Modulation of oscillatory activity in the cortico-subthalamic pathway by electrical stimulation in rodents and humans

Thesis

Parkinson’s disease (PD) is a debilitating motor disorder characterized by degeneration of dopaminergic cells in the Basal Ganglia (BG). This loss of dopaminergic neurons gives rise to abnormal synchronization of neuronal activity in the beta frequency range (around 20 Hz) across the cortico-basal ganglia network in parkinsonian humans and animals. Interestingly, in tremor patients the phase of ongoing peripheral oscillation can be exploited with electrical ‘phase interference’, whereby cortical stimulation on specific phases of the tremor dampens both the pathological neuronal activity and resulting symptoms. Computational modelling suggests that the amplitude of beta oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Harnessing the phase of a pathological neural activity, therefore, may be a promising way to increase the specificity and efficacy of stimulation protocols for deep brain stimulation (DBS) treatment of motor disorders. The principal aim of this study was to examine the 1) effect of stimulation phase-in supressing and amplifying the amplitude of the ongoing pathological beta oscillations of the motor cortex and subthalamic nucleus (STN); and 2) investigate the phase relationship between and the power of ongoing beta oscillations in these brain areas. Complimentary experiments were carried out in PD patients undergoing microelectrode mapping for the implantation of DBS electrodes as well as in the 6-OHDA hemi-lesioned rat model of PD. In awake PD patients displaying beta oscillations we recorded cortical EEG, STN LFP as well as multiunit activity from the STN. The data obtained from these human intraoperative recordings revealed that electrical stimulation arriving on consecutive cycles of a specific phase of the subthalamic oscillation can suppress its amplitude and coupling to cortex. Additionally, combining data recorded from Parkinsonian rats and awake PD patients we demonstrate that the amplitude of beta oscillations in the cortex and the STN ramp up when these assemblies were at their most common phase alignment (“preferred phase”). Our data suggests that phase-dependent stimulation could thus be a valuable strategy for treating brain diseases and probing the function of oscillations in the healthy brain. These results provide further evidence that periods of particular phase alignments between nodes of the cortical-basal ganglia circuit can lead to amplification of oscillations at the same frequency.

Authors: Kormann, E

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford