OpenUCT :: Browsing by Author "Meintjes, Ernesta M"

Browsing by Author "Meintjes, Ernesta M"

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Open Access
4D flow and displacement sensitive MR imaging of upper arm arterio-venous connections for haemodialysis
(2016) Jermy, Stephen; Meintjes, Ernesta M; Franz, Thomas; Auger, Daniel A
Chronic Kidney Disease (CKD) is a disease that causes kidney damage, often leading to the patient requiring haemodialysis treatment. Haemodialysis treatment requires a vascular access method, commonly Arteriovenous (AV) fistulae and grafts. These access methods must be regularly assessed to ensure the access remains unblocked and the flow rate is normal. Phase Contrast MRA (PC-MRA) is a versatile Magnetic Resonance Imaging (MRI) modality which is capable of imaging and quantifying blood flow in vivo. It is for this reason that this imaging technique was used to image blood flow in the vasculature of the upper arm of volunteers and haemodialysis patients with either an AV fistula or graft. This imaging technique is capable of producing temporally resolved Three-dimensional (3D) datasets (known as "Four-dimensional (4D)" flow) of blood flow in major vessels. Velocities are phase encoded between -π and π based on the chosen Velocity Encoding Constant (venc). To successfully characterise all velocities in the volume it is necessary to set the venc to be approximately equal to the highest velocity found in the vessel. Any lower venc value will cause phase wrapping, an imaging artefact causing all higher velocities to be wrapped by a multiple of 2 π. However, the increase in sensitivity to high velocities reduces the overall specificity of the velocities, especially for low velocities. Due to the pulsatile nature of blood flow in arterial vessels, a large range of velocities are encountered, while venous flow is more constant but lower than the peak arterial flow value. For this reason and due to the length of the 4D flow scans, 20-30 minutes, it would be preferable to perform one scan at a relatively low venc and correct any phase wrapping during post-processing. In this study, we performed both Two-dimensional (2D) PC-MRA scans at various locations in the upper arm and 4D PC-MRA scaans with similar venc settings. The purpose of the study was to implement and test several methods of phase unwrapping to remove phase wrapping artefacts from affected areas within the PC-MRA datasets.
Restricted
Abnormal diastolic and systolic septal motion following pericardiectomy demonstrated by cine DENSE MRI
(Clinics Cardive, 2008) Spottiswoode, Bruce; Russell, James B; Moosa, Sulaiman; Meintjes, Ernesta M; Epstein, Frederick H; Mayosi, Bongani M
Constrictive pericarditis can lead to paradoxical interventricular septal motion. Displacement encoding with stimulated echoes (DENSE) magnetic resonance imaging (MRI) provides a method for quantifying myocardial motion and strain. A case of constrictive pericarditis is presented and the diastolic ‘septal bounce’ is clearly evident in both anatomical and DENSE ciné MRI images. (See video link to full-text electronic article). The postoperative systolic septal wall-motion abnormality of cardiac surgery is portrayed with greater precision by DENSE than anatomical ciné MRI images.
Open Access
Comparison of resting state functional networks in HIV infected and uninfected children at age 9 years
(2018) Stoltsz, Werner Heinrich; Meintjes, Ernesta M; du Plessis, Lindie
Over 2.5 million children are infected with HIV, the majority of whom reside in Sub-Saharan Africa. Treatment coverage is steadily gaining momentum, reducing mortality and morbidity. Yet little is known about brain development in HIV-infected (HIV+) children who are on highly-active antiretroviral therapy (ART), with viral load suppression from a young age. Here, we use resting state fMRI (rs-fMRI) to examine the impact of HIV and ART on the development of functional networks in 9-year-old vertically HIV-infected children compared to age-matched controls of similar socioeconomic status. We present analyses for a sample of 40 HIV+ (9.2 ± 0.20 years; 16 males) children from the Children with HIV Early Antiretroviral (CHER) clinical trial (Cotton et al. 2013; Violari et al. 2008) and 24 uninfected (12 exposed; 12 males; 9.6 ± 0.52 years) controls from an interlinking vaccine trial (Madhi et al. 2010). Scans were performed at the Cape Universities Body Imaging Centre (CUBIC) in Cape Town, South Africa. We investigated HIV-related differences in within- and between-network functional connectivity (FC) using independent component analysis(ICA) and seed-based correlation analysis (SCA). For SCA, seeds were placed in the structural core, in regions implicated in HIV-related between-group differences at age 7 years, and in regions associated with neuropsychological domains impaired in our cohort. In addition, we evaluated associations of past and present immune health measures with within-network connectivity using ICA. We found no HIV-related intra-network FC differences within any ICA-generated RSNs at age 9 years, perhaps as a result of within-network connectivity not being sufficiently robust at this age. We found a positive association of CD4%, both current and in infancy, with functional integration of left lobule 7 into the cerebellum network at age 9 years. Long-term impact of early immune health supports recently-revised policies of commencing ART immediately in HIV+ neonates. ii Compared to uninfected children, HIV+ children had increased FC to several seeds. Firstly, to seeds associated with the planning and visual perception neuropsychological domains. Secondly, to structural core seeds in the extrastriate visual cortex (of the medial visual network) and the right angular gyrus (of the temporoparietal network). Finally, to left paracentral (somatosensory network) and right precuneus (posterior DMN) seeds previously revealing between-group differences at age 7 years. The connections with greater FC in HIV+ children may variously indicate functional recruitment of additional brain capacity, immature excess of short-range connections, and/or immature excess of between-network connections. In conclusion, despite early ART and early virologic suppression, HIV+ children demonstrate instances of abnormal FC at age 9 years. Disruption to visual cortex is marked, consistent with indications from neuropsychological testing that visual perception is disrupted. The profile of HIV- and/or ART-related effects on FC differs considerably between the two ages of 7 and 9 years, but both show characteristics of immature functional organisation compared with age-matched controls.
Open Access
Connectivity analysis of brain function in children with foetal alcohol spectrum disorder and control children during number processing
(2008) Herron, Robyn; Meintjes, Ernesta M
Maternal drinking during pregnancy is a significant problem in the Western Cape, South Africa, with an accompanying high incidence of children diagnosed with foetal alcohol spectrum disorder (FASD). Little is known about the neural correlates governing the disorder that manifest as behavioural abnormalities and cognitive impairments, particularly in arithmethic calculation, repeatedly reported in affected children. The effect of prenatal alcohol exposure on number processing in children was investigated in a functional magnetic resonance imaging (fMRI) study (Meintjes et al., 2007). The results indicate significant differences in activation between alcohol-exposed and non-exposed control children during Exact Addition and Proximity Judgement tasks. This raised the question of whether the groups of children differ in functional connectivity during the number processing tasks. Therefore, the objective of this study was to analyse connectivity between functionally specialised brain areas in the previously collected fMRI data. The fMRI data of 14 controls and 7 alcohol-exposed children for Exact Addition and 15 controls and 9 alcohol-exposed children for Proximity Judgement was available for analysis. A primary aim was to determine normal functional connectivity in control children during number processing and a secondary aim, to investigate any differences in functional connectivity in children with FASD.
Open Access
Development and validation of a quantitative choline food frequency questionnaire for use with drinking and non-drinking pregnant women in Cape Town, South Africa
(BioMed Central, 2018-11-22) Carter, R Colin; Jacobson, Sandra W; Booley, Sharmilah; Najaar, Baheya; Dodge, Neil C; Bechard, Lori J; Meintjes, Ernesta M; Molteno, Christopher D; Duggan, Christopher P; Jacobson, Joseph L; Senekal, Marjanne
Background Although animal and human studies have demonstrated interactions between dietary choline and fetal alcohol spectrum disorders, dietary choline deficiency in pregnancy is common in the US and worldwide. We sought to develop and validate a quantitative food frequency questionnaire (QFFQ) to estimate usual daily choline intake in pregnant mothers. Methods A panel of nutrition experts developed a Choline-QFFQ food item list, including sources with high choline content and the most commonly consumed choline-containing foods in the target population. A data base for choline content of each item was compiled. For reliability and validity testing in a prospective longitudinal cohort, 123 heavy drinking Cape Coloured pregnant women and 83 abstaining/light-drinking controls were recruited at their first antenatal clinic visit. At 3 prenatal study visits, each gravida was interviewed about alcohol, smoking, and drug use, and administered a 24-hour recall interview and the Choline-QFFQ. Results Across all visits and assessments, > 78% of heavy drinkers and controls reported choline intake below the Dietary Reference Intakes adequate intake level (450 mg/day). Women reported a decrease in choline intake over time on the QFFQ. Reliability of the QFFQ across visits was good-to-acceptable for 2 of 4 group-level tests and 4 of 5 individual-level tests for both drinkers and controls. When compared with 24-hr recall data, validity of the QFFQ was good-to-acceptable for 3 of 4 individual-level tests and 3 of 5 group-level tests. For controls, validity was good-to-acceptable for all 4 individual-level tests and all 5 group-level tests. Conclusions To our knowledge, this is the first quantitative choline food frequency screening questionnaire to be developed and validated for use with both heavy and non-drinking pregnant women and the first to be used in the Cape Coloured community in South Africa. Given the high prevalence of inadequate choline intake and the growing evidence that maternal choline supplementation can mitigate some of the adverse effects of prenatal alcohol exposure, this tool may be useful for both research and future clinical outreach programs.
Open Access
Development of a 3D radial MR Imaging sequence to be used for (self) navigation during the scanning of the fetal brain in utero
(2016) Morgan, Leah; Meintjes, Ernesta M; Van der Kouwe, Andre
Imaging the fetal brain in utero is challenging due to the unpredictable motion of the fetus. Although ultra-fast MRI sequences are able to image a 2D slice in under a second, thus limiting the time in which fetal motion can corrupt images, Cartesian sampling makes these sequences sensitive to signal misregistration and motion-corruption. Corruption of a single 2D slice renders it impossible to reconstruct 3D volumes from these slices without complex slice-to-volume registration. There is a need for motion-robust sequences that can produce high-resolution 3D volumes of the fetal brain. The Siemens Cardiovascular sequence was edited to produce a new radial readout that sampled a 3D spherical volume of k-space with successive diametric spokes. The diameter end points map a spiral trajectory on the surface of a sphere. The trajectory was modified so that multiple sub-volumes of data are sampled during a single acquisition where M is the number of sub-spirals and N is the number of diametric spokes per sub-spiral. This allows reconstruction of individual sub-volumes of data to produce a series of low-resolution navigator images that can be co-registered to provide information on motion during the acquisition. In this way, a segmented sequence suited to self-navigation was developed. Imaging parameters for the 3D radial sequence were optimised based on theoretical calculations and scans performed in adult brains and abdomens. Optimum values for M and N needed to be determined. Increasing M for a constant total number of projections improves the temporal accuracy of motion tracking at the expense of decreased signal to noise ratio in the navigator images. The effects of breathing and rigid body motion on image quality were also compared between 3D radial and equivalent 3D Cartesian acquisitions. Custom reconstruction code was written to separate the incoming scan data according to the sub-spiral trajectories described within the sequence such that individual navigator images could be reconstructed. Successive sub-spiral images were co-registered to the first navigator image to quantify motion during the acquisition. The resulting transformation matrices were then applied to each sub-spiral image after reconstruction and co-registered sub-spiral images combined in image space to generate the final 3D volume. To improve the quality of navigator images, a method is presented to perform navigator image reconstruction at a lower base resolution, thus reducing streaking artifacts and improving the accuracy of image co-registrations. Finally, the methods developed were applied to two fetal scans. The radial sequence was shown to be more motion-robust than an equivalent Cartesian sequence. The minimum number of diametric spokes that provided navigator images that could be accurately co-registered when scanning an adult brain was N=256, which could be acquired in 1.25 s. For abdominal scans, the minimum number of spokes was N=1024, which could be acquired in about 6 s when water excitation is applied. However, the latter could potentially be reduced by reconstructing navigator images at a lower base resolution. Although fetal scans demonstrated poor image contrast, navigator images were able to track motion during the acquisition demonstrating the potential use of this method for self-navigation. In conclusion, a motion-robust radial sequence is presented with potential applications for prospective navigation during fetal MRI.
Open Access
Differences in resting state functional networks in HIV infected and uninfected children at age 7 years
(2015) Toich, Jadrana; Meintjes, Ernesta M; Holmes, Martha; Taylor, Paul A
Although early administration of highly active antiretroviral therapy (HAART) in infants provides the brain some protection against HIV damage, few studies have examined the long-term effects of HIV infection and HAART on neurodevelopment, and none have measured their impact on functional brain networks in young children. We use resting state functional magnetic resonance imaging (RS-fMRI) to explore differences in functional connectivity (FC) in HIV infected children stable on HAART and in HIV uninfected children. The 9 resting state networks (RSNs) identified using independent component analysis (ICA) included the visual lingual gyrus, visual occipital gyrus, salience, dorsal attention, auditory, motor, executive control, posterior default mode network (pDMN) and default mode network (DMN) . No significant group level differences were found in any RSNs using ICA. However, seed-based correlation analysis ( SCA ) revealed two regions where uninfected children had a higher FC compared to infected children (p < 0. 05 corrected for multiple comparison); specifically, between a seed in the left cingulate gyrus of the DMN and the left middle frontal gyrus, and between a seed in the right middle frontal gyrus of the executive control network and the right supramarginal gyrus. Consistent with our findings, previous RS-fMRI studies in HIV infected adults have reported reduced connectivity compared to uninfected adults in numerous DMN regions and executive control network. However, in contrast to the adult literature, in which a number of areas within the networks have been implicated, we only observed a focal effect in each of the two RSNs. Given that some of the RSNs are still undergoing major developments at age 7 years (i.e . time of scan for the children), the reduced FC may represent delayed network maturation within the infected cohort , with potential effects on cognitive functioning, information processing and memory recall abilities . Furthermore, positive associations were found between the clinical CD4/CD8 at time of enrollment and two regions within the dorsal attention and auditory networks. These results were independent of treatment arm and suggest that reduced FC in these networks at age 7 years are a result of poor immune function in early infancy (6-8 weeks of age), supporting the notion of in itiating ART immediately in HIV infected infants.
Open Access
Diffusion tensor imaging point to ongoing functional impairment in HIV-infected children at age 5, undetectable using standard neurodevelopmental assessments
(2020-05-19) Ackermann, Christelle; Andronikou, Savvas; Saleh, Muhammad G; Kidd, Martin; Cotton, Mark F; Meintjes, Ernesta M; Laughton, Barbara
Background Perinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts. Methods DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard–Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter. Results 38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5. Conclusion Even directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study.
Open Access
Effects of HIV and different anti-retroviral therapy (ART) regimes on brain structure in HIV infected children at age 7
(2015) Nwosu, Emmanuel Chukwubuikem; Meintjes, Ernesta M; Robertson, Frances C
By 2013, more than 300, 000 children were living with HIV-infection in South Africa. The World Health Organization (WHO) recommended early aggressive antiretroviral therapy (ART) initiation to manage HIV in children, based on studies that reported this protocol as effective in reducing mortality and HIV progression. Early ART initiation in HIV-infected children generated new concern about the long-term effects on neurodevelopment. There is still much to understand about the outcome of HIV and early ART on children's brain structure and neurocognitive skills. This study therefore investigated the effects of HIV and early ART on brain morphometry in 7-year old children using magnetic resonance imaging (MRI). Participants were 99 Xhosa children (56 HIV-infected children 43 uninfected controls, 50 boys, mean age = 7.21 ± 0.14 years) from the neuroimaging follow-on study of the Children with HIV Early Antiretroviral (CHER) trial. T1-weighted structural MRI data were acquired on a 3T Allegra (Siemens, Erlangen, Germany) within 6 months of their 7th birthday. In the CHER trial, HIV-infected infants were randomized at 7 weeks of age into three arms, two of which received immediate ART for either 40 or96 weeks. The third arm received ART when clinically or immunologically indicated by WHO 2006criteria. At age 7 years, all children were stable on ART. Scans were performed in accordance with protocols approved by the human research ethics committees of Stellenbosch and Cape Town Universities; all parents provided written informed consent and children provided oral assent. MRI scans were analysed with FreeSurfer's automated processing stream (http://freesurfer.net/) to generate measures of cortical thickness, local gyrification index (LGI), and regional (corpus callosum, bilateral caudate, hippocampus, putamen, thalamus, and lateral ventricle) and global brain volumes. Vertex-wise and region of interest (ROI) comparisons were performed between and within HIV infected and uninfected children. Relationships between morphometric and clinical data were investigated. Our results showed no significant difference in cortical thickness between HIV-infected and uninfected children. Uninfected children had greater gyrification than HIV-infected children in a left medial parietal region while HIV-infected children had smaller volumes of the bilateral putamen (p=0.001)and right hippocampus (p=0.01), and smaller total white (p=0.001) and gray (p=0.02) matter volumes. There was no effect of duration of ART in HIV-infected children except in the left hippocampus where longer (96 weeks) duration was associated with greater volume. There was no significant relationship between cortical thickness at age 7 and immunological status at enrollment, but regional (caudal middle frontal, pars orbitalis, lateral occipital and superior parietal regions) gyrification showed a relationship with immune system parameters (CD4 count, CD4percentage and CD4/CD8 ratio) respectively. A healthier immune system at enrollment - CD4percentage and CD4/CD8 ratio - was associated with reduced volume in the caudate nucleus, while longer cumulative duration on ART was associated with increased volume of the bilateral thalamus at age 7. There was no difference in brain volume or cortical thickness measures between HIV-exposed but uninfected (HEU) children and HIV-unexposed uninfected (HUU), but HEU children had greater gyrification in the left precuneus region which may be abnormal due to HIV/ART exposure in utero. In conclusion, LGI and subcortical volumes were affected in HIV-infected children but their cortical thickness was not affected. This may likely have effects on neurodevelopmental skills and cortical folding development.
Open Access
The effects of HIV-1 infection on subcortical brain structures in children receiving ART : a structural MRI study
(2015) Randall, Steven Ronald; Meintjes, Ernesta M; Warton, Christopher
INTRODUCTION This project investigated volumetric differences in certain subcortical structures as measured on high-resolution structural Magnetic Resonance Imaging (MRI) scans traced manually. The sample comprised 79 5-year old children, 52 with HIV and 27 uninfected controls. Infected children were all stable on antiretroviral therapy (ART) and were from the Children with HIV early antiretroviral (CHER) cohort who have been followed since birth. The study aimed to investigate the long-term effects of HIV and ART on the developing brain. While high-resolution structural data has been analysed using automated FreeSurfer to determine volume and cortical thickness, manual tracing remains the gold standard. Thus, manual tracing was used to validate automated measures and investigate subtle group differences in selected regions of interest. METHODS Extensive clinical data were available for all participants in the study. MR images were AC-PC transformed and converted to analyse format. Structures were traced using MultiTracer software. Structures selected included the caudate, nucleus accumbens (NA), putamen (Pu), globus pallidus (GP) and corpus callosum (CC). Four of these structures occur bilaterally. Tracing was performed in 79 subjects. Three subjects were excluded due to poor quality images or pathology; 5 HIV-1 infected children were excluded as they were not randomized between treatment groups. Certain subjects were retraced for inter and intrarater reliabilities. The effect and association of ethnicity, age, birthweight and sex as possible confounders were investigated. As the groups were not well matched for ethnicity, all Cape Coloured children were excluded from further analyses. Analysis of variance was used to test the effect on structure size between HIV-1 infected children and controls, as well as between 3 treatment arms (ART deferred until clinical criteria were met, early ART for 40 weeks, early ART for 96 weeks) and uninfected controls. Analysis of covariance was used to control for the possible confounding effects of sex and age. Each structure was tested for possible association with clinical variables (CD4, CD8, CD4/CD8 ratio and CD4%) both at enrolment and time of scanning. Linear regressions were modelled using clinical variables that showed significant correlation with structure size whilst controlling for covariates. Congruence between automated FreeSurfer and manual segmentation were evaluated via Bland-Altman, Pearson r and Cronbach's alpha.
Open Access
Exploring the prevalence of developmental reading difficulties in Children with Fetal Alcohol Spectrum Disorders
(2009) Bromley, Katie Rachael; Meintjes, Ernesta M
Background. As part of a large ongoing research programme concerned with the teratogenic effects prenatal alcohol exposure has on the developing brain, this study investigated whether developmental reading difficulties are present in school-going children with fetal alcohol spectrum disorders (FASD). Whereas the diagnostic facial anomalies associated with FASD are well documented, cognitive deficits remain largely unexplored. Some neuropsychological reviews include deficits in reading as part of the FASD cognitive profile; however, the extant empirical research investigating reading abilities in children with FASD is limited. Therefore, the specific objectives of the current study were to explore the prevalence and characteristics of developmental reading skill deficits in a sample of children with FASD. Methods. Participants were 46 children (9-13 years) who had previously been diagnosed as either prenatally exposed or non-exposed. Of the 32 exposed children, 7 met the criteria for fetal alcohol syndrome (FAS), 3 met the criteria for partial FAS (pFAS) and 22 did not meet the criteria for diagnosis of FAS/pFAS but were still heavily exposed (and were thus characterized as &amp;acirc;other heavily exposed&amp;acirc;, or OHE). All participants were administered the Neale Analysis of Reading Ability (NARA; a measure of reading speed, accuracy, and comprehension) and the Phonological Assessment Battery (PhAB; a measure of phonological awareness, processing speed and fluency). Independent samples t-tests and one-way analyses of covariance (ANCOVAs) were performed to determine if there were statistically significant between-group differences in a two-group (exposed versus non-exposed) or three-group (FAS/pFAS versus OHE versus control) comparison. Multiple regression-based analyses were performed to determine if a relationship existed between a continuous measure of prenatal alcohol exposure and the outcome measures. Within each of these analyses an estimate of IQ was used to determine if the effects seen were present even with that covariate taken into account. Results. None of the two- or three-group analyses showed any statistical significance on the PhAB or NARA outcome variables. Participants in the FAS/pFAS and OHE groups performed significantly differently on the PhAB non-phonological fluency performance measure; this between-group difference was not in the predicted direction, however, and probably resulted from artifactual factors. Results from the multiple regression-based analyses showed that associations between the predictor variable (level of prenatal alcohol exposure) and two outcome variables (phonological production speed and reading rate abilities) approached, but did not reach, statistical significance. 7 Conclusion. Overall, the data suggest that impairments in phonological awareness, phonological processing speed, verbal fluency, and developmental reading difficulties are not characteristic of the cognitive profile of children with FASD. These findings are not conclusive, however, due to several limitations in the current study. These limitations are discussed and provide interesting insight into the process of assessing phonological abilities and reading skills in this population. Further research, using a broader range of assessment tools and a larger sample size, is necessary in order to provide a more detailed and definitive analysis of these abilities. Nonetheless, the current study shows that the evaluation of reading and phonological disorders in FASD is an important and worthwhile endeavour.
Open Access
Neural correlates of deficits in affect regulation in methamphetamine abusers with and without a history of psychosis
(2015) Uhlmann, Anne; Stein, Dan J; Meintjes, Ernesta M
Methamphetamine dependence has been associated with neurological damage resulting in potentially long-lasting changes in cognitive-affective processes, a range of behavioral problems and psychiatric disorders, including psychosis. Poor emotional control and maladaptive social behaviors have been linked to abnormalities in brain function and structure. However, the links between alterations in neurocircuitries, affect dysregulation, and psychotic symptoms in methamphetamine dependence are yet to be fully elucidated. This project aimed to delineate emotion regulation capabilities as well as brain structure and function in methamphetamine-dependent individuals, patients with a history of methamphetamine-associated psychosis, and healthy adults. The four cross-sectional studies presented here investigated socio-emotional behaviour using self-report questionnaires and social cognition tasks; and assessed neural activation during incidental emotion regulation, measured in an affect labelling task as part of functional magnetic resonance imaging. Additionally, structural magnetic resonance imaging and diffusion tensor imaging were employed to determine grey matter and white matter structural abnormalities, respectively, and to correlate findings with the presence/absence of affect dysregulation and psychotic symptoms. Both methamphetamine-dependent groups showed deficits in emotion regulation abilities, as evidenced by increased levels of aggression, impulsivity, and emotion reactivity. Further, social cognition capacities, including recognising emotions and inferring mental states of others, were diminished in both groups, with greater functional decrements in patients with methamphetamine-associated psychosis. These patients further demonstrated grey matter loss in frontotemporal brain regions and hippocampi, as well as globally reduced white matter integrity, compared to methamphetamine-dependent individuals; and structural deficits in prefrontal and temporal brain regions were associated with impaired affect regulation. Frontolimbic hypoactivation during emotion perception further suggests a role of diminished emotional salience attribution in the pathogenesis of methamphetamine-associated psychosis. Whereas methamphetamine-dependent individuals displayed prefrontal hyperactivation during affect labelling, potentially reflecting a compensatory activation to sufficiently regulate affect, or suggesting a cognitive bias towards the negative facial emotions. Longitudinal data and prospective research designs are needed to address the issue of causality as well as the issue of changes in brain structure and function over time as addiction and related psychopathology progress. Therapies targeting socio-emotional perception and affect regulation skills ultimately may help improve social functioning and mitigate relapse rates.
Open Access
Neuroimaging and behavioral investigation of declarative memory in South African children prenatally exposed to alcohol
(2018) Lewis, Catherine Elizabeth; Thomas, Kevin G F; Jacobson, Joseph; Jacobson, Sandra W; Meintjes, Ernesta M
Prenatal alcohol exposure (PAE) is associated with a range of physical, growth, and neurobehavioral deficits characteristic of individuals with fetal alcohol spectrum disorders (FASD). Although declarative memory impairment is a key feature of the neurocognitive profile of FASD, the mechanisms underlying this deficit require further clarification. The aim of this cross-sectional research was to examine, both directly and indirectly (via bottom-up and top-down processes), a critical cognitive mechanism that supports successful declarative memory functioning (viz., memory encoding), in children with FASD. Data were collected from a sample (N = 88) of South African children with and without PAE. In Study I, I used a blocked design functional magnetic resonance imaging (fMRI) paradigm to investigate neural activation during visual perception, a lower-order cognitive process essential to memory encoding. The task elicited bilateral category-specific activation during the visual perception of objects and scenes in all participants. The absence of between-group differences suggests that functional recruitment of brain regions during basic visual perception is less susceptible to the effects of PAE than during higher-order processes supporting memory encoding. In Study II, I used an event-related fMRI paradigm to investigate neural activation during memory encoding itself. All participants demonstrated similar memory performance accuracy and recruited extensive bilateral networks during memory encoding. However, participants with a diagnosis of fetal alcohol syndrome (FAS) or partial FAS (PFAS) activated additional regions associated with attentional function. Within the FAS/PFAS group, higher exposure levels were associated with smaller activation increases in the parahippocampal gyri and greater activation increases in the right hippocampal formation during encoding. Data from this study therefore suggest that children with FAS/PFAS recruited more extensive neural resources to support successful memory encoding during this task. In Study III, I used a behavioral source memory paradigm to investigate higher-order executive processes essential for memory encoding. Despite similar recognition accuracy across all diagnostic groups, participants in the FAS/PFAS group showed impaired memory for source details. This pattern of impairment was only partially mediated by working memory performance. These three studies provide novel clarification of the neural and cognitive mechanisms underlying declarative memory impairments in children with FASD.
Open Access
Neuroimaging study of prenatal alcohol exposure effects on structural and functional connectivity in children
(2015) Fan, Jia; Meintjes, Ernesta M; Taylor, Paul A
Fetal alcohol spectrum disorders (FASD) describe the spectrum of cognitive, behavioural and neurological impairments associated with prenatal alcohol exposure (PAE). Diffusion tensor imaging (DTI) and resting-state functional MRI (rs-fMRI) were used to assess effects of PAE on microstructural integrities of cerebellar and cerebral white matters (WM) and on resting-state functional connectivity (RSFC) in gray matter (GM) in children with varying degrees of FASD severity (fetal alcohol syndrome (FAS) and partial FAS (PFAS)), as well as nonsyndromal heavily exposed (HE) children. Children with FAS revealed lower fractional anisotropy (FA) bilaterally in the superior peduncles. Mean diffusivity (MD) was higher in the left middle peduncle in children with FAS or PFAS (FAS/PFAS). Mediation of effects of PAE on eyeblink conditioning (EBC) provided statistical evidence that poorer microstructural integrity in these regions may play an important role in the EBC deficit observed in children with FASD. The FAS/PFAS children also revealed lower FA and/or higher MD in 7 cortical WM regions and lower RSFC in 5 GM regions within 5 networks. Four of the 7 WM and 3 of the 5 GM regions also showed alterations in HE children, providing evidence that alterations in nonsyndromal children are less extensive and that some regions appear to be relatively spared. Alterations in DTI parameters (FA and MD) were dose dependent in many, but not all, of the regions where group differences were detected, specifically in the left (L) and right (R) superior peduncles, L middle peduncle, L inferior longitudinal fasciculus, medial (M) splenium of the corpus callosum (CC), and M isthmus of the CC. The WM deficits were attributable to increased radial diffusivity (RD) rather than decreased axial diffusivity (AD), suggesting poorer axon packing density and/or myelination. Increasing alcohol exposure was associated with reduced fractional amplitude of low frequency fluctuations (fALFF), indicating changes in functional connectivity in the default mode, salience, and dorsal attention networks. The locations of the WM alterations found with DTI suggest that the compromised RSFC found in 3 of the 5 networks could be attributable to WM deficits in tracts providing intra-network connections.
Open Access
The neurostructural effects of prenatal exposure to methamphetamine in an infant population in the Western Cape
(2017) Warton, Fleur Louise; Meintjes, Ernesta M; Warton, Christopher M R
Prenatal methamphetamine exposure is associated with functional and neurostructural alterations, but neuroimaging investigations of these effects in infants are almost non-existent. Studies in neonates permit a degree of separation of drug exposure effects from potential confounders in the postnatal environment. Magnetic resonance imaging (MRI) was used to investigate the neurostructural effects of prenatal methamphetamine exposure on neonates recruited from a Cape Town community. Mothers were recruited during pregnancy and interviewed regarding methamphetamine use. Women in the exposure group used methamphetamine at least twice per month during pregnancy, while control mothers did not use methamphetamine. MRI scans were acquired within the first postnatal month. Anatomical images were processed using FreeSurfer and subcortical and cerebellar structures manually segmented with Freeview. Volumes were regressed with methamphetamine exposure (days/month of pregnancy) and related confounding variables, including total brain volume, gestational age at scan, exposure to cigarette smoking and infant sex. Diffusion data were processed with FSL, and diffusion tensors and tensor parameters determined using AFNI. Probabilistic tractography defined white matter connections between target regions. For the first analysis, five major white matter networks (commissural, and bilateral projection and association networks) were defined between spherical targets. For the second analysis, regions traced in the anatomical study were used as targets. Averaged DTI parameters were then calculated for each connection, and multiple regression analysis determined associations between DTI parameters and methamphetamine exposure at network level and in the individual connections. Methamphetamine exposure was associated with reduced caudate nucleus volume bilaterally, and in the right caudate following adjustment for confounders. Exposure was associated with reduced fractional anisotropy in all major white matter networks, and in individual connections within the limbic meso-cortico-striatal circuit. Exposure was associated with increased radial diffusivity in a subset of these. These results support findings in older children of methamphetamine-induced neurostructural damage, and demonstrate that such effects are already measurable in neonates. Corticostriatal circuit changes may underlie the impaired executive function observed in prenatally exposed children, and suggest a specific mechanism of damage in dopaminergic-related circuits that is consistent with the neurotoxic actions of methamphetamine.
Open Access
Parietal dysfunction in children with prenatal alcohol exposure
(2017) Woods, Keri; Meintjes, Ernesta M
The parietal lobe has been shown to be one of the regions most affected by prenatal alcohol exposure. Functional domains dependent on intact parietal functioning, including mathematical and visuospatial ability, have been consistently implicated in fetal alcohol spectrum disorders. This thesis examines, in children, using blood oxygenation level dependent (BOLD) functional Magnetic Resonance Imaging, the effect of prenatal alcohol exposure on brain activation during symbolic and nonsymbolic number processing, and place learning in a virtual environment. These functional domains were investigated using tasks of proximity judgment and exact addition to assess neural correlates of symbolic number processing in 65 children (mean age ± SD = 9.45 ± 0.42 years), nonsymbolic number comparison at varying difficulties in 34 children (11.55 ± 1.15 years), and place learning in a virtual reality computer generated (CG) arena in 57 children (9.44 ± 0.42 years; 29 boys). In the symbolic number processing tasks greater prenatal alcohol exposure was related to less activation in the right horizontal intraparietal sulcus known to mediate mental representation and manipulation of quantity. Children with fetal alcohol syndrome and partial fetal alcohol syndrome appeared to compensate for this deficit by increased activation of the left angular gyrus during the proximity judgment task. Syndromal children with fetal alcohol syndrome or partial fetal alcohol syndrome also demonstrated poor recruitment of the right horizontal intraparietal sulcus during nonsymbolic number comparison, indicating that mental representation and manipulation of quantity are impaired in children with heavy prenatal alcohol exposure, irrespective of the representation format used. This impairment was compensated for by the left angular gyrus, with only exposed children needing to recruit the left angular gyrus to a greater extent as number comparison task difficulty increased. Further, reduced activation of the right posterior superior parietal lobule in children with increasing prenatal alcohol exposure suggests that exposed children may be less able to employ the attentional systems associated with number processing. Notably, activation of nonsyndromal heavily exposed children was impaired in the right posterior superior parietal lobule, but spared in the right horizontal intraparietal sulcus. In boys only, prenatal alcohol exposure was associated with poorer place learning and reduced activation during place learning in the precuneus and posterior cingulate, as well as parahippocampal gyrus, frontal and temporal lobes, caudate, insula, claustrum, lentiform nucleus and thalamus. In girls, prenatal alcohol exposure was not associated with place learning performance or activation during place learning in any regions. These results confirm that boys and girls use different navigation strategies that rely on different brain regions and suggest that the regions used by boys are more susceptible to alcohol damage, while the regions used by girls are relatively spared. In conclusion, all the tasks investigated showed prenatal alcohol exposure related alterations in parietal function, with the impairments being widespread throughout the parietal lobe bilaterally. Notably, activation of the bilateral precuneus was affected by prenatal alcohol exposure in both the spatial navigation and nonsymbolic number comparison tasks. It is possible that this is a key region linking the deficits in number processing and visuospatial skills in children with prenatal alcohol exposure.
Open Access
Quantifying right ventricular motion and strain using 3D cine DENSE MRI
(BioMed Central Ltd, 2011) Auger, Daniel; Zhong, Xiaodong; Meintjes, Ernesta M; Epstein, Frederick H; Spottiswoode, Bruce S
Background: The RV is difficult to image because of its thin wall, asymmetric geometry and complex motion. DENSE is a quantitative MRI technique for measuring myocardial displacement and strain at high spatial and temporal resolutions [1,2]. DENSE encodes tissue displacement directly into the image phase, allowing for the direct extraction of motion data at a pixel resolution. A free-breathing navigator-gated spiral 3D cine DENSE sequence was recently developed [3], providing an MRI technique which is well suited to quantifying RV mechanics. Methods: Whole heart 3D cine DENSE data were acquired from two normal volunteers, after informed consent was obtained and in accordance with protocols approved by the University of Virginia institutional review board. The endocardial and epicardial contours were manually delineated to identify the myocardium from surrounding anatomical structures. A 3D spatiotemporal phase unwrapping algorithm was used to remove phase aliasing [4], and 3D Lagrangian displacement fields were derived for all cardiac phases. Midline contours were calculated from the epicardial and endocardial contours, and tissue tracking seed points were defined at pixel spaced intervals. A 3D tracking algorithm was implemented as a direct extension of the 2D tracking algorithm presented in [4], producing midline motion trajectories from which strain was calculated. Tangential 1D strain was calculated in the longitudinal and circumferential cardiac directions. Strain time curves are computed representing the free wall of the RV. Results: Figure 1 illustrates the RV free wall mean tangential 1D strain time curves for approximately 3/4 of the cardiac cycle over the apical-mid section of the heart for one volunteer. Results show measurements ranging between -0.1 and -0.25, and further illustrate a greater displacement in the longitudinal direction. Results compare favorably with studies using myocardial tagging and DENSE[5,6].
Open Access
Semi-automated left ventricular segmentation based on a guide point model approach for 3D cine DENSE cardiovascular magnetic resonance
(2014-01-14) Auger, Daniel A; Zhong, Xiaodong; Epstein, Frederick H; Meintjes, Ernesta M; Spottiswoode, Bruce S
Abstract Background The most time consuming and limiting step in three dimensional (3D) cine displacement encoding with stimulated echoes (DENSE) MR image analysis is the demarcation of the left ventricle (LV) from its surrounding anatomical structures. The aim of this study is to implement a semi-automated segmentation algorithm for 3D cine DENSE CMR using a guide point model approach. Methods A 3D mathematical model is fitted to guide points which were interactively placed along the LV borders at a single time frame. An algorithm is presented to robustly propagate LV epicardial and endocardial surfaces of the model using the displacement information encoded in the phase images of DENSE data. The accuracy, precision and efficiency of the algorithm are tested. Results The model-defined contours show good accuracy when compared to the corresponding manually defined contours as similarity coefficients Dice and Jaccard consist of values above 0.7, while false positive and false negative measures show low percentage values. This is based on a measure of segmentation error on intra- and inter-observer spatial overlap variability. The segmentation algorithm offers a 10-fold reduction in the time required to identify LV epicardial and endocardial borders for a single 3D DENSE data set. Conclusion A semi-automated segmentation method has been developed for 3D cine DENSE CMR. The algorithm allows for contouring of the first cardiac frame where blood-myocardium contrast is almost nonexistent and reduces the time required to segment a 3D DENSE data set significantly.
Open Access
Simultaneous DTI and rs-fMRI using the navigated diffusion sequence
(2016) Mofya, Mwape; Meintjes, Ernesta M; Alhamud, Alkathafi Ali; Taylor, Paul A
Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) experiments are normally performed separately. The idea of extracting inherently co-registered activation/connectivity maps and diffusion parameters has resulted in efforts to develop methods for simultaneous fMRI and DTI data acquisition. Recently, a 3D echo planar imaging (EPI) acquisition was successfully inserted after each DTI volume to perform real-time motion correction, with the two sequence protocols remaining separate. We examined using a single 3D EPI acquisition, inserted following each DTI volume acquisition (hereafter called the single nav sequence), modified to acquire BOLD resting state fMRI (rs-fMRI) data. We also investigated inserting a second 3D EPI acquisition in the middle of each DTI volume acquisition (hereafter called the double nav sequence) to increase fMRI temporal resolution. Two adult subjects were scanned with the navigated sequences and the standard separate 2D EPI BOLD and DTI acquisitions for comparison. Preprocessing and analysis of data was performed using FATCAT, AFNI , FSL and in-house Python scripts. Four standard resting state networks (RSNs) were visually identified using the navigated diffusion sequences. While RSNs were apparent in the single nav case, they were quite noisy and in some cases entire regions did not show connectivity. The double nav connectivity maps were more similar to the standard BOLD connectivity maps in terms of the spatial extent of the regions showing connectivity to the seed. The whole brain distributions of fractional anisotropy (FA) and mean diffusivity (MD) were similar among the different acquisition protocols. The jackknife standard error was comparable between the navigated and standard protocols. Further comparisons of diffusion data made using probabilistic tractography and connectivity matrices showed overall small differences indicating that connections derived from the standard DTI, single nav and double nav protocols were overall similar. We have therefore shown a significant "proof of concept" of successfully acquiring simultaneous DTI and rs-fMRI data, and therefore for investigating brain structural and functional connectivity simultaneously.
Open Access
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
(2017) Gerhold, Mathew Michael; Meintjes, Ernesta M; Andrew, Colin
Fetal alcohol spectrum disorders (FASDs) are a spectrum of disorders that occur due to prenatal alcohol exposure (PAE). Response inhibition refers to the ability to inhibit/suppress a prepotent behavioural tendency set in motion during an experimental task. Our research explored neocortical processing in heavy-exposed children from Cape Town, South Africa, performing the Go/NoGo response inhibition task. We utilised event-related electroencephalographic methodologies to examine event-related potentials (ERP) and eventrelated changes in induced oscillatory power - event-related desynchronisation (ERD)/eventrelated synchronisation (ERS). Across visual and auditory Go/NoGo tasks, we observed equivalent levels of inhibitory control between heavy-exposed (HE) participants and normally-developing controls; however, HEs demonstrated significantly slower reaction times relative to the control group. In an auditory ERP study, we observed a number of alcohol-related changes in ERP waveform morphology, such as decreased P2 amplitude, reduced P3 amplitude, and longer P3 peak latency. In addition, within the HE group, late in the trials, a slow-wave component was observed in both experimental conditions. A significant difference in N2 amplitude across conditions that has consistently been observed in normally-developing samples was not observed in the HE group. We extended previous research findings in the visual domain by analysing induced oscillatory responses. We observed within the normally-developing sample: (1) in both experimental conditions, a frontal induced beta-band ERS related to decision-making; and (2) in the NoGo-condition, a frontal gamma-band ERS related to cognitive-control. Within the HE group, the beta-ERS was not observed in either of the experimental conditions, neither was the gamma-ERS observed in the NoGo-condition. Frontal induced beta-power was predictive of performance accuracy in the HE group, but not in the control group. The observed alcohol-related effects were not explained and/or mediated by IQ (WISC-IQ), socio-economic circumstances, comorbid ADHD, or teratogenic effects related to postnatal lead exposure and prenatal cigarette-smoke exposure. Our results point to alterations in scalp-measured event-related neocortical oscillatory dynamics and slower processing of task demands due to heavy PAE. These alcohol-related effects are observable on ERP component measures, primarily related to conflict-monitoring and attention-based processing. PAE also affects induced classes of neocortical oscillatory dynamics related to decision-making and cognitive-control processes required to inhibit a prepotent motor-response.