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[00:00:51] Sara Schaefer:
Certainly well deserved. So let's dive right in.
So you start your article by talking a little bit about the short versus long duration response to levodopa. What exactly drives the long duration response, and what do we know about what makes patients more or less likely to develop this response?
[00:01:11] Mario Zappia:
The long duration response is a well known response of a pharmacological response to levodopa. But during the years, it was not very well exploited. The long duration response is a clinical benefit deriving from chronic administration of the drug that appears after days or weeks after starting the treatment, and when we stop the treatment, this response decay with some days or weeks.
Then the long duration response is clinical improvement different from the short duration response. The short duration response is the response to a single dose of the drug. Instead, the long duration response is benefit deriving from chronic treatment. Usually in the early stage of Parkinson's disease, many patients develop this response and the response could be maintained also in the later stage.
But we have to recognize is this response just to give to patients the maximum benefit deriving from this response.
[00:02:23] Sara Schaefer:
So when we think about Levodopa kinetics in the clinic, we're usually thinking about the short duration response, but there's this underlying basal response that can develop over time.
[00:02:33] Mario Zappia:
Yeah.
[00:02:33] Sara Schaefer:
In the paper, we're also gonna get into the methods which include tasks of motor learning. So I wanted to start with a little bit of a background on what motor learning is and what do we know about the physiological underpinnings of motor learning specifically in Parkinson's disease?
[00:02:50] Mario Zappia:
The motor learning is a set of process that derives from exercise and that produce a transient or permanent changes in motor performance.
Motor learning is due to modification in cerebral neuroplasticity, and we can observe this modification by investigating neurophysiological parameters that could be modified by these changes.
[00:03:24] Sara Schaefer:
So how is motor learning affected in Parkinson's patients?
[00:03:29] Mario Zappia:
Motor learning is usually impaired in Parkinson patients, and this could be a problem also for the neurological rehabilitation for these patients. But we have to make effort just to obtain a better motor learning from our patients.
From this point of view, the development of long duration response as we demonstrated in our study could be a good pharmacological strategy also to facilitate motor learning and the changes in neuroplasticity at cortical level.
[00:04:07] Sara Schaefer:
So that segues nicely into my next question, which is how did you conduct your study?
[00:04:12] Mario Zappia:
We conducted our study with 41 patients. The patients were drug naive Parkinson disease patients, and they underwent treatment for 15 days, two weeks of levodopa with levodopa. The interdose interval between each dose of 250 milligrams was 24 hours, because we know that with this regimen early patients with Parkinson's disease could develop the long duration response. Not all the patients develop this response in this way, we can have patients with develop the response and patients without the response. This gave us the opportunity to study a modification of neurophysiological parameters in patients with the long duration response and patient without the long duration response. Patients underwent also to an training of motor exercise related to finger sequence of finger tapping and are group of patients did not make a motor exercise. So in this way, we have four group of patients, patients with a long duration response, patients without the long duration response, and patients with a long duration response who underwent a motor strain, a motor training, and patients with motor response who did not undergo to the motor training. These four groups were compared at the baseline by testing the neurophysiological parameters that is the auditory evoked potential P 300 the motor evoked potential induced by single transcranial magnetic simulation and the so-called bari shaft potential, a promoter potential that precede motor movement.
We investigated this parameter at the beginning of the treatment and after 15 days of treatment and we observed the change induced by the long duration response and by the motor exercise.
[00:06:20] Sara Schaefer:
And what did you find in these four groups? And in your answer, if you could also tell our listeners what you hoped to determine using the specific neurophysiological markers that you used, you mentioned that you felt these were a good surrogate markers for cortical excitability and also therefore cortical neuroplasticity.
[00:06:45] Mario Zappia:
These are simple neurophysiological markers, but they gave us an idea about the cortical plasticity in different area. For instance, primary motor cortex or peral, frontal peral regions and so on. So what we observe is that this parameter modify in patients who achieve the long duration response, who underwent to motor exercise learning, they modified especially the latency of these parameters. Patients who did not achieve the response, the long duration response did not change these parameters, even if they underwent to motor exercise. The conclusion was that the long duration response is necessary to make change in neurophysiological marker of neuroplasticity. But if patients with a long duration response, underwent also to the motor exercise, these two treatment have a sort of synergistic effects because the group of patients who achieve the long duration response and who underwent to motor training had the better change in neurophysiological marker, especially as I said, the latency of these parameters.
[00:08:14] Sara Schaefer:
And do I read correctly that these parameters, you also tested them before and after an actual levodopa dose to see whether the short duration response was also partially responsible for these changes in the neurophysiological markers and did not find that it was relevant.
Is that correct?
[00:08:31] Mario Zappia:
Yes, thank you for this question because it is the main question levodopa acts in different way. The short duration response, that is the response that we usually know in the clinical practice is not relevant to modify cortical accessibility. Only the long duration response may change cortical acceptability.
So, for instance, patients who did not achieve the long duration response, we can study the short duration response at the end of treatment. So, if only the clinical improvement associated with a short duration response may determine the change in cortical acceptability, we should observe also change of our parameters in this condition, but we never observe this change. So our findings suggest that levodopa act on neuroplasticity only through the long duration response.
[00:09:33] Sara Schaefer:
That's fascinating and very elegantly done.
[00:09:35] Mario Zappia:
Thank you very much.
[00:09:37] Sara Schaefer:
I do have one final question we think of the short duration response obviously dopamine is hitting the receptors, dopamine is cleared from the receptors.
What is actually going on with the long duration response at the synaptic level? Do we know?
[00:09:50] Mario Zappia:
Really, we don't know. We could hypothesize that a series of events downstream, the synaptic level could be induced by a tonic release of dopamine, such as probably the long duration response is behind this tonic release of dopamine.
But really we don't know at molecular level what happens. For sure, we could hypothesize that there is at synaptic level major strength between synapsis and probably modification at level of basal ganglia and cortical cerebral cortex network.
[00:10:39] Sara Schaefer:
And finally, for those half of the patients in the study who did not achieve a long duration response, is there hope for those patients?
[00:10:48] Mario Zappia:
No, we used for experimental purpose a short period of treatment, 15 days. But all patients in the early stage could reach this response by prolonging the treatment. So our study, in my opinion, has two main endpoints. The first one is that as a therapeutical approach, we have to search for the achievement of the long duration response in our patients because the clinical benefit deriving from this response is a clinical benefit without dyskinesia, 'cause the dyskinesia in this patients could be, at least at the peak. But after 24 hours, we can observe clinical benefit without dyskinesia, but there is not only a clinical benefit, there is also a change in cortical acceptability. And the second main point is that by exploiting this action of the long duration response, we could have some relevant results in neuro rehabilitation because if the long duration response facilitate the effect of motor exercise on cerebral cortex then is better to achieve this response for patients who need motor rehabilitation.
[00:12:10] Sara Schaefer:
What do you see as the next steps in looking into this phenomenon?
[00:12:15] Mario Zappia:
Probably we need the animal model to study better the response and clarify what are the mechanism at cellular level and at synaptical level. These are only clinical study on patients using marker of neurophysiology.
[00:12:35] Sara Schaefer:
Thank you for sharing this interesting data with us today, and again, congratulations on your award.
[00:12:41] Mario Zappia:
Thank you very much. I would like to thank all my group and especially Dr. Giorgia Sciacca, who was the first author of this article, and I wish also to dedicate this award to my mentor, professor Aldo Quadron.
Thank you very much.