The relationship between cardiac activity, behaviour and endogenous oxytocin and vasopressin in Prader-Willi Syndrome: An exploratory study.

This study aimed to increase our understanding of cardiac activity abnormalities in Prader-Willi Syndrome (PWS) and the relationship between cardiac activity, PWS behaviours thought to be associated with cardiac vagal tone and endogenous oxytocin and vasopressin levels. We compared cardiac activity (respiratory sinus arrhythmia (RSA), low-frequency heart rate variability (LF-HRV), heart period) in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. RSA, LF-HRV, and heart period were lower in individuals with PWS than in the control group. In the control group, RSA was higher for females than males. However, for those with PWS, there was no difference between the sexes. Individuals with the mUPD genetic subtype had lower RSA and LF-HRV than participants with the PWS deletion subtype and compared to typically developing controls, no difference was found between the latter two groups. Heart period was also lower for those with mUPD compared to controls. Higher RSA reduced the odds of having temper outbursts and skin-picking. RSA was lower in those with PWS and psychosis compared to those with PWS without psychosis. Finally, we found RSA correlated with vasopressin for those with mUPD but not deletion. There was no relationship between RSA and oxytocin plasma or saliva levels. Our findings suggest autonomic dysfunction in PWS that is more marked in mUPD than deletion and potentially due to greater loss of parasympathetic activity in mUPD.

Fetal alcohol spectrum disorder resources for health professionals: a scoping review.

OBJECTIVES: This scoping review aimed to identify and critically appraise resources for health professionals to identify, diagnose, refer, and support individuals with fetal alcohol spectrum disorder (FASD)-including the extent to which the resources are appropriate for use in communities with First Nations Peoples. METHOD: Seven peer-reviewed databases (April 2022) and 14 grey literature websites (August 2022) were searched. The reference lists of all sources that underwent full-text review were handsearched, and FASD experts were consulted for additional sources. Resources were assessed using the Appraisal of Guidelines for REsearch and Evaluation II instrument and an adapted version of the National Health and Medical Research Council FORM Framework and iCAHE Guideline Quality Checklist. RESULTS: A total of 41 resources underwent data extraction and critical appraisal, as screening and/or diagnosis guidelines were excluded because they are covered in other reviews. Most were recently published or updated (n=24), developed in the USA (n=15, 36.6%) or Australia (n=12, 29.3%) and assisted with FASD patient referral or support (n=40). Most management guidelines scored 76%-100% on overall quality assessment (n=5/9) and were recommended for use in the Australian context with modifications (n=7/9). Most of the guides (n=15/22) and factsheets (n=7/10) received a 'good' overall score. Few (n=3/41) resources were explicitly designed for or with input from First Nations Australians. CONCLUSION: High-quality resources are available to support health professionals providing referrals and support to individuals with FASD, including language guides. Resources should be codesigned with people living with FASD to capture and integrate their knowledge and preferences.

Efficacy of cannabinoids in neurodevelopmental and neuropsychiatric disorders among children and adolescents: a systematic review.

A better understanding of the endocannabinoid system and a relaxation in regulatory control of cannabis globally has increased interest in the medicinal use of cannabinoid-based products (CBP). We provide a systematic review of the rationale and current clinical trial evidence for CBP in the treatment of neuropsychiatric and neurodevelopmental disorders in children and adolescents. A systematic search of MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Trials was performed to identify articles published after 1980 about CBP for medical purposes in individuals aged 18 years or younger with selected neuropsychiatric or neurodevelopmental conditions. Risk of bias and quality of evidence was assessed for each article. Of 4466 articles screened, 18 were eligible for inclusion, addressing eight conditions (anxiety disorders (n = 1); autism spectrum disorder (n = 5); foetal alcohol spectrum disorder (n = 1); fragile X syndrome (n = 2); intellectual disability (n = 1); mood disorders (n = 2); post-traumatic stress disorder (n = 3); and Tourette syndrome (n = 3)). Only one randomised controlled trial (RCT) was identified. The remaining seventeen articles included one open-label trial, three uncontrolled before-and-after trials, two case series and 11 case reports, thus the risk of bias was high. Despite growing community and scientific interest, our systematic review identified limited and generally poor-quality evidence for the efficacy of CBP in neuropsychiatric and neurodevelopmental disorders in children and adolescents. Large rigorous RCTs are required to inform clinical care. In the meantime, clinicians must balance patient expectations with the limited evidence available.

The relationship between endogenous oxytocin and vasopressin levels and the Prader-Willi syndrome behaviour phenotype.

Background: Oxytocin and vasopressin systems are altered in Prader Willi syndrome (PWS). However, investigations into endogenous oxytocin and vasopressin levels as well as clinical trials evaluating the effect of exogenous oxytocin on PWS symptoms have had mixed results. It is also unknown whether endogenous oxytocin and vasopressin levels are associated with certain PWS behaviours. Method: We compared plasma oxytocin and vasopressin and saliva oxytocin levels in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. We also compared neuropeptide levels between gender and genetic subtypes within the PWS cohort and examined the relationship between neuropeptide levels and PWS behaviours. Results: While we did not measure a group difference in plasma or saliva oxytocin levels, plasma vasopressin was significantly lower in individuals with PWS compared to controls. Within the PWS cohort, saliva oxytocin levels were higher in females compared to males and individuals with the mUPD compared to the deletion genetic subtype. We also found the neuropeptides correlated with different PWS behaviours for males and females and for genetic subtypes. For the deletion group, higher plasma and saliva oxytocin levels were related to fewer behaviour problems. For the mUPD group, higher plasma vasopressin levels were related to more behaviour problems. Conclusion: These findings support existing evidence of a vasopressin system defect in PWS and for the first time identify potential differences in the oxytocin and vasopressin systems across PWS genetic subtypes.

Progressive resistance training in young people with Prader-Willi syndrome: protocol for a randomised trial (PRESTO).

INTRODUCTION: Preliminary evidence suggests that progressive resistance training may be beneficial for people with Prader-Willi Syndrome (PWS), a rare genetic condition that results in muscle weakness and low muscle tone.To establish whether community-based progressive resistance training is effective in improving the muscle strength of people with PWS; to determine cost-effectiveness; and, to complete a process evaluation assessing intervention fidelity, exploring mechanisms of impact, understanding participant experiences and identifying contextual factors affecting implementation. METHODS AND ANALYSIS: A multisite, randomised controlled trial will be completed. Sixty participants with PWS will be randomised to receive either progressive resistance training (experimental) or non-progressive exercise (placebo control). Participants will be aged 13 to 60 years, be able to follow simple instructions in English and have no contraindications to performing progressive resistance training. The experimental group will complete progressive resistance training two times weekly for 24 weeks supervised by an exercise professional at a community gym. The control group will receive all aspects of the intervention except progressive overload. Outcomes will be assessed at week 25 (primary endpoint) and week 52 by a blinded assessor. The primary outcome is muscle strength assessed using one repetition maximum for upper limb and lower limb. Secondary outcomes are muscle mass, functional strength, physical activity, community participation, health-related quality of life and behaviour. Health economic analysis will evaluate cost-effectiveness. Process evaluation will assess safety and intervention fidelity, investigate mechanism of impact, explore participant experiences and identify contextual factors affecting implementation. Data collection commenced in February 2020 and will conclude in September 2023. ETHICS AND DISSEMINATION: Ethical approval was obtained from The Royal Children's Hospital Human Research Ethics Committee (HREC/50874/RCHM-2019) under the National Mutual Acceptance initiative. Research governance approvals were obtained from five clinical sites. Results will be disseminated through published manuscripts, conference presentations, public seminars and practical resources for stakeholder groups. TRIAL REGISTRATION NUMBER: ACTRN12620000416998; Australian and New Zealand Clinical Trial Registry.

Assessment of protein inclusions in cultured cells using automated image analysis.

Proteinaceous inclusions are associated with neurodegenerative diseases and cell models are often used to determine genetic and chemical modifiers of their formation. This protocol involves the usage of automated microscopy and machine learning-based image analysis to accurately quantify the levels of protein inclusion formation in cultured cells from fluorescence microscopy images. This protocol is highly scalable and can be applied to a few images or large datasets. For complete details on the use and execution of this protocol, please refer to McAlary et al. (2022).

Fetal alcohol spectrum disorder resources for health professionals: a scoping review protocol.

INTRODUCTION: People with fetal alcohol spectrum disorder (FASD) encounter a range of health and allied health providers and require specialised support to ensure health services are provided safely and effectively. Not all health professionals possess the knowledge or expertise required for the identification, assessment, referral and management of FASD. Accessible resources for understanding and managing FASD can help create awareness in health professionals and ensure patients receive the correct diagnosis and timely access to the necessary supports and services. The aim of this scoping review is to identify and analyse FASD resources for health professionals. METHODS AND ANALYSIS: A comprehensive search of eight databases (MEDLINE, Scopus, PsycINFO, CINAHL, PubMED, EMBASE, Web of Science and Trip Medical Database) and nine grey literature databases (FASD Hub, NOFASD Australia, National Organisation for FASD, FASD United, HealthInfoNet, Proof Alliance, Child Family Community Australia, Foundation for Alcohol Research & Education and the Australian Department of Health websites) will be conducted using three search engines including PubMed, Ovid and Google advanced search (search dates: October 2021 to May 2022). Consultations will also be carried out with international and national experts in the diagnosis/management of FASD to obtain any additional relevant published or unpublished resources. Inclusion criteria were developed to guide the selection of resources that are publicly available, primarily focused on FASD and curated for health professionals for the identification, management or referral of FASD. Critical appraisal process will be executed using the Appraisal of Guidelines for REsearch & Evaluation II (AGREE II) tool to assess the quality of selected resources. ETHICS AND DISSEMINATION: Ethical approval is not required for the scoping review. Scoping review results will be presented at relevant national and international conferences and published in peer-reviewed journals. Search results will be made available to ensure reproducibility and transparency.

Bigiswun Kid Project: a longitudinal study of adolescents living with high rates of prenatal alcohol exposure, fetal alcohol spectrum disorder and early life trauma in remote Australian Aboriginal communities.

INTRODUCTION: The Lililwan Project was the first Australian population-based prevalence study of fetal alcohol spectrum disorder (FASD) using active case ascertainment. Conducted in 2010-2011, the study included 95% of all eligible children aged 7-9 years living in the very remote Aboriginal communities of the Fitzroy Valley, Western Australia. Women from Marninwarntikura Women's Resource Centre, a local Aboriginal-led organisation, are concerned that some participants from the study are struggling in adolescence so partnered with researchers from the University of Sydney to follow up the Lililwan cohort in 2020-2022 at age 17-19 years.The overarching aim of the Bigiswun Kid Project is to identify adolescents' needs and build knowledge to inform services to improve the health and well-being of adolescents in remote Aboriginal communities. The specific aims are to: (1) provide a voice to adolescents and their families to understand the health and well-being status of the Lililwan cohort at 17-19 years. (2) Examine relationships between exposures during pregnancy, birth characteristics, and health and neurodevelopment at 7-9 years, and positive/adverse adolescent outcomes at 17-19 years. This information will identify prenatal and early life factors that predict good health and well-being in adolescence. (3) Determine whether management plans provided in the Lililwan Project were followed, and identify past and present service gaps, support needs and barriers to service use. (4) Determine if key physical characteristics of FASD change between childhood and adolescence in this Aboriginal population. ETHICS AND DISSEMINATION: Approved by the Kimberley Aboriginal Health Planning Forum and relevant ethics committees.

Fetal alcohol spectrum disorder resources for educators: A scoping review.

Children with foetal alcohol spectrum disorder (FASD) can experience neurodevelopmental, physical, psychological and behavioural impairments that can result in a disrupted school experience. However, educators often have limited knowledge or experience in the identification and support of students with FASD, and there is a critical need for effective tools and resources to ensure students with FASD are supported in their ongoing learning and development. This scoping review aimed to identify and evaluate publicly available educator resources that aid in the identification, and support of students with FASD in primary/elementary school. In addition, educators and FASD experts were consulted to obtain feedback on currently available resources, and key issues and priorities for FASD resources. In total, 124 resources were identified by searching peer-reviewed and grey literature databases, app stores, podcast services and contacting FASD experts. Information was found on identification (23 resources) and support of students with FASD (119 resources). No resources provided information on the referral. Most resources were average (40%) to good (33%) quality, as measured by a composite tool based on adaptions of the NHMRC FORM Framework and iCAHE Guideline Quality Checklist. A minority of resources had been formally evaluated (7%). Review findings and consultations with experts and educators indicate a critical need for referral guides, evidence-based short-format resources and centralised access for school communities to high-quality resources. Taken together, this study has identified key areas for future resource development and research to better support primary school students with FASD.

Illuminating amyloid fibrils: Fluorescence-based single-molecule approaches.

The aggregation of proteins into insoluble filamentous amyloid fibrils is a pathological hallmark of neurodegenerative diseases that include Parkinson's disease and Alzheimer's disease. Since the identification of amyloid fibrils and their association with disease, there has been much work to describe the process by which fibrils form and interact with other proteins. However, due to the dynamic nature of fibril formation and the transient and heterogeneous nature of the intermediates produced, it can be challenging to examine these processes using techniques that rely on traditional ensemble-based measurements. Single-molecule approaches overcome these limitations as rare and short-lived species within a population can be individually studied. Fluorescence-based single-molecule methods have proven to be particularly useful for the study of amyloid fibril formation. In this review, we discuss the use of different experimental single-molecule fluorescence microscopy approaches to study amyloid fibrils and their interaction with other proteins, in particular molecular chaperones. We highlight the mechanistic insights these single-molecule techniques have already provided in our understanding of how fibrils form, and comment on their potential future use in studying amyloid fibrils and their intermediates.

Fetal Alcohol Spectrum Disorder resources for educators working within primary school settings: a scoping review protocol.

INTRODUCTION: Many children affected by Fetal Alcohol Spectrum Disorder (FASD) exhibit neurocognitive delays that contribute to secondary consequences, including a disrupted school experience. Educators often have limited knowledge or experience in the identification, referral, management and accommodation of students with FASD. Effective resources and tools for educators are crucial to ensure these students are supported in their ongoing learning, development and school participation. This scoping review aims to identify and evaluate resources for educators that aid in the identification, management, or accommodation of students with FASD. METHODS AND ANALYSIS: A search will be conducted in 9 peer-reviewed and 11 grey literature databases, Google search engine, two app stores and two podcast streaming services (planned search dates: November 2020 to February 2021). Relevant experts, including researchers, health professionals and individuals with lived experience of FASD, will be contacted in February and March 2021 to identify additional (including unpublished) resources. Resources will be selected based on registered, prespecified inclusion-exclusion criteria, and the quality of included resources will be critically appraised using a composite tool based on adaptions of the National Health and Medical Research Council FORM Framework and the iCAHE Guideline Quality Checklist. Relevant experts will also be requested to provide feedback on included resources. ETHICS AND DISSEMINATION: Ethical approval for this scoping review was obtained from the University of Sydney Human Research Ethics Committee (2020/825). Results of the review will be disseminated through a peer-reviewed publication, conference presentations, and seminars targeting audiences involved in the education sector. TRIAL REGISTRATION: Open Science Framework: osf.io/73pjh.

The characteristics of temper outbursts in Prader-Willi syndrome.

The purpose of this study was to develop a comprehensive understanding of temper outbursts in Prader-Willi syndrome (PWS). A survey was developed from interviews conducted with individuals with PWS and their caregivers. The survey was completed by 101 primary caregivers. The findings suggest that outburst frequency decreases with age while duration increases. Adolescents exhibited more severe behaviors than children or adults. No differences were found across gender or genetic subtype. Provocations fit into three themes: goal blockage, social injustice, and difficulty dealing with change. Distracting the person or giving them space to calm down were the only management strategies judged effective. Risperidone, sertraline, and fluoxetine were the most common medications prescribed for outbursts, though parents reported only minor effects.

A review of clinical trials of oxytocin in Prader-Willi syndrome.

PURPOSE OF REVIEW: PWS is a severe developmental disability for which there is no known treatment. The oxytocin system is currently a primary target for intervention. The aim of this article is to review the evidence for the efficacy of intranasal oxytocin in PWS. RECENT FINDINGS: To date, there have been five clinical trials of oxytocin in PWS. Four of these studies reported that oxytocin improved behaviors. However, each of these studies suffered important limitations that likely influenced the findings. For example, one study did not include a control group. Another study did not statistically analyze the effects of oxytocin on behavior. The final two studies used study-specific measures for which psychometric properties have not been assessed. SUMMARY: Because of these limitations, the most appropriate conclusion to draw from the existing studies is that there is currently no convincing evidence that intranasal oxytocin improves symptoms of PWS. However, this does not mean that oxytocin is not involved in PWS. Rather, it suggests that further work is needed to understand the nature of the PWS oxytocin abnormality.

Microstructural white matter tract alteration in Prader-Willi syndrome: A diffusion tensor imaging study.

Prader-Willi Syndrome (PWS) is a genetic disorder characterized by infantile hypotonia, hyperphagia, hypogonadism, growth hormone deficiency, intellectual disability, and severe emotional and behavioral problems. The brain mechanisms that underpin these disturbances are unknown. Diffusion tensor imaging (DTI) enables in vivo investigation of the microstructural integrity of white matter pathways. To date, only one study has used DTI to examine white matter alterations in PWS. However, that study used selected regions of interest, rather than a whole brain analysis. In the present study, we used diffusion tensor and magnetic resonance (T 1-weighted) imaging to examine microstructural white matter changes in 15 individuals with PWS (17-30 years) and 15 age-and-gender-matched controls. Whole-brain voxel-wise statistical analysis of FA was carried out using tract-based spatial statistics (TBSS). Significantly decreased fractional anisotropy was found localized to the left hemisphere in individuals with PWS within the splenium of the corpus callosum, the internal capsule including the posterior thalamic radiation and the inferior frontal occipital fasciculus (IFOF). Reduced integrity of these white matter pathways in individuals with PWS may relate to orientating attention, emotion recognition, semantic processing, and sensorimotor dysfunction.

Reduced gamma-aminobutyric acid is associated with emotional and behavioral problems in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by infantile hypotonia, hypogonadism, small hands and feet, distinct facial features and usually intellectual impairment. The disorder is associated with severe behavioral disturbances which include hyperphagia leading to morbid obesity, temper outbursts, skin-picking, and compulsive behaviors. While the brain mechanisms that underpin these disturbances are unknown these behaviors suggest a lack of inhibition and thus gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter may be implicated. In the present study, we investigated in vivo brain GABA and its relationship with emotion and behavior in individuals with PWS. Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed on 15 individuals with PWS and 15 age- and gender-matched typically developing controls. GABA levels were measured in the parieto-occipital lobe. All other metabolite levels (N-acetyl aspartate, myo-Inositol, glutathione, glutamate, and glutamine + glutamate) were measured in the anterior cingulate cortex (ACC). GABA levels were significantly lower in the participants with PWS who had clinically significant emotional and behavioral problems relative to typically developing control participants and participants with PWS who did not have emotional and behavioral problems within the clinically significant range. GABA levels were negatively correlated with total behavioral problem scores as well as temper outbursts, skin-picking, depression, social relating difficulties, and a tendency to be self-absorbed. Our data suggests that alterations of the GABAergic system may play an important role in aspects of the pathophysiology of PWS. Pathological mechanism found in PWS may be relevant to understanding the control of similar behaviors in the general population. © 2016 Wiley Periodicals, Inc.

The Developmental Trajectory of Self-Injurious Behaviours in Individuals with Prader Willi Syndrome, Autism Spectrum Disorder and Intellectual Disability.

In the present study we examined the nature and developmental trajectory of self-injurious behaviour in Prader Willi syndrome (PWS) and autism spectrum disorder (ASD). The development of interventions is greatly aided by understanding gene to behaviour pathways, and this requires an accurate description of the behaviour phenotype, that is, which types and natural history of self-injurious behaviour are more common in PWS and ASD and which are shared with other forms of developmental disability. Self-injury displayed by individuals with PWS and individuals with ASD was compared with that reported in a group of individuals with intellectual disability due to mixed aetiology (ID group). Three self-injurious behaviours (head banging, skin-picking and hitting and/or biting self) were measured on five occasions over 18 years using the Developmental Behaviour Checklist (DBC) a well-validated caregiver report measure. Rates of skin picking were higher in individuals with PWS and hitting and/or biting self was higher in individuals with ASD compared to the ID group. Rates of head banging were similar across the three groups. Over time, skin-picking and head banging increased with age for individuals with ASD and hitting and/or biting self increased for the PWS group. In the PWS and mixed ID groups head banging decreased with age. These findings suggest that the typology and developmental trajectories of self-injurious behaviours differ between those with PWS and ASD.

The developmental trajectory of disruptive behavior in Down syndrome, fragile X syndrome, Prader-Willi syndrome and Williams syndrome.

The aim of this study was to investigate the developmental trajectories of verbal aggression, physical aggression, and temper tantrums in four genetic syndrome groups. Participants were part of the Australian Child to Adult Development Study (ACAD), which collected information from a cohort of individuals with an intellectual disability at five time points over 18 years. Data were examined from a total of 248 people with one of the four following syndromes: Down syndrome, Fragile X syndrome, Prader-Willi syndrome, or Williams syndrome. Changes in behaviors were measured using validated items from the Developmental Behavior Checklist (DBC). The results indicate that, while verbal aggression shows no evidence of diminishing with age, physical aggression, and temper tantrums decline with age before 19 years for people with Down syndrome, Fragile X syndrome, and William syndrome; and after 19 years for people with Prader-Willi syndrome. These findings offer a somewhat more optimistic outlook for people with an intellectual disability than has previously been suggested. Research is needed to investigate the mechanisms predisposing people with PWS to persistence of temper tantrums and physical aggression into adulthood.

Cognitive and behavioural aspects of Prader-Willi syndrome.

PURPOSE OF REVIEW: To provide a review of the recent advances in the diagnosis and treatment of psychiatric disorders in Prader-Willi syndrome (PWS). RECENT FINDINGS: Research in the last 12 months has provided a descriptive prognosis of psychosis in PWS and highlighted the possible genes associated with the increased risk of psychosis for those with maternal uniparental disomy (mUPD). Several studies investigating social and communication skills have shown people with PWS to have difficulty with core, receptive and expressive language skills, interpreting emotional valence in faces, playing with children of their own age, understanding personal space and a developmental delay in the theory of mind. These social and communication deficits are often more pronounced in those with mUPD. Two recent clinical trials of oxytocin provide mixed results and highlight the need for an improved understanding of the neurobiological characteristics of the PWS brain. A recent pilot study suggests N-acetylcysteine may be a viable treatment for skin picking. SUMMARY: Recent advances have contributed to our understanding of the emotional and behavioural problems associated with PWS, and provided directions for further research.

A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) have a significant reduction in the number of oxytocin-producing neurons (42%) in the hypothalamic paraventricular nucleus. A number of animal studies and observations of humans show that lesions in this region can produce PWS-like symptoms. Given the evidence for potential oxytocin deficiency, we tested the effects of a course of intranasal oxytocin on PWS symptoms. Thirty individuals with PWS aged 12-30 years participated in an 18-week randomized double-blind placebo-controlled crossover trial. Participants received 8 weeks of oxytocin and 8 weeks of placebo with a minimum 2-week washout period. The first 11 participants received the following oxytocin doses: 24 IU (twice daily) B.I.D for participants 16 years and over and 18 IU B.I.D for participants 13-15 years. The dose was increased for the remaining 18 participants to 40 IU B.I.D for participants 16 years and over and 32 IU B.I.D for 13-15 years. Measures used to assess changes were standardized well-accepted measures, including the Developmental Behavior Checklist-Monitor, Parent, Teacher, and Adult; The Yale-Brown Obsessive Compulsive Scale; The Dykens Hyperphagia questionnaire; Reading The Mind in the Eyes Test; Epworth Sleepiness Scale and the Movie Stills. Oxytocin had little impact on any measure. The only significant difference found between the baseline, oxytocin, and placebo measures was an increase in temper outbursts (P = 0.023) with higher dose oxytocin. The lack of effect of oxytocin nasal spray may reflect the importance of endogenous release of oxytocin in response to exogenous oxytocin.