Postgraduate studies: research track

Thesis title: Differences in callosal and subcortical volumes and associated neurobehavioural deficits in children with prenatal alcohol exposure

Stevie Biffen’s thesis focuses on the effects of prenatal alcohol exposure (PAE) on the brain. It investigated subsequent behavioural deficits associated with neuroanatomical volume reduction. She measured the corpus callosum (CC), hippocampus, caudate nuclei and nucleus accumbens on structural magnetic resonance images of children aged 9-11 yrs. This was done using manual tracing and repeated with an automated segmentation program, FreeSurfer. A comparison between the two methods showed that the latest version of FreeSurfer performed similarly to manual tracing. This confirms that computer-based automated methods may be as accurate as a trained neuroanatomist. Clinically, she found that increased daily intake and frequency of alcohol consumption is associated with smaller CC, hippocampi and caudate nuclei size. She also showed that children with fetal alcohol syndrome show deficits in inter-hemispheric transfer and decreased CC size was related to poorer transfer between brain hemispheres and partially mediated the negative effects of prenatal alcohol exposure on IQ.

Supervisor: Professor EM Meintjes (Human Biology)

Co-supervisor: Dr CD Warton (Human Biology)

Thesis title: On the application and generation of subsensory electrical nerve stimulation for the improvement of vibration perception in patients with HIV-related sensory neuropathy

David Karpul’s thesis focuses on a potential treatment to recover lost touch sensitivity in patients with HIV. The treatment applies small electric currents to the peripheral nerves to affect the way nerve signals are generated and transmitted. The thesis examines the effect of the treatment on HIV patients with reduced touch sensitivity and finds that it has the potential to improve touch sensitivity, but that more research is required before it can be used in practice. One of the limiting factors in this field of research is that the equipment to apply the electrical currents cannot be used outside of the laboratory. The thesis addresses this by developing a complete and thoroughly tested electronic stimulator for nonlaboratory environments. The device is significantly smaller and lighter than all other available equipment and is the first such design that shows promise to be used in long term treatments of this kind.

Supervisor: A/Professor J Heckmann (Medicine)

Co-supervisor(s): A/Professor P Breen and Professor A van Schaik (The MARCS Institute for Brain, Behaviour and Development; Western Sydney University)

Thesis title: Human subjective homologues of established basic emotion correlations in lower mammals: a neuro-psychoanalytic study

Eleni Pantelis’s thesis is based on research which tested Jaak Panksepp’s theory that depression is based in the normal mammal ‘separation distress’ reaction, which unfolds over two phases: (1) ‘protest’ and (2) ‘despair’. The first phase is characterised by depleted levels of the brain chemical endorphin (acting on mu type receptors) and the second by depleted dopamine (acting at D2 type receptors). Panksepp’s theory comes from animal research in which the manipulation of these chemicals produced behaviours that looks like panic and depression respectively. However, animals cannot tell us how they feel. Eleni Pantelis studied the effects of manipulating these brain chemicals in human volunteers who described the subjective effects of the drugs upon their mood. Her results broadly confirm Panksepp’s theory although the psychological effects of the drugs were more complex than expected. This was attributed to the larger cortex of humans which results in cognitive distortion and elaboration of raw emotions.

Supervisor: Professor M Solms (Psychology)

Thesis title: A vector based approach for high frequency prospective correction of rigid body motion in Magnetic Resonance Imaging (MRI)

Adam van Niekerk’s thesis focuses on the correction of head motion within a magnetic resonance imaging (MRI) scanner. Motion is most prevalent in the ill, reducing the diagnostic value of images. Adam’s research aims to address this problem by measuring and correcting for patient motion at high frequency throughout the acquisition of data. To achieve this, he has designed and fabricated a series of novel markers that are wireless and free from scanner specific calibration, allowing them to be easily used in any MRI scanner. The devices synchronise to the MRI scanner with sub-microsecond precision and measure the changing magnetic fields within the imaging bore. These vector observations are combined with measurements of the direction of the static magnetic field to measure and correct subject pose roughly once every few milliseconds. Not only are diagnostic quality images achieved with severe patient motion, but also improved image quality in conventionally still patients.

Supervisor: Professor E Meintjes (Human Biology)

Co-supervisor: A/Professor A van der Kouwe (Harvard Medical School, Harvard University)

Thesis title: Functioning, disability, health and quality of life in adults with cerebral palsy more than 25 years after selective dorsal rhizotomy

Berendina Veerbeek’s thesis examines adults with cerebral palsy (CP) who underwent selective dorsal rhizotomy (SDR) in childhood, and the challenges these adults face while aging. SDR is a non-reversible procedure to address spasticity in lower extremities of children with CP. This procedure was refined and reintroduced by clinicians at the Red Cross Children’s Hospital in the early 1980’s and is currently the most widely used procedure worldwide. Many studies on the short-term outcomes of SDR show positive results for physical status and daily activities. Studies with a long-term follow-up of minimal five years are limited. Berendina Veerbeek demonstrated positive and stable outcomes of SDR more than 25 years after surgery in studies on: (1) physical status, quality of life and level of anxiety and depression; (2) gait; (3) spinal deformities and pain; and (4) daily activities, participation and functional mobility. These results can assist parents, caregivers and clinicians in making decisions about the most effective treatment option.

Supervisor: Dr NG Langerak (Surgery)

Co-supervisor(s): Professor RP Lamberts (Human Biology) and Professor AG Fieggen (Surgery)

Thesis title: Treatment of HIV associated neurocognitive disorders

Eric Decloedt’s thesis focuses on the treatment of HIV associated neurocognitive disorders in Black South African HIV-infected patients. He conducted a randomised placebo-controlled trial to assess the efficacy of lithium to improve neurocognition in patients with moderate to severe HIV associated neurocognitive disorders despite treatment with antiretroviral therapy. He found that lithium does not improve neurocognition. He investigated genetic associations with plasma and cerebrospinal fluid exposure of antiretroviral drugs and explored the relationship between antiretroviral drug concentrations and neurocognitive performance. He identified several novel genetic associations with exposure to the antiretroviral efavirenz and its metabolites in cerebrospinal fluid and plasma.

Supervisor: Professor G Maartens (Medicine)

Co-supervisor(s): Professor JA Joska (Psychiatry and Mental Health) and Dr PZ Sinxadi (Medicine)

Thesis title: Structural brain connectivity of HIV-positive children: a graph network analysis study

Jean-Paul Fouche’s thesis focuses on the investigation of brain structure in children born infected with HIV. Children were scanned with magnetic resonance imaging, and data were analysed using a graph theory approach. Brain areas affiliated with language, social and cognitive development showed a different pattern of connections in children with HIV, compared to healthy children. This project is especially relevant to South Africa and other lower to middle-income countries in the world where there are large populations of children who have been infected with HIV at birth. This work also forms the basis for further investigation of brain changes over time in this cohort of children.

Supervisor: Professor DJ Stein (Psychiatry and Mental Health)

Co-supervisor(s): Professor J Hoare (Psychiatry and Mental Health) and Professor E Meintjes (Human Biology)

Thesis title: Neuroimaging and behavioral investigation of declarative memory in South African children prenatally exposed to alcohol

Catherine Lewis’s PhD emerged out of her postgraduate research interest in clarifying the pattern of learning and memory impairments associated with prenatal alcohol exposure for development of specialised clinical interventions. Using neuroimaging and behavioral paradigms, Catherine Lewis examined, directly and indirectly, a critical cognitive mechanism (memory encoding) that supports declarative memory functioning. Data were collected from 88 children, some with and some without prenatal alcohol exposure (PAE). She demonstrated that neural activation of key brain regions during perception of basic visual information, a lower order cognitive process essential to encoding, is relatively spared in those with PAE (Study 1). However, her direct examination of neural activation during encoding suggested that participants diagnosed with foetal alcohol syndrome (FAS) or partial FAS (i.e. the most severe outcomes associated with PAE) activate compensatory networks to facilitate 9encoding (Study 2). Additionally, children with FAS/PFAS recalled fewer contextual details associated with memory items, a deficit only partially mediated by the higher-order executive process of working memory (Study 3). Catherine Lewis’s data, when drawn together, provide novel clarification of neural and cognitive mechanisms underlying declarative memory impairments in foetal alcohol spectrum disorders.

Supervisor: A/Professor KGF Thomas (Psychology)

Co-supervisor(s): Professor SW Jacobson (Psychiatry and Mental Health; and Psychiatry and Behavioral Neurosciences, Wayne State University), Professor JL Jacobson (Psychiatry and Mental Health; and Psychiatry and Behavioral Neurosciences, Wayne State University); Professor CD Molteno (Psychiatry and Mental Health) and Professor EM Meintjes (Human Biology)

Thesis title: The effects of prenatal and early-postnatal ethanol exposure on rat brain neurochemistry and behaviour

Patricia Swart’s thesis presents protein changes in the brain after alcohol exposure using animal models of fetal alcohol spectrum disorder (FASD). The proteomic profiles of the prefrontal cortex and hippocampus demonstrate a wide-range of long-term, region-specific ethanol-induced protein changes. The results highlight the importance of timing, pattern, route of ethanol administration and age at analysis. In addition, Patricia accounted for the possibility of additional early-life adversity, which is likely to occur after prenatal-alcohol exposure, by pairing an animal model of FASD with the maternal separation model of early-life stress. Interestingly, maternal separation stress reduced prenatal-ethanol-induced changes in behaviour and proteins in the brain. This highlighted a significant interaction between prenatal-alcohol exposure and early-life stress. The results presented in this thesis contribute valuable insight to the field of FASD by providing a better understanding of ethanol’s effect on the brain and the complexity of animal models used to study this multifaceted disorder.

Supervisor: Emeritus Professor VA Russell (Human Biology)

Co-supervisor(s): Dr J Dimatelis (Human Biology)

Thesis title: The influence of methylphenidate on heart rate and brain connectivity

Keelyn van Breda’s thesis reports that a central nervous system stimulant, methylphenidate (commercially known as Ritalin), increases heart rate at rest immediately preceding handgrip exercise. She shows that this is related to functional connectivity changes in the higher brain centres that modulates the autonomic nervous system. She goes on to show that methylphenidate ingestion increases handgrip force output and grip heart rate with a subsequent decrease in central autonomic network (CAN) connectivity. This suggests that the methylphenidate induced changes in CAN activity may have played a role in the improved exercise performance. Keelyn van Breda further found that the above ergogenic effects of methylphenidate during handgrip exercise may be particularly relevant in subjects who habitually engage in low vs. high levels of physical activity. This was evidenced by the finding that methylphenidate ingestion resulted in greater functional uncoupling and greater heart rate increases during exercise in subjects who habitually engage in low vs high levels of physical activity.

Supervisor: Dr L Rauch (Human Biology)

Co-supervisor(s): Dr M King (Human Biology), Professor DJ Stein (Psychiatry and Mental Health) and Dr M Jankiewicz (Human Biology)

Thesis title: The effects of testosterone on embodiment: implications for social power

Donné van der Westhuizen’s thesis follows recent trends in the neurosciences in which the body is seen as a constituting factor in mental experience and behaviour. Her general aim has been to contribute to the literature on the embodied basis of power, and to do so by asking whether a change in the neurochemistry associated with social power has any effect on the representation and experience of the body She ran three experiments in which participants were administered a single 0.5mg dosage of either testosterone or placebo. She found that testosterone improved the subjects’ perception of internal physiological signals, stabilised their thermal regulation under conditions of illusory changes in body ownership, and increased their feeling of being in control of actions. Donné van der Westhuizen’s work contributes to our theoretical understanding of power; and it suggests that the motivational impetus for social status might be rooted, from an embodied cognition perspective, in an implicit drive to maintain control of the physical body.

Supervisor: Professor M Solms (Psychology)

Co-supervisor(s): Professor J van Honk (Utrecht University)

Thesis title: The functional neurophysiological sequelae associated with high frequency dream recallers

Mariza van Wyk’s thesis research investigates the proposition that the brains of high frequency dream recallers (HFRs) function differently from the brains of low frequency dream recallers (LFRs). Her findings include that the effects of this difference in functioning include HFRs showing stronger personality traits associated with altruism, empathy, and cooperative behaviour compared to LFRs. Furthermore, they show that there is also a difference in sleeping patterns – HFRs wake up more often throughout the night, especially from stage 2 non-rapid eye movement (NREM) sleep, as well as spending more time awake after sleep onset. An increased number of awakenings and longer periods 9 of wakefulness potentially facilitate the encoding of dreams into memory, leading to higher rates of dream recall in HFRs. Contrary to popular belief, Mariza van Wyk’s results from her study provide strong evidence that NREM sleep, as opposed to rapid eye movement (REM) sleep, is of particular importance in relation to dream recall frequency in the population on which she focused.

Supervisor: Professor M Solms (Psychology)

Co-supervisor(s): Dr G Lipinska (Psychology)

Thesis title: A study of event-related electrocortical oscillatory dynamics associated with cued motor- response inhibition during performance of the Go/NoGo task within a sample of prenatally alcohol- exposed children and age-matched controls

Matthew Gerhold’s thesis is in the area of alcoholism and alcohol-related disorders, focusing on how foetal alcohol exposure affects brainwave activity and associated cognitive processes at later stages of human development (preadolescence and adolescence). The observed alcohol-related changes in the electrical fields of the human brain are related to cognitive processes, such as inwardly directed attention towards decision-making processes and reallocation of cognitive resources in order to deal with movement-related demands. These processes enable humans to adapt to cues that prompt a shift away from specific movement patterns to alternative inhibited states. This study is the first to demonstrate the effect of prenatal alcohol exposure on brainwave activity related to decision-making processes in a developing, alcohol-exposed sample. It is also the first study to demonstrate decision- making linked brainwave activity, previously only observed in adult samples, within a normally-developing control group. In addition, the study creates important and novel insights into signal- processing methods applied to the study of brainwave data.

Supervisor: Professor E Meintjes (Human Biology)

Co-supervisor(s): Dr C Andrew (Human Biology)

Thesis title: Testosterone influences the social-emotional brain and modulates responsiveness to emotive and arousing cues: An fMRI based study of the effects of acute testosterone administration

Sarah Heany’s thesis investigates the role of testosterone in the brain’s responses to threatening stimuli. Although testosterone has been long associated with increased aggression and even reducing types of anxious behaviours, the underlying neural mechanisms are not yet understood. In this thesis a series of specially designed experiments arouse affective responses in healthy women, and their neural activity is recorded using fMRI techniques. The main finding of the thesis is the detection of decreased connectivity between the left orbitofrontal cortex and the subcortical threat network in the face of escapable threat. This finding allows an understanding of the neural mechanisms through which testosterone acts on responsivity to a threatening environment and can help to explain behavioural changes associated with testosterone. This finding also has implications for the study of certain types of psychopathology where related dysregulation of brain activity is noted.

Supervisor: Professor D Stein (Psychiatry and Mental Health)

Co-supervisor(s): Professor J van Honk (Psychiatry and Mental Health)

Thesis title: Associations between Sleep Architecture, Cortisol Concentrations, Cognitive Performance, and Quality of Life in Patients with Addison’s Disease

Recent literature in the neurosciences suggests that there are mechanistic relations between sleep disruption and cognitive (particularly memory) deficits, and that varying concentrations of the hormone cortisol may play a particularly important role in mediating those relations. Because patients with Addison’s disease (AD) experience consistent and predictable periods of sub- and supra- physiological cortisol concentrations (due to lifelong glucocorticoid replacement therapy), and because they frequently report disrupted sleep and poor memory, those presenting with that endocrinological disorder form an ideal population to use in studies testing hypotheses about the ways in which (a) disrupted sleep is related to impaired consolidation of previously learned material (and, hence, poor performance on tests assessing memory for that material), and (b) cortisol concentrations may mediate this relationship between sleep and memory. This dissertation presents four studies that, together, tested those hypotheses. Study 1 (n = 60 per group) found that patients with AD self-reported significantly more disturbed sleep and poorer cognition and quality of life compared to matched healthy controls. Importantly, our analyses suggested that disrupted sleep, and not AD per se, accounted most strongly for the reported cognitive impairment. Study 2 (n = 35 per group) found that patients had significantly poorer objectively-measured declarative memory performance compared to matched healthy controls, but that other domains of cognition were relatively unimpaired. Study 3 (n = 10 per group) suggested that matched healthy controls retained significantly more declarative information than patients. Importantly, while controls retained significantly more declarative information when a period of sleep, rather than waking, separated learning from recall, patients derived no such benefit. Study 4 (n = 7 per group) suggested that, relative to matched healthy controls, patients had different patterns of night-time cortisol secretion, accompanied by significantly reduced slow-wave sleep. Together, these four studies suggest that, despite being on replacement 2 medication, patients with AD still experience disrupted sleep and memory deficits. These disruptions and deficits may be related to the failure of replacement regimens to restore a normal circadian rhythm of cortisol secretion. This pattern of results provides support for existing theoretical frameworks which posit that (in AD and other neuroendocrine, neurological, or psychiatric disorders) disrupted sleep is an important biological mechanism that underlies, at least partially, the memory impairments that patients frequently report experiencing. With specific regard to patients with AD, the findings presented here suggest that future initiatives aimed at improving patients’ cognitive performance (and, indeed, their overall quality of life) should prioritise optimizing sleep. More generally, this dissertation advances our understanding of sleep as a critical biological process essential for cognitive well-being.

Supervisor: A/Prof. KGF Thomas

Co-supervisor(s): Dr Ian Ross and Pedro Wolf

Thesis title: Associations between sleep and cognitive-affective functioning in Posttraumatic Stress Disorder

Gosia Lipinska’s thesis research explores whether the sleep disruptions typical of post-traumatic stress disorder (PTSD) are essentially related to the cognitive and emotional difficulties characteristic of the disorder. Women with PTSD, with trauma experience but no PTSD, and with no psychopathology completed neutral memory, emotional memory and emotional reactivity tasks before and after 8- hour periods of sleep and waking. The research generated two important results. First, PTSD- diagnosed individuals slept more lightly than other participants and retained less neutral information after a night of sleep than the others. This pattern of results was predicted only by the degree to which rapid eye movement (REM) sleep was fragmented during the night. Second, after a sleep-filled but not wake-filled delay, all participants recognised pictures with varying valence and arousal properties equally accurately and demonstrated attenuated emotional reactivity to these pictures. Gosia Lipinski’s thesis-research findings bolster the neuroscientific view of sleep as a critical biological process linked integrally to psychological wellbeing.

Supervisor: A/Professor KGF Thomas (Psychology)

Thesis title: Profiling medulloblastoma and juvenile pilocytic astrocytoma brain tumours in a South African paediatric cohort

Omesan Nair’s thesis investigates the molecular profiles of the two most common types of childhood brain tumours in a South African cohort. Brain tumours in children are one of the most challenging diseases to treat, especially in developing world circumstances. Epidemiological and outcome data are lacking in the developing world, and in general there are very few molecular biology programs. There are currently no reliable data on presentation of disease, the spectrum of tumours treated, how these are treated, and what the outcomes are, much less 23 molecular characterisation of tumours, for children in South Africa. Therefore, this thesis investigates the malignant Medulloblastoma and the less aggressive Juvenile Pilocytic Astrocytoma, with respect to their molecular biology and their clinical correlates to begin to address these gaps.

Supervisor: Professor A Figaji (Surgery)

Co-supervisor(s): Professor JM Blackburn (Integrative Biomedical Sciences)

Thesis title: Perinatal psychological distress in the South African context: the road to task shifting evidence-based interventions

Maxine Spedding’s thesis focuses on using Registered Counsellors to task shift an evidence-based therapy intervention to treat perinatal psychological distress in public health settings. She starts by using secondary data to estimate the prevalence rates of antenatal psychological distress, as well as the associated risk and protective factors. Thereafter, she explores the perceptions that pregnant women have of perinatal mental illness, including their views on causes and most appropriate treatments. After demonstrating high prevalence rates amongst a large Western Cape sample, as well as finding that women 26 show a preference for talking therapies such as psychotherapy and counselling, she piloted an adapted counselling intervention delivered by a Registered Counsellor. She found that psychological distress was significantly reduced, while functioning in social, work and family life were all improved. The intervention was deemed feasible and acceptable to both participants and stakeholders.

Supervisor: A/Professor KR Sorsdahl (Psychiatry and Mental Health)

Co-supervisor(s): Professor DJ Stein (Psychiatry and Mental Health) and Dr T Naledi (Public Health & Family Medicine)

Thesis title: The relationship between elevated night-time glucocorticoid activity and dreaming: a perspective on sleep-dependent memory consolidation

Ridwana Timol’s doctoral research investigated relationships between corticosteroid exposure, sleep organisation, sleep-dependent memory processing, and dream content in order to examine the neuroanatomical foundations of those relationships. The work was organised in three studies. Studies one and two showed that, relative to healthy controls, corticosteroid-exposed individuals (that is individuals either being treated for asthma or who had been exposed to a single Prednisone dose) had elevated night-time glucocorticoid activity and disrupted sleep organisation. These two studies also showed that glucocorticoid activity had an indirect influence on sleep-dependent memory processing by disrupting the organisation of SWS and of REM sleep, and that it also influenced dream content. Study three found significantly smaller hippocampal volume in asthmatics relative to controls. In summary, the thesis shows that findings about asthmatics’ hippocampal volume data, as well as their patterns of night-time cortisol and sleep disruptions, suggest that further investigation is warranted into the implications of subtle neural dysfunction and consequent atypical brain development on cognitive function and quality of life in corticosteroid-exposed individuals.

Supervisor: A/Professor KGF Thomas (Psychology)

Thesis title: The neurostructural effects of prenatal exposure to methamphetamine in an infant population in the Western Cape

Fleur Warton’s thesis uses magnetic resonance imaging (MRI) to investigate the effects of prenatal methamphetamine exposure on the central nervous system in neonates recruited from the Cape Flats region of the Western Cape. Methamphetamine exposure has been associated with structural and functional changes in the brain in older children. Structural MRI is used to measure potential volume changes in regions of the brain hypothesised to be affected by methamphetamine, following which potential white matter changes are investigated using diffusion tensor imaging. The results suggest that infants with prenatal exposure exhibit reduced volumes of the caudate nucleus and poorer white matter integrity in fibres connecting regions involved in cognitive and emotional control. These changes may underlie the impaired executive function exhibited by these children.

Supervisor: Professor EM Meintjes (Human Biology)

Co-supervisor(s): Dr CMR Warton (Human Biology)