LINKERS Project
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 898265
Locomotor Issues In Parkinsonian's Mesencephalic Locomotor Region and Subtahalamic Nucleus
Summary of the context and overall objectives of the project:
Parkinson disease (PD) is the most common movement disorder. Dysfunction of basal ganglia circuits in PD leads to characteristic motor deficits including bradykinesia, with hypometria and reduced electromyographic (EMG) activity, tremor, and frequently gait disorders with start hesitation or freezing of gait (FOG) associated with increased falling. On the one hand, there is a large literature on the postural adjustments during gait initiation and the biomechanics of ongoing gait in healthy and patient populations. On the other hand, neuronal recording in the pallidum, subthalamic nucleus (STN), substantia nigra pars reticulata (SNpr) and mesencephalic locomotor region (i.e., the MLR, constituted of both pedunculopontine and cuneiform nuclei, PPN and CuN, respectively) demonstrated activity related to movement and locomotion in rats, cats, primates and humans. Deep Brain Stimulation (DBS), particularly STN- and MLR-DBS, can effectively alleviate postural and locomotor deficits in PD, although the neural mechanisms and the precise role of each structure in locomotion is still matter of debate. We developed and used a task allowing us to decipher the neural activity during different locomotor behaviour in implanted parkinsonians patients. We characterized these associations in PD patients using neuro-muscular, neuro-kinematic and neuro-neuronal (STN-STN, MLR-MLR) coherence in different locomotor paradigms under different treatment conditions and hypothesized that neural activity would be differently modulated depending on the site of implantation (MLR or STN), the cognitive load and the dopaminergic state.
My objectives are two-fold:
1- Characterize neuronal activity of the STN and MLR during initiation and termination of and walking with motor or cognitive load, and before and during half-turn, in patients with PD.
2- Determine the relationship between STN and MLR neuronal activities and walking performance (measures using specific kinetic and kinematic parameters, as well as the occurrence of FOG episodes), the neuroneuronal coupling between both STN or MLR, and the neuro-muscular coupling between STN or MLR neuronal activity and lower limbs muscles activities during walking.
Work performed during the project:
I first developed a behavioral task requiring different biomechanical adjustments known to imply different types of neuronal modulations. Experiments were carried out in the absence or with cognitive interference (B) as well as with or without dopaminergic treatment.
We then acquired deep brain neuronal (i.e., local field potentials) and gait parameters recordings including kinematics (behavioural data), kinetics (i.e., bottom left), EMG (i.e., bottom right). Correlations between neuronal and biomechanics events during gait, gait initiation, U-turn and freezing of gait episodes were made to characterize and quantify modulations of the power of the neuronal signal.
Finally, modulations informed us on the role of the STN and MLR during gait and biomechanical events and might serve as a biomarker of the disease.
Progress beyond the state of the art and potential impacts:
More than demonstrating the feasibility of using such a complex task with severely impacted patients in which we could test performances in different conditions, we showed, according to the pioneer studies and current theory, that neural activity was modulated in specific frequency bands. Moreover, such modulations were differently modulated depending on the implanted site (PPN, CuN or STN) and altered with or without cognitive load and dopaminergic treatment. Furthermore, we also showed using the behavioural aspect of the task that, clinically speaking, the implantation in the MLR to alleviate gait disorders in severely affected parkinson’s disease patients was not relevant.
This research project made an important contribution to a poorly studied but important aspect of motor control in PD. From a knowledge transfer point of view, it has provided important information to clinicians and researchers using DBS to ameliorate postural difficulties and FOG. From an interdisciplinary point of view, it helped neurologists to refine diagnosis as well as foster the core of knowledge and helped targeting new avenues of treatment to rehabilitation professionals involved in the non-invasive treatments of PD.