Electrophysiological signals for closed-loop deep brain stimulation in Parkinson’s disease

Continuous high-frequency deep brain stimulation (DBS) in the subthalamic nucleus (STN) is an established treatment for Parkinson’s disease (PD). Current developments focus on trying to widen the therapeutic window of such treatments. Closed-loop DBS, where stimulation is dynamically controlled by feedback from biomarkers of pathological brain circuit activity, is one such development. Numerous electrophysiological signals extracted from local field potentials (LFPs) or electrocorticography (ECoG) in the basal ganglia-thalamo-cortical circuit relate to symptom severity and have consequently been proposed as real-time biomarkers. These signals include phase-amplitude coupling, beta-oscillatory bursts, single neuronal firing patterns, and features of waveform morphology. The neuronal basis and interdependency of these signals, however, are poorly understood. To address this a two-fold approach was taken. First, subthalamic macro- and micro electrode recordings of LFPs and single unit activity were studied in human PD patients undergoing DBS-surgery. Simultaneously recorded ECoGs were analysed in order to relate previously proposed cortical biomarkers to subthalamic neuronal activity. Second, selective optogenetic stimulation of basal-ganglia or cerebellar receiving thalamus was deployed in rodents to investigate if cortical electrophysiological signals observed in PD could be generated from driving inputs to motor thalamus. In human PD patients, phase-amplitude coupling in the STN was found to reflect the locking of spiking activity to network beta oscillations and this coupling increased progressively with beta-burst duration, suggesting subthalamic beta bursts to capture higher levels of input-output synchronisation. Furthermore, cortical beta bursts were associated with several other cortical and subthalamic biomarkers and cortical waveform sharpness was linked to subthalamic neuronal synchronisation. In rodents, cortical phase-amplitude coupling in the ECoG could be produced by driving basal-ganglia, but not cerebellar recipient thalamus. Thus, providing experimental evidence to a theory of a basal-ganglia-thalamic origin of cortical phase-amplitude coupling in PD. Overall, this thesis gives novel insights into the neuronal basis of electrophysiological biomarkers in PD with direct implications for future closed-loop DBS trials.