Noninvasive neuromodulation of a novel cerebellar satiety network in Prader-Willi syndrome: Design and methodology of a pilot clinical trial

Overeating and hyperphagia (excessive appetite) are behavioral characteristics of Prader-Willi Syndrome (PWS) that are challenging for individuals and families to manage. Considerable research and clinical efforts have been made to discover methods to reduce hyperphagia in PWS, including studies guided by the understanding that maladaptive behaviors stem from dysfunction in pathways in the brain responsible for appetite and food intake. These studies have included investigations testing the potential to modulate food intake behavior by targeting “traditional” brain pathways associated with appetite (including the hypothalamus and prefrontal regions). To date, these efforts have not translated to effective treatments. Our recent research used a combined translational approach which examined these pathways in animal models and in individuals with PWS and identified a new brain pathway, the cerebellum-ventral striatum circuit, in regulating appetite and satiation (Low et al., 2021). In the current study, we are testing whether safe, non-invasive modulation of this circuit, using transcranial magnetic stimulation (TMS), can impact the function of the cerebellum-ventral striatum circuit and reduce food intake. To do this, we are recruiting 12 individuals with PWS to complete study visits involving brain imaging (MRI), 5 consecutive days of cerebellar TMS, and behavioral testing. Outcomes include feasibility and tolerability of cerebellar TMS, brain activation in the cerebellar-ventral striatum circuit in response to food cues, and food-related/hyperphagic behavior. To date, one individual with PWS has completed the full TMS course, with no reported side effects. Upon completion, findings from this small pilot study will provide mechanistic understanding of neuromodulatory effects of cerebellar TMS in PWS at neural and behavioral levels, laying the foundation for the development of future clinical trials on cerebellar TMS as a standalone or add-on treatment for hyperphagia in PWS, towards a goal of reducing the challenges associated with hyperphagic behavior for individuals with PWS and their families.

Reference
Low, A.Y.T., Goldstein, N., Gaunt, J.R. et al. Reverse-translational identification of a cerebellar satiation network. Nature 600, 269–273 (2021). https://doi.org/10.1038/s41586-021-04143-5