Parkinsonism-Related Oscillations in the Cortico-Basal Ganglia-Thalamic Network during Movement: Beyond the Frequency Range – Mov-oscill-CBGT

In Parkinson's disease (PD), akinesia and levodopa-induced dyskinesias (LIDs) are accompanied by synchronous and pathological neuronal oscillations in the cortico-subcortical network encompassing the basal ganglia and the thalamus (CGBT) with frequencies ranging from theta to gamma band. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the reference surgical treatment for patients suffering from Parkinson's disease (PD) at the advanced stage of the disease with motor fluctuations. However, DBS appears to be more effective if stimulation is applied only when needed. Thus, closed-loop adaptive DBS strategies based on the emergence/existence of beta neuronal oscillations in the STN of akinetic parkinsonian patients have been developed. In these stimulation protocols, the stimulation is applied chronically but its intensity is adjusted to the amplitude of beta oscillations recorded in the STN. However, the link between abnormal oscillatory activity within the CGBT network and clinical phenomenology remains to be clarified. Moreover, the expression of oscillatory activity at a given frequency may vary in different neuronal populations of the CGBT network, thus possibly reflecting different generating mechanisms and leading to varied motor correlates. In this project, we will identify the links between the characteristics of abnormal oscillatory activity in the CGBT network, not only their frequency, but also their amplitude, their phase/coherence relationship, and the motor disturbances observed in the non-human primate model of Parkinson’s disease and in PD patients. Neural recordings will be made in the different structures of the CBGT network in animals and in motor cortices and the STN in PD patients. These recordings will be performed during the execution of a motor task common to animals and humans in order to determine if there are similarities in terms of behavior and neuronal activity changes in the CBGT network between the 2 species. The advantage of controlling the parameters of the movement by placing the animal and the patients in similar experimental conditions is to facilitate the transposition of the results from the animal to the human and to allow the correlations between the behavior and the neuronal activities. We will thus study the motor performances and the time course of normal (in animals) and abnormal movements (akinesia and LID in animals and patients) as well as the temporal relationships (phase/coherence relationship) and frequential relationship of the neural activities recorded between the different structures of the CBGT network. In animals, we will be able to compare the behavior and neuronal activities before and after rendering them parkinsonian, in the absence of treatment (hypokinesia) and with levodopa treatment (hyperkinesia). In PD patients, we will proceed in a similar way by comparing behavior and neuronal activities after a L-Dopa withdrawal (hypokinesia) and after L-Dopa intake (hyperkinesia). This exploratory and translational approach will allow us to develop new DBS protocols (when to stimulate in relation to movement, with what frequency, stimulation pattern and amplitude) in parkinsonian monkeys which can eventually be applied in the future to PD patients, in hypo- and hyperkinetic conditions.