The Developmental Trajectory of Contour Integration in Autism Spectrum Disorders

Sensory input is inherently ambiguous and complex, so perception is believed to be achieved by combining incoming sensory information with prior knowledge. One model envisions the grouping of sensory features (the local dimensions of stimuli) to be the outcome of a predictive process relying on prior experience (the global dimension of stimuli) to disambiguate possible configurations those elements could take. Contour integration, the linking of aligned but separate visual elements, is one example of perceptual grouping. Kanizsa-type illusory contour (IC) stimuli have been widely used to explore contour integration processing. Consisting of two conditions which differ only in the alignment of their inducing elements, one induces the experience of a shape apparently defined by a contour and the second does not. This contour has no counterpart in actual visual space – it is the visual system that fills-in the gap between inducing elements. A well-tested electrophysiological index associated with this process (the IC-effect) provided us with a metric of the visual system’s contribution to contour integration. Using visually evoked potentials (VEP), we began by probing the limits of this metric to three manipulations of contour parameters previously shown to impact subjective experience of illusion strength. Next we detailed the developmental trajectory of contour integration processes over childhood and adolescence. Finally, because persons with autism spectrum disorders (ASDs) have demonstrated an altered balance of global and local processing, we hypothesized that contour integration may be atypical. We compared typical development to development in persons with ASDs to reveal possible mechanisms underlying this processing difference. Our manipulations resulted in no differences in the strength of the IC-effect in adults or children in either group. However, timing of the IC-effect was delayed in two instances: 1) peak latency was delayed by increasing the extent of contour to be filled-in relative to overall IC size and 2) onset latency was delayed in participants with ASDs relative to their neurotypical counterparts

Biological Role and Disease Impact of Copy Number Variation in Complex Disease

In the human genome, DNA variants give rise to a variety of complex phenotypes. Ranging from single base mutations to copy number variations (CNVs), many of these variants are neutral in selection and disease etiology, making difficult the detection of true common or rare frequency disease-causing mutations. However, allele frequency comparisons in cases, controls, and families may reveal disease associations. Single nucleotide polymorphism (SNP) arrays and exome sequencing are popular assays for genome-wide variant identification. To limit bias between samples, uniform testing is crucial, including standardized platform versions and sample processing. Bases occupy single points while copy variants occupy segments. Bases are bi-allelic while copies are multi-allelic. One genome also encodes many different cell types. In this study, we investigate how CNV impacts different cell types, including heart, brain and blood cells, all of which serve as models of complex disease. Here, we describe ParseCNV, a systematic algorithm specifically developed as a part of this project to perform more accurate disease associations using SNP arrays or exome sequencing-generated CNV calls with quality tracking of variants, contributing to each significant overlap signal. Red flags of variant quality, genomic region, and overlap profile are assessed in a continuous score and shown to correlate over 90% with independent verification methods. We compared these data with our large internal cohort of 68,000 subjects, with carefully mapped CNVs, which gave a robust rare variant frequency in unaffected populations. In these investigations, we uncovered a number of loci in which CNVs are significantly enriched in non-coding RNA (ncRNA), Online Mendelian Inheritance in Man (OMIM), and genome-wide association study (GWAS) regions, impacting complex disease. By evaluating thoroughly the variant frequencies in pediatric individuals, we subsequently compared these frequencies in geriatric individuals to gain insight of these variants\u27 impact on lifespan. Longevity-associated CNVs enriched in pediatric patients were found to aggregate in alternative splicing genes. Congenital heart disease is the most common birth defect and cause of infant mortality. When comparing congenital heart disease families, with cases and controls genotyped both on SNP arrays and exome sequencing, we uncovered significant and confident loci that provide insight into the molecular basis of disease. Neurodevelopmental disease affects the quality of life and cognitive potential of many children. In the neurodevelopmental and psychiatric diseases, CACNA, GRM, CNTN, and SLIT gene families show multiple significant signals impacting a large number of developmental and psychiatric disease traits, with the potential of informing therapeutic decision-making. Through new tool development and analysis of large disease cohorts genotyped on a variety of assays, I have uncovered an important biological role and disease impact of CNV in complex disease

Methylation Quantitative Trait Loci Associated with PTSD in a South African Population

Thesis (MSc)--Stellenbosch University, 2021.ENGLISH ABSTRACT: Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder characterised by symptoms of intrusive thoughts, avoidance behaviours, hyper-arousal and negative alterations to cognition and mood. PTSD is unique among psychiatric disorders in that it is a consequence of trauma exposure. Yet, studies previously conducted in the USA have shown that although 50-85% of individuals will encounter a traumatic event in their lifetime, the prevailing prevalence of PTSD lies approximately between 1.3 and 12.2%. This discrepancy serves to highlight the existence of factors granting individuals contingent resistance or vulnerability to the development of PTSD. While the molecular mechanisms elemental to PTSD remain largely unknown, prior heritability estimates and epigenome-wide association studies have suggested that the disorder presents both genetic and epigenetic components that mediate risk and resilience to PTSD. This study aimed to integrate genomic and epigenetic data to identify methylation quantitative trait loci (mQTLs) associated with PTSD. Variants of interest were identified through a polygenic risk score (PRS) model constructed to predict PTSD case-control status through the translation of European-derived PRS to a local South African population. The PRS model was subsequently assessed to determine whether DNA methylation variation in our sample was associated with an elevated polygenic risk burden for PTSD. Positional and dosage analysis was then conducted to investigate how any risk-conferring alleles identified were associated with specific methylated regions. PRS were constructed using data pertaining to the Psychiatric Genomic Consortium’s largest multi-ethnic genome-wide association study, but were not able to predict case-control status in a cohort of PTSD cases (n = 164) and trauma-exposed controls (n = 163) (p = 0.064). However, upon extracting the most predictive variants, the study was able to identify 44,614 mQTLs acting across 250 variants and 26,344 CpG probes. Moreover, the study identified evidence of substantial interconnectivity between the discovered mQTLs, wherein CpG sites were found to interact with a median of 2 different variants (IQR = 1 – 2) and each variant was found to interact with a median of 3 CpG probes (IQR = 1 – 10.5). Our results further support the hypothesis that the development of PTSD is dependent on an interconnected network of molecular interactions and highlight the need for future studies dedicated towards optimising PRS construction in multi-ethnic populations.AFRIKAANS OPSOMMING: Posttraumatiese stresversteuring (PTSV) is ‘n komplekse psigiatriese versteuring wat gekenmerk word deur simptome van indringende gedagtes, vermydingsgedrag, hiper-opwinding en negatiewe veranderinge aan kognisie en gemoedstoestand. PTSV is uniek onder psigiatriese versteurings omdat dit die gevolg is van blootstelling aan trauma. Tog het studies wat voorheen in die VSA gedoen is, getoon dat alhoewel 50-85% van alle individue gedurende hul leeftyd ‘n traumatiese gebeurtenis sal ervaar, die heersende voorkoms van PTSV ongeveer tussen 1.3 en 12.2% is. Hierdie teenstrydigheid beklemtoon die bestaan van faktore wat individue voorwaardelike weerstand of kwesbaarheid vir die ontwikkeling van PTSV bied. Alhoewel die molekulêre meganismes van PTSV grotendeels onbekend is, het vorige oorerflikheidsramings en epigenoom-wye assosiasie studies voorgestel dat die versteuring beide genetiese en epigenetiese komponente bevat wat die risiko en elastisiteit vir PTSV beinvloed. Hierdie studie het ten doel gehad om genomiese en epigenetiese data te integreer om die kwantitatiewe eienskap loci van metilering (mQTLs) geassosieer met PTSV te identifiseer. Variante van belang is geïdentifiseer deur middel van ‘n poligeniese risikotelling (PRT) model wat geskep is om die PTSV geval-kontrole status te voorspel deur die toepassing van Europese-afgeleide PRT na ‘n plaaslike Suid-Afrikaanse bevolking. Die PRT-model was vervolgens ondersoek om te bepaal of DNA-metilerings variasie in ons monster geassosieer is met ‘n verhoogde poligeniese risikolas vir PTSV. Posisionele- en doseringsanalises is daarna gedoen om te ondersoek hoe enige geïdentifiseerde risiko-allele geassosieer word met spesifieke gemetileerde streke. PRT is geskep met behulp van data wat verband hou met die grootste multi-etniese genome-wye assosiasie studie van die Psigiatriese Genomiese Konsortium, maar kon nie die geval-kontrole status in ‘n groep PTSV-gevalle (n = 164) en trauma-blootgestelde kontroles (n = 163) voorspel nie (p= 0.064). Na die onttrekking van die mees voorspellende variante kon die studie egter 44,614 mQTLs identifiseer wat interaksie toon met 250 variante en 26,344 CpG-posisies. Daarbenewens het die studie bewyse van aansienlike interkonnektiwiteit tussen die geïdentifiseerde mQTLs waargeneem, waarin gevind is dat CpG-posisies interaksie het met ‘n mediaan van 2 verskillende variante (IKV = 1 - 2), as ook dat elke variant interaksie het met ‘n mediaan van 3 CpG-posisies (IKV = 1 – 10.5). Ons resultate ondersteun verder die hipotese dat die ontwikkeling van PTSV afhanklik is van ‘n onderling gekoppelde netwerk van molekulêre interaksies en beklemtoon die behoefte aan toekomstige studies wat daarop gemik is om PRT-konstruksie in multi-etniese bevolkings te optimaliseer.Master

Augmentation of Brain Function: Facts, Fiction and Controversy. Volume III: From Clinical Applications to Ethical Issues and Futuristic Ideas

The final volume in this tripartite series on Brain Augmentation is entitled “From Clinical Applications to Ethical Issues and Futuristic Ideas”. Many of the articles within this volume deal with translational efforts taking the results of experiments on laboratory animals and applying them to humans. In many cases, these interventions are intended to help people with disabilities in such a way so as to either restore or extend brain function. Traditionally, therapies in brain augmentation have included electrical and pharmacological techniques. In contrast, some of the techniques discussed in this volume add specificity by targeting select neural populations. This approach opens the door to where and how to promote the best interventions. Along the way, results have empowered the medical profession by expanding their understanding of brain function. Articles in this volume relate novel clinical solutions for a host of neurological and psychiatric conditions such as stroke, Parkinson’s disease, Huntington’s disease, epilepsy, dementia, Alzheimer’s disease, autism spectrum disorders (ASD), traumatic brain injury, and disorders of consciousness. In disease, symptoms and signs denote a departure from normal function. Brain augmentation has now been used to target both the core symptoms that provide specificity in the diagnosis of a disease, as well as other constitutional symptoms that may greatly handicap the individual. The volume provides a report on the use of repetitive transcranial magnetic stimulation (rTMS) in ASD with reported improvements of core deficits (i.e., executive functions). TMS in this regard departs from the present-day trend towards symptomatic treatment that leaves unaltered the root cause of the condition. In diseases, such as schizophrenia, brain augmentation approaches hold promise to avoid lengthy pharmacological interventions that are usually riddled with side effects or those with limiting returns as in the case of Parkinson’s disease. Brain stimulation can also be used to treat auditory verbal hallucination, visuospatial (hemispatial) neglect, and pain in patients suffering from multiple sclerosis. The brain acts as a telecommunication transceiver wherein different bandwidth of frequencies (brainwave oscillations) transmit information. Their baseline levels correlate with certain behavioral states. The proper integration of brain oscillations provides for the phenomenon of binding and central coherence. Brain augmentation may foster the normalization of brain oscillations in nervous system disorders. These techniques hold the promise of being applied remotely (under the supervision of medical personnel), thus overcoming the obstacle of travel in order to obtain healthcare. At present, traditional thinking would argue the possibility of synergism among different modalities of brain augmentation as a way of increasing their overall effectiveness and improving therapeutic selectivity. Thinking outside of the box would also provide for the implementation of brain-to-brain interfaces where techniques, proper to artificial intelligence, could allow us to surpass the limits of natural selection or enable communications between several individual brains sharing memories, or even a global brain capable of self-organization. Not all brains are created equal. Brain stimulation studies suggest large individual variability in response that may affect overall recovery/treatment, or modify desired effects of a given intervention. The subject’s age, gender, hormonal levels may affect an individual’s cortical excitability. In addition, this volume discusses the role of social interactions in the operations of augmenting technologies. Finally, augmenting methods could be applied to modulate consciousness, even though its neural mechanisms are poorly understood. Finally, this volume should be taken as a debate on social, moral and ethical issues on neurotechnologies. Brain enhancement may transform the individual into someone or something else. These techniques bypass the usual routes of accommodation to environmental exigencies that exalted our personal fortitude: learning, exercising, and diet. This will allow humans to preselect desired characteristics and realize consequent rewards without having to overcome adversity through more laborious means. The concern is that humans may be playing God, and the possibility of an expanding gap in social equity where brain enhancements may be selectively available to the wealthier individuals. These issues are discussed by a number of articles in this volume. Also discussed are the relationship between the diminishment and enhancement following the application of brain-augmenting technologies, the problem of “mind control” with BMI technologies, free will the duty to use cognitive enhancers in high-responsibility professions, determining the population of people in need of brain enhancement, informed public policy, cognitive biases, and the hype caused by the development of brain- augmenting approaches

PSYCHOPATHOLOGY AND PHILOSOPHY IN RELATION TO THE EXISTENCE OF HUMAN BEING

The analysis of mental disorders necessarily requires careful and multilayered reflection. Psychiatry is indeed focused on complex phenomena and symptoms that can be only partly traced back to merely quantitative objectifiable data. This is the reason why we witness a growing methodological and conceptual \u201cmutual enlightenment\u201d between philosophy and psychiatry. Whereas philosophy offers notions that can help to take into account also the qualitative aspects and the lived experiences of pathologies, clinical psychiatry seems to represent one of the most relevant practical fields for philosophy to test its explan- atory capacity in relation to its many important issues. The history of phenomenological psychopathology, in particular, shows that philosophers have demonstrated a keen interest in the practical consequences of these issues in the field of clinical psychopathology

The anthropometric, environmental and genetic determinants of right ventricular structure and function

BACKGROUND Measures of right ventricular (RV) structure and function have significant prognostic value. The right ventricle is currently assessed by global measures, or point surrogates, which are insensitive to regional and directional changes. We aim to create a high-resolution three-dimensional RV model to improve understanding of its structural and functional determinants. These may be particularly of interest in pulmonary hypertension (PH), a condition in which RV function and outcome are strongly linked. PURPOSE To investigate the feasibility and additional benefit of applying three-dimensional phenotyping and contemporary statistical and genetic approaches to large patient populations. METHODS Healthy subjects and incident PH patients were prospectively recruited. Using a semi-automated atlas-based segmentation algorithm, 3D models characterising RV wall position and displacement were developed, validated and compared with anthropometric, physiological and genetic influences. Statistical techniques were adapted from other high-dimensional approaches to deal with the problems of multiple testing, contiguity, sparsity and computational burden. RESULTS 1527 healthy subjects successfully completed high-resolution 3D CMR and automated segmentation. Of these, 927 subjects underwent next-generation sequencing of the sarcomeric gene titin and 947 subjects completed genotyping of common variants for genome-wide association study. 405 incident PH patients were recruited, of whom 256 completed phenotyping. 3D modelling demonstrated significant reductions in sample size compared to two-dimensional approaches. 3D analysis demonstrated that RV basal-freewall function reflects global functional changes most accurately and that a similar region in PH patients provides stronger survival prediction than all anthropometric, haemodynamic and functional markers. Vascular stiffness, titin truncating variants and common variants may also contribute to changes in RV structure and function. CONCLUSIONS High-resolution phenotyping coupled with computational analysis methods can improve insights into the determinants of RV structure and function in both healthy subjects and PH patients. Large, population-based approaches offer physiological insights relevant to clinical care in selected patient groups.Open Acces