This proposed proof of concept study follows an earlier trial of vagus nerve stimulation, using a surgically implanted medical device, in three people with PWS to investigate whether such treatment might reduce the over-eating behaviour characteristic of people with PWS. Whilst the effects on eating were equivocal, two of the three participants, both of whom had histories of severe temper outbursts, reported a remarkable improvement in these behaviors. Both asked that the VNS remained activated and recent enquiry now over two years since it was first implanted indicates that outbursts remain absent or very minimal. As this study was investigating the effects of VNS on eating behaviour the necessary before and after measures on other behaviors were not recorded. In response to an application for funding for a large trial of VNS in PWS the UK grant body advised that more systematic preliminary data was required before such a full trial could be justified. Since then external (rather than surgically implanted) vagus nerve stimulators have become available in the UK and it is the use of these stimulators that we propose to investigate in this proof of concept study. In addition, at a recent meeting held in Bethesda hosted by the Foundation, the possible reasons for why VNS might be effective were considered and this knowledge has further informed this re-application.
The aims of this study are as follows: a) to obtain preliminary evidence to justify a full trial of vagus nerve stimulation from an externally worn medical device to treat the problem behaviors characteristically associated with PWS; b) to establish the acceptability of the external vagus nerve stimulator and the feasibility of recruiting to, and the most appropriate methodology for, such a trial; c) by comparing specific measures before treatment and during treatment to determine whether specific physiological markers (such as variation in heart rate with respiration) are predictive of those who respond to the intervention.
We will identify individuals with PWS meeting the necessary inclusion criteria for such a trial through the UK PWS Association and known services for people with PWS in the UK. Six participants with evidence of a minimum of, on average, one functionally significant temper outburst a week, who have the capacity to consent, will be invited to participate in a trial of an externally worn vagus nerve stimulator with baseline measures of behaviour for two months followed by eight months wearing the stimulator for four hours a day using an approved stimulus protocol. We will use different repeat measures of behavior before and during VNS including diary ratings, questionnaires and qualitative interviews to determine the best outcome measures and use ambulatory monitoring and other measures to investigate markers potentially indicative of a positive behavioural response to VNS. Assuming benefits are observed this study will inform an application for an enlarged trial.
Transcutaneous vagus nerve stimulation (t-VNS): A novel effective treatment for temper outbursts in adults with Prader-Willi Syndrome indicated by results from a non-blind study. Manning KE, Beresford-Webb JA, Aman LCS, Ring HA, Watson PC, Porges SW, Oliver C, Jennings SR, Holland AJ. (2019) . PLoS ONE 14(12): e0223750.
Mechanistic insights into the genetics of affective psychosis from Prader-Willi syndrome. Aman LCS, Manning KE, Whittington JE, Holland AJ. Lancet Psychiatry. 2018 Apr;5(4):370-378.
Tony Holland, MD
The University of Cambridge, United Kingdom