The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of midbrain and pons. The PPN in animal models appears topographically organised and functionally related to locomotion and arousal. In Parkinson’s disease, the PPN degenerates and is susceptible to abnormal basal ganglia output. In patients with Parkinson’s disease, low frequency PPN stimulation is proposed to improve gait freezing and postural instability. However, the therapeutic mechanisms, optimal clinical application and precise effects on gait and posture of PPN stimulation are unclear. Here, a topographic arrangement of the PPN was supported by local field potential recordings in parkinsonian patients. In the PPN region, beta oscillations were recorded rostrally and alpha oscillations caudally. Alpha oscillations, consistent with their putative role in allocating attention, correlated with gait performance and attenuated with gait freezing. Thus the caudal PPN subregion may be the most relevant target for gait disorders. Accordingly, an unblinded clinical study suggested that stimulation of the caudal PPN subregion was beneficial for gait freezing, postural instability and falls. In a double-blinded study using spatiotemporal gait analysis, caudal PPN stimulation reduced triggered gait freezing, with bilateral stimulation more effective than unilateral. However, akinesia including akinetic gait did not improve with PPN stimulation. Accordingly, dopaminergic medication requirements did not change. Mechanisms underlying gait freezing and PPN stimulation were explored with reaction time experiments. Parkinsonian patients with severe gait freezing and postural instability demonstrated a ‘block’ to pre-programmed movement. This was evidenced by prolonged simple reaction times and the absence of ‘StartReact’, whereby pre-prepared responses are normally accelerated by loud acoustic stimuli. PPN stimulation improved simple reaction time and restored Startreact. The relief of this ‘motor block’ with PPN stimulation may therefore explain the associated improvement in gait freezing and postural instability, as these tend to occur in circumstances requiring triggered, pre-prepared adjustments.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and DBS of the pedunculopontine nucleus (PPN) have been shown to be effective surgical therapies for Parkinson’s disease (PD). To better understand the PPN and STN as DBS targets for PD, this research compares the anatomy, electrophysiology, and motor control roles of these nuclei. PPN and STN connections were examined in vivo in human subjects and in the non-human primate using probabilistic diffusion tractography. Both the PPN and STN were connected with each other and with the motor cortex (M1) and basal ganglia. After studying these anatomical connections in primates, their functional significance was further explored in an anesthetized rat model of PD. Examination of the electrophysiological relationship between the PPN and basal ganglia in the presence of slow cortical oscillatory activity suggested that excitatory input from the STN may normally modulate PPN spike timing but that inhibitory oscillatory input from the basal ganglia output nuclei has a greater effect on PPN spike timing in the parkinsonian brain. To examine transmission and modulation of oscillatory activity between these structures at higher frequencies, LFP activity was recorded from the PPN and STN in PD patients performing simple voluntary movements. Movement-related modulation of oscillatory activity predominantly occurred in the α (8-12 Hz) and low β (12-20 Hz) frequencies in the STN but in the high β (20-35 Hz) frequencies in the PPN, supporting observations from rodent studies suggesting that oscillatory activity is not directly transmitted from the STN to the PPN in PD. Finally, to better understand the roles of the STN and PPN in large-scale movement, the effects of STN and PPN DBS on gait abnormalities in PD patients were studied. DBS of the STN appeared to improve gait by optimising executive gait control while DBS of the PPN appeared to restore autonomic gait control. These results have several implications for DBS patient selection, surgical targeting, and for understanding the mechanisms underlying DBS efficacy.

The functions of sleep remain enigmatic. One of the dominant, yet more contentious hypotheses is that sleep is involved in memory consolidation. A large body of evidence supports the role of rapid eye movement (REM) sleep in memory consolidation, especially in rodents. In humans, the role of REM sleep in memory consolidation has also been investigated, however it is unclear if it supports only one type of memory, or consolidation for several memory systems. Recent evidence suggests that non-REM is also involved in memory consolidation. The role of theta activity during REM and sleep spindles during non-REM may provide electrophysiological signatures reflecting memory consolidation processes. The studies presented here attempt to further investigate the electrophysiological characteristics of the learning-dependent changes in REM and slow wave sleep (SWS) in rats. A 2-stage model of memory consolidation is outlined here, and both steps of the model were investigated. Consistent with previous studies, REM increases were observed following avoidance training. During this period, theta power during REM sleep was increased compared to non-learning rats. Increased sleep spindle density during SWS was observed following REM increases. When REM sleep was suppressed by infusing the GABAB agonist baclofen into the pedunculopontine nucleus, avoidance performance acquisition was impaired. Baseline sleep spindles predicted whether rats were able to learn to make avoidance responses. Results suggest that both REM and SWS may be sequentially involved in memory consolidation processes. Discrete periods (windows) exist for REM and SWS when memory consolidation processes appear to take place. Theta activity during REM sleep from 17- 20 h on the first post-training day and sleep spindles during SWS from 21-24 h on the first post- training day are increased in learning rats and are related to memory performance. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2009-10-26 12:07:47.515