Prenatal opioid exposure has been studied in relation to infants' medical outcomes. However, large gaps exist in the literature supporting early identification of atypical neurobehavior and motor development of infants with prenatal opioid exposure. The purpose of the study was to investigate whether prenatal opioid exposure has a negative influence on a newborn infant’s neurobehavior and motor development to aid in the early identification of potential delays. Using a prospective quasi experimental design, infants motor development using the Test of Infant Motor Performance (TIMP) and neurobehavior using the NICU Neonatal Network Scale (NNNS) was assessed on 58 infants in a hospital setting. Even after statistically controlling for covariates both the TIMP and the six out of twelve subscales of the NNNS: attention, handling, self-regulation, arousal, excitability, and stress were significantly different between the two groups of infants. Infants’ TIMP z-scores were significantly correlated with the NNNS subscales of attention, handing, self-regulation, arousal, excitability, hypertonicity, non-optimal reflexes, and stress. The findings highlight the similarities between the two groups and the outcome measures used for early identification of infants at-risk for delays following prenatal opioid exposure. The neonatal outcomes described here, including growth deficits, motor delays and altered neurobehavior are critical given their association with longer-term health and developmental impacts.

Small interfering RNAs (siRNAs) are a promising class of drugs for treating genetically-defined diseases. Therapeutic siRNAs enable specific modulation of gene expression, but require chemical architecture that facilitates efficient in vivodelivery. siRNAs are informational drugs, therefore specificity for a target gene is defined by nucleotide sequence. Thus, developing a chemical scaffold that efficiently delivers siRNA to a particular tissue provides an opportunity to target any disease-associated gene in that tissue. The goal of this project was to develop a chemical scaffold that supports efficient siRNA delivery to the brain for the treatment of neurodegenerative diseases, specifically Huntington’s disease (HD). HD is an autosomal dominant neurodegenerative disorder that affects 3 out of every 100,000 people worldwide. This disorder is caused by an expansion of CAG repeats in the huntingtin gene that results in significant atrophy in the striatum and cortex of the brain. Silencing of the huntingtin gene is considered a viable treatment option for HD. This project: 1) identified a hyper-functional sequence for siRNA targeting the huntingtin gene, 2) developed a fully chemically modified architecture for the siRNA sequence, and 3) identified a new structure for siRNA central nervous system (CNS) delivery—Divalent-siRNA (Di-siRNA). Di-siRNAs, which are composed of two fully chemically-stabilized, phosphorothioate-containing siRNAs connected by a linker, support potent and sustained gene modulation in the CNS of mice and non-human primates. In mice, Di-siRNAs induced potent silencing of huntingtin mRNA and protein throughout the brain one month after a single intracerebroventricular injection. Silencing persisted for at least six months, with the degree of gene silencing correlating to guide strand tissue accumulation levels. In Cynomolgus macaques, a bolus injection exhibited significant distribution and robust silencing throughout the brain and spinal cord without detectable toxicity. This new siRNA scaffold opens the CNS for RNAi-based gene modulation, creating a path towards developing treatments for genetically-defined neurological disorders.

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<p>This thesis presents research investigating structural neural correlates of major depressive disorder (MDD). Although there are clear clinical differences between early- and late-onset MDD, they are still subject to the same diagnostic criteria and treatment strategy. Whether these differences translate into differences in cortical structure was examined in this study. By directly comparing early-onset (EOD) and late-onset (LOD) patients, we test whether age-of-onset results in changes in the extent or spatial pattern of cortical thinning.</p> <p>Chapter 1 provides a general background on the cerebral cortex, followed with a focus on cortical thickness. Chapter 2 presents a comprehensive review of the clinical and neurobiological literature on major depressive disorder as it pertains to age-of-onset. Three working hypotheses regarding the differences between early- and late-onset depression are presented and discussed.</p> <p>The results presented in this thesis show that there are both differences and similarities in cortical thickness between patients with EOD and LOD, with differences reflecting spatial extent, region-specificity, and magnitude of thickness differences. We confirmed the hypothesis of greater thinning in the dorsal lateral prefrontal cortex in depressed patients compared to healthy controls. We also correlated cortical thickness with clinical variables, which resulted in the finding of a positive correlation in the posterior cingulate cortex with illness severity.</p> <p>Few studies have used age-of-onset as a factor, which may account for some of the heterogeneity and inconsistent results seen in studies of MDD. We found that depression onset in early life is associated with greater disturbances in cortical thickness than LOD, possibly reflecting atypical development. These results provide novel insights into vulnerability and how development of depression is differentially affected by age.</p> / Master of Science (MSc)

<p>Aging erodes motivation, cognition, sensory modalities and physical capacities, effectively depleting quality of life. Declining sensory, cognitive and motor function are reliable biomarkers of aging and mortality risk. These declines are associated with dysregulation of systemic and cellular processes. We developed a complex dietary supplement (DSP) designed to ameliorate five mechanisms of aging (oxidative processes, inflammation, mitochondrial function, insulin resistance and membrane integrity). Remarkably, normal mice fed the DSP retained youthful functionality into old ages, reflecting slower aging rates. Marked improvements in motor function, memory capacity, spatial learning, muscle strength, visual acuity, olfaction, fecundity and important behavioral functions were observed in aging supplemented mice. Conversely, untreated control animals showed age-related declines in all of the above. Functional improvements were associated with reduced oxidative damage, elevated mitochondrial activity, positive cellular energy balance, improved glucose tolerance, boosted neurotransmitters, greater synaptic density and higher neuronal numbers throughout the brain. A 30% reduction in cancer rates was also documented for DSP treated p53+/- mice. The vast functional benefits greatly exceed the modest longevity extension (11%) in normal supplemented mice. For aging humans, maintaining functionality and performance into later years may provide greater socioeconomic and health benefits than simply prolonging lifespan. Implications of these findings extend to common age-related pathologies including dementia and neurodegenerative diseases, diabetes, cancer, sarcopenia and age-related macular degeneration. Although identifying the role of specific ingredients remains outstanding, results provide proof of principle that complex dietary cocktails can powerfully ameliorate biomarkers of aging and modulate mechanisms considered ultimate goals for aging interventions.</p> / Doctor of Philosophy (PhD)

Attention uses sensory inputs and goals to select information from our environment. Monkey electrophysiological literature demonstrates that visuo-tactile bimodal neurons (respond to visual and tactile stimuli presented on/near the hand) facilitate multisensory integration. Human behavioral studies show that hand position/function bias visual attention. Event-related potentials (ERPs) reveal the cortical dynamics coordinating visual inputs, body position, and action goals. Early, sensory ERPs (N1) indicate multisensory integration. Later, cognitive ERPs (P3) reflect task-related processing. Study 1 investigates a discrepancy between monkey and human literatures. Monkey studies demonstrate bimodal neuron responses equidistantly around the whole hand, but human studies demonstrate attentional bias for grasping space. In a visual detection paradigm, participants positioned their hand so target and non-target stimuli appeared near the palm or back of the hand; ERPs were measured. N1 components indicated no amplitude differences between Palm vs. Back conditions, but P3 components revealed greater target vs. non-target differentiation for Palm conditions. Results suggest cortical timing underlies grasping vs. whole hand bias differences: early processing does not differentiate using hand function, but cognitive processing does when stimuli are discriminated for action. Study 2 investigates whether proprioceptive inputs facilitate visual processing. In a visual detection paradigm, participants viewed stimuli presented between occluders blocking view of a hand positioned either near or far from the stimuli. N1 amplitudes were similar for near and far conditions, but P3 amplitudes for target/non-target differences were accentuated for near conditions. Proprioceptive effects emerge later in processing. ERP reveals the cortical dynamics underlying hand position effects on vision.

Thesis (MEng)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Muscular dystrophy, spinal cord injury, or amyotrophic lateral sclerosis (ALS) are injuries and disorders that disrupts the neuromuscular channels of the human body thus prohibiting the brain from controlling the body. Brain computer interface (BCI) allows individuals to bypass the neuromuscular channels and interact with the environment using the brain. The system relies on the user manipulating his neural activity in order to control an external device. Electroencephalography (EEG) is a cheap, non-invasive, real time acquisition device used in BCI applications to record neural activity. However, noise, known as artifacts, can contaminate the recording, thus distorting the true neural activity. Eye blinks are a common source of artifacts present in EEG recordings. Due to its large amplitude it greatly distorts the EEG data making it difficult to interpret data for BCI applications. This study proposes a new combination of techniques to detect and correct eye blink artifacts to improve the quality of EEG for BCI applications. Independent component analysis (ICA) is used to separate the EEG signals into independent source components. The source component containing eye blink artifacts are corrected by detecting each eye blink within the source component and using a trained wavelet neural network (WNN) to correct only a segment of the source component containing the eye blink artifact. Afterwards, the EEG is reconstructed without distorting or removing the source component. The results show a 91.1% detection rate and a 97.9% correction rate for all detected eye blinks. Furthermore for channels located over the frontal lobe, eye blink artifacts are corrected preserving the neural activity. The novel combination overall reduces EEG information lost, when compared to existing literature, and is a step towards improving EEG pre-processing in order to provide cleaner EEG data for BCI applications. / AFRIKAANSE OPSOMMING: Spierdistrofie, ’n rugmurgbesering, of amiotrofiese laterale sklerose (ALS) is beserings en steurnisse wat die neuromuskulêre kanale van die menslike liggaam ontwrig en dus verhoed dat die brein die liggaam beheer. ’n Breinrekenaarkoppelvlak laat toe dat die neuromuskulêre kanale omlei word en op die omgewing reageer deur die brein. Die BCI-stelsel vertrou op die gebruiker wat sy eie senuwee-aktiwiteit manipuleer om sodoende ’n eksterne toestel te beheer. Elektro-enkefalografie (EEG) is ’n goedkoop, nie-indringende, intydse dataverkrygingstoestel wat gebruik word in BCI toepassings. Nie net senuwee aktiwiteit nie, maar ook geraas , bekend as artefakte word opgeneem, wat dus die ware senuwee aktiwiteit versteur. Oogknip artefakte is een van die algemene artefakte wat teenwoordig is in EEG opnames. Die groot omvang van hierdie artefakte verwring die EEG data wat dit moeilik maak om die data te ontleed vir BCI toepassings. Die studie stel ’n nuwe kombinasie tegnieke voor wat oogknip artefakte waarneem en regstel om sodoende die kwaliteit van ’n EEG vir BCI toepassings te verbeter. Onafhanklike onderdeel analise (Independent component analysis (ICA)) word gebruik om die EEG seine te skei na onafhanklike bron-komponente. Die bronkomponent wat oogknip artefakte bevat word reggestel binne die komponent en gebruik ’n ervare/geoefende golfsenuwee-netwerk om slegs ’n deel van die komponent wat die oogknip artefak bevat reg te stel. Daarna word die EEG hervorm sonder verwringing of om die bron-komponent te verwyder. Die resultate toon ’n 91.1% opsporingskoers en ’n 97.9% regstellingskoers vir alle waarneembare oogknippe. Oogknip artefakte in kanale op die voorste lob word reggestel en behou die senuwee aktiwiteit wat die oorhoofse EEG kwaliteit vir BCI toepassings verhoog.

Reinforcement learning occurs when organisms adapt the propensities of given behaviours on the basis of associations with reward and punishment. Currently, reinforcement learning models have been validated in minimalist environments in which only 1-2 environmental stimuli are present as possible predictors of reward. The exception to this is two studies in which the responses of the dopamine system to configurations of multiple stimuli were investigated, however, in both cases the stimuli were presented simultaneously rather than in a sequence. Therefore, we set out to understand how current models of reinforcement learning would respond under more complex conditions in which sequences of events are predictors of reward. In the two experimental chapters of this thesis, we attempted to understand whether midbrain dopaminergic neurons would respond to occasion setters (Chapter 3), and to the overexpectation effect (Chapter 4). In addition, we ran simulations of the behavioural paradigms using temporal difference models of reinforcement learning (Chapter 2) and compared the predictions of the model with the behavioural and neurophysiological data. In Chapter 3, by performing single-neuron recording from VTA and SNpc dopaminergic cells, we demonstrated that our population of neurons were most responsive to the latest predictor of reward, the conditioned stimulus (CS) and not the earliest, the occasion setter (the OS). This is in stark contrast with the predictions of the model (Chapter 2), where the greatest response is seen at the OS onset. We also showed at a neural level that there was only a weak enhancement of the response to the discriminative stimulus (SD) when this was preceded by the OS. On the other hand, at a behavioural level, bar pressing was greatest when the SD was preceded by the OS, demonstrating that rats could use the information provided by the OS, but that dopamine was not controlling the conditioned response. In Chapter 4, our population of dopaminergic neurons showed that they would preferentially respond to only one of the two conditioned stimuli (CSA, CSB) in the overexpectation paradigm. The predictions of the model (Chapter 2) suggested that when the two stimuli would be presented in compound, there would be an inhibitory response if the reward magnitude was kept constant and an excitatory response if the reward magnitude was doubled. The lack of neural firing to one of the two conditioned stimuli, however, does not make for easy interpretation of the data. Perhaps, one of the conditioned stimuli acted as if it were overshadowing the other, resulting in no response to the second CS. Interestingly, at a behavioural level, we did not see increased licking frequency to the compound stimuli presentation, a result that is somewhat at odds with the previous literature. Overall, the results of our experimental chapters suggest that the role that midbrain dopaminergic neurons play in reinforcement learning is more complex than that envisaged by previous investigations.

Reactive oxygen species (ROS) is cytotoxic to the cell and is known to contribute to secondary cell death following primary traumatic brain injury (TBI). We described in our study that PN is the main mediator for both lipid peroxidation and protein nitration, and occurred almost immediately after injury. As a downstream factor to oxidative damage, the peak of Ca2+-dependent, calpainmediated cytoskeletal proteolysis preceded that of neurodegeneration, suggesting that calpain-mediated proteolysis is the common pathway leading to neuronal cell death. The time course study clearly elucidated the interrelationship of these cellular changes following TBI, provided window of opportunity for pharmacological intervention. Furthermore, we conducted a pharmacological study to solidify our hypothesis. First of all, we tested the potency of a membrane permeable, catalytic scavenger of PN-derived free radicals, tempol for its ability to antagonize PN-induced oxidative damage. Tempol successfully inhibited PNinduced protein nitration at dosages of 30, 100 and 300mg/kg. Moreover, early single dose of 300mg/kg was administered and isolated mitochondria were examined for respiratory function and oxidative damage level. Our data showed that tempol reduced mitochondrial oxidative damage, and maintained mitochondrial function within normal limits, which suggested that tempol is efficiently permeable to mitochondrial membrane and mitochondrial oxidative damage is essential to mitochondrial dysfunction. Next, we found that calpainmediated proteolysis is reduced at early treatment with a single dose of tempol. However, the effect of tempol on calpain is short-lived possibly due to systematic elimination. In our multiple dose study, tempol showed a significant inhibitory effect on SBDPs. Consequently, we measured neuordegeneration with the de Olmos aminocupric silver staining method at 7 days post-injury and detected a significant decrease of neuronal cell death. Together, the time course study and pharmacological study strongly support the hypothesis that PN is the upstream mediator in secondary cell death in the CCI TBI mouse model. Moreover, inhibition of PN-mediated oxidative damage with the antioxidant, tempol, is able to attenuate multiple downstream injury mechanisms. However, targeting PN alone may be clinically impractical due to its limited therapeutic window. This limitation may be overcome in future studies by a combination of multiple therapeutic strategies.