Cerebellar Rhythmic Entrainment with Transcranial Magnetic Stimulation: A new approach for the study of cerebellar connections with the cortex.

Project Information

cRETMS

Grant agreement ID: 897941

DOI

10.3030/897941

Project closed

EC signature date 11 March 2020

Start date 1 January 2021

End date 28 February 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 184 707,84

EU contribution

€ 184 707,84

Coordinated by

INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE
France

Periodic Reporting for period 1 - cRETMS (Cerebellar Rhythmic Entrainment with Transcranial Magnetic Stimulation: A new approach for the study of cerebellar connections with the cortex.)

Reporting period: 2021-01-01 to 2022-12-31

Summary of the context and overall objectives of the project

Humans have the ability to adapt their actions according to environmental demands. Flexible realization of intentions and goals relies on making online predictions, processing external feedback and changing behaviour when needed. Imagine playing golf, and a light wind blowing towards the left. To send the ball in the right direction, you will need to adapt your stroke to compensate for the drift of the wind. If you are new to golf, correctly aiming your stroke may be challenging, and you may reach the target after numerous trials and errors. Particularly, the errors from prior strokes and the resulting feedback will be essential to adapt your movement. Adaptation is one of the most important features of the nervous system, as impairments of the brain network appointed to motor adaptation can seriously impact daily life. The cerebellum exerts a key role in adapting to environmental changes. It forms and stores internal models, i.e. sensory predictions based upon the expected movement results and compares them with actual sensory reafference. If a mismatch is detected, changes to the motor plan are implemented. Although the functional mechanisms of this process have been well studied in humans, the temporal dynamics mediating cerebellar activity are largely unknown, as most evidence comes mainly from direct recordings in animal models.

This project aims at characterizing temporal biomarkers responsible to shape cerebellar local activity and its communication with other brain areas involved in the adaptation to environmental changes. Specifically, it aims to 1) characterize cerebellar oscillatory activity both at rest and during motor adaptation, 2) determine the relationships between the cerebellar oscillatory activity, its structural connections with areas and structures of the motor network, and motor adaptation, 3) assess whether externally and non-invasively boosting such oscillations can improve visuomotor adaptation.

Preliminary results show two possible biomarkers subtending the communication between the cerebellum and the cortex that support motor adaptation, i.e. beta (20 Hz) and gamma frequency (40 Hz). As a side project (not initially considered within MCSA goals), we were also able to show that by modulating gamma activity with transcranial alternate current stimulation (tACS), it is possible to improve motor adaptation in Writer’s cramp (WC) dystonic patients who show abnormal cerebellar gamma oscillatory activity in the cerebellum.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the first study, we aimed to identify the oscillations supporting the communication between the cerebellum and the cortex and determine whether this dialogue is shaped by their structural connections. To this aim, we combined two cutting-edge techniques already used, independently, for the study of cortical connectivity: transcranial magnetic stimulation concurrent to electroencephalography (TMS-EEG) and diffusion magnetic resonance imaging (dMRI). DMRI is a type of MRI sequence that assesses the local fiber orientations and infers long-range pathways connecting distant regions of the brain (fiber tractography). DMRI has excellent spatial resolution but does not provide any temporal information on brain signalling dynamics. On the other hand, online TMS-EEG allows (via EEG) the measure of changes in brain oscillatory activity either during TMS single-pulses or brief bursts tuned in frequency and phase. By using EEG and its high temporal resolution, one can extract the information on the responses induced by TMS and evaluate the temporal dynamics of connections between brain areas (i.e. cerebellum and the cortex). We have collected the data from n=20 healthy participants who underwent both dMRI and TMS-EEG. Additionally, resting state fMRI datasets were also recorded for each individual. Data analysis is still ongoing, but current preliminary analyses support the tolerability and feasibility of cerebellar TMS-EEG recordings, and our ability to assess signs of communication through oscillations between the cerebellum and the frontal cortex while minimizing unspecific effects (responses triggered by the TMS clicking sound, scalp-tapping, etc).

The second part of my work consisted of addressing two research questions: (1) does pre-movement beta oscillatory activity (20 Hz) reflect the ability of the cerebellar-cortical network to adapt to the changes of the environment? (2) can we enhance motor adaptation by entraining cerebellar oscillations? In the first study, we analysed the data of 17 healthy participants performing a visuomotor adaptation task while their brain oscillatory activity was recorded with magnetoencephalography (MEG). We aimed to characterize pre-movement oscillatory related to the adaptation to visual biases. Preliminary results show a modulation of anticipatory beta activity (20 Hz) based on motor adjustments due to the bias, localized in a network including the right cerebellum (crus II), the left parietal inferior lobule and the right frontal inferior lobe. Finally, I also collaborated on a second study in which we analysed data from 16 Writer’s Cramp (WC) dystonic patients and age- and gender-matched healthy controls who performed the visuomotor task during MEG recordings. Here, we aimed at determining whether cerebellar oscillations related to motor adaptation are affected in WC patients. Furthermore, we wanted to determine whether it is possible to boost motor adaptation by driving cerebellar oscillations with transcranial alternating current stimulation (tACS). Transcranial ACS is an electrical non-invasive stimulation technique that can entrain brain oscillations and modulate motor performance. Our results show that anticipatory cerebellar activity in WC patients, compared to healthy controls, was normal at beta frequency but abnormal at gamma frequency, which was also related to aberrant adaptation. Furthermore, tACS (but not placebo stimulation) was able to compensate for cerebellar gamma dysrhythmia and increase patients’ learning performance via modulation of a thalamic relay. The findings of the second study are currently being submitted for publication.

The results of this project have been presented at 2 national and 3 international conferences (1 poster award). One study is being prepared for submission to a top-tier journal and one abstract has been published.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Although the human cerebellar architecture has been well studied, the electrophysiological mechanisms mediating cerebellar activity are largely unknown. Here, with three different experiments, we have identified oscillations mediating cerebellar activity and its communication with the cortex. Furthermore, we have set up a novel way to assess cerebellar connectivity (TMS-EEG). The results of this project add to the current understanding of cerebellar oscillations and their role in motor adaptation and cerebellar communication with distal cortical areas. In turn, our findings could have a potential impact on clinical practice as they may inform possible interventions in the treatment of neurological patients with motor deficits by targeting and modulating cerebellar oscillations with non-invasive brain stimulation.