Hyperphagia (extreme overeating) is the most significant factor contributing to obesity in Prader-Willi syndrome (PWS) and considered a cardinal feature. PWS is recognized as the most common syndromic cause of life-threating obesity, but no medications are currently available to decrease appetite or lessen obesity in PWS.
Preliminary studies have shown that a weak, non-invasive form of brain stimulation called transcranial direct current stimulation (tDCS) reduces food cravings and overeating in a small number of adults with PWS (N=5) in a combined study from Kansas University Medical Center and Harvard University. We will continue to investigate the use of tDCS using a 9 volt radio battery as a source of electrical current to control eating behaviors with 40 adults with PWS from the Prader-Willli Homes of Oconomowoc, WI (P-WHO) over the course of two years. During the first year, we measured the effects of tDCS with 20 adult participants with PWS by examining participants’ startle eyeblinks in response to sound while looking at a series of food and non-food pictures on a computer screen. This task has now been completed. Based on previous research eyeblink response in participants exposed to sound will vary while viewing positive, negative, or neutral pictures and can be used to assess food eating drive. During the second year, we will measure the effect of brain stimulation with 20 adult participants with PWS by examining brain wave activity and reactions (event-related brain potentials) to the same series of pictures, but without startle response. We will also be tracking the tDCS stimulation effects through eating questionnaires, behavioral and cognitive measures, weight and food intake during both years of study. This study will help determine if the use of tDCS brain stimulation would be an effective noninvasive inexpensive treatment to control food cravings and overeating in adults with PWS and impact favorably on brain activity measurable using event-related potentials (ERPs) in identifying differences before and after tDCS sessions.
Research Outcomes: Public Summary
Prader-Willi syndrome (PWS) is a rare genetic disorder affecting multiple systems leading to life-threatening obesity if not externally controlled. PWS is caused by errors of genomic imprinting and generally from a paternal de novo chromosome 15q11-q13 deletion. As the individual with PWS approaches early childhood, food-seeking and hoarding commences with obsessions leading to hyperphagia and subsequent obesity without strict caloric restriction and food security programs in place. Individuals with PWS have decreased metabolic rate, low muscle mass and strength with decreased physical activity along with lower energy expenditure and physical activity, all contributing to obesity onset and severity. Individuals with PWS develop dysfunction of the hypothalamic – pituitary – adrenal (HPA) axis which often leads to endocrinopathies, hypogonadism and hypogenitalism with distinctive patterns of maladaptive or aberrant behaviors. Earlier studies using brain imaging and neuro-physiological screening (e.g., EEGs, fMRIs) have found reduced processing speed related to sensory function in PWS particularly those having maternal disomy 15, the second most common genetic defect in PWS compared with those with the deletion. Deficits in specific EEG tracings related to early modality or specific inhibition patterns have been reported during late general inhibition of N200 and P300 peaks, respectively. Those with PWS and the deletion (DEL) subtypes show impairments only for N200 modulation. Children studied with PWS have also shown significantly reduced white matter changes in brain microstructure particularly with those having maternal disomy 15 (UPD) subclasses and brain activity differences compared to controls following meal-time events indicating processing and brain function disturbances when responding to stimuli. Further studies are needed to examine EEG patterns, event-related potential (ERP) responses to food and non-food stimuli impacted by transcranial direct current stimulation (tDCS) in PWS; a major focus of our investigations. In our study funded by FPWR, we identified a remarkable difference in ERP amplitude and morphology between deletion (DEL) and UPD adult subject groups. The ERP amplitude for the DEL subtype was significantly larger than the UPD which interfered with our interpretation of study findings when combined with the small sample size. There was a trend (p=.08) for faster reaction time to GO in the active tDCS group (n=5) which could reflect increase in attention. The rate of accuracy was fairly high for both Go and NoGo responses in active and sham groups requiring more analysis and interpretation of data and possible testing in the future with a larger sample size with correlation with brain imaging (function, volume and structure) of males and females with the two PWS molecular classes.
Merlin Butler, PhD
University of Kansas Medical Center Research Institute