Early onset of sleep/wake disturbances in a progressive macaque model of Parkinson’s disease

Davin, Aurélie; Chabardès, Stéphan; Belaïd, Hayat; Fagret, Daniel; Djaileb, Loïc; Dauvilliers, Yves; David, Olivier; Torres, Napoléon; Piallat, Brigitte

doi:10.1038/s41598-022-22381-z

Cited by 13 publications

(16 citation statements)

References 71 publications

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“…The NHPs exhibited significant altered wake/sleep behavior in the parkinsonian state compared to the healthy state (as already described in different NHP model of PD 30 , 31 , 33 and also observed in patients with advanced PD 34 , 35 ). MPTP-treated animals showed EDS, characterized by a decrease in sleep latency, an inability to maintain long periods of wakefulness, and prominent disorganization of naps.…”

Section: Discussionsupporting

confidence: 73%

“…However, the MPTPtreated NHPs model exhibited sleep/wake disturbances similar to that observed in PD patients. Thus, MPTP-treated NHPs experience disorganization of nighttime sleep with reduced sleep quality and EDS characterized by sleep episodes occurring more rapidly in the morning and spreading through the middle of the day, as described in a recent study conducted by our group 33 and others 30,31,55 . We also acknowledge the limited number of animals used in the present study, due to ethical considerations concerning animal use; however, our results were consistent across animals.…”

Section: Discussionmentioning

confidence: 65%

“…The MPTP-treated NHP model is known to mimic both motor symptoms and nonmotor symptoms of PD [30][31][32] . In a previous paper, we fully characterized the sleep/wake disturbances in this model 33 , demonstrating its usefulness to evaluate the effect of target and parameters settings of a novel DBS method on EDS. For this purpose, the NHPs were equipped with a telemetric device to monitor the different wake and sleep stages as well as a DBS lead connected to an implanted stimulator in the PPN area.…”

Section: Introductionmentioning

confidence: 99%

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Excessive daytime sleepiness in a model of Parkinson’s disease improved by low-frequency stimulation of the pedunculopontine nucleus

Davin

Chabardès

Devergnas

et al. 2023

npj Parkinsons Dis.

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Patients with Parkinson’s disease often complain of excessive daytime sleepiness which negatively impacts their quality of life. The pedunculopontine nucleus, proposed as a target for deep brain stimulation to improve freezing of gait in Parkinson’s disease, is also known to play a key role in the arousal system. Thus, the putative control of excessive daytime sleepiness by pedunculopontine nucleus area stimulation merits exploration for treating Parkinson’s disease patients. To this end, two adult nonhuman primates (macaca fascicularis) received a deep brain stimulation electrode implanted into the pedunculopontine nucleus area along with a polysomnographic equipment. Stimulation at low frequencies and high frequencies was studied, in healthy and then MPTP-treated nonhuman primates. Here, we observed that MPTP-treated nonhuman primates suffered from excessive daytime sleepiness and that low-frequency stimulation of the pedunculopontine nucleus area was effective in reducing daytime sleepiness. Indeed, low-frequency stimulation of the pedunculopontine nucleus area induced a significant increase in sleep onset latency, longer continuous periods of wakefulness and thus, a partially restored daytime wake architecture. These findings may contribute to the development of new therapeutic strategies in patients suffering from excessive daytime sleepiness.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

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Excessive daytime sleepiness in a model of Parkinson’s disease improved by low-frequency stimulation of the pedunculopontine nucleus

Davin

Chabardès

Devergnas

et al. 2023

npj Parkinsons Dis.

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“…After recordings of the baseline during the healthy state, monkeys were chronically intoxicated by intramuscular injections of MPTP under light anesthesia (Ketamine 2-4 mg/kg), based on a previous study (Davin et al, 2022). This progressive protocol, allowing a long non-motor phase to mimic the clinical pathology, consisted in small injections of MPTP (0.2-0.5 mg/kg, in NaCl 0.9%) every two weeks until the parkinsonian syndrome was stable.…”

Section: Mptp Treatmentmentioning

confidence: 99%

Subthalamic nucleus activity dynamics preceding clinical manifestations in a progressive Parkinson’s disease model

Bertrand,

Chabardes,

De Leiris

et al. 2024

Preprint

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BackgroundParkinson’s disease (PD) is clinically diagnosed based on motor impairments related to akinesia, rigidity, and tremor. These symptoms are delayed in the course of the disease and that contributes strongly to its late diagnosis. Cognitive and limbic symptoms may precede motor symptoms, thus opening an earlier diagnostic window, but their early kinetics need to be better characterized. Furthermore, despite adapted medications, these non-motor symptoms evolve and worsen over time. Surgical treatment with high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN), whereas significantly improves motor symptoms, does not address specifically the non-motor symptoms. A better temporal characterization of the onset of non-motor symptoms combined with adapted parameters of stimulation of DBS could potentially optimize the surgical treatment.ObjectiveWe aimed to correlate STN activity with the early phase of motor, cognitive, and limbic symptoms of PD and to propose specific STN-DBS paradigm of stimulation to take over all symptoms.MethodsLocal field potentials of the STN were recorded in two non-human primates (Macaca fascicularis) while performing a behavioral task allowing the assessment of motor, cognitive, and limbic reward-related behavioral components. In parallel, a progressive model of PD, consisting in small injections of 1-methyl-4-phenyl-1,2,3,6-tetrhydropyridine (MPTP, 0.2-0.5mg/kg), was used to characterize behavior for several months until the appearance of motor symptoms. Finally, when a parkinsonian syndrome was well established and stable, behavioral effects of high- (HFS, 130Hz) and low- (LFS, 4Hz) frequency stimulations were investigated.ResultsAfter the first MPTP injections, we observed a gradual progression of the parkinsonian syndrome from stage 1 without any symptoms, to stage 3 with limbic, cognitive, and motor symptoms. In addition, each stage was associated with specific changes in STN electrophysiological activities. Stage 1, with no significant symptoms although MPTP intoxication has begun, was marked by a decrease in the power of reward-related gamma/theta oscillations. Stage 2 was characterized by an early decline in motivation and the appearance of decreased theta-band activity during decision-making. Later, an increase in error on Switch trials was reported, illustrating the stage 2’, and a decrease in beta-gamma power after motor movement occurred. Finally, stage 3 was characterized by an increase in motor response time, while retaining all the STN neuronal changes.ConclusionOur results suggest a progressive timeline in the onset of behavioral impairments with first limbic symptoms, followed by cognitive and then motor symptoms. Furthermore, specific electrophysiological biomarkers of each symptom are found early in the STN and can predict their onset and help to better understand their pathophysiology. Finally, we propose a combined stimulation with HFS in dorsal STN and LFS in ventral STN to optimize STN-DBS and reduce both motor and non-motor symptoms.

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“…While several human and NHP studies have demonstrated that SWS is disrupted in advanced parkinsonism 11,22,23 , whether SWS dysfunction occurs during the early phase of dopaminergic system degeneration is not clear in the literature. A comparison of SWS in idiopathic REM sleep behavior disorder (RBD, often a prodromal stage of PD) patients and healthy controls have shown variable results [24][25][26][27][28] .…”

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confidence: 99%

Excessive cortical beta oscillations are associated with slow-wave sleep dysfunction in mild parkinsonism

Verma,

Nandakumar,

Acedillo

et al. 2023

Preprint

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Increasing evidence associates slow-wave sleep (SWS) dysfunction with neurodegeneration. Using a within-subject design in the nonhuman primate model of Parkinson’s disease (PD), we found that reduced SWS quantity in mild parkinsonism was accompanied by elevated beta and reduced delta power during SWS in the motor cortex. Our findings support excessive beta oscillations as a mechanism for SWS dysfunction and will inform development of neuromodulation therapies for enhancing SWS in PD.

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Early onset of sleep/wake disturbances in a progressive macaque model of Parkinson’s disease

Cited by 13 publications

References 71 publications

Excessive daytime sleepiness in a model of Parkinson’s disease improved by low-frequency stimulation of the pedunculopontine nucleus

Excessive daytime sleepiness in a model of Parkinson’s disease improved by low-frequency stimulation of the pedunculopontine nucleus

Subthalamic nucleus activity dynamics preceding clinical manifestations in a progressive Parkinson’s disease model

Excessive cortical beta oscillations are associated with slow-wave sleep dysfunction in mild parkinsonism

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