Proof of concept study of vagus nerve stimulation
Prader-Will syndrome (PWS) is a genetically determined neurodevelopmental disorder characterised from childhood by excessive eating, severe obesity, sex and growth hormone deficiencies, intellectual disabilities, and problem behaviours (e.g. excessive repetitive and ritualistic behaviours, mild irritability and verbal and physical outbursts, which can sometimes last for hours). In the earlier pilot study, which was to determine whether vagus nerve stimulation helped reduce the over-eating behaviour associated with PWS, it was found that vagus nerve stimulation (VNS) was safe and acceptable, but that any effects on the overeating behaviour were equivocal. However, in two of the three participants who had a previous history of problem behaviours, there were unexpected and marked improvements in these behaviours reported by the participants and their families (Manning et al., 2015). As the pilot study had been designed to investigate the eating behaviour, the researchers did not have longitudinal data on the rates of these behaviours over time. Given this observation, a further trial has been undertaken with the primary aim of determining whether VNS, now from an externally worn medical device using an established stimulus protocol, is associated with a significant difference in the number and severity of problem behaviours.
There have been positive changes but the device used was reported by participants as not easy to use and frequently became dislodged. It also took some months to have a positive effect. For these reasons, the trial of different devices has been proposed (Alpha-Stim AID and Monarch).
Alpha-Stim AID, due to the location of the electrode placement (clipped to the earlobes), is able to simulate a branch of the vagus nerve that is situated nearby (Feusner er al., 2012) but has a different stimulus protocol and the way it is worn is easier. This device is approved for the treatment of anxiety, sleep disorder and depression. Monarch, according to Polyvagal theory, is able to regulate the myelinated vagal pathways to the heart that calm physiological state but has a stimulus protocol that may be more feasible for people to comply with. Monarch is approved for the treatment of epilepsy, ADHD and depression. Both devices (Alpha-Stim AID and Monarch) are CE marked and, like the previous device (Nemos), have very good safety records.
Problem behaviours have a significant effect on the level of independence and quality of life of those with PWS and impact also on those who support them (Mazaheri et al., 2013). The UK PWS Association repeatedly receive requests for help following placement breakdown and, in some cases, the fact that the criminal justice system has become involved because of the behaviour. In over 800 queries received by the PWS Association in 2013, 25% of them were about severe problem behaviours (information from Jackie Waters, UK PWSA). In the absence of these outbursts support ratios could be reduced and the person with PWS could be more independent. This novel intervention, if effective, will enable people with PWS to live a more independent life without concerns that minor environmental triggers will result in episodes of severe problem behaviour which then escalate to prolonged outbursts associated with verbal or physical aggression. The researchers predict that such treatment would significantly decrease health and social care costs and improve quality of life for people with PWS and those who support them.
The primary objective of this proposed amendment to our protocol is to determine whether the use of the Alpha-Stim AID device and/or the Monarch device, using established protocols, are more acceptable to people with PWS than the Nemos device. This amendement will also determine whether the devices are associated with significantly fewer and less severe episodes of informant recorded outbursts, compared to no stimulation, thereby providing further evidence for their approval and use in the treatment of problem behaviours in people with PWS.
Additionally, there are a number of secondary objectives:
- To establish the percentage in each group who respond positively to the Alpha-Stim AID and/or Monarch device with a clinically significant reduction of 50% or more and identify cognitive, autonomic and neural biomarkers associated with a positive response
- In addition to collecting evidence on efficacy, to investigate safety and acceptability of the treatment in order to inform further studies and determine whether the Alpha-Stim AID and/or Monarch device is the most appropriate for a future major clinical trial
- To investigate the characteristics of the behaviours that improve and the putative autonomic and neural mechanisms that are likely to mediate any reduction in such behaviours, in order to better understand the circumstances whereby the use of Alpha-Stim AID and/or Monarch might be generalized to treating problem behaviours more widely
- To assess potential effects of Alpha-Stim AID and/or Monarch on weight and energy expenditure.
The study takes the form of a longitudinal single case design. Data will be collected from participant home records detailing problem behaviours over the last 12 weeks, which will constitute the baseline data. An active treatment phase will last for 12 weeks, where participants will wear the Alpha-Stim AID or Monarch device turned on for 1 hour per day, consistent with established protocol. Towards the end of the active phase, there will be an analysis of efficacy for each individual participant and if Alpha-Stim AID or Monarch is beginning to help, researchers may ask the participant if they are willing to wear the device for longer, up to a maximum of 24 weeks.
Secondary behavioural outcomes: at the beginning, middle and end of each phase interviews of informants will be undertaken using valid and reliable questionnaires including the Challenging Behaviour Interview (Oliver et al., 2003), Behaviour Problems Inventory (Rojahn et al., 2001) and the Aberrant Behaviour Checklist, (Aman et al., 1985); , the Personal Wellbeing Index (Cummins & Lau, 2005).
In order to better understand what predicts a positive behavioural response, we will explore possible psychological and neural brain biomarkers by undertaking the following assessments at similar time points on up to three occasions during the trial: the Mood, Interests and Pleasure Questionnaire (Ross & Oliver, 2003); and tests of attention and set shifting using go/no go tasks established for use by people with PWS (Woodcock et al 2009, 2010). Saliva cortisol measures will also be recorded across the course on up to three separate days during the course of study (at waking, 30 minutes post-waking, 45 minutes post-waking, 1 hour post-waking and then four more times throughout the day at approximately +3h, +6h, +9h and +14h after waking).
Heart rate variability will be derived from ECG and respiration measured using an Intelesens (Belfast) 3-axis ‘Zensor’ wearable monitor. For each participant ECG recording will take place in 24-hour blocks, (which we (Bhatoa and Ring 2015) have previously observed to be acceptable to adults with intellectual disability and their carers), with such blocks being recorded monthly, once prior to the start of stimulation and twice during the active condition.
Sleep monitoring at the participants’ home will also be regularly undertaken, due to the association of increased risk of sleep apnoea in both VNS and PWS, using as Somnoscreen TM plus RC system (SOMNOmedics, Germany). This uses a three electrode ECG, pulse oximeter and movement sensors to record heart rate, blood oxygen desaturations and sleeping position throughout the night.
Regular records concerning weight (ca. weekly) and caloric intake (daily) are often kept by the residential settings in which the participants live. Where available, these will be obtained for the duration of study participation in order to investigate whether Alpha-Stim AID and/or Monarch has any effect on weight or energy expenditure
Outcome measures and possible impact
The primary outcome measures are the number and severity of operationally defined outbursts as measured using participant and informant diaries.
Secondary behavioural outcomes will include:
- Percentage of responders with a clinically significant reduction of 50% or more in the rate of problem behaviours
- Scores on specific valid and reliable rating scales repeated over time including the Challenging Behaviour Checklist, Behaviour Problems Inventory, Aberrant Behaviour Checklist, Repetitive Behaviour Questionnaire, and Life Exepeiences Checklist
- The identification of cognitive, autonomic and neural biomarkers associated with positive behavioural outcomes
- Findings from qualitative interviews of family or support staff
This study provides a grounding for future studies involving a larger cohort of people with PWS and intellectual disabilities generally who suffer from problem behaviours. If shown to be effective, this intervention will enable people with PWS and intellectual disabilities generally to be more independent, with support ratios able to be reduced without concerns that minor environmental triggers will result in prolonged and sever episodes of problem behaviour. T-VNS would significantly decrease health and social care costs and improve quality of life for people with PWS and intellectual disability and also those who support them.