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We're going to be talking about her recent paper in the Movement Disorders journal, Frequency Selective Suppression of Essential Tremor via Transcutaneous Spinal Cord Stimulation. Thank you for joining us today.
[00:00:48] Dr. Anna Latorre: Thanks for inviting me. It's my pleasure.
[00:00:51] Dr. Sara Schaefer: I'm going to start really simple here. This may seem like a simple question, but it's actually not so simple. What is essential tremor [00:01:00] and what is the current gap in treatment?
[00:01:03] Dr. Anna Latorre: Yes, you're right. It might not be so simple. Defining essential tremor sounds straightforward, but it has been a topic of much debate in the recent years. According to the latest consensus from the MDS, it is an isolated tremor syndrome characterized by bilateral upper limb action tremor that persists for at least three years without other neurological signs.
If other neurological signs of a certain significance are present, it is classified as ET-plus. But apart from the definition, what is new here is viewing ET as a syndrome rather than a single entity that allows for existence of multiple etiologies. This means that bilateral action tremor is an extremely common manifestation of a central nervous system disorders and the causes are various.
This broader view, however, reflects why there is still [00:02:00] so much disagreement on it is prevalence, symptoms and progression as well as pathology on the other side. Our limited understanding of it is mechanism impacts the treatment. And this is why our treatments are mostly symptomatic and partially effective.
Indeed, available treatments can be divided between oral medication interventional procedures, including botulinum toxin injections, invasive or non invasive brain surgery. Pharmacological treatments such as propranolol, primidol provide symptomatic relief for only 37 percent of patients, and the benefits are often limited.
Importantly, about half of patients discontinues this medication due to side effects, especially the elderly who are most affected by ET. Botulinum toxin offers benefits for selected cases, and for patients unresponsive to these treatments, there are surgical [00:03:00] approaches which have the advantage to target neural circuits associated with tremor.
This could be DBS or lesional interventions such as MRI guided focus ultrasounds. And they have effective outcomes, but these procedures are not always feasible and too invasive for some. Also, they come with the risk of complication and habituation, for instance, which is a reduced response over time, can be observed in a proportion of patients.
For all these reasons, the treatment of ET is still an unmet need.
[00:03:35] Dr. Sara Schaefer: So you mentioned, DBS and things like that, getting at that pathophysiological circuit, underlying ET. Can you talk a little bit more about what we know about those mechanisms that led your team to consider transcutaneous spinal cord stimulation as a possible treatment modality, for tremor?
[00:03:56] Dr. Anna Latorre: Yes essential tremor exact [00:04:00] pathophysiology is not fully understood yet. However, the cerebellotalemocortical loop is widely accepted as a principal neural circuit involving ET and as well as other action tremors. Several pieces of evidence suggest that this pathological oscillation is driven by the cerebellum.
For instance, a recent animal study, highlighted also in a hot topic in the last issues of MDJ journal, showed the population of neurons of the olivocerebellar circuit drive the frequency dependent oscillation typical of ET, confirming the cerebellum's significant role. Based on this observation, our team has previously applied alternating current stimulation over the cerebellum and face lock to the tremor OBT patients, showing that the simulation can alter cerebellar activity and induce a reduction of tremor amplitude in this patient.
However, also peripheral nerve simulation applied with different protocols is shown promising [00:05:00] results in tremor suppression so far. So it seems that the perturbation of the flow of the oscillatory activity driving tremor at different levels from its of its propagation, so from its source, the cerebellum to the muscles, can potentially suppress it.
So the idea with transcutaneous spinal cord stimulation was to disrupt tremor generating circuits by targeting the spinal cord, which is easily accessible through non invasive stimulation. And similarly to peripheral nerve stimulation, our intent was to recruit afferent pathways projecting to the tremor oscillatory network.
There are two possible mechanisms that we have considered. One, the activation of afferent fibers by the stimulation, which can disrupt central tremor activity. and two, that group 1A and cutaneous afferent could reduce tremor through reciprocal inhibition or modulating cortical [00:06:00] muscular transmission of tremor drive.
[00:06:03] Dr. Sara Schaefer: So you mentioned a couple of other types of stimulation transcutaneous cerebellar stimulation peripheral stimulation. How do those differ from transcutaneous spinal cord stimulation? I really just how does transcutaneous spinal cord stimulation work? What does it look like for the patient?
What's it look like for the provider? Can you paint us a picture?
[00:06:26] Dr. Anna Latorre: Yes, so when we talk about current stimulation in this context is alternating current stimulation. So for tremor suppression the type of stimulation is similar wherever you apply it, it could be the cerebellum, could be the spinal cord and could be, of course, on the peripheral system.
More specifically, transcutaneous spinal cord stimulation is a new non-invasive type of neuromodulation technique, which has been primarily used to modulate spinal networks [00:07:00] in condition like spinal cord injury to improve spasticity, and that's been shown to increase excitability of local spinal networks via dorsal root afference, which then acts on descending motor pathways. In practice, it's actually very simple because it involves delivery of constant current through an active electrode, which is the cathode, placed on the skin over the spinous processes. In our study, it was between C5 C6. And then there are two additional electrodes which serve as anodes positioned over each clavicle.
So the current is provided by a battery driven stimulator. In our case, we deliver a bifascic symmetric rectangular pulses. And to prevent the recruitment of motor neurons, so to avoid interfering with motor control, stimulation intensity was set below the motor threshold. However, it was still above the sensory [00:08:00] threshold, so patients could feel the tingling sensation at the back of the neck, but the intensity was calibrated to patient's tolerance to guarantee there was no discomfort.
So the setup is very simple. We use three electrodes placed. around the neck. There is a small stimulator to deliver the current and it's not unpleasant. It's a little bit easier to apply this over the neck rather than the cerebellum. This is why we also thought about this option compared to prior studies.
[00:08:31] Dr. Sara Schaefer: Well, It does sound very straightforward. Almost something that a patient might be able to do at home sometime in the future. Tell us about your study.
[00:08:39] Dr. Anna Latorre: Yes, so in this study we explore for the first time the potential of this technique to modify the propagation of tremor to the muscles in ET syndrome. It was an exploratory study, so we use an open loop approach, which means that stimulation was not adapted to the tremor characteristics, [00:09:00] but we tested different frequency to see if any would influence tremor reduction.
Our hypothesis was that stimulation and a tremor frequency. So deliver at the same frequency of the tremor would be the most effective. But without prior data, we also tried frequency slightly outside this range, one lower and one higher. So the lower one was 1 hertz, Because studies on brain and peripheral stimulation suggest that this frequency acts on inhibitory mechanisms.
So the point was to inhibit, to act on inhibitory circuitry to stop the tremor, improve the tremor. The higher frequency was 21 hertz, which was used with the intent to target the excitability of afferent interneurons located in the dorsal root. And also because it's aligned with the corticospinal transmission motor control.
We also included a control condition with trapezius stimulation to exclude that the [00:10:00] tremor suppression could be mediated by the recruitment of cutaneous afferent fibers, so not the dorsal root. And the experiment consisted of 60 second tremor recording, during which patients had to hold their arms straight, and this was under each condition.
So at this tremor frequency stimulation, 1x stimulation, 21x, and trapezius stimulation. And also without stimulation, which of course was used as a baseline to compare the tremor changes during the actual intervention. And tremor was recorded by a triaxial accelerometer placed on the dorsum of the hand.
And to ensure unbiased results, participants weren't told which frequency was being used.
[00:10:45] Dr. Sara Schaefer: What did your data show?
[00:10:47] Dr. Anna Latorre: The main finding was a significant reduction in tremor amplitude when transcutaneous spinal cord stimulation was applied at the tremor frequency. This reduction became statistically [00:11:00] significant in the last half of the 60 seconds, so from 30 seconds onwards. suggesting a gradual building up of effect.
To give a more immediate idea about the degree of tremor amplitude improvement, apart from the so called zeta score, we offered a percentage of tremor reduction, which was about 35-40%. compared to baseline. Stimulation at 21 Hz didn't alter tremor, while 1Hz produced a mild no significant reduction of tremor likely due to a general inhibitory effect.
Trapezius stimulation on the other hand increased tremor amplitude and possibly due to muscle twitches spreading to the affected muscle sets we observed clinically. Another intriguing and unexpected finding that I would like to mention is that during stimulation at the tremor frequency, a subgroup of patients exhibited consistent [00:12:00] synchronization between the tremor phase and the delivered stimulation.
So a phenomenon that is known as entrainment. So the alignment of these two faces was associated with a reduction in tremor amplitude, suggesting a potential causal link between stimulation induced entrainment and the suppression of the tremor.
[00:12:22] Dr. Sara Schaefer: And how do your results help to elucidate how transcutaneous spinal cord stimulation may actually be physiologically impacting tremor in these patients?
[00:12:33] Dr. Anna Latorre: So this study provides early evidence that this stimulation might interfere with tremor propagation, but the exact mechanism needs further investigation. So we can only infer what are the main uh, mechanism, how tSCS might reduce tremor. One involves stimulation of the dorsal root afferent. So, We can assume that the activation of the dorsal [00:13:00] root with a short pulse of stimulation would be followed by a period of suppression.
And since tremor and stimulation are not coherent, tremor and dorsal root inputs would oppose each other, resulting in tremor reduction. A similar mechanism is postulated for tremor suppression also during peripheral stimulation. However, during spinal cord stimulation might be more effective because of the anatomical separation between sensory motor fibers and the stimulation of large number of afferents compared to peripheral nerve stimulation.
Additionally, another possibility Is that the activation of large, medium afferent fibers in the dorsal root might disrupt the tremor genic circuit through rine pathways projecting into the tremor network via the thalamus or the cerebellum on the other side. It is possible that engaging sensory pathway we can.
Trans [00:14:00] synaptically converge on motor pools leading to a reduction of alternating muscle activity. So in this case, the effect of the stimulation on tremor could be attributed to the modulation of spinal reflexes as Group 1a afference are known to contribute to tremor amplification.
through reciprocal inhibition. So the simultaneous activation of agonist antagonist afferents may reduce the alternating pattern typical of tremor. However, an interplay between spinal and supraspinal effect cannot be excluded. A final notice on the entrainment that we observed, this likely contributed to the effectiveness of the stimulation and about a third of the responders.
This was a surprise because commonly it is thought that entrainment increased tremor amplitude. At least this is what has been observed in thalamic stimulation. However, phase dependent modulation with alternating current does not [00:15:00] consistently impact amplitude and amplitude suppression does not always correspond with significant phase entrainment.
So this finding is intriguing and warrants further exploration.
[00:15:12] Dr. Sara Schaefer: So you mentioned spinal versus supraspinal impacts. It made me wonder if you have moved the transcutaneous spinal cord stimulator around to different parts of the spinal cord to see if the impacts are different depending on where you're stimulating. Obviously you were stimulating the cervical roots and these were upper extremity tremors that you were looking at.
Can you speak to that at all?
[00:15:41] Dr. Anna Latorre: this is a very interesting question. Actually, we didn't do any other explorative stimulation through up or down the spinal cord, at least in this study, but it's something that we might explore. As you well said, we selected this level because of the upper limb tremor. And in [00:16:00] previous studies where this has been applied for spasticity, it was mostly applied at the lumbar level just to act on the legs.
But there are some evidence to believe that of course there might be an influence through afferent pathways at other levels of the spinal cord. So it might be possible that you, that there is a change in spinal cord excitability if you apply different levels of the spinal cord.
[00:16:29] Dr. Sara Schaefer: Do you have any thoughts on how long in effect this may be and how often or how continuously stimulation may need to be used in order to benefit patients? You found that patients did better in the second half of your 60 second block, right? Do you have any sense of whether once the stimulator is turned off, they continue to have improvement in the tremor?
Maybe you don't have enough information as this was an exploratory study. As you [00:17:00] mentioned do you have enough information at all to postulate on how the future of this might be or look in clinical practice
[00:17:09] Dr. Anna Latorre: This is a particular interesting aspect, of course, as it might have the most significant implication for patient treatment. And you're right, we didn't explore this aspect in this study, but we have some from the prior work, there is a sustained effect. After the stimulation, for instance, in the study on the cerebellar alternating current simulation we noticed that was a brief improvement of the tremor also at the end of the stimulation, suggesting that prolonged or repeated session of stimulation could lead to long lasting lasting effect.
Maybe through inducing neuroplasticity changes, as it happens for this type of stimulation. And as you said, we notice a build up effect, so the tremor [00:18:00] improved after. 30 seconds. So it is another suggestion that maybe if we apply for prolonged time or differently repeated session, there might be a build up effect that makes the stimulation, the effect of the simulation to last longer.
Wanted just to conclude with, we don't have evidence, but I suppose that daily hour or maybe repeated session might be beneficial, but this is an important aspect to clarify.
[00:18:33] Dr. Sara Schaefer: In your view, what are the next steps or maybe what are the next steps that your lab is even preparing?
[00:18:40] Dr. Anna Latorre: Well, Just considering what we just said, it's important to clarify whether continuous stimulation is essential or if the benefits build up of a repeated session can be feasible. But apart from that our next steps focus on three main objectives. [00:19:00] First, it is to understand the mechanisms by which the tSCS modulates tremor, which could offer critical insight into the pathophysiology of ET.
I believe, I strongly believe that addressing the underlying mechanism of this condition is key to effective treatment. So we need to do a little bit more research on this regard. Second, we need to identify the optical stimulation protocol. For instance, testing whether continuous or closed loop phase locked stimulation, in which stimulation is aligned in real time to the tremor's frequenting phase, may yield better results.
Finally, we plan to confirm whether the stimulation reliably improves kinetic tremor, so during tasks, which is a primary concern for patients, they want to know that they can hold a cup, they can use a knife, not just that the tremor improves when holding a posture. And also we would like to explore whether these [00:20:00] benefits could be extended to other types of action tremor, for instance, dystonic tremor.
So together, these next steps should guide us in enhancing transcutaneous spinal cord stimulation as a practical therapeutic option for ET, hopefully.
[00:20:16] Dr. Sara Schaefer: You made a, an important point, which is that this research is helpful to try to figure out the underlying pathophysiology of ET and also simultaneously looks at it as a therapeutic option. So that makes it extra exciting.
Thank you very much for joining us and telling us all about your study.
[00:20:37] Dr. Anna Latorre: Thanks for inviting me. It's been very nice talking to you. [00:21:00]