tDCS for Tourette syndrome

[00:00:42] Dr. Davide Martino: Thank you very much, Sarah. Thank you for having me.

[00:00:45] Dr. Sara Schaefer: Let's start with the gap in therapeutic care of patients with tics and Tourette syndrome. I'm sure anyone who treats these patients knows that you can definitely run into a wall in terms of treatment. But for those of our listeners who [00:01:00] may not treat these patients, where is the gap?

[00:01:03] Dr. Davide Martino: Yes, there are certainly a few therapeutic gaps still existing for people for the treatment of people with tics and Tourette and behavioral approaches are the first line and certainly the least invasive, but still The access to proficient therapists is really not possible in every geographical region.

And the online versions of these therapies that have been developed still need more development and dissemination plans. Also, a good half of patients are not treated satisfactorily with medications. This is due to either limited efficacy or potential toxicity, especially for dopamine receptor blockers.

So there is still a solid rationale in exploring other routes, such as neuromodulation and other, especially non invasive options. We know that deep brain stimulation can be used, is of course invasive, [00:02:00] and does not help all patients with, who have a severe or malignant persistent tic disorder.

The non invasive brain stimulation strategies might augment, might act synergistically with other treatment approaches like behavioral or even pharmacological. So there is increased interest in exploring this avenue and more studies are being designed to combine non invasive brain stimulation to other approaches.

[00:02:24] Dr. Sara Schaefer: And I'll remind our listeners that we do have a recent episode called combined habit, reversal and acceptance and commitment therapies for tics, which talks about some strategies regarding these behavioral approaches. So you mentioned these noninvasive stimulation methods. Can you explain the differences between them?

There's transcranial magnetic stimulation, transcranial direct current stimulation. What are the similarities and differences? And how do they work? And also how long do the effects typically last?

[00:02:59] Dr. Davide Martino: yeah [00:03:00] certainly, both TMS and transcranial current stimulation are non invasive brain stimulation modalities, but they work in different ways, and they have also distant effects. We can say that TMS uses magnetic fields using a coil placed on the scalp. And what it does is induce electrical currents in specific areas of the brain, which can directly trigger action potentials in neurons.

And so it's known to have potential efficacy to directly either stimulate or inhibit brain regions. And it's in fact approved for this to treat depression and OCD. But transcranial direct current stimulation, on the other hand, delivers a constant electrical current, which is weak. between one and two milliamp usually through two electrodes that are placed on the skull.

And what this electrical current does is alter the resting membrane potential of neurons, making them more or less [00:04:00] likely to fire. So it does not directly trigger action potentials, but modulates membrane potential. And the areas in which it is researched typically have to do With promoting plastic changes mostly in rehabilitation, also in depression, you will have heard about cognitive enhancement approaches and so on. Another potential advantage over TMS for tDCS is that it's cheaper and it's exportable. And so it could be used relatively easily by patients at home, which is obviously not the case for TMS, at least not yet. And so in the context of this research, being a modulator of neuronal activity, tDCS appears suitable to modulate the plastic rearrangement of behaviors that are hyperlearned, like the production or the suppression of tics. The effect duration is still quite unclear and it depends a lot on on [00:05:00] the number of sessions that are delivered and obviously on the characteristics of the stimulation parameters and I should say also target region and condition or function that is being targeted. it, there's not a one single answer to that question, unfortunately, yet.

[00:05:19] Dr. Sara Schaefer: Yeah, a lot of parameters and for the patient, what is this look or feel like? I've personally had TMS and it's a weird, contraction of the of the scalp muscles. What do these things feel like for the provider and for the patient?

[00:05:36] Dr. Davide Martino: Yeah. I mean, Yes, you're right. There's for tDCS, there is no feeling of muscle contraction. One usually feels a relatively faint. sensation that resembles a burning itch, which is usually well tolerated by the vast majority of people. What's really surprising is how fast, during the stimulation session, an individual can habituate to this [00:06:00] sensory experience and then filter it out, usually after about a minute or so, which is also the time when we ramp down the stimulation in the sham condition of an experiment.

What often remains visible sometimes is redness on the skin or the scalp. where the electrodes are positioned, usually without any consequence. And this is mostly due to the electrical resistance and can be minimized, actually, by using a larger amount of conductive gel or or solution, depending on the system that one is using, and mostly performing a stable and reliable positioning or montage of the electrodes.

[00:06:37] Dr. Sara Schaefer: In your study, you targeted the supplementary motor cortex via transcranial direct current stimulation. So that modulator type of stimulation what is the rationale and previous literature to support that particular target in patients with Tourette syndrome?

[00:06:55] Dr. Davide Martino: So over, over the years in, the approach with non-invasive [00:07:00] brain stimulation and tic disorders cortical targets have been selected mostly based on a conceptualization of tics as pre potent actions that are modulated. By some form of inhibitory control that during development increases in efficiency.

So regions that act as hubs, as neural hubs, involved in generating actions and generating or modulating urges to act for example, the medial frontal cortical areas. Like the supplementary motor area are really promising non invasive brain stimulation targets for Tourette syndrome. There's evidence that the SMA is hyper excitable in people with Tourette immediately before tic onset.

And it's also been reported that people with Tourette syndrome, there is an increased connectivity between SMA and the basal ganglia. There is enhanced functional coupling between the [00:08:00] SMA and M1 during pre movement or movement phases of both tics and voluntary self paced finger tapping movements in people with DRED.

So overall, this supports the rationale for a therapeutic application of inhibitory modulation of the SMA in Tourette. And so we choose to explore this approach. through cathodal tDCS where the cathode is positioned over the brain region that one tends to modulate, in this case the SMA and which at the current, the, we adopted in the study, which is 1 milliamp, pretty low, is expected to suppress the resting membrane potential of the target region.

So exert an inhibitory modulation on the firing of our target region, which was the SMA.

[00:08:52] Dr. Sara Schaefer: That's so interesting. So keeping all of this in mind, how did you design your study? What were the methods of your [00:09:00] study?

[00:09:00] Dr. Davide Martino: So we wanted to try to draw as many conclusions as we could and generalizable. So this was a proof of principle study. But because we wanted to to try and draw some conclusions. We designed it as a double blind. Sham controlled study with a parallel group and obviously randomized and so what we tested was the efficacy, as I mentioned, of one milliamp cathodal tDCS over the SMA.

In individuals with Tourette over 16 years of age, we wanted to tackle some of the problems that previous non invasive brain stimulation studies had encountered. And so we, first of all, enrolled a naturalistic and representative sample of patients. So we allowed stable ongoing treatments and other comorbidities apart from autism or other major psychiatric conditions, but we allowed ADHD and OCD as well.

Because these represent the rule rather than the exception in Tourette syndrome, we [00:10:00] applied an intensified protocol of repeated sessions over five consecutive days. And this is in line with evidence showing that repeated tDCS may be more effective in inducing plasticity, although less is known about the optimal interval, but anyway.

And and also we leverage the notion that another modality, which is repetitive TMS of the SMA, showed greater efficacy with a higher number of sessions. So we did repeated sessions. We did not use a rest condition during the stimulation, but we asked participants to actively suppress tics to improve homogeneity of brain activity during the stimulation sessions, but also try to guide tDCS effects by Tourette related brain activity, which is tic suppression.

So in other words, trying to promote synergistic effects. And finally, we selected secondary outcome measures that included [00:11:00] video based tic rating measures, Which most studies haven't done. So our primary endpoint was the mean change in the Yale Global Tic Severity Score, the total tic severity score from visit one, before the first stim session, and the visit one week after the fifth and last consecutive day of stimulation.

And this score is composed by the sum of sub scores for motor and for phonic tics. And this was our primary endpoint.

[00:11:31] Dr. Sara Schaefer: And what did you find?

[00:11:33] Dr. Davide Martino: Yeah, so we we achieved our sample size or minimal sample size requested by our power calculation. So we had 12 patients in each of the two arms real and sham stim. And so our main analysis did not show a main effect of treatment on the main outcome. We only found a trend towards a significant [00:12:00] treatment by visit interaction.

But when we analyzed separately the two subscores that compose the primary outcome measure so motor and phonic tic subscores, we observed a main effect of the treatment, which was significant. of the treatment by visit interaction for the motor tic subscore, showing greater reduction of this subscore in the active arm compared to the sham arm.

And whereas we did not find the same thing for the phonic tic subscore, we also did not find significant effects on the video rating of tics. Or on the severity of comorbidities like ADHD, OCD, anxiety or depression. But we found a significantly lower score for the pre monetary urges for tics in the active arm compared to the sham arm.

And finally, I think this is important to also to point out, is that the tolerability of the procedure was very high [00:13:00] and did not differ between the two arms. So there was no difference in tolerability between real and sham stimulation. And interestingly. Also, due to the low effect size overall participants weren't able to guess correctly whether they had received real or sham, which I think in this particular context, I think it's probably more of a plus than a minus.

[00:13:23] Dr. Sara Schaefer: There are so many interesting things about your results. I find it interesting that the premonitory urge went down, given that you said that the SMA seems to be hyperactive before a tic occurs. And also very interesting that motor tics were reduced, but not phonic tics. And you discuss a little bit in your discussion section about why that physiologically might be the case.

Can you speak to that a little bit?

[00:13:48] Dr. Davide Martino: Yes, this is obviously not an easy question to answer because there isn't a lot of evidence, particularly from human studies. But I should first of all say that a simple explanation for these findings is the [00:14:00] relatively low or moderate severity of our participants tics in general, but especially the phonic tics.

So we cannot totally rule out a floor effect. But overall although we don't have strong signals coming from human studies, animal models of tics suggest that there are neurobiological differences between tic like movements that do not engage the phonatory system we could say the voice, even though we cannot really talk about voices for animal models, but basically communication driven phonatory emissions and animal models that do engage these phonatory emissions.

These models show a potentially greater role of the networks that connect the cortex, basal ganglia, and cerebellar outflow incompassing SMA in motor tics. Whereas there's a [00:15:00] higher relevance of limbic networks, including the ventral striatum and the anterior cingulate. for models that try to replicate and reproduce vocal tics.

 I have to admit that this is a speculative interpretation, and it should be considered just as a possible interpretation. We definitely need more evidence to confirm this. In fact, we know now that limbic regions of the cortex are key structures for tics in general. In particular, the insula and the anterior cingulate are important in the urge tic complex, regardless of whether it involves the voice or not.

[00:15:36] Dr. Sara Schaefer: So maybe some additional or alternative targets within the limbic circuit might be...

[00:15:42] Dr. Davide Martino: The insula is a very interesting target, and not an easy one for this type of stimulation, but it's certainly very interesting.

[00:15:51] Dr. Sara Schaefer: And you mentioned that you were taking patients who were stable, but. Getting other [00:16:00] interventions and you mentioned that in your paper that many of the patients had just received training and habit reversal therapy and we're actively suppressing tics during the treatment period by design.

It's interesting your discussion regarding this on how this active suppression during the treatment period may act synergistically with tDCS treatment. Can you explain that to our listeners?

[00:16:26] Dr. Davide Martino: Yeah, sure. I mean, This is really at the core, as I mentioned before, of the rationale and the neurobiology of transcranial current stimulation. The role of this stimulation is eminently neuromodulatory. So part of this encompasses promoting plastic rearrangements that can then facilitate neurobiological effects of other interventions.

This is the concept of neuromodulation. So with respect to our specific choice of stimulating participants [00:17:00] while they were using savvily active behavioral strategies like competing motor responses that we, for example one of the main strategies using in habit reversal therapy. We did this to leverage on the concept of activity selectivity, which suggests that already active brain networks may be more susceptible to modulation by tDCS.

Of course we did this in a relatively light way because not all of these patients had received full courses of CBIT, but I mentioned that they all had been formally trained in developing competing motor responses and a good proportion of them were trained. Actually, all of them were trained with the traditional CBIT material and had received a number of sessions of treatment for CBIT. So they were all capable of adopting because they already had selected [00:18:00] competing motor responses. They were actually doing these competing motor responses throughout the stimulation sessions.

[00:18:06] Dr. Sara Schaefer: What do you see as next steps to try to determine whether tDCS might be a viable option for patients with tics and Tourette syndrome? 

[00:18:19] Dr. Davide Martino: Yes well, because the effect size was not very high I do think that it's important to replicate this finding in a larger sample size, possibly multicentric, but we definitely need to link this clinical effect to a mechanism or to a biomarker. And the best way to do this is probably functional MRI to confirm that this stimulation is modulating networks.

That are related to the target and to take physiology and that this ultimately correlates also or can even predict the clinical effect. The ideal situation is to deliver TMS or at least [00:19:00] demonstrate also before the actual intervention the same type of stimulation, at least in one session on directly inside the scanner.

We can do this now. And this would be also an, another very nice way to demonstrate that we are producing an effect that is real and and reproducible and has a very clear connectivity marker readout which was obviously lacking in this study.

And and also we have high resolution ways to deliver TMS where we use traditional. Sorry, TMS, tDCS. We we use traditional montages for tDCS, but we have now although they're not very much applied yet, but we have high resolution montages that can optimize the delivery of the electric current to the target.

And we should be using these rather than the the more traditional sponge electrode systems that we've used in this study.

[00:19:55] Dr. Sara Schaefer: Thank you for this fascinating discussion and for joining us today.[00:20:00] 

[00:20:00] Dr. Davide Martino: Thank you very much for having me, Sara.