Manipulating and Optimising Brain Rhythms for Enhancement of Sleep
Condition: Parkinson Disease; MSA - Multiple System Atrophy; Chronic Pain; Epilepsy
MeSH terms: Parkinson Disease; Multiple System Atrophy; Shy-Drager Syndrome; Chronic Pain
Study type: Interventional

Summary: 
      Treatment of sleep disturbances is mainly attempted through drug administration. However,
      certain drugs are associated with unwanted side effects or residual effects upon awakening
      (e.g. sleepiness, ataxia) which can increase the risks of falls and fractures. In addition,
      there can be systemic consequences of long-term use. An alternative method of manipulating
      sleep is by stimulating the brain to influence the electroencephalogram (EEG). To date, there
      have been mixed results from stimulating superficial areas of the brain and, as far as we
      know, there has been no systematic attempt to influence deep brain activity.

      Many patients suffering from movement disorders, such as Parkinson's Disease (PD) and
      Multiple Systems Atrophy (MSA), also have disrupted sleep. Currently, at stages where drug
      treatment no longer offers adequate control of their motor symptoms, these patients are
      implanted with a deep brain stimulation system. This involves depth electrodes which deliver
      constant pulse stimulation to the targeted area. A similar system is used in patients with
      severe epilepsy, as well as some patients with chronic pain.

      The aim of this feasibility study is to investigate whether we can improve sleep quality in
      patients with deep brain stimulators by delivering targeted stimulation patterns during
      specific stages of sleep. We will only use stimulation frequencies that have been proven to
      be safe for patients and frequently used for clinical treatment of their disorder. We will
      examine the structure and quality of sleep as well as how alert patients are when they wake
      up, while also monitoring physiological markers such as heart rate and blood pressure. Upon
      awakening, we will ask the patients to provide their subjective opinion of their sleep and
      complete some simple tests to see how alert they are compared to baseline condition which
      would be either stimulation at the standard clinical setting or no stimulation.

      We hope that our study will open new ways of optimising sleep without the use of drugs, in
      patients who are implanted with depth electrodes. We also believe that our findings will
      broaden the understanding of how the activity of deep brain areas influences sleep and
      alertness.
    

Detailed description: 
      This is a feasibility study that will take place in two UK sites: the John Radcliffe Hospital
      (Oxford) and the Surrey Sleep Research Centre, University of Surrey. The identification,
      consent and screening of patients will take place in Oxford, and the sleep assessments will
      take place in Surrey. A parallel study will also be conducted at US sites (Mayo Clinic,
      Rochester MA, and UCSF, CA) under the same funding but this will be reviewed by their local
      IRB. De-identified data may be shared between sites for analyses purposes. This will be done
      securely in an encrypted fashion while participants will be made fully aware of this.

      Participants will be identified during their routine clinic visits with the Functional
      Neurosurgery team (John Radcliffe Hospital) and invited to participate in the study.
      Screening of interested potential participants will take into account pre-operative
      assessment data. Testing will ensue (within a variable period from screening, but within the
      aforementioned study timeline), over two visits to the Surrey Sleep Research Centre, each
      consisting of two nights. The maximum duration between consent and first study visit will be
      three months, while there will be a minimum of two weeks between each study visit to allow
      for preliminary analyses. Informed consent and baseline sleep recordings will be obtained
      over the first night of the first visit to Surrey, with the remaining nights consisting of
      stimulation trials. Questionnaires, daytime vigilance testing, autonomic parameters and
      cortisol levels will be collected. No long-term follow-up is planned at this stage.

      With regards to data collection processes, the population of patients visiting the Surrey
      site will have already been implanted with a DBS system (such as an Activa PC/PC+S
      (Medtronic) or an Abbot/St Jude device). The investigators will leverage rules from the
      current AASM guidelines, technologies and methods for manual and automated sleep scoring
      using standard scalp polysomnography as well as novel methods we previously developed for
      sleep scoring using intracranial electrophysiology. To avoid contamination of the
      electrophysiology monitoring amplifiers by the stimulation protocol, a combination of bipolar
      stimulation and sampling-stimulate rate interactions will be used. For example, we will apply
      know-how from the Activa PC+S work to place any residual artefacts into bands of little
      physiological interest (DC, 50/60Hz, etc.). A preliminary assessment of amplifier performance
      will provide assurance that we will be able to maintain sleep staging accuracy over the
      course of our experiments.

      For perturbations, the CE-marked clinician programmer will be used (especially at the
      open-loop stage) or a research variant thereof. In this study, high-frequency (HF) is
      specified at a stimulation range from 41Hz to 250Hz, while low frequency (LF) will be defined
      as 2-40Hz. All perturbations will be within the clinical range used and approved for DBS
      patients. A combination of subjective and objective measurements of sleep quality and
      efficiency to measure the impact of any sleep perturbations will be used.

      The following objective metrics will be derived from visual/manual polysomnography (gold
      standard) & automated algorithm sleep staging:

        1. Total sleep time.

        2. Number of sleep cycles (switches of non-rapid eye movement (NREM) and rapid eye movement
           (REM) sleep).

        3. Initial sleep and REM latencies (Time from beginning of study to the first stage of
           sleep, and from beginning of sleep to first REM sleep onset).

        4. Duration of N1, N2, N3, and REM stages, and the duration of NREM (sum of
           N1,N2,N3)stages.

        5. Sleep efficiency (100*total sleep time/time in bed).

        6. Number of awakenings during night, including arousals per hour and duration of time
           spent awake after initial sleep onset (i.e., wake after sleep onset time)

        7. Apnoea-hypopnea and respiratory disturbance indices (the frequency of stop or reduced
           breathing episodes, and respiratory arousals per hour)

        8. Periodic limb movement indices (the frequency of periodic leg movements of sleep per
           hour)

        9. Measures of arousal during sleep

             1. behavioural macrostate observations such as eye opening or blinking that can be
                assessed in video recordings

             2. microarousal observations defined exclusively by cortical fast frequency shifts
                (ie, >14 Hz rhythms) lasting 3 seconds or longer, with or without added autonomic
                measures of tachycardia.

             3. Spectral composition of the sleep stage specific EEG over the 0.25-32 Hz frequency
                range Salivary samples to characterize awakening levels of cortisol will be
                obtained in the Surrey Sleep Research Centre at the end of each night.

      Questionnaires will be administered to patients such as those listed below (not all
      necessary):

      Upon enrolment/prior to the participant's visit:

        -  Pittsburgh Sleep Quality Index (PSQI) (Buysse et al 1989)

        -  Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating
           Scale (MDS-UPDRS) (last amendment 2019, original article Goetz et al 2008)

        -  Parkinson's Disease Sleep Scale (PDSS) (Trenkwalder et al. 2011)

        -  Patient sleep diary (bedtime, awakening time, arousals/sleep disturbances, perceived
           sleep quality)

      During the visits to the Surrey Sleep Research Centre:

        -  Karolinska Sleepiness Scale (KSS) (Akerstedt and Gillberg, 1990)

        -  Samn Perelli Fatigue Scale (Samn and Perelli, 1982)

        -  Profile of Mood States Scale (POMS) (McNair, Lorr and Doppleman, 1971)

      With regards to collecting data relevant to cognitive performance, we will focus on
      assessments of sleep inertia as measured by performance characteristics assessed by tasks
      listed below:

        -  Digit Symbol Substitution Test (DSST) (as in Boyle et al. 2012)

        -  Psychomotor Vigilance Task (PVT) (as in Santhi et al. 2013)

        -  N-back task (Santhi et al. 2013)

        -  Karolinska Drowsiness Test (KDT) (Akerstedt and Gillbert, 1990)
    

Intervention name(s): Deep brain stimulation
Intervention type(s): Device
Intervention description(s): Electrical pulses from implanted generator that has already been implanted for therapeutic reasons
Intervention model: Single Group Assignment
Intervention model description: Evaluation of symptomatology "on" and "off" deep brain stimulation
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: sleep; Electroencephalography; Deep brain stimulation