Basal ganglia beta oscillations during sleep underlie Parkinsonian insomnia.

Sleep disorders are among the most debilitating comorbidities of Parkinson's disease (PD) and affect the majority of patients. Of these, the most common is insomnia, the difficulty to initiate and maintain sleep. The degree of insomnia correlates with PD severity and it responds to treatments that decrease pathological basal ganglia (BG) beta oscillations (10-17 Hz in primates), suggesting that beta activity in the BG may contribute to insomnia. We used multiple electrodes to record BG spiking and field potentials during normal sleep and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in nonhuman primates. MPTP intoxication resulted in severe insomnia with delayed sleep onset, sleep fragmentation, and increased wakefulness. Insomnia was accompanied by the onset of nonrapid eye movement (NREM) sleep beta oscillations that were synchronized across the BG and cerebral cortex. The BG beta oscillatory activity was associated with a decrease in slow oscillations (0.1-2 Hz) throughout the cortex, and spontaneous awakenings were preceded by an increase in BG beta activity and cortico-BG beta coherence. Finally, the increase in beta oscillations in the basal ganglia during sleep paralleled decreased NREM sleep, increased wakefulness, and more frequent awakenings. These results identify NREM sleep beta oscillation in the BG as a neural correlate of PD insomnia and suggest a mechanism by which this disorder could emerge.

Desynchronization of slow oscillations in the basal ganglia during natural sleep.

Slow oscillations of neuronal activity alternating between firing and silence are a hallmark of slow-wave sleep (SWS). These oscillations reflect the default activity present in all mammalian species, and are ubiquitous to anesthesia, brain slice preparations, and neuronal cultures. In all these cases, neuronal firing is highly synchronous within local circuits, suggesting that oscillation-synchronization coupling may be a governing principle of sleep physiology regardless of anatomical connectivity. To investigate whether this principle applies to overall brain organization, we recorded the activity of individual neurons from basal ganglia (BG) structures and the thalamocortical (TC) network over 70 full nights of natural sleep in two vervet monkeys. During SWS, BG neurons manifested slow oscillations (∼0.5 Hz) in firing rate that were as prominent as in the TC network. However, in sharp contrast to any neural substrate explored thus far, the slow oscillations in all BG structures were completely desynchronized between individual neurons. Furthermore, whereas in the TC network single-cell spiking was locked to slow oscillations in the local field potential (LFP), the BG LFP exhibited only weak slow oscillatory activity and failed to entrain nearby cells. We thus show that synchrony is not inherent to slow oscillations, and propose that the BG desynchronization of slow oscillations could stem from its unique anatomy and functional connectivity. Finally, we posit that BG slow-oscillation desynchronization may further the reemergence of slow-oscillation traveling waves from multiple independent origins in the frontal cortex, thus significantly contributing to normal SWS.

Entrainment to sleep spindles reflects dissociable patterns of connectivity between cortex and basal ganglia.

Sleep spindles are crucial for learning in the cortex and basal ganglia (BG) because they facilitate the reactivation of previously active neuronal ensembles. Studying field potentials (FPs) and spiking in the cortex and BG during sleep in non-human primates following pre-sleep learning, we show that FP sleep spindles are widespread in the BG and are similar to cortical spindles in morphology, spectral content, and response to the pre-sleep task. Further, BG spindles are concordant with electroencephalogram (EEG) spindles and associated with increased cortico-BG correlation. However, spindles across the BG differ markedly in their entrainment of local spiking. The spiking activity of striatal projection neurons exhibits consistent phase locking to striatal and EEG spindles, producing phase windows of peaked cross-region spindling. In contrast, firing in other BG nuclei is not entrained to either local or EEG sleep spindles. These results suggest corticostriatal synapses as the main hub for offline cortico-BG communication.

Spontaneous pauses in firing of external pallidum neurons are associated with exploratory behavior.

Spontaneous pauses in firing are the hallmark of external pallidum (GPe) neurons. However, the role of GPe pauses in the basal ganglia network remains unknown. Pupil size and saccadic eye movements have been linked to attention and exploration. Here, we recorded GPe spiking activity and the corresponding pupil sizes and eye positions in non-human primates. We show that pauses, rather than the GPe discharge rate per se, were associated with dilated pupils. In addition, following pause initiation there was a considerable increase in the rate of spontaneous saccades. These results suggest that pauses are a powerful mechanism by which the GPe may influence basal ganglia downstream structures and play a role in exploratory behavior.

Etiologies of insomnia in Parkinson's disease - Lessons from human studies and animal models.

Sleep disorders are integral to Parkinson's disease (PD). Insomnia, an inability to maintain stable sleep, affects most patients and is widely rated as one of the most debilitating facets of this disease. PD insomnia is often perceived as a multifactorial entity - a consequence of several of the disease symptoms, comorbidities and therapeutic strategies. Yet, this view evolved against a backdrop of a relative scarcity of works trying to directly dissect the underlying neural correlates and mechanisms in animal models. The last years have seen the emergence of a wealth of new evidence regarding the neural underpinnings of insomnia in PD. Here, we review early and recent reports from patients and animal models evaluating the etiology of PD insomnia. We start by outlining the phenomenology of PD insomnia and continue to analyze the evidence supporting insomnia as emanating from four distinct subdivisions of etiologies - the symptoms and comorbidities of the disease, the medical therapy, the degeneration of non-dopaminergic cell groups and subsequent alterations in circadian rhythms, and the degeneration of dopaminergic neurons in the brainstem and its resulting effect on the basal ganglia. Finally, we review emerging neuromodulation-based therapeutic avenues for PD insomnia.

Dissociable roles of ventral pallidum neurons in the basal ganglia reinforcement learning network.

Reinforcement learning models treat the basal ganglia (BG) as an actor-critic network. The ventral pallidum (VP) is a major component of the BG limbic system. However, its precise functional roles within the BG circuitry, particularly in comparison to the adjacent external segment of the globus pallidus (GPe), remain unexplored. We recorded the spiking activity of VP neurons, GPe cells (actor) and striatal cholinergic interneurons (critic) while monkeys performed a classical conditioning task. Here, we report that VP neurons can be classified into two distinct populations. The persistent population displayed sustained activation following visual cue presentation, was correlated with monkeys' behavior and showed uncorrelated spiking activity. The transient population displayed phasic synchronized responses that were correlated with the rate of learning and the reinforcement learning model's prediction error. Our results suggest that the VP is physiologically different from the GPe and identify the transient VP neurons as a BG critic.