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Functional MRI (fMRI) signals are robustly detectable in white matter (WM) but they have been largely ignored in the fMRI literature. Their nature, interpretation, and relevance as potential indicators of brain function remain under explored and even controversial. Blood oxygenation level dependent (BOLD) contrast has for over 25 years been exploited for detecting localized neural activity in the cortex using fMRI. While BOLD signals have been reliably detected in grey matter (GM) in a very large number of studies, such signals have rarely been reported from WM. However, it is clear from our own and other studies that although BOLD effects are weaker in WM, using appropriate detection and analysis methods they are robustly detectable both in response to stimuli and in a resting state. BOLD fluctuations in a resting state exhibit similar temporal and spectral profiles in both GM and WM, and their relative low frequency (0.01-0.1 Hz) signal powers are comparable. They also vary with baseline neural activity e.g. as induced by different levels of anesthesia, and alter in response to a stimulus. In previous work we reported that BOLD signals in WM in a resting state exhibit anisotropic temporal correlations with neighboring voxels. On the basis of these findings, we derived functional correlation tensors that quantify the correlational anisotropy in WM BOLD signals. We found that, along many WM tracts, the directional preferences of these functional correlation tensors in a resting state are grossly consistent with those revealed by diffusion tensors, and that external stimuli tend to enhance visualization of specific and relevant fiber pathways. These findings support the proposition that variations in WM BOLD signals represent tract-specific responses to neural activity. We have more recently shown that sensory stimulations induce explicit BOLD responses along parts of the projection fiber pathways, and that task-related BOLD changes in WM occur synchronously with the temporal pattern of stimuli. WM tracts also show a transient signal response following short stimuli analogous to but different from the hemodynamic response function (HRF) characteristic of GM. Thus there is converging and compelling evidence that WM exhibits both resting state fluctuations and stimulus-evoked BOLD signals very similar (albeit weaker) to those in GM. A number of studies from other laboratories have also reported reliable observations of WM activations. Detection of BOLD signals in WM has been enhanced by using specialized tasks or modified data analysis methods. In this mini-review we report summaries of some of our recent studies that provide evidence that BOLD signals in WM are related to brain functional activity and deserve greater attention by the neuroimaging community.
Copyright © 2019 Elsevier Inc. All rights reserved.
BACKGROUND AND PURPOSE - The purpose of the study is to characterize diffusion tensor imaging indices in the developing spinal cord, evaluating differences based on age and cord region. Describing the progression of DTI indices in the pediatric cord increases our understanding of spinal cord development.
MATERIALS AND METHODS - A retrospective analysis was performed on DTI acquired in 121 pediatric patients (mean, 8.6 years; range, 0.3-18.0 years) at Monroe Carell Jr. Children's Hospital at Vanderbilt from 2017 to 2018. Diffusion-weighted images (15 directions; = 750 s/mm; slice thickness, 5 mm; in-plane resolution, 1.0 × 1.0 mm) were acquired on a 3T scanner in the cervicothoracic and/or thoracolumbar cord. Manual whole-cord segmentation was performed. Images were masked and further segmented into cervical, upper thoracic, thoracolumbar, and conus regions. Analyses of covariance were performed for each DTI-derived index to investigate how age affects diffusion across cord regions, and 95% confidence intervals were calculated across age for each derived index and region. Post hoc testing was performed to analyze regional differences.
RESULTS - Analyses of covariance revealed significant correlations of age with axial diffusivity, mean diffusivity, and fractional anisotropy (all, < .001). There were also significant differences among cord regions for axial diffusivity, radial diffusivity, mean diffusivity, and fractional anisotropy (all, < .001).
CONCLUSIONS - This research demonstrates that diffusion evolves in the pediatric spinal cord during development, dependent on both cord region and the diffusion index of interest. Future research could investigate how diffusion may be affected by common pediatric spinal pathologies.
© 2019 by American Journal of Neuroradiology.
OBJECTIVE - To assess white matter integrity in patients with essential tremor (ET) and Parkinson disease (PD) with moderate to severe motor impairment.
METHODS - Sedated participants with ET (n = 57) or PD (n = 99) underwent diffusion tensor imaging (DTI) and fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity values were computed. White matter tracts were defined using 3 well-described atlases. To determine candidate white matter regions that differ between ET and PD groups, a bootstrapping analysis was applied using the least absolute shrinkage and selection operator. Linear regression was applied to assess magnitude and direction of differences in DTI metrics between ET and PD populations in the candidate regions.
RESULTS - Fractional anisotropy values that differentiate ET from PD localize primarily to thalamic and visual-related pathways, while diffusivity differences localized to the cerebellar peduncles. Patients with ET exhibited lower fractional anisotropy values than patients with PD in the lateral geniculate body ( < 0.01), sagittal stratum ( = 0.01), forceps major ( = 0.02), pontine crossing tract ( = 0.03), and retrolenticular internal capsule ( = 0.04). Patients with ET exhibited greater radial diffusivity values than patients with PD in the superior cerebellar peduncle ( < 0.01), middle cerebellar peduncle ( = 0.05), and inferior cerebellar peduncle ( = 0.05).
CONCLUSIONS - Regionally, distinctive white matter microstructural values in patients with ET localize to the cerebellar peduncles and thalamo-cortical visual pathways. These findings complement recent functional imaging studies in ET but also extend our understanding of putative physiologic features that account for distinctions between ET and PD.
© 2018 American Academy of Neurology.
PURPOSE - Functional magnetic resonance imaging with BOLD contrast is widely used for detecting brain activity in the cortex. Recently, several studies have described anisotropic correlations of resting-state BOLD signals between voxels in white matter (WM). These local WM correlations have been modeled as functional-correlation tensors, are largely consistent with underlying WM fiber orientations derived from diffusion MRI, and appear to change during functional activity. However, functional-correlation tensors have several limitations. The use of only nearest-neighbor voxels makes functional-correlation tensors sensitive to noise. Furthermore, adjacent voxels tend to have higher correlations than diagonal voxels, resulting in orientation-related biases. Finally, the tensor model restricts functional correlations to an ellipsoidal bipolar-symmetric shape, and precludes the ability to detect complex functional orientation distributions (FODs).
METHODS - We introduce high-angular-resolution functional-correlation imaging (HARFI) to address these limitations. In the same way that high-angular-resolution diffusion imaging (HARDI) techniques provide more information than diffusion tensors, we show that the HARFI model is capable of characterizing complex FODs expected to be present in WM.
RESULTS - We demonstrate that the unique radial and angular sampling strategy eliminates orientation biases present in tensor models. We further show that HARFI FODs are able to reconstruct known WM pathways. Finally, we show that HARFI allows asymmetric "bending" and "fanning" distributions, and propose asymmetric and functional indices which may increase fiber tracking specificity, or highlight boundaries between functional regions.
CONCLUSIONS - The results suggest the HARFI model could be a robust, new way to evaluate anisotropic BOLD signal changes in WM.
© 2018 International Society for Magnetic Resonance in Medicine.
PURPOSE - Given no definite consensus on the accepted autograft orientation during peripheral nerve injury repair, we compare outcomes between reverse and normally oriented autografts using an advanced magnetic resonance imaging technique, diffusion tensor imaging.
METHODS - Thirty-six female Sprague-Dawley rats were divided into 3 groups: sham-left sciatic nerve isolation without injury, reverse autograft-10-mm cut left sciatic nerve segment reoriented 180° and used to coapt the proximal and distal stumps, or normally oriented autograft-10-mm cut nerve segment kept in its normal orientation for coaptation. Animals underwent sciatic functional index and foot fault behavior studies at 72 hours, and then weekly. At 6 weeks, axons proximal, within, and distal to the autograft were evaluated using diffusion tensor imaging and choline acetyltransferase motor staining for immunohistochemistry. Toluidine blue staining of 1-μm sections was used to assess axon count, density, and diameter. Bilateral gastrocnemius/soleus muscle weights were compared to obtain a net wet weight. Comparison of the groups was performed using Mann-Whiney U or Kruskal-Wallis H tests to determine significance.
RESULTS - Diffusion tensor imaging findings including fractional anisotropy, radial diffusivity, and axial diffusivity were similar between reverse and normally oriented autografts. Diffusion tensor imaging tractography demonstrated proximodistal nerve regeneration in both autograft groups. Motor axon counts proximal, within, and distal to the autografts were similar. Likewise, axon count, density, and diameter were similar between the autograft groups. Muscle net weight at 6 weeks and behavioral outcomes (sciatic functional index and foot fault) at any tested time point were also similar between reverse and normally oriented autografts.
CONCLUSIONS - Diffusion tensor imaging may be a useful assessment tool for peripheral nerve regeneration. Reversing nerve autograft polarity did not demonstrate to have an influence on functional or regenerative outcomes.
We describe the development of the first digital atlas of the normal squirrel monkey brain and present the resulting product, VALiDATe29. The VALiDATe29 atlas is based on multiple types of magnetic resonance imaging (MRI) contrast acquired on 29 squirrel monkeys, and is created using unbiased, nonlinear registration techniques, resulting in a population-averaged stereotaxic coordinate system. The atlas consists of multiple anatomical templates (proton density, T1, and T2* weighted), diffusion MRI templates (fractional anisotropy and mean diffusivity), and ex vivo templates (fractional anisotropy and a structural MRI). In addition, the templates are combined with histologically defined cortical labels, and diffusion tractography defined white matter labels. The combination of intensity templates and image segmentations make this atlas suitable for the fundamental atlas applications of spatial normalization and label propagation. Together, this atlas facilitates 3D anatomical localization and region of interest delineation, and enables comparisons of experimental data across different subjects or across different experimental conditions. This article describes the atlas creation and its contents, and demonstrates the use of the VALiDATe29 atlas in typical applications. The atlas is freely available to the scientific community.
PURPOSE - We aimed to identify non-invasive imaging parameters that can serve as biomarkers for the integrity of the spinal cord, which is paramount to neurological function. Diffusion tensor imaging (DTI) indices are sensitive to axonal and myelin damage, and have strong potential to serve as such biomarkers. However, averaging DTI indices over large regions of interest (ROIs), a common approach to analyzing the images of injured spinal cord, leads to loss of subject-specific information. We investigated if DTI-tractography-driven, subject-specific demarcation approach can yield measures that are more specific to impairment.
METHODS - In 18 individuals with chronic spinal cord injury (SCI), subject-specific demarcation of the injury region was performed using DTI tractography, which yielded three regions relative to injury (RRI; regions superior to, at, and below injury epicenter). DTI indices averaged over each RRI were correlated with measures of residual motor and sensory function, obtained using the International Standard of Neurological Classification for Spinal Cord Injury (ISNCSCI).
RESULTS - Total ISNCSCI score (ISNCSCI-tot; sum of ISNCSCI motor and sensory scores) was significantly (p < 0.05) correlated with fractional anisotropy and axial and radial diffusivities. ISNCSCI-tot showed strongest correlation with indices measured from the region inferior to the injury epicenter (IRRI), the degree of which exceeded that of those measured from the entire cervical cord-suggesting contribution from Wallerian degeneration.
CONCLUSION - DTI tractography-driven, subject-specific injury demarcation approach provided measures that were more specific to impairment. Notably, DTI indices obtained from the IRRI region showed the highest specificity to impairment, demonstrating their strong potential as biomarkers for the SCI severity.
Previous research suggests that exposure to early life stress (ELS) affects the structural integrity of the uncinate fasciculus (UF), a frontolimbic white matter tract that undergoes protracted development throughout adolescence. Adolescence is an important transitional period characterized by the emergence of internalizing psychopathology such as anxiety, particularly in individuals with high levels of stress sensitivity. We examined the relations among sensitivity to ELS, structural integrity of the UF, and anxiety symptoms in 104 early adolescents. We conducted structured interviews to assess exposure to ELS and obtained subjective and objective ratings of stress severity, from which we derived an index of ELS sensitivity. We also acquired diffusion MRI and conducted deterministic tractography to visualize UF trajectories and to compute measures of structural integrity from three distinct segments of the UF: frontal, insular, temporal. We found that higher sensitivity to ELS predicted both reduced fractional anisotropy in right frontal UF and higher levels of anxiety symptoms. These findings suggest that fibers in frontal UF, which are still developing throughout adolescence, are most vulnerable to the effects of heightened sensitivity to ELS, and that reduced structural integrity of frontal UF may underlie the relation between early stress and subsequent internalizing psychopathology.
© The Author (2017). Published by Oxford University Press.
Functional MRI (fMRI) has evolved from simple observations of regional changes in MRI signals caused by cortical activity induced by a task or stimulus, to task-free acquisitions of images in a resting state. Such resting state signals contain low frequency fluctuations which may be correlated between voxels, and strongly correlated regions are deemed to reflect functional connectivity within synchronized circuits. Resting state functional connectivity (rsFC) measures have been widely adopted by the neuroscience community, and are being used and interpreted as indicators of intrinsic neural circuits and their functional states in a broad range of applications, both basic and clinical. However, there has been relatively little work reported that validates whether inter-regional correlations in resting state fluctuations of fMRI (rsfMRI) signals actually measure functional connectivity between brain regions, or to establish how MRI data correlate with other metrics of functional connectivity. In this mini-review, we summarize recent studies of rsFC within mesoscopic scale cortical networks (100μm-10mm) within a well defined functional region of primary somatosensory cortex (S1), as well as spinal cord and brain white matter in non-human primates, in which we have measured spatial patterns of resting state correlations and validated their interpretation with electrophysiological signals and anatomic connections. Moreover, we emphasize that low frequency correlations are a general feature of neural systems, as evidenced by their presence in the spinal cord as well as white matter. These studies demonstrate the valuable role of high field MRI and invasive measurements in an animal model to inform the interpretation of human imaging studies.
Copyright © 2017 Elsevier Inc. All rights reserved.
Sphingolipids serve important structural and functional roles in cellular membranes and myelin sheaths. Plasma sphingolipids have been shown to predict cognitive decline and Alzheimer's disease. However, the association between plasma sphingolipid levels and brain white matter (WM) microstructure has not been examined. We investigated whether plasma sphingolipids (ceramides and sphingomyelins) were associated with magnetic resonance imaging-based diffusion measures, fractional anisotropy (FA), and mean diffusivity, 10.5 years later in 17 WM regions of 150 cognitively normal adults (mean age 67.2). Elevated ceramide species (C20:0, C22:0, C22:1, and C24:1) were associated with lower FA in multiple WM regions, including total cerebral WM, anterior corona radiata, and the cingulum of the cingulate gyrus. Higher sphingomyelins (C18:1 and C20:1) were associated with lower FA in regions such as the anterior corona radiata and body of the corpus callosum. Furthermore, lower sphingomyelin to ceramide ratios (C22:0, C24:0, and C24:1) were associated with lower FA or higher mean diffusivity in regions including the superior and posterior corona radiata. However, although these associations were significant at the a priori p < 0.05, only associations with some regional diffusion measures for ceramide C22:0 and sphingomyelin C18:1 survived correction for multiple comparisons. These findings suggest plasma sphingolipids are associated with variation in WM microstructure in cognitively normal aging.
Copyright © 2016 Elsevier Inc. All rights reserved.