Investigating psychosis in Prader-Willi syndrome: developing cognitive, electrophysiological and neuroimaging approaches
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder resulting from the absent expression of maternally imprinted, paternally expressed genes located in the chromosomal region 15q11-13. This absence of expression is usually either due to a paternal deletion or maternal uniparental disomy (mUPD). Both genetic subtypes share the same core clinical symptoms, such as developmental delays, intellectual disability, hyperphagia, behavioural and social difficulties, and a heightened risk for anxiety and depression. However, only people with PWS due to mUPD seem to be at particularly high risk for developing psychosis. Research on the causes of this differential risk is very scarce. This PhD study aims to propose potential mechanisms of psychosis in PWS and design and develop a study to test them. I hypothesised that the GABA/glutamate equilibrium is disrupted in PWS due to the absence of paternal expression. In addition, the overexpression of maternal genes on chromosome 15 would cause cholinergic dysfunction in people with mUPD and further disrupt GABAergic, glutamatergic, dopaminergic and cholinergic functions, increasing the probability of psychotic symptoms. In line with the predictive processing model of psychosis, the neurotransmitter disruptions proposed would cause a reduction in the use of priors to formulate predictions, detect and generate prediction errors, and update the prediction system. A case-control study comprising clinical, cognitive, neuroimaging, and remote behavioural testing was designed to investigate the hypotheses. The study was organised into four modules. The EEG module comprised the Global-Local paradigm, a sensory gating paradigm, and resting state. The MRS module measured metabolites in the anterior cingulate cortex, the auditory and visual cortex. The cognitive module contained measures of IQ, processing speed and working memory. The behavioural module was added during the COVID-19 pandemic to enable online data collection and focused on measuring the use of priors in perception. All modules were assessed for use in a PWS population and were feasible, with adjustments. Nineteen participants took part in at least part of the study, demonstrating its feasibility in a PWS population. Because of time constraints, COVID-19, and resources available, not all participants completed all measures. For the same reasons, only the EEG Global-Local data was analysed. The EEG paradigms were collected on 19 participants (11 with deletion, 4 with mUPD), and the global-local paradigm was analysed. Preliminary analysis revealed that people with mUPD have smaller P300 in response to an oddball paradigm than deletion and control participants. Participants with deletion have smaller P300 responses than controls showing impaired attention switching and a flaw in the predicting coding system of people with PWS, particularly in those with mUPD. Contrary to what was expected, the mismatch negativity response to the oddball paradigm was not different between mUPD and controls but was significantly earlier in the deletion group. This could indicate a chronic fight or flight state having the potential to disrupt neurotransmission, interoception and perception further, causing additional disruption of the predictive processing system. A planned analysis of the remaining measures is presented in this thesis and will be applied in the future when sufficient data is analysed.
Prader-Willi syndrome, Psychosis, genetic cause of psychosis, Predictive coding, EEG, Global-Local paradigm, Mismatch negativity, P50 sensory gating, MRI, MRS, Online assessments
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