Schizophrenia and bipolar disorder are common, severe, and disabling psychotic disorders, which are difficult to research. We argue that the genetically determined neurodevelopmental disorder Prader-Willi syndrome (PWS), which is associated with a high risk of affective psychotic illness, can provide a window into genetic mechanisms and associated neural pathways. People with PWS can all show non-psychotic psychopathology and problem behaviours, but the prevalence of psychotic illness differs markedly by genetic subtype; people with PWS due to chromosome 15 maternal uniparental disomy have higher prevalence of psychotic illness compared with patients with PWS due to 15q11-13 deletions of paternal origin. On the basis of this observation and the neural differences between genetic subtypes, we hypothesise that the combined effects of the absent expression of specific maternally imprinted genes at 15q11-13, and excess maternally imprinted or paternally expressed genes on chromosome 15, affect the γ-aminobutyric acid-glutamatergic pathways and associated neural networks that underpin mood regulation and sensory processing, resulting in psychotic illness. We propose a model of potential mechanisms of psychosis in PWS, which might be relevant in the general population, and should inform future research.

Genetically determined neurodevelopmental syndromes are frequently associated with a particular developmental trajectory, and with a cognitive profile and increased propensity to specific mental and behavioural disorders that are particular to, but not necessarily unique to the syndrome. How should these mental and behavioural disorders best be conceptualised given that similar symptoms are included in the definition of different mental disorders as listed in DSM-5 and ICD-10? In addition, a different conceptual framework, that of applied behavioural analysis, has been used to inform interventions for what are termed ‘challenging behaviours’ in contrast to types of interventions for those conditions meeting diagnostic criteria for a ‘mental disorder’. These syndrome-specific developmental profiles and associated co-morbidities must be a direct or indirect consequence of the genetic abnormality associated with that syndrome, but the genetic loci associated with the syndrome may not be involved in the aetiology of similar symptoms in the general population. This being so, should we expect underlying brain mechanisms and treatments for specific psychopathology in one group to be effective in the other? Using Prader-Willi syndrome as an example, we propose that the conceptual thinking that informed the development of the Research Domain Criteria provides a model for taxonomy of psychiatric and behavioural disorders in genetically determined neurodevelopmental syndromes. This model brings together diagnostic, psychological and developmental approaches with the aim of matching specific behaviours to identifiable neural mechanisms.

Temper outbursts are a severe problem for people with Prader-Willi Syndrome (PWS). Previous reports indicate that vagus nerve stimulation (VNS) may reduce maladaptive behaviour in neurodevelopmental disorders, including PWS. We systematically investigated the effectiveness of transcutaneous VNS (t-VNS) in PWS. Using a non-blind single case repeat measures modified ABA design, with participants as their own controls, t-VNS was evaluated in five individuals with PWS [three males; age 22–41 (M = 26.8)]. After a baseline phase, participants received four-hours of t-VNS daily for 12 months, followed by one month of daily t-VNS for two-hours. The primary outcome measure was the mean number of behavioural outbursts per day. Secondary outcomes included findings from behavioural questionnaires and both qualitative and goal attainment interviews. Four of the five participants who completed the study exhibited a statistically significant reduction in number and severity of temper outbursts after approximately nine months of daily four-hour t-VNS. Subsequent two-hour daily t-VNS was associated with increased outbursts for all participants, two reaching significance. Questionnaire and interview data supported these findings, the latter indicating potential mechanisms of action. No serious safety issues were reported. t-VNS is an effective, novel and safe intervention for chronic temper outbursts in PWS. We propose these changes are mediated through vagal projections and their effects both centrally and on the functioning of the parasympathetic nervous system. These findings challenge our present biopsychosocial understanding of such behaviours suggesting that there is a single major mechanism that is modifiable using t-VNS. This intervention is potentially generalizable across other clinical groups. Future research should address the lack of a sham condition in this study along with the prevalence of high drop out rates, and the potential effects of different stimulation intensities, frequencies and pulse widths.

The notion that sensitivity to the statistical structure of the environment is pivotal to perception has recently garnered considerable attention. Here we investigated this issue in the context of hearing. Building on previous work (Sohoglu & Chait, 2016b), stimuli were artificial 'sound-scapes' populated by multiple (up to 14) simultaneous sources ('auditory objects') comprised of tone-pip sequences, each with a distinct frequency and pattern of amplitude modulation. Sequences were either temporally regular or random.We show that listeners' ability to detect abrupt appearance or disappearance of a source is facilitated when scene sources were characterized by a temporally regular fluctuation pattern. The patterning of the changing source as well as that of the background (non-changing) sources contribute independently to this effect. Remarkably, listeners benefit from regularity even when they are not consciously aware of it. These findings establish that perception of complex acoustic scenes relies on the availability of detailed representations of the regularities automatically extracted from each scene source.

Highlights Perception relies on sensitivity to predictable structure in the environment. We used artificial acoustic scenes to investigate this in the auditory modality. Listeners track the temporal structure of multiple concurrent acoustic streams. Sensitivity to predictable structure supports auditory scene analysis, even when scenes are complex. Benefit of regularity observed even when listeners are unaware of the predictable structure.