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

Abstract

Temper outbursts are a severe problem for people with Prader-Willi Syndrome (PWS). Previous reports indicate that vagus nerve stimulation (VNS) may reduce maladaptive behaviour in neurodevelopmental disorders, including PWS. We systematically investigated the effectiveness of transcutaneous VNS (t-VNS) in PWS. Using a non-blind single case repeat measures modified ABA design, with participants as their own controls, t-VNS was evaluated in five individuals with PWS [three males; age 22–41 (M = 26.8)]. After a baseline phase, participants received four-hours of t-VNS daily for 12 months, followed by one month of daily t-VNS for two-hours. The primary outcome measure was the mean number of behavioural outbursts per day. Secondary outcomes included findings from behavioural questionnaires and both qualitative and goal attainment interviews. Four of the five participants who completed the study exhibited a statistically significant reduction in number and severity of temper outbursts after approximately nine months of daily four-hour t-VNS. Subsequent two-hour daily t-VNS was associated with increased outbursts for all participants, two reaching significance. Questionnaire and interview data supported these findings, the latter indicating potential mechanisms of action. No serious safety issues were reported. t-VNS is an effective, novel and safe intervention for chronic temper outbursts in PWS. We propose these changes are mediated through vagal projections and their effects both centrally and on the functioning of the parasympathetic nervous system. These findings challenge our present biopsychosocial understanding of such behaviours suggesting that there is a single major mechanism that is modifiable using t-VNS. This intervention is potentially generalizable across other clinical groups. Future research should address the lack of a sham condition in this study along with the prevalence of high drop out rates, and the potential effects of different stimulation intensities, frequencies and pulse widths.

Behavioral features in Prader-Willi syndrome (PWS): consensus paper from the International PWS Clinical Trial Consortium

“…Dysregulation of the autonomic nervous system may be another key mechanism underlying temper outbursts in PWS. A small pilot study [ 58 ] indicated that stimulation of the vagus nerve decreased temper outbursts for some individuals with PWS, suggesting the role of the autonomic nervous system in this behavioral feature.…”

“…It has been used in a previous clinical trial examining the potential utility of oxytocin for treating behavioral challenges in PWS [ 53 ]. Alternatively, the Challenging Behavior Interview has shown utility in a small study assessing the impact of vagus nerve stimulation on temper outbursts in PWS [ 58 ]. Finally, the Aberrant Behavior Checklist (ABC-2 [ 60 ]; irritability scale) which has been used widely in studies on those with intellectual disability may provide a useful validated measure of temper outbursts in PWS.…”

Vagus Nerve Stimulation as a Gateway to Interoception

“…Considerations under ongoing debate include optimal stimulation locations on the ear (Burger and Verkuil, 2018), potential differences in signal paths between VNS and tVNS, and the longevity of the effect after stimulation ceases. It seems that although cognitive effects of VNS may be detectable after short periods of stimulation, even 20 min (e.g., Colzato et al, 2017b), attenuation of certain clinical symptoms may require much longer stimulation durations (e.g., Manning et al, 2019) point to reduction in number and severity of temper outbursts in Prader-Willi Syndrome with 4 h/daily stimulation (as recommended for epilepsy), applied for 6-9 months, but a prompt return of the symptoms in all 5 participants when the stimulation was subsequently reduced to 2 h. Researchers should also consider making age related adjustments, e.g., (Koo et al, 2001) point out that in children younger than 12 stimulation settings may require a higher stimulus current or longer pulse along with lower stimulus frequency than adults (e.g., stimulation at 20 Hz or lower instead of e.g., 30 Hz), as a child's vagus nerve has slower conduction velocity. The effects of VNS on heart rate need to be considered as well.…”

“…Though direct tests on such tasks are yet to be done, there is promising evidence that tVNS facilitates attentional switching in conflict situations, such as a number version of the Simon task (Fischer et al, 2018), allows rapid attentional adaptation (Colzato et al, 2017b), and improves response selection in sequential action (Jongkees et al, 2018). In the clinical domain, tVNS has been shown to reduce temper outbursts in Prader-Willi Syndrome (Manning et al, 2019), further reinforcing the notion that it improves interoceptive processing at the high level implicated in executive control.…”

Defining Mental and Behavioural Disorders in Genetically Determined Neurodevelopmental Syndromes with Particular Reference to Prader-Willi Syndrome

“…This pattern is similar to what is observed in young children. Observations of marked reductions in the frequency and severity of such behaviours by the use of vagus nerve stimulation might indicate that the mechanism resulting in the high risk for such behaviours is the presence of a low threshold of the autonomic nervous system to respond in a rapid flight/fight mode when faced with an actual or perceived threat [27,28]. Thus, the mechanism is one of impaired emotional regulation, potentially for developmental reasons.…”