This thesis investigates the functional neuroanatomy of SAD [Social Anxiety Disorder] using an activation likelihood-estimate meta-analysis (ALE meta-analysis), and explores the structural basis of SAD using a cortical thickness and subcortical gray matter volume analysis.

Background: Methamphetamine (MA) abuse is a growing problem in the world and especially in South Africa’s Western Cape. Amphetamine-type stimulants have become the second most widely abused illicit drugs worldwide. Admission data from substance abuse treatment centres in the Western Cape show the fastest increase for any drug ever noted in the country in MA related admissions. MA has neurotoxic effects on the brain leading, amongst other effects, to white matter (WM) changes. Moreover, increased levels of aggression are commonly found in individuals with MA abuse. Although behavioural deficits are well described, the underlying mechanisms are still poorly understood. While previous studies have examined WM abnormalities relating to cognitive impairment, none have investigated associations between WM integrity in individuals with MA dependence and aggression. Methods: Diffusion Tensor Imaging (DTI) was used to investigate WM changes in 40 individuals with MA dependence and 40 matched healthy control subjects. Aggression was measured with the Buss & Perry Questionnaire in 40 MA users and 36 controls. Two approaches to assess WM integrity in the brain were employed. First, whole brain voxel wise comparison across subjects using tract based spatial statistics (TBSS) in FSL was used. Fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (λ║) and perpendicular diffusivity (λ┴) were compared between the two groups. Second, a region of interest (ROI) approach was used, which focused on three WM tracts in the frontal brain, commonly found to play a role in aggressive behaviour: (1) the genu of the corpus callosum (CC), (2) the cingulum and (3) the uncinate fasciculus.

Includes bibliographical references. / Repeated maternal separation (MS) has been reported to induce changes in hypothalamic-pituitary- adrenal (HPA) axis activity leading to abnormal stress responses later in life. Such alterations have also been linked to poor cognitive function. In contrast, exercise enhances cognitive function. Previously, we reported that MS improved object location memory. However, exercise had no effect on object location memory despite increases in levels of synaptophysin and phospho-extracellular signal-regulated protein kinase (pERK) in the hippocampus of non-separated-exercised rats. In the current study, the same MS technique and three-week voluntary exercise regimen were tested to determine their effect on spatial learning in young adult Sprague-Dawley (SD) rats. A total of 144 rats were either maternally separated from postnatal day 2 to 14 or designated as controls. At postnatal day 50, rats were transferred to cages with attached running wheels. Approximately half of the rats were allowed to exercise voluntarily in the wheels whilst the wheels attached to the cages of the remaining non-exercising rats were immobilised. Rats were divided into 3 cohorts. Cohort 1 provided baseline levels of pERK, mitogen-activated protein kinase phosphatase-1 (MKP-1) and brain derived neurotrophic factor (BDNF) after exercise. Cohorts 2 and 3 were trained in the Morris Water Maze (MWM) 1 and 15 days post-exercise, respectively. Consistent with our previous findings, pERK was increased in non-separated-exercised rats post-exercise. MKP-1, the regulator of pERK, was also increased in the non-separated-exercised group. BDNF was decreased in the MS non-exercised group but augmented by exercise. All groups trained immediately after exercise performed similarly in the MWM but MS rats from cohort 3 had better reversal spatial memory. According to these results, repeated MS decreased neurotrophic factors but did not alter the plasticity-related proteins measured in this study. However, this phenomenon was not associated with performance in the spatial learning and memory task in the MWM. These current observations support our previous findings that MS can cause adaptations that lead to improved learning and memory in adulthood.

Background Autism Spectrum Disorder (ASD) affects individuals from all continents, cultures and socio-economic backgrounds. It presents differently in different individuals and functional outcomes can be highly variable dueto the heterogenous nature of ASD. The context or environment in which individuals live interacts with the core characteristics of ASD to determine functional ability or disability. For this reason the World Health Organization International Classification of Functioning, Disability and Health (ICF) includes environmental factors when measuring and describing functioning. ICF core sets for ASD were recently developed, and included a qualitative study with perspectives from five highly divergent countries (Canada, Sweden, India, Saudi Arabia and South Africa). It is, however, not known whether functional themes in these diverse environments were similar or different. We hypothesized that environmental factors would predominate in low-resource settings where they would be perceived as barriers to functioning. Objectives The purpose of this study was therefore to examine the association between context and functional ability/disability in children with ASD. We aimed firstly, to understand the global landscape of parental perceptions of functioningin their children with ASD. Secondly, we set out to compare and contrast parental perceptions of functioning in two of the most divergent countries that participated in the ICF core set development study. We were interested in the frequency of functional items reported by parents/caregivers from a high- income country and a low/middle income country. We were also interested in the content of the functional items reported by parents/caregivers in these two countries. We selected Sweden as example of a high-income country (HIC), and South Africa, as example of a low/middle-income country (LMIC). Methods To meet the first aim, we performed a scoping review. Two researchers conducted a comprehensive search of peer reviewed studies published between 1990 and June 2016. Full-text of all included articles were accessed and summarized using thematic analysis. Key findings relating to the scoping review question were linked to ICF-CY first or second-level categories. To meet the second aim, we performed secondary analysis of qualitative data from the ICF ASD core set study. Using frequency and content analysis we compared South African (n=22) and Swedish (n=13) participants. The identified ICF-CY categories were ranked and compared for similarities and dissimilarities in frequency of reporting and analyzed for similarities and dissimilarities in the content of themes. Results Thirty three studies were included in the scoping review, and most were conducted in HIC (n = 25/33, 76%) with only six studies in LMIC (n = 6/33, 18%). Two studies compared perspectives from LMIC and HIC (n = 2/33, 6%). Functional themes from HIC included a range across the ICF bio- psychosocial framework with body functions, activities & participation, environmental factors and personal factors all represented. Functional themes from LMIC were predominantly focused on environmental and personal factors. We did, however, acknowledge that different methodologies may have biased findings in HIC versus LMIC. Secondary analysis of the ICF ASD Core set qualitative study therefore used data collected in identical manner in South Africa and Sweden. Complete frequency agreement was seen in 4 ICF categories in thetwo countries - three activities & participation categories (carrying out daily routines, dressing, complex interpersonal interactions), and one environmental factor (immediate family). Obvious differences in frequency of reporting were observed in one environmental factors category (health professionals), six body functions categories (e.g. involuntary movement functions, gait patterns, basic cognitive functions, and mental functions of language), and three activities & participation categories (managing one’s own behaviour, speaking, and undertaking a single task). Only three ICF categories (immediate family, attention functions, products and technology for personal use in daily living) differed in content between South Africa and Sweden. Two additional categories were identified namely health professionals and sensory processing. Conclusions Contrary to our hypotheses few differences in parent/caregiver perspectives about environmental factors relevant to functioning in ASD emerged. Perceptions more frequently differed regarding body functions andactivities & participation. The content of perceptions were, with a few exceptions, similar. Our results suggest that the interaction between context and functioning is more complex than we predicted and highlights the importance of subjective perception of contextual factors in relation to functional ability/disability. Given the universality of findings, our results therefore support the global usefulness of the recently developed ICF core sets for ASD. We recommend that more comparative studies on ASD and functioning should be conducted, and that similar comparisons in other disorders where core sets have been developed, such as ADHD, may also be of value.

Includes abstract. Includes bibliographical references.

Maternal separation (MS) has been shown to produce depression-like symptoms in male Sprague Dawley rats. The underlying mechanisms responsible for the development of these depression-like behaviors are unknown. However, a growing body of evidence suggests that a reduction in neurogenesis may be a key-mediating factor. Voluntary wheel running is a form of exercise that increases neurogenesis and decreases depression-like behaviour in rats. However, the exact molecular role of neurogenesis in exercise-induced antidepressant effects still remains unanswered. This requires new tools to explore the interact ion between exercise and neurogenesis in vivo. To this end, the novel mitotic-marker, 5-ethynyl-2'-deoxyuridine (EdU), and Ki-67, an endogenous marker of cell proliferation, was characterised in order to study neurogenesis in an MS rat model of depression. Furthermore, this study aimed to provide insight into the effect of voluntary exercise on cell genesis and survival. To characterise EdU labelling of cells in vivo, male Sprague Dawley rats (Characterisation rats n =13) were injected with 50 mg/kg EdU a s noted in the literature. The optimal time point to inject the EdU label to measure mitotic activity was found to be post-natal day (PND) 60. MS or non-maternal separation (NMS) was conducted from PND 2-14 on experimental rats (n=39). From PND 54 - 74, ex perimental rats were housed in cages with attached running wheels (R) or locked running wheels (NR). All experimental rats were injected with 50 mg/kg EdU on PND 60 and transcardially perfused on PND 74 using Phosphate Buffered Saline (PBS) followed by fre sh 4% paraformaldehyde. Whole brains were then removed from the skull and placed in 4% paraformaldehyde for three hours. The brains were transferred to a 30% sucrose solution, stored in sucrose for 3-5 days and thereafter mounted in optimal cutting mediu m (OCT) and sectioned using a cryostat. Brain sections of 40 μm from 6.96 to 5.52 mm anterior to the inter-aural line were taken as dorsal and 50 μm sections from 3.84 to 2.76 mm were analyzed as ventral. The marker, EdU was detected in rat brains using t he Click-iT EdU Alexa Fluor 488 detection kit. Three molecular marker combinations were used to detect different factors for both dorsal and ventral hippocampi: (1) EdU/GFAP/NeuN, to establish how many EdU labelled cells survive to become neurons or astroc ytes (2) EdU/DCX to determine how many EdU labelled cells that have survived for 14 days are immature neurons and (3) Ki-67/DCX to indicate how many mitotically active cells are immature neurons on PND 74. Brain sections were then scanned using a confocal microscope whereby EdU stained nuclei were manually counted and cell phenotypes identified. The molecular marker combination one and two revealed no differences between treatment groups in the number of EdU-labelled cells in the dorsal and ventral hippoca mpi. However, a significant correlation was found between EdU/GFAP positive cells and EdU/NeuN positive cells in the ventral hippocampus when all treatment groups were pooled (r = 0.82, n=18, p < 0.0001). The third molecular marker combination revealed sig nificant differences in neurogenesis between groups. The MS+R group had fewer dorsal hippocampal Ki-67/DCX cells relative to NMS+R and NMS+R had significantly higher Ki-67/DCX cell count relative to NMS+NR rats. In the ventral hippocampus MS+R rats had few er Ki-67/DCX cells compared to NMS+R rats. The link between neurons and astrocytes in the ventral hippocampi corresponds with reports that an increase in neurons is linked to the presence of astrocytes. However, it may also be due to unavoidable variation in the intensity of the stain. The third molecular marker combination (Ki-67/DCX) revealed the most significant finding of this study. It showed that voluntary wheel running significantly increased the number of Ki-67/DCX co-labelled neurons in the dorsal hippocampus of NMS+R rats relative to NMS+NR which is in agreement with the literature that suggests exercise increases neurogenesis. The literature also reports that stress decreases neurogenesis and interestin gly MS+R rats had a lower cell count than NMS+R rats. This may indicate an interaction between early life stress and exercise-induced neurogenesis. This finding further suggests that MS alters neurogenesis in adult life and attenuates the effect of exercis e on the ventral hippocampus.

Methamphetamine (MA) has been shown to have a detrimental relationship with on neuronal integrity and viability, and has been associated with decreased executive function. The association of acute and short-term MA abstinence on brain metabolism, in adult MA abusers, is understudied. Negative relationships with brain metabolism, cognitive development and executive functioning in prenatally MA exposed children are reported, however these studies are limited. The aim of this study was to investigate the relationship between MA and brain metabolism in adults after acute and short-term abstinence. An additional aim was to investigate neurometabolite changes and relationship with general cognitive ability over time in prenatally MA exposed children.

Background: When an individual's brain appears ‘older' than expected based upon their chronological age, they may be at an increased risk for developing brain-related diseases and cognitive decline. There is growing evidence of advanced brain ageing in neuropsychiatric diseases. Social anxiety disorder (SAD) is a disabling mental illness, which has been associated with both structural brain deficits and advanced biological ageing. However, brain age research has yet to be conducted in adults diagnosed with SAD. The present study investigated whether adults with SAD showed an advanced brain ageing process, compared to healthy controls (HCs), and whether brain ageing in SAD patients is associated with clinical characteristics. Method: A systematic review of the literature was conducted to identify knowledge gaps in brain age research in psychiatric disorders before commencing with the present dissertation. Hereafter, a secondary data analysis of a large multi-site dataset was performed. T1-weighted structural MRI scans of 387 participants (SAD n=174, HC n=213) between the ages 18 and 60 years were included. These structural scans were segmented using both FreeSurfer and SPM12, after which they underwent quality control procedures. Brain age was estimated by two different machine learning models – Tobias Kaufmann's brain age model and James Cole's BrainageR. The primary outcome for analysis was the brain age gap (BAG), calculated by subtracting a participants' chronological age from their estimated brain age. General linear models were run to determine whether there was a significantly larger positive BAG in the SAD group (Kaufmann model n=100, Cole model n=155) compared to the HC group (Kaufmann model n=138, Cole model n=197) after adjusting for age, mean centred age2 and sex. The association between BAG and comorbid depression and anxiety, as well as medication use and symptom severity, was also assessed. Results: In the present study sample, predicted age was more strongly associated with chronological age for the Cole model estimates than the Kaufmann model estimates (Cole: Pearson correlation = 0.828, MAE = 4.78, SD = 3.96, versus Kaufmann: Pearson correlation = 0.576, MAE = 11.93, SD = 6.93). With the Kaufmann model, the SAD group had a significantly larger BAG than the HC group of almost one year (mean difference = 0.943 year, SE = 0.40, p = .019). In addition, with the Kaufmann model, patients without psychiatric comorbidities had a significantly larger BAG than HCs, of more than one year (mean difference = 1.242 year, SE = 0.49, p = .038). No difference was observed in BAG between patients with comorbidities and HCs (mean difference = 0.983 year, SE = 0.85, p = .749). In contrast, with the Cole model, the SAD group did not have a significantly larger BAG than the HC group (mean difference = 0.513 year, SE = 0.49, p = .383). Moreover, the Cole model found no significant difference in BAG between SAD patients with and without comorbidities, or between each of these groups and HCs (all p > .708). Finally, no significant associations were observed between the BAG and symptom severity and the BAG and medication use in SAD patients in the Cole or Kaufmann models. Conclusion: This study observed contradictory evidence for a larger BAG between patients with SAD than HCs. The differences observed between the Cole model and the Kaufmann model may be a result of the different information used to estimate brain age (voxel-based volumetric data, compared to cortical thickness/surface area and subcortical/cerebellar volumes, respectively). The models demonstrated largely overlapping confidence intervals for group mean difference in BAG, suggesting that if there is a positive BAG in adults diagnosed with SAD, it is likely to be small. This should be verified in future research by using multiple different machine learning models based on different feature sets, to obtain more reliable and robust brain age estimates.

It is clear that in order to perceive the external environment in its entirety, inputs from multiple sensory systems (i.e. modalities) must be combined with regard to each object in the environment. Humans are highly vision-dependent creatures, with a large portion of the human cortex dedicated to visual perception and many multimodal areas proposed to integrate vision with other modalities. Recent studies of multimodal integration have shown crossmodal facilitation (increased performance at short stimulus onset asynchronies, SOA s) and/or inhibition of return ( IOR ; decreased performance at long SOAs) for detection of a target stimulus in one modality following a location-specific cue in a different modality. It has also been shown that unimodal systems maintain some level of plasticity through adulthood, as revealed through studies of sensory deprivation (i.e. unimodal areas respond to multimodal stimuli), and especially through perceptual learning ( PL )--a well-defined type of cortical plasticity. Few studies have attempted to investigate the specificity and plasticity of crossmodal effects or the contexts in which multimodal processing is necessary for accurate visual perception. This dissertation addresses these unanswered questions of audiovisual ( AV ) crossmodal cuing effects by combining findings from unimodal perceptual learning with those of multimodal cuing effects as follows: (1) the short- and long-term effects of audiovisual crossmodal cuing, as well as the plasticity of these effects were systematically examined using spatially specific audiovisual training to manipulate crossmodal associations using perceptual learning; (2) neural correlates of these plastic crossmodal effects were deduced using monocular viewing tests (discriminating simple and complex stimuli) following monocular and orientation specific crossmodal perceptual training; and (3) psychophysical boundaries of plasticity within and among these mechanisms as dependent on task/training type and difficulty were determined by varying stimulus salience and looking at post-PL changes in response operating characteristics.

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