Browsing by Author "Jankiewicz, Marcin"
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- ItemOpen AccessCharacterising the structural brain connectome in Alzheimer's disease and its relation to cognitive intra-individual variability.(2022) Lee, Shao-Hsuan Stephanie; Jankiewicz, Marcin; Robertson, Frances; Christ, BjörnResearch on Alzheimer's disease (AD) has shown white matter (WM) degeneration and structural connectome disruptions measured by diffusion tensor imaging (DTI) as well as increased reaction time intra-individual variability (RT IIV) on neurocognitive testing. However, the relationship between these changes measured on these different modalities remains unexplored. To explore possible relationships between these alterations, this study used tractography to identify WM changes, as indexed by fractional anisotropy (FA) and mean diffusivity (MD), followed by a graph theory-based analysis of the brain structural connectome, and investigated the relationship between these graph theory metrics and RT IIV in 16 AD patients and 20 healthy elderly controls. Within AD patients, we identified WM tracts with lower FA and higher MD mostly located in the cortical and subcortical temporal lobes, such as the hippocampus subregions, compared to healthy elderly controls. We also observed higher FA in the WM tracts within the thalamus as well as between the thalamus and brainstem in AD patients. In the structural brain connectome of these patients, there were regions with altered nodal strength, transitivity, and local efficiency relative to the controls' connectome. Conversely to many studies, we found increases in nodal efficiency across multiple regions and higher global efficiency in AD patients compared to healthy elderly controls. Finally, higher global efficiency was correlated with increased RT IIV on the CRT task in AD patients. In AD, a positive relationship between transitivity in the left cingulate cortex and RT IIV as well as between nodal efficiency in the left cortical temporal lobe and mean RT on the CRT task were observed. On the other hand, lower transitivity in the right thalamus and increased RT IIV, as well as lower transitivity and longer mean RT were found on both the SRT and CRT tasks in AD patients. Our results may show evidence of disruptions and compensatory mechanisms in WM tracts and network metrics in AD. Together, these results revealed WM changes, topological alterations of the brain structural connectome in AD and that these findings can be used in combination with IIV to predict cognitive decline or progression of AD.
- ItemOpen AccessDTI-based tractographic analysis of white matter alterations in HIV infected children(2019) Madzime, Joanah; Jankiewicz, Marcin; Holmes, Martha; Meintjes, ErnestaDespite early combination antiretroviral therapy (cART) administration, children born with human immunodeficiency virus (HIV) continue to demonstrate neurodevelopmental abnormalities. Often, there is a link between structural and functional abnormalities. Previously, we found HIV-associated changes in white matter and functional networks in a cohort of 7-year-old HIV infected (HIV+) children who intiatied early cART compared to uninfected controls. To explore possible relationships between these alterations, we used tractography to identify HIV-related abnormalities within structural connections located in functional resting state networks. Within HIV+ children (n=61), we identified white matter (WM) tracts with lower mean fractional anisotropy (FA) and/or higher mean diffusivity (MD) located in several functional networks, including the somatosensory, auditory, salience, default mode network (DMN), motor and basal ganglia networks compared to uninfected controls (n=46). Among the uninfected controls, children born to HIV+ mothers (exposed uninfected, HEU) (n=19) showed WM alterations (higher FA) compared to HIV unexposed uninfected children (HUU) (n=27) within tracts in the posterior DMN, visual (occipital lobe and lingual gyrus), salience and motor networks. The observed WM alterations in HIV+ children point to demyelination/dysmyelination within six networks. Four of these networks – the basal ganglia, default mode, salience and somatosensory – were all found to have altered functional connectivity in a previous study; therefore, these results point to damage or developmental delay in white matter may be related to or responsible for the HIV-associated functional abnormalities. The observed WM alterations in the HEU children suggest that even exposure to HIV and/or antiretroviral therapy (ART) also has long-term effects on axonal integrity in the developing brain.
- ItemOpen AccessThe influence of methylphenidate on heart rate and brain connectivity(2018) Van Breda, Keelyn; Rauch, Laurie; Stein, Dan J; King, Michael; Jankiewicz, MarcinThe central governor model (CGM) proposes that muscle recruitment is regulated by the brain through subconscious homeostatic control of afferent feedback. It has been suggested that the dopaminergic system plays a key role in the CGM, with dopaminergic activation leading to lower fatigue thresholds. Key neural circuits, including the central autonomic network (CAN), may also play a role in altering thresholds by reducing conscious bodily awareness, known as interoception. However, few studies have directly examined the dopaminergic neurotransmitter system and CAN connectivity, during exercise-induced fatigue. Although there is reason to suspect that subjects with high activity (HA) and low activity (LA) levels have different fatigue thresholds, potential differences in dopaminergic function and related circuity have not been compared across these groups. In this thesis, I was therefore interested in examining the impact of a dopaminergic agent, methylphenidate (MPH) on: a) brain connectivity at rest before exercise and during exercise, b) on heart rate (HR) at rest before exercise and during exercise. Furthermore, c) I was interested in whether the effect of MPH administration (MA) on HR and functional connectivity (FC), between CAN regions, pre-exercise impacted HR and FC during exercise and whether this differed between HA and LA subjects. In order to measure the effect of MA on brain connectivity at rest and during exercise I used a functional magnetic resonance imaging (fMRI) scanner. To measure the effect of MA on fatigue thresholds, I used a MRI compatible handgrip device which recorded grip force output during a fatiguing handgrip task. To measure HR before and during handgrip exercise I used a MRI compatible electrocardiogram (ECG) machine. My first study aimed to determine the effect of MA on resting state (R-fMRI) FC between CAN regions and its correlation with HR before exercise. My second study aimed to see the effect of MA on task HR, force output and, FC and EC between CAN regions, during a fatiguing handgrip task. My third study aimed to see the effect of MA on the relationship between HR and FC pre-exercise and HR and FC during exercise and whether this differed between LA and HA subjects. I found that: 1.) MA decreased R-fMRI FC between CAN regions, and that this was associated with an increase in HR during resting state 2.) MA decreased FC between CAN regions with an associated increase in task HR and force output during a fatiguing handgrip task 3.) After MA, R-fMRI FC determines task FC independent of HR 4.) MA significantly increased task HR in LA but not HA subjects 5.) After MA, R-fMRI FC determines task FC independent of HR in LA but not HA subjects. Taken together, the functional uncoupling of CAN regions and increased HR after MA suggests that MA increases the fatigue threshold by diverting attention away from interoceptive cues, such as HR. However, this finding may be more relevant in LA subjects, where MA is also associated with increased HR during exercise.
- ItemOpen AccessMultimodal neuroimaging signatures of early cART-treated paediatric HIV - Distinguishing perinatally HIV-infected 7-year-old children from uninfected controls(2020) Khobo, Isaac Lebogang; Robertson, Frances; Jankiewicz, Marcin; Holmes, MarthaIntroduction: HIV-related brain alterations can be identified using neuroimaging modalities such as proton magnetic resonance spectroscopy (1H-MRS), structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and functional MRI (fMRI). However, few studies have combined multiple MRI measures/features to identify a multivariate neuroimaging signature that typifies HIV infection. Elastic net (EN) regularisation uses penalised regression to perform variable selection, shrinking the weighting of unimportant variables to zero. We chose to use the embedded feature selection of EN logistic regression to identify a set of neuroimaging features characteristic of paediatric HIV infection. We aimed to determine 1) the most useful features across MRI modalities to separate HIV+ children from HIV- controls and 2) whether better classification performance is obtained by combining multimodal MRI features rather than using features from a single modality. Methods: The study sample comprised 72 HIV+ 7-year-old children from the Children with HIV Early Antiretroviral Therapy (CHER) trial in Cape Town, who initiated combination antiretroviral therapy (cART) in infancy and had their viral loads suppressed from a young age, and 55 HIV- control children. Neuroimaging features were extracted to generate 7 MRI-derived sets. For sMRI, 42 regional brain volumes (1st set), mean cortical thickness and gyrification in 68 brain regions (2nd and 3rd set) were used. For DTI data: radial (RD), axial (AD), mean (MD) diffusivities, and fractional anisotropy (FA) in each of 20 atlas regions were extracted for a total of 80 DTI features (4th set). For 1H-MRS, concentrations of 14 metabolites and their ratios to creatine in the basal ganglia, peritrigonal white matter, and midfrontal gray matter voxels (5th, 6th and 7th set) were considered. A logistic EN regression model with repeated 10-fold cross validation (CV) was implemented in R, initially on each feature set separately. Sex, age and total intracranial volume (TIV) were included as confounders with no shrinkage penalty. For each model, the classification performance for HIV+ vs HIV- was assessed by computing accuracy, specificity, sensitivity, and mean area under the receiver operator characteristic curve (AUC) across 10 CV folds and 100 iterations. To combine feature sets, the best performing set was concatenated with each of the other sets and further EN regressions were run. The combination giving the largest AUC was combined with each of the remaining sets until there was no further increase in AUC. Two concatenation techniques were explored: nested and non-nested modelling. All models were assessed for their goodness of fit using χ 2 likelihood ratio tests for non-nested models and Akaike information criterion (AIC) for nested models. To identify features most useful in distinguishing HIV infection, the EN model was retrained on all the data, to find features with non-zero weights. Finally, multivariate imputation using chained equations (MICE) was explored to investigate the effect of increased sample size on classification and feature selection. Results: The best performing modality in the single modality analysis was sMRI volumes
- ItemOpen AccessThe influence of low physical activity levels versus extreme physical activity levels on brain structure and working memory(2020) Paruk, Tasneem Yusuf; Jankiewicz, Marcin; Rauch, Laurie; King, MichaelBackground: Habitual levels of moderate to vigorous levels of physical activity (MVPA) levels are associated with positive health outcomes and improvement in cognitive function. A challenge facing optimal health outcomes is determining optimal levels of physical activity levels; people can engage in extreme sedentary or high levels of physical activity. For example, levels of low physical activity and participation in ultra-endurance events are increasing. However, the impact of extreme physical activity levels on brain matter volume and working memory is not well understood. This thesis thus investigated the relationship between different levels of MVPA, brain structure, and working memory. The aim of the thesis was to understand the relationship between large volumes of physical activity with global and regional brain matter volumes using brain imaging, and the impact of physical activity on cognitive function using the N-back task. The first part of the thesis examined how habitually high or low levels of MVPA differently impacted brain matter volume in healthy individuals. Whilst, the second part of the thesis investigated the differences in working memory between the low active and high active groups. Methods: Participants aged 20-59 years, were split into a High Activity (HA) group (N = 12, 27.9 ± 26.6 years) that exercised for > 9 hours of per week (MVPA > 540 minutes) and a Low Activity (LA) group (N = 9, 28.33 ± 11.192 years) that exercised < 2 hours (MVPA < 120 minutes). Total and regional brain matter volumes were measured using Magnetic Resonance Imaging (MRI) and analysed using Voxel-Based Morphometry (VBM). Habitual levels of physical activity were measured using the Global Physical Activity Questionnaire (GPAQ). For the second part of this thesis, we tested participants aged 20-59 years. Participants were split into a High Activity (HA) group (N = 6, 24.86 ± 4.67 years) that exercised for > 9 hours of per week (MVPA > 540 minutes) and a Low Activity (LA) group (N = 6, 30.14 ± 15.31 years) that exercised < 2 hours (MVPA < 120 minutes). Working memory was compared between the two groups using a PC-based N-back task. Results: The HA group had greater total brain matter and total white matter volumes vs. the LA group, and brain matter volumes were positively associated with increasing physical activity levels. However, the HA group had reduced regional brain volumes in the postcentral gyrus, middle frontal lobe, and the sub-lobar thalamus. HA and LA groups did not differ in working memory performance on the N-back task. Conclusion: Larger than normal amounts of weekly PA was associated with increased total brain matter and total white matter volumes, however, the volume of three regional brain areas were reduced.
- ItemOpen AccessThe influence of maternal HIV and ART exposure on neonate brain white matter integrity and organisation(2022) Magondo, Ndivhuwo; Holmes, Martha; Jankiewicz, MarcinImproved legislation and widespread access to treatment has led to a new cohort of children who have in utero exposure to maternal HIV, but remain HIV negative through the use of antiretroviral therapy (ART), known as HIV exposed-uninfected (HEU) children. While HEU infants and children are healthier than their infected peers, they experience some developmental delays as compared to uninfected unexposed populations. Few brain imaging studies have been done in HEU infants and children, and so the effects of the exposure to in utero HIV and ARVs on their neurodevelopment are not well understood. As this population matures, there is a need for studies to determine how HIV as well as ART exposure in utero and at birth affect white matter (WM) structure and its connectivity. This study used diffusion tensor imaging (DTI) tractography and graph theory to examine the possible influence of HIV and ART exposure in utero on neonate WM integrity (as measured by DTI parameters) and organisation (evaluated with graph theory measures). We hypothesised that HIV exposure will alter WM integrity, however structural organisation will remain unchanged across groups. We investigated HIV exposure and ART duration group differences in fractional anisotropy (FA) and mean diffusivity (MD) of the WM connections in the brain, as well as graph measures including strength, local efficiency, nodal efficiency, global efficiency, transitivity, and modularity. To examine these differences, a linear regression analysis was performed between the groups while correcting for maternal weight gained per week of pregnancy and maternal education. The study found that, regardless of when ART is started by the mothers, certain regions and tracts in the brain are seemingly influenced by HIV exposure. Infants whose mothers have been on ART pre-conception have higher MD values than their unexposed and uninfected peers, while those who have been exposed to ART postconception were shown to have lower FA values than their unexposed and uninfected counterparts. These results imply that ART duration influences WM integrity and may be neuroprotective for FA, which is more related to WM integrity, but not for MD, which relates to WM organisation. ARV exposure duration and CD4 count are shown to be positively associated with FA tracts, while CD4 count is negatively associated with MD. This relationship highlights the potential impact of maternal immune health on fetal brain development. While there are structural differences in certain WM tracts, the overall structural organisation remains unchanged, as no graph theory measures yielded significant results besides nodal efficiency. The brain's dense connective network may bridge gaps from damage in specific tracts throughout the connectome.
- ItemOpen AccessTissue Parameter Mapping in Children with Fetal Alcohol Spectrum Disorders(2020) Fourie, Marilize; Jankiewicz, Marcin; Meintjies, ErnestaBackground: Fetal alcohol spectrum disorders (FASD), which are caused by prenatal alcohol exposure (PAE), affects people around the world. Certain communities in South Africa have among the highest reported incidences of fetal alcohol syndrome (FAS) in the world. Although PAE-related brain alterations have been widely documented, the mechanisms whereby alcohol affects the brain are not clearly understood. MRI relaxation parameters T1, T2, T2* and proton density (PD), are basic tissue properties that reflect the underlying biology. The present study aims to advance our understanding of how PAE alters the microstructural properties of tissue by examining PAE-related changes in these tissue parameters in adolescents with FASD. Methods: The final sample used in this study consisted of 53 children from a previously studied longitudinal cohort (Jacobson et al., 2008) and 12 additionally recruited subjects. Of the 65 participants, 18 were diagnosed with FAS or partial FAS (PFAS) and made up the FAS/PFAS group, 18 were diagnosed as heavily exposed non-syndromal (HE) and 29 were age matched controls. Subjects were scanned at the Cape Universities Body Imaging Centre (CUBIC) located at Groote Schuur Hospital on a 3T Siemens Skyra MRI. Structural images were obtained using the MEMPRAGE sequence. From these images T1, T2, T2* and PD parameter maps were constructed and segmented into 43 regions of interest (ROI) using Freesurfer, FSL and AFNI. Linear regression analyses were used to analyse group differences as well as correlations between parameter values and the amount of alcohol the mother consumed during pregnancy. Results: Significant T1 differences were found in the caudate, cerebellar cortex, hippocampus, accumbens, putamen, choroid plexus, ventral diencephalon (DC), right vessel and ventricles. Significant T2 differences were found in the caudate, brain stem, corpus callosum (CC), amygdala, cerebral cortex, choroid plexus, vessels and ventricles. Significant T2* differences were found in the cerebellar cortex, optic chiasm and ventricles. Significant PD differences were found in the hippocampus and left lateral ventricle. The exploratory nature of this study resulted in none of the results surviving FDR correction for multiple comparisons. Conclusions: Overall, our findings point to regional PAE-related increases in water content and cellular and molecular changes in underlying tissue of the anatomical structure. Exceptions were the right cerebral cortex, brain stem, hippocampus, amygdala and ventral diencephalon where our findings point to less free water and increased cell density, and cerebellar cortex where simultaneous reductions in T1 and T2* suggest the possibility of increased iron content. In highly myelinated white matter structures, such as the CC and optic chiasm, our results point to PAErelated demyelination, and possibly increased iron. These findings extend previous knowledge of effects of PAE and demonstrate that tissues are affected at a microstructural level.