Oxytocin and the autonomic nervous system in Prader Willi syndrome

Study one: There is a reduction in the number of neurons that produce oxytocin in people with PWS. This, along with a range of other evidence supports the likelihood that abnormalities in the oxytocin system are key to the problems of PWS. However, studies examining the levels of oxytocin in PWS as well as clinical trials evaluating the effect oxytocin has on PWS symptoms has led to mixed results.

We propose to test two explanations for this. Firstly, there are two forms of oxytocin in the human body a 9-amino-acid form and an extended form. Recent studies have shown that people with ASD have reduced levels of the 9-amino-acid active form of oxytocin, but increased levels of the extended form of oxytocin. It is possible that a similar abnormality between oxytocin forms may also exist in PWS. An alternative or complimentary hypothesis is that the oxytocin receptor, a cell that binds to oxytocin and triggers activity, may be suppressed in PWS, making individuals with PWS unable to respond to either form of oxytocin, and would have a functional deficiency in activity in the oxytocin system, even when high levels of oxytocin are administered. Vasopressin is very similar in structure to oxytocin. So it may be that if people with PWS have reduced oxytocin neurons then vasopressin receptors may be responding to administered oxytocin. We propose to examine plasma levels of the two forms of oxytocin vasopressin in PWS. In addition, we will measure DNA levels of the oxytocin gene. The results of this study will help to understand the nature of the oxytocin abnormality associated with PWS and direct future oxytocin or vasopressin interventions.

Study two: A pilot study exploring the effect of vagal nerve stimulation (VNS) therapy in 3 people with PWS unexpectedly led to improvements in maladaptive behaviours. These findings are in line with the polyvagal theory, which hypothesizes that people can switch from being defensive to socially engaging by inhibiting primitive brain regions that activate the fight, flight or freeze responses. The vagal nerve controls these brain regions. Vagal nerve activity can be measured using Respiratory sinus arrhythmia (RSA). Several studies have shown that low level of RSA is associated with reduced emotional control, increased hostility at times of conflict, increased anxiety as well as higher levels of internalising and externalising problems. We intend to investigate whether respiratory sinus arrhythmia abnormalities exist in PWS and how such abnormalities may relate to emotional and behavioural problems and oxytocin/vasopressin abnormalities associated with PWS. Such findings will help specify the physiological underpinnings of maladaptive behaviours of PWS, and show if manipulations of the parasympathetic system are indicated.

The Foundation for Prader-Willi Research UK is a co-sponsor of this project.

Research Outcomes:

Reduced gamma-aminobutyric acid is associated with emotional and behavioral problems in Prader-Willi syndrome. Rice LJ, Lagopoulos J, Brammer M, Einfeld SL.  American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2016 Dec;171(8):1041-1048.