Periodic Reporting for period 1 - LINKERS (Locomotor issues in Parkinsonian's Mesencephalic Locomotor Region and Subthalamic nucleus)
Berichtszeitraum: 2020-12-01 bis 2022-11-30
Idiopathic Parkinson disease (PD) affects 1–2 per 1000 of the population at any time and its prevalence is increasing with age to affect 1% of the population above 60 years. Due to a dopaminergic depletion, PD impacts motor function and is characterized by bradykinesia, rigidity and resting tremor. Furthermore, as long the disease progresses axial symptoms appear such as gait disorders, falls and freezing of gait episodes. PD does not decrease life expectancy but have an important impact on the quality of life. Accordingly, and due to an ageing of the population, both the number of PD patients and the burden on the social healthcare systems will increase.
If dopamine supplementation is useful at early stage of the disease, it leads to dyskinesia and motor fluctuations in addition with dopa resistant symptoms declared in later stage of the disease. Among available treatment, Deep brain stimulation (DBS) via the implantation of electrodes has been pushed forward to, both, alleviate dopa-resistant signs and enhance dopaminergic treatment effects. However, literature is sparse, and some discrepancy exists in the literature in terms of population and brain area to target. Since Freezing of gait (FOG) and falls worsen over time and represent the dominant motor disabilities in advanced Parkinson’s, we developed a program aimed to record neuronal activity during walking and examine the role of both brain structures (i.e. the subthalamic nucleus (STN) and mesencephalic locomotor region (MLR)) known to be involved in the regulation of gait pattern in human.
Our objectives were two-folds:
1- Characterize neuronal activity of the STN and MLR during initiation and termination of walking, free walking and walking with motor or cognitive load, before and during half-turn.
2- Determine the relationship between STN and MLR neuronal activities and walking performance (measured using specific kinetic and kinematic parameters, as well as the occurrence of FOG episodes)
This program is important for society since ameliorating PD treatment and alleviating symptoms will ameliorate the quality of life of PD patients and will decrease the burden on public health costs.
As conclusions, this program showed in implanted parkinsonians that suffer from gait disorders several specific modulations of the neural activity in different frequency band known to be involved in the production of movement and the cognitive engagement in a motor task respectively. These modulations were present in both structures but differently modulated during gait events or during an increase in the cognitive involvement in the task. This project also allowed to gain insight in the neural signature of the Parkinson’s disease. Conversely, we demonstrated that DBS was not as effective in both structures to alleviate postural and gait disorders. Finally, this program also participates to decipher the circuitry of the basal ganglia an important but poorly studied network in the brainstem.
If dopamine supplementation is useful at early stage of the disease, it leads to dyskinesia and motor fluctuations in addition with dopa resistant symptoms declared in later stage of the disease. Among available treatment, Deep brain stimulation (DBS) via the implantation of electrodes has been pushed forward to, both, alleviate dopa-resistant signs and enhance dopaminergic treatment effects. However, literature is sparse, and some discrepancy exists in the literature in terms of population and brain area to target. Since Freezing of gait (FOG) and falls worsen over time and represent the dominant motor disabilities in advanced Parkinson’s, we developed a program aimed to record neuronal activity during walking and examine the role of both brain structures (i.e. the subthalamic nucleus (STN) and mesencephalic locomotor region (MLR)) known to be involved in the regulation of gait pattern in human.
Our objectives were two-folds:
1- Characterize neuronal activity of the STN and MLR during initiation and termination of walking, free walking and walking with motor or cognitive load, before and during half-turn.
2- Determine the relationship between STN and MLR neuronal activities and walking performance (measured using specific kinetic and kinematic parameters, as well as the occurrence of FOG episodes)
This program is important for society since ameliorating PD treatment and alleviating symptoms will ameliorate the quality of life of PD patients and will decrease the burden on public health costs.
As conclusions, this program showed in implanted parkinsonians that suffer from gait disorders several specific modulations of the neural activity in different frequency band known to be involved in the production of movement and the cognitive engagement in a motor task respectively. These modulations were present in both structures but differently modulated during gait events or during an increase in the cognitive involvement in the task. This project also allowed to gain insight in the neural signature of the Parkinson’s disease. Conversely, we demonstrated that DBS was not as effective in both structures to alleviate postural and gait disorders. Finally, this program also participates to decipher the circuitry of the basal ganglia an important but poorly studied network in the brainstem.
The work was performed as follows:
• Development of a behavioural task to rigorously explore the contribution of the STN and the MLR to the gait initiation, termination, and locomotion episodes in 30 Parkinson’s disease patients undergoing DBS surgery.
• Recording of neural activity in the different walking phases or with environmental constraints, in controlled experimental tasks.
• Determination of gait events and correlation with modulation of neural activity in both brain structures
• Assessing the quality of the recordings
• Designing and development of analysis tools and homemade programs
• Analysis of the modulation of neural activity in different environmental constraints and medication state
• Synthesis, writing and dissemination of preliminary results.
Overall, we succeeded to record modulation of neural activity during gait and its initiation, a clinically important but poorly studied motor behaviour, in PD patients suffering from dopa-resistant gait and postural disorders. Our work indicates specific modulation of neural activity in different band of frequency in both the STN and the MLR during gait initiation and walking. More specifically, our results are coherent with the current theory stating that synchronization in lower (i.e. alpha) frequency band characterize the involvement in a task and that desynchronization in higher (i.e. beta) band is necessary to perform a movement. We also observed a clear influence of dopamine on both the cognitive involvement in a task and the motor output since the power of modulation is different with or without dopaminergic treatments. Considering this, dopamine might give some flexibility to alleviate the cognitive involvement allocated to the task and enhance the production of movement in a gait initiation perspective.
• Development of a behavioural task to rigorously explore the contribution of the STN and the MLR to the gait initiation, termination, and locomotion episodes in 30 Parkinson’s disease patients undergoing DBS surgery.
• Recording of neural activity in the different walking phases or with environmental constraints, in controlled experimental tasks.
• Determination of gait events and correlation with modulation of neural activity in both brain structures
• Assessing the quality of the recordings
• Designing and development of analysis tools and homemade programs
• Analysis of the modulation of neural activity in different environmental constraints and medication state
• Synthesis, writing and dissemination of preliminary results.
Overall, we succeeded to record modulation of neural activity during gait and its initiation, a clinically important but poorly studied motor behaviour, in PD patients suffering from dopa-resistant gait and postural disorders. Our work indicates specific modulation of neural activity in different band of frequency in both the STN and the MLR during gait initiation and walking. More specifically, our results are coherent with the current theory stating that synchronization in lower (i.e. alpha) frequency band characterize the involvement in a task and that desynchronization in higher (i.e. beta) band is necessary to perform a movement. We also observed a clear influence of dopamine on both the cognitive involvement in a task and the motor output since the power of modulation is different with or without dopaminergic treatments. Considering this, dopamine might give some flexibility to alleviate the cognitive involvement allocated to the task and enhance the production of movement in a gait initiation perspective.
The accurate characterization of neural activity changes in crucial but understudied brainstem regions during gait initiation and different gait phases is a clear research achievement. Indeed, being able to get insights on the neural activity through direct recording of deep brainstem structures in human is rare and pitfalls are numerous including wrong localization of recording site and non-uniform population due to the individual characteristic of the disease. Furthermore, very few clinical studies investigated concomitantly gait initiation and forward walking. Being able to do so as ecologically as possible using a “real” walking task is also a clear innovation. Indeed, most laboratories used a tapping task with feet or separate walking from its initiation in two different tasks making them two different behaviours and not a continuum in the motor repertoire. Also being able to target anatomically such specific brainstem structure as STN and MLR was challenging, however we used a brain atlas specifically designed in the team by experts in neuroanatomy and neurosurgery who helped to strengthen our results and interpretation. Results of the project include publication of preliminary results based on the long- and short-term effects of DBS on gait performances as well as 2 oral communications in international congresses. Results have been welcomed by the scientific and fostered fruitful discussions.
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. Furthermore, even if it seems too early for a solid claim, policy makers could eventually use the results to assess strategy improving health burden and well-being of European citizens “at large”. Finally, Neurosurgeons using Deep brain stimulation may also use the results of this project to investigate loss or improvement of their patient’s behaviour and disease progression after surgery.
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. Furthermore, even if it seems too early for a solid claim, policy makers could eventually use the results to assess strategy improving health burden and well-being of European citizens “at large”. Finally, Neurosurgeons using Deep brain stimulation may also use the results of this project to investigate loss or improvement of their patient’s behaviour and disease progression after surgery.