Sleep Homeostasis in Parkinson's Disease
Sleep Homeostasis in Parkinson's Disease
Parkinson's disease is characterized in the advanced phases by an altered response to
 dopaminergic therapy for the occurrence of abnormal movements called dyskinesias, that
 worsens the quality of life of the patient and exposes him to comorbidities. Several data
 show a reduction in the amount of slow wave sleep that correlates inversely with disease
 duration. Since this stage of sleep is linked to mechanisms of deletion of superfluous
 information the investigators hypothesize that the onset of dyskinesias is related to such
 alteration of sleep.

 -This study is aimed to investigate, by means of high-density electroencephalography
 (hd-EEG), the sleep and in particular the slow wave in order to clarify the relations with
 the development of dyskinesias.
Wakefulness in PD is frequently interrupted by sleep episodes, even rapid eye movement sleep
 (REM), whilst nocturnal sleep is disturbed by abnormal motor activity interference, such as
 REM sleep behaviour disorder (RBD) or periodic limb movements (PLMS). Several lines of
 evidence have suggested a close relation between sleep-wake changes and dopaminergic
 degeneration in PD(1-7) while sleep disorders commonly precede the clinical motor onset by
 many years (8,9). On the other hand, morning motor performance improvement is frequently
 mentioned by patients, mainly in those with long disease duration and motor fluctuation
 (10,11). Of note, the same state of vigilance can profoundly influence some clinical PD
 features (for instance rigidity) as well as basal ganglia neuronal activity(12).

 Few reports have shown changes in sleep architecture: a reduction of the amount of SWS in
 parallel with disease duration (13-15) has been observed, but no study, so far, has addressed
 how sleep may impact on LID. Once these abnormal movements develop, they are difficult to
 treat and negatively affect the quality of life and the treatment costs of PD patients
 (16,17). Although levodopa represents, so far, the more effective treatment for PD patients
 (18,19) to ameliorate the cardinal signs such as bradykinesia/akinesia and rigidity (20), as
 the disease progresses, these benefits are in some measure abolished by the emergence of
 dyskinesia (21). During the early stages PD patients experience a rather satisfying quality
 of life that is impeded in the advanced stages by the emerging of these involuntary movements
 frequently at the peak of the levodopa effect (16,22,23). In other words, when the patients
 experience these motor complications (shortening motor response and development of
 dyskinesia) the delivery of levodopa without inducing dyskinesia becomes increasingly
 difficult (21,24-27).

 Several efforts have been made in order to find "pure" anti-dyskinetic drugs that are able to
 uncouple the anti-akinetic effect from the dyskinetic response. Serotoninergic receptor
 agonists were claimed to be drugs against dyskinesia (28), however, it was observed that they
 may also impair levodopa efficacy (29-31). As of today, no clinical effective therapies are
 able to alleviate dyskinesia without worsening parkinsonism.

 Great efforts have been made to clarify LID pathogenesis, emphasizing the role of pulsative
 stimulation of striatal receptors by dopaminergic treatment (25) and more recently, on
 molecular changes of postsynaptic (32,33) or presynaptic mechanisms (34). Although no
 conclusive results on LID pathogenesis have been achieved, indeed disease duration (i.e. the
 degree of dopaminergic degeneration) rather than long-term use of levodopa, seems to play a
 crucial role (22,23). This notion can be inferred from clinical practice, but is also evident
 in MPTP-induced parkinsonism in humans in which the extended dopaminergic lesion caused
 within a few days the development of dyskinesias undistinguishable from those in the
 idiopathic form (35).

 General Aim:

 The study is aimed 1) to define abnormal cortical synaptic homeostasis, measured by means of
 SWS and waking EEG evoked responses, as key components for the development of LID; 2) to
 analyse the impact of anti-dyskinetic effect of rTMS on the SWA in additional ten PD patient
 with LID.

 Specific aims:

 1. To compare, in the four groups of subjects (control, de novo, advanced without
 dyskinesia, and advanced with dyskinesia), changes of the EEG features of NREM sleep:
 slow wave/slow oscillation and sleep spindles. A significant reduction of the
 physiological reduction of SWA in dyskinetic patients in comparison with the other
 groups is expected.

 2. To identify the homeostatic reduction of cortical synaptic strength (downscaling) in the
 four categories of subjects by comparing late sleep (i.e. towards morning) SWA with
 early sleep (i.e. at the beginning of the night) SWA as well as by comparing the
 overnight changes in the amplitude of EEG somatosensory, auditory and visual evoked
 responses recorded before and after sleep. The study is aimed to demonstrate the
 reduction/absence of a physiological downscaling in dyskinetic patients versus the other
 groups.

 3. To analyse the effect of rTMS on SWA of PD patients with LID in order to demonstrate a
 recovery of physiological downscaling of SWA in these patients parallel to the reduction
 of dyskinesia.
Inclusion Criteria:

 -  clinical characteristics of the patients must be according the UK (United Kingdom)
 Brain Bank

 Exclusion Criteria:

 -  anamnestic obstructive sleep apneas syndrome

 -  known cognitive deterioration or with MMSE (Mini-Mental State Examination) ≤24/30

 -  depression ≥ 20 of the BDI scale (Beck Depression Inventory)