New light on neurocognitive processes linked to autism and attention deficit and hyperactivity disorder in childhood : studies of eye movements in twins

Visual attention and oculomotor response inhibition have been associated with Autism Spectrum Disorder (ASD) and Attention Deficit and Hyperactivity Disorder (ADHD) respectively. The aim of this thesis was to increase our knowledge about these cognitive functions relevant to ASD and ADHD in early infancy and childhood using eye tracking and twin modelling. Study 1 assessed the relative contribution of genetic and environmental influences to attentional networks and visual disengagement (using the gap overlap task) in a sample of twins from the general population, aged 9-14 years. It also assessed whether visual disengagement was associated with autistic traits. Gaze shift latencies across conditions were driven by shared genetic factors. Additionally, there were unique genetic influences to gaze shift latencies in the gap condition. In line with previous work, autistic traits were found to be heritable. There was no association between visual disengagement and autistic traits. Study 2 investigated the relative contribution of genetic and environmental factors to oculomotor response inhibition (using the antisaccade task) and the degree to which oculomotor response inhibition was associated with ADHD traits in the same twin sample. Oculomotor response inhibition in the form of premature anticipatory eye movements was heritable and associated to parent rated inattentive traits. This association was partially due to shared genetic factors. Study 3 investigated how visual disengagement relates to other cognitive developmental processes and behaviors, socioeconomic status and biological sex in early infancy. Gaze shift latencies in the overlap, baseline and gap conditions, of the Gap Overlap task, differed as a function of socioeconomic status and sex. No other associations between visual attention and developmental measures were observed. Thus, in summary, while these findings do not support neither a phenotypic nor a genetic link between visual disengagement and ASD, they support such association between oculomotor response inhibition and inattention (a core component of ADHD). Finally, these findings highlight the influence of sociodemographic factors on individual differences in visual attention in early infancy, thus underscoring the importance of understanding all sources of variation in attentional functions in childhood

Exploring the gut-brain axis in Attention-Deficit Hyperactivity Disorder

There is a bidirectional interaction between the gut and the brain, termed the gut-brain axis (GBA), involving e.g. the gut microbiota, and connecting the peripheral intestinal elements to the central nervous system (CNS). The GBA is increasingly recognized as a vital factor in the development and prognosis of neurological and psychiatric disorders. Of particular interest in this thesis is the signaling from gut microbiota to brain and back which is enabled through neural, endocrine, immune, and humoral pathways. Studies in germ-free and antibiotic-treated animal models have created a significant body of knowledge on the GBA and its role in regulating behavior. There are fewer studies using human subjects or with human materials. This thesis is focused on both clinical and biological aspects of GBA in attention-deficit hyperactivity disorder (ADHD). ADHD is a common childhood-onset psychiatric and neurodevelopmental disorder, which is characterized by having problems with paying attention and/or excessive activity and impulsivity, along with impairments on daily function and emotion regulation. ADHD is highly heritable and has high comorbidity with other psychiatric disorders and a higher-than-normal co-occurrence with some inflammatory disorders (e.g. asthma, eczema, rhinitis, celiac disease). However, ADHD is diagnosed primarily based on clinical observations of behaviors. Biomarkers for diagnosis and approaches for new therapy are lacking and the pathophysiology is poorly understood. This thesis consists of five studies attempting to explore some aspects of the GBA in neurodevelopmental and psychiatric disorders, with a focus on ADHD, utilizing a nationwide population-based cohort, a case-control design, a randomized controlled trial (RCT) and an in vitro model. It covers different aspects of the GBA, including gut microbiota and related antibiotic exposure, probiotic and prebiotic intervention, derived metabolites, inflammatory mediators, as well as the associations with clinical observations. Specifically, in Study I, we investigated whether exposure to antibiotic drugs, in utero and first two years after birth was associated with a risk for childhood-onset psychiatric disorders. Using Finnish nationwide registers, we found that antibiotic exposure was associated with a 10–50% increased risk for development of sleep disorders, ADHD, conduct disorders, mood disorders and anxiety disorders, which were accompanied by an increased risk for psychotropic drug use in childhood. The association with prenatal antibiotic exposure was neither explained completely by confounding factors related to family, nor by factors related to maternal infections. In Study II, we used a case-control design to study plasma levels of four inflammatory mediators: C-reactive protein (CRP), serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) in ADHD and their associations with medication and clinical symptoms. We found that ADHD patients had higher levels of sICAM-1 and sVCAM-1 than healthy controls, especially in children currently on ADHD medication. Among adult participants with ADHD, sICAM-1 levels were positively associated with comorbid autism symptoms, and CRP levels were associated with GI symptoms and emotion dysregulation. In Study III, a double-blind RCT was conducted to determine whether a synbiotic (Synbiotic 2000), consisting of a mixture of three lactic acid bacteria and four fibers had effects on symptoms, daily functioning, and comorbid traits in ADHD patients. We found that Synbiotic 2000, compared to placebo, significantly reduced typical restricted, repetitive and stereotyped behaviors of autism symptoms in children, and alleviated problems with goal-directed behavior of emotion regulation in adults. The effects on autism symptoms and problems with emotion regulation were stronger in the subgroup with higher sVCAM-1 levels. In Study IV, using data from the same RCT as in study III, we investigated the effects of Synbiotic 2000 on plasma levels of immune activity markers and short-chain fatty acids (SCFAs) in ADHD. Adults with ADHD had at baseline higher levels of pro-inflammatory vascular adhesion molecules (sICAM-1, sVCAM-1) and lower levels of the anti-inflammatory interleukin (IL)-10 compared to controls. Synbiotic 2000, compared to placebo treatment, was associated with reduced the levels of IL-12/IL-23p40 in children on ADHD medication, and suggestively associated with reduced sICAM-1 levels and increased propionic acid levels in children. Moreover, in adult patients we found lower baseline levels compared to controls of formic acid and propionic acid. No obvious effects of Synbiotic 2000 were found on plasma levels of SCFAs. However, we found IL-10 levels correlating positively with formic acid and acetic acid at baseline for both children and adults with ADHD. In child patients, sVCAM-1 correlated negatively with acetic acid and propionic acid while sICAM-1 correlated negatively with acetic acid. In adult patients, a negative correlation was observed between sVCAM-1 and formic acid at baseline. In Study V, an in vitro model was used to explore the effects of three SCFAs: acetate, propionate and butyrate, on cell growth and cell death of early stage human neural progenitor cells (hNPCs). We found that acetate, propionate and butyrate at low μM levels, relevant to physiological levels, significantly increased the proliferation of hNPCs and induced more cells to undergo mitosis, while the SCFAs at high mM levels had toxic effects on hNPCs. In support of this, the SCFA exposure to hNPCs changed the expression of genes involved in neurogenesis, proliferation and apoptosis. These studies provide support of a role of components influenced by the GBA, including gut microbiota, immune activity markers and bacterial metabolites in clinical and biological aspects of ADHD. Finally, these studies contribute to a better understanding of the GBA in ADHD

A minority within a minority: An exploration into the prevalence of neurodevelopmental disorders in looked after children and the effects on health and social wellbeing

Looked after children (Lac) continue to be one of the most vulnerable groups in society and many go on to attain poor health and social outcomes. Research on neurodevelopmental disorders (NDDs) in the general population is relatively well documented, however, research on Lac with NDDs is extremely limited. The aims of this thesis were to explore the prevalence of NDDs in the Lac population and if feasible compare rates to children who are not looked after (non-Lac). It further aimed to explore the impacts, challenges, barriers or wider factors that the Lac with a NDD might encounter or experience. To address the aims of this thesis, several methods have been used to collate data which are detailed in Chapters 2, 3, 4 and 5. Chapter 2 consists of a systematic review and meta-analysis which compares the prevalence of NDDs in Lac versus non-Lac and further explores the impacts on the Lac with a NDD. Twelve studies met eligibility. Six studies met eligibility for a meta-analysis and the remaining six studies are described as a narrative. In the review, there was a higher prevalence of ADHD and autism in the Lac population compared to their non-lac peers. The review also highlighted several adverse impacts and outcomes for the Lac with a NDD in the areas of care placement, criminal involvement, medication prescription, mental health services, emotional and physical abuse. Chapter 3 describes a brief narrative review which examines five studies that were not eligible for the systematic review but were important to further explore as they highlighted adverse impacts for the Lac with a NDD. This chapter examines these studies in more detail and relates the findings to wider literature. Similar adverse outcomes and impacts like those found in the systematic review were found but several additional adverse impacts and outcomes in areas of sexual abuse, homelessness, suicidal ideation, learning difficulties and physical health difficulties were also identified for the Lac with a NDD. As I could not interview Lac themselves, Chapter 4 describes a small q qualitative study, which was conducted to gain an insight into the perspectives and opinions of social workers on the little explored subject of NDDs in this population. Several broad topics were explored in areas of family, services and outcomes by means of interviews. Ten semi structured interviews were held, and a thematic analysis was utilised to analyse, code and identify themes. Themes involved perceptions of NDDs, perceptions of diagnosis, access to service provision, impact on care settings, impacts on health and social wellbeing, parental factors and social worker challenges and needs. Chapter five describes an electronic data linkage cohort study which investigates whether the prevalence rates attained from the meta-analysis for Lac reflect current prevalence estimates in Wales. It further examines whether there is similarity in several of the key findings detailed in the other chapters, in relation to services. Six health and administrative datasets held in the ‘Secured Anonymised Information Linkage (SAIL) databank at Swansea University were linked to explore and compare prevalence rates of NDDs and service usage in the Lac population compared to all children/young persons (Acyp) with a NDD in Wales. There was a higher prevalence of attention/deficit hyperactivity disorders, autistic spectrum disorders, developmental disorder of scholastic disorders, unspecified, eating disorders and reactive attachment disorders in Lac compared to Acyp in Wales. The results also highlight the mean age, gender of the first event/episode in which a NDD was identified within the dataset and the mean age, gender at time-of-service referrals to secondary health care services. In addition to this, results further highlight the educational support provision for both Lac and Acyp with a NND who have been placed in the ‘educated other than school’ (EOTAS) setting. The final chapter integrates all the findings of this thesis into a brief discussion and highlights any similarities, parallels, or ambiguities, followed by recommendations for research, policy and practice. My thesis proposes that more research is needed to support and understand the higher prevalence rates of NDDs in the already vulnerable Lac population. The identified impacts on the Lac with a NDD and the challenges, barriers and wider factors that these children may experience, or encounter may place these children at higher risk of adverse outcomes. More research in these areas would be beneficial to meeting the unique needs of the Lac with a NDD, particularly from a preventative and safeguarding perspective

Zur Diagnostik und Differentialdiagnostik der Autismus-Spektrum-Störungen

Autismus-Spektrum-Störungen (engl. Autism-Spectrum-Disorders, ASD) sind definiert über Auffälligkeiten in der sozialen Interaktion und Kommunikation sowie restriktive und repetitive Verhaltensweisen. ASD sind eine Gruppe komplexer, heterogener Störungen, die mit vielen Komorbiditäten einhergehen und bei deren Diagnostik zahlreiche relevante Differentialdiagnosen zu beachten sind. Die Symptomatik wandelt sich zudem in Bezug auf die Kernsymptome und mögliche Begleitsymptome über die Lebensspanne und in Abhängigkeit von zahlreichen Faktoren. Dies macht die Diagnostik der ASD zu einer großen Herausforderung. Die Verfügbarkeit valider und reliabler diagnostischer Instrumente ist essentiell, um eine möglichst optimale therapeutische Versorgung zu gewährleisten. Der vorliegende Kumulus stellt vier separate Studien zu Aspekten der Diagnostik und Differentialdiagnostik der Autismus-Spektrum-Störungen vor. Die ersten beiden Studien untersuchten die diagnostische Güte der Diagnostischen Beobachtungsskala für Autistische Störungen (ADOS) für die diagnostische Einschätzung von Kindern, Jugendlichen und Erwachsenen mit Verdacht auf ASD unter besonderer Berücksichtigung relevanter Differentialdiagnosen und Geschlechtsunterschiede. Die Ergebnisse sprechen für eine gute Einsetzbarkeit des Instruments in der klinischen Praxis, jedoch mit deutlichen Einschränkungen für bestimmte differentialdiagnostische Subgruppen. Aufgrund dieser Befunde erscheint eine individuelle und institutionelle Spezialisierung dringend angeraten. Die dritte Studie untersuchte die diagnostische Güte der ADOS in der klinischen Alltagspraxis unter Berücksichtigung von Merkmalen der Diagnostizierenden, der Durchführung und individueller Fallcharakteristiken. Die Ergebnisse weisen darauf hin, dass die ADOS in der klinischen Praxis mit sehr unterschiedlichen diagnostischen Ergebnissen assoziiert ist. Zur Sicherung einer ausreichend hohen Reliabilität sind regelmäßige Supervision und Fortbildungen zur Kalibrierung der diagnostischen Entscheidungen zu empfehlen. Die vierte Studie schließlich befasste sich mit Möglichkeiten der Differenzierung von ASD mithilfe der Erfassung von Emotionserkennungsleistungen unter Berücksichtigung von ADHS-Symptomen. Es zeigte sich, dass komorbide ADHS-Symptome, möglicherweise vermittelt über Reaktionszeiten, bei Kindern mit ASD einen Einfluss auf die Emotionserkennungsleistung haben und dass eine Verstärkung der Defizite vor allem bei älteren Kindern zum Tragen kommt. In der Diagnostik der ASD ist daher ein besonderes Augenmerk auf komorbide ADHS-Symptome zu richten, um individuell angepasste therapeutische Interventionen einleiten zu können

An Investigation of Gait and Language Function in Children With Autism Spectrum Disorder

This study examined gait and language function in children with ASD. Results suggested that in comparison to TD peers, children with ASD demonstrated shorter, slower steps with increased swaying. These gait disturbances also appeared to be more pronounced in children with poorer language abilities and greater ASD symptom severity

Zur Diagnostik und Differentialdiagnostik der Autismus-Spektrum-Störungen

Autismus-Spektrum-Störungen (engl. Autism-Spectrum-Disorders, ASD) sind definiert über Auffälligkeiten in der sozialen Interaktion und Kommunikation sowie restriktive und repetitive Verhaltensweisen. ASD sind eine Gruppe komplexer, heterogener Störungen, die mit vielen Komorbiditäten einhergehen und bei deren Diagnostik zahlreiche relevante Differentialdiagnosen zu beachten sind. Die Symptomatik wandelt sich zudem in Bezug auf die Kernsymptome und mögliche Begleitsymptome über die Lebensspanne und in Abhängigkeit von zahlreichen Faktoren. Dies macht die Diagnostik der ASD zu einer großen Herausforderung. Die Verfügbarkeit valider und reliabler diagnostischer Instrumente ist essentiell, um eine möglichst optimale therapeutische Versorgung zu gewährleisten. Der vorliegende Kumulus stellt vier separate Studien zu Aspekten der Diagnostik und Differentialdiagnostik der Autismus-Spektrum-Störungen vor. Die ersten beiden Studien untersuchten die diagnostische Güte der Diagnostischen Beobachtungsskala für Autistische Störungen (ADOS) für die diagnostische Einschätzung von Kindern, Jugendlichen und Erwachsenen mit Verdacht auf ASD unter besonderer Berücksichtigung relevanter Differentialdiagnosen und Geschlechtsunterschiede. Die Ergebnisse sprechen für eine gute Einsetzbarkeit des Instruments in der klinischen Praxis, jedoch mit deutlichen Einschränkungen für bestimmte differentialdiagnostische Subgruppen. Aufgrund dieser Befunde erscheint eine individuelle und institutionelle Spezialisierung dringend angeraten. Die dritte Studie untersuchte die diagnostische Güte der ADOS in der klinischen Alltagspraxis unter Berücksichtigung von Merkmalen der Diagnostizierenden, der Durchführung und individueller Fallcharakteristiken. Die Ergebnisse weisen darauf hin, dass die ADOS in der klinischen Praxis mit sehr unterschiedlichen diagnostischen Ergebnissen assoziiert ist. Zur Sicherung einer ausreichend hohen Reliabilität sind regelmäßige Supervision und Fortbildungen zur Kalibrierung der diagnostischen Entscheidungen zu empfehlen. Die vierte Studie schließlich befasste sich mit Möglichkeiten der Differenzierung von ASD mithilfe der Erfassung von Emotionserkennungsleistungen unter Berücksichtigung von ADHS-Symptomen. Es zeigte sich, dass komorbide ADHS-Symptome, möglicherweise vermittelt über Reaktionszeiten, bei Kindern mit ASD einen Einfluss auf die Emotionserkennungsleistung haben und dass eine Verstärkung der Defizite vor allem bei älteren Kindern zum Tragen kommt. In der Diagnostik der ASD ist daher ein besonderes Augenmerk auf komorbide ADHS-Symptome zu richten, um individuell angepasste therapeutische Interventionen einleiten zu können

Learning Disabilities

Learning disabilities are a heterogeneous group of disorders characterized by failure to acquire, retrieve, or use information competently. They are the most severe and chronic form of learning difficulty in children. They can be present at birth or acquired as a result of illness, exposure to toxins, poor nutrition, medical treatment, sociocultural deprivation, or injury. Learning problems typically consist in failure to acquire reading, writing, or math skills, which are traditionally considered core domains. This book explores the epidemiology, neurobiological bases, and diagnostic tools necessary for a comprehensive assessment of children with learning disabilities. It also presents examples of children with specific learning disabilities and explains possible intervention strategies

Functional activity in the early human brain of infants at low and high risk of atypical development

From the first cortical cell spiking at mid gestation, brain activity is responsible for myriad processes in neural development. “What fires together wires together” has nearly become the motto of those studying activity dependent brain maturation, yet the distinct spatiotemporal dynamics that regulate activity changes in early development in humans remain poorly understood. Preclinical studies have demonstrated early development specific activity patterns are disrupted in animal models for neurodevelopmental disorders; further suggesting a better understanding of activity development could also shine light on what might be driving atypical maturation in humans.Fast acquisition functional magnetic resonance imaging coupled with a neonatal dedicated imaging system now make it possible to study brain activity patterns in finer detail than ever before in a new-born baby. These tools can be used to study not only typical activity patterns, but to investigate whether activity differs in babies that have a family history of Autism or other developmental disorders. Studies in 6-month-old infants already suggest activity patterns differ between individuals with and without a family history of Autism.In this thesis, I first investigated different characteristics of functional activity development in a large cohort of term born infants with no family history of any psychiatric condition. I found that sensory regions, namely somatosensory and visual, appear more mature than other regions showing high levels of synchronous activity and higher power in faster frequency bands during the perinatal time window. Next, I compared the same functional measures in a cohort of neonates with family history of Autism and other disorders, with a cohort that had no history of such conditions. Here I found that new-borns with a family history of psychiatric conditions had distinct activity patterns in somatosensory, motor, visual and cerebellar networks. Last, I questioned whether distinct activity patterns would also be present in regions responsible for social function in new-born infants with a family history of Autism, and I found that to be the case in fusiform, parietal, cingulate and insular cortices.This thesis provides evidence of rapidly changing activity patterns in the perinatal time window and demonstrates for the first time the presence of different activity patterns in neonates at risk of atypical development. Characterization of typical and atypical activity patterns requires further work but could represent a benchmark in the identification of infants who are vulnerable to atypical development and may benefit most from early intervention