Role of Sleep on Motor Learning in Parkinson's Disease and Healthy Older Adults

Towards Retention of Motor Learning in Parkinson's Disease: Understanding Sleep-related Effects of Consolidation

People with Parkinson's disease (pwPD) often present difficulty consolidating newly learned skills into long-term memory. Sleep facilitates motor memory consolidation in healthy adults, especially in combination with targeted memory reactivation (TMR). TMR works by adding associated sounds during learning that are replayed during sleep and thus reinforce the recently formed neural connections. Importantly, recent work suggested that consolidation during sleep may be preserved in pwPD, but robust findings are lacking and have not involved TMR. The objective of the present study is to address this imperative question by investigating the effect of napping on motor memory consolidation by experimentally manipulating exposure to sleep and TMR for the first time. Concretely, the investigators will first compare the effect of a 2-hour nap to that of a wake control period in pwPD and healthy age-matched controls. A validated motor sequence learning task will be used to test for behavioral markers of motor learning and polysomnography with electroencephalography (EEG) will be conducted to study the neural correlates of sleep-related motor learning effects. In a second experiment, the investigators will then test the effects of adding TMR during post-learning sleep, by comparing performance on two motor sequences of which only one is reactivated during post-learning napping using auditory TMR.

PwPD often fail to retain training effects via the process of motor memory consolidation, by which newly acquired skills transform intro robust and long-lasting motor memories without further practice. Compromised consolidation leads to an inevitable deterioration of daily functioning while hindering the prolonged effects of rehabilitation even in the early stages of the disease (Nieuwboer et al. 2008). Intriguingly, post-training sleep facilitates consolidation in healthy adults (King et al. 2017a) and this effect may be preserved in pwPD (Terpening, 2013). Targeted Memory Reactivation (TMR) is a technique tested in young adults, whereby auditory stimuli are added during motor learning. The learning-related sounds are then replayed during post-training non-rapid eye movement (NREM) sleep to reinforce the recently formed neural connections (Diekelmann et al. 2012). The overarching hypothesis of this project is that bouts of sleep and TMR will improve the consolidation of motor memories and markers of neuroplasticity in pwPD and older adults.

To test this, the investigators will employ a 'napping' protocol that accounts for circadian effects while allowing performance after diurnal sleep to be directly compared to that of a wake control group (King et al. 2017a). Consolidation will be defined as the change in Motor Sequence Learning (MSL) of finger tapping after a post-training period of either napping or wakefulness compared to the end of initial training. To further indicate robust consolidation, changes in performance will be assessed after a 24h retention period without further practice as well as during a dual-task as a measure of motor automaticity. A parallel group design will allow within group comparison (nap/wake) as well as between pwPD and controls. In a second study, the effects of TMR on consolidation will be compared across groups using a serial reaction time task (SRT).

The first objective (Experiment 1) is to determine whether a 2-hour nap improves the immediate consolidation, 24h retention and dual task interference of an MSL task as compared to a similar period of diurnal wakefulness in people with pwPD and healthy age-matched controls and whether the degree of performance change is different between these groups. Hypothesis 1: The investigators expect to find improved consolidation, 24h retention and reduced dual-task interference of MSL performance following a post-training nap compared to wakefulness in both groups. Possibly, improvements are less apparent in pwPD compared to controls due to their cortico-striatal impairments.

The second objective (Experiment 2) is to determine whether TMR improves immediate consolidation, 24h retention and dual task interference in pwPD and healthy older adults by comparing performance on two learned motor sequences before and after a 2-hour nap period, during which one of the two sequences is replayed using auditory TMR. Hypothesis 3: TMR during napping will improve immediate consolidation, 24h retention and dual task interference of the SRT in both healthy elderly and PD.

Participants first undergo screening, during which demographics, cognitive capacity and disease severity indexes (including dexterity tests) will be obtained prior to undergoing a diagnostic screening night with polysomnography (PSG) to assess for sleep disorder features. Participants will also complete a test battery on sleep quality scales and mood and wear an Actigraphy watch at home for at least five days and nights prior to the first experiment.

During experiment 1, participants learn the MSL by self-initiating a 5-element finger sequence that is presented on screen. After learning, participants will be equipped with PSG, which includes EEG. Based on blinded randomization, they will nap for 2 hours or lie on the bed but remain awake for a similar duration. The wake PSG will ensure that no participant in the wake group falls asleep. Participants will then enjoy a 30-45min break to counter sleep inertia effects, prior to being re-tested on the MSL (Retest 1). The next day, participants will be re-assessed on the MSL for 24h retention testing (Retest 2).

During experiment 2, similar procedures will be followed as described above except that participants will learn two new finger sequences that are auditory cued, by means of a serial reaction time task (SRT). For the SRT, participants view a row of empty squares presented in the middle of the screen and each time a square is highlighted the participant is instructed to tap the finger that is spatially associated to that square as quickly and accurately as possible, i.e. a serial reaction time task. The difference between the MSL task of experiment 1 and the SRT task of experiment 2 is therefore that during experiment 1 participants self-initiate a sequence that is explicitly shown to them, whereas in experiment 2 the sequence is cued. The order of sequence blocks during learning and retest as well as the sequence selected for TMR will be randomized across participants. Performance on both sequences will be re-assessed after the break, and again at 24h retention without auditory cues.

The MSL and SRT tests in both experiments will be preceded by a psychomotor vigilance test as an objective measure of the participants' vigilance on the day and include a single- and dual-task condition.

Power calculation:

Based on the findings by Terpening et al. (2013) and Dan et al. (2015), a minimum of 16 subjects per group (NAP, WAKE) will be required according to our power analysis based on the MSL-outcomes using β=0.20 and α=0.05 to detect a significant group difference. To account for potential dropouts, the recruitment target is set 20% higher to ensure adequate power in our final analysis. As such, a total of 40 PD patients and 40 healthy elderly controls will be recruited for experiment 1 (i.e. 20 in each NAP/WAKE group). The best sample estimation at this time for experiment 2 is based on previous TMR studies in younger adults also recruiting 16 subjects per nap/wake group (Antony et al. 2012). Therefore, we will target to recruit a total of 20 PD and 20 healthy elderly controls for Experiment 2, again accounting for 20% potential dropout.

Inclusion Criteria:

• Right handed
• Can read and understand Dutch
• Age equal or greater than 40 years
• PwPD will have a clinical diagnosis of idiopathic Parkinson's disease made by a Neurologist
• Completed written informed consent approved by the assigned medical ethical committee

Exclusion Criteria:

• Receiving deep brain stimulation
• Enrollment in an interventional trial for Parkinson's disease therapy
• Severe sleep apnea determined as an Apnea/Hypopnea index (AHI) > 30 during the screening polysomnography (PSG)
• Cognitive impairment that could question the participant's ability to provide voluntary informed consent as determined by an Mini Mental State Examination score <24
• Co-morbidities that would hamper interpretation of MSL or SRT learning, such as musculoskeletal abnormalities, as determined by a Neurologist or Physical Therapist.