Microcircuit Electrophysiological Functional Relationships in the Cortico-Basal Ganglia Network with Deep Brain Stimulation in Parkinson's Disease

Objective: This dissertation aims to learn about the neural networks involved with using deep brain stimulation (DBS) to treat Parkinson’s disease (PD) and increase our understanding of the mechanism of DBS. The particular focus is on examining network dynamics in the cortico-basal ganglia (BG) circuit and how DBS modulates functional connectivity in the cortico-BG circuit. The overarching hypothesis of this work is that DBS changes electrophysiological environments to alter the brain’s activity on a network level, examined here in the cortico-BG network in PD. Background: Deep brain stimulation (DBS) is the therapeutic use of chronic electrical stimulation of the brain via an implanted electrode and is a treatment for a variety of neurological disorders. The brain is an electrically active organ, containing neurons that communicate in circuits using action potentials (APs) and local field potentials (LFPs). We can infer information about how neurons communicate by studying these signals, how they behave in PD, and how they respond to DBS. PD is a neurodegenerative disease that manifests motor symptoms of bradykinesia, tremor, and rigidity, as well as a host of non-motor symptoms including cognitive impairment. It is characterized by a loss of dopamine (DA) neurons in the substantia nigra (SN), which has downstream effects on the function of the cortico-BG network. The cortico-BG network is an intricate web of connections between anatomical areas that regulates movement. DBS is used to treat the motor symptoms of PD with widespread success and has long-lasting efficacy. The DBS electrodes are placed into subcortical structures in the cortico-BG network, most commonly the subthalamic nucleus (STN) and the globus pallidus internus (GPi). There are many theories concerning how DBS works, and this project sought to provide increased mechanistic understanding. Empirical evidence attests to the effectiveness of DBS as a treatment for PD and how it must change some pathological activity to restore motor function. I hypothesized that rather than changing individual neuron properties, DBS acts on neuronal microcircuits embedded in the greater cortico-BG network as part of its neuromodulatory mechanism. Methods: Data was recorded during surgery for DBS electrode implantation from 2 sources: a microelectrode placed in the surgical target (STN or GPi) and a µ-electrocorticography (ECoG) grid placed on the motor association cortex. In one group of subjects, as the microelectrode was lowered along the surgical trajectory, we stopped at multiple sites with neuronal activity for periods of approximately 0.5-5 minutes. In another subset of subjects, DBS was applied across subtherapeutic, thereapeutic and supratherapeutic frequencies. The electrophysiological functional relationships between the STN or GPi and the cortex were studied using through examining APs and LFPs and their temporal and spatial connectivity. Additionally, I examined the DBS waveform and the relationship between the electromotive force (EMF) generated by DBS and distance to the recording electrode. Results: A subset of individual neurons in the STN has an electrophysiological functional relationship to the local electrical environment, and another subset of STN neurons has functional connectivity with the cortex as measured with the AP aligned average LFP. These electrophysiological connections have a high degree of spatial specificity, differing between neighboring neurons and within a few millimeters on the cortex. The effect of DBS on these microcircuits was an increase in LFP power in the alpha band (8-12 Hz) during 140 Hz stimulation. DBS modulated activity in the cortico-BG network at a therapeutically relevant frequency of 140 Hz, but not at subtherapeutic and supratherapeutic frequencies. The DBS waveform is attenuated as distance from the source of stimulation (the DBS lead) increases. Conclusions: The STN and the motor association cortex had an intricate and complex functional connectivity with a high degree of spatial specificity. The topographies of these functional connections varied across neurons and on a sub-centimeter scale on the cortex. When DBS was applied changes in these functional connections were seen with stimulation delivered at 140 Hz. These microcircuits are embedded within in the larger cortico-BG network and are affected by a therapeutically relevant frequency of DBS. The pathological activity in the cortico-BG network is modulated on fine temporal and spatial scales, which explains some of the short-latency effect of DBS on motor symptoms. Significance: We expect the outcomes of this project to be a better understanding of the electrophysiological mechanisms underlying the therapeutic effects of DBS. The broader implications of this research include improving DBS as an intervention and expanding its application to other neurological disorders. Examining the cortico-BG circuit is important in the effort to understand both normal and abnormal motor information processing and to improve neuromodulation therapies