SENCE

Deficits in motor functions in Parkinson’s disease (PD) have usually been attributed to dysfunctional output of the basal ganglia (BG) to the motor system. However, the nature of the motor impairments caused by dopamine depletion is still debated. Moreover, efficient control of movement relies on optimal integration of peripheral sensory feedback signals and predictions of the sensory consequences of the movement, assumed to be generated by internal models in the cerebellum. It has been shown that patients with PD suffer from somatosensory impairments, including proprioceptive deficits. Also, anatomical and functional cerebellar anomalies in PD have been reported. In human patients suffering from PD, we will investigate the potential behavioural and electrophysiological correlates of somatosensory and cerebellar anomalies, as well as the effects of dopaminergic medication and Deep Brain Stimulation (DBS) thereon. Our project builds on three main recent findings. Namely, 1) primary effect of dopamine on somatosensory input in the striatum has been demonstrated, which may be responsible for increased sensory-proprioceptive noise; 2) bidirectional connections between the BG and the cerebellum have been uncovered, through which BG deregulation may directly interact with cerebellar predictive functions; 3) influence of dopamine level on reliance on current sensory information has been shown, which implies that optimal combination of sensory input and sensory prediction may be compromised in PD. Moreover, exaggerated synchronisation of beta-band oscillations in the BG is now considered a hallmark of PD. Dopaminergic medication and DBS both help to normalise oscillatory activity, which correlates with improved motor functions. In agreement with the idea that faulty BG output to the motor system is the main cause of motor impairment, these regulatory effects have usually been considered in relation to efferent motor signals and examined within the BG-cortical motor loops. However, our previous work in healthy adults has demonstrated that the functional roles of beta-band oscillations in movement control extend far beyond the functions classically attributed to the BG-cortical motor network. We will analyse beta-band oscillatory deregulations as well as dopamine medication and DBS effects in relation to afferent somatosensory signal-processing and within extended BG–cortex–cerebellum circuits. Our project combines advanced recording and stimulation techniques, data-analysis methods and modelling. We will exploit experimental paradigms combining psychophysics involving a robotic device with cortical and subcortical electrophysiological recording in order to characterise movement control and somatosensory/proprioceptive deficits. We will analyse trial-by-trial relationships between beta-band activity and behaviour through a novel approach based on the analysis of the brief transient bursts of beta-band oscillations (beta bursts) sustaining beta-band activity. We will collect an original multimodal neuroimaging dataset, comprising anatomical, diffusion-weighted and functional MRI, as well as FDG-PET, and fuse structural and functional information to robustly identify abnormalities in both the somatosensory processing network and the cerebellum. Importantly, we will contrast the impacts of different DBS protocols, conventional continuous “open-loop” DBS and adaptive “closed-loop” DBS, in which stimulation is triggered by on-line detection of beta bursts in the subthalamic LFP. The emergent effects of stimulation on beta-band activity and network dynamics will be simulated through a computational approach, which will allow testing and optimising in silico for more effective stimulation schemes for desynchronisation.