Neurophysiological dysconnectivity across multiple resting state brain networks and cognitive impairment in children with Prader-Willi Syndrome

Abstract Prader-Willi Syndrome (PWS) is a rare genetic condition with multifaceted physical, behavioural and cognitive difficulties that is characterized by hyperphagia and low executive functioning. Food-seeking behaviours may be moderated by hormonal, cognitive, and psychological factors, and are thought to be mediated in part by functional brain abnormalities. Here, we used an experimental protocol integrating eyes opens resting state magnetoencephalography (MEG) - a high-resolution neurophysiological imaging technique - and neuropsychological profiling to understand the relationship between executive functioning, and intrinsic brain activity & functional connectivity in a prospective, cross-sectional cohort with PWS, and a sex-, age- and BMI-matched control group. We observed lower executive functioning in PWS as well as functional dysconnectivity across multiple channels of brain synchrony - in other words, across multiple frequency bands that mediate communication within and between brain networks - in the visual, attentional, and the default mode networks. Moreover, we found ‘brain-wide’ changes in the topological structure of brain networks in those with PWS, with increased ‘hubness’ of functional networks, but decreased centrality. However, none of these measures survived multiple comparison correction after correlating with neuropsychological outcomes, although there were moderate effect sizes (degree of association). This is the first study to combine neuropsychology and neurophysiological imaging to show that functional synchrony in multiple brain networks is dysregulated in PWS. Competing Interest Statement BTD is Chief Science Officer at MYndspan Ltd. The remaining authors report no competing interests. Funding Statement This study was funded by the Foundation for Prader Willi Research. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Hospital for Sick Children Ethics Board. Written informed consent was obtained from all caregivers of participants in accordance with the Declaration of Helsinki. Participants assented when required by the Hospital for Sick Children Ethics Board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors