To our knowledge, this is the first report that significant sleep disturbances in PD are related to the side of motor symptom onset. After controlling for mood scores, we found that both RPD and LPD reported more frequent sleep disturbances than did the control group. LPD experienced more nocturnal hallucinations, disturbing dreams, and excessive daytime sleepiness than RPD. The differences between LPD and RPD were not accounted for by differences in age, disease severity, medication type or dosage, as the groups did not differ on any of these factors, nor in mood, as all analyses were performed after adjusting for differences in mood scores. The differences between LPD and RPD in self-reported sleep disturbances were not accounted for by differences in EEG-measured sleep architecture as no such differences emerged when overnight polysomnography was performed. In addition, the greater frequency of reported daytime dozing in LPD than RPD cannot be accounted for by obstructive sleep apnea, as polysomnographic findings revealed the presence of sleep apnea in four patients with RPD and none with LPD.
Though the physiological substrates of hallucinations and dreaming are yet to be completely understood, there is some evidence that in PD, vivid dreaming and sleep disruptions may serve as precursors to hallucinations (35
). Dreaming and visual hallucinations are related to REM sleep and may be mediated by the ponto-geniculo-occipital (PGO) waves (37
) that have been detected in animals during REM sleep and implicated in dream-related internal stimulus generation and visual perceptions (39
). Because the PGO generator (nucleus pedunculopontinus) and other brainstem regions directly involved in the control of sleep/wake cycles are linked to the neurodegenerative process of PD (41
), it has been suggested that abnormal PGO activity could be responsible for generation of vivid dreaming as well as hallucinations during wakefulness in these patients (38
The basal ganglia may play an important role in regulating sleep/wake activity. Neuroimaging studies in healthy adults have demonstrated particularly robust increases in activation of the basal ganglia during transition from wakefulness to slow wave and to REM sleep (42
). The basal ganglia are involved in the mediating network that connects the brainstem to the cortex and this network contains multiple back-projections to the pedunculopontine tegmentum. The role of the basal ganglia in sleep/wake activity may therefore be the regulation of ascending thalamocortical activation and rostral transmission of PGO waves from the brainstem through the thalamus to the forebrain (42
Alterations in right-hemispheric cortical activation via asymmetrical basal ganglia functioning may explain disturbed visual processing and more frequent dreaming in patients with LPD. The basal ganglia neural networks are part of the thalamocortical circuit projecting to cortical areas involved in higher-order visual processing (44
). Imaging studies of patients with Dementia with Lewy Bodies and of patients with PD have demonstrated selective activation of right-hemisphere brain regions (i.e., right parietal and temporal areas) (45
) in patients with visual hallucinations. In normal adults, despite the general deactivation of the parietal and frontal cortices during REM sleep dreaming, there is selective activation of the right parietal operculum (47
). In LPD, abnormal functioning of the basal ganglia-thalamocortical circuitry may increase the thalamic input to right temporo-parietal areas (48
) and lead to abnormal PGO activity (38
). Consequently, these alterations in right-hemispheric cortical activation may result in disturbed visual processing and more frequent dreaming in patients with LPD.
Right-hemisphere dysfunction may also account for more frequent daytime dozing in LPD. Excessive daytime sleepiness is a common non-motor symptom that occurs in approximately 30% of non-demented patients with PD (49
). Right-hemisphere neural networks have been implicated in arousal and vigilance levels in healthy adults (50
), and these right-hemisphere vigilance functions are particularly sensitive to sleep deprivation (53
). There is also evidence for a functional deterioration of the fronto-temporo-parietal network in the right hemisphere of patients with narcolepsy, a disorder characterized by the loss of hypocretin-secreting neurons (54
). Although no studies have examined laterality in the loss of hypocretin neurons of the hypothalamus, in patients with PD there is significant loss of these neurons (55
), increasing with disease severity and progression (56
). Impairment in right-hemisphere functions consequently could account for more frequently reported excessive daytime sleepiness in LPD.
Hallucinations and excessive daytime sleepiness in PD are considered by some to be a side effect of dopaminergic medication rather than a part of the disease process. Several studies have demonstrated, however, that hallucinations are not related to dose or duration of medication (57
) and high-dose levodopa infusions do not induce hallucinations in PD (61
). With respect to daytime sleepiness, though, there is compelling evidence for dopaminergic medication as a direct cause of drowsiness (62
); it is clear that other disease-related factors may also contribute to the development of daytime somnolescence (22
). In our sample, daytime sleepiness and hallucinations in LPD alone could not be attributed solely to the use of dopaminergic medications, as there were no LPD-RPD differences in dose of either levodopa or dopamine agonists.
An important limitation of our study is the low representation of women, especially in the PD groups. Gender differences have been reported for non-motor symptoms of PD, with women presenting more often with depression and men presenting more often with behavioral disturbances (68
). Likewise, gender differences appear to exist for sleep disorders, with women reporting a higher prevalence of insomnia and restless legs syndrome, whereas REM behavior sleep disorder, characterized by loss of normal muscle atonia and acting-out of dreams, is more common in men (69
). Underlying the gender differences in both sleep and non-motor symptoms of PD may be distinct pathophysiological mechanisms, which underscores the importance of including both men and women in future studies of the etiology and symptomatology of PD.
In our sample, RPD presented with higher scores on a measure of stress, anxiety and depression than did the LPD and control group. In all three groups, these symptoms were related to the subjective sleep disturbances, with those endorsing more mood symptoms also reporting higher frequency of sleep-related problems. There is evidence that mood symptoms impact sleep complaints in both younger and older adults, with those expressing a greater degree of sleep problems also reporting more mood symptoms such as depression and anxiety (70
). In the current study, adjusting for mood symptoms highlighted significant differences between patients with LPD and RPD on the dreams, hallucinations and daytime dozing items of the sleep questionnaire, thereby emphasizing the group differences in sleep disturbances that are intrinsic to the disease rather than secondary to other disease-related symptoms such as depression and anxiety (71
The current study did not find any hemispheric differences in sleep architecture between LPD and RPD. Polysomnography limited to 24 hours, however, may have missed important sleep disorders that are common in PD, namely REM behavior sleep disorder and restless legs syndrome. In light of the current finding of side-of-onset differences in sleep-related disturbances, it is important for future studies examining a wider range of objective sleep measures in PD to consider side of symptom onset.
In summary, we found an effect of side of motor symptom onset on sleep disturbances in PD. In particular, there were differences in the frequency of reported distressing/vivid dreams, hallucinations and daytime dozing. Research is needed to understand how the side of symptom onset is related to specific sleep disorders such as REM behavior sleep disorder and restless legs syndrome, which are common in PD and are likely related to the neuropathologic process of the disease. Elucidating the etiology of sleep disturbances in PD is important as identification and early treatment of these disturbances may substantially enhance the quality of life in patients with this disease.