Characterizing Intracranial Hemodynamics in Sickle Cell Anemia: Impact of Patient-Specific Viscosity.

PURPOSE: Pediatric and adult patients with sickle cell anemia (SCA) are at increased risk of stroke and cerebrovascular accident. In the general adult population, there is a relationship between arterial hemodynamics and pathology; however, this relationship in SCA patients remains to be elucidated. The aim of this work was to characterize circle of Willis hemodynamics in patients with SCA and quantify the impact of viscosity choice on pathophysiologically-relevant hemodynamics measures. METHODS: Based on measured vascular geometries, time-varying flow rates, and blood parameters, detailed patient-specific simulations of the circle of Willis were conducted for SCA patients (n = 6). Simulations quantified the impact of patient-specific and standard blood viscosities on wall shear stress (WSS). RESULTS: These results demonstrated that use of a standard blood viscosity introduces large errors into the estimation of pathophysiologically-relevant hemodynamic parameters. Standard viscosity models overpredicted peak WSS by 55% and 49% for steady and pulsatile flow, respectively. Moreover, these results demonstrated non-uniform, spatial patterns of positive and negative WSS errors related to viscosity, and standard viscosity simulations overpredicted the time-averaged WSS by 32% (standard deviation = 7.1%). Finally, differences in shear rate demonstrated that the viscosity choice alters the simulated near-wall flow field, impacting hemodynamics measures. CONCLUSIONS: This work presents simulations of circle of Willis arterial flow in SCA patients and demonstrates the importance and feasibility of using a patient-specific viscosity in these simulations. Accurately characterizing cerebrovascular hemodynamics in SCA populations has potential for elucidating the pathophysiology of large-vessel occlusion, aneurysms, and tissue damage in these patients.

Comparative neuroanatomy of the lumbosacral spinal cord of the rat, cat, pig, monkey, and human.

The overall goal of this work was to create a high-resolution MRI atlas of the lumbosacral enlargement of the spinal cord of the rat (Sprague-Dawley), cat, domestic pig, rhesus monkey, and human. These species were chosen because they are commonly used in basic and translational research in spinal cord injuries and diseases. Six spinal cord specimens from each of the studied species (total of 30 specimens) were fixed, extracted, and imaged. Sizes of the spinal cord segments, cross-sectional dimensions, and locations of the spinal cord gray and white matter were quantified and compared across species. The lumbar enlargement spans spinal cord levels L3-S1 in rats, L4-S1 in cats, L3-S1 in pigs, L2/L3-L7/S1 in monkeys, and T12/L1-S1/S2 in humans. The enlargements in pigs and humans are largest and most similar in size (length and cross-sectional area); followed by monkeys and cats; and followed by rats. The obtained atlas establishes a neuroanatomical reference for the intact lumbosacral spinal cord in these species. It can also be used to guide the planning of surgical procedures of the spinal cord and technology design and development of spinal cord neuroprostheses, as well as precise delivery of cells/drugs into target regions within the spinal cord parenchyma.

Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate.

We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital-parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.

Measuring relative timings of brain activities using fMRI.

Functional MRI (fMRI) has previously been shown to be able to measure hundreds of milliseconds differences in timings of activities in different brain regions, even though the underlying blood oxygenation level-dependent (BOLD) response is delayed and dispersed on the order of seconds. This capability may contribute towards the study of communication within the brain by assessing the temporal sequences of various brain processes (mental chronometry). The practical limit of fMRI for detecting the relative timing of brain activity is not known. We aimed to detect fine differences in the timings of brain activities beyond those previously measured from fMRI data in human subjects. We introduced known delays between the onsets of visual stimuli in a controlled, sparse event-related design and investigated if the temporal shifts in the corresponding average BOLD signals were detectable. To maximize sensitivity, we used high spatial and temporal resolution fMRI at ultrahigh field (7 T), in conjunction with a novel data-driven technique for voxel selection using graph-based visualizations of self-organizing maps and Granger causality to measure relative timing. This approach detected timing differences as small as 28ms in visual cortex in individual subjects. For signal extraction, the self-organizing map approach outperformed other common techniques including independent component analysis, voxelwise univariate linear regression analysis and a separate localizer scan. For relative timing measurement, Granger causality outperformed time-to-peak calculations derived from an inverse logit curve fit. We conclude that high-resolution imaging at ultrahigh field, signal extraction via self-organizing map, and appropriate use of Granger causality permit the detection of small timing differences in fMRI data, despite the intrinsically slow hemodynamic response.

Hemodynamic characteristics of the vertebrobasilar system analyzed using MRI-based models.

The vertebrobasilar system (VBS) is unique in human anatomy in that two arteries merge into a single vessel, and it is especially important because it supplies the posterior circulation of the brain. Atherosclerosis develops in this region, and atherosclerotic plaques in the vertebrobasilar confluence can progress with catastrophic consequences, including artery occlusion. Quantitative assessments of the flow characteristics in the VBS could elucidate the factors that influence flow patterns in this confluence, and deviations from normal patterns might then be used to predict locations to monitor for potential pathological changes, to detect early signs of disease, and to evaluate treatment options and efficacy. In this study, high-field MRI was used in conjunction with computational fluid dynamics (CFD) modeling to investigate the hemodynamics of subject-specific confluence models (n = 5) and to identify different geometrical classes of vertebrobasilar systems (n = 12) of healthy adult subjects. The curvature of the vessels and their mutual orientation significantly affected flow parameters in the VBS. The basilar artery geometry strongly influenced both skewing of the velocity profiles and the wall shear stress distributions in the VBS. All five subjects modeled possessed varying degrees of vertebral asymmetry, and helical flow was observed in four cases, suggesting that factors other than vertebral asymmetry influence mixing of the vertebral artery flow contributions. These preliminary studies verify that quantitative, MR imaging techniques in conjunction with subject-specific CFD models of healthy adult subjects may be used to characterize VBS hemodynamics and to predict flow features that have been related to the initiation and development of atherosclerosis in large arteries. This work represents an important first step towards applying this approach to study disease initiation and progression in the VBS.

High-resolution imaging of expertise reveals reliable object selectivity in the fusiform face area related to perceptual performance.

The fusiform face area (FFA) is a region of human cortex that responds selectively to faces, but whether it supports a more general function relevant for perceptual expertise is debated. Although both faces and objects of expertise engage many brain areas, the FFA remains the focus of the strongest modular claims and the clearest predictions about expertise. Functional MRI studies at standard-resolution (SR-fMRI) have found responses in the FFA for nonface objects of expertise, but high-resolution fMRI (HR-fMRI) in the FFA [Grill-Spector K, et al. (2006) Nat Neurosci 9:1177-1185] and neurophysiology in face patches in the monkey brain [Tsao DY, et al. (2006) Science 311:670-674] reveal no reliable selectivity for objects. It is thus possible that FFA responses to objects with SR-fMRI are a result of spatial blurring of responses from nonface-selective areas, potentially driven by attention to objects of expertise. Using HR-fMRI in two experiments, we provide evidence of reliable responses to cars in the FFA that correlate with behavioral car expertise. Effects of expertise in the FFA for nonface objects cannot be attributed to spatial blurring beyond the scale at which modular claims have been made, and within the lateral fusiform gyrus, they are restricted to a small area (200 mm(2) on the right and 50 mm(2) on the left) centered on the peak of face selectivity. Experience with a category may be sufficient to explain the spatially clustered face selectivity observed in this region.

Multishot versus single-shot pulse sequences in very high field fMRI: a comparison using retinotopic mapping.

High-resolution functional MRI is a leading application for very high field (7 Tesla) human MR imaging. Though higher field strengths promise improvements in signal-to-noise ratios (SNR) and BOLD contrast relative to fMRI at 3 Tesla, these benefits may be partially offset by accompanying increases in geometric distortion and other off-resonance effects. Such effects may be especially pronounced with the single-shot EPI pulse sequences typically used for fMRI at standard field strengths. As an alternative, one might consider multishot pulse sequences, which may lead to somewhat lower temporal SNR than standard EPI, but which are also often substantially less susceptible to off-resonance effects. Here we consider retinotopic mapping of human visual cortex as a practical test case by which to compare examples of these sequence types for high-resolution fMRI at 7 Tesla. We performed polar angle retinotopic mapping at each of 3 isotropic resolutions (2.0, 1.7, and 1.1 mm) using both accelerated single-shot 2D EPI and accelerated multishot 3D gradient-echo pulse sequences. We found that single-shot EPI indeed led to greater temporal SNR and contrast-to-noise ratios (CNR) than the multishot sequences. However, additional distortion correction in postprocessing was required in order to fully realize these advantages, particularly at higher resolutions. The retinotopic maps produced by both sequence types were qualitatively comparable, and showed equivalent test/retest reliability. Thus, when surface-based analyses are planned, or in other circumstances where geometric distortion is of particular concern, multishot pulse sequences could provide a viable alternative to single-shot EPI.

Data-driven optimization and evaluation of 2D EPI and 3D PRESTO for BOLD fMRI at 7 Tesla: I. Focal coverage.

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) is commonly performed using 2D single-shot echo-planar imaging (EPI). However, single-shot EPI at 7 Tesla (T) often suffers from significant geometric distortions (due to low bandwidth (BW) in the phase-encode (PE) direction) and amplified physiological noise. Recent studies have suggested that 3D multi-shot sequences such as PRESTO may offer comparable BOLD contrast-to-noise ratio with increased volume coverage and decreased geometric distortions. Thus, a four-way group-level comparison was performed between 2D and 3D acquisition sequences at two in-plane resolutions. The quality of fMRI data was evaluated via metrics of prediction and reproducibility using NPAIRS (Non-parametric Prediction, Activation, Influence and Reproducibility re-Sampling). Group activation maps were optimized for each acquisition strategy by selecting the number of principal components that jointly maximized prediction and reproducibility, and showed good agreement in sensitivity and specificity for positive BOLD changes. High-resolution EPI exhibited the highest z-scores of the four acquisition sequences; however, it suffered from the lowest BW in the PE direction (resulting in the worst geometric distortions) and limited spatial coverage, and also caused some subject discomfort through peripheral nerve stimulation (PNS). In comparison, PRESTO also had high z-scores (higher than EPI for a matched in-plane resolution), the highest BW in the PE direction (producing images with superior geometric fidelity), the potential for whole-brain coverage, and no reported PNS. This study provides evidence to support the use of 3D multi-shot acquisition sequences in lieu of single-shot EPI for ultra high field BOLD fMRI at 7T.

An FMRI study of number processing in children with fetal alcohol syndrome.

BACKGROUND: Number processing deficits are frequently seen in children exposed to alcohol in utero. METHODS: Functional magnetic resonance imaging was used to examine the neural correlates of number processing in 15 right-handed, 8- to 12-year-old children diagnosed with fetal alcohol syndrome (FAS) or partial FAS (PFAS) and 18 right-handed, age- and gender-matched controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, using Proximity Judgment and Exact Addition tasks. RESULTS: Control children activated the expected fronto-parietal network during both tasks, including the anterior horizontal intraparietal sulcus (HIPS), left posterior HIPS, left precentral sulcus, and posterior medial frontal cortex. By contrast, on the Proximity Judgment task, the exposed children recruited additional parietal pathways involving the right and left angular gyrus and posterior cingulate/precuneus, which may entail verbally mediated recitation of numbers and/or subtraction to assess relative numerical distances. During Exact Addition, the exposed children exhibited more diffuse and widespread activations, including the cerebellar vermis and cortex, which have been found to be activated in adults engaged in particularly challenging number processing problems. CONCLUSIONS: The data suggest that, whereas control children rely primarily on the fronto-parietal network identified in previous studies to mediate number processing, children with FAS/PFAS recruit a broader range of brain regions to perform these relatively simple number processing tasks. Our results are consistent with structural neuroimaging findings indicating that the parietal lobe is relatively more affected by prenatal alcohol exposure and provide the first evidence for brain activation abnormalities during number processing in children with FAS/PFAS, effects that persist even after controlling statistically for group differences in total intracranial volume and IQ.

An fMRI study of magnitude comparison and exact addition in children.

By contrast to the adult literature, in which a consistent parietofrontal network for number processing has been identified, the data from studies of number processing in children have been less consistent, probably due to differences in study design and control conditions. Number processing was examined using functional magnetic resonance imaging in 18 right-handed children (8-12 years) from the Cape Coloured community in Cape Town, South Africa, using Proximity Judgment and Exact Addition (EA) tasks. The findings were consistent with the hypothesis that, as in adults, the anterior horizontal intraparietal sulcus (HIPS) plays a major role in the representation and manipulation of quantity in children. The posterior medial frontal cortex, believed to be involved in performance monitoring in more complex arithmetic manipulations in adults, was extensively activated even for relatively simple symbolic number processing in the children. Other areas activated to a greater degree in the children included the left precentral sulcus, which may mediate number knowledge and, for EA, the head of the caudate nucleus, which is part of a fronto-subcortical circuit involved in the behavioral execution of sequences. Two regions that have been linked to number processing in adults - the angular gyrus and posterior superior parietal lobule - were not activated in the children. The data are consistent with the inference that although the functional specialization of the anterior HIPS may increase as symbolic number processing becomes increasingly automatic, this region and other elements of the parietofrontal network identified in adults are already reliably and robustly activated by middle childhood.

Multiscale pattern analysis of orientation-selective activity in the primary visual cortex.

Although orientation columns are less than a millimeter in width, recent neuroimaging studies indicate that viewed orientations can be decoded from cortical activity patterns sampled at relatively coarse resolutions of several millimeters. One proposal is that these differential signals arise from random spatial irregularities in the columnar map. However, direct support for this hypothesis has yet to be obtained. Here, we used high-field, high-resolution functional magnetic resonance imaging (fMRI) and multivariate pattern analysis to determine the spatial scales at which orientation-selective information can be found in the primary visual cortex (V1) of cats and humans. We applied a multiscale pattern analysis approach in which fine- and coarse-scale signals were first removed by ideal spatial lowpass and highpass filters, and the residual activity patterns then analyzed by linear classifiers. Cat visual cortex, imaged at 0.3125 mm resolution, showed a strong orientation signal at the scale of individual columns. Nonetheless, reliable orientation bias could still be found at spatial scales of several millimeters. In the human visual cortex, imaged at 1 mm resolution, a majority of orientation information was found on scales of millimeters, with small contributions from global spatial biases exceeding approximately 1 cm. Our high-resolution imaging results demonstrate a reliable millimeters-scale orientation signal, likely emerging from irregular spatial arrangements of orientation columns and their supporting vasculature. fMRI pattern analysis methods are thus likely to be sensitive to signals originating from other irregular columnar structures elsewhere in the brain.

The neural correlates of calculation ability in children: an fMRI study.

Most studies investigating mental numerical processing involve adult participants and little is known about the functioning of these systems in children. The current study used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of numeracy and the influence of age on these correlates with a group of adults and a group of third graders who had average to above average mathematical ability. Participants performed simple and complex versions of exact and approximate calculation tasks while in the magnet. Like adults, children activated a network of brain regions in the frontal and parietal lobes during the calculation tasks, and they recruited additional brain regions for the more complex versions of the tasks. However, direct comparisons between adults and children revealed significant differences in level of activation across all tasks. In particular, patterns of activation in the parietal lobe were significantly different as a function of age. Findings support previous claims that the parietal lobe becomes more specialized for arithmetic tasks with age.

Temporal sampling requirements for reference region modeling of DCE-MRI data in human breast cancer.

PURPOSE: To assess the temporal sampling requirements needed for quantitative analysis of dynamic contrast-enhanced MRI (DCE-MRI) data with a reference region (RR) model in human breast cancer. MATERIALS AND METHODS: Simulations were used to study errors in pharmacokinetic parameters (K(trans) and v(e)) estimated by the RR model using six DCE-MRI acquisitions over a range of pharmacokinetic parameter values, arterial input functions, and temporal samplings. DCE-MRI data were acquired on 12 breast cancer patients and parameters were estimated using the native resolution data (16.4 seconds) and compared to downsampled 32.8-second and 65.6-second data. RESULTS: Simulations show that, in the majority of parameter combinations, the RR model results in an error less than 20% in the extracted parameters with temporal sampling as poor as 35.6 seconds. The experimental results show a high correlation between K(trans) and v(e) estimates from data acquired at 16.4-second temporal resolution compared to the downsampled 32.8-second data: the slope of the regression line was 1.025 (95% confidence interval [CI]: 1.021, 1.029), Pearson's correlation r = 0.943 (95% CI: 0.940, 0.945) for K(trans), and 1.023 (95% CI: 1.021. 1.025), r = 0.979 (95% CI: 0.978, 0.980) for v(e). For the 64-second temporal resolution data the results were: 0.890 (95% CI: 0.894, 0.905), r = 0.8645, (95% CI: 0.858, 0.871) for K(trans), and 1.041 (95% CI: 1.039, 1.043), r = 0.970 (95% CI: 0.968, 0.971) for v(e). CONCLUSION: RR analysis allows for a significant reduction in temporal sampling requirements and this lends itself to analyze DCE-MRI data acquired in practical situations.

Aberrant functional activation in school age children at-risk for mathematical disability: a functional imaging study of simple arithmetic skill.

We used functional magnetic resonance imaging (fMRI) to explore the patterns of brain activation associated with different levels of performance in exact and approximate calculation tasks in well-defined cohorts of children with mathematical calculation difficulties (MD) and typically developing controls. Both groups of children activated the same network of brain regions; however, children in the MD group had significantly increased activation in parietal, frontal, and cingulate cortices during both calculation tasks. A majority of the differences occurred in anatomical brain regions associated with cognitive resources such as executive functioning and working memory that are known to support higher level arithmetic skill but are not specific to mathematical processing. We propose that these findings are evidence that children with MD use the same types of problem solving strategies as TD children, but their weak mathematical processing system causes them to employ a more developmentally immature and less efficient form of the strategies.

New approach for correcting distortions in echo planar imaging.

A new method is described that can correct the distortions due to multiple off-resonance effects in echo planar imaging, including those caused by B(0) field inhomogeneities, eddy currents, and gradient waveform imperfections. The proposed method uses a phase encoded acquisition and is as effective as the method of Chen and Wyricz (Chen and Wyricz, Magn Reson Med 1999;41:1206-1213) in correcting for distortions. Unlike Chen and Wyricz's approach, this new method works directly in distorted space and requires fewer scans. It also avoids the difficulties of phase unwrapping inherent in field mapping methods. Results using this new method with phantoms and human head scans at 3.0 T demonstrate the efficacy of the method in correcting distortions in both spin echo echo planar imaging (EPI) and gradient echo EPI.

Neuronal representation of occluded objects in the human brain.

Occluding surfaces frequently obstruct the object of interest yet are easily dealt with by the visual system. Here, we test whether neural areas known to participate in motion perception and eye movements are regions that also process occluded motion. Functional magnetic resonance imaging (fMRI) was used to assess brain activation while subjects watched a moving ball become occluded. Areas activated during occluded motion included the intraparietal sulcus (IPS) as well as middle temporal (MT) regions analogous to monkey MT/MST. A second experiment showed that these results were not due to motor activity. These findings suggest that human cortical regions involved in perceiving occluded motion are similar to regions that process real motion and regions responsible for eye movements. The intraparietal sulcus may be involved in predicting the location of an unseen target for future hand or eye movements.

A comparison of bound and unbound audio-visual information processing in the human cerebral cortex.

Human speech has auditory (heard speech) and visual (seen speech) qualities. The neural representation of audiovisual integration in speech was investigated using functional magnetic resonance imaging (fMRI). Ten subjects were imaged while viewing a face in four different conditions: with speech and mouth movements synchronized, with speech and mouth movements desynchronized, during silent speech, or while viewing a static face. Subtractions of the different sets of images showed that lipreading primarily activated the STG/STS. Synchronized audio-visual speech and desynchronized audio-visual speech activated similar areas. Regions activated more in the synchronized versus the desynchronized conditions were considered to be those involved in cross-modal integration. One dominant activation focus was found near the left claustrum, a subcortical region. A region-of-interest analysis of the STS and parietal areas found no difference between audio-visual conditions. However, this analysis found that synchronized audio-visual stimuli led to a higher signal change in the claustrum region. This study extends previous results, using other sensory combinations, and other tasks, indicating involvement of the claustrum in sensory integration.