Clinical reviewSleep disturbances in Parkinson's disease: The contribution of dopamine in REM sleep regulation☆
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disease, afflicting about 1% of people over 65 y old and 4–5% of people over 85 y old.1, 2 At presentation, the major clinical features include the asymmetric onset of bradykinesia, rigidity, rest tremor and disturbances in balance. While sleep disturbances have only recently been recognized in PD and other movement disorders, such frequent afflictions were originally reported in James Parkinson's initial description of the disorder: “…the sleep becomes much disturbed. The tremulous motion of the limbs occurs during sleep, and augments until they awaken the patient, and frequently with much agitation and alarm”.3 These sleep disturbances primarily include insomnia, abnormal movements during sleep (e.g., periodic limb movements [PLM], rapid eye movement [REM] sleep behavior disorder [RBD]) and excessive daytime sleepiness.4 These disturbances have an important impact on the patient's quality of life, increasing the risk of self or bed-partner injuries (due to RBD/PLM) and/or the risk of driving or machinery accidents (due to the excessive daytime sleepiness). They may precede the cardinal motor features of the disease by many years, and therefore may serve as early biomarkers of the premotor phase of PD.5, 6
The specific mechanisms of these sleep disturbances are far from being fully understood, but they do include an apparent dopaminergic component that is still discussed in the literature. Due to the multiple variables (e.g., age, medication, depression, anxiety, cognitive decline, etc.) in PD, it is difficult to attribute the sleep disturbances exclusively to the degeneration of nigrostriatal dopaminergic neurons. Therefore, animal models may improve our knowledge of both the physiopathology of sleep alterations in PD in general and of the role of dopaminergic lesions in particular.
In recent years, most relevant published articles have narrowly focused on findings that contest the hypothesis that dopaminergic neurons of the substantia nigra pars compacta (SNpc) and of the ventral tegmental area (VTA) do not display robust alterations in firing rate across sleep-wake states.7, 8, 9 It was demonstrated that dopamine (DA)-containing neurons exhibit enhanced activity in bursts of spikes associated with REM sleep.10 Despite the supposed static firing rate of dopaminergic neurons throughout sleep-wake states, extracellular concentrations of DA in the striatum and prefrontal cortex are significantly elevated during periods of wakefulness.11 Another study has demonstrated the existence of changes in DA release in both the medial prefrontal cortex and the nucleus accumbens as a function of sleep-wake state in rats.12 The authors hypothesized that during REM sleep, the elevated levels of DA observed in the medial prefrontal cortex and in the nucleus accumbens could contribute to the specific cognitive processes that take place during this state. In light of these results, several other studies have provided useful information about the participation of DA in sleep regulation and the associated implications in PD.
In this article, we will review current evidence addressing the dopaminergic link between sleep and PD, focusing most closely on those studies that explore the mechanisms by which PD and sleep may be intertwined, whether as predictors or consequences of dopaminergic neurodegeneration. A comprehensive understanding and overview of the relationship between sleep regulation and PD is needed to guide future research in the field as well as facilitate the clinical management of the disease.
Section snippets
Procedure
To identify potential studies of interest, literature searches were performed using the electronic database SCOPUS, covering all publications from January 2000 up to (and including) January 2012. The search terms, employed either isolated or in combination (with the operator AND), were as follows: “sleep”, “Parkinson's disease”, “dopamine” and “substantia nigra pars compacta.” We included studies that (i) reported original data; (ii) reported empirical data, including review articles; (iii)
Sleep disturbances in PD
Nearly all patients with PD have sleep disturbances, and studies show that this pattern usually emerges early in the disease course.13, 14, 15 The causes of sleep disturbances are multifactorial, but the pathological degeneration of classical sleep regulation centers in the brainstem and thalamocortical pathways is likely to be an important factor. Sleep disturbances are secondarily promoted by nocturnal manifestations of the disease and by the side effects of pharmacological treatment. Lastly,
The prototypical stages of degeneration
Typically, PD is the result of the degeneration of neurons in the SNpc, which leads to the subsequent reduction of dopaminergic input to the striatum. Moreover, there is a degeneration of neurons of selected brainstem nuclei (LC, raphe nuclei, dorsal motor nucleus of the vagus), cortical neurons (particularly within the cingulated gyrus and the entorhinal cortex), the nucleus basalis of Meynert and of preganglionic sympathetic and parasympathetic neurons. In the soma of these neurons, the
A proposal for dopaminergic control of REM sleep
Episodes of excessive daytime somnolence after MPTP injections in monkeys have been anecdotally reported as a prominent feature of parkinsonism.50, 59 The first report to provide evidence of sleep disruption by MPTP demonstrated a selective REM sleep suppression that lasted 6–9 d after the last dose of the neurotoxin in cats.60 Almost one decade later, additional studies have elucidated different details on this topic. Almirall and colleagues demonstrated a strong relationship between motor
Conclusions
A substantial portion of the literature now links perturbations in the dopaminergic system with the sleep disturbances observed in PD. Although many questions remain, evidence suggests that SNpc and VTA may largely account for the well-documented association between sleep disturbances and PD. More recently, several reports have employed experimental models of PD in which neurochemical and electrophysiological data are quantified. These studies reinforce the hypothesis that the PPT and LDT,
Acknowledgments
This paper was supported by the CNPq Casadinho/Procad Grant No: 552226/2011-4. MMSL is recipient of Fundação Araucária - Governo do Estado do Paraná fellowship. The author has declared that no conflict of interests exists.
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2021, Biomedicine and PharmacotherapyCitation Excerpt :The classical hallmarks of PD include progressive degeneration of dopaminergic neurons in substantia nigra and appearance of Lewy bodies in survival neurons [1–4]. In addition to motor symptoms, PD patients clinically manifest with a variety of non-motor symptoms, such as gastrointestinal discomfort, cognitive deficits, sleep disturbances, and affective disorders [5–7]. Depression is one of the most common psychiatric comorbidities [8,9].
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This article is dedicated to my father Prof. João de Meira Santos Lima (in memoriam) who devoted his professional life to education, literature and poetry.
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The most important references are denoted by an asterisk.