EEG as a translational biomarker and outcome measure in fragile X syndrome

Targeted treatments for fragile X syndrome (FXS) have frequently failed to show efficacy in clinical testing, despite success at the preclinical stages. This has highlighted the need for more effective translational outcome measures. EEG differences observed in FXS, including exaggerated N1 ERP amplitudes, increased resting gamma power and reduced gamma phase-locking in the sensory cortices, have been suggested as potential biomarkers of the syndrome. These abnormalities are thought to reflect cortical hyper excitability resulting from an excitatory (glutamate) and inhibitory (GABAergic) imbalance in FXS, which has been the target of several pharmaceutical remediation studies. EEG differences observed in humans also show similarities to those seen in laboratory models of FXS, which may allow for greater translational equivalence and better predict clinical success of putative therapeutics. There is some evidence from clinical trials showing that treatment related changes in EEG may be associated with clinical improvements, but these require replication and extension to other medications. Although the use of EEG characteristics as biomarkers is still in the early phases, and further research is needed to establish its utility in clinical trials, the current research is promising and signals the emergence of an effective translational biomarker

Comparison of the autism and schizophrenia spectrums

Although they share a number of clinical features, autism and schizophrenia are usually distinguished by their different ages of onset and certain discriminating features such as major impairments to communication in the former and positive psychotic symptoms in the latter. However, the recognition that these conditions are part of broader spectrums of impairment has led to the definition of disorders which do not show such marked and discriminating features, such as autism spectrum disorders (ASD) and schizotypal personality disorder (SPD). Reviewing the historical development of these concepts and areas of potential overlap or difference between them revealed that they have both shared and discriminating features, but no study to date has directly compared them. Three experiments were therefore conducted to compare ASD and SPD using clinical, neuropsychological and functional magnetic resonance imaging (fMRI) techniques. In the clinical experiment, standardised measures were used to determine if it was possible to distinguish between the groups, and to allow their quantitative comparison. It was possible to distinguish between ASD and SPD in most cases, although 17% of the population tested met criteria for both conditions. This ‘comorbid’ (CM) group were therefore considered separately. When a single diagnosis could be allocated, there were clear overlaps of clinical features between the conditions and each condition showed more traits of the other than were seen in controls. The overlaps were most prominent for negative schizotypal traits which did not differ between the groups. The CM group were more affected than either the ASD or SPD groups across multiple domains. All groups had high levels of previously undiagnosed psychopathology. In the neuropsychological experiment, tests of social cognition, executive function and central coherence / local-global processing bias were employed. The similarities between the ASD and SPD groups were striking. Both showed similar evidence of impairment in social cognition and executive function, although there was some evidence of greater impairment in working memory in the ASD group. Differences were seen using a test of local-global processing bias, although these were potentially confounded by differences in general intellectual ability. Two fMRI tasks were conducted: a working memory task (a letter based n-back task) and a social judgment task (where individuals made judgements of either gender or approachability from a picture of a face). The former did not distinguish between the ASD and SPD groups. In the latter, individuals with SPD showed significantly greater activation than the ASD group in several brain regions known to be associated with social cognition, with the controls scoring in-between the two. Although they show marked clinical and brain functional overlaps, the results of the fMRI task of social judgement suggest that it is correct to consider ASD and SPD as separate diagnostic entities. The findings are consistent with the idea that, although both conditions are associated with impairments in understanding the mental states of others (mentalising), the mechanism which underlies these differs between the groups, with ASD associated with hypo-mentalising and SPD associated with hyper-mentalising

Overlapping phenotypes - a clinical and magnetic resonance imaging investigation of schizotypy and pervasive developmental disorders in adolescents with cognitive impairment

Introduction: The neurobiological bases of pervasive developmental disorders (PDD) and schizotypy are not well established. In addition there are clinical overlaps between the two which can make diagnostic determination difficult. The primary aim of this thesis was to explore the relationship between PDD and schizotypy by examining their associated clinical and brain structural features in a group of cognitively impaired adolescents. Methods: 138 adolescents receiving special educational assistance and 62 typically developing controls were recruited. Schizotypal features were measured using the Structured Interview for Schizotypy (SIS) and PDD features were measured using the Social Communication Questionnaire (SCQ). Each participant also received a standardised clinical interview and a magnetic resonance imaging (MRI) scan. Whole brain volume, midsagittal corpus callosum area and prefrontal lobe volume and gyrification index (GI) were measured using automated, semi-automated and manual region of interest techniques. The subjects in special education were considered in different groupings in three main analyses. In the first, the SIS was used to divide the subjects into those with and without schizotypal features. In the second, the standard SCQ cut-offs were used to divide the subjects into those with autism, those with non-specific pervasive developmental disorder (PDD-NOS) and those with neither. Finally, both the SIS and the SCQ were used contemporaneously to divide the subjects into 6 groups: schizotypal; autistic; PDD-NOS; comorbid schizotypy and autism; comorbid schizotypy and PDD-NOS; and neither schizotypal nor autistic. In each analysis the groups were compared to each other and to the controls with respect to the clinical features and brain structural measures. Results: The schizotypal subjects showed an increase in right prefrontal volume and changes in the anterior and posterior corpus callosum relative to those without schizotypy and the controls. The autism group had reduced right prefrontal GI relative to the other groups as well as anterior callosal changes. The PDD-NOS group had the highest level of psychiatric symptomatology on the CIS, in particular those who were comorbid for PDD-NOS and schizotypy. This comorbid group, both clinically and structurally resembled the schizotypy group rather than the PDD-NOS group. Conclusions: Distinct neuroanatomical differences can be seen in educationally impaired adolescents with schizotypal features and in those with autistic features. These can be related to the observed clinical impairment and may help to distinguish these disorders in the future. It is possible that adolescents with features of both schizotypy and PDD-NOS suffer from an underlying schizophrenia spectrum disorder rather than an autistic spectrum disorder

Clinical and behavioural features of SYNGAP1-related intellectual disability: a parent and caregiver description

BACKGROUND: SYNGAP1-related intellectual disability (ID) is a recently described neurodevelopmental disorder that is caused by pathogenic variation in the SYNGAP1 gene. To date, the behavioural characteristics of this disorder have mainly been highlighted via the prevalence of existing diagnoses in case series. We set out to detail the behavioural features of this disorder by undertaking interviews with those who have a child with SYNGAP1-related ID to allow them to describe their child’s behaviour. METHODS: We conducted 27 semi-structured interviews with parents and caregivers which covered basic information (e.g., age, gender), family history, perinatal history, past medical history, developmental history, epilepsy, behavioural history, and a general description of their child’s behaviour. RESULTS: Using a mixed quantitative and qualitative approach, the responses from the parents indicated that those with SYNGAP1-related ID showed high rates of autism spectrum disorder (52%), difficulties with fine and gross motor skills, delays in language development, and a high prevalence of epilepsy (70%). A qualitative analysis highlighted their general behaviour affected the themes of daily living skills, distress-related behaviours, emotional regulation, difficulties with change, a lack of danger awareness, and sensory differences. Sensory features described involved auditory, visual, tactile, gustatory, and proprioceptive themes. CONCLUSIONS: Our findings and behavioural descriptions provide important insights as well as implications for the diagnosis and care of those with SYNGAP1-related ID. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11689-022-09437-x