OpenUCT :: Browsing by Subject "Neuroscience"

Browsing by Subject "Neuroscience"

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Open Access
Affective agnosia: a core affective processing deficit in the alexithymia spectrum
(2020-09-04) Lane, Richard D; Solms, Mark; Weihs, Karen L; Hishaw, Alex; Smith, Ryan
Abstract Affective agnosia, an impairment in knowing how one feels emotionally, has been described as an extreme deficit in the experience and expression of emotion that may confer heightened risk for adverse medical outcomes. Alexithymia, by contrast, has been proposed as an over-arching construct that includes a spectrum of deficits of varying severity, including affective agnosia at the more severe end. This perspective has been challenged by Taylor and colleagues, who argue that the concept of affective agnosia is unnecessary. We compare these two perspectives by highlighting areas of agreement, reasons for asserting the importance of the affective agnosia concept, errors in Taylor and colleagues’ critique, and measurement issues. The need for performance-based measures of the ability to mentally represent emotional states in addition to metacognitive measures is emphasized. We then draw on a previously proposed three-process model of emotional awareness that distinguishes affective response generation, conceptualization and cognitive control processes which interact to produce a variety of emotional awareness and alexithymia phenotypes - including affective agnosia. The tools for measuring these three processes, their neural substrates, the mechanisms of brain-body interactions that confer heightened risk for adverse medical outcomes, and the differential treatment implications for different kinds of deficits are described. By conceptualizing alexithymia as a spectrum of deficits, the opportunity to match specific deficit mechanisms with personalized treatment for patients will be enhanced.
Open Access
Blushing and gaze avoidance in social anxiety disorder : a structural neuroanatomical investigation
(2014) Van der Merwe, Nicolina Thandiwe; Stein, Dan J; Malcolm-Smith, Susan; Brooks, Samantha J
Background: Social anxiety disorder (SAD) is a common psychiatric condition characterised by fear and avoidance of social situations. Lifetime prevalence is 5-16% and co-morbidity with other mood and substance abuse disorders is common. Symptoms including cognitive, behavioural and physiological components vary between individuals. Of these, blushing and gaze fear and avoidance are regarded as cardinal symptoms. First line treatment of SAD involves SSRIs and cognitive behavioural therapy, while surgery may also be considered for excessive blushing. Blushing and gaze avoidance are thought to have an evolutionary adaptive advantage, promoting the display of submissive behaviour and appeasement in threatening situations. MRI research has demonstrated differences on functional and structural neuroimaging between patients with SAD and healthy controls (HCs). However, little is known about the neurocircuitry underlying gaze fear and avoidance or increased blushing propensity or how the severity of these traits correlate with the neuroimaging differences found in SAD. In this research, I explored the neuroanatomy of blushing propensity and gaze fear and avoidance in the context of SAD. Methods: 18 SAD patients and 18 HCs underwent structural MRI scans and self-report scales were administered to assess their symptom severity, blushing propensity and gaze fear and avoidance. Structural data was analysed using voxel-based morphometry (VBM). Regression and contrast analyses were used to correlate blushing propensity and gaze anxiety and avoidance symptoms with brain volumes, controlling for total grey matter volume, age and level of education. Results: Anxiety, blushing propensity and gaze fear and avoidance symptoms were all significantly higher in SAD patients (p<0.001). Brainstem volumes were increased for higher blushing scores a (p<0.01), while the volumes of left inferior parietal lobe b (p=0.04) and left occipital cortex a (p<0.01) were decreased. With increased gaze fear and avoidance, there were associated decreases in the right posterior cingulate cortex a (p<0.01), right occipital lobe b (p=0.03) and right fusiform gyrus a (p<0.01). Increased blushing and gaze symptom severity considered together, was associated with increased brainstem volume a (p<0.01) and decreased pons/cerebellum b (p=0.001), right cerebellum b (p=0.009), left cerebellum c (p<0.001) and left inferior parietal lobe a (p<0.1), volumes. Contrast analysis of SAD and HC brain volumes revealed a greater grey matter volume in HCs in the regions of left occipital cortex (p<0.01), left anterior cingulate (p<0.01) and right inferior parietal lobe (p<0.01) when compared to SAD patients. Increased symptom severity in SAD was significantly associated with higher volumes in the left premotor cortex (p<0.01), right hippocampus (p<0.01), left orbitofrontal cortex (p<0.01) and right superior temporal cortex (p<0.01). Possible areas for of interest for volume differences between SAD and HCs include total grey matter volume (d =0.83), left and right anterior cingulate cortex (d =0.68 and d =0.65), and left and right dorsolateral prefrontal cortex (d =0.55 and d =0.54), yet these differences were not significantly different. (a uncorrected peak levels b uncorrected cluster level, c corrected cluster level). Conclusion: Differences in brain volumes pertaining to blushing and gaze fear and avoidance in SAD patients may be a contributing factor or a consequence of these core symptoms, and a potential biomarker for SAD. Future studies could build on this preliminary research with increased sample sizes, and determine the possible effects of reduced symptom severity and treatment options on brain structure and function. Most importantly, an investigation of the genetic underpinnings and functional neural correlates of blushing and gaze avoidance behaviour may enhance our understanding of the complex aetiology of these cardinal SAD symptoms, thereby improving our understanding of SAD as a psychiatric disorder and facilitating better patient care and management.
Open Access
Cerebral autoregulation in children with traumatic brain injury: Comparing the autoregulatory index (ARI) to pressure reactivity index (PRx) and their associations with cerebral physiological parameters
(2017) Patel, Maryam; Figaji, Anthony; Enslin, Johannes M N
As an important hemodynamic mechanism, pressure autoregulation protects the brain against inappropriate fluctuations in cerebral blood flow subject to changing cerebral perfusion pressures. In acute neurological illnesses, including traumatic brain injury in children, impaired autoregulation is associated with a worse prognosis. It also has important clinical implications for managing blood pressure and intracranial pressure. Two common methods of measuring pressure autoregulation reported in the adult literature have been rarely reported in children. This pilot study aimed to examine the relationship between two autoregulatory indices, namely PRx (pressure reactivity index) and ARI (autoregulatory index) in children with severe TBI. The study also examined their relationship with the response of clinically relevant variables such as intracranial pressure (ICP), brain oxygenation (PbtO2) and local cerebral blood flow (loCBF) to dynamic testing. The study is a retrospective cohort study of prospectively collected data conducted at the Red Cross Children Hospital. We analyzed the results of 18 patients in 28 tests of autoregulation to determine the static state of autoregulation by calculating the autoregulatory index (ARI). These tests were done by controlled elevation of blood pressure to evaluate changes in transcranial Doppler-derived flow velocity of the middle cerebral artery. Concomitant recordings were made of ICP, PbtO2, and loCBF. Secondly, we also calculated the PRx as a moving correlation co-efficient between slow changes in blood pressure and ICP. Two time epochs of PRx were examined in relation to the static tests: 1 hour before and after the test, and 12 hours before and after the test. The results included 28 tests done for ARI and 27 calculations for PRx epochs; all tests had ICP and PbtO2 data and 23 had loCBF. PRx and ARI showed no significant relationship between them. However, there was a significant relationship between ARI and ΔICP (p=0.04), i.e. when autoregulation was weak the change in ICP with a change in blood pressure was greater; and between PRx and ΔPbtO2 (p=0.04). There was a trend in correlation analysis between loCBF and PRx but not in the linear mixed effects model In conclusion, the study showed no correlation between the two autoregulatory indices, PRx and ARI, probably because they assess different aspects of autoregulation. However, significant relationships exist between ARI and ΔICP as well as PRx and ΔPbtO2, which generate interesting hypotheses about autoregulation and have clinical implications. Both autoregulatory indices have benefits and limitations. Further studies on such relationships, taking into consideration a larger sample group, inclusion of unstable patients, and utilization of the same range in BP for calculating the indices, are recommended.
Open Access
Cognitive therapy, working memory training, and the treatment of Methamphetamine Use Disorder - a functional MRI study
(2020) Dias, Angelo Ridge; Ipser, Jonathan; Brooks, Samantha
Background: In recent years, methamphetamine use disorder (MUD), which is associated with adverse outcomes and represents a significant public health burden, has become highly prevalent in Cape Town, South Africa. Protracted methamphetamine (MA) use has been linked with neural dysfunction and working memory deficits. Although current treatments have shown limited efficacy in addressing MUD, recent evidence indicates the potential of utilizing tailored brief cognitive therapy programs and working memory training to improve outcomes. The current study aims to investigate the potential impact of brief cognitive therapy and using working memory training as an adjunct in the treatment of MUD. Methods: Participants were recruited from an in-patient drug rehabilitation centre in Cape Town. The sample (n = 26) consists of male patients (between the ages of 18–50) diagnosed with MUD. MUD patients were randomly split into 2 groups that received 4 weeks of treatment, i.e. treatment as usual (cognitive therapy only (NT) (n= 12)) and cognitive therapy with working memory training (CT) (n = 14). Neuroimaging and psychological data were collected from participants pre- and post- intervention to assess the relative impact of said interventions. Results: Behavioural outcome measures and the n-back working memory task adapted for fMRI were measured and compared pre- and post- intervention. No significant differences were present between groups prior treatment on behavioural measures, demographic measures, and fMRI activity. The brief cognitive therapy appeared to reduce depression and impulsivity scores over the course of the intervention, with scores slightly lower in the CT group. An FDR corrected whole-brain repeated measures ANOVA on the main effect of group indicated significant activation in the left posterior cingulate, left anterior cingulate, and left lingual gyrus. Post hoc t-tests were then conducted to follow up the group main effect and significant differences under FDR correction were observed in the NT group (in contrast to the CT group) indicating significantly more activity in the left superior temporal gyrus, left insula, right posterior declive, and right lingual gyrus. Significant differences were also observed under FDR correction on a posthoc test on the CT group (in contrast to the NT group) indicating significantly less activity in the left lingual gyrus, left posterior declive, and right cuneus. 5 Conclusions: The findings tentatively suggest that the working memory training adjunct may have slightly enhanced working memory maintenance brain function relative to the treatment as usual group post-intervention. The evidence also suggests that there may have been inefficient neural functioning in the treatment as usual group during the working memory task compared to the group receiving the working memory training adjunct. The results demonstrated that brief cognitive therapy treatment did somewhat reduce depressive symptoms and impulsivity in this study, with indications of subtle treatment gains in the cognitive training group. Overall, the current study (despite numerous limitations) provides preliminary and tentative evidence of the possible benefits of brief term cognitive therapy and the potential promise of using working memory training as a treatment adjunct.
Open Access
Comparison of Magnetic Resonance Spectroscopy (MRS) data in children with and without HIV at 11-12 years
(2020) Graham, Amy; Robertson, Frances; Meintjes, Ernesta
Although HIV and antiretroviral drugs have been shown to cause damage in the brain, the long-term impacts of perinatal infection, early treatment and exposure in children at 11 years, remain unclear. The effects of HIV and antiretroviral therapy (ART), whilst indistinguishable, can be investigated at a chemical level through proton magnetic resonance spectroscopy (1H-MRS). Previous studies in children have largely focused on individual metabolite changes. However, several adult studies have now advanced beyond this to address patterns of metabolic activity that are altered with HIV infection. Using a 3T Skyra scanner, 136 children (76 HIV+, 30 HEU, 30 HU; 71 males) between the ages of 11.0- 12.5 years, and from a similar socioeconomic background, were scanned. In this study metabolite concentrations were quantified within the basal ganglia (BG), midfrontal gray matter (MFGM) and peritrigonal white matter (PWM). We utilised linear regression to investigate individual metabolite differences, comparing HIV-infected (HIV+) children from the Children with HIV Early Antiretroviral Therapy (CHER) trial, and HIV-exposed-uninfected (HEU) children, to HIV-unexposed (HU) children. Pearson's correlation analysis, factor analysis and logistic regression were then used to study alterations in metabolic patterns between HIV+ and HIV-uninfected (HIV-) children. Analysis of the data was carried out in R. We found elevated total choline in the BG (p = 0.03) and MFGM (p < 0.001) of HIV+ children, as well as reduced PWM total NAA (p = 0.03) and total creatine (p = 0.01). Altered metabolite concentrations were further observed in HEU children. Additionally, we identified a cross-regional coupling of choline which distinguishes HIV+ from HIV- children (p < 0.001). These findings indicate that multiregional inflammation and PWM axonal damage are occurring in HIV+ children at 11 years. Ultimately, the consequences of perinatal HIV acquisition, in spite of early treatment, continue to be seen at 11 years, as do the impacts of exposure.
Open Access
Differences in callosal and subcortical volumes and associated neurobehavioural deficits in children with prenatal alcohol exposure
(2019) Biffen, Stevie Crystal; Meintjes, Ernesta; Warton, Christopher
Certain high-risk communities in the Western Cape Province of South Africa where heavy maternal prenatal alcohol consumption is perpetuated by historical and societal challenges, have some of the highest prevalence rates of fetal alcohol syndrome (FAS) in the world. FAS has lifelong behavioural and cognitive consequences. Neuroimaging research aims to link deficits in brain structure and function to behavioural outcomes. Manual tracing is considered the gold standard of neuroanatomical volumetric analysis. Combined with neurobehavioural testing it can provide links between structure and function, but is time consuming and labour intensive. Automated segmentation programmes, such as FreeSurfer, are a faster alternative. The challenge is creating automated programmes that can provide results that are comparable to manual tracing, especially in a clinical sample. The aims of this thesis were to investigate (1) the effects of prenatal alcohol exposure (PAE) on the sizes of the caudate nucleus, nucleus accumbens, hippocampus and corpus callosum (CC) and potential relations of regional volumes with IQ and verbal learning, (2) to compare the performance of manual and automated segmentation methods in identifying alcohol-related changes in brain morphometry, and (3) to examine the effects of PAE on inter-hemispheric transfer during adolescence and potential relations of CC size with inter-hemispheric transfer deficits. Participants for this project were recruited from the Cape Town Longitudinal Cohort for whom alcohol exposure data were gathered prospectively from the mothers during pregnancy using the timeline follow-back approach. Participants had been diagnosed previously by two expert dysmorphologists as either control, non-syndromal heavily exposed (HE), partial FAS (PFAS) or FAS. High-resolution T1-weighted images were acquired using a sequence optimized for morphometric neuroanatomical analysis on a Siemens 3T Allegra MRI scanner for 71 right-handed children (9 FAS, 19 PFAS, 24 HE and 19 non-exposed controls) from this cohort at ages 9-11 years. Bilateral caudate nuclei, nucleus accumbens and hippocampi and the CC were manually traced using Multitracer. FreeSurfer was used for automated segmentation. All structures were segmented with both FreeSurfer versions 5.1 and 6.0 to compare progress within development of automated segmentation algorithms. Associations of volumes from manual tracing with IQ and performance on the California Verbal Learning Test-Children’s Version (CVLT-C) were also examined. Inter-hemispheric transfer was assessed using a finger localization task (FLT) administered to 74 participants (12 FAS, 16 PFAS, 14 HE, and 32 controls) from the same cohort at ages 16-17 years. Of these, 34 participants had completed MRI at 9-11 years. Higher levels of PAE were associated with reductions in CC area, as well as bilateral volume reductions in caudate nuclei and hippocampi, effects that remained significant after controlling for alcohol-related reductions in TIV (total intracranial volume). Amongst dysmorphic children (FAS/PFAS), poorer performance on the CVLT-C was related to larger hippocampi and smaller CC. Smaller CC was also associated with lower IQ and partially mediated the effect of PAE on IQ. Manual and automated comparisons showed good agreement in the caudate nuclei, which are simpler to segment, moderate to good agreement in the smaller, more complex nucleus accumbens and hippocampi, and poor agreement in the CC. The latter is not surprising, however, in view of the fact that manual tracing measured the average area of the CC on a mid-sagittal slice, while FreeSurfer measures CC volume over a number of contiguous slices. After controlling for confounders and adjustment for smaller TIV, the latest FreeSurfer version 6.0 provided evidence of alcohol-related volumetric brain reductions comparable to manual segmentation. Only the most severely affected children with FAS demonstrated inter-hemispheric transfer deficits, with the number of transfer-related errors tending to increase with decreasing CC volume among children with PAE. This study confirms and extends evidence of PAE-related decreases in subcortical and CC size and that callosal volume partially mediates alcohol-related impairment in IQ. Although FreeSurfer v 6.0 achieves automated segmentations that are comparable to manual tracing, even in a paediatric clinical sample, performance is more reliable in some structures than others. Improvement and standardization of CC segmentation is especially important given the vulnerability of the CC and its critical role in domains affected by PAE, including verbal learning, IQ and inter-hemispheric transfer of information.
Open Access
The effect of exercise on spatial learning and hippocampal proteins in maternally separated adult rats
(2014) Makena, Nokuthula; Russell, Vivienne A; Bugarith, Kishor
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.
Open Access
The effect of voluntary exercise on adult hippocampal neurogenesis in maternally separated rats
(2016) Hardcastle, Natasha Sema; Russell, Vivienne A; Lang, Dirk M; Marais, L
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.
Open Access
Endoscopic repair of cerebrospinal fluid leaks
(2018) Mohammed, Ben Husien; Semple, Patrick Lyle; Lubbe, Darlene
Developmental Venous Anomalies are a normal variant that may be associated with other cerebral vascular malformation they have bean previously referred to Venous angiomas. DVAs are the most frequently encountered cerebral vascular malformation and their incidence is reported to be high as 2.6%. DVAs are classified into two types based on draining veins. Either deep or superficial. Those that drain into subependymal veins are classified as deep and those that drain into cortical pial veins are classified as superficial. The trans-cerebral veins join either the deep or superficial venous systems by crossing a varying length of the brain parenchyma. Controversy surrounds their exact clinical significance, as DVAs are rarely symptomatic. The symptoms displayed by a patient can be related to a lesion that is associated with DVAs, such as a cavernoma. Study Aim: To describe the patients presenting to a single unit over a 10-year period with symptoms attributable to a DVA. Results: Out of 19 patients in the database with the diagnosis of DVA, 10 were identified where the clinical presentation was directly related to the DVA. Seven of the patients presented with haemorrhage, 6 had parenchymal bleeds and one was intraventricular. Two patients had neurological deficit, 1 was transient and one was progressive. One patient had sudden severe headache with no evidence of haemorrhage on CT scan. The age range was from 14 to 55 with a mean of 32,7 years. Four patients were male and 6 were female. Of the patients that presented with haemorrhage only one had a fistula, three other patients with haemorrhage had evidence on DSA of stenosis of the large collector vein, In the remaining 3 patients no reason for the bleed could be detected. One patient presented with left hemianopia that resolved after several hours, DSA showed minimal caput medusa with delayed filling of the collector vein. The other patient that presented with progressive neurological deficit in the form of progressive leg spasticity and dysarthria, Angiography showed a large collecting vein that drains in the jugular bulb was stenosed. The last patient that presented with sudden sever headaches, with no haemorrhage identified on CT scan, On DSA there was early filling of the DVA veins compared to other cerebral veins and two prominent posterior communicating thalamoperforating vessels were seen. Conclusion: Developmental venous anomalies are the commonest vascular malformation, and are rarely symptomatic unless associated with a cavernoma. In patients that have symptoms linked to DVAs (Haemorrhage, neurological deficit, sudden sever headaches) overall they have a good outcome, and the deficit related to a DVA tend to improve overtime, except for one patient that we had in our group, the DVA draining the pons and the cerebellar hemisphere had a tight outflow stenosis, that lead to progressive neurological deficit. In general, the majority of DVAs that are symptomatic do well.
Open Access
Exploring the determinants of chloride homeostasis in neurons using biophysical models
(2018) Düsterwald, Kira M; Raimondo, Joseph V
Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl ions via activated GABAA and glycine receptors. As a result, changes to the neuronal driving force for Cl- are thought to play pivotal roles in many physiological and pathological brain processes. Established theories regarding the determinants of Cl- driving force have recently been questioned based on new experimental data. However, it is experimentally difficult to distinguish the respective contributions of the multiple, dynamically interacting mechanisms which may be important in Cl- homeostasis. Here I present biophysical models of Cl- homeostasis using the pump-leak formulation. By means of numerical and novel analytic solutions, I demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Importantly, I show that while impermeant anions can contribute to setting [Cl- ]i in neurons, they have a negligible effect on the driving force for Cl locally and cell-wide. In contrast, I demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signalling in neurons. This prediction is supported by a meta-analysis of multiple experimental studies, which demonstrates a strong correlation between the expression of the cationchloride cotransporter KCC2 and intracellular Cl concentration. My findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.
Open Access
Exploring the effects of classical immune activation on circuit excitability and cell viability in the mouse brain
(2021) Tinelli, Sasha; Raimondo, Joseph; de Lange, Anja
Epilepsy directly affects approximately 50 million people globally and is the most common neurological disorder in sub-Saharan Africa, mainly due to high rates of neuroinfections and head trauma experienced by people in the region. A common factor in these causes of acquired epilepsy is their association with significant neuroinflammation, which is thought to drive the epileptogenic process. Although epilepsy exerts a heavy toll on the health, wellbeing and socio-economic outcomes of Africans, there are still major deficits in our understanding of how infections and inflammatory processes drive seizure development. Using the hippocampal organotypic brain slice culture model in mouse brains, I investigated the effects of classical immune activation on circuit excitability and cell viability. To initiate inflammation, I administered lipopolysaccharide (LPS), an endotoxin derived from gramnegative bacteria, and interferon-gamma (IFNy), a cytokine typically released by lymphocytes, to brain slices on varying time scales. I used enzyme-linked immune-sorbent assays to show that this reliably induced the release of the proinflammatory cytokines TNFα and IL-6 from the brain slices. I used patch-clamp electrophysiology to assess both the intrinsic electrical characteristics as well as the synaptic strength between pyramidal neurons after immune activation. I found no changes in the basic membrane properties of pyramidal neurons after short term neuroinflammation, but I did observe changes to the function of hippocampal networks at intermediate (24 hours) and lengthy (72 hours) time scales of immune activation in the form of significantly reduced spontaneous excitatory and inhibitory postsynaptic current frequencies and amplitudes. In addition, I developed an assay to determine neuronal survival to monitor the health of neurons in brain slices after immune activation and report that hippocampal organotypic brain slice cultures that were immuneactivated for 72 hours do not appear to experience either apoptotic or necrotic cell death. Taken together, these data constitute a valuable contribution towards understanding how inflammatory mechanisms drive changes to neuronal function, which could be relevant for understanding epileptogenesis in infectious and inflammatory causes of epilepsy.
Open Access
Feasibility of a smartphone application to identify young children at risk for Autism Spectrum Disorder in a low-income community setting in South Africa
(2018) Kümm, Aubrey Jonathan; de Vries, Petrus J
Introduction and aims More than 90% of children with Autism Spectrum Disorder (ASD) live in low- and middle-income countries (LMIC) where there is a great need for culturally appropriate, scalable and effective early identification and intervention tools. Smartphone technology and application (‘apps’) may potentially play an important role in this regard. The Autism&Beyond iPhone App was designed as a potential screening tool for ASD risk in children aged 12-72 months. Here we investigated the technical feasibility and cultural acceptability of a smartphone app to determine risk for ASD in children aged 12-72 months in a naturalistic, low-income South African community setting. Methodology 37 typically-developing African children and their parents/carers were recruited from community centres in Khayelitsha Township, Cape Town, South Africa. We implemented a mixed-methods design, collecting both quantitative and qualitative data from participants in 2 stages. In stage 1, we collected quantitative data. With appropriate ethics and consent, parents completed a short technology questionnaire about their familiarity with and access to smartphones, internet and apps, followed by electronic iPhone-based demographic and ASD-related questionnaires. Next, children were shown 3 short videos of 30s each and a mirror stimulus on a study smartphone. The smartphone front facing (“selfie”) camera recorded video of the child’s facial expressions and head movement. Automated computer algorithms quantified positive emotions and time attending to stimuli. We validated the automatic coding by a) comparing the computer-generated analysis to human coding of facial expressions in a random sample (N=9), and b) comparing automated analysis of the South African data (N=33) with a matched American sample (N=33). In stage 2, a subset of families were invited to participate in focus group discussions to provide qualitative data on accessibility, acceptability, and cultural appropriateness of the app in their local community. Results Most parents (64%) owned a smartphone of which all (100%) were Android based, and many used Apps (45%). Human-automated coding showed excellent correlation for positive emotion (ICC= 0.95, 95% CI 0.81-0.99) and no statistically significant differences were observed between the South African and American sample in % time attending to the video stimuli. South African children, however, smiled less at the Toys&Rhymes (SA mean (SD) = 14% (24); USA mean (SD) = 31% (34); p=0.05) and Bunny video (SA mean (SD) = 12% (17); USA mean (SD) = 30% (0.27); p=0.006). Analysis of focus group data indicated that parents/carers found the App relatively easy to use, and would recommend it to others in their community provided the App and data transfer were free. Conclusion The results from this pilot study suggested the App to be technically accurate, accessible and culturally acceptable to families from a low-resource environment in South Africa. Given the differences in positive emotional response between the groups, careful consideration should be given to identify suitable stimuli if % time smiling is to be used as a global marker for autism risk across cultures and environments.
Open Access
Global mental health and neuroethics
(BioMed Central Ltd, 2015) Stein, Dan; Giordano, James
BACKGROUND: Global mental health is a relatively new field that has focused on disparities in mental health services across different settings, and on innovative ways to provide feasible, acceptable, and effective services in poorly-resourced settings. Neuroethics, too, is a relatively new field, lying at the intersection of bioethics and neuroscience; it has studied the implications of neuroscientific findings for age-old questions in philosophy, as well as questions about the ethics of novel neuroscientific methods and interventions.DISCUSSION:In this essay, we address a number of issues that lie at the intersection of these two fields: an emphasis on a naturalist and empirical position, a concern with both disease and wellness, the importance of human rights in neuropsychiatric care, and the value of social inclusion and patient empowerment.SUMMARY:These different disciplines share a number of perspectives, and future dialogue between the two should be encouraged.
Open Access
HIV-associated neurocognitive disorders biomarkers and the response to antiretroviral therapy
(2012) Cross, Helen Margot; Combrinck, MI
This study aimed to determine whether highly active antiretroviral therapy (HAART) improved cognitive function in HIV positive people in South Africa, and whether this effect differed according to the CNS penetration-effectiveness (CPE) of the regimen used. I also investigated potential HIV-Associated Neurocognitive Disorders (HAND) biomarkers (serum neopterin, osteopontin and neurofilament H) to determine their relationship to the severity of cognitive impairment at baseline in HAART-naïve patients, and whether initial levels of these biomarkers related to the change in cognitive function a year later.
Open Access
Identification of natural TSC-Associated Neuropsychiatric Disorders (TAND) clusters
(2017) Leclezio, Loren; De Vries, Petrus J
Tuberous Sclerosis Complex (TSC) is associated with many learning, behavioural, neurodevelopmental and psychiatric difficulties. Over 90% of individuals with TSC will have some of these concerns yet no more than 20% receive support and treatment, even though these issues may cause the greatest burden of disease in TSC. The Neuropsychiatry Panel at the 2012 TSC Consensus Conference coined the term TAND (TSC-Associated Neuropsychiatric Disorders) to capture the multidimensional concerns seen in TSC, and recommended that each person with TSC should be screened for TAND every year. To facilitate the process, a TAND Checklist was designed. Many professionals and families feel overwhelmed by the complexity of TAND and say that they do not know where to start and how to access relevant information, tips or 'next step' approaches. This may in part be due to the multi-dimensionality of TAND, and in part due to lack of access to clear, useful and evidence-based resources for TAND. This project aimed to address the complexity of TAND. The hypothesis was that, even though each individual will typically have their own unique TAND profile, there will be key natural TAND Clusters - combinations of behaviours across multi-dimensional levels - that will simplify further evaluations and treatment. The study was performed over 36 months, in two phases using a mixed-methods approach. Phase I was a pilot phase. TAND Checklist data were collected from 56 individuals with TSC in South Africa (n=20) and in Australia (n= 36). Using R, these data were explored with various multivariate data analysis techniques to identify suitable analysis methods for the identification of potential natural TAND clusters. WARD's cluster analysis method rendered six TAND clusters with good face validity, and convergence with a six-factor exploratory factor analysis solution. Pilot results suggested that a combination of cluster analysis and exploratory factor analysis methods may be able to identify clinically-meaningful natural TAND clusters. Phase II set out to replicate and expand on pilot results. TAND checklist data were collected from n=453 across six international TSC sites, and the multivariate analysis techniques identified in phase I were applied. WARD's method rendered seven natural TAND clusters with good clinical face validity. This data-driven strategy identified a 'Scholastic' cluster of TAND manifestations, a 'Neuropsychological' cluster, a 'Mood/Anxiety' cluster, an 'ASD-like' cluster, a 'Behaviours that Challenge' cluster, a 'Hyperactive/Impulsive' cluster, and an 'Eating/Sleeping' cluster. Results showed significant convergence with an exploratory factor analysis solution. The larger-scale study findings were remarkably consistent with pilot findings, supporting the robustness of these naturally occurring clusters. We propose that the seven natural TAND clusters identified can in future be used to generate clinical toolkits for use in real-life setting. In addition, findings suggest that the aetiology and molecular treatments of TAND may also show differential clustering across human and animal models, pointing towards novel hypotheses regarding neuropsychiatric phenomena in TSC to be explored in future studies.
Open Access
Investigating neural responses in models of neurocysticercosis
(2020) Tomes, Hayley Sarah; Raimondo, Joseph Valentino; Kellaway, Lauriston
Epilepsy is more frequent in sub-Saharan Africa than the rest of the world due to high levels of brain infections by larvae of the pig cestode Taenia solium, a condition termed neurocysticercosis. Despite the large nature of the problem, little is known about how neurocysticercosis modulates neuronal responses to result in the development of seizures. In this thesis I have used the cestode Taenia crassiceps to develop multiple in vitro and in vivo models of neurocysticercosis in rodents. Utilising patch-clamp electrophysiology in organotypic hippocampal brain slices and chronic, wireless electrocorticographic recordings in freely moving animals I have explored how cestode larvae affect neuronal excitability in the brain across a range of time scales. First I demonstrate that homogenate of Taenia crassiceps larvae has a strong, acute excitatory effect on neurons, which is sufficient to trigger seizurelike events. The excitatory component of the homogenate was found to strongly activate glutamate receptors and not acetylcholine receptors nor acid-sensing ion channels. An enzymatic assay showed that the larval homogenate contains high levels of glutamate, explaining its acute excitatory effects on neurons. In the second part of my thesis I demonstrate that longer-term incubation of Taenia crassiceps homogenate with organotypic brain slices over the course of a day does not affect the intrinsic properties of pyramidal neurons nor the excitability of the neuronal network. In the final part of my thesis I established an in vivo model of neurocysticercosis. I found that intradermal inoculation together with multiple intracerebral injections of Taenia crassiceps homogenate did not result in the development of seizures over 3 months of chronic electrocorticography recordings. In addition, the seizure-threshold to picrotoxin, an excitotoxin, was not altered by Taenia crassiceps homogenate injection. Immunohistological analysis of the tissue below the injection site revealed no difference in astrocytes nor the number of microglia. However, microglial processes were observed to be retracted in the Taenia crassiceps group reflecting a moderate neuroinflammatory response. Together the data in my thesis provides novel insight into the acute and chronic effects of Taenia crassiceps homogenate on the excitability of neuronal networks with relevance to our understanding of neurocysticercosis.
Open Access
Investigating pupillometry as a novel mechanism for detecting emotional regulation difficulties in individuals with PTSD
(2017) Ginton, Lee; Stein, Dan J; Thomas, Eileen
Objective: Individuals with posttraumatic stress disorder (PTSD) have been found to exhibit emotional regulation difficulties. However, much remains to be learned about the specific neural mechanisms that underlie such difficulties. This study aimed to use eye tracking to investigate the mechanisms underlying emotional regulation difficulties in individuals with PTSD. Method: A total of 87 trauma-exposed mothers (34 PTSD positive and 53 non-PTSD controls) completed an eye tracking assessment in which pupillary dilation in response to emotionally valenced stimuli was measured. The participants also completed two self-report measures of emotional regulation. Results: The PTSD group exhibited increased pupillary dilation to positively valenced stimuli compared to the trauma-exposed, non-PTSD group. In contrast, there was no difference between the two groups using self-report measures of emotional regulation. Additionally, there were no associations between self-report measures and pupillary response to emotionally valenced stimuli. Conclusion: The findings may reflect impaired parasympathetic nervous system processes in individuals with PTSD. The finding that eye tracking, but not emotional regulation questionnaires, differentiated the groups may reflect the point that self-report measures are biased by an individual's ability and willingness to respond. These findings need to be followed up with additional experiments to delineate parasympathetic and other mechanisms involved in underpinning emotional regulation difficulties in PTSD.
Open Access
Investigating the Influence of Methamphetamine on brain metabolism using 1H-MRS
(2016) Burger, Antoinette; Howells, Fleur M; Stein, Dan J
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.
Open Access
Locus-coeruleus norepinephrine system function in a developmental animal model of schizophrenia: the socially isolated rat
(2017) Atmore, Katherine H; Howells, Fleur M; Russell, Vivienne A; Stein, Dan J
Introduction: Schizophrenia is a chronic, debilitating mental disorder characterised by positive, negative and cognitive symptoms. Current treatment regimens fail to adequately address the cognitive and negative symptoms of the disorder. Social isolation rearing (SIR) is a well-established developmental adversity paradigm which is used as an animal model of schizophrenia and usually studied in male rats. Previous SIR studies have found attentional abnormalities in isolated rats in behavioural tests which correspond to the results of studies investigating the cognitive symptoms of schizophrenia in patient trials. Isolated rats also display abnormal social responses which may be of relevance to the negative symptoms of schizophrenia. The primary aim of this study was to build on existing SIR literature by performing behavioural tests in socially isolated rats to address attentional function. Neurochemical investigations were performed on projections of the locus coeruleus norepinephrine system, known to be involved in attentional function, as research on this system is surprisingly sparse. The secondary aim of the study was to address the negative symptoms of schizophrenia using ultrasonic vocalisation recording to investigate the calling behaviour of isolated rats in response to a novel context. The study included both male and female rats so that sex differences could be studied in the context of social isolation. Methodology: Sprague-Dawley rats were weaned at postnatal day (p) 21 and randomly allocated to one of four housing groups; female socialised (n=50), female isolated (n=50), male socialised (n=38) and male isolated (n=38). Socialised animals were housed 4 per cage (single sex) and isolated animals were housed alone. Animals were weighed and cages cleaned weekly as part of a minimal handling protocol required for SIR. After 8 weeks in their housing conditions (p78-82) rats underwent one of two behavioural paradigms: three phase novel object recognition or ultrasonic vocalisation recordings. Between p90-94 animals were rapidly decapitated and the hippocampus and prefrontal cortex were dissected out for use in one of two neurochemical analyses. For in-vitro superfusion experiments the tissue was used immediately to quantify functional release of radioactively-labelled norepinephrine when stimulated with glutamate under varying conditions. Enzyme linked immunosorbent assays (ELISA) and bicinchoninic acid (BCA) protein assays was performed to quantify norepinephrine and glutamate concentrations expressed in relation to the wet weight of the tissue and amount of protein in the tissue. Results: Behavioural and neurochemical changes were induced by the SIR model. Isolated animals were found to respond to novel objects abnormally compared to control animals. During initial exposure to a novel environment in the first phase of the novel object recognition test isolated animals demonstrated hypoactivity. An overall reduction in the fractional release of norepinephrine when stimulated with combinations of glutamate and gamma-aminobutyric acid (GABA) was demonstrated in the hippocampus of isolated rats. Sex differences were evident in a number of experiments. Female rats were found to be hyperactive in the three phases of the novel object recognition test compared to males and also had elevated hippocampal norepinephrine activity as well as an increased concentration of norepinephrine in this area. Male rats on the other hand had an elevated prefrontal cortex norepinephrine activity and concentration. Conclusion: The SIR paradigm is able to induce behavioural and neurochemical changes in both female and male rats. The results of this study reinforce the usefulness of SIR as a model for schizophrenia as the way in which isolated animals responded to novel objects was different to their socialised counterparts. This difference implies an abnormal attentional response which corresponds to the cognitive symptoms described in schizophrenia. Furthermore, the neurochemical experiments performed in this study are the first of their kind and provide preliminary evidence for the GABAergic mechanisms underlying attentional abnormalities associated with SIR. The prevalence of sex differences throughout testing also provides strong evidence for the inclusion of both sexes in future studies to avoid the omission of potentially important findings. Future studies to refine and build on neurochemical analyses in developmental models of schizophrenia, such as SIR will potentially provide a mechanistic understanding of cognitive dysfunction as well as useful translational information for treating the human disorder.
Open Access
Magnesium recurarisation differences between no reversal, neostigmine/glycopyrrolate reversal and sugammadex reversal of neuromuscular block in an in vivo rat model
(2016) Van den Berg, Maurits Matthew; Kellaway, Lauriston A; James, Michael F; Swanevelder, Justiaan
The neuromuscular junction (NMJ) is a synapse with one of the highest safety margins in the human body. The use of neuromuscular blocking agents to inhibit neuromuscular transmission is sufficient to produce skeletal muscle paralysis, a mechanism used to facilitate muscle relaxation during surgery. Residual neuromuscular block postoperatively has been found to be a major risk factor for postoperative complications. Sudden reinstatement of neuromuscular block (recurarisation), through use of magnesium, has also been observed clinically. This has led to a reluctance to use magnesium postoperatively for fear of recurarisation. Recurarisation following reversal of neuromuscular blockade with neostigmine or sugammadex has not been evaluated in a formal study, and for this reason, this study investigated recurarisation after 30 mg/kg magnesium sulphate (MgSO4) following reversal of neuromuscular blockade with neostigmine, two dosages of sugammadex or when reversal was omitted. Prior to investigating recurarisation, the effects of magnesium on neuromuscular transmission in the absence of neuromuscular blocking agents was investigated, in order to determine a standard clinical dose that did not produce detectable, by Train-of-Four Ratio (TOF-R) or Twitch 1 height (%T1), neuromuscular impairment.