pick the underpinnings of dystonia?
[00:08:38] Dr. Anna Sadnicka: So, I remain completely fascinated by dystonia because I think we have so much work to do in terms of our understanding, and I think some of the themes that we've been discussing already are what we need to lean on.
We need to be trying to assess the network. We need to be thinking about what level of the brain we're exploring, trying to link [00:09:00] level of mechanism across different scales of the nervous system. Trying to bring in this very disparate literature that we have at the moment to create models that give us better information to feed into our treatments.
[00:09:13] Dr. Francesca Morgante: So we know that for sure there are many networks involved. There are fundamental nodes, but still one major problem in our field is how to correlate the specific abnormality of brain level with the generation of dystonic symptom. Until we want answered that research question, we would be unable to develop better treatment and ultimately treatment is what we want to develop out from this neurophysiological studies.
I would like to thank Anna for her time and thanks Anna.
[00:09:52] Dr. Anna Sadnicka: Thank you Francesca.
[00:09:53] Dr. Francesca Morgante: And I will once again talk to you next episode. Bye.