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Cantor-Graae, Elizabeth. "Neurodevelopmental aspects of schizophrenia." Lund : Dept. of Psychology, Lund University, 1995. http://catalog.hathitrust.org/api/volumes/oclc/39749040.html.
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Nalty, Theresa. "Neurodevelopmental theory of autism /." Thesis, Connect to this title online; UW restricted, 2005. http://hdl.handle.net/1773/7583.
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Wood, Graham. "Neurodevelopmental models of Schizophrenia." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18659.
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Despite the obvious problems of modeling a disorder that is characterized by deficits in higher cognitive functions in lower animals, animal models of schizophrenia have aided in the advancement of the developmental hypothesis of schizophrenia. In fact, using three different animal models of schizophrenia, two of which we developed in our laboratory, we have been able to add support to the hypothesis. First, using NCAM knockout mice, which completely lack the neurodevelopmental molecule PSA-NCAM, we established the first genetic model of schizophrenia that not only presents with sensorimotor gating deficits but ventricular enlargement, both of which have been repeatedly demonstrated in schizophrenics. Next, we used neonatal Endo-N injections to enzymatically remove PSA from NCAM to demonstrate that only a brief disruption of neurodevelopment if sufficient to cause dopaminergic hyper-responsiveness. Finally, while trying to establish a genetic marker for the strain specific vulnerability to neonatal ventral hippocampal lesions (nVH) in Fisher and Lewis rat, we in fact discovered that the vulnerability is solely due to environmental factors, namely, the frequency of arched back nursing (ABN). Then making use of the variation in ABN in Sprague Dawley rats we established a new model in which nVH lesioned rats are separated into groups raised by dams with a High or Low frequency of ABN. Using this model, we demonstrated that the early environment is leading to disruption of the medial prefrontal cortex (MPFC), as characterized by working memory deficits, lack of MPFC control of locomotion and decreased anxiety, only in nVH lesioned rats raised by High ABN dams. Furthermore, we established that the early environment is not leading to sparing of function of the VH since nVH lesioned rats raised by both High and Low ABN dams have deficits on reference memory. Therefore, we have confirmed that genetic factors can lead to deficits in neurodevelopment that cause deficits paMalgré les difficultés apparentes liées à la modélisation d'un trouble mental caractérisé par une déficience au niveau des fonctions cognitives supérieures chez les espèces inférieures, la modélisation animale de la schizophrénie a permis des avancements quant aux hypothèses proposées sur le développement de la schizophrénie. En effet, en faisant appel à trois différents modèles animaux de schizophrénie, lesquels furent conçus dans nos laboratoires, nous avons su renforcer ces hypothèses. D'abord, en utilisant des souris mutantes N-CAM, lesquelles présentaient une absence totale de molécules neurodéveloppementales PSA-N-CAM, nous avons mis au point le premier modèle de schizophrénie présentant non seulement des déficiences de filtrage sensoriel, mais aussi une hypertrophie ventriculaire, deux éléments fréquemment observés chez les schizophrènes. Ensuite, nous avons fait appel à des injections Endo-N afin de scinder enzymatiquement l'isoforme PSA de la N-CAM, dans le but de démontrer qu'une simple perturbation même très brève du développement neurologique est suffisante pour engendrer une hyperréactivité dopaminergique. Enfin, en tentant d'établir un marqueur génétique pour la souche déterminée de vulnérabilité aux lésions néonatales de l'hippocampe ventral (nVH) chez les rat Fisher et Lewis, nous avons en fait constaté que la vulnérabilité était dû strictement à des facteurs environnementaux, à savoir, la fréquence d'allaitement avec le dos arqué (ABN). En faisant appel à la variation au niveau du ABN chez des rat Sprague Dawley, nous avons pu établir un nouveau modèle dans lequel des souris furent divisées en groupes de mères faisant souvent usage ou non de l'allaitement avec le dos arqué. Par le biais de ce modèle, nous avons pu démontrer que le premier environnement peut mener à une perturbation du cortex médial préfrontal (CMPF), caractérisée par la perte de mémoire opérationnel
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Bell, Rachel Ann. "The neurodevelopmental hypothesis of schizophrenia." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312764.
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Andrew, Morag Jane. "Neurodevelopmental and visual outcomes of infants at risk of neurodevelopmental disability following dietary supplementation in infancy." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:2c4a24e3-4924-4085-bad0-fb054622cb7f.
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Background: Docosahexaenoic acid (DHA), choline and uridine-5-monophosphate (UMP) are important brain nutrients which form phosphatidylcholine, the most abundant brain membrane phospholipid. DHA, choline and UMP supplementation increases rodent brain phospholipids, synaptic components, functional brain connectivity and cognitive performance. This novel pilot study supplemented infants at risk of neurological impairment (ARNI) with a nutrient combination containing these neurotrophic compounds. Aims: 1) In a double blind randomised control trial (RCT), investigate if intake of a specific nutrient combination improves neurodevelopmental and visual outcome in infants ARNI. 2) Using novel measures of cortical visual function, investigate the effect of perinatal brain injury severity, gestational age at birth and sex upon visuocognitive development in infants at risk of neurodevelopmental impairment. Method: Recruitment was from UK neonatal units. Eligibility: ≤ 31 weeks, weight < 9th percentile; < 31 weeks with ≥ Grade II intraventricular haemorrhage (IVH) or preterm white matter injury (PWMI); 31-40 weeks with ≥ Grade II IVH or PWMI, ≥ Sarnat Grade II HIE or defined brain MRI abnormalities. Stratification was by sex, gestation and brain injury severity. Randomised infants received neurotrophic supplementation or placebo, for 2 years. Primary outcome was Bayley Scales of Infant Development III (BSID III) composite cognitive score (CCS) after 2 years. Secondary outcomes included BSID III composite language score (CLS) and BSID III composite motor score (CMS). Cortical visual measures were pattern reversal visual event related potential (PR-VERP) latency (transient and calculated), orientation reversal visual event related potentials (OR-VERP), and the Fixation Shift test (FS). Functional behavioural vision was assessed using the Atkinson Battery of Child Development for Examining Functional Vision (ABCDEFV). Local Ethics Committee approval was granted. Results: 62 neonates were recruited. After 2 years, mean CCS in the intervention group was 87.7 (SD 20.4) and 81.6 (SD 18.5) in the placebo group (mean difference = 2.28, p=0.13; -0.2, 18.2). Mean CLS in the intervention group was 91.5 (SD 20.1) and 83.2 (SD 19.6) in the placebo group (mean difference = 2.74, p=0.1; -2.4, 18.3). CMS was similar in both groups. In relation to trial visual outcome measures, more infants in the placebo group gave a statistically significant OR-VERP response than in the intervention group (p=0.03). There were no statistically significant differences between the placebo and intervention on any other trial visual outcome measure. Cohort analyses indicate that transient PR-VERP latency is prolonged in children at risk of neurodevelopmental disability compared to typically developing infants (mean difference = -23.3, p=0.015, 95% CI -42.10 - -4.54). Calculated PR-VERP latency is prolonged to an even greater extent in children at risk of neurodevelopmental disability compared to typically developing infants (mean difference -148.6, p=0.000, 95% CI -179.7- -117.43), and remains prolonged across the age range tested. Conclusions: 1) The difference in CCS and CLS between intervention and placebo groups represents a clinically significant effect size. Use of neurotrophic micronutrient supplementation in infants ARNI warrants exploration in a large multicentre RCT. 2) Calculated PR-VERP latency may be a more appropriate outcome measure of cortical visual function than transient PR-VERP latency in infants at risk of neurodevelopmental disability.
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Golbano, Rodríguez Arantxa. "Neurodevelopmental alterations in X-linked adrenoleukodystrophy." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669358.
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La adrenoleucodistrofia ligada al cromosoma X (X-ALD, de sus siglas en inglés) es una enfermedad rara causada por mutaciones en el transportador peroxisomal ABCD1, presentando dos formas de manifestación clínica de neurodegeneración: demielinización aguda y letal en el cerebro de niños con la forma cerebral de X-ALD (CCALD), y degeneración crónica de los tractos de la médula espinal y neuropatía periférica en adultos con adrenomielopatía (AMN). Las alteraciones psiquiátricas son un signo temprano de CCALD y coexisten con la neurodegeneración periférica de la médula espinal en AMN, poniendo de manifiesto la patología cerebral. Teniendo en cuenta que la X-ALD es una condición genética quisimos determinar si las alteraciones psiquiátricas observadas pueden ser debidas, al menos en parte, a la formación aberrante de circuitos cerebrales durante el desarrollo y no a la neurodegeneración. Con este objetivo, usamos una aproximación de arriba hacia abajo, partiendo de datos de transcriptomas de pacientes, donde hemos buscado vías de neurodesarrollo desreguladas, hasta modelos murinos de X-ALD in vitro basados en el silenciamiento de los genes Abcd1 y Abcd2 para diseccionar la compartimentalización entre neuronas y astrocitos. Se presentan cuatro resultados principales. Primero, existen vías de neurodesarrollo desreguladas en CCALD, AMN y en los cultivos neuronales deficientes en ABCD, asociado con alteración en los procesos de neuritogénesis, espinogénesis, y axonogénesis. Segundo, un crecimiento aberrante de las espinas sinápticas es en parte debido a alteraciones en la vía canoníca de señalización Wnt puesto que la espinogénesis se recupera parcialmente mediante la activación de la vía de señalización Wnt tras la inhibición farmacológica de GSK-3. Tercero, la síntesis de colesterol y la localización del mismo se encuentran cambiadas en los astrocitos deficientes en ABCD. Cuarto, el silenciamiento de los transportadores ABCD causa alteraciones metabólicas en astrocitos incluyendo disminución de la oxidación de ácidos grasos, incremento del ratio NAD+/NADH, depleción de ATP, y disminución de la cantidad total de glutatión sugiriendo el deterioro conjunto de la defensa antioxidante y la bioenergética. Quinto, los astrocitos X-ALD presentan una señalización de calcio mediada por agonistas alterada y estrés del retículo endoplamático. Concluimos que i) la X-ALD presenta un componente de neurodesarrollo que puede explicar los síntomas psiquiátricos, y quizá contribuir a la progresión de la forma CCALD, y a la conversión de la AMN en una forma cerebral de la enfermedad, y ii) la deregulacion metabólica y de la excitabilidad en astrocitos apoya la disfunción global de los astrocitos que puede poner en peligro el papel computacional y homeostático de los astrocitos en los circuitos cerebrales.X-linked adrenoleukodystrophy (X-ALD) is a rare disease caused by mutations in the peroxisomal ABCD1 transporter, with two major clinical manifestations of neurodegeneration: acute and lethal brain demyelination in the child cerebral X-ALD (CCALD), and chronic degeneration of spinal-cord tracts and peripheral neuropathy in the adult adrenomyeloneuropathy (AMN). Psychiatric alterations are an early sign of CCALD and coexist with spinal-cord and peripheral neurodegeneration in AMN, revealing concomitant brain pathology. Since X-ALD is a genetic condition, we sought to determine whether psychiatric alterations could be due, at least in part, to abnormal formation of brain circuits during brain development and not to neurodegeneration. To this end, we used a top-down approach, moving from patient transcriptome data, where we searched for dysregulated neurodevelopmental pathways, to in vitro murine models of X-ALD based on Abcd1/Abcd2 silencing to dissect out astrocyte versus neurons compartmentalization. There are four major findings. First, developmental pathways are dysregulated in CCALD, CAMN and in ABCD-null neuronal cultures, associated with altered neuritogenesis, spinogenesis, and axonogenesis. Second, aberrant spine growth is in part due to alterations in canonical Wnt signalling alteration since the spinogenesis is partially rescued by activation of WNT pathways by pharmacological GSK-3 inhibition. Third, cholesterol synthesis and localization is changed in ABCD-null astrocytes. Four, silencing of ABCD transporters causes metabolic alterations in astrocytes including fatty acid oxidation impairment, increase of the ratio NAD+/NADH, ATP depletion, decreases in total glutathione, suggesting joint impairment of antioxidant defense and bioenergetics. Fifth, X-ALD astrocytes present altered agonist-induced calcium signaling and ER stress. We conclude that i) X-ALD has a neurodevelopmental component that may account for psychiatric symptoms, and perhaps contribute to the progression of CCALD, and to the conversion of AMN into a cerebral condition, and ii) metabolic and excitability dysregulation in astrocytes support global astrocytic dysfunction that may jeopardize computational and homeostatic role of astrocytes in neural circuits.
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Suades, González Elisabet 1981. "Socio-environmental exposures and neurodevelopmental disorders." Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/664809.
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Introduction
The influence of the environment, and its interplay with genetics, can account for up to half of the variance of neurodevelopmental disorders. In this thesis we reviewed previous literature on air pollution and neuropsychological development. We studied the trajectories of attention development in children. Finally, we explored any association between socio-environmental factors and warning signs of dyslexia and ADHD (attention deficit hyperactivity disorder) symptoms.
Methods
This thesis is part of the BREATHE (BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn) and the INMA (INfancia y Medio Ambiente) projects.
Results
(1) We encountered sufficient evidence for an association between outdoor air pollution and a negative impact on the neuropsychological development of children. (2) We detected an ongoing development of some attention processes in primary school children, differentiating patterns by gender and ADHD symptoms. (3) Daily levels of traffic-related ambient air pollution were associated with daily variations in attention processes in primary school children. (4) Prenatal, and at some extent postnatal, exposure to NO2 at the residence address increased the risk of presenting signs of dyslexia in primary school children. (5) Within a total of 23 socio-environmental factors, only male gender, younger relative age, psychosocial adversity, smoking and prenatal exposure to alcohol associated with ADHD symptoms at preschool age using a novel method for handling correlated data.
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Conclusions
Traffic-related air pollution, smoking, alcohol, gender, relative age and psychosocial adversity were identified as important determinants of neurodevelopmental disorders.Introducció La influència del medi ambient, i la seva interacció amb la genètica, pot explicar fins a la meitat de la variància dels trastorns del neurodesenvolupament. En aquesta tesi s’ha fet una revisió sobre la contaminació atmosfèrica i el desenvolupament neuropsicològic. S’han estudiat les trajectòries del desenvolupament de l'atenció en nens/es. Finalment, s’ha explorat l’associació entre factors socioambientals i indicadors d’alt risc de dislèxia i símptomes de TDAH (trastorn per dèficit d’atenció i hiperactivitat). Mètodes Aquesta tesi forma part dels projectes BREATHE (BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn) i INMA (INfància i Medi Ambient). Resultats (1) Hem trobat suficient evidència d’una associació entre la contaminació atmosfèrica i un impacte negatiu en el desenvolupament neuropsicològic dels nens/es. (2) Hem detectat trajectòries del desenvolupament de l’atenció en nens/es de primària, diferenciant patrons per gènere i símptomes de TDAH. (3) Els nivells diaris de contaminació atmosfèrica relacionada amb el trànsit es van associar amb variacions diàries en els processos atencionals en nens/es de primària. (4) L'exposició prenatal, i en certa mesura la postnatal, a la contaminació atmosfèrica relacionada amb el trànsit va augmentar el risc de presentar indicadors de dislèxia en els nens/es d'educació primària. (5) D’entre un total de 23 factors socio ambientals, només el gènere masculí, menys edat relativa (els nens/es més petits de la classe), l'adversitat psicosocial, el tabaquisme i l'exposició prenatal a l’alcohol es van associar amb símptomes de TDAH a l'edat preescolar utilitzant un mètode novedós per analitzar dades correlacionades. xii Conclusions La contaminació atmosfèrica relacionada amb el trànsit, el tabaquisme, l'alcohol, el gènere, l’edat relativa i l'adversitat psicosocial es van identificar com a determinants importants dels trastorns del neurodesenvolupament.
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Feron, Franciscus Joseph Maria. "Studies on neurodevelopmental issues in children." [Maastricht : Maastricht : Universiteit Maastricht ] ; University Library, Universiteit Maastricht [host], 2007. http://arno.unimaas.nl/show.cgi?fid=8301.
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Yu, Ka-ki Kevin, and 余嘉棋. "Neuroimaging meta-analysis in neurodevelopmental disorders." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47753171.
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Background and Objectives: ‘Neurodevelopmental disorders’ is often synonymously used with childhood developmental disorders such as autism spectrum disorder (ASD), however, increasingly new lines of evidence from genetics and epidemiology suggests having schizophrenia and bipolar disorder to be included as well. For example, there is a strong tendency for schizophrenia and bipolar disorder to occur in people with ASD and shared aetiological factors such as prenatal infection and maternal vitamin D deficiency during pregnancy have all been linked with increased risks in all three conditions. To investigate into this, I have turned to brain imaging, a technique which has opened up a new horizon for neurobiologists. Typically, neuroimaging studies focus on one disorder, matching patients with healthy volunteers and compare their brain structures volumetric differences. On the other hand, such studies are limited by various factors including small ample size, low power, no psychiatric control group, and sample or design heterogeneity.
Methods: To summarize all the data into a more meaningful biological representation, Anatomical Likelihood Estimation (ALE), a cutting edge meta-analytic approach was applied. The rationale behind ALE is that it identifies brain differences most consistently reported across studies, while filtering away differences that are least documented. In this thesis, a novel application of ALE known as “dual disorder ALE” is introduced, which serves to estimate the extent of brain regional differences implicated in either disorder – in other words, a method to quantify which areas of the brain are more likely to be affected by ASD, schizophrenia or bipolar disorder.
Findings: The analysis is separated into two parts. First, dual disorder ALE technique was applied to investigate the relationship between ASD and first-episode schizophrenia. Data from 25 MRI studies was extracted comprising 660 participants (308 ASD, 352 schizophrenia) and 801 healthy controls. In ASD and FE schizophrenia, there were similar brain differences near the limbic-striato-thalamic circuitry, and distinctive brain differences including amygdala, caudate, frontal and medial gyrus for schizophrenia and putamen for ASD. In the second part comparing bipolar disorder and schizophrenia, data from 651 schizophrenic patients, 540 bipolar patients, and 1438 healthy controls was used, and matched one-to-one by pairing up bipolar disorder studies with corresponding schizophrenia studies to minimize confounders. The ALE result indicated that there are substantial overlaps across the two disorders, with schizophrenia having more extensive brain differences than bipolar disorder.
Conclusions: Both parts of the analysis suggest that there are similar aetiological pressures affecting neurodevelopmental disorders including ASD, schizophrenia and bipolar disorder.published_or_final_version
Psychiatry
Master
Master of Philosophy
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McConnell, B. A. "Neurodevelopmental outcome and prenatal Doppler performance." Thesis, Queen's University Belfast, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390885.
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Trickett, Jayne K. "Sleep in children with neurodevelopmental disorders." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8328/.
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Profiles of sleep disturbance and sleep quality of children with the specific neurodevelopmental disorders of Smith-Magenis syndrome (SMS), Angelman syndrome (AS), autism spectrum disorder (ASD) and tuberous sclerosis complex (TSC) and the relationships between behavioural and health characteristics, age and sleep were described in these groups. Interview data demonstrated that children with AS's sleep disturbance had a negative impact on both parents and children. A homogeneous sleep disturbance profile of severe night waking and early morning waking affected over 70% of children with SMS but more heterogeneous profiles were found for children with AS, TSC and ASD using cross-group questionnaire data comparisons and when compared to typically developing (TD) children. A heightened risk of sleep-related breathing disorders was identified for children with AS and SMS. Compared to TD children, children with SMS had significantly earlier morning wake times and children with AS and SMS had significantly earlier bedtimes according to actigraphy and sleep diary data. Increased daytime sleepiness in children with SMS was associated with increased overactivity and impulsivity. This thesis includes the largest samples of actigraphy data for children with SMS and AS to date. The importance of aetiology of intellectual disability in the profiling of sleep disturbance was evidenced. Areas for further assessment and intervention include sleep-related breathing disorders for children with AS and SMS and individualized assessment of circadian rhythm disorders for both groups.
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Halvardson, Jonatan. "Sequence based analysis of neurodevelopmental disorders." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-287407.
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In this thesis the main focus is the use of methods and applications of next generation sequencing in order to study three of the most common neurodevelopmental disorders: intellectual disability, epilepsy and schizophrenia. A large fraction of the genes in our genome produce several distinct transcript isoforms through the process of splicing and there is an increasing amount of evidence pinpointing mutations affecting splicing as a mechanism of disease. In Paper I we used exome capture of RNA in combination with sequencing in order to enrich for coding sequences. We show that this approach enables us to detect lowly expressed transcript and splice events that would have been missed in regular RNA sequencing using the same coverage. In Paper II we selectively depleted the different transcripts of Quaking (QKI), a gene previously associated to schizophrenia. Using RNA sequencing we show that the effects of depletion differ between transcripts and that the QKI gene is a potential regulator of the Glial Fibrillary Acidic Protein (GFAP), a gene implicated in several diseases in the central nervous system. De-novo mutations are frequently reported to be causative in neurodevelopmental disorders with a strong genetic component, such as epilepsy and intellectual disability. In Paper III we used exome sequencing in family trios where the child was diagnosed with both intellectual disability and epilepsy, focusing on finding de-novo mutations. We identified several previously unknown disease causing mutations in genes previously known to cause disease and used previously published interaction and mutation data to prioritize novel candidate genes. The most interesting result from this study are the implication of the HECW2 gene as a candidate gene in intellectual disability and epilepsy. In Paper IV we used RNA sequencing of post mortem brain tissue in a large cohort of schizophrenics and controls. In this study we could show that the immune system and more specifically the complement system was dysregulated in a large fraction of patients. Further, using co-expression network we also found some evidence suggesting genes involved in axon development and maintenance.
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Marriott, Elise. "Parents with neurodevelopmental disorders and their children." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:c5db001c-26df-4c3a-afc3-96c572050c1a.
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Adults with neurodevelopmental disorders, such as Attention-Deficit Hyperactivity Disorder (ADHD) or Autism Spectrum Disorder (ASD) face a varying degree of associated challenges and impairment. However, there is a scarcity of literature regarding those adults who go on to become parents. Understanding the experiences of parents with neurodevelopmental disorders and their children is vital in providing the appropriate, specialist support. The first paper systematically reviewed the literature relating to parental ADHD and child externalising, internalising, social and cognitive outcomes. Despite the well-established link between parental ADHD and child ADHD, little is known about other important child outcomes. Twenty-one eligible studies were identified, synthesised and critiqued. The review found that parental ADHD was associated with child externalising problems. However, this was not found for child oppositional defiance disorder. Parenting and parental gender were highlighted as important moderating and mediating factors. Due to low study numbers and quality issues, results were inconclusive regarding child internalising, social and cognitive outcomes. The review highlighted the importance of future research, theory and services addressing the needs of both parents with ADHD and their children. The second paper sought to explore the parenting experiences of adults with ASD who have children with ASD. Little is known about these parents, despite the challenges known to be associated with adult ASD and with parenting a child with ASD. Eight parents were interviewed, and data was analysed using Interpretative Phenomenological Analysis, revealing four superordinate themes. These captured parents' experiences of the parent-child relationship, the personal impact of parenting, the acceptance and challenge of living with a child with ASD and managing the complexities of professional services. These findings highlighted the need to provide integrated services which address the multiple needs of families with ASD. Future research and theoretical implications were also considered.
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Mattan, Natalia Soledad. "Genetic and environmental factors and neurodevelopmental disease." Diss., Restricted to subscribing institutions, 2009. http://proquest.umi.com/pqdweb?did=1905048731&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Vrcelj, Katarina. "Genotype and phenotype relationships in neurodevelopmental disorders." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:a7a9d22c-c92d-4078-9065-b9a9275c49a9.
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NeuroDevelopmental Disorders (NDDs) are a group of heterogeneous neuropsychiatric conditions, encompassing Developmental Delay (DD), Intellectual Disability (ID), Autism Spectrum Disorder (ASD) and Gilles de la Tourette Syndrome (GTS). NDDs often involve a life-long need of supportive services and represent a major economic and societal burden in Europe and the United States. Hitherto, no safe and effective treatment strategies are available, underpinning the urgency of deciphering their elusive aetiology. NDDs have a strong genetic component. Accordingly, the mechanistic understanding of disease involves (1) the description of mutational landscapes, (2) the molecular and cellular of characterisation of genetic variants and (3) their integration at circuit and system levels. In this thesis, we tackled these theoretical underpinnings to provide insights into the genetics of NDDs and the onset of associated clinical abnormalities. Firstly, aiming to shape the genetic architecture of GTS, a condition characterised by the presence of motor and vocal tics, we undertook a whole-genome CNV study of a cohort of Danish GTS cases and healthy controls. Using statistical and functional genomics approaches, we proposed novel potential candidate genes and implicated the disruption of early neurodevelopmental and late synaptic processes in the aetiology of GTS. Secondly, to elucidate the vast phenotypic heterogeneity of NDDs, we conducted a systematic investigation of genotype and phenotype relationships in DD, ID and ASD. Taking advantage of extensive phenotypic and genetic data available for DD/ID and ASD patients, we grouped individuals based on their functional rare CNV and gene disruptions but did not to identify distinguishing clinical archetypes. Instead, we showed converging molecular perturbations underlie the onset of globally more similar clinical presentations and investigated the role of common variants in modulating their expressivity. Lastly, we established the relevance of mouse models in the study of human disease. By applying comprehensive genomics approaches to over 1,000 mouse neuroanatomical knockouts, we implicated early neurodevelopmental and adult synaptic processes in the aetiology of ID and brain malformations. Furthermore, we showed that functionally converging genetic disturbances translate at the phenotypic level and proposed novel candidate ID genes.
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Bothma, Jó-Marié van der Merwe. "A neurodevelopmental movement programme for 4-8 year old hearing impaired children in the rural QwaQwa region of South Africa / Jó-Marié van der Merwe Bothma." Thesis, North-West University, 2012. http://hdl.handle.net/10394/9721.
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Being hearing impaired does not only affect a child’s academic performance, but can also influence a child’s overall development and ability to succeed academically. Evidence suggests that the outlay in early childhood has a large impact on a child’s readiness to learn. Neurodevelopmental movement programmes are generally not accepted as evidenced-based practice and their effect on academic performance is often underrated. Movement, however, is regarded by many as essential to learning and there seems to be a positive interchange between the brain and the body.
This study reports on the influence of a neurodevelopmental movement programme on the development, behaviour and performance on a neurodevelopmental evaluation scale of four to eight year-old children with hearing impairment children. The study furthermore provides a report of the results of the psychometric assessment in the form of a neurodevelopmental profile for this specific sample. Children were selected from a special needs school in the rural QwaQwa Free State area of South Africa. Two groups of children (an experimental and comparison group) were used in this study, with both groups undergoing a pretest and posttest phase using three test batteries (Griffiths Mental Developmental Scales- Extended Revised, Child Behaviour Checklist, and a neurodevelopmental evaluation scale). The experimental group was subjected to a fourteen-week neurodevelopmental movement programme. The comparison group underwent a placebo intervention. The results indicate that the children in the experimental group showed an improvement in some aspects of specific development following the intervention (locomotor functioning, performance related abilities, and practical reasoning skills). General developmental age showed significant improvement in both the experimental group and the comparison group. No behavioural aspects showed significant improvements following the intervention, whereas some neurodevelopmental aspects, such as the vestibular system (Tandem Walk and One Leg Stand) and the reflex system (TLR – reflex) showed significant improvements. The results of this empirical investigation aid in understanding the impact of movement programmes on a child with hearing disability’s general development and neurodevelopmental development.Thesis (PhD (Psychology))--North-West University, Potchefstroom Campus, 2013.
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Latal, Hajnal Beatrix. "Prediction of neurodevelopmental outcome after neonatal brain injury /." Zürich, 2006. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253353.
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López, Sánchez Marcos 1986. "Contribution of unexplored genomic variations to neurodevelopmental disorders." Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/663913.
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Neurodevelopmental disorders are a group of conditions with impairments of the personal, social, academic or occupational behaviour. Autism spectrum disorder is a neurodevelopmental disorder with a high genetic component with a large fraction still unknown. In this dissertation we analyse two unexplored genomic variants: Chromosomal mosaicism and Ancestral polymorphic inversions. Chromosomal mosaic events are responsible for a small but significant proportion of patients with ASD (0.45%), with the additional detection of two loss of chromosome Y events. In addition, we developed a bioinformatic tool that improves previous methods to detect loss of chromosome Y: MADloy. In the study of ancestral polymorphic inversions, inv8p23.1 and inv17q21.31 inversions were associated with autism risk. Improvements on the method to genotype ancestral polymorphic inversions allowed the prediction of a novel inversion in 22q11.21 region which has been validated by fiber-FISH.Els trastorns del neurodesenvolupament son un grup de condicions amb discapacitats conductuals en els àmbits personals, socials, acadèmics o ocupacionals. Els trastorns d’espectre autista són un trastorn del neurodesenvolupament amb una gran component genètica, part de la qual encara es desconeguda. En aquest treball analitzem dues variants genòmiques poc explorades: els reordenaments cromosòmics en mosaic I les inversions ancestrals polimòrfiques. Els reordenaments cromosòmics en Mosaic son responsables d’una significant però petita proporció dels pacients amb trastorn d’espectre autista (0.45%), amb la detecció addicional de dues pèrdues del cromosoma Y. Addicionalment, s’ha desenvolupat una eina bioinformàtica que millora els mètodes previs per detectar la pèrdua de cromosoma Y: MADloy. En l’estudi de les inversions ancestrals polimòrfiques, les inversions inv8p23.1 i inv17q21.31 s’han associat amb el risc d’autisme. Millores en el mètode de genotipació de les inversions ha permès la predicció de una nova inversió localitzada a la regió 22q11.21 que s’ha validat per fiber-FISH.
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Nakubulwa, Mable. "Developing multidimensional metrics for evaluating paediatric neurodevelopmental disorders." Thesis, Aston University, 2016. http://publications.aston.ac.uk/28813/.
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Healthy brain functioning depends on efficient communication of information between brain regions, forming complex networks. By quantifying synchronisation between brain regions, a functionally connected brain network can be articulated. In neurodevelopmental disorders, where diagnosis is based on measures of behaviour and tasks, a measure of the underlying biological mechanisms holds promise as a potential clinical tool. Graph theory provides a tool for investigating the neural correlates of neuropsychiatric disorders, where there is disruption of efficient communication within and between brain networks. This research aimed to use recent conceptualisation of graph theory, along with measures of behaviour and cognitive functioning, to increase understanding of the neurobiological risk factors of atypical development. Using magnetoencephalography to investigate frequency-specific temporal dynamics at rest, the research aimed to identify potential biological markers derived from sensor-level whole-brain functional connectivity. Whilst graph theory has proved valuable for insight into network efficiency, its application is hampered by two limitations. First, its measures have hardly been validated in MEG studies, and second, graph measures have been shown to depend on methodological assumptions that restrict direct network comparisons. The first experimental study (Chapter 3) addressed the first limitation by examining the reproducibility of graph-based functional connectivity and network parameters in healthy adult volunteers. Subsequent chapters addressed the second limitation through adapted minimum spanning tree (a network analysis approach that allows for unbiased group comparisons) along with graph network tools that had been shown in Chapter 3 to be highly reproducible. Network topologies were modelled in healthy development (Chapter 4), and atypical neurodevelopment (Chapters 5 and 6). The results provided support to the proposition that measures of network organisation, derived from sensor-space MEG data, offer insights helping to unravel the biological basis of typical brain maturation and neurodevelopmental conditions, with the possibility of future clinical utility.
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Chen, Wenxiong. "Neonatal hyperbilirubinemia long-term neurophysiological and neurodevelopmental outcomes /." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37489380.
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Chen, Wenxiong, and 陈文雄. "Neonatal hyperbilirubinemia: long-term neurophysiological and neurodevelopmental outcomes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37489380.
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Wolfe, K. A. "Copy number variation in co-morbid neurodevelopmental disorders." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10047506/.
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Copy number variants (CNVs) have been implicated in the pathogenesis of clinically distinct neurodevelopmental disorders (NDDs), indicating common underlying pathophysiology. Yet, the frequency, genetic architecture, and phenotypic role of pathogenic CNVs in adults with co-morbid neurodevelopmental phenotypes has not yet been systematically investigated. Adults with intellectual disability (ID) and psychiatric co-morbidities were recruited from ID psychiatry services across the UK (N=202). Using a genotype-first approach, chromosomal microarray analysis (CMA) was undertaken, and variants were categorised using the NHS regional genetics service (RGCs) clinical pipeline. Genetic and phenotypic data was combined with two independent samples to enable frequency analyses (N=599). Targeted recruitment of individuals with 2q13 CNVs was undertaken via a patient support group, RGCs and the online rare CNV database DECIPHER (N=25). The frequency of pathogenic CNVs was 11%, rising to 13% in the replication cohort. Both novel and recurrent loci were found to harbour pathogenic CNVs, with 70% at established NDD risk loci. A significantly higher population frequency of CNVs was identified in NDD risk regions (10%), compared with schizophrenia (3.1%, p < 0.0001) and ID/autism spectrum disorder (6.5%, p < 0.0008) populations. Phenotypic characterisation of CNVs at the 2q13 region suggests an early-onset neuropsychiatric phenotype with a high incidence of attention deficit hyperactivity disorder (ADHD) and challenging behaviours. There is a high yield of pathogenic CNVs in patients with co-morbid neurodevelopmental phenotypes. In the main part, distinct loci are not involved in co-morbid NDD risk, but risk arises from the same loci identified in single disorder cohorts. Detailed phenotypic investigation of the 2q13 locus indicates that pleiotropy exists, however there is a preferential psychiatric outcome – in this instance ADHD. Understanding the factors which modulate a CNV region with a high general risk for NDDs to a preferential neuropathological pathway will be key to understanding the complex hierarchy of psychiatric nosology and developing successful therapeutic interventions.
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Kurian, Manju Ann. "Molecular genetic investigation of autosomal recessive neurodevelopmental disorders." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1126/.
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Development of the human brain occurs in a number of complex pre- and postnatal stages which are governed by both genetic and environmental factors. Aberrant brain development due to inherited defects may result in a wide spectrum of neurological disorders which are commonly encountered in the clinical field of paediatric neurology. In the work for this thesis, I have investigated the molecular basis and defined the clinical features of three autosomal recessive neurological syndromes. I studied a cohort of children with early onset epileptic encephalopathy and, in one family, identified a novel homozygous pathogenic mutation of PLCB1. I have also utilised autozygosity mapping techniques to study consanguineous families with a complex motor disorder, infantile parkinsonism-dystonia, and identified loss-of function mutations in the gene encoding the dopamine transporter (SLC6A3). Subsequent acquisition of a cohort of similarly affected children allowed detailed clinical and molecular characterisation of this novel disorder, dopamine transporter deficiency syndrome. Finally I have delineated the clinical and genetic features of PLA2G6-associated neurodegeneration. The identification of disease-causing genes contributes greatly to understanding the disease mechanisms underlying such early-onset disorders, and also provides novel insights into normal human neurodevelopment.
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Bokobza, Cindy. "Neurodevelopmental impact of perinatal inflammation : targets for neuroprotection?" Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7082.
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Le consensus général concernant les troubles neuro-développementaux, notamment les troubles du spectre autistique (TSA), est qu’ils proviennent de défauts de développement précoces dans la formation du cerveau. Ceci entraînant une modification des circuits neuronaux responsables du comportement pathologique. La prématurité est souvent liée à la survenue d'une inflammation et les nouveau-nés prématurés courent un risque dix fois plus élevé de développer des symptômes analogues aux TSA que les nourrissons nés à terme. De plus, des études cliniques ont démontré des processus neuro-inflammatoires dans différentes régions du cerveau chez les enfants autistes nés à terme : dans le cortex frontal, l'hippocampe et le cervelet. Le principal relais de la réponse environnementale dans le cerveau, y compris les réactions inflammatoires, sont les cellules microgliales, macrophages résidents du cerveau qui surveillent en permanence leur environnement. De plus, au cours du développement, la microglie joue un rôle crucial lors de l’élagage synaptique et de la myélinisation menant à la formation d'un cerveau mature. Dans un contexte inflammatoire, la microglie est activée et participe à la libération locale de cytokines pro-inflammatoires. Notre hypothèse est donc qu’une exposition à l'inflammation périnatale aurait un impact sur les anomalies du développement neurologique conduisant à un TSA. En utilisant un modèle murin d’inflammation périnatale induite par une injection d’IL-1? entre le jour postnatal (P)1-5, ce projet démontre (i) qu’il existe une inflammation région-spécifique et du lien entre l’inflammation périnatale et l’apparition de phénotypes de type autistiques à différents stades du développement ; et (ii) nous avons réussi à identifier deux nouvelles cibles potentielles pour limiter les anomalies du développement neurologique : les microARNs et le récepteur 5HT-7. Ce projet innovant a pour objectif d'identifier des marqueurs de diagnostic potentiels facilitant la détection précoce des TSA chez les prématurés sur la base d'indicateurs inflammatoires et de nouvelles cibles thérapeutiques pour la neuroprotectionA general consensus regarding neurodevelopmental disorders including Autism Spectrum Disorder (ASD) is that they originate from early development defects in brain formation, leading to altered neuronal circuitry responsible for the pathological behavior. Preterm birth is often linked to the occurrence of inflammation and preterm infants have a ten times higher risk of developing ADS-like symptoms than infants born at term. Moreover, some clinical studies reported ongoing neuroinflammation processes in different brain regions in autistic infants including frontal cortex, hippocampus and cerebellum. The major relay of the environmental response in the brain, including inflammatory responses, is microglia cells, the brain resident macrophages that continuously survey their local environment. Moreover, during development microglia play a critical role during the synaptic pruning and myelination to contribute to the formation of a mature brain. In an inflammatory context, MG are activated and participated to the local release of pro-inflammatory cytokines. Our hypothesis is, therefore, that an exposition to perinatal inflammation impacts on neurodevelopmental defects leading to ASD. Using a mouse model of perinatal inflammation induced by IL-1? injection between post-natal day (P)1-5, this project demonstrates that i) there is region specific inflammation and an impact of perinatal inflammation on the onset of ASD-like phenotypes at different developmental stages in mice and (ii) we successfully identify two new potential targets to limit neurodevelopmental defects: microRNAs and the 5HT-7 receptors. This innovative project has as objective to identify potential diagnosis markers to facilitate an early detection of ASD in premature infants based on inflammatory indicators and new therapeutic targets for neuroprotection
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Steinberg, Julia. "Functional genomics analyses of neuropsychiatric and neurodevelopmental disorders." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:e47d1ac2-de92-47d8-864b-dac0bf6669e8.
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Recent large-scale genome-wide studies for many human disorders have identified associations with numerous genetic variants. The biological interpretation of these variants presents a major challenge. In particular, the identification of biological pathways underlying the association could provide crucial insights into the disease aetiologies. In this thesis, I used functional genomics approaches to increase our understanding of neuropsychiatric and neurodevelopmental disorders. Firstly, in an integrative analysis of autism spectrum disorder (ASD), I looked into the role of genes targeted by Fragile-X Mental Retardation Protein ("FMRP targets"). I found evidence that FMRP targets contribute to ASD via two distinct aetiologies: (1) ultra-rare and highly penetrant single disruptions of embryonically upregulated FMRP targets ("single-hit aetiology") or (2) the combination of multiple less penetrant disruptions of synaptic FMRP targets ("multiple-hit aetiology"). In particular, I developed a pathway-association test sensitive to multiple-hit aetiologies. Secondly, I carried out an integrative analysis of bipolar disorder, following up a previously identified association with long-term potentiation. The association was not consistent across independent SNP and CNV datasets. Thirdly, I addressed the difficulty in identifying functional relationships between genes by integrating different datasets into a gene functional-linkage network tuned to the nervous system ("NsNet"). NsNet identified functional links between the genes disrupted by de novo loss-of-function mutations in ASD and, separately, in schizophrenia probands more sensitively than a general functional-linkage network. Fourthly, I considered the challenge of interpreting the phenotypic impact of gene disruptions, focusing on the identification of haploinsufficient genes. I constructed a gene haploinsufficiency score based on genome-wide datasets. Compared to existing approaches, the new score performed better in identifying less-studied haploinsufficient genes. This work both extends the methodology to detect the contribution of genetic variation to neuropsychiatric disorders and also yields insights into the variant genes and the pathways that underlie them. Firstly, in an integrative analysis of autism spectrum disorder (ASD), I looked into the role of genes targeted by Fragile-X Mental Retardation Protein ("FMRP targets"). I found evidence that FMRP targets contribute to ASD via two distinct aetiologies: (1) ultra-rare and highly penetrant single disruptions of embryonically upregulated FMRP targets ("single-hit aetiology") or (2) the combination of multiple less penetrant disruptions of synaptic FMRP targets ("multiple-hit aetiology"). In particular, I developed a pathway-association test sensitive to multiple-hit aetiologies. Secondly, I carried out an integrative analysis of bipolar disorder, following up a previously identified association with long-term potentiation. The association was not consistent across independent SNP and CNV datasets. Thirdly, I addressed the difficulty in identifying functional relationships between genes by integrating different datasets into a gene functional-linkage network tuned to the nervous system ("NsNet"). NsNet identified functional links between the genes disrupted by de novo loss-of-function mutations in ASD and, separately, in schizophrenia probands more sensitively than a general functional-linkage network. Fourthly, I considered the challenge of interpreting the phenotypic impact of gene disruptions, focusing on the identification of haploinsufficient genes. I constructed a gene haploinsufficiency score based on genome-wide datasets. Compared to existing approaches, the new score performed better in identifying less-studied haploinsufficient genes. This work both extends the methodology to detect the contribution of genetic variation to neuropsychiatric disorders and also yields insights into the variant genes and the pathways that underlie them.
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Doser, Rachel Lynne, and Rachel Lynne Doser. "The Altered Roles of Glia in Neurodevelopmental Disorders." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/624962.
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For many decades in neuroscience, glial cells were thought almost exclusively to provide
passive, primarily metabolic, support for the billions of neurons in our central nervous system
(CNS). Today, however, the three types of CNS glial cells, astrocytes, oligodendrocytes, and
microglia, are known to play a myriad of active roles that are necessary for normal
neurodevelopment. Astrocytes have been found to regulate neurogenesis, support neuronal
migration, promote axon elongation, guide the growth of processes, induce synapse formation,
and modulate synaptic strength. Oligodendrocytes were thought to be important only for
myelination of axons, but it has become clear that they are dynamic modulators of axonal
conduction velocity and providers of metabolic support. Similarly, microglia were known almost
exclusively as the immune cells of the CNS; however, recent research has exposed their
importance in the regulation of cell number, cell differentiation, maturation of neural circuits,
and synaptic remodeling. Recent findings suggest that aberrant glial cell function contributes to
some of the unusual pathology seen in Noonan syndrome, schizophrenia, cerebral palsy, autism
spectrum disorder, and other neurodevelopmental disorders. Moreover, new insights about the
details of neuron-glia interactions allow for speculations about how altered glial cell function
could actively contribute to abnormal neurodevelopment.
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Bilgin, Ayten. "Infant regulatory problems : neurodevelopmental vulnerability and sensitive parenting." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/91110/.
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Infant regulatory problems (crying, sleeping, feeding) are a common concern for parents and practitioners. Although there is now good evidence of the long-term adverse influences of infant regulatory problems on mental health, in particular if they co-occur together (multiple regulatory problems), important gaps remain regarding the precursors of regulatory problems. In particular, it is unclear whether and how sensitive parenting and/or neurodevelopmental vulnerability are involved in the development of multiple regulatory problems. Furthermore, do regulatory problems impair the development of the infants’ relationship to their mothers, i.e. attachment? This thesis explores neurodevelopmental vulnerability and sensitive parenting as precursors of multiple regulatory problems, and whether multiple regulatory problems increase the likelihood of insecure and/or disorganised attachment. The thesis consists of four studies and uses preterm birth as a natural model to assess neurodevelopmental vulnerability due to the interruption caused by preterm birth on the key processes of brain development. Study 1, a meta-analysis, explored the relationship between neurodevelopmental vulnerability and maternal sensitivity by comparing maternal sensitivity in preterm and full-term infants. Findings indicate that having an infant with neurodevelopmental vulnerability does not alter mothers’ sensitive parenting. In Study 2, using the Growth of at risk Infants (GAIN) study, the effect of neurodevelopmental vulnerability on regulatory problems across the first 18 months was investigated. Very preterm/very low birth weight infants experienced more multiple regulatory problems at term and 18 months compared to full-term infants. In Study 3, the longitudinal relationship between neurodevelopmental vulnerability, maternal sensitivity and multiple regulatory problems across infancy was explored allowing for reciprocal associations between maternal sensitivity and multiple regulatory problems across infancy. Both maternal sensitivity and multiple regulatory problems were moderately persistent from term to 18 months. Consistent with our previous findings, it was revealed that neurodevelopmental vulnerability had an enduring impact on multiple regulatory problems. On the other hand, maternal sensitivity at term had only a short-term negative impact on multiple regulatory problems at 3 months. No evidence for a reciprocal influence of maternal sensitivity and multiple regulatory problems was found. Finally, Study 4 examined whether early multiple regulatory problems at 3 and 6 months increase the likelihood of insecure and/or disorganised attachment. Findings revealed that multiple regulatory problems as early as 3 months increased the risk of both insecure and in particular, disorganised attachment at 18 months. In conclusion, neurodevelopmental vulnerability increases the risk of multiple regulatory problems, which are moderately persistent across the first 18 months of life. Furthermore, multiple regulatory problems do not impair maternal sensitivity but have adverse effects on the infants’ relationship with their mothers by increasing the risk of insecure and disorganised attachment. Clinicians should be aware that multiple regulatory problems are a significant potential risk factor for poorer infant-mother relationship.
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Constance, Jordan Marie. "SOCIAL INFORMATION PROCESSING IN ADOLESCENTS WITH NEURODEVELOPMENTAL DISABILITIES." OpenSIUC, 2017. https://opensiuc.lib.siu.edu/dissertations/1493.
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The present study examined social information processing in a sample of teenagers with various comorbid neurodevelopmental disabilities and typically developing controls. Crick and Dodge’s (1996) model of social information processing was used as the theoretical framework for the current study. Specifically, emotion recognition of self and others, attribution biases, and outcome expectations were measured in adolescents with and without a neurodevelopmental disability. Performance on these social measures was compared to caregiver ratings of social skills, and was also compared across diagnostic groups. 52 adolescents with a diagnosis of autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or learning disability participated in the current study, as well as 51 typically developing control participants. Analyses showed that individuals with any neurodevelopmental disability were less accurate at recognizing sadness in others and at identifying their own feelings and emotions. An interaction between participant group and sex was found, such that females with a neurodevelopmental disability were most likely to report feeling badly after acting aggressively and reported that acting aggressively would be difficult, but that they believed aggression would result in a successful social outcome. Males with a neurodevelopmental disability believed the opposite, that acting aggressively would be socially unsuccessful, but that they would feel good about themselves and that acting aggressively would be easy. Additionally, caregiver ratings of social skills were positively related to participants’ abilities to identify their own feelings, and negatively related to participants’ ratings of the ease of aggressive social encounters. Interestingly, although diagnostic group differences were predicted on these measures, few were found. This research has implications for clinical and educational work with individuals with neurodevelopmental disabilities. First, individuals with any neurodevelopmental disability appeared to have similar social impairments, suggesting that deficits may be related to the presence of any diagnosis, rather than one in particular. Analysis of the steps of social information processing in this population is useful for teachers and clinicians when trying to plan social skills interventions.
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Proctor-Williams, Kerry. "Neurodevelopmental Outcomes for Infants with Neonatal Abstinence Syndrome." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/1827.
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Emerson, Sarah Elizabeth. "Neurodevelopmental Roles of Semaphorin6A/PlexinA2 Signaling in Zebrafish." ScholarWorks @ UVM, 2019. https://scholarworks.uvm.edu/graddis/1058.
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ABSTRACT
A multitude of complex cellular changes are required throughout development in order for a single cell to transform into a fully functioning organism. Cellular events including proliferation, migration, and differentiation have to be carefully controlled in order for development to proceed correctly. In order to study such dynamic processes, in vivo models are often utilized. Using the zebrafish (Danio rerio) as a model system, we have investigated the role of an axon guidance signaling pair, Semaphorin6A (Sema6A) and PlexinA2 (PlxnA2), in neurodevelopment.
A previous investigation into the developmental expression patterns of sema6A and plxnA2 in zebrafish, revealed overlapping expression in the developing eye. At this early stage, the cells in the optic vesicles are undifferentiated retinal precursor cells (RPCs) and therefore do not require Sema/Plxn signaling for their canonical axon guidance role. To understand what the function of this early expression was, we knocked down both sema6a and plxna2 and observed 1) a loss of cohesion of RPCs within optic vesicles, and 2) a decrease in RPC proliferation (Ebert et al., 2014). Because these phenotypes were seen at an early stage and given that many developmental processes are dependent on genetic regulation, we hypothesized that Sema6A/PlxnA2 signaling could be regulating transcription of downstream target genes. To investigate this, we performed a microarray experiment and uncovered 58 differentially regulated genes (Emerson et al., 2017a). Prior to our study, it was not known that Sema/Plxn signaling led to changes in gene transcription.
In an effort to understand the contribution of identified candidate genes to early sema6A/plxnA2 knockdown phenotypes, candidate genes with predicted functions in proliferation and migration were investigated. First, we show that rasl11b is important for regulation of RPC proliferation in the developing optic vesicles. Second, we show that shootin-1 is important in optic vesicle migration, retinal pigmented epithelium formation and optic tract patterning. Furthermore, PlxnA2 regulation of shootin-1 levels is important in sensory and motor axon patterning and branching in the peripheral nervous system.
Belonging to a large family of proteins with the ability to cross talk, Semas and Plxns rely on spatially and temporally differential expression patterns to perform their tissue-specific roles. Here, we used in situ hybridization to comprehensively uncover the neuronal expression patterns of the PlxnA family in the early developing zebrafish (Emerson et al., 2017b). In addition, we present for the first time that zebrafish have two genes for PlxnA1, A1a and A1b, which show divergent expression patterns.
Semas and Plxns are critical for many aspects of development and together, this body of work provides further insight into the downstream signaling mechanisms and roles of these essential developmental signaling proteins.
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Aguilar, Valles Argel. "Prenatal inflammation and neurodevelopmental disorders: The role of cytokines." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97028.
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Prenatal infection has been linked to the development of schizophrenia in the offspring, most likely through the maternal inflammatory response triggered by infection. A number of studies in animal models demonstrated that acute inflammatory episodes were sufficient to trigger brain alterations in the adult offspring, especially in the mesolimbic dopamine (DA) system, involved in the pathophysiology of schizophrenia. The aim of this research program was to identify which elements of the maternal inflammatory response are implicated in the alteration of the mesolimbic DA neurotransmission of the offspring. The pro-inflammatory interleukin (IL)-6, the anti-inflammatory IL-1 receptor antagonist (ra) and the immune modulator leptin were of particular interest. To investigate this, a model of aseptic clinical trauma was used, which consisted of a localized intramuscular injection of turpentine oil (TURP). This approach allows for the study of the endogenous mediators whilst avoiding the direct targeting of the foetal compartment, since the exogenous immunogen remains at the site of injection. In the work presented here it was demonstrated that maternal inflammatory response to TURP varied with the gestational day (GD), which was associated with the magnitude of the behavioural effects in the offspring. Early TURP treatment, at GD 15, induced significant impairments in pre-pulse inhibition and the cued-task of the Morris-water maze, whereas it enhanced cued-fear conditioning and locomotor response to AMPH; these effects were largely absent when TURP was given to the dam at GD 18. Neutralization of IL-6 and IL-1ra, the main circulating mediators induced by TURP, during the maternal acute inflammatory response at GD 15 prevented the effects of prenatal TURP on enhanced locomotor response to AMPH and increased synthesis of DA in the nucleus accumbens of the offspring. Leptin, a cytokine-like hormone implicated in inflammation, appeared to be involved in the induction of enhanced behavioural plasticity following repeated AMPH administration. Finally, it was demonstrated that inflammation induced an IL-6-mediated hypoferremia that was involved in the induction of enhanced sensitization to AMPH and tyrosine hydroxylase in the nucleus accumbens. Collectively, the work presented in this thesis provides extensive and novel evidence showing that several immune mediators affect neurodevelopment of the mesolimbic DA system directly or via secondary mechanisms, and may be involved in the increased risk for schizophrenia in the human population.L'infection chez la mère a été liée au développement de la schizophrénie chez l'enfant, probablement due à la réponse inflammatoire déclenchée par l'infection. De nombreuses études utilisant des modèles animaux ont démontré que l'inflammation est suffisante pour déclencher des altérations dans le cerveau chez la progéniture adulte, en particulier dans le système dopaminergique mésolimbique (DA), impliqué dans la physiopathologie de la schizophrénie. L'objectif de ce programme de recherche était d'identifier quels éléments de la réponse inflammatoire sont impliqués dans les changements observés dans la neurotransmission DA de la progéniture. La cytokine pro-inflammatoire interleukine (IL)-6, l'antagoniste du récepteur de l'IL-1 (IL-1ra) et la leptine ont été d'un intérêt particulier. Pour induire une réponse inflammatoire, un modèle de traumatisme clinique aseptique a été utilisé. Il s'agissait d'une injection intramusculaire de l'essence de térébenthine (TURP), qui évite de cibler directement le compartiment fœtal par l'immunogène. Dans le travail présenté ici, il a été démontré que la réponse inflammatoire maternelle induite par la TURP varie selon le jour de gestation (JG), où celle-ci a été associée à l'ampleur des effets sur le comportement de la progéniture. Lorsque administré au JG 15, la TURP a induite des déficiences importantes dans l'inhibition de pré-pulse et dans le labyrinthe aquatique de Morris, alors qu'elle a accentué la peur conditionnée et la réponse locomotrice à l'AMPH. Ces effets ont été largement absents lorsque la TURP a été donnée au JG 18. La neutralisation de l'IL-6 et de l'IL-1ra lors de la réponse inflammatoire de la mère au JG 15 a empêché les effets de la TURP sur la réponse locomotrice à l'AMPH et l'augmentation de la synthèse de DA dans le noyau accumbens de la progéniture. La leptine quand à elle, semble être impliquée dans l'induction de la plasticité comportementale après des administrations répétées d'AMPH. Finallement, il a été démontré que l'inflammation déclenche l'hypoferremie, une réduction de fer dans la circulation et le placenta, qui a été impliqué dans l'induction de la sensibilisation à l'AMPH et à l'hydroxylase de tyrosine dans le noyau accumbens. Collectivement, le travail présenté dans cette thèse fournit de nombreux et nouveaux éléments montrant que plusieurs médiateurs immunitaires affectent le développement neurologique du système DA et peuvent être impliqués dans le risque accru de schizophrénie dans la population.
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Davis, Emma E. "Neurodevelopmental outcome following cerebellar tumour sustained in early childhood." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/12201/.
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Mounting evidence from imaging studies, developmental disorders and typically-developing children suggests that different domains of functioning are more closely related than previously considered. This is reflected in theories of development which are increasingly recognising that developmental progression should be considered as an integrated process, with associations between domains. The extent of the interrelation between cognitive and motor skills remains unclear despite previous investigations. Examination of this relationship in typically-developing children is important to clarify the nature of this link, thereby informing theories of development for both typical and atypical populations. This thesis investigated the underlying nature of the association between cognitive and motor domains to establish the extent of interrelation and whether this link alters across development. As the cerebellum has been hypothesised to be instrumental in this relationship (Diamond, 2000), the role of the cerebellum was investigated by examining cognitive and motor development in children treated for cerebellar tumour in the preschool years (N=15). The impact of cerebellar injury on development of scholastic and attentional skills was also investigated, together with the influence of factors affecting prognosis. The interrelation of cognitive and motor skills in typically-developing children (N=248; 4-11 years) was found to be underpinned by a link between visual processing abilities and fine manual motor skills. Despite fluctuations in correlations between other aspects of cognitive and motor functioning, this core relationship remained constant, furthering evidence that cognitive and motor development are linked from an early age. A similar pattern of correlations was seen for the patient sample, suggesting that development in these domains remains tightly linked despite damage to an underlying component of the anatomical network. This suggests that the patients are demonstrating a developmental delay, rather than deviation; their trajectory does not appear to be qualitatively different from that of typically-developing children, rather development appears to be more constrained than suggested by some hypotheses (e.g. Karmiloff-Smith, 1992). Cerebellar damage was therefore found to impact on the two domains similarly, offering support to a „universal cerebellar transform‟ (Schmahmann, 2000b) conceptualisation of cerebellar functioning. Both cognitive and motor skills were found to be compromised following a cerebellar tumour, although no specific impact of cerebellar damage was reported on scholastic skills, above and beyond general cognitive deficit. Attention was found to be impaired in the patient sample, with sustained attention most closely related to functioning in cognitive, academic and motor skills, suggesting that a deficit in this basic underlying process underlies difficulties in other domains. In addition, sustained attention was implicated in the association between visual processing and fine manual control in the patient sample, suggesting that this core link may be further underpinned by more basic cognitive processes. Effective rehabilitation may therefore target sustained attention, as this appears to be related to functioning in the other domains assessed in this study, as well as recognising that an integrated approach across domains is likely to yield maximum benefits. Of the potential moderating factors investigated, age at diagnosis and tumour type/treatment were found to be the most reliable predictors of outcome. This research highlights the importance of a case-study approach, and the clinical importance of individual investigation of each child‟s needs for rehabilitation.
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Hiten, Cristina Elizabeth. "NUTRIENT AND MEDICATION INTAKE OF CHILDREN WITH NEURODEVELOPMENTAL DISORDERS." UKnowledge, 2009. http://uknowledge.uky.edu/gradschool_theses/638.
Full textAbstract:
The incidence of autism continues to rise with no cure or understanding of the cause of the disorder. Approximately one in 150 children will be diagnosed with an (ASD) Autism Spectrum Disorder although recent prevalence data suggest one in 91. The objective of the study is to assess medicinal intake regarding prescription and nonprescription medications of children with Autism Spectrum Disorders and its affect on their nutritional status compared to age, and sex matched healthy children. The study included families of children with autism in which they completed questionnaires and 24‐hour recalls. There were 26 children used within the questionnaire and 13 were utilized in the 24‐hour recall, ranging in age from 2‐11. Results demonstrated that children with autism were not deficient in relation to vital nutrients needed for neurological function. Prescription and nonprescription medications also did not pose many side effects; however, there was slight weight gain in their utilization. Information from the assessments of the child’s nutritional needs and drug nutrient interaction will allow parents, paraprofessionals and healthcare professionals to provide education to families.
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Linsell, Louise. "Prediction of neurodevelopmental outcome in children born extremely preterm." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:dbf00f22-2cfc-4d1d-bcf5-e8274cfdbbe0.
Full textAbstract:
Background: The survival rate of preterm children has risen steadily due to advances in obstetric and neonatal intensive care. Children born extremely preterm (≤28 weeks of gestation) are at high risk of long term developmental problems, including cerebral palsy, motor and cognitive impairment, visual and auditory deficits and behavioural problems. This can have serious implications for their quality of life and that of their family and carers. These children take up a disproportionate amount of neonatal intensive care unit resources and overall costs, and as they grow up are more likely to require additional health and social care services beyond routine care to compensate for their functional limitations. The early identification and management of factors that mediate long term outcome is necessary to assist healthcare professionals in selecting appropriate treatment pathways, and to develop, target and evaluate interventions. Many risk factor analyses for neurodevelopmental impairment have been published in preterm populations, but this vast literature has not been formally summarised. Furthermore, there is a dearth of studies reporting longitudinal analysis of neurodevelopmental trajectories from early childhood to adulthood. Objectives: The first aim of this thesis was to perform a comprehensive systematic review of the world literature over the last two decades, to consolidate the evidence about the prognosis of neurodevelopmental outcome in children born very preterm or with very low birth weight. The second aim was to conduct a longitudinal analysis of a cohort of extremely preterm participants followed up into early adulthood to investigate the trajectories of long term sequelae over time, and to examine the association of neurodevelopmental course in relation to the predictive factors identified in the systematic review. Methods: A systematic review was conducted using MEDLINE, EMBASE and PyscINFO databases to identify studies published between January 1 1990 and June 1 2014 reporting multivariable prediction models for the neurodevelopment of children born ≤32 weeks of gestation or with a birth weight ≤1250 grams (protocol registration number CRD42014006943). Seventy-eight studies reporting 222 risk factor models for neurodevelopmental outcome were identified. Two independent reviewers extracted key information about study design, outcome definition, risk factor selection, model development, reporting, and conducted a risk of bias assessment. To address the second objective of the study, a longitudinal analysis of cognitive and behavioural trajectories was conducted using a prospective, population-based cohort study in the United Kingdom and the Republic of Ireland. Three hundred and fifteen surviving infants born less than 26 completed weeks of gestation recruited at birth in 1995 and 160 term-born classroom peers recruited at age six were followed-up to 19 years. Participants were invited for up to four standardized, blinded cognitive assessments and the parent-completed Strengths and Difficulties Questionnaire was used to assess behavioural problems. Results: The systematic review of risk factors for motor impairment in children born very preterm or with very low birth weight provided strong evidence that neonatal brain injury is a robust prognostic factor for cerebral palsy, and some evidence that the use of postnatal steroids increases the risk and the use of antenatal steroids reduces the risk of cerebral palsy. There was moderate evidence that male sex was prognostic for motor impairment at school age in children free of major disability. The systematic review of risk factors for cognitive impairment identified male sex, non-white ethnicity, lower levels of parental education and lower birth weight as significant predictors of global cognitive dysfunction in early infancy, with parental education having a sustained impact after five years of age. There was also evidence that male sex was predictive of delayed language development in early infancy. Gestational age was found to be of limited use as prognostic factor for cerebral palsy, motor and cognitive impairment in cohorts restricted to ≤32 weeks of gestation. There was a dearth of good quality studies investigating risk factors for behavioural problems and psychiatric disorders and the findings of this review were inconclusive. The only factors that appeared to be consistent predictors of general behavioural problems were markers of socio-economic deprivation, neurodevelopmental or cognitive delay, and an abnormal behavioural screen in early infancy. In the longitudinal analysis of the prospective, population-based cohort of extremely preterm children, cognitive trajectories were stable in both the extremely preterm and term-born groups over time with persistent deficit in the extremely preterm group of 25.2 IQ points (95% CI: -27.8 to -22.6, p<0.001) and only minimal catch-up over time. Participants with neonatal brain injury and of male sex had the largest deficits, but a lower level of maternal education and earlier gestational age at birth were also associated with reduced IQ scores. Behavioural problems were also more prevalent among the extremely preterm participants who had a mean Total Difficulties Score of 4.81 points above their term-born peers (95% CI: 3.76 to 5.87, p<0.001) and which persisted over the time period. Behavioural difficulties were mainly due to hyperactivity, inattention and peer problems and were strongly associated with a positive behavioural screen in early infancy. Conclusions: The most robust predictors of poor neurodevelopmental outcome identified by the systematic review were neonatal brain injury, male sex, and markers of social disadvantage. The unclear findings for many risk factors may reflect differences in study design, study population, methodological quality and lack of standardization of measures. Or it may simply reflect the fact that prognostic modelling in such a heterogeneous population is challenging and complex, with multiple risk factors acting sequentially over time, and often with the existence of multiple impairments within the same individual. The main conclusions from the longitudinal analysis of children born extremely preterm is that being born too soon appears to place limits on brain plasticity and function which is not recovered over time; with the most vulnerable being males and those with evidence of brain injury early in life. These structural abnormalities may disturb neurodevelopmental processes and impede the brain from maintaining a normal developmental trajectory. If extremely preterm children fail to achieve optimum levels of cognitive function and are still experiencing behavioural problems once they have reached maturity, then this has implications for health and well-being in later adulthood and old age. Cognitive test scores in infancy and early childhood reflect early adult outcomes and a positive behavioural screen in infancy is strongly associated with early adult behavioural outcomes. Recommendations: The systematic review revealed some shortcomings in methodology and reporting that could be improved in future studies, and confirmed that that there is a dearth of properly designed and well-conducted prognostic modelling studies in this field. The findings and recommendations of this critical review should be used as a basis for the design, analysis and reporting of future studies seeking to develop multivariate risk factor or prognostic models in this population. There is an urgent need for larger population cohorts followed up routinely beyond two years as subtle outcomes such as impairment of executive function and fine motor skills cannot be reliably assessed at this age, and the natural course of some disorders may have their onset later in childhood.Studies with larger sample sizes and greater power are needed for studying less common conditions in preterm populations and there should be more standardisation of outcome and risk factor measurements, particularly with the use of standard diagnostic evaluations to assess psychiatric disorders. Future studies should include a term-born comparison group and adopt appropriate statistical analysis techniques to analyse longitudinal outcome data and the impact of risk factors on these trajectories. Additional research is required to improve the prediction of individual differences, and to identify the neuropathological differences underlying different developmental trajectories and their interaction with environmental influences over time.
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Asch, Ruth H. "Neurodevelopmental Consequences of Maternal Omega-3 Fatty Acid Deficiency." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1583154907162725.
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Mullegama, Sureni. "Uncovering the molecular pathways of MBD5 in neurodevelopmental disorders." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/459.
Full textAbstract:
Neurodevelopmental disorders (NDs) are a growing public health concern. These complex disorders cause failure of normal brain development, which leads to intellectual disability (ID) or autism in 3% of children. Accurate diagnosis of NDs is difficult due to complex overlapping phenotypes. Moreover, associations between phenotypically similar NDs and their overlapping molecular mechanisms remain unidentified. The chromosome 2q23.1 region is a newly discovered disease region. We have recently identified a novel ND, 2q23.1 deletion syndrome. The phenotype includes severe ID, significantly delayed speech, behavioral problems, seizures and short stature. This syndrome shares characteristics in common with other genetic syndromes, including Smith-Magenis (SMS, RAI1), Pitt-Hopkins (PTH, TCF4), Angelman (AS, UBE3A) and Rett (RTT, MECP2) syndromes, including ID, speech impairment, and seizures, in addition to other autism spectrum disorder (ASD)-associated phenotypes (associated with mutation of MBD1). The methyl-CpG binding domain protein 5 (MBD5) is thought to be the causative gene for the core phenotype seen in del2q23. We propose that MBD5 is a dosage dependent gene, wherein deletion or duplication results in two distinct syndromes. We hypothesize that deletions, mutations, and duplications in MBD5 and its associated overlapping gene networks are responsible for causing the phenotype seen in 2q23.1 disorders. Furthermore, we hypothesize that syndromic neurodevelopmental genes are involved in common biological networks that, when dysregulated, result in the overlapping phenotypes present in many of these neurodevelopmental disorders. We first show that the causative gene for 2q23.1 deletion syndrome is MBD5. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosome 2q23.1, acquiring 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints, aligned microdeletions to determine the critical region, assessed effects on mRNA expression, and examined medical records, photos, and clinical evaluations. We identified MBD5 as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency, intellectual disability, epilepsy, and autistic features. Sixteen alterations disrupted MBD5 alone, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. We surveyed MBD5 coding polymorphisms among 747 ASD subjects compared to 2,043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG binding domain missense variant, G79E (p=0.012). Thus, we establish that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. Secondly, we show that MBD5 is a dosage dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes intellectual disability, motor delay, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 680 kb to 53.7 Mb, encompassing a region that includes MBD5. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation, or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage sensitive gene critical for normal development. Dup(2)(q23.1) causes a phenotype similar to del(2)(q23.1) and other NDs, like SMS and autism, suggesting shared molecular pathways. Finally, chromatin-modifying genes play an important role in the genetic etiology of many NDs, including intellectual disability, epilepsy, and autism. Many monogenic NDs are caused by chromatin modifying genes, including 2q23.1 deletion and duplication, SMS, RTT, AS, fragile X syndrome (FXS), and PTH. Many of these disorders have overlapping features that include language, sleep, and behavioral anomalies. Investigation of relative gene expression by quantitative PCR and microarray of cell lines from individuals with disorders due to altered expression of MBD5, RAI1, MECP2, UBE3A, TCF4, and MBD1 revealed molecular signatures that allowed for the generation of a novel neurodevelopmental molecular network supporting the overlapping features across these syndromes. Further, knockdown of MBD5 and RAI1 in SH-SY5Y and HEK293T cell lines expanded the repertoire of genes involved in these pathways and showed that other chromatin modifying genes, as well as developmental genes are dysregulated. Pathway analyses showed that MBD5 and RAI1 function in chromatin remodeling, circadian rhythm, neuronal development, and cell growth/survival pathways. From these studies, precise gene dosage of chromatin modifying genes, such as RAI1 and MBD5 are clearly a requirement for normal neurodevelopment and function. Taken together, these studies have given us insight into the role of MBD5 as a dosage sensitive gene in two NDs. Furthermore, we gained insight of how dosage effects of MBD5 and RAI1 affect molecular pathways that are linked to neuronal and behavioral development. We have unveiled pathways and genes, which are important to normal human development, neurodevelopment and behavior. These findings support further investigations into the relationships among causative neurodevelopmental genes, which will lead to common points of regulation that may be targeted toward therapeutic intervention.
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Kim, Seol-Hee. "Acetaminophen Associated Neurotoxicity and its Relevance to Neurodevelopmental Disorders." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6717.
Full textAbstract:
Autism is a lifelong neurodevelopmental disorder. The etiology of autism still remains unclear due to the heterogeneous and complex nature of the disorder, however synergistic actions between genetic components and environmental factors have been suggested. Acetaminophen (APAP) is one of the most popular over-the-counter drugs that possess antipyretic and analgesic effects. It is considered a relatively safe and effective within therapeutic doses. Recently, early exposure to APAP has been suggested to be one of the underlying cause of autism. Children are often prescribed APAP to lessen fever or irritability after vaccination during the first year, and APAP may adversely affect the normal brain development. In order to better understand the association with APAP and autism, we used an inbred mouse strain BTBR T+tf/J (BTBR). BTBR exhibits behavioral deficits that mimic the core behavioral deficits of human autism. In the study, investigated 1) if BTBR mice showed differences in thiol biochemistry and EAAT3 levels in brain compared with C57BL/6J (C57) mice, 2) if early exposure to APAP induced behavioral changes worsening the autistic phenotypes of BTBR in adolescence, and 3) if APAP exposure in neonatal mice induced possible toxicity at various doses. As a result, we observed that BTBR mice have significantly lower plasma sulfate levels and EAAT expression levels in the frontal cortex compared to C57 mice. Surprisingly, neonatal therapeutic dose of APAP administration did not induce behavioral changes in both C57 and BTBR in adolescence. However, we showed that a supratheraputic dose of APAP significantly elevated levels of oxidative stress marker in the brain. Overall, the results suggested that BTBR mice would be a useful mouse model to investigate effects of various environmental factors that have been associated with autism. In addition, early exposure to APAP at supratherapeutic doses may negatively affect normal brain development.
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TOMBOLINI, STEFANO. "NEURODEVELOPMENTAL OUTCOMES OF PRETERM INFANTS. Neurosviluppo del neonato pretermine." Doctoral thesis, Università Politecnica delle Marche, 2022. http://hdl.handle.net/11566/295729.
Full textAbstract:
Il tasso di sopravvivenza dei bambini pretermine è aumentato costantemente grazie ai progressi della
terapia intensiva neonatale e dell’ostetricia. I neonati pretermine sono ad alto rischio di problemi di
sviluppo a lungo termine, tra cui paralisi cerebrale, disturbi motori e cognitivi, deficit visivi e uditivi e
problemi comportamentali. Ciò può avere gravi implicazioni per la loro qualità di vita e per quella della
loro famiglia. Questi bambini richiedono una grande quantità di risorse e di costi all'unità di terapia
intensiva neonatale, e man mano che crescono hanno maggiori probabilità di richiedere servizi
sociosanitari aggiuntivi oltre alle cure di routine per compensare i loro limiti funzionali.
L'identificazione e la gestione precoce dei fattori che influiscono sull’outcome a lungo termine, è
necessaria per assistere gli operatori sanitari nella selezione dei percorsi di trattamento più appropriati,
in relazione al deficit del bambino. L' incidenza di disabilità nei bambini pretermine della nostra TIN è
inferiore a quella di altri ospedali in Europa e USA. Ciò indica la buona qualità delle cure offerte ai
neonati nel reparto di Ancona.
Questa tesi riporta i dati sullo sviluppo neurologico di bambini nati prematuri della regione Marche.
Inoltre, è stata studiata anche l'associazione tra l'ossigenazione cerebrale alla nascita utilizzando la
spettroscopia nel vicino infrarosso (NIRS) e il neurosviluppo.The survival rate of preterm children has risen steadily due to advances in obstetric and neonatal intensive care. Preterm infants are at high risk of long-term developmental problems, including cerebral palsy, motor and cognitive impairment, visual and auditory deficits and behavioral problems. This can have serious implications for their quality of life and that of their family and cares. These infants take up a disproportionate amount of neonatal intensive care unit resources and overall costs, and as they grow up are more likely to require additional health and social care services beyond routine care to compensate for their functional limitations. The early identification and management of factors that mediate long term outcome is necessary to assist healthcare professionals in selecting appropriate treatment pathways, and to develop, target and evaluate interventions. This thesis reported neurodevelopmental data of preterm infants of Marche’s region. Furthermore, the association between cerebral oxygenation at birth using Near Infrared Spectroscopy (NIRS) and neurodevelopment has been also studied.
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FERRARA, SILVIA. "NEUROINFLAMMATION AND DEFECTIVE MYELINATION IN POLYMICROGYRIA." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/543392.
Full textAbstract:
Polymicrogyria (PMG) is a condition characterized by abnormal prenatal brain development and excessive number of ectopic small gyri in the cerebral cortex. PMG patients present an excessive number of abnormally small gyri separated by shallow sulci, associated with fusion of the overlying molecular layer of the cerebral cortex. The topographic distribution of PMG may be focal, multifocal or diffuse; unilateral or bilateral; symmetric or asymmetric. Clinical manifestations have a large spectrum, ranging from isolated selective impairment of cognitive functions to severe encephalopathy and intractable epilepsy. The severity of neurological manifestations and the age at presentation are in part influenced by the extent and localization of the cortical malformations but may also depend on its specific aetiology. The pathogenesis is still poorly understood, several causative gene mutations have been recently found, but also other causes has been identified (prenatal infections, ipoxia).
Experimentally, the mouse model of polymicrogyria (PMG) displays the formation of ectopic microgyri in the mouse cortex, enhanced excitatory and inhibitory synaptic transmission accompanied by increased connectivity in the paramicrogyral cortex and higher susceptibility to epilepsy in vitro.
Besides the alteration in the cortical layering, the molecular, morphological and behavioural analysis of PMG mice reveal a significant astrogliosis and microglial activation, indicating the occurrence of an inflammatory process. In addition, a diffuse cortical hypomyelination is evident in brain slices
stained for myelin basic protein (MBP). Furthermore, PMG mice displayed altered EEG profile and defective motor skills such as reduced brawn. All these features make PMG model suitable for the study of the pathology and to investigate possible therapeutic approaches.
Here we found that transplantation of human neural stem cells (hNSCs), which has been demonstrated to exert positive effects on inherited or acquired myelination disorders and to dampen brain inflammation, plays a beneficial effect on the pathological condition of PMG ameliorating the myelination defect by promoting oligodendrocyte precursors proliferation and remodelling of myelin fibres. Our data also show that hNSC transplantation restores normal EEG brain activity and improves motor performances. Moreover, we tried a pharmacological blockade of IL-1R activation by the IL-1R antagonist: anakinra. We found that this treatment leads to a significant improvement of EEG and motor skills in adult PMG mice thus suggesting a possible role of inflammation at the root of the pathology and identifying a therapeutic time window for the treatment.
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Lamb, Janine A. "A molecular genetic study of autism : evidence for a susceptibility locus on chromosome 7." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365429.
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Orós, López Daniel. "Perinatal and neurodevelopmental outcome of late-onset growth restricted fetuses." Doctoral thesis, Universitat de Barcelona, 2010. http://hdl.handle.net/10803/2504.
Full textAbstract:
DE LA TESIS:"Resultado perinatal y del neurodesarrollo en fetos con retraso de crecimiento intrauterino de instauración tardía"
TEXTO:
El retraso de crecimiento intrauterino es una de las patologías más graves del desarrollo fetal, asociándose con un incremento la mortalidad intrauterina, mortalidad perinatal y prematuridad, siendo un conocido factor de riesgo para el desarrollo de déficits neurológicos durante la infancia y la adolescencia. Se considera "pequeños" a todos los fetos con un peso por debajo del percentil 10 para su edad gestacional y sexo. Pero no todos los fetos "pequeños" son verdaderos retrasos de crecimiento. La búsqueda de variables clínicas que nos ayuden a diferenciar los fetos "pequeños normales" de los "retrasos de crecimiento intrauterino" (RCIU) ha sido uno de los focos más activos de investigación en medicina fetal durante los últimos 20 años.
El aumento de las resistencias vasculares placentarias, expresado por la elevación del índice de pulsatilidad de la arteria umbilical (AU), es el criterio diagnóstico más aceptado. La introducción del Doppler de la AU ha demostrado mejorar el resultado y reducir la mortalidad perinatal. Actualmente se asume que los fetos con un peso por debajo del percentil 10 y un aumento de las resistencias vasculares placentarias son RCIU, siendo los fetos con una resistencia vascular placentaria normal, fetos pequeños normales, a los que denominamos "pequeños para edad gestacional" (PEG).
Sin embargo, recientes publicaciones han puesto en duda el valor de la arteria umbilical para definir cuando un feto pequeño tiene bajo riesgo, encontrando que los fetos PEG también presentan resultado perinatal subóptimo, así como una mayor incidencia de un amplio espectro de alteraciones sutiles del desarrollo cerebral que se pueden expresar como alteraciones del comportamiento, desordenes neuromusculares, problemas en el aprendizaje y alteraciones de la conducta.
Los estudios incluidos en este proyecto son parte de una línea de investigación sobre la circulación cerebral de los fetos con retraso de crecimiento, y su capacidad de predicción de daños neurológicos.
El primer proyecto tiene por objeto determinar las tendencias longitudinales y tipo de cambio de los índices de pulsatilidad Doppler de la arteria cerebral uterina, umbilical y cerebral media en fetos PEG inicio tardío desde el diagnóstico hasta el parto.
El objetivo del segundo proyecto fue evaluar el desarrollo neuroconductual neonatal de fetos RCIU nacidos a término sin insuficiencia placentaria. Muchos estudios han encontrado asociaciones entre los fetos con RCIU precoz y el desarrollo del neurocomportamiento, sensorial y disfunciones cognitivas. Resultados a largo plazo de los bebés prematuros con RCIU ha revelado un perfil específico de las dificultades neurocognitivas con pobre funcionamiento ejecutivo, falta de flexibilidad y de creatividad, así como problemas del leguaje. Algunos estudios han relacionado estas dificultades en la infancia con trastornos de conducta ya presentes en el período neonatal, un momento en que las influencias ambientales son todavía mínimos. Algunos estudios también han informado a largo plazo de las desventajas cognitivas los niños con RCIU de instauración tardía, pero no hay información sobre el desarrollo neuroconductual de los bebés nacidos a término con RCIU sin insuficiencia placentaria.
El tercer proyecto fue dirigido para analizar si la investigación Doppler de la ACA es superior a la investigación Doppler de la arteria cerebral media en la predicción de resultados perinatales adversos en fetos PEG sin insuficiencia placentaria. Diversos estudios en fetos RCIU han demostrado una redistribución regional de suministro de sangre en el cerebro, que contribuye a la jerarquía regional en el deterioro del cerebro, haciendo que ciertas áreas más susceptibles que otras a la hipoxia. El lóbulo frontal del cerebro, se abastece principalmente por la ACA, es una de estas estructuras muy sensibles en los niños crónicamente hipóxicos. El estudio de ésta arteria podría ser superior a los parámetros estándar que se utiliza para detectar la redistribución del cerebro, la ACM, para la detección de los fetos en una fase temprana de la hipoxia cerebral.
Teniendo en cuenta lo anteriormente expuesto, nuestras hipótesis de trabajo serán:
a) Hipótesis conceptual
· Un porcentaje de fetos con retraso de crecimiento de aparición tardía, con función placentaria normal, han estado expuestos a hipoxia leve en el útero.
b) Hipótesis secundarias
· El seguimiento longitudinal de fetos con retraso de crecimiento de aparición tardía demuestra que los índices de pulsatilidad Doppler de la arteria cerebral anterior (ACA), la arteria cerebral media (ACM) y la relación cerebro-placentaria
(CPR) presentan modificaciones antes y de forma más frecuentes que la arteria umbilical (AU) materna y de las arterias uterinas (AUT).
· Los fetos con retraso de crecimiento de aparición tardía con función placentaria normal, tienen peores resultados perinatales, así como un desarrollo neuroconductuales neonatal subóptimo.
· Los fetos con retraso de crecimiento de aparición tardía con signos de redistribución hemodinámica cerebral presentan disrrupciones neurológicas que afectan a la neuroconducta neonatal.
De este modo, los objetivos establecidos serán los siguientes:
a) OBJETIVO PRINCIPAL
· Estudiar la evolución temporal de los parámetros Doppler en fetos con retraso de crecimiento de aparición tardía para evaluar su asociación con resultados perinatales adversos y neuroconductuales.
b) OBJETIVOS ESPECÍFICOS
· Describir al final del embarazo la tendencia de los índices de pulsatilidad longitudinal de Doppler de la arteria cerebral media, umbilical y materna arterias uterinas a finales de los fetos con retraso de crecimiento de aparición tardía
· Evaluar el desarrollo neuroconductual y los resultados perinatales de los fetos con un peso fetal estimado inferior al p10 y Doppler de la arteria umbilical normal.
· Evaluar el desarrollo neuroconductual y el resultado perinatal de los fetos con retraso de crecimiento de aparición tardía con signos de redistribución de intrauterina cerebral definido por el estudio Doppler de las arterias cerebrales anterior y media.
Los resultados de esta investigación se obtuvieron mediante un estudio longitudinal prospectivo de dos cohortes (Cohorte Caso y Cohorte Control), con un total de 116 pacientes en cada rama (tasa de aceptación: 90%) en la muestra inicial. El trabajo se realizó en la Unidad de Crecimiento Fetal del Materno-Fetal del Departamento de Medicina del Hospital Clínico de Barcelona entre noviembre de 2007 y agosto de 2009.
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Terry, Anna May Emily. "Auditory evoked electrophysiological measures as biomarkers for neurodevelopmental communication disorders." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/auditory-evoked-electrophysiological-measures-as-biomarkers-for-neurodevelopmental-communication-disorders(493ce49f-1eb6-4385-bd82-6846dac594fc).html.
Full textAbstract:
Three studies were conducted to address gaps in knowledge pertaining to the use of auditory evoked electrophysiological measures as potential biomarkers for neurodevelopmental communication dis-orders. Some subjects with these disorders demonstrate auditory tem-poral processing deficits, which may have a basis in impaired myelin within the auditory brainstem. Given their sensitivity to such deficits and their feasibility for use with very young infants, electrophysiolog-ical measures make feasible candidates as biomarkers for these disor-ders. In particular, a subset of neonatal Intensive Care Unit graduates show a transient failure of the auditory brainstem response (ABR) at newborn hearing screening that may indicate an onset of impaired myelin. The study in Chapter Three was conducted to investigate the hypothesis that this transient failure may be associated with communi-cation difficulties in later childhood. No association was found be-tween this transient failure and communication ability. However, pa-rental concern over general development of a child was found to be a potentially useful marker for children who demonstrated communica-tion difficulties. Some subjects with neurodevelopmental communica-tion disorders also show atypical frequency following responses (FFRs). The FFR is not currently used in a clinical setting, despite evidence that it may be more sensitive to auditory temporal processing deficits than the ABR. The results of the study in Chapter Four showed that group delay latency of the FFR, which represents where in the auditory brainstem the response is likely to be generated, occurs significantly later than latency of the click-evoked ABR wave V, which signals the offset of this response. These results indicate that the FFR may reflect auditory processing efficiency in separate struc-tures of the auditory brainstem and therefore, provide more insight into temporal synchronicity than the ABR alone. However, the study in Chapter Five found that the FFR could not distinguish adults with a neurodevelopmental communication disorder from a control group. In contrast, adults with Autism Spectrum Disorder (ASD) could be distinguished from a control group by the wave III-V inter-peak latency of the click-evoked ABR. Prolongation of this inter-peak latency was also found in adults with a demyelinating disorder. These results suggest that the auditory temporal processing deficits in ASD may have a basis in impaired myelination that can be measured by inter-peak interval latency of the click-evoked ABR. However, a behavioural measure of speech-in-noise ability was found to be a more important predictor of the presence of a communication disorder than the wave III-V inter-peak latency. Overall, the findings of the studies in this thesis shed new light on the potential usefulness of auditory evoked electrophysiological measures as potential biomarkers for neurodevelopmental communication disorders.
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Hines, Rochelle M. "Modeling neurodevelopmental disorders : expression of neuroligin adhesion molecules in vivo." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/7974.
Full textAbstract:
At post synaptic sites, the neuroligin (NL) family of proteins is thought to play an important role in synapse maturation, and regulation of excitatory and inhibitory synapses. Being selectively enriched at either excitatory (NL1,3) or inhibitory (NL2) synapses, NL’s have been shown to regulate the ratio of excitation to inhibition (E/I ratio), a process critical for normal brain development. In addition, NLs have been linked to neurodevelopmental disorders through genetic studies. To advance our understanding of synaptic regulation by NLs, and their potential role in synaptic dysfunciton in neurodevelopmental disorders, we have developed strains of transgenic mice which overexpress either HA tagged-NL1, or -NL2 under control of the Thy1 promoter.
Detailed behavioural analysis of TgNL2 mice revealed anxiety, stereotyped jumping behaviour, and impairments in social approach and reciprocal social interactions. These animals also displayed fronto-parietal seizure activity as shown by chronic in vivo EEG recording. Synapse analysis in TgNL2 frontal cortex revealed changes in the number and morphology of synapses compared to wildtype littermates. A small change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool and an overall reduction in the E/I ratio. In addition, the frequency of miniature inhibitory synaptic currents was also found to be increased in the frontal cortex of TgNL2 mice.
Behavioural assessment of TgNL1 mice revealed deficits in memory acquisition and retrieval in water maze paradigms. Golgi and electron microscopy analysis revealed changes in synapse morphology indicative of increased maturation of excitatory synapses. In parallel, electrophysiological examination indicated a shift in the E/I ratio towards increased excitation. Further experiments revealed impairment in the induction of long term potentiation.
These data demonstrate that altered expression of members of the NL family in vivo leads to altered synapse number and morphology, which potentially underlies the profound behavioural changes. We also observed a predominant effect of NL2 expression on inhibitory synapses, with NL1 primarily influencing excitatory synapses, supporting the idea that NL’s may act to regulate the E/I ratio. In addition this data may provide insight into the pathology and symptoms of neurodevelopmental disorders such as autism thought be be caused by synaptic abnormalities.
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Jary, Sally Louise. "Assessing neurodevelopmental outcome in infants with severe perinatal brain injury." Thesis, University of Bristol, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665148.
Full textAbstract:
Historically the evaluation and reporting of neurodevelopmental outcomes following perinatal brain injury have been limited to good outcome/poor outcome or disabled/not disabled. More infants are surviving and new treatments to protect the brain require careful testing. Sensitive measures of evaluating developmental outcome in infants with the poorest outcome are required. The aims of this thesis are to describe developmental measures widely used; to examine data arising from a key developmental measure in two groups of children with perinatal brain injury; to use the data to quantify the abilities of even the most severely affected and to compare these findings with neuroimaging in infants with Post Haemorrhagic Ventricular Dilatation (PHVD); and to compare findings of two different editions of the key measure in a group of infants with Neonatal Encephalopathy (NE). Formal assessment at 2 years using the Bayley Scales of Infant Development (Bayley-2) confirmed wide-ranging, but frequently poor outcome, in infants with PHVD. Bayley Developmental Quotients (DQ), used in preference to conventional Bayley-2 Index scores, were found to differentiate between grades of functional ability and disability, even in the most severely delayed infants. Bayley DQ correlated strongly with parenchymal lesion area measured on neonatal cranial ultrasound scans but increasing ventricular size was not associated with reductions in Bayley DQ in infants with preceding grade 3 IVH. Cerebral, thalamic and cerebellar brain volumes from MRI scanning at term age were found to be significantly affected in this cohort. Smaller brain volumes were associated with decreasing Bayley DQ and with motor development in particular. These findings have the potential to enhance the precision of outcome prediction in infants with PVHD which may be of use to clinicians in informing early direction of care and in providing information to families about developmental challenges facing their baby. Comparative study of Bayley-2 scores with revised Bayley Scales of Infant and Toddler Development (Bayley-3) in infants with NE, found higher than expected Bayley-3 scores particularly in those with severe delay. Increased Bayley-3 cut-off thresholds for severe disability are recommended when comparing outcomes using different versions of the test.
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Maroofian, Reza. "Defining the genetic causes of neurodevelopmental disorders in the Amish." Thesis, St George's, University of London, 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.753988.
Full textAbstract:
Neurodevelopmental disorders (NDDs) are defined as highly prevalent and debilitating paediatric neurological conditions caused by impairments in brain growth and development. A major contribution to our understanding in this field has been made through the study of monogenic disorders, which are individually rare, but which occur at higher frequencies in genetically isolated populations. This PhD project forms part of a long running research program called ‘Windows of Hope’, which aims to investigate the genetic causes of NDDs in Amish families to aid scientific understanding of these diseases, to provide diagnostic, management and treatment benefits for families. Families with individuals affected by undiagnosed forms of NDD were investigated using whole genome SNP genotyping to map candidate gene loci, identify structural chromosomes and copy number variations. Using whole exome sequencing to identify known and new candidate gene mutations with follow-up sequencing and functional studies. These studies defined a wide range of known genetic causes of NDDs, and identified disorders involving rare genomic chromosomal rearrangements, providing diagnoses for several families. In addition, these studies contributed to the definition of two new autosomal recessive forms of NDDs (B4GALNT1 and KPTN), providing novel biological insight into the roles of these molecules in neuronal structure and brain function. Additionally, the role of mutations in SNIP1 as a cause of severe syndromic NDD were confirmed, contributing to the understanding of the clinical variability of this condition. Finally, improved characterisation of the genetic and epigenetic outcomes in DNMT3A-overgrowth syndrome and intellectual disability (OGID) were made possible through the study of a gonosomal mutation in a large Amish family with multiple affected individuals. The amalgamation of the work detailed in this thesis expands the scientific and medical understanding of the molecular aetiology of NDDs, and improves genetic testing and management strategies for Amish patients as well as families worldwide with these forms of NDDs.
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Thompson, Mary Clare. "Neurodevelopmental outcome of the high risk infant in Cape Town." Doctoral thesis, University of Cape Town, 2000. http://hdl.handle.net/11427/25807.
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The outcome of high risk infants provides an important audit of neonatal care. This audit renders valuable information to clinicians, parents and health care planners. Available outcome data from the developing world are sparse and urgently needed. This work was compiled with three aims in mind: to provide data from Cape Town on outcome of high risk infants (including both infants of very low birthweight and infants who have survived hypoxic ischaemic encephalopathy); to evaluate selected early neurodevelopmental assessments of these infants; and to propose a protocol for their effective follow-up. Three separate cohorts were selected and studied in order to achieve these aims. A prospective six-year follow-up study of infants with birth weights less than 1250 g was undertaken at Groote Schuur Hospital's Neonatal Intensive Care Unit. The aim of the study was to document the morbidity, mortality and neurodevelopmental outcome of these infants. Of 235 liveborn infants, 143 (61 %) survived to discharge. Better survival was documented for infants who weighed more than 900 g and were over 30 weeks gestation and whose mothers attended antenatal care. One hundred and six infants (83% of survivors) underwent clinical assessment at one year of age and were evaluated with the Griffiths Scales of Mental Development. Ninety six (91 %) of these survivors were seen and tested at two years of age and 80 (76%) were seen at six years of age together with 70 matched controls who had normal birthweights. Of the 106 infants assessed at one year of age, six infants were diagnosed as cerebral palsied, six were globally developmentally delayed without signs of cerebral palsy and one infant showed significant motor delay with a normal developmental quotient. At two years of age one further infant had cerebral palsy and nine more infants were developmentally delayed. At six years of age five infants had cerebral palsy, one was intellectually disabled and three were intellectually borderline. The major disability rate at one year of age was 11%, at two years of age was 22% and at six years of age was eight percent. The incidence of low birthweight children with possible learning disability was three times that of their matched controls and overall, the low birthweight children scored significantly less in all developmental measures. Forty-five infants who developed hypoxic ischaemic encephalopathy after birth were studied prospectively. A numeric scoring system for the assessment of hypoxic ischaemic encephalopathy during the neonatal period which had previously been developed at Groote Schuur Hospital was tested. The value of the score in predicting neurodevelopmental outcome at one year of age was assessed. Thirty five infants were evaluated at 12 months of age by full neurological examination and the Griffiths Scales of Mental Development. Five infants were assessed at an earlier stage, 4 who died before 6 months of age and one infant who was hospitalised at the time of the 12-month assessment. Twenty three (58%) of the infants were normal, 17 (42%) were abnormal, 16 with cerebral palsy and one with developmental delay. 25 infants were re-evaluated at 3 years of age. 15 of these 25 had been normal at one year of age and were evaluated with ten controls who had had an uneventful perinatal course. The Hypoxic lschaemic Encephalopathy Score was highly predictive for outcome. The best correlation with outcome was a combination of the peak score and evaluation on day seven; giving a positive predictive value of 92% and a negative predictive value of 100% for abnormal outcome, with a sensitivity of 100% and specificity of 93%. At three years of age the HIE survivors without cerebral palsy scored as well as their matched controls on Griffiths developmental evaluation. In these normal survivors no correlation between severity of HIE and developmental quotient was demonstrated. Infants with neurodevelopmental abnormality need to start therapy early and because of this, should be detected as soon as possible. Currently, no widely accepted method of early evaluation exists. A Perinatal Risk Rating, the Dubowitz Neurological Assessment and the Infant Neuromotor Assessment were compared in terms of predicting neurodevelopmental outcome at one year of age. A cohort of 130 consecutive neonatal intensive care unit graduates were selected according to high risk criteria. Each infant was examined at term gestational age on the Dubowitz Neurological Assessment and a Perinatal Risk Rating was allocated. The study infants were seen again at 18 weeks corrected age, when an Infant Neuromotor Assessment was done, and at one year of age the Griffiths Scales of Mental Developmental and full neurological examination were carried out. Of the 130 infants assessed at term, all were seen at 18 weeks. Thereafter five were lost to follow-up and two died. The outcome of all the remaining 123 infants is known. Prediction of a normal outcome at 1 year of age on the Dubowitz Neurological Assessment was 96% and for the Perinatal Risk Rating, 98%, but for an abnormal outcome they predicted only 56% and 42% respectively. The Infant Neurological Assessment at 18 weeks of age predicted a normal outcome at one year in 99% and an abnormal outcome in 82%. Very low birthweight infants are at higher risk for cerebral palsy and intellectual disability. In Groote Schuur Hospital, at six years of age, the major disability rate for infants with birthweights less than 1250 g was eight percent. Forty percent of term infants who survived hypoxic ischaemic encephalopathy had cerebral palsy with associated intellectual disability. The use of the Perinatal Risk Rating is appropriate in newborn facilities where cranial ultrasound is available. Otherwise the Dubowitz Neurological Assessment is an appropriate screening tool in the newborn period. Use of the Hypoxic Ischaemic Encephalopathy Score is recommended for clinical evaluation, prognostication and risk rating. It is proposed that high risk infants should be evaluated at 18 weeks corrected age with the Infant Neuromotor Assessment at a tertiary centre. If this assessment is normal, the infant can then be discharged to community clinic follow-up. Infants with more than one deviant sign at this age need continued review and those with more than three signs should be referred for neurodevelopmental therapy to a comprehensive neurodevelopmental clinic. Even those high-risk infants whose assessments are normal should be enrolled in a pre-school centre at five years of age to facilitate detection of learning problems prior to school entry.
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McLaughlin, Colleen. "NEURODEVELOPMENTAL FUNCTIONS FOR A TOLL RECEPTOR-DIRECTED IMMUNE SIGNALING PATHWAY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case154409968857386.
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Menzies, Caitlin. "Characterization of Metabolic Alterations in Mouse Models of Neurodevelopmental Disorders." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/42256.
Full textAbstract:
Background: Prevalence of metabolic disturbances is higher among individuals with neurodevelopmental disorders (NDDs), yet this association has been poorly studied. Investigation into human disease remains challenging, as a complete pathophysiological understanding relies on accurate modeling and highly controlled variables. As such, genetically engineered mouse models are increasingly used to gain insight into the biology of human NDDs, but preclinical research focus has been mainly on behavioral and neurophysiological abnormalities. Mouse models engineered to embody human-equivalent genetic variations can display discrepancies to human phenotypes, therefore a thorough characterization of mouse phenotypes must be conducted in order to evaluate how accurately a mouse model embodies a human phenotype. Also, mouse models can help discover unsuspected abnormalities that can be further validated in humans.
Objective: In this study, we sought to investigate the metabolic alterations derived from NDD-associated genetic polymorphisms in previously-validated genetic mouse models. Due to the similarities in NDD-associated phenotypic expression, we hypothesized that our NDDs of interest would express similar metabolic signatures. Further, we anticipated that we might uncover unknown metabolic anomalies, and that sex may alter these differences.
Methods: We used the Comprehensive Lab Animal Monitoring System coupled to EchoMRI, as well as quantification of key plasma metabolites by liquid chromatography-mass spectrometry to characterize and compare basal metabolism in three mouse models of NDDs, namely Down syndrome (Dp(16)Yey/+ mice), 16p11.2 deletion syndrome (16p11.2df/+ mice) and Fragile X syndrome (Fmr1-/- KO mice) and their wild-type (WT) counterparts.
Results: Our study reveals that each mouse model expresses a unique metabolic signature that is sex-specific, independent of the amount of food consumed and minimally influenced by physical activity. We found striking differences in body composition, respiratory exchange ratio, caloric expenditure and concentrations of circulating plasma metabolites related to mitochondrial function.
Conclusion: Providing novel insight into NDD-associated metabolic alterations provides a basis for future studies aimed at understanding physiological mechanisms and provides a point of reference for research aimed at detecting changes in response to intervention.
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D'Gama, Alissa Maria. "It Takes Brains: Germline and Somatic Mutations in Neurodevelopmental Disorders." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493415.
Full textAbstract:
The human brain can be affected by many diseases during its development, and human genetics studies can illuminate the genetic etiology of these diseases, which is critical for understanding disease pathophysiology, improving diagnoses, and developing effective therapies. In this thesis, I study genetic factors underlying neurodevelopmental disorders, focusing on the intractable epilepsy syndromes focal cortical dysplasia (FCD) and hemimegalencephaly (HME) and on autism spectrum disorder (ASD). My work investigates the role of both germline mutations, which are present in all cells of an affected individual, and somatic, or post-zygotic, mutations, which are present in only a subset of cells of an affected individual and frequently are undetectable in blood DNA.
FCD and HME are associated with intractable epilepsy, and show a small cortical region (FCD) or an entire cortical hemisphere (HME) that is radiographically and histologically abnormal, suggesting causation by somatic mutations. Our work and others have implicated mammalian target of rapamycin (mTOR) pathway mutations in these disorders. Studying 83 patients with FCD or HME using deep sequencing, we show that FCD and HME are caused by mutations that activate the mTOR pathway, and we expand the allelic and locus heterogeneity of these disorders, implicating mutations in DEPDC5 in HME and sporadic FCD and in TSC2 in HME. Overall, we identify pathogenic mutations, mostly somatic, in 22 patients with FCD or HME, representing almost half for whom brain tissue was available. We show for both FCD and HME that indistinguishable radiologic and histologic lesions can be caused by multiple genetic mechanisms, including somatic activating point mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5 and TSC2, usually with somatic loss-of-function mutations in the second allele of the same gene limited to the lesion. We also show that mutations in the same gene, and in some cases the same mutant allele, can cause a spectrum of phenotypes, from FCD to HME to bilateral brain overgrowth, likely reflecting both the developmental time window and progenitor cell type in which the mutation occurred. Single cell studies show that the mutations are enriched in specific cell types, and how the cell types involved reflect the progenitor cell type in which the mutation occurred.
Single nucleotide variants (SNVs), particularly loss-of-function mutations, are also significant contributors to the risk of autism spectrum disorder (ASD), which is characterized by deficits in social interaction and communication and restricted and repetitive behaviors, interests, or activities. Compared to FCD and HME, ASD is a relatively common neurodevelopmental disorder with greater genetic heterogeneity. We report the first deep sequencing study of 55 postmortem ASD brains for SNVs in 78 ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering, deleterious, or loss-of-function compared to controls, with recurrent deleterious mutations in well-known ASD genes like SCN2A, suggesting these mutations contribute to ASD risk. In six cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD cases and one Fragile X premutation case show deleterious somatic point mutations in ASD genes, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis. As for FCD and HME, our results suggest that ASD pathogenesis can involve interactions between somatic and germline mutations in some cases, emphasizing how the developmental history of the human brain modifies the germline genome.
Taken together, these studies show that different combinations of germline and somatic mutations contribute to both rare and common neurodevelopmental disorders, and that the time and place a mutation occurs is critical for determining its consequences in the human brain. We also demonstrate the utility of deep sequencing to discover somatic mutations, which may contribute to many other neurodevelopmental and neuropsychiatric diseases.Medical Sciences
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Hill, Sheri L. "Language, behavior, and neurodevelopmental delay in children of adolescent mothers /." Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/9132.
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