Investigating the Cause of Mental Illness in PWS Using Magnetic Resonance Spectroscopy (MRS)

Funding Summary

Dr. Holland is a psychiatrist with a long-standing interest in understanding why individuals with PWS are susceptible to mental illness.  In this funded project, he will use a brain imaging technique called “magnetic resonance spectroscopy” to look at levels of the neurotransmitter, GABA, in the brain. Dr. Holland thinks that differences in GABA levels might be the reason for the behavioral problems and psychosis in PWS. This project will also look at brain structure, cognition, and genetic subtypes of PWS as potential risk factors for mental illness in PWS. The goal of this research is to develop strategies to help prevent psychiatric problems in PWS.

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Lay Abstract

Past research has demonstrated that people with Prader-Willi Syndrome (PWS) are at risk for developing major behavioural problems and serious psychotic illness, the latter from as young as 12 years of age and predominately affecting those with a specific genetic form of PWS referred to as mUPD, with prevalence rates of psychotic illness of 60% by early adult life. Funding is request to support a complementary project, linked to an on-going study. This additional project will use an advanced scanning technique (Magnetic Resonance Spectroscopy, MRS) to investigate differences between people with one or other of the two main genetic subtypes of PWS and a typically developing group of similar age, in brain levels of an inhibitory brain transmitter (GABA) in specific brain areas. We hypothesise that differences in brain GABA may explain this high risk for behavioural disorders and psychotic illness. The existing study is comparing 30 people with PWS aged 12 years and older (15 with each of the two main genetic forms of PWS) and also an aged-matched typically developing control group. Assessments for the on-going study include informant and participant interviews for behaviour problems and psychiatric symptomatology, specific cognitive assessments, and EEG investigations. The hypotheses for this study were identified following a systematic review of the relevant scientific literature both in PWS and of other populations at risk for schizophrenia (Aman et al 2018). To develop further the present study, in this study we are proposing to seek the agreement of participants taking part to also undergo MRS neuroimaging to obtain a more direct measure of GABA and other brain transmitters in designated brain areas. Using established MRS analytical techniques we will compare GABA in these brain areas within and between the two PWS groups and the typically developing sibling control group. We will undertake further secondary analyses investigating the relationship between brain GABA levels and age and gender, the presence or not of psychiatric symptomatology, EEG findings, and scores on cognitive tests. In addition, as part of the MRS study, we will use MRI neuroimaging techniques that allow the visualisation and measurement of brain structure.

Behavioural problems and psychotic illness have a devastating effect on function and on quality of life and impacts markedly on the family. At present the immediate treatment is often the use of anti-psychotic medications, such use may be appropriate for mental illness but not so for behavioural problems. If we had a better understanding of the brain basis for these disorders in people with PWS this would allow a much more targeted approach selecting medications and psychological interventions informed by the known brain and cognitive abnormalities. Given the high risk for psychotic illness with age in people with PWS due to mUPD the long term aim is to be able to prevent the psychosis developing in the first place and, for example, to undertake a trial of preventative treatment. The first step in that direction is to understand the underling brain mechanisms.

Research Outcomes: Public Summary

The study has shown that complex and demanding MRI and MRS brain scanning is possible and acceptable to people with PWS and initial analysis of the quality of the data shows that comparisons between those at high risk for psychotic illness (people with PWS due to a UPD) and those whose risk is significantly less (people with PWS due to a deletion) will be possible.
We have established a neuroimaging protocol that works well for people with PWS and have completed MRI and MRS scans on 11 (the 12th is this week) participants with UPD and 12 participants with deletion aged 12 years and older. Preliminary analysis of the structural MRI scans have shown significant differences in cortical structures between the two groups. The areas of the brain of particular interest for MRS are those that have been implicated from studies of psychotic illness in the general population - the auditory, cingulate gyrus and the occipital cortices. The spectra obtained using MRS will enable the investigation of differences in brain transmitters between genetic types of PWS, such as the neurotransmitters GABA, glutamate, and N-acetyl aspartic acid (NAA). This is difficult data to collect as it requires the participant to lie very still for at least 20 mins for each of the brain areas examined along with additional time 12 mins for the MRI scan - data is still to be fully analysed but we have found it to be of acceptable quality.
This has been a challenging study as particularly people with PWS due to a UPD are difficult to recruit as they may be mentally unwell at the time, feel less comfortable about taking part, and find it more difficult to manage the demands of scanning. We are very grateful to those people with PWS who were able to help and also to their families and support workers. Those who did take part were proud to have done it and have volunteered to help in future studies.

Research Outcomes: Publication

Psychotic illness in people with Prader-Willi syndrome: a systematic review of clinical presentation, course and phenomenology. Aman LCS, Lester SD, Holland AJ, Fletcher PC.  Orphanet J Rare Dis. 2024 Feb 15;19(1):69. doi: 10.1186/s13023-024-03026-y. PMID: 38360662; PMCID: PMC10870655.