Periodic Reporting for period 1 - CORLID (Cortical markers of L-DOPA-induced dyskinesias)
Periodo di rendicontazione: 2019-01-15 al 2021-01-14
Parkinson’s disease (PD) is a neurodegenerative disorder that affects about 1% of the population over 55. After more than 50 years, dopaminergic treatment is still the gold standard in PD therapy, although, as the disease progresses, several motor complications may arise. One of the most common and debilitating are known as L-DOPA-induced dyskinesias (LIDs), a condition that is observed in up to 80% of patients within five years of L-DOPA or dopaminergic agonists treatment. Although the exact neural mechanisms are still unclear, recent studies suggested that LIDs might be a consequence of an abnormal control of brain plasticity, i.e. the brain's ability to change and adapt as a result of experience. The target of this research project is to investigate the presence of neural signs, i.e. biomarkers, that can predict the development of LIDs in early PD patients. This is a topic of critical relevance: if LIDs development would be predictable from previous cortical dysfunction, it will be possible to adjust the DA therapy, in terms of dose and duration, basing on the grade of LID risk. To this aim, the present project will take advantage of different non-invasive neurophysiological techniques able to stimulate specific brain areas (i.e. transcranial magnetic stimulation, TMS) and record their neurophysiological activity (i.e. electroencephalogram, EEG; electromyogram, EMG).
During the last two years, despite the COVID-19 pandemic, most of the activitie planned for the present project have been successfully accomplished. As a first step, I reached a complete independence in implementing a TMS-EMG setup also combining other neurophysiological techniques. This setup was important for my studies to non-invasively stimulate the primary motor cortex (M1) of the participants with TMS and record the muscle activity from the hand with EMG. I also learned how to collect measures with more complicated TMS protocols such as paired-pulse, twin-coil, repetitive TMS (rTMS) and theta-burst stimulation (TBS). Once the experimental setup was ready, I started the patient’s recruitment. Among the 53 participants tested, all the planned healthy volunteers, i.e. 20, completed the neurophysiological evaluation; 19 out to 20 non-LID patients completed the neurophysiological evaluation and the clinical follow-up; 14 out to 20 LID-patients completed the neurophysiological evaluation and the clinical follow-up. In specific, each of the 53 participants has the following datasets:
• 2 TMS-EEG datasets during a Go/NoGo task
• 2 EEG dataset during a Go/NoGo task
• 1 behavioral dataset during Go/NoGo task
• 1 TMS-EEG dataset with two coils, at rest
• 3 TMS-EMG datasets
• 2 clinical datasets (only for PD patients)
A part from the data collection, a few months were spent in the preprocessing steps of these data. In particular, EEG data underwent a long process of cleaning, segmentation and filtering. After the preprocessing steps, I complete the analysis of the most part of data collected for study 1. One of the main results of this analysis is the finding of a cortical biomarker of inhibitory deficit in PD patients, which was the main aim of the Study 1 of the present project (Annex 1 of Grant Agreement). This cortical marker, termed TMS-evoked N100, is a TMS-evoked potential (TEP) with negative polarity, occurring at 100 ms from the TMS pulse. The TMS-evoked N100 has been previously investigated in pharmacological TMS-EEG investigations conducted in healthy volunteers (e.g. Premoli et al., 2014; DOI: 10.1523/JNEUROSCI.5089-13.2014) and has been related to the activity of GABA(B)-ergic interneurons of the primary motor cortex (M1). We investigated the TMS-evoked N100 for the first time in PD patients, during an inhibitory cognitive test, i.e. a Go/NoGo task. We found out that this potential was higher in amplitude when healthy volunteers have to inhibit a motor response (NoGo condition) whereas in PD patients we observed no modulation. In addition, we observed that the number of times in which the patient wrongly produced a motor response when I had to inhibit it, i.e. false alarm, was correlated to the modulation of the TMS-evoked N100, i.e. the smaller the N100 the higher the number of false alarms.
At the moment I am still interpreting the results of Study 2 and Study 3. Study 2 was aimed to investigate connectivity between the inferior frontal gyrus, the supplementary motor area and the primary motor cortex with a double TMS coil approach. Study 3 was aimed at investigate plasticity mechanism in terms of long-term potentiation and long-term depotentiation with electromyographic measures, such as motor-evoked potentials.
Dissemination of results was another main activity of the present projects. All the planned deliverables regarding dissemination were successfully achieved. The updating on research progress for patients and caregivers, was successfully achieved until February 2020 when, due to the COVID-19 pandemic, we have to interrupt activities with the physical presence of the patients or their caregivers. Thus, information and updating on the project progress continued only online by emails and newsletters. Dissemination of data to the scientific community, was successfully achieved by means of scientific posters, scientific talks and symposiums. Specifically, I presented one scientific poster at the 8th SINDEM (Associazione autonoma aderente alla SIN per le demenze) Winter Seminar on Dementia and Neurodegenerative Disorders (January 22-24th 2020, Bressanone, Italy). Preliminary results of the project were presented in several scientific congresses and meetings such as the SIPF (Società Italiana di Psicofisiologia) congress (November 28th 2020, virtual congress) and the 1st Virtual Research Retreat FSL (February 18th 2021, virtual congress) and at the Symposium “Combining TMS and EEG to investigate cortical brain connectivity: issues and new insights” at the 7th International Conference on Non-invasive Brain Stimulation (10-14 November 2020, virtual symposium). As regards the dissemination through scientific manuscript and press release, I did not publish and scientific paper on this data yet, but two MSc thesis have been written on the data of Study 1 (Student: Silvia Ajao, University of Padua; Student: Andrea Roncaioli, University Sapienza of Rome). I plan to finish to write a first manuscript by June 2020.
• 2 TMS-EEG datasets during a Go/NoGo task
• 2 EEG dataset during a Go/NoGo task
• 1 behavioral dataset during Go/NoGo task
• 1 TMS-EEG dataset with two coils, at rest
• 3 TMS-EMG datasets
• 2 clinical datasets (only for PD patients)
A part from the data collection, a few months were spent in the preprocessing steps of these data. In particular, EEG data underwent a long process of cleaning, segmentation and filtering. After the preprocessing steps, I complete the analysis of the most part of data collected for study 1. One of the main results of this analysis is the finding of a cortical biomarker of inhibitory deficit in PD patients, which was the main aim of the Study 1 of the present project (Annex 1 of Grant Agreement). This cortical marker, termed TMS-evoked N100, is a TMS-evoked potential (TEP) with negative polarity, occurring at 100 ms from the TMS pulse. The TMS-evoked N100 has been previously investigated in pharmacological TMS-EEG investigations conducted in healthy volunteers (e.g. Premoli et al., 2014; DOI: 10.1523/JNEUROSCI.5089-13.2014) and has been related to the activity of GABA(B)-ergic interneurons of the primary motor cortex (M1). We investigated the TMS-evoked N100 for the first time in PD patients, during an inhibitory cognitive test, i.e. a Go/NoGo task. We found out that this potential was higher in amplitude when healthy volunteers have to inhibit a motor response (NoGo condition) whereas in PD patients we observed no modulation. In addition, we observed that the number of times in which the patient wrongly produced a motor response when I had to inhibit it, i.e. false alarm, was correlated to the modulation of the TMS-evoked N100, i.e. the smaller the N100 the higher the number of false alarms.
At the moment I am still interpreting the results of Study 2 and Study 3. Study 2 was aimed to investigate connectivity between the inferior frontal gyrus, the supplementary motor area and the primary motor cortex with a double TMS coil approach. Study 3 was aimed at investigate plasticity mechanism in terms of long-term potentiation and long-term depotentiation with electromyographic measures, such as motor-evoked potentials.
Dissemination of results was another main activity of the present projects. All the planned deliverables regarding dissemination were successfully achieved. The updating on research progress for patients and caregivers, was successfully achieved until February 2020 when, due to the COVID-19 pandemic, we have to interrupt activities with the physical presence of the patients or their caregivers. Thus, information and updating on the project progress continued only online by emails and newsletters. Dissemination of data to the scientific community, was successfully achieved by means of scientific posters, scientific talks and symposiums. Specifically, I presented one scientific poster at the 8th SINDEM (Associazione autonoma aderente alla SIN per le demenze) Winter Seminar on Dementia and Neurodegenerative Disorders (January 22-24th 2020, Bressanone, Italy). Preliminary results of the project were presented in several scientific congresses and meetings such as the SIPF (Società Italiana di Psicofisiologia) congress (November 28th 2020, virtual congress) and the 1st Virtual Research Retreat FSL (February 18th 2021, virtual congress) and at the Symposium “Combining TMS and EEG to investigate cortical brain connectivity: issues and new insights” at the 7th International Conference on Non-invasive Brain Stimulation (10-14 November 2020, virtual symposium). As regards the dissemination through scientific manuscript and press release, I did not publish and scientific paper on this data yet, but two MSc thesis have been written on the data of Study 1 (Student: Silvia Ajao, University of Padua; Student: Andrea Roncaioli, University Sapienza of Rome). I plan to finish to write a first manuscript by June 2020.
IMPORTANCE OF RESULTS
Overall, the presented results were successful in highlighting the presence of a deficit in inhibitory mechanisms in PD, in line with several evidences acquired with different approaches. However, exploiting the advanced methodology of the combined TMS-EMG-EEG technique, it was also possible to acknowledge that the TMS-evoked N100 component might be the most sensible marker to investigate inhibitory mechanisms in PD. This finding could have a potential impact from a clinical point of view, being a non-invasive measure able to assess in vivo inhibitory deficits in PD patients at cortical level.
Overall, the presented results were successful in highlighting the presence of a deficit in inhibitory mechanisms in PD, in line with several evidences acquired with different approaches. However, exploiting the advanced methodology of the combined TMS-EMG-EEG technique, it was also possible to acknowledge that the TMS-evoked N100 component might be the most sensible marker to investigate inhibitory mechanisms in PD. This finding could have a potential impact from a clinical point of view, being a non-invasive measure able to assess in vivo inhibitory deficits in PD patients at cortical level.