Browsing by Author "Meintjes Ernesta"

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    Open Access
    Effects of HIV on longitudinal development of the fronto-striatal resting state networks in children from 7 to 11 years
    (2023) Brown, Cayleigh; Robertson, Frances; Meintjes Ernesta
    Despite the early initiation of antiretroviral therapy (ART), human immunodeficiency virus (HIV) in children is still associated with neurodevelopmental delay, with findings of neurocognitive deficits in executive, motor and language function. The basal ganglia (BG) develop early in childhood and are known to be affected by HIV. Their main function is to control goal-directed behaviours. Although the BG are strongly interconnected with the cerebral cortex through fronto-striatal pathways, little is known about frontostriatal network maturation during childhood or how perinatal HIV-infection (PHIV) affects its development. Using seed-based correlation analysis (SCA) of resting state functional magnetic resonance imaging (rs-fMRI), we conducted a longitudinal analysis to examine the effects of age and HIV on functional connectivity (FC) between the BG and the frontal cortex. Rs-fMRI data were collected at ages 7, 9 and 11 from children with perinatal HIV (CPHIV) who were part of the Children with HIV Early AntiRetroviral (CHER) trial (n=79), along with age-matched uninfected children from similar neighbourhoods (n=80). For SCA, BG seeds and frontal cortex regions of interest (ROIs) were selected from known cortico-BGthalamic functional networks. The BG seeds comprised the bilateral putamen, caudate, globus pallidus (GP) and thalamus. Functional regions located in the dorsolateral prefrontal cortex (DLPFC), paracentral lobule and pars opercularis were chosen as frontal ROIs because of their association with executive, motor and language function, respectively. FC was obtained via correlations between rs-fMRI time-series from the BG seeds and frontal ROIs. Linear mixed effect models were used to examine individual and synergistic effects of age and HIV status on FC. We found age-related increases in FC between BG seeds and both DLPFC and pars opercularis regions, while age-related FC decreases were seen between the BG and paracentral lobule. HIV-related alterations in FC were seen between the paracentral lobule and left and right caudate (P = 0.043 and P = 0.02) and GP (P = 0.023 and P = 0.041), and between the right pars opercularis and left and right putamen (P = 0.015 and P = 0.01), left caudate (P = 0.02) and left and right GP (P = 0.001 and P = 0.048). Attenuated FC between the BG and paracentral lobule and right pars opercularis suggests that HIV alters primarily motor function and inhibitory control, a component of executive function, in childhood. In contrast, there was no effect of HIV on FC of the BG to the DLPFC, a connection which is also considered to be important for executive functioning. Interaction of HIV and age on FC between the BG and paracentral lobule shows that although FC typically decreases with age, it remains unchanged in CPHIV. Similarly, increased FC between the BG and right pars opercularis with age in the control group but relatively constant FC in CPHIV provides evidence that HIV may hinder typical age-related development of BG FC.
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    Open Access
    Potential benefits and neural correlates of acupuncture treatment with or without physiotherapy on resting state functional connectivity in ischemic stroke patients with unilateral limb dysfunction
    (2024) Fouch, Sone; Fan, Jia; Meintjes Ernesta
    Introduction: Stroke patients often have lasting physical and cognitive impairments, leading to functional dependence even after discharge from hospital. Acupuncture has been recommended by the World Health Organisation (WHO) as an adjunctive treatment for stroke. Physiotherapy serves as the primary rehabilitation approach in South Africa and numerous other Western nations. Despite their widespread use, the precise mechanisms underlying both acupuncture and physiotherapy remain elusive, and the neurological alterations following extended rehabilitation programs are yet to be defined. Resting-state functional magnetic resonance imaging (rs-fMRI) is a non-invasive technique used to map brain regions that are temporally correlated, indicative of functional connectivity, during periods of rest. In the present study, treatment-related alterations in brain RSFC in ischaemic stroke patients with unilateral limb dysfunction were randomised to receive either 1) True Acupuncture (TA), 2) TA and Physiotherapy (PT), or 3) PT and Sham Acupuncture (SA), representing a placebo or nonacupoint acupuncture. Methods: Right-handed participants were recruited from the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, including 23 stroke patients (58.5±8.0 yrs.) and 10 healthy controls (53.9±6.9 yrs.). As part of a stroke rehabilitation programme, stroke patients were assigned to one of the three treatment arms: TA alone (6 participants), TA with PT (7 participants), or SA with PT (10 participants). Each participants received 5 sessions over 3 weeks. Fugl-Meyer Assessment (FMA) data were collected before, after, and during (on day 8) treatment. MRI scans were performed on a 3T Skyra Scanner (Siemens, Erlangen, Germany) before and after the 3-week rehabilitation programme, including rs-fMRI using a gradient echo EPI sequence and T1-weighted structural images using an MPRAGE sequence. Healthy controls underwent a single scan without treatment. Rs-fMRI data were pre-processed using AFNI_proc.py. Eleven resting-state networks (RSNs) were identified through group independent component analysis (ICA) using FSL-MELODIC in data from the healthy controls. Dual regression and randomise in FSL were then applied to identify the clusters within the identified resting state networks (RSNs) showing significant differences (at p<0.01; cluster size threshold at α<0.05). The mean Z-score within each cluster was subsequently correlated to the FMA scores. Results: Before treatment, lower RSFC in 2 clusters in the precuneus within the Default Mode Network (DMN) and the Ventral Attention Network were found in the TA with PT group compared to the TA only and SA with PT groups. No significant differences in mean Z-scores within these two clusters were seen among the three groups after treatment. After treatment, differences in RSFC among groups were found in five regions within three networks, including the cingulate gyrus and the precuneus in the DMN, the orbitofrontal cortex in the executive control network, and the inferior and superolateral occipital lobe in the visual network. In all five of these regions, patients receiving TA+PT showed a significantly higher RSFC compared to individuals in the other groups. There were no significant differences in RSFC between groups in these five regions before treatment. After receiving TA+PT treatment, patients demonstrated higher resting-state functional connectivity (RSFC) compared to themselves before treatment in nine regions spanning four resting-state networks (RSNs), including the bilateral precuneus, right (R) anterior calcarine sulcus, R primary motor cortex, and left (L) angular gyrus in the first DMN; the bilateral precuneus in the second DMN; the R visual cortex, R posterior lingual gyrus and L visual cortex in the visual network; and the R posterior cingulate sulcus in the ventral attention network. However, after SA+PT treatment, individuals in the group exhibited lower RSFC compared to themselves before treatment in two regions within two networks, including the R postcentral gyrus in the somatosensory network and the L lingual gyrus in the visual network. All three treatment groups showed a significant increase in FMA scores from before treatment, to after treatment. No significant differences were found when comparing FMA scores between treatment groups. The TA+PT group's results showed a significant positive correlation between RSFC and FMA scores. Conclusions: Stroke patients who received one of three treatments demonstrated improved FMA scores, with no significant differences in FMA scores observed among the three treatment arms after treatment. Patients in the TA+PT group showed significant changes in key brain regions associated with cognition, sensorimotor integration, and motor function. Specifically, increases in RSFC within the precuneus, motor cortex, and posterior cingulate sulcus, which are involved in neural recovery and cognitive improvement. In contrast, the SA+PT group exhibited RSFC decreases within somatosensory and visual networks, indicating a different pattern of neural recognition. After treatment, patients in the TA+PT group exhibited higher RSFC in the precuneus in the DMN and executive control network. These findings highlight the potential efficacy of combining TA with PT for stroke rehabilitation, suggesting that this approach may facilitate positive neural adaptations. However, the study also highlights the necessity for further investigation with larger sample sizes and extended treatment durations to comprehensively grasp the efficacy and underlying mechanisms of this integrated approach
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    Open Access
    The influence of HIV and ART exposure on neonate brain volumes
    (2023) Olagunju, Aishah; Holmes, Martha; Meintjes Ernesta
    Introduction: There is growing evidence that maternal health in pregnancy influences the infant neurodevelopment. However, there are limited studies including broad metrics of maternal health when studying typical and atypical infant neurodevelopment. Although the human immunodeficiency virus (HIV) is a global pandemic, South Africa has the biggest and most high-profile HIV epidemic. Over the past decade, South Africa has reduced vertical transmissions of HIV, from improvements in antiretroviral medicines and the widespread accessibility of prevention programs. An outcome of this achievement is an increasing population of HIV-exposed-uninfected (HEU) infants and children. Despite improved outcomes compared to their peers living with HIV, HEU infants and children are at risk of neurodevelopmental delays in relation to HIV–unexposed–uninfected (HUU) children. As a result, there is a need to better understand the outcome of HIV/ART exposure on the fetal/infant/child brain. This study aimed to investigate the effect(s) of HIV and duration of ART exposure and the potential impact of additional maternal health factors during pregnancy on neonate brain volumes. Methods: Using magnetic resonance imaging (MRI), T1-weighted brain images of neonates were acquired. Infants included those whose mothers initiated ART preconception (HEU-pre), those whose mothers initiated ART post-conception (HEU-post) and infants born to mothers living without HIV or HIV unexposed uninfected (HUU). The data were quality checked and volumes were determined using the infant FreeSurfer tool. Statistical analysis was done in R to identify maternal health factors related to neonatal volumes as well as volumetric group differences due to HIV and ART exposure. Results: This analysis included 151 infants (49 HEU-pre; 48 HEU-post; 54 HUU; mean age 1.8 weeks; 50.3% male). Across all newborns, maternal Harvard Trauma Questionnaire (HTQ) score during pregnancy was associated with bilateral amygdala volumes. Within HEU infants, maternal CD4 count was associated with right thalamus and caudate volumes bilaterally. Group analysis showed a significant decrease in mean caudate volume bilaterally in the HEUpost group (left hemisphere p=0.006; right hemisphere p=0.009), as well as reduced right amygdala volume after controlling for maternal HTQ assessed in pregnancy. There was also a significant increase in the left lateral ventricle (p=0.04) and a decrease in the left cerebral white matter of HEU-pre infants (p=0.03). Conclusion: This study observed volumetric differences in HEU infants dependent on timing of maternal ART initiation, maternal immune health and maternal trauma assessed during pregnancy.
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    The longitudinal effects of HIV and ART on the developing brain: a structural MRI study using manual segmentation
    (2024) Randall, Steven; Holmes, Martha; Meintjes Ernesta
    Background: Previous neuroimaging research into the effects of HIV in paediatric populations receiving treatment has reported brain abnormalities across a variety of ages and modalities. There are limited longitudinal studies, which would clarify if the observed changes represented developmental delay or ongoing damage. In addition, most neuroimaging studies do not include links to functional, immunological, or genetic outcomes which aid in understanding the consequence, mechanisms and factors underlying the brain imaging abnormalities. There is a need for longitudinal work and interdisciplinary crosssectional imaging studies to comprehend the consequences of the current literature. To address literature gap, this thesis builds on a cross-sectional study, by the same author, of this group of 106 children who were perinatally infected with HIV (PHIV), and form part of “Children with HIV early antiretroviral”(CHER) trial who have been followed since birth (Violari et al. 2008; Laughton et al. 2012; Cotton et al. 2013). The study showed larger subcortical gray matter and smaller white matter in children with perinatal HIV infection compared to controls, at 5 years of age. This thesis presents a longitudinal follow-up to assess whether these morphometric differences persisted into later childhood, as well as assess possible early contributors that may exacerbate or predict certain highlighted disturbances observed from 5 to 10 years of age. We aim to determine if the volumetric abnormalities observed at age 5 years represent developmental delay or ongoing injury due to HIV infection. In addition, we seek to identify potential early immune markers and the 5-year-old volume changes to better understand contributing factors. Methods: MRI scans were obtained at ages 5, 7, and 9 years, on a 3 T Allegra MRI (Siemens, Erlangen, Germany), and 10 years 3 T Skyra Siemens. Images were manually traced, by the author, for volumes of basal ganglia structures and corpus callosum using MultiTracer. Twenty-seven individuals were rescanned to assess whether incorporation and integration of 10 year old scanner data with scans from previous ages on a different scanner was possible, as a result of decommissioning the 3 T Allegra scanner. Volumetric growth curves were fit for forty children using mixed effects models with subject-specific random effects, with adjustment for possible two-way interactions between age and diagnosis. We investigated linear, quadratic, cubic and logarithmic fits for each volume. A panel of 44 soluble blood biomarkers were obtained at enrolment for a small sample of infants living with HIV. Cytokine concentrations were Z-score transformed and principle component analysis (PCA) performed. Results: Manual segmentation was reproducible across the different 3 T scanners within this pediatric sample allowing for volumetric data to be combined into one model without a scanner confounder. Across volumes, logarithmic models performed best. Age-related decreases were observed across children in the bilateral caudate and globus pallidus, as well as the corpus callosum. HIV-related alterations to growth trajectories were observed in the right nucleus accumbens and bilateral putamen, driven by volume abnormalitiesreported at 5 years. HIV-related corpus callosum reductions previously reported at age 5 did not alter the growth trajectories. PCA analysis identified a component associated negatively with subcortical volumes. Association with the derived component variable suggest that during the period of initial infection, in infancy, an increase of IL-10, IP-10, LBP and IFN-α, and accompanying decrease in IL-17F and CD40L contribute to smaller basal ganglia volumes at 5 years. Conclusions: This thesis expands cross sectional volumetric work which identified basal ganglia and corpus callosum volume abnormalities in 5-year-old PHIV children. Longitudinal analysis found the 5-year-old volumetric changes were likely HIV-related developmental delays, as volumes differences did not persist. The volume increases in the putamen affected the growth trajectories in PHIV and were related to early immunological factors associated with proinflammatory effects, immune activation and immune dysfunction. The volume decreases in the corpus callosum did not affect the age-related trajectory, and no cytokines related to volume abnormalities at 5 years. While cross sectional HIVrelated results in PHIV are concerning, more work is needed to contextualize their consequences on growth and function.