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[00:00:38] Dr. Alfonso Fasano: And so before we get started, can you tell us a bit about yourself, where you work what your interests are so that the listeners can have a sense of, will have the pleasure to hearing from.
[00:00:50] Dr. Rick Helmich: Yes, I work in Nijmegen in the Netherlands at the Radboud University Medical Center where I work as a neurologist specializing in movement disorders. And about [00:01:00] half of my time, I work at the Donners Institute also in Nijmegen, where I'm mainly doing imaging work in movement disorders and with a particular interest in tremor.
[00:01:10] Dr. Alfonso Fasano: Very good. And when I was thinking about putting together this series of interviews, I immediately thought of you and you're interested in neuroimaging to as a window into understanding. how we shake. So I will start with a very simple question How's the MRI of typical Parkinson's patients with tremor or an essential tremor or someone with dystonic tremor? So how's the typical structural MRI so the very basic neuroimaging first level of investigation that we do in these patients?
Is it useful to understanding tremor?
[00:01:43] Dr. Rick Helmich: Typically not so much. So in Parkinson's disease, we usually do an MRI to rule out structural causes but patients with and without tremor have basically the same MRI. If you would do it for clinical purposes. And the same [00:02:00] holds for essential tremor, dystonic tremor.
Usually the MRI is normal and in most patients with a bilateral tremor without other neurological signs, it is not really necessary to make an MRI. There are particular cases where an MRI is useful. For example, if you suspect a cerebellar tremor then there might be atrophy of the cerebellum pointing in a useful direction or if you are suspecting a Holmes tremor, then it is important to look for a lesion.
Sometimes with dedicated sequences, for example, iron sensitive sequences to look for microglia. So in those instances, it is useful. Yes.
[00:02:42] Dr. Alfonso Fasano: And when we get to more sophisticated ways of analysis, for example, more form a tree I'm aware of studies done in essential tremor looking at the Cerebellum. What do you make of it?
[00:02:52] Dr. Rick Helmich: Yeah, so for essential tremor, the evidence is really mixed with regard to morphometry. So there are studies [00:03:00] showing cerebellar atrophy in essential tremor, and that relates to the hypothesis that essential tremor is caused by oscillations that are generated in the cerebellum. But there are also studies showing that those regions that are implicated in tremor such as the thalamus or the dentate nucleus are in fact larger in people with essential tremor.
So the evidence is really mixed. And I think one problem in the field is that the typical data sets of tremor patients used for MRI are relatively small.
[00:03:39] Dr. Alfonso Fasano: Yeah, I agree. Okay, but now let's move to, I would say, one of your favorite topics, functional MRI. So can you tell us a little bit about what functional MRI is, how it's done and why can be helping the understanding of tremor?
[00:03:55] Dr. Rick Helmich: Yeah, functional MRI measures the blood oxygen [00:04:00] reuptake, so the BOLD signal, which is sensitive to blood flow to a particular brain region. And these images are collected very rapidly. So every, say, two seconds, an image of the entire brain is collected. And it is rather precise anatomically in the sense that usually we have a voxel resolution of about two or three millimeters isotropic.
And of course, the first problem you think of when looking at fMRI in tremor is that all tremors are much faster than two seconds. A typical tremor. has a frequency of four to five or six hertz. And you cannot capture that frequency with fMRI because it is too slow. And, I think where fMRI becomes interesting is when you look at brain signals that fluctuate with tremor power over time.
[00:05:00] And there fMRI can be used to investigate tremor because these fluctuations in tremor severity or tremor power are much slower. So they occur over the time course of multiple seconds, sometimes minutes. And then it becomes interesting because then you can look which brain regions have a bold time course that has the same shape or dynamics as tremor power over time.
[00:05:29] Dr. Alfonso Fasano: This is extremely interesting and and I know that you've done several studies indeed using functional MRI in tremor. And I will start with maybe one of your favorite topics, if not your favorite topic Parkinson's disease tremor. Can you guide us through the theory that dimmer switch theory, that you came out with?
[00:05:47] Dr. Rick Helmich: Yeah that research line started with the paradox that Parkinson patients with tremor have a tremor that is very different from the [00:06:00] other symptoms that they have, like bradykinesia and rigidity. The tremor doesn't respond as well to dopaminergic treatment the tremor severity does not correlate with the degree of dopamine depletion in the striatum, measured for example with dot scan or PET and yet the tremor is very easily or very effectively treated with deep brain stimulation at two different circuits, namely, In the basal ganglia, for example, GPI or STN DBS, but also in a very different circuit cerebellar circuit, namely in the ventral intermediate nucleus of the thalamus, which receives input from the cerebellum, not from the basal ganglia.
So it seems at that time that there are two different circuits being involved in Parkinson's tremor, the cerebellar circuit and the basal ganglia. And that is why we started investigating that topic. And the hypothesis [00:07:00] was that these two circuits have different contributions to tremor. And what we showed with fMRI is that whenever the tremor started to increase, so when it changed from very little tremor to a lot of tremor there was a transient activity of the basal ganglia, the GPI.
And when the tremor was up and running, sort of high amplitude those episodes were correlated with activity in the cerebellotalamic cortical circuit, so the cerebellum, the VIM, and the motor cortex, and that led us to propose that the basal ganglia form a switch that trigger tremor episodes, but then the cerebellotelamic cortical circuit takes over and amplifies that signal leading to a visible tremor.
[00:07:51] Dr. Alfonso Fasano: Wow, this is fascinating. And I still remember when I read your article, I think it was Published in Brain. And one thing that this is more of a curiosity that [00:08:00] came to my mind when I saw the article is dimmer switch. That's so intuitive. Everybody can understand anybody with a lamp at home can understand.
Did you come up with this idea or was it from someone else?
[00:08:12] Dr. Rick Helmich: No we came up with that idea. We wanted to have something intuitive that sort of summarizes the complex findings behind it.
[00:08:20] Dr. Alfonso Fasano: Very good. So, and now moving on from Parkinson's to other tremors I've used a functional MRI to understand other types of tremor.
[00:08:29] Dr. Rick Helmich: Yeah, we've used it also for dystonic tremor and there it becomes a bit more tricky because many dystonic tremors are typically more severe during action than during rest which is different from Parkinson's tremor. And that introduces a methodological challenge, which is that you have to ask subjects in the scanner to perform actions in order to evoke the tremor. And that in itself is not so difficult, but what is then more difficult is to disentangle [00:09:00] the voluntary action from the involuntary tremor. And for that we've developed some methods,
using multiple regression analysis to really separate these two processes to but that is a bit more complex now in dystonic tremor and that is also a quite interesting tremor because it also involves multiple circuits like basal ganglia and cerebellar circuits. And what we found in dystonic tremor is a massive activity of the cerebellum. So much more than in Parkinson's disease tremor.
Next to also abnormal tremor related activity in the globus pollidus and the motor cortex. So the same suspects, the same regions as in parkinson's tremor, but much more involvement of the cerebellum.
[00:09:46] Dr. Alfonso Fasano: Very interesting. But this aligns also with many theories of the crucial role of the cerebellum in the pathophysiology of dystonia. But this is topic for another podcast perhaps. And so this is a Parkinson's tremor. We talked about this sonic [00:10:00] tremor. I've done work in other type of tremor, like Holme's tremor or essential tremor or, functional tremor?
[00:10:07] Dr. Rick Helmich: Now, Holme's tremor we did have a paper showing in a single case of Holme's tremor due to a micro bleed in the mesencephalon that indeed there was on an individual level tremor related activity in the cerebellum and the motor cortex of that patient. That also made me curious in the sense that if we can see it in an individual patient can we then use fMRI also for individual cases in the future, for example, to get a grip on individual pathophysiology which could be used for treatment.
So that is one thing we are working on now. Essential tremor, I haven't published about that. There's other people in the Netherlands, for example, Arthur Buijink in Amsterdam who has done similar work as we have done in essential tremor, also showing [00:11:00] the large role of the cerebellum and the motor cortex in ET.
[00:11:04] Dr. Alfonso Fasano: So, Generally speaking as you indicated earlier, there are always the usual suspects, cerebellum, basal ganglia, motor cortex, obviously has the final output that are at the basis of the tremor pathophysiology. But in a more general framework, if someone asks you.
How do we shake? Why do we shake? What's the basis of tremor? Can we have a common pathophysiology that applies to everything, including physiological tremor?
[00:11:34] Dr. Rick Helmich: Yeah. So I think in any tremor, the cerebellothalamic cortical circuit is involved and there are oscillations, oscillatory rhythmic activity in this circuit produces the tremor. And that is the case for any tremor that I know. The question is, how does this circuit, why does this circuit start to produce these oscillations?
And there, I think there are [00:12:00] different mechanisms involved in different tremors. For example, in essential tremor one influential hypothesis says that these oscillations come from one region in the cerebellothalamic cortical circuit, which is the cerebellum due to abnormal climbing fibers.
And these are transmitted to the VIM and to the motor cortex. However, there's also other hypothesis for essential tremor saying that it is not so much one particular brain region that starts to generate these oscillations, but it is rather an instability in the circuit. For example, due to cell damage in purkinje cells in the cerebellum, and that this instability in the circuit causes an oscillation in a similar way as for example, cerebellar damage causes intention tremor or overshoot in ataxia.
[00:12:58] Dr. Alfonso Fasano: That's very interesting. And I will [00:13:00] agree with you, although I will argue that, not every tremor necessarily has to rely on the circuits.
I mentioned, for example, physiological tremor. And as we know, there is a peripheral component to it. And then obviously when there's a central component, then you might argue that this is the circuit. I do wonder though in functional tremor, whether we should be looking at the same structures. I don't know whether you have any knowledge in that regard or ideas or hypothesis about how functional tremor is actually generated.
[00:13:27] Dr. Rick Helmich: Yeah, that's an interesting question. So, we haven't looked at that ourselves. I would expect that a similar circuit is activated which is basically the cerebellar thalamic cortical circuit, which is equipped in humans to generate rhythmic movements, whether they are voluntary or involuntary.
And I would expect that in functional tremor, There's additional activity in regions outside of this circuit that activates this circuit and some studies hint at, for example, the prefrontal [00:14:00] cortex. Other circuits hint at the angular gyrus where abnormal activity has been seen in patients with different functional movement disorders.
[00:14:09] Dr. Alfonso Fasano: Yeah, no, I realize this is not an easy question. But I will agree with you that because this is something we have seen in other functional disorders that usually they insist on the same regions seen in the nonfunctional counterpart, but I guess that's an open question at the moment.
And speaking about it. And that's my last question to you. Where do you think the field should be going in trying to understand how we shake?
[00:14:34] Dr. Rick Helmich: Yeah, so That's a good question. I think there are multiple directions where the field should be going. So one thing is that what we're seeing in other disorders like Parkinson's disease and Alzheimer's is that there are large databases being generated that really allow us to look in detail in hundreds of individuals.
And these databases are missing for [00:15:00] disorders like essential tremor and dystonic tremor. So I think one thing we should be doing is team up and generate large databases to look into. Another thing that we should solve as a field is the unclear diagnostic boundaries between many tremor disorders.
For example, essential tremor plus, dystonic tremor, tremor associated with dystonia. And that is a difficult task, but I think we should do that in larger databases. The other thing that might really have an impact is the effect of wearables. So we are seeing a lot of research on wearables and I think they can be very informative not only about the impact of tremor in daily life, but also about patterns that we see in fluctuations in tremor.
For example, the relationship with stress, the relationship with certain movements that people make, the circadian rhythm, these kinds of things. And I [00:16:00] think what is truly interesting is the emergence of non invasive stimulation procedures that can target deep brain regions. For example, the transcranial ultrasonic stimulation, so the TUS, not the HIFU, but the TUS that can reach deep targets and that can interfere with tremor related activity there.
[00:16:23] Dr. Alfonso Fasano: Amazing. Thank you. You really covered so many exciting new avenues and agree with all you've said. So once again thank you, Rick, for accepting this invitation to be one of our guests for this special podcast on tremor. I also want to thank the listeners for tuning in and hearing from Rick this very exciting topic. And for sure in the future, we'll have a lot more to cover.
And I'm sure we'll be hosting you one day, Rick in a few years from now, probably to go over what's been discovered. Meanwhile, I'm sure many more things will come. So thank you once again.
[00:16:57] Dr. Rick Helmich: My pleasure, Alfonso. And I hope we get some new [00:17:00] stuff in the next years. Thanks for listening.
[00:17:02] Dr. Alfonso Fasano: I'm pretty sure you will. Thank you.