Distinct alterations in white matter properties and organization related to maternal treatment initiation in neonates exposed to HIV but uninfected.

HIV exposed-uninfected (HEU) infants and children are at risk of developmental delays as compared to HIV uninfected unexposed (HUU) populations. The effects of exposure to in utero HIV and ART regimens on the HEU the developing brain are not well understood. In a cohort of 2-week-old newborns, we used diffusion tensor imaging (DTI) tractography and graph theory to examine the influence of HIV and ART exposure in utero on neonate white matter integrity and organisation. The cohort included HEU infants born to mothers who started ART before conception (HEUpre) and after conception (HEUpost), as well as HUU infants from the same community. We investigated HIV exposure and ART duration group differences in DTI metrics (fractional anisotropy (FA) and mean diffusivity (MD)) and graph measures across white matter. We found increased MD in white matter connections involving the thalamus and limbic system in the HEUpre group compared to HUU. We further identified reduced nodal efficiency in the basal ganglia. Within the HEUpost group, we observed reduced FA in cortical-subcortical and cerebellar connections as well as decreased transitivity in the hindbrain area compared to HUU. Overall, our analysis demonstrated distinct alterations in white matter integrity related to the timing of maternal ART initiation that influence regional brain network properties.

Reduced white matter maturation in the central auditory system of children living with HIV.

Introduction: School-aged children experience crucial developmental changes in white matter (WM) in adolescence. The human immunodeficiency virus (HIV) affects neurodevelopment. Children living with perinatally acquired HIV (CPHIVs) demonstrate hearing and neurocognitive impairments when compared to their uninfected peers (CHUUs), but investigations into the central auditory system (CAS) WM integrity are lacking. The integration of the CAS and other brain areas is facilitated by WM fibers whose integrity may be affected in the presence of HIV, contributing to neurocognitive impairments. Methods: We used diffusion tensor imaging (DTI) tractography to map the microstructural integrity of WM between CAS regions, including the lateral lemniscus and acoustic radiation, as well as between CAS regions and non-auditory regions of 11-year-old CPHIVs. We further employed a DTI-based graph theoretical framework to investigate the nodal strength and efficiency of the CAS and other brain regions in the structural brain network of the same population. Finally, we investigated associations between WM microstructural integrity outcomes and neurocognitive outcomes related to auditory and language processing. We hypothesized that compared to the CHUU group, the CPHIV group would have lower microstructural in the CAS and related regions. Results: Our analyses showed higher mean diffusivity (MD), a marker of axonal maturation, in the lateral lemniscus and acoustic radiations, as well as WM between the CAS and non-auditory regions predominantly in frontotemporal areas. Most affected WM connections also showed higher axial and radial diffusivity (AD and RD, respectively). There were no differences in the nodal properties of the CAS regions between groups. The MD of frontotemporal and subcortical WM-connected CAS regions, including the inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and internal capsule showed negative associations with sequential processing in the CPHIV group but not in the CHUU group. Discussion: The current results point to reduced axonal maturation in WM, marked by higher MD, AD, and RD, within and from the CAS. Furthermore, alterations in WM integrity were associated with sequential processing, a neurocognitive marker of auditory working memory. Our results provide insights into the microstructural integrity of the CAS and related WM in the presence of HIV and link these alterations to auditory working memory.

Distinct alterations in white matter properties and organization related to maternal treatment initiation in neonates exposed to HIV but uninfected.

HIV exposed-uninfected (HEU) infants and children are at risk of developmental delays as compared to uninfected unexposed (HUU) populations. The effects of exposure to in utero HIV and ART regimens on the HEU the developing brain are not well understood. In a cohort of 2-week-old newborns, we used diffusion tensor imaging (DTI) tractography and graph theory to examine the influence of HIV and ART exposure in utero on neonate white matter integrity and organisation. The cohort included HEU infants born to mothers who started ART before conception (HEUpre) and after conception (HEUpost), as well as HUU infants from the same community. We investigated HIV exposure and ART duration group differences in DTI metrics (fractional anisotropy (FA) and mean diffusivity (MD)) and graph measures across white matter. We found increased MD in white matter connections involving the thalamus and limbic system in the HEUpre group compared to HUU. We further identified reduced nodal efficiency in the basal ganglia. Within the HEUpost group, we observed reduced FA in cortical-subcortical and cerebellar connections as well as decreased transitivity in the hindbrain area compared to HUU. Overall, our analysis demonstrated distinct alterations in white matter integrity related to the timing of maternal ART initiation that influence regional brain network properties.

A review of the auditory-gut-brain axis.

Hearing loss places a substantial burden on medical resources across the world and impacts quality of life for those affected. Further, it can occur peripherally and/or centrally. With many possible causes of hearing loss, there is scope for investigating the underlying mechanisms involved. Various signaling pathways connecting gut microbes and the brain (the gut-brain axis) have been identified and well established in a variety of diseases and disorders. However, the role of these pathways in providing links to other parts of the body has not been explored in much depth. Therefore, the aim of this review is to explore potential underlying mechanisms that connect the auditory system to the gut-brain axis. Using select keywords in PubMed, and additional hand-searching in google scholar, relevant studies were identified. In this review we summarize the key players in the auditory-gut-brain axis under four subheadings: anatomical, extracellular, immune and dietary. Firstly, we identify important anatomical structures in the auditory-gut-brain axis, particularly highlighting a direct connection provided by the vagus nerve. Leading on from this we discuss several extracellular signaling pathways which might connect the ear, gut and brain. A link is established between inflammatory responses in the ear and gut microbiome-altering interventions, highlighting a contribution of the immune system. Finally, we discuss the contribution of diet to the auditory-gut-brain axis. Based on the reviewed literature, we propose numerous possible key players connecting the auditory system to the gut-brain axis. In the future, a more thorough investigation of these key players in animal models and human research may provide insight and assist in developing effective interventions for treating hearing loss.

Multimodal magnetic resonance neuroimaging measures characteristic of early cART-treated pediatric HIV: A feature selection approach.

Children with perinatally acquired HIV (CPHIV) have poor cognitive outcomes despite early combination antiretroviral therapy (cART). While CPHIV-related brain alterations can be investigated separately using proton magnetic resonance spectroscopy (1 H-MRS), structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and functional MRI (fMRI), a set of multimodal MRI measures characteristic of children on cART has not been previously identified. We used the embedded feature selection of a logistic elastic-net (EN) regularization to select neuroimaging measures that distinguish CPHIV from controls and measured their classification performance via the area under the receiver operating characteristic curve (AUC) using repeated cross validation. We also wished to establish whether combining MRI modalities improved the models. In single modality analysis, sMRI volumes performed best followed by DTI, whereas individual EN models on spectroscopic, gyrification, and cortical thickness measures showed no class discrimination capability. Adding DTI and 1 H-MRS in basal measures to sMRI volumes produced the highest classification performance validation accuracy = 85 % AUC = 0.80 . The best multimodal MRI set consisted of 22 DTI and sMRI volume features, which included reduced volumes of the bilateral globus pallidus and amygdala, as well as increased mean diffusivity (MD) and radial diffusivity (RD) in the right corticospinal tract in cART-treated CPHIV. Consistent with previous studies of CPHIV, select subcortical volumes obtained from sMRI provide reasonable discrimination between CPHIV and controls. This may give insight into neuroimaging measures that are relevant in understanding the effects of HIV on the brain, thereby providing a starting point for evaluating their link with cognitive performance in CPHIV.

Self-navigated prospective motion correction for 3D-EPI acquisition.

PURPOSE: Although 3D EPI is more susceptible to motion artifacts than 2D EPI, it presents some benefits for functional MRI, including the absence of spin-history artifacts, greater potential for parallel imaging acceleration, and better functional sensitivity in high-resolution imaging. Here we present a self-navigated 3D-EPI sequence suitable for prospective motion-corrected functional MRI without additional hardware or pulses. METHODS: For each volume acquisition, the first 24 of the 52 partitions being acquired are accumulated to a new feedback block that was added to the image reconstruction pipeline. After zero-filling the remaining partitions, the feedback block constructs a volumetric self-navigator (vSNav), co-registers it to the reference vSNav acquired during the first volume acquisition, and sends motion estimates to the sequence. The sequence then updates its FOV and acquires subsequent partitions with the adjusted FOV, until the next update is received. The sequence was validated without and with intentional motion in phantom and in vivo on a 3T Skyra. RESULTS: For phantom scans, the FOV was updated 0.704 s after acquisition of the vSNav partitions, and for in vivo scans after 0.768 s. Both phantom and in vivo data demonstrated stable motion estimates in the absence of motion. For in vivo acquisitions, prospective head-pose estimates using the vSNav's and retrospective estimates with FLIRT (FMRIB's Linear Image Registration Tool) agreed to within 0.23 mm (< 10% of the slice thickness) and 0.14° in all directions. CONCLUSION: Depending when motion occurs during a volume acquisition, the proposed method fully corrects the FOV and recovers image quality within one volume acquisition.

Altered White Matter Tracts in the Somatosensory, Salience, Motor, and Default Mode Networks in 7-Year-Old Children Living with Human Immunodeficiency Virus: A Tractographic Analysis.

Introduction: Even with the increased access and early initiation of combination antiretroviral therapy, children with perinatally acquired human immunodeficiency virus (CPHIV) continue to demonstrate white matter alterations. Children perinatally HIV-exposed, but uninfected (CHEU) alike show differences in white matter integrity compared with children who are HIV-unexposed and uninfected (CHUU). Objectives: Mapping white matter connections that link gray matter regions that form resting-state (RS) functional networks may demonstrate whether structural and functional connectivity alterations in HIV infection and exposure may be related. We hypothesized reduced structural connectivity in CPHIV within the default mode network (DMN), visual, ventral DMN (vDMN), somatosensory, salience, auditory, motor, executive, basal ganglia, and posterior DMN (pDMN). We also hypothesized that CHEU will have increased structural connectivity compared with CHUU in the vDMN, somatosensory, pDMN, dorsal attention, salience, auditory, motor and basal ganglia. Methods: Study participants were 61 seven-year-old CPHIV and 46 age-matched children who are HIV uninfected (CHU) (19 CHEU). We used diffusion tensor imaging-based tractography to investigate white matter connections that link gray matter regions within RS functional networks. Results: We found altered white matter integrity in the somatosensory, salience, default mode, and motor networks of CPHIV compared with CHU. The superior temporal cortex, superior frontal cortex, and putamen were affected in all four networks and have also been reported to demonstrate morphological alterations in the same cohort. In CHEU, white matter integrity was higher in the visual network, pDMN, and motor network compared with CHUU. Conclusion: Our results suggest that altered white matter integrity may influence gray matter morphology and functional network alterations. Impact statement The long-term effects of human immunodeficiency virus (HIV) and exposure on the developing brain in the combination antiretroviral therapy era are still not well known. We use diffusion tensor imaging-based tractography to explore these effects on white matter connections that link gray matter regions within functional networks. Our findings provide a context for HIV-associated white matter and connectivity abnormalities.

White Matter Abnormalities in Children with HIV Infection and Exposure.

Background: Due to changes in guidelines and access to treatment, more children start combination antiretroviral therapy (ART) in infancy. With few studies examining the long-term effects of perinatal HIV infection and early ART on neurodevelopment, much is still unknown about brain maturation in the presence of HIV and ART. Follow-up studies of HIV infected (HIV+) children are important for monitoring brain development in the presence of HIV infection and ART. Methods: We use diffusion tensor imaging (DTI) to examine white matter (WM) in 65 HIV+ and 46 control (HIV exposed uninfected (HEU) and HIV unexposed uninfected (HU)) 7-year-old children. This is a follow up of a cohort studied at 5 years, where we previously reported lower fractional anisotropy (FA) in corticospinal tract (CST) and mean diffusivity (MD) increases in inferior/superior longitudinal fasciculi (ILF/SLF), inferior fronto-occipital fasciculus (IFOF) and uncinate fasciculus (UF) in HIV+ children compared to uninfected controls. In addition, we also found a difference in FA related to age at which ART was initiated. Results: At 7 years, we found two regions in the left IFOF and left ILF with lower FA in HIV+ children compared to controls. Higher MD was observed in a similar region in the IFOF, albeit bilaterally, as well as multiple clusters bilaterally in the superior corona radiata (SCR), the anterior thalamic radiation (ATR) and the right forceps minor. Unlike at 5 years, we found no impact on WM of ART initiation. In HEU children, we found a cluster in the right posterior corona radiata with higher FA compared to HU children, while bilateral regions in the CST demonstrated reduced MD. Conclusions: At age 7, despite early ART and viral load (VL) suppression, we continue to observe differences in WM integrity. WM damage observed at age 5 years persists, and new damage is evident. The continued observation of regions with lower FA and higher MD in HIV+ children point to disruptions in ongoing white matter development regardless of early ART. Lastly, in HEU children we find higher FA and lower MD in clusters in the CST tract suggesting that perinatal HIV/ART exposure has a long-term impact on WM development.

Highly-accelerated Bloch-Siegert |B1+| mapping using joint autocalibrated parallel image reconstruction.

PURPOSE: To reconstruct accurate single- and multichannel Bloch-Siegert transmit radiofrequency (|B(1)(+)|) field maps from highly accelerated data. THEORY AND METHODS: The approach is based on the fact that the |B(1)(+)|-to-phase encoding pulse for each transmit coil and off-resonance frequency applies a unique phase shift to the same underlying image. This enables joint reconstruction of all images in a Bloch-Siegert acquisition from an augmented set of virtual receive coils, using any autocalibrated parallel imaging reconstruction method. RESULTS: Simulations with an eight channel transmit/receive array head coil at 7T show that accurate |B(1)(+)| maps can be produced at acceleration factors of 16× and 6× for Cartesian and spiral sampling, respectively. A phantom experiment with a six channel transverse electromagnetic (TEM) transceive array coil allowed accurate reconstruction at 16× acceleration. 7T in vivo experiments performed using 32 channel receive and two-channel transmit coils further demonstrate the proposed method's ability to produce high-quality |B(1)(+)| maps at accelerations of 32× and 8× for Cartesian and spiral trajectories, respectively. Reconstruction accuracy is improved using disjoint k-space sampling patterns between acquisitions. CONCLUSION: The proposed approach allows high acceleration factors in Bloch-Siegert |B(1)(+)| mapping and can significantly reduce the scan time requirements for mapping the |B(1)(+)| fields of transmit arrays.

Quantitative magnetization transfer imaging of human brain at 7 T.

Quantitative magnetization transfer (qMT) imaging yields indices describing the interactions between free water protons and immobile macromolecular protons. These indices include the macromolecular to free pool size ratio (PSR), which has been shown to be correlated with myelin content in white matter. Because of the long scan times required for whole-brain imaging (≈20-30 min), qMT studies of the human brain have not found widespread application. Herein, we investigated whether the increased signal-to-noise ratio available at 7.0 T could be used to reduce qMT scan times. More specifically, we developed a selective inversion recovery (SIR) qMT imaging protocol with a i) novel transmit radiofrequency (B(1)(+)) and static field (B(0)) insensitive inversion pulse, ii) turbo field-echo readout, and iii) reduced TR. In vivo qMT data were obtained in the brains of healthy volunteers at 7.0 T using the resulting protocol (scan time≈40 s/slice, resolution=2 × 2 × 3 mm(3)). Reliability was also assessed in repeated acquisitions. The results of this study demonstrate that SIR qMT imaging can be reliably performed within the radiofrequency power restrictions present at 7.0 T, even in the presence of large B(1)(+) and B(0) inhomogeneities. Consistent with qMT studies at lower field strengths, the observed PSR values were higher in white matter (mean±SD=17.6 ± 1.3%) relative to gray matter (10.3 ± 1.6%) at 7.0 T. In addition, regional variations in PSR were observed in white matter. Together, these results suggest that qMT measurements are feasible at 7.0 T and may eventually allow for the high-resolution assessment of changes in composition throughout the normal and diseased human brain in vivo.

Improved encoding pulses for Bloch-Siegert B1(+) mapping.

A new family of optimized encoding pulses for Bloch-Siegert (BS) |B(1)(+)| mapping is introduced, as well as an algorithm to design them. The pulses are designed by numerical maximization of BS sequence sensitivity, subject to constraints that ensure low on-resonance excitation. The pulses are in all cases characterized by a constant envelope and U-shaped frequency sweep. They are validated in simulations, 7T in vivo experiments, and an experiment to measure their on-resonance excitation, and are compared to a Fermi pulse conventionally used in the BS method. The pulses are shown to produce larger phase shifts in a shorter time and with lower on-resonance excitation than the Fermi pulse, which results in lower SAR and improved |B(1)(+)| accuracy in areas of the body with large main field inhomogeneities.

Slice-selective excitation with B1⁺-insensitive composite pulses.

Spatially selective excitation pulses have been designed to produce uniform flip angles in the presence of the RF and static field inhomogeneities typically encountered in MRI studies of the human brain at 7 T. Pulse designs are based upon non-selective, composite pulses numerically optimized for the desired performance over prescribed ranges of field inhomogeneities. The non-selective pulses are subsequently transformed into spatially selective pulses with the same field-insensitive properties through modification of the spectral composition of the individual sub-pulses which are then executed in conjunction with an oscillating gradient waveform. An in-depth analysis of the performance of these RF pulses is presented in terms of total pulse durations, slice profiles, linearity of in-slice magnetization phase, sensitivity to RF and static field variations, and signal loss due to T(2) effects. Both simulations and measurements in phantoms and in the human brain are used to evaluate pulses with nominal flip angles of 45° and 90°. Target slice thickness in all cases is 2mm. Results indicate that the described class of field-insensitive RF pulses is capable of improving flip-angle uniformity in 7 T human brain imaging. There appears to be a subset of pulses with durations ≲10 ms for which non-linearities in the magnetization phase are minimal and signal loss due to T(2) decay is not prohibitive. Such pulses represent practical solutions for achieving uniform flip angles in the presence of the large field inhomogeneities common to high-field human imaging and help to better establish the performance limits of high-field imaging systems with single-channel transmission.

Evaluation of non-selective refocusing pulses for 7 T MRI.

There is a continuing need for improved RF pulses that achieve proper refocusing in the context of ultra-high field (≥ 7 T) human MRI. Simple block or sinc pulses are highly susceptible to RF field inhomogeneities, and adiabatic pulses are generally considered too SAR intensive for practical use at 7 T. The performance of the array of pulses falling between these extremes, however, has not been systematically evaluated. The aim of this work was to compare the performances of 21 non-selective refocusing pulses spanning a range of durations and SAR levels. The evaluation was based upon simulations and both phantom and in vivo human brain experiments conducted at 7 T. Tested refocusing designs included block, composite block, BIR-4, hyperbolic secant, and numerically optimized composite waveforms. These pulses were divided into three SAR classes and two duration categories, and, based on signal gain in a 3-D spin echo sequence, practical recommendations on usage are made within each category. All evaluated pulses were found to produce greater volume-averaged signals relative to a 180° block pulse. Although signal gains often come with the price of increased SAR or duration, some pulses were found to result in significant signal enhancement while also adhering to practical constraints. This work demonstrates the signal gains and losses realizable with single-channel refocusing pulse designs and should assist in the selection of suitable refocusing pulses for practical 3-D spin-echo imaging at 7 T. It further establishes a reference against which future pulses and multi-channel designs can be compared.

Composite RF pulses for B1+-insensitive volume excitation at 7 Tesla.

A new class of composite RF pulses that perform well in the presence of specific ranges of B0 and B1+ inhomogeneities has been designed for volume (non-selective) excitation in MRI. The pulses consist of numerous (approximately 100) short (approximately 10 micros) block-shaped sub-pulses each with different phases and amplitudes derived from numerical optimization. Optimized pulses are designed to be effective over a specific range of frequency offsets and transmit field variations and are thus implementable regardless of field strength, transmit coil configuration, or the subject-specific spatial distribution of the static and RF fields. In the context of 7 T human brain imaging, both simulations and phantom experiments indicate that optimized pulses result in similar on-resonance flip-angle uniformity as BIR-4 pulses but with the advantages of superior off-resonance stability and significantly reduced average power. The pulse design techniques presented here are thus well-suited for practical application in ultra-high field human MRI.

Practical considerations for the design of sparse-spokes pulses.

Sparse-spokes pulses are 2D slice-selective pulses that effectively mitigate inhomogeneities in the transmitted RF field and reduce unwanted RF artifacts in MR images. Here we consider the practical design of such pulses for high-field MRI and demonstrate limitations of the technique. We analyze the performance of pulses considering input noise as well as other effects such as saturation and T2( *) relaxation. We discuss in detail the correspondence between the reduction of RF inhomogeneities and the fidelity of the input parameters, such as the transmit B1+ field map and combined phase of the main B0 field and eddy-currents. Results include simulations, utilizing 7 T field maps acquired in phantoms and in-vivo, as well as in-vivo experiments. The necessary performance of system hardware components to achieve significant improvements is described.

Mammalian target of rapamycin regulates the growth of mammary epithelial cells through the inhibitor of deoxyribonucleic acid binding Id1 and their functional differentiation through Id2.

Organ development requires the integration of multiple extracellular signals to assure a proper balance between proliferation and differentiation and to achieve and maintain specialized functions. Considerable progress has been made in the study of hormones and growth factors and in the understanding of the regulated intracellular pathways and transcriptional events that contribute to mammogenesis. Cell culture experiments have pointed out crucial pathways and components, which were subsequently validated in vivo experiments. We found that the mammalian target of rapamycin (mTOR) pathway is essential for both growth and differentiation of mammary epithelial cells and that the action of mTOR is mediated through the induction of the helix-loop-helix transcriptional regulators Id1 and Id2. Pharmacological inhibition of mTOR activity in HC11 mammary epithelial cells reduced cellular proliferation and prevented the lactogenic hormone-induced expression of milk proteins. Treatment of female mice with rapamycin impaired mammary gland differentiation and milk protein synthesis. The effects of mTOR on proliferation and differentiation require the functions of the helix-loop-helix proteins Id1 and Id2. Rapamycin treatment of HC11 cells resulted in a suppression of Id1 expression and an inhibition of proliferation. This effect of rapamycin was reversed by the forced expression of Id1. Rapamycin also prevented the induction of Id2 by lactogenic hormones and milk protein gene expression. Expression of a Id2 transgene bypassed the requirement of mTOR activity for beta-casein induction. These data suggest that mTOR activity has distinguishable functions in the proliferative and the differentiated state of mammary epithelial cells: it is a prerequisite for proliferation through the induction of Id1 and for differentiation-specific gene expression through the induction of Id2. The relative strengths of these proliferation and differentiation signals reflected by the expression levels of the individual Id proteins are crucial to the functional life cycle of mammary epithelial cells and might be disturbed in tumorigenesis.