Pharmacological and Electroceutical Modulations of Local Field Potentials in Parkinson’s Disease

Parkinson’s disease (PD) is a complex neurodegenerative disorder with motor and cognitive symptoms caused by loss of dopaminergic neurons in the basal ganglia. There is no cure but treatment options such as dopaminergic medication and deep brain stimulation (DBS) can help relieve the symptoms. Despite decades of clinical use, the underlying electro-pathophysiology of these treatments are still not clear. In this dissertation, we have investigated the modulations of local field potentials (LFPs) recorded from the subthalamic nucleus (STN) of patients with PD. To do so reliably, we first presented an online processing pipeline that helps refine the targeting of STN intraoperatively. We benchmarked this system against the gold-standard clinical practice involving single unit activity (SUA) with a randomized and double blinded pilot study. In patients referred for bilateral DBS, we implanted one hemisphere with SUA guidance and the other with LFP randomly. Then, we compared the clinical improvement assessed by a blinded neurologist. Our results suggested that our LFP-based targeting approach performed equally or better at localizing the STN and can be utilized as an additional feedback modality in the operating room, as it does not require any additional hardware or surgical procedures. Next, with a well-localized STN, we studied the pharmacological modulations of LFPs with dopaminergic medication over unique 24-hour-long recordings from externalized DBS leads. The reasoning behind such long recordings was that the medications have long wash-in and wash-out times and it is important to replicate observations. Thus, each of our nine patients had a chance to take their medications three times during the recordings. We not only observed power changes in the LFP spectra in the beta (12-30 Hz) and high-frequency (200-400 Hz) bands, as reported previously, but also reported strong non-linear cross-frequency coupling between these bands for the first time in the ON state. Prior to this observation, the coupling in the STN was considered to be purely pathological, as it was consistently reported in the unmedicated state only. However, our observations suggest that the coupling can have impeding or enhancing effects on the normal processes depending on the coupled frequencies. Finally, we investigated the electroceutical modulations of the LFPs with therapeutic and non-therapeutic DBS. Due to the fast-acting nature of stimulation therapy, we performed the recordings intraoperatively in eight patients. Interestingly, we observed -for the first time- high-frequency (200-400 Hz) activity in the STN only during therapeutic stimulation, similar to medicated patients and healthy non-human primates. The consistent appearance of this activity in healthy and treated basal ganglia with medication and DBS prompts that there may be LFP oscillations specific to the healthy and diseased states, and that these oscillations can further our understanding of the pathophysiology of PD and can be used for the development of novel tools for diagnostic purposes such as target localization, and for treatment purposes such as selection of optimal stimulus parameters and adaptive/closed-loop DBS.