Sleep Homeostasis in Parkinson's Disease
Condition: Parkinson Disease
MeSH terms: Parkinson Disease
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Healthy volunteers and patients with parkinson disease
      
Keywords: Dyskinesia; Slow Wave Sleep