Thesis (MSc)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: Although the neurodevelopmental therapy (NDT) treatment approach is used extensively in the management of children with cerebral palsy, there is currently very little documented research to support its efficacy. The purpose of this study was to evaluate the efficacy of NDT in terms of its effect on motor function in a group of 10 cerebral palsy children. A multiple simple single-subject design was used in which the children each acted as their own controls. A 5 week baseline period, during which no intervention was received by the children, was followed by a 5 week intervention phase during which the children received twice weekly NDT treatment. The children were assessed at the beginning and end of each phase using the Gross Motor Function Measure (GMFM), and an assessment tool, which allowed the establishment of individualised outcome measures, called TELER. The group of children demonstrated no statistically significant gains in motor function on either of the outcome measures during the baseline phase of the study. However during the intervention phase the overall improvements demonstrated by the group on both the GMFM and TELER were statistically significant. Nine out of the ten children achieved greater improvements in their goal total GMFM scores during the intervention phase than during the baseline phase. Similarly all of the children achieved a greater number of clinically significant improvements on the TELER outcome measures. NDT was beneficial and useful in promoting motor function in this group of cerebral palsy children. / AFRIKAANSE OPSOMMING: Alhoewel die Neuro-ontwikkelingsterapie (NOT) behandelingsbenadering wydeverspreid gebraik word in die behandeling van kinders met serebrale verlamming, is daar huidiglik baie min gedokumenteerde navorsing om die effektiwiteit daarvan te staaf. Die doel van hierdie studie was om die effektitiwiteit van NOT te evalueer met betrekking tot die impak daarvan op die motoriese funksie van ‘n groep van 10 kinders met serebrale verlamming. ‘n Veelvuldige eenvoudige enkeling -subjek raamwerk is gebruik waarvolgens die kinders elk as hul eie kontrolegoep ageer het. ‘n 5-weke basislyn fase, waartydens die kinders aan geen intervensies onderwerp is nie, is gevolg deur ‘n 5-weke intervensie fase waartydens die kinders twee keer per week NOT behandeling ontvang het. Die kinders is geevalueer aan die begin en einde van elke fase met die Oorhoofse Motoriese Funksie Maatstaf (OMFM)/Gross Motor Function Measure (GMFM), asook ‘n evalueringsmaatstaf genaamd TELER, wat die bepaling van geindivualiseerde resultate moontlik gemaak het. Die groep kinders het geen statistics bewese vordering in motoriese fiinksies getoon volgens beide die evalueringsmaatstawwe tydens die basislyn fase van die studie nie. Daarteenoor het die groep tydens die intervensie fase oorhoofs gesproke statistics bewese vordering getoon met betrekking tot beide die OMFM en die TELER. Nege uit die 10 kinders het groter vordering getoon met hul totale OMFM resultate tydens die intervensie fase as gedurende die basislyn fase. A1 die kinders het tegelykertyd ‘n groter hoeveelheid substantiewe kliniese verbeterings getoon met betrekking tot hul TELER uitkomste. NOT was voordelig en nuttig in terme van die verbetering van motoriese funksie in die groep van serebraal verlamde kinders.

Thesis (MScSportSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Autism Spectrum Disorder (ASD) has been described as a neuro-developmental disorder influencing the social interaction and communication skills of individuals. Those with ASD have been observed to experience sensory input challenges, which could result in motor delays. Descriptive research was conducted with two case studies, who were boys aged 6- and 8-years, diagnosed with ASD. The purpose of the study was to design and implement a Sensory-Motor Integration (SMI) programme for each boy and to assess the effect it had on the sensory motor skills of the boys over time. At the start of the intervention, the boys were assessed with three neuro-developmental and diagnostic evaluations (Social Communication Questionnaire, Autism Diagnostic Interview Revised and Autism Diagnostic Observation Schedule-2nd Edition) conducted by a psychiatrist to re-affirm their previous ASD diagnoses. The two boys (Subject A and Subject G) participated in individualised sessions of 30 minutes each, twice a week for seven months. The SMI programme focused on vestibular and somato-sensory (proprioceptor) variables. The Quick Neurological Screening Test-3 (QNST III) and the Sensory Input Systems Screening Test (SISST) were used to evaluate the latter at baseline. These were repeated regularly, every 4 to 5 weeks, over the 7-month period and included a retention test of 5 weeks. Based on the results from the subtests of the motor skill tests, a self-designed SMI programme was integrated into the planning of the intervention programme for each boy according to their sensory-motor needs. Subject A showed improvement in the following vestibular subtests in the QNST-III: Stand on one leg (67%) and Tandem walk (83%) and retaining his standard from the Post-test to the Retention test. For muscle tone ability and proprioception, the Arm and leg extension subtest also demonstrated improvement (67%) from the Pre-to the Post-test. The results of the subtest were not retained over the retention period and increased only slightly being 33% from the baseline score. The proprioceptive function of Subject A showed great improvement in the following QNSTIII subtests: Finger to nose (67%), Rapidly reversing repetitive hand movements (88%) and Left and right discrimination (67%). The results of vestibular-related subtests for Subject G showed improvement in the following: Stand on one leg (33%) and the Arm and leg extension task (33%). Some of the scores of Subject G started in the functional category of “severe discrepancy”; however there was improvement in the following proprioceptionrelated subtests: Finger to nose (43%), Thumb and finger circles (20%), and Reversing repetitive hand movements (86%). Although Subject G showed gradual improvement over time, his two sensory systems struggled to integrate with the more complex tasks. The outcome of the individualised SMI programmes showed that the sensory-motor skills improved by enhancing the stimulation of their vestibular and somato-sensory (proprioception) function. Regarding the SISST, Subject A progressed from a ‘fail’ to ‘pass’, in the following test items: the Tonic Labyrinthine Supine (TLS), Tonic Labyrinthine Prone (TLP), Positive Support Reflex (PSR) and the Ocular Alignment test items. Results from the Vestibular test for both Subject A and Subject G appeared to be ‘hypo-vestibular’ (under-stimulated) according to the Post- Rotary Nystagmus test (PRN) score at baseline. These scores were inconsistent during the intervention. The only test item to show positive improvement for Subject G was the Equilibrium Reactions. Lastly, both Subject A and Subject G remained in the ‘fail’ category for Kinaesthesis, which may indicate their ongoing poor proprioception and spatial orientation. There is a need for further research in the area of sensory-motor individualised programmes for children with ASD. Suggestions for future research interventions are to conduct the individualised programmes either over a longer period of time and more frequently at three times a week. / AFRIKAANSE OPSOMMING: Outisme Spektrum Versteuring (OSV) word beskryf as 'n neuro-ontwikkelingsversteuring wat die sosiale interaksie en kommunikasie van individue beïnvloed. Daar is waargeneem dat diegene met OSV, uitdagings met betrekking tot sensoriese insette ervaar, wat kan lei tot motoriese agterstande. Beskrywende navorsing is toegepas met twee gevalle-studies. Die ouderdom van die twee seuns wat met outisme gediagnoseer was, was 6- en 8-jaar oud. Die doel van die studie was om ʼn Sensories-Motoriese Integrasie (SMI) program te ontwikkel en te implementeer as intervensie wat op elk van die seuns spesifiek toegespits is. Die intervensie-program het voorsiening gemaak om aan die uitvoering van bepaalde motoriese vaardighede aandag te skenk en om die uitwerking daarvan oor die 7-maande tydperk te assesseer. Die twee seuns (Geval A en Geval G) het individuele sessies van 30 minute elk twee keer per week bygewoon. Die SMI program het op die vestibulêre en somato-sensoriese (proprioseptor) sisteme gefokus om hul vermoë en vordering waar te neem. Aan die begin van die studie is drie neuro-ontwikkelings- en diagnostiese meetinstrumente (SCQ, ADIR-R en ADOS) deur 'n psigiater gelei om die vorige OSV diagnose van die seuns te bevestig. Die “Quick Neurological Screening Test” (QNST III) en die “Sensory Input Systems Screening Test“ (SISST) is benut om hul aanvangsvermoë as basislyn te bepaal. Hierdie toetse was gereeld herhaal, elke 4 tot 5 weke oor ʼn tydperk van 7 maande en het ʼn retensie toets van 5 weke ingesluit. Op grond van die resultate van die sub-toetse van die vermelde motoriese vaardigheidstoetse, is die self-ontwerpte SMI intervensie-program vir elke seun, volgens sy persoonlike sensoriese-motoriese behoeftes, beplan. Geval A het verbetering getoon in die volgende QNST-III sub-toets: Staan op een been (67%) en Tandemloop (83%), en handhaaf sy standaard vanaf die na-toets tot en met die retensie toets. Vir spiertonus en propriosepsie, het die Arm- en been-ekstensie sub-toets ook ʼn verbetering (67%) van die voor-toets tot die na-toets getoon. Die resultaat van hierdie subtoets is nie oor die hele tydperk gehandhaaf nie, en het net effens verhoog (33%) van die basislyn telling. Die proprioseptiewe funksie van Geval A het 'n groot verbetering in die volgende QNST-III sub-toetse getoon: Vinger na neus (67%), Vinnige omkeer, herhalende hand bewegings (88%) en Links en regs diskriminasie (67%). Geval G se resultate vir die vestibulêre-verwante sub-toetse het verbetering in die volgende getoon: Een been staan (33%) en Arm- en Been-ekstensie (33%). Sommige van die resultate van Geval G het op 'n ernstige diskripansie begin, maar daar was verbetering in die volgende proprioseptiewe verwante sub-toetse: Vinger na neus (43%), Duim en vinger sirkels (20%) en Vinnige omkeer, herhalende hand bewegings (86%). Ten spyte daarvan dat Geval G ʼn geleidelike verbetering oor tyd getoon het, het sy twee sensoriese stelsels gesukkel om met die meer komplekse take met mekaar te integreer. Die uitkoms van die geïndividualiseerde SMI programme het getoon dat die sensoriesemotoriese vaardighede by beide seuns verbeter as gevolg van die verbeterde stimulering van hul vestibulêre en somato-sensoriese (proprioseptiewe) funksie. Die SSIST resultate toon dat Geval A van ‘druip’ na ‘slaag’ in die volgende toetsitems gevorder het: Tonic Labyrinthine Supine (TLS), Tonic Labyrinthine Prone (TLP), Positive Support Reflex (PSR) en die Ocular Alignment toetsitems. Resultate van die vestibulêre toets, blyk dit dat sowel Geval A as Geval G ‘hipo-vestibulêr’ (onder-gestimuleer) was volgens die “Post-Rotary Nystagmus toets” (PRN) meting wat by die basislyn toetsing behaal is. Hierdie tellings was veranderlik tydens die intervensie. Die enigste toetsitem wat ʼn positiewe verbetering by Geval G getoon het, was die Ekwilibriumsreaksie. Laastens, beide Geval A en Geval G het in die ‘druip’ kategorie vir Kinestese gebly wat daarop dui dat hul swak propriosepsie en ruimtelike oriëntasie steeds teenwoordig was. Daar is 'n behoefte aan verdere navorsing op die gebied van sensoriese-motoriese individuele programme vir kinders met OSV. Toekomstige navorsing wat individuele programme benut, moet oorweeg om die intervensie oor ʼn langer tydperk (bv. een jaar) te laat geskied met meer sessies per week (bv. drie sessies).

In vitro models are often used both to characterize and test therapeutics for neurodevelopmental disorders (‘NDDs’). While in vitro models have extraordinary potential to develop therapies for patients, they have historically been confounded by absence of robust phenotypes and/or in vitro phenotypes that fail to translate from laboratory bench to bedside. Within this thesis work, we attempt to address three areas in which in vitro models may be improved – gene selection, model validation and identification of disease-relevant functional assays suited for therapeutic testing. Publicly available databases aggregating identified and annotated disease-causing variants for Mendelian diseases have rapidly expanded over the past two decades. Elucidating mechanisms of disease and developing therapies using in vivo model systems often is both time and cost intensive. Thus, determining which subsets of genes are more likely to generate addressable signals in a dish may lead to more effective drug development. In chapter 1, we identify a set of genes ideally suited for therapeutic inhibition. Specifically, we leverage the aforementioned large genetic databases to identify a set of genes likely to act through a gain-of-function mechanism that are both tolerant to loss-of-function mutations and in the druggable genome. In chapter 2, we aim to characterize the degree of conservation of transcriptomic dysregulation between a human in vitro cortical organoid (‘hCOs’) model, and two mouse models of a severe neurodevelopmental disorder resulting from HNRNPU deficiency. Human model systems may improve upon animal models when human pathogenesis and patient phenotypes are divergent from animal models due to species-specific etiology. However, human model systems often lack the heterogeneity and cell-type specificity and maturity seen in primary fetal samples. Importantly, some mouse models of HNRNPU deficiency have muted phenotypes compared with human patients. We hypothesized that while there are distinctions between humans and mice with HNRNPU deficiency, there will be overlap in transcriptomic dysregulation between human and mouse models. In fact, we find 45-day-old HNRNPU+/- hCOs have consistent transcriptomic dysregulation to embryonic mouse models, but not to perinatal mice. Our findings suggest hCOs are a viable model for characterizing HNRNPU deficiency; however, such models may only be appropriate for elucidating a transcriptomic disease state at a specific developmental time period. Functional assays for neurodevelopmental disorders can aid in understanding whether transcriptomic dysregulation is relevant to patient symptoms, as genomic findings may not always correlate to disease-relevant phenotypes. Further, relevant functional phenotypes can then be utilized for testing potential therapeutics. Importantly, seizures are commonly present in a significant subset of neurodevelopmental disorders and seizure phenotypes have been described as driven by aberrant synchrony in neuronal networks. Using a multielectrode array platform, investigators can use a variety of computational methods to quantify aspects of synchrony in vitro. In chapter 3a, we introduce topological approaches capable of identifying novel synchrony phenotypes in primary neuronal networks from mouse models of neurodevelopmental disorders. Certain mouse models will be confounded by species-specific pathogenesis and/or vastly different developmental timelines and fail to generalize to human patients, motivating the need for functionally active and physiologically relevant human in vitro models. In chapter 3b, we attempt to generate human networks with balanced levels of excitation and inhibition and find confounding lack of functional maturation of inhibitory neuronal subtypes in 90-day-old stem cell-derived neuronal networks. Future work generating in vitro human neuronal networks with functionally mature inhibitory neurons would complement the findings in chapters 1 and 2 and allow for more efficient therapeutic development strategies that may lead to improved patient outcomes.

Aim: The aim of the study is to gain deeper understanding into the lived experiences of parents at a stimulation centre in KwaZulu-Natal, South Africa, and the coping strategies they employ in caring for their children with Autism Spectrum Disorder (ASD). Significance: As literature has focused on international studies this study has provided deeper understanding of the lived experiences and coping strategies of parents of children with ASD in a local setting within South Africa. Experiences across the age spectrum of children, gendered differences in coping and the meaning behind having a child with ASD provides a unique outlook on ASD as opposed to literature that focuses on other areas. Methods: Eleven parents participated in semi-structured interviews. These interviews were triad, dyad or one-on-one interviews. Interviews were audiotaped and transcribed verbatim once completed. Thematic analysis was used to analyze the data and extract themes. Findings: The lived experiences of parents included stressful and devastating experiences as well as positive meaning. Daily challenges were navigated by positive and negative coping strategies with gendered differences in coping being evident. Parents expressed mixed feelings about the benefits of support groups and provided a road map of advice for other parents of children with ASD. Conclusion: Parents of children with ASD undergo enormous stress and emotional upheaval in caring for their children. However in addition to negative experiences, they gain some positive meaning and see it as character building. Their experiences provide useful information for other parents undergoing the same journey. / Thesis (M.O.T.)-University of KwaZulu-Natal, Durban, 2013.