Neuronal activity in the pedunculopontine nucleus and globus pallidus in patients with movement disorders

Abstract

Deep brain stimulation (DBS) is a safe and effective treatment for several neurological disorders, including Parkinson’s disease (PD), dystonia, essential tremor, and Tourette’s syndrome (TS), and is typically offered to patients with severe symptoms that are not adequately managed by medical therapy. In the DBS procedure, electrodes are implanted into subcortical brain regions and chronic electrical stimulation is delivered through these electrodes. Neuronal activity is recorded during these surgeries with microelectrodes to ensure accurate electrode placement, and stimulation of the correct brain region. Microelectrode recordings (MER) offer a unique opportunity to study the function of human brain regions with excellent spatial and temporal resolution that is unmatched by any other recording or imaging modality. A thorough understanding of subcortical brain structures at a cellular and network level is essential for understanding the function of these regions and their involvement in neurological disease. I have studied the properties of single neurons and networks of neurons in the pedunculopontine nucleus (PPN) and globus pallidus internus (GPi) of patients undergoing deep brain stimulation surgery for the treatment of movement disorders. Magnetic resonance imaging (MRI) and computed tomography (CT) was used to identify the anatomical structures in which recordings were made. The activity of single units was extracted from MER using wavelet-based spike sorting. Networks of neurons were identified using cross-correlation analysis. The PPN is a brainstem structure that plays a central role in the initiation and maintenance of gait. I have characterised the activity of neurons in the PPN from patients with PD undergoing DBS surgery to treat gait freezing. Two populations of neurons were identified (wide-spiking and narrow-spiking) on the basis of their action potential duration, and differences in firing properties were observed between these two groups. Wide-spiking neurons occurred in greater proportion in the caudal PPN, and are likely to be cholinergic neurons. PPN neurons responded to movement and imagined gait with increased or decreased activity. Networks of PPN neurons discharged in synchrony, and these networks were dynamically modulated by passive movement and imagined gait, with movement and gait activating different networks of neurons. Additionally, activity of PPN neurons was phase locked to alpha oscillations, and phase locking was decreased during passive movement and imagined gait. These results show that different synchronous networks are activated during initial motor planning and actual motion, and suggest that changes in gait initiation in PD may result from disrupted network activity in the PPN. The anteromedial GPi has limbic functions and this thesis provides the first characterisation of single unit activity in this region in patients with TS. Two populations of neurons were identified in the GPi on the basis of firing rate and pattern. One population of neurons had low firing rate and regular firing patterns, and was likely to consist of border cells. The other population of neurons had a higher firing rate and a pattern of long bursts separated by short pauses. Correlated activity was observed between GPi neurons. Both populations of neurons had abnormally low firing rates. These findings indicate that Tourette syndrome is associated with abnormal neuronal activity in the anteromedial GPi. It is therefore possible that these abnormal patterns of activity have a causal role in the generation of tics and premonitory urges. Activity in the GPe was also studied, and GPe neurons had similar discharge characteristics to GPi neurons, which is vital knowledge for surgical targeting of the GPi. In summary, this thesis has characterised single unit activity in the PPN and GPi in patients with movement disorders, showing that networks of neurons in the PPN are involved in the planning of gait, and that neurons in the anteromedial GPi have abnormal firing rate and firing patterns in TS. These findings provide novel knowledge of the neuronal activity in the human PPN and GPi, and further advance our understanding of the role of these subcortical brain regions in motor function and neurological disease.